Awake proning in non-intubated patients

The physiological benefits and improvement in clinical outcomes with prone ventilation are well established in patients who are intubated and mechanically ventilated (1). Would the favorable physiological effects of the prone position benefit non-intubated, spontaneously breathing patients with acute hypoxemic respiratory failure? In light of an increasing number of patients with COVID-19 pneumonia and constrained healthcare resources worldwide, awake proning is being explored as a possible intervention to avoid invasive mechanical ventilation. There were early reports of the prone positioning in non-intubated, spontaneously breathing patients in lung transplant recipients (2), and in acute hypoxemic respiratory failure in patients with acute respiratory distress syndrome (ARDS) (3).  

Lung injury and the supine position 

The force of diaphragmatic contractility is greater in the dependent areas of the lung. This results in a more negative pleural pressure being exerted in the dependent areas compared to non-dependent areas during spontaneous breathing in patients with lung injury. As a result, airflow occurs across a gradient from the non-dependent to dependent alveoli; this leads to hyperinflation injury to the dependent lung. Injury may occur even with normal spontaneously generated tidal volumes. This pendelluft movement of air from the non-dependent to the dependent areas of the lung may provoke self-inflicted lung injury in patients who have vigorous spontaneous respiratory efforts (4). In the prone position, when the diseased lung becomes non-dependent, the diaphragmatic contraction may distribute lung stress more uniformly, with a relatively less likelihood of propagation of lung injury. 

The posterior lung mass is greater compared to the anterior parts of the lung. In the supine position, the dependent lung bears the weight of the anterior, non-dependent lung, and the mediastinal structures, including the heart. This leads to compression collapse of dependent areas of the lung in the supine position. The other important consideration is the greater perfusion of the dependent lung, which is unrelated to gravitational changes. Thus, in ARDS, the dorsal areas of the lung, which are involved to a greater extent, receive disproportionately higher perfusion, leading to a significant increase in the shunt fraction across the lung. This is one of the important reasons for arterial hypoxemia in patients with ARDS. 

Physiology of prone positioning

When patients with ARDS assume the prone position, two important changes occur. First, the dorsal areas of the lung, which were collapsed or de-recruited, become non-dependent. The dorsal lung is freed from the mechanical effects of gravity, leading to significant alveolar recruitment. The sternum supports the mediastinum anteriorly. Second, due to the gravitational effect, perfusion improves to the anterior regions of the lung, which are already better ventilated compared to the posterior regions. This change of predilection of perfusion to better-ventilated areas improves overall ventilation-perfusion matching, thus improving gas exchange. Furthermore, change from the supine to the prone position results in improved mobilization of secretions from the dorsal areas of the lung. 

The improved recruitment that occurs in the prone position results in better ventilation and oxygenation, mitigating the impact of hypoxic pulmonary vasoconstriction. Consequently, blood flow improves across the lungs, thus reducing the afterload to the right ventricle, leading to improved function.

Prone position in non-intubated patients with lung injury: the evidence

The prone position is well-established to improve clinical outcomes, including mortality, among patients who are intubated and mechanically ventilated (1). Recently, there has been increasing interest in using the prone position in non-intubated patients with acute hypoxemic respiratory failure. The outbreak of COVID-19 pneumonia across the world resulted in a surge of hypoxic patients in resource-constrained health care settings. “Awake proning” in non-intubated patients has emerged as a possible intervention to improve respiratory parameters. 

In a retrospective study, Scaravilli et al. evaluated the effect of the prone position in spontaneously breathing, non-intubated patients with acute hypoxemic respiratory failure. In this study of 15 patients, different modalities of respiratory support were used, including oxygen mask, high-flow nasal cannula (HFNC), helmet CPAP, or non-invasive ventilation (NIV). The type of respiratory support and FiO2 were unaltered on assuming the prone position. Prone positioning resulted in a significant increase in the PaO2/FiO2 ratios; however, the effect dissipated when patients were turned back to the supine position. No changes were observed in the respiratory rate, hemodynamic status, the PaCO2, and pH levels (5).  

In an observational cohort study, 20 patients with ARDS of variable etiology were placed in the prone position in combination with HFNC or NIV. Improvement in oxygenation was assessed in four groups: those who had HFNC or NIV alone, and those who had either HFNC or NIV combined with prone positioning. The primary endpoint, the requirement for endotracheal intubation, occurred in 9 of 20 patients. The PaO2/FiO2 ratio among patients who received the HFNC-prone combination was significantly higher in those who did not require intubation. The authors concluded that prone positioning combined with HFNC, if applied early, may help avoid intubation in patients with moderate ARDS (6). 

One of the initial experiences with prone positioning in non-intubated, spontaneously breathing patients with COVID-19 infection was reported from the Jiangsu province in China. Among patients with moderate to severe ARDS due to COVID-19 pneumonia, Sun et al. observed improved oxygenation in awake, non-intubated patients with prone positioning. They attributed improved outcomes among their patients and a reduced requirement for intubation to a combination of awake proning, restrictive fluid therapy, and the use of NIV (7).  

In an observational cohort study, 50 patients with confirmed COVID-19 infection by RT-PCR were enrolled from an academic emergency department in New York City. The median SaOwith supplemental oxygen was 84% (IQR: 75–90). Patients assumed the prone position on their own. At 5 minutes after proning, the SaO2 increased significantly, to a median value of 94% (IQR: 90–95%) (p = 0.001). Thirteen patients required endotracheal intubation and mechanical ventilation within 24 hours of presenting to the emergency department. Among the remaining 37 patients, five were intubated subsequently. This study revealed improved SaOon assuming the prone position among awake, non-intubated, spontaneously breathing patients (8).   

A prospective study was conducted among consecutive, spontaneously breathing, non-intubated patients with COVID-19 pneumonia and acute hypoxemic acute respiratory failure in a single center in France. Among 24 patients who were enrolled, 15 tolerated the prone position for more than 3 hours. Six patients experienced a 20% improvement in the PaO2/FiO2 ratio after assuming the prone position. Among these, three patients sustained the improvement in PaO2/FiO2 ratios after reassuming the supine position. There was no significant difference noted in the PaO2 levels before assuming the prone position and after re-supination. No major complications were noted with prone positioning (9). 

NIV in the prone position

Is prone positioning a feasible option among patients who are on NIV? Sixty-two patients with COVID-19 infection and mild to moderate ARDS were studied in Milan, Italy. These patients were treated in the general wards and received mask CPAP support of 10 cm of H2O with an FiO2 of 0.6. In case of a poor response to CPAP, patients were turned to the prone position. Fifteen patients were turned prone; all the patients experienced a reduction in the respiratory rate in the prone position that was sustained after re-supination. The SaO2 and PaO2/FiO2 ratios improved in all 15 patients when they were in the prone position; this improvement was sustained after re-supination in 12 patients. Eleven patients experienced an improved level of comfort when they were prone. On follow-up at 14 days, one patient required intubation and required ICU transfer, while one patient died. Nine patients were discharged home, one patient did not require proning any more, while three patients continued to require intermittent pronation (10).  

A practical approach to awake proning

As a first step, the ability of the patient to assume the prone position and re-supine independently or with minimal assistance needs to be assessed. Patients must be hemodynamically stable and able to communicate. Document the FiO2, the oxygen support device, and the SaO2 at baseline. If the PaO2/FiO2 ratio is less than 150 mm Hg, awake proning may not be appropriate. Patients are placed in the prone position supported by their arms, using a pillow to allow unobstructed passage of the oxygen tubing. Additional pillows may be placed under the hips or legs, to enable patient comfort. The initial duration of the prone position may be 1 hour, after which the patient may be allowed to re-supine. The change in respiratory rate and SaOlevels must be diligently monitored when the patient is in the prone position. If improvement is noted, allow proning for longer periods, for up to 3 hours at a time or as long as the patient remains comfortable. Pronation may be continued for 2–4 hours per session, about 2–4 times per day as tolerated (11). 


  • The physiological advantages of the prone position in acute hypoxemic respiratory failure include improved recruitment of the dorsal lung and more favorable ventilation-perfusion matching.
  • Previous case series have revealed improved oxygenation with awake proning.
  • Early experience suggests that improved PaO2/FiO2 ratios and reduced respiratory rates may ensue from awake proning in patients with COVID-19 infection.
  • Awake proning may be combined with conventional modalities of respiratory support in spontaneously breathing patients, including nasal cannulae, oxygen masks, HFNC, and NIV.
  • Sustained improvement in oxygenation may not occur once re-supination occurs; hence, longer periods of proning, several times a day, may be required. 
  • Awake proning may also be a viable option for patients in whom invasive ventilation may be considered futile. 
  • Future studies are required to investigate if early awake proning may reduce the requirement for invasive ventilation.


1.         Guérin C, Reignier J, Richard J-C, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159–68. 

2.         Feltracco P, Serra E, Barbieri S, Milevoj M, Michieletto E, Carollo C, et al. Noninvasive high-frequency percussive ventilation in the prone position after lung transplantation. Transplant Proc. 2012 Sep;44(7):2016–21. 

3.         Valter C, Christensen AM, Tollund C, Schønemann NK. Response to the prone position in spontaneously breathing patients with hypoxemic respiratory failure. Acta Anaesthesiol Scand. 2003 Apr;47(4):416–8. 

4.         Yoshida T, Torsani V, Gomes S, De Santis RR, Beraldo MA, Costa ELV, et al. Spontaneous Effort Causes Occult Pendelluft during Mechanical Ventilation. Am J Respir Crit Care Med. 2013 Nov 7;188(12):1420–7. 

5.         Scaravilli V, Grasselli G, Castagna L, Zanella A, Isgrò S, Lucchini A, et al. Prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: A retrospective study. J Crit Care. 2015 Dec;30(6):1390–4.

6.         Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care [Internet]. 2020 Jan 30 [cited 2020 May 19];24. Available from:

7.         Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care. 2020 Mar 18;10(1):33. 

8.         Caputo ND, Strayer RJ, Levitan R. Early Self‐Proning in Awake, Non‐intubated Patients in the Emergency Department: A Single ED’s Experience During the COVID‐19 Pandemic. Kline J, editor. Acad Emerg Med. 2020 May;27(5):375–8. 

9.         Elharrar X, Trigui Y, Dols A-M, Touchon F, Martinez S, Prud’homme E, et al. Use of Prone Positioning in Nonintubated Patients With COVID-19 and Hypoxemic Acute Respiratory Failure. JAMA [Internet]. 2020 May 15 [cited 2020 May 19]; Available from:

10.       Sartini C, Tresoldi M, Scarpellini P, Tettamanti A, Carcò F, Landoni G, et al. Respiratory Parameters in Patients With COVID-19 After Using Noninvasive Ventilation in the Prone Position Outside the Intensive Care Unit. JAMA [Internet]. 2020 May 15 [cited 2020 May 19]; Available from:

11.       “Massachusetts General Hospital Prone Positioning for Non-Intubated Patients Guideline.”

COVID-19 update: April 24, 2020

The COVID-19 pandemic continues to wreak death and devastation across most parts of the world. The curve may have flattened in many parts of Europe, but the worst may not yet be over for the US. We are still unclear about the trajectory in India. In the meantime, theories abound regarding mechanisms of causation of the disease, and the quest for the elusive magic bullet goes on. Let us briefly look at noteworthy information that has emerged in the past week. 

The New York experience

Richardson et al. evaluated a large case series of 5,700 patients admitted to 12 hospitals under Northwell Health, the biggest health care provider in New York (1). They analyzed the clinical characteristics and outcomes of patients hospitalized over a 35-day period between March 1, 2020, and April 4, 2020. All patients tested positive for SARS-CoV-2 by RT-PCR on the nasopharyngeal sample. Patients were followed up until they were discharged alive or dead, or until the study endpoint. On April 4, 2020, the final follow-up date, 2634 (46.2%) patients were either discharged alive or dead, while 3066 were still undergoing continued treatment in hospital.  

The median age of patients was 63 (IQR: 52–75) years, with a distinct male preponderance (60.3%). Common comorbidities included hypertension (56%), obesity (BMI ≥30, 41.7%), morbid obesity (BMI ≥35, 19%), and diabetes mellitus (33.8%). Lymphopenia (less than 1,000/microliter) was observed in 3387 (60%) patients. Important clinical outcomes are depicted in Table 1. 

Table 1. Important clinical outcomes of the New York case series

Dead or discharged alive at follow-up2634/5700 (46.2%)
Discharged alive 2081/2634 (79%)
Dead553 (21%)
Outcomes of ventilated patients
Total number of ventilated patients during the study period 1151/5700 (20.2%)
Ventilated patients who were dead/discharged alive at follow-up320/1151 (27.8)
Patients who continued to be on ventilation at follow-up831 (72.2%)
Mortality among ventilated patients at follow up282/1151 (24.5%)

Renal replacement therapy was required in 81 (3.2%) patients. The overall median length of hospital stay (from admission to death or discharge) was 4.1 (IQR, 2.3–6.8) days.

ACE-inhibitors and angiotensin receptor blockers

The SARS-CoV-2 binds to the ACE2 receptors to gain access into cells. This has led to the hypothesis that ACE inhibitors and ARBs may upregulate ACE2 expression, leading to increased severity of illness among COVID-19 patients (2). In contrast, inhibition of the renin-angiotensin system and increased levels of ACE2 may have a protective effect in acute lung injury (2). Investigators at the King’s College and Princess Royal University Hospitals, London, studied a cohort of 205 patients hospitalized with COVID-19 infection. Among these patients, 37 (18%) were on ACE-inhibitors (ACE-I). On serial logistic regression analysis, the primary endpoint of death or admission to the ICU occurred in 5/37 (14%) patients who were on ACE-I compared to 48/168 (29%) of patients who were not on ACE-I (odds ratio: 0.29, CI: 0.10–0.75, p <0.01). Although limited by small sample size, this study does not suggest an increase in severity of illness among COVID-19 patients who are on ACE-I (3). A possible protective effect needs to be evaluated among larger cohorts of patients. 


Conflicting evidence and unfulfilled promises continue with the use of hydroxychloroquine in COVID-19 infection. 

A previous randomized controlled trial from China had revealed a shorter time to relief of symptoms and more rapid resolution of consolidation on CT-imaging with the use of HCQ (4). In a recent randomized controlled trial from China, HCQ was administered in a dose of 1200 mg daily for 3 days, followed by 800 mg daily for a period of 2–3 weeks. Patients in the control group received standard of care alone. The primary endpoint, viral clearance on RT-PCR at 28 days, was not significantly different between groups (85.4% Vs. 81.3%, P = 0.341). RT-PCR negativity was also similar between groups at days 4, 7, 10, 14, and 21. Relief of symptoms at 28 days was also similar; however, on post hoc analysis, after the elimination of possible confounding effects of anti-viral drugs, HCQ seemed to be more efficacious in the alleviation of symptoms. 

In spite of several case series and a few controlled studies, the efficacy of HCQ among patients with COVID-19 infection remains unclear.  


The anti-parasitic agent, ivermectin, effective against several parasites, has been shown to have anti-viral activity against several viruses, including dengue viruses, the West Nile Virus, Venezuelan equine encephalitis virus, and influenza. Investigators from the Monash University in Australia had previously demonstrated a 5000-fold reduction in viral RNA at 48 hours in cell cultures with a single dose of ivermectin (5). 

A registry-based, multicenter, observational, case-controlled study was performed using prospectively collected data on patients with COVID-19 infection between January 1, 2020, and March 31, 2020. Data were collected from a registry, including 169 hospitals in North America, Europe, and Asia. For each Ivermectin-treated patient, a matched control (non-ivermectin treated) was identified using propensity-score matched criteria. Propensity matching was performed using age, gender, race or ethnicity, and the presence of comorbidities; qSOFA as used to match severity. Among 68,230 patients who were screened, 704 patients received ivermectin. The control group included 704 propensity-matched patients. Ivermectin was administered in a mean dose of 150 mcg/kg body weight. The overall mortality was significantly lower in the ivermectin-treated group (1.4% Vs. 8.5%, p < 0.0001). Among patients who were mechanically ventilated, the mortality was 7.3% in the ivermectin group compared to 21.3% in the control group (p < 0.001) (6). Adequately powered, randomized controlled trials are required to confirm possible improvement in clinical outcomes with ivermectin treatment in COVID-19 infection. 

Clinical and laboratory features of fatal cases of COVID-19

Tu et al. evaluated the clinical and laboratory characteristics and complications among 25 consecutive fatal cases of COVID-19 at the Wuhan University Zhongnan Hospital. They observed higher levels of IL-6, C-reactive protein, and D-dimer among patients who died compared to those who survived. An abnormal coagulation profile was noted in all non-survivors, and 24 (96%) patients had elevated D-dimer levels. IL-6 and CRP levels were high among all non-survivors, suggesting an intense cytokine storm. These findings offer information regarding the characteristics of severe COVID-19 infection and support further investigation regarding the use of immunomodulators (7).   

Prone positioning in awake, non-intubated patients

The use of the prone position in the intubated patient is well established to improve oxygenation and clinical outcomes (8). The prone position may improve oxygenation by selective redistribution of blood flow to areas of the lung that are better ventilated and allow recruitment of collapsed areas of the lung. With the increasing spread of COVID-19 across the world, there has been an upsurge of interest in positioning unintubated, spontaneously breathing patients in the prone position. The strategy of awake proning is of particular interest in patients who are hypoxic but appear reasonably comfortable at the onset of illness. 

In one of the earlier studies, awake prone positioning in unintubated patients was carried out in 15 patients with acute respiratory distress syndrome of variable etiology. The prone position was well-tolerated by all except two patients. No significant change in the respiratory rate or hemodynamic parameters were noted on assuming the prone position. With the use of the same levels of FiO2 and PEEP, prone positioning resulted in an increase in the PaO2/FiO2 ratios without any change in the pH and PCO(9). 

A recently published study evaluated the use of non-invasive ventilation or high flow nasal cannula combined with intermittent prone positioning among patients with acute respiratory distress syndrome. Two sessions of prone positioning were carried out daily, each lasting for 2 hours. Intubation could be avoided in 11 of the 20 patients studied. The authors observed that the early application of prone positioning with high-flow nasal cannula, especially in moderate ARDS with a baseline SpO2 > 95%, may reduce the requirement for intubation (10). Awake proning has also been described as part of the critical care management in a Chinese protocol for COVID-19 pneumonia (11). In light of the available evidence and anecdotal experience, the use of awake proning in unintubated patients may be a feasible option, particularly in resource-constrained settings. Patients who are hemodynamically stable and able to position themselves may be suitable candidates for awake proning. 


  • A large case series of COVID-19 from New York revealed important predisposing comorbidities, including included hypertension, obesity, and diabetes mellitus. More than half of the study patients remained in hospital at the time of follow-up. Among 1,151 patients who were invasively ventilated, 831 continued to be on ventilation at the completion of the study period.
  • Emerging new evidence suggests that ACE-I and ARBs may not impact the severity of COVID-19 infection.
  • A new randomized controlled trial re-establishes the relative lack of efficacy of HCQ in viral clearance and symptom alleviation.
  • Ivermectin, an antiparasitic drug, resulted in improved survival in COVID-19 patients in a propensity-matched, registry-based study.
  • An abnormal coagulation profile and increased levels of cytokines seem to characterize patients who develop severe disease. 
  • Prone positioning of awake, unintubated patients may improve oxygenation and reduce the requirement for invasive ventilation.   


1.         Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA [Internet]. 2020 Apr 22 [cited 2020 Apr 24]; Available from:

2.         Perico L, Benigni A, Remuzzi G. Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade. Nephron. 2020 Mar 23;1–9.

3.         Bean D, Kraljevic Z, Searle T, Bendayan R, Pickles A, Folarin A, et al. Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital Trust [Internet]. Infectious Diseases (except HIV/AIDS); 2020 Apr [cited 2020 Apr 24]. Available from:

4.         Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial [Internet]. Epidemiology; 2020 Mar [cited 2020 Apr 1]. Available from:

5.         Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Apr 3;104787. 

6.         Patel A. Usefulness of Ivermectin in COVID-19 Illness [Internet]. Rochester, NY: Social Science Research Network; 2020 Apr [cited 2020 Apr 24]. Report No.: ID 3580524. Available from:

7.         Tu W-J, Cao J, Yu L, Hu X, Liu Q. Clinico-laboratory study of 25 fatal cases of COVID-19 in Wuhan. Intensive Care Med [Internet]. 2020 Apr 6 [cited 2020 Apr 24]; Available from:

8.         Guérin C, Reignier J, Richard J-C, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159–68. 

9.         Scaravilli V, Grasselli G, Castagna L, Zanella A, Isgrò S, Lucchini A, et al. Prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: A retrospective study. J Crit Care. 2015 Dec;30(6):1390–4. 

10.       Ding L, Wang L, Ma W, He H. Efficacy and safety of early prone positioning combined with HFNC or NIV in moderate to severe ARDS: a multi-center prospective cohort study. Crit Care. 2020 Dec;24(1):28. 

11.       Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care. 2020 Mar 18;10(1):33. 

COVID-19 update: April 11, 2020

The COVID-19 pandemic has spread to 210 countries, affecting approximately 1.7 million people and resulting in more than 103,000 deaths until now. More than one-third of the world population, including India, is currently in lockdown. Although the epidemic curve has flattened in some countries, others continue to struggle. There has been an upsurge of literature on clinical experience and therapeutic interventions in the past week. 

Italy has been through the most daunting health crisis, following the first report of a young man who was admitted with atypical pneumonia at a Lombardy hospital on 20th February, 2020. He reported positive for SARS coronavirus 2, followed by 36 new cases over the next 24 hours. What followed was an explosive transmission of the disease that reached catastrophic proportions. 

From Lombardy, Italy

Graselli et al. reported on 1591 patients who were treated in 72 hospitals of the Lombardy ICU network between 20th February and 18th March, 2020. Among 1591 patients included, the median age was 63 (IQR: 56–70) years. The majority of patients were males (82%); 68% had comorbidities, hypertension being most common. Data on respiratory support was available in 1300 patients; among these patients, 1150 (88%) required invasive mechanical ventilation, and 137 (11%) received non-invasive ventilation. The median PEEP level was 14 (IQR: 12–16), and the median PaO2/FiO2 ratio was 160 mm Hg (IQR: 114–220). The FiOrequirement was more than 0.5 in 89% of patients. At the time of follow-up on 25th March, 2020, data was available on 1581 patients; 405 (26%) of patients had died, 920 (58%) were still in ICU, and 256 (16%) were discharged from the ICU (1). This study clearly shows that critically ill patients with COVID-19 have a protracted and complicated clinical course with high mortality. 

Coagulopathy in COVID-19

A fulminant coagulopathy can occur in patients with COVID-19 pneumonia. Endothelial dysfunction leads to excessive thrombogenesis and inhibition of fibrinolysis, resulting in a hypercoagulable state. Furthermore, hypoxia is well known to trigger the procoagulant pathway leading to venous thrombosis. Microthrombosis was observed in the pulmonary vessels on autopsy of a critically ill patient with COVID-19 (2). In a study of 183 consecutive patients with COVID-19, D-dimer and fibrin degradation products were higher, and the prothrombin and partial thromboplastin times were more prolonged among non-survivors compared to survivors. Among non-survivors, 71.4% had evidence of disseminated intravascular coagulation compared to 0.6% among survivors (3). 

The incidence of thrombotic events, including acute pulmonary embolism, deep vein thrombosis, acute ischemic stroke, acute myocardial infarction, and arterial embolism was evaluated in 182 COVID-19 patients admitted to three hospitals in the Netherlands. Thrombotic events were noted in 31% of patients in this study, acute pulmonary embolism being the most common complication (82%). Increasing age and the presence of coagulopathy were independent predictors of thrombotic events (4). Clinically significant coagulopathy with the presence of antiphospholipid antibodies was reported among three patients with COVID-19 (5). 

A retrospective observational study was performed in Wuhan, China, in patients with COVID-19, comparing patients who received anticoagulant therapy with unfractionated or low molecular weight heparin with those who had no anticoagulant treatment. On multivariate logistic regression analysis, patients with a SIC score (a scoring system that includes the platelet count, INR, and the SOFA score) of 4 or higher who were treated with unfractionated or low molecular weight heparin had a significantly lower 28-day mortality compared to those who did not receive anticoagulant therapy (6). 

The question arises, do we anticoagulate patients with COVID-19? 

In light of a high incidence of thrombotic complications among patients with COVID-19, the International Society of Thrombosis and Haemostasis (ISTH) recommends the administration of prophylactic low-molecular-weight heparin to all hospitalized patients in the absence of active bleeding, if the platelet count is more than 25,000/μl, regardless of the INR and APTT. This strategy is expected to reduce the incidence of a sepsis-like coagulopathy and prevent venous thromboembolism (7).   

The cytokine storm and secondary hemophagocytic histiocytosis (sHLH)

A profound, rapidly fatal cytokine storm can occur in viral infections and culminate in sHLH, characterized by multiorgan failure. The main features of sHLH include cytopenias  associated with high serum ferritin levels and severe acute respiratory distress syndrome. Mortality in COVID-19 patients has been shown to be associated with high ferritin levels, suggesting infection-related hyperinflammatory response to be the causative mechanism (8). Attenuation of the intense cytokine storm is a possible modality of treatment in COVID-19 pneumonia. Patients with COVID-19 should be screened for a hyperinflammatory syndrome with regular blood counts and serum ferritin levels. The options for cytokine inhibition include corticosteroids and intravenous immunoglobulin. A randomized controlled trial with tocilizumab, an IL-6 blocker, is currently recruiting patients in China (9). 


The nucleotide analog remdesivir has in vitro activity against SARS-CoV-2. It was used on a compassionate basis in 61 patients with COVID-19 who had an oxygen saturation of less than 94% on room air or required supplemental oxygen. Remdesivir was administered intravenously in a dose of 200 mg on day 1, followed by 100 mg per day for 9 days. Clinical outcomes of 53 of the 61 patients were analyzed. At baseline, 30 patients (57%) were invasively ventilated and four patients were on extracorporeal membrane oxygenation (ECMO). The median follow-up period was 18 days. The level of the oxygen support device (ECMO, invasive mechanical ventilation, non-invasive ventilation, high-flow oxygen, or low-flow oxygen) could be scaled down in 36 patients (68%). Seventeen of 30 patients (57%) who were invasively ventilated could be extubated. Twenty-five patients (47%) had been discharged, and seven (13%) had died at the time of follow up. The mortality among invasively ventilated patients was 18% (6/34); mortality was 5% (1/19) among those who did not receive invasive ventilation (10).  

Hydroxychloroquine – same investigators, new study

Previous studies on hydroxychloroquine use in COVID-19 have been of poor quality with conflicting results. Against this background, Raoult et al. reported on another cohort of 1061 patients who were treated with the hydroxychloroquine-azithromycin combination for a minimum period of 3 days and followed up for 9 days. This study is available in the abstract form (11). The mean age was of patients was 43.6 years; in 973 patients (91.7%) a “good clinical outcome” and virological cure occurred. Forty-six patients (4.3%) experienced “a poor outcome” with 10 patients requiring intensive care. Five patients (0.47%) aged between 74–95 years died, while 31 patients required 10 or more days of hospitalization. The investigators did not observe any cardiac toxicity among the study patients. A major weakness of this study, yet again, similar to previous studies by the same group, is the lack of a control arm. 

QT prolongation with the hydroxychloroquine-azithromycin combination 

Changes in the QT interval was studied in 84 patients with COVID-19 who received the hydroxychloroquine-azithromycin combination. The maximal prolongation of the corrected QT interval (QTc) was observed between days 3 and 4 of treatment. Severe QTc prolongation of more than 500 ms was observed in 11% of patients. Acute kidney injury was a predictor of prolonged QTc on multivariate analysis; baseline QTc was not a predictor of prolongation. This study suggests that the hydroxychloroquine-azithromycin combination can lead to severe prolongation of QTc, and regular monitoring is required, especially among patients with renal dysfunction. 


The anti-parasitic agent, ivermectin, effective against several parasites, has been shown to have anti-viral activity against several viruses, including dengue viruses, the West Nile Virus, Venezuelan equine encephalitis virus, and influenza. Investigators from the Monash University in Australia demonstrated a 5000-fold reduction in viral RNA at 48 hours in cell cultures with a single dose of ivermectin. Although widely used and considered safe in humans, it remains to be seen whether the usual clinical dose will be effective in SARS-CoV-2 infection. Further pre-clinical testing and clinical trials are required to evaluate its efficacy in COVID-19. 


  1. In a retrospective observational study from Lombardy, Italy, the majority of patients admitted to the ICU were men in the older age group. The large majority of patients required invasive mechanical ventilation with relatively high mortality. 
  2. A fulminant coagulopathy with extensive thrombosis can occur in patients with SARS-CoV-2 infection. Low-molecular-weight heparin should be considered in all hospitalized patients in the absence of active bleeding, if the platelet count is more than 25,000/μl. 
  3. An intense cytokine storm can occur in patients with COVID-19 leading to sHLH, and multiorgan failure. Corticosteroids and intravenous immunoglobulin are therapeutic options in this setting. Tocilizumab, an IL-6 blocker, is currently being investigated. 
  4. Remdesivir has shown in vitro activity against SARS-CoV-2. Promising results were observed in a small case series and further evaluation is required in controlled studies. 
  5. Yet another case series from the Marseilles group claims improved clinical outcomes and effective viral clearance with the use of the hydroxychloroquine-azithromycin combination. 


1.         Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA [Internet]. 2020 Apr 6 [cited 2020 Apr 11]; Available from:

2.         Luo W, Yu H, Gou J, Li X, Sun Y, Li J, et al. Clinical Pathology of Critical Patient with Novel Coronavirus Pneumonia (COVID-19). 2020 Feb 27 [cited 2020 Apr 11]; Available from:

3.         Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844–7. 

4.         Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Apr;S0049384820301201. 

5.         Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 8;NEJMc2007575. 

6.         Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost [Internet]. 2020 Mar 27 [cited 2020 Apr 11]; Available from:

7.         Brady L. Stein MD. Coagulopathy Associated with COVID-19. NEJM J Watch [Internet]. 2020 Apr 6 [cited 2020 Apr 11];2020. Available from:

8.         Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Mar 3; 

9.         Chinese Clinical Trial Register (ChiCTR) – The world health organization international clinical trials registered organization registered platform [Internet]. [cited 2020 Apr 11]. Available from:

10.       Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10;NEJMoa2007016. 

11.       Abstract_Raoult_EarlyTrtCovid19_09042020_vD1v.pdf [Internet]. [cited 2020 Apr 11]. Available from:

COVID-19 update: April 3, 2020

It has been a long, hard week of complete lockdown in India. We have not seen a significant impact yet, it is probably too early. However, there is a disturbing trend in the number of new COVID-19 cases, although, thankfully, the mortality has remained low. Many other countries are struggling, with a seemingly uncontrollable increase in new cases in the US. However, New York city, one of the worst-hit, may have seen the worst and the curve may be flattening (1). Italy appears to be finally riding out the storm after several weeks of utter despair. At the time of writing, more than a million people have been infected all over the world, leaving a staggering trail of death. 

Let us look at some of the impactful new studies that have been published in the past week on COVID-19.

A new randomized controlled trial on hydroxychloroquine (HCQ)

Two controlled studies have already been published with the use of HCQ in COVID-19. A more rapid viral clearance was noted in a French study (2), while a pilot study from China revealed no difference between the HCQ-treated and control groups regarding the time to defervescence or progression of changes on CT imaging (3). 

In the newest study on HCQ for the treatment for COVID-19, Chen et al. conducted a randomized, parallel-group trial at the Renmin Hospital, in Wuhan, China, over a 24-day period. The study included patients with RT-PCR proven COVID-19 pneumonia who presented with a mild illness, with oxygen saturation of > 93% on air or a PaO2/FiO2 ratio of > 300 mm Hg. Patients who were critically ill were excluded from the study. In the intervention arm, HCQ was administered in a dose of 200 mg twice daily from days 1–5 of treatment, while patients in the control group received standard care. Patients in both groups received oxygen therapy, antiviral and antibacterial agents, intravenous immunoglobulin, and corticosteroids.

The study included 31 patients in each arm. The main endpoint was the time to clinical recovery, defined as normalization of body temperature, and relief from cough, for more than 72 hours. Among patients who received HCQ, the time to temperature normalization was 2.2 ± 0.4 days compared to 3.2 ± 1.3 days in the control arm, the difference being statistically significant. The time to remission of cough, 2.0 ± 0.2 vs. 3.1 ± 1.5 days, was also significantly less among HCQ treated patients. 

The authors also compared changes in CT findings between groups over a 6-day period. HCQ-treated patients showed significantly more improvement in consolidation on CT (80.6% vs. 54.8%); 61.3 patients in the HCQ group revealed a significant resolution of consolidation. In the control group, four patients progressed to severe illness, compared to none in the HCQ group. Mild adverse reactions were noted in two patients who received HCQ (4). Although a pilot study of a small sample size, this study suggests possible benefit with HCQ in patients who are less severely ill. However, we need more robust data before it may be routinely used in the treatment of patients with COVID-19. 

Report from Seattle

In a case series from the US, Bhatraju et al. reported on 24 ICU patients from nine hospitals in the Seattle area. Data were available until the March 23, 2020, and patients were followed up for at least 14 days.  Comorbidities were common, including diabetes mellitus (58%), chronic kidney disease (21%), and asthma (14%). All patients presented with acute hypoxemic respiratory failure. Bilateral lung opacities were seen on the chest radiograph in 23 patients; CT-imaging was performed in 5 patients, which revealed bilateral ground-glass opacities in four patients and pulmonary nodules in one patient. 

High-flow nasal cannula was used in 10 (24%) patients, and invasive mechanical ventilation was carried out in 18 (75%) patients; five (28%) patients were prone ventilated. Vasopressors were required in 17 (71%) patients; 14 patients continued to be hypotensive for longer than 12 hours post-intubation. No patient received non-invasive ventilation or extracorporeal membrane oxygenation. Interestingly, similar to previous reports (5), ventilation was possible with relatively low driving and plateau pressures, and the respiratory system compliance was reasonably well-preserved. However, the PaO2/FiO2 ratios remained poor, with the lowest values observed on day 3 (median: 134; IQR: 108–171). Among the 18 ventilated patients, 6 patients were extubated by day 31. 

At the 14-day follow-up, 12 (50%) patients had died, while three (13%) continued to require mechanical ventilation; four (17%) were discharged from the ICU but continued to be in hospital. Five patients (21%) were discharged from hospital (6). 

Case-fatality ratio and infection fatality ratio of COVID-19

Verity et al. attempted to overcome biases in the estimation of the case-fatality ratio and infection fatality ratio in a model-based analysis. The case-fatality ratio is the proportion of all diagnosed cases (tested positive) that eventually leads to death;  the infection fatality ratio comprises of all patients with infection, including those who are asymptomatic, and hence, remain undiagnosed. Thus, the infection fatality ratio, with a larger denominator, will be lower than the case-fatality ratio. Based on this model, the best estimate of the case-fatality ratio in China was 1·38% (1·23–1·53). Mortality was substantially higher among older age groups. It was 6·4% (5·7–7·2) among those aged ≥60 years compared to 0·32% (0·27–0·38) in those less than 60 years old.  The infection fatality ratio for China was 0·66% (0·39–1·33), and increased with age (7). 

The Italian experience

Gattinoni et al., from their initial experience in Italy, note that COVID-19-related ARDS is characterized by several atypical features. Even in the face of severe hypoxemia, lung compliance remained fairly well-preserved. Among their first 16 patients with COVID-19, the respiratory system compliance was 50.2 ± 14.3 ml/cm H2O, associated with a high shunt fraction of nearly 50%. They hypothesize that the large increase in intrapulmonary shunt may be due to the loss of hypoxic pulmonary vasoconstriction and continued perfusion of non-ventilated lung tissue. The apparent response to recruitment maneuvers and prone positioning may be due to a more favorable redistribution of perfusion to better-ventilated areas of the lung, resulting from changes in gravitational forces and application of pressure. They suggest early intubation and mechanical ventilation among patients who demonstrate a high respiratory drive, characterized by forceful respiratory efforts. Forceful spontaneous efforts on non-invasive ventilation may lead to patient self-inflicted lung injury. Besides the adverse effects related to high transpulmonary pressures, the alveolar pressure may drop significantly lower than the end-expiratory pressure during vigorous spontaneous respiratory efforts. The intravascular pressure within the pulmonary blood vessels decreases proportionally; however, the pleural pressure decreases to a greater extent, thus, increasing the transmural pulmonary vascular pressure. The increase in the transmural pulmonary vascular pressure combined with increased capillary permeability results in leakage of fluid from within the capillaries and may worsen pulmonary edema (8). The authors also warn against the use of high PEEP levels in poorly recruitable lungs, which may lead to hemodynamic instability and fluid retention (5). 

Does convalescent plasma help? 

Convalescent plasma is recommended for the empirical treatment of Ebola Virus Disease (EVD) and Middle East Respiratory Syndrome (MERS). Shen et al. evaluated the effect of convalescent plasma transfusion among a series of five critically ill patients with COVID-19 pneumonia. Patients had severe pneumonia with ARDS and experienced rapid disease progression with persistent high viral loads. All were ventilated and had PaO2/FiO2 ratios less than 300 mm Hg. Convalescent plasma with a SARS-CoV-2 specific antibody (IgG) binding titer greater than 1:1000 from was derived from five donors who had recovered from laboratory-confirmed COVID-19 infection. 

The study subjects were on antiviral therapy and methylprednisolone. Following transfusion of convalescent plasma, defervescence occurred within 3 days in four patients. The SOFA scores decreased, and the PaO2/FiO2 ratios increased within 12 days. The viral loads diminished and turned negative within 12 days after transfusion. Resolution of ARDS was noted at 12 days post-transfusion; three patients were weaned off from ventilation within 2 weeks. At day 37 post-transfusion, three patients had been discharged from hospital; the other two were in a stable clinical condition (9).  Similar to the beneficial effects noted in patients with EVD and MERS, convalescent plasma holds promise as possible therapy, especially among patients with severe COVID-


  • Three controlled studies have been published so far evaluating the efficacy of HCQ in the treatment of COVID-19 infection. Initial results from small studies hold promise but need to be confirmed in larger randomized controlled studies. There are many studies currently recruiting patients with hydroxychloroquine alone and in combination with antiviral drugs.  
  • A report from Seattle, in the US, corroborates with previous findings among critically ill patients with COVID-19 pneumonia. This study revealed severe hypoxemia, requirement for mechanical ventilation, hypotension requiring vasopressors, and high mortality. 
  • Variable mortality rates are reported across the globe. This may be due to the difference in the number of patients who are tested positive, relative to the actual number of patients who are infected.  
  • The initial Italian experience suggests severe hypoxemia in spite of reasonably preserved lung compliance. The authors postulate that a large increase in the intrapulmonary shunt due to inhibition of the hypoxic pulmonary vasoconstrictor response may cause an increase in the shunt fraction. 
  • A small case series from China suggests the efficacy of convalescent plasma in severely ill patients with COVID-19 infection. 


1.         Harris JE. The Coronavirus Epidemic Curve Is Already Flattening in New York City [Internet]. Rochester, NY: Social Science Research Network; 2020 Mar [cited 2020 Apr 3]. Report No.: ID 3563985. Available from:

2.         Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar;105949. 

3.         Chen Jun LD, Chen Jun LD. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ Med Sci. 2020 Mar 6;49(1):0–0. 

4.         Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial [Internet]. Epidemiology; 2020 Mar [cited 2020 Apr 1]. Available from:

5.         Gattinoni L, Coppola S, Cressoni M, Busana M, Chiumello D. Covid-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2020 Mar 30;rccm.202003-0817LE. 

6.         Bhatraju PK, Ghassemieh BJ, Nichols M, Kim R, Jerome KR, Nalla AK, et al. Covid-19 in Critically Ill Patients in the Seattle Region — Case Series. N Engl J Med. 2020 Mar 30;NEJMoa2004500. 

7.         Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Mar;S1473309920302437. 

8.         Brochard L, Slutsky A, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med. 2017 Feb 15;195(4):438–42. 

9.         Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA [Internet]. 2020 Mar 27 [cited 2020 Apr 3]; Available from:

COVID-19 update: 26th March, 2020

We are entering an extremely crucial phase of the COVID-19 pandemic, with many countries, including India, closing their borders and enforcing complete lockdown. Clinicians are passing through a learning curve with increasing real-world experience. New information regarding the causative virus, transmission control, and innovative modalities of treatment are being addressed. This review attempts to summarize recent developments that may help clinicians who may have to care for COVID-19 infected patients. 

Mode of transmission

Does airborne spread occur? 

The virus that causes COVID-19 disease, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is transmitted primarily through droplets and fomites. Does it spread through aerosols? It has significant implications for healthcare workers, as a much higher level of protection is necessary to combat aerosol spread. The stability of SARS-CoV-2 in aerosols and different types of surfaces was evaluated by van Doremalen et al. (1). Aerosols of particle size less than 5 microns containing the virus were generated. The viability of the virus was tested in the aerosol and on plastic, steel, copper, and cardboard surfaces. The SARS-CoV-2 virus remained viable in aerosols during the 3-h duration of the experiment, with a reduction in the infectious titer over time. The virus was more stable on plastic and steel surfaces and could be detected for up to 72 h, although at a largely reduced titer. 

The findings of this experimental study suggest the plausibility of aerosol transmission of the SARS-CoV-2 virus and reassert the importance of the use of personal protective equipment (PPE) that offers aerosol protection.  

Specific treatment modalities 

Hydroxychloroquine (HCQ) 

Discovered in 1934, and extensively used in the treatment of malaria for decades, chloroquine may exhibit anti-viral activity through several mechanisms. It may inhibit pH-dependent steps involved in viral replication, besides inhibition of the generation and release of TNF-alpha and IL-6 (2). It may suppress cellular autophagy, leading to the inhibition of viral replication (3). 

In a pilot study, patients with confirmed COVID-19 disease were randomized to receive HCQ 400 mg/d for 5 days compared to standard care. Clearance of viral nucleic acid from pharyngeal swabs occurred in 13/15 (86.7%) patients in the HCQ group and 14/15 (93.3%) patients in the control group. There was no difference between the HCQ-treated and control groups regarding the time to defervescence or progression of changes on CT imaging (4). 

In a French study, 20 patients with confirmed COVID-19 disease received HCQ 600 mg/d; azithromycin was added based on the clinical situation. Sixteen patients from another center acted as controls. By day 3, 50% of HCQ-treated patients tested negative for the virus by RT-PCR compared to 6.3% in the control group; by day 6, 70% among the treated group tested negative compared to 12.5% in the control group. The addition of azithromycin seemed to augment viral clearance (5).  

However, the outcomes of six patients from the treatment group were not reported in this study. Clinical worsening occurred in three patients requiring ICU admission and one patient died, while treatment was discontinued in two other patients. There was no mortality or requirement for ICU admission in the control group. Hence, apart from early viral clearance, this study does not demonstrate any clinical benefit associated with the use of HCQ. 

The use of hydroxychloroquine is currently being evaluated in several clinical trials as pre- or post-exposure prophylaxis for COVID-19 infection. No data are currently available to guide the dose or duration of prophylactic HCQ. 

Lopinavir-ritonavir combination 

Does specific anti-viral therapy help in COVID-19 disease? 

In a recently published randomized controlled trial, Cao et al. evaluated the efficacy of the lopinavir-ritonavir combination among patients with an oxygen saturation of less than 94% while breathing room air or P/F ratio of less than 300 mm Hg. The primary endpoint was the time interval from randomization to improvement by two points on a seven-category scale or hospital discharge, whichever occurred earlier. There was no difference between the anti-viral combination and standard care in the primary outcome. No significant difference was observed in the 28-d mortality between groups. Besides, there was no difference in the number of patients with detectable viral RNA at different points of time during the course of treatment (6). This study suggests that the lopinavir-ritonavir combination may not improve clinical outcomes or reduce viral shedding in patients with COVID-19 disease. 

A post-hoc analysis of patients who received treatment within 12 days of disease onset revealed reduced mortality among patients who received the lopinavir– ritonavir combination. Whether earlier treatment would favorably influence clinical outcomes needs further rigorous research.

High-flow nasal cannula (HFNC) and non-invasive ventilation (NIV)

In resource-limited situations, high-flow nasal oxygen may be initiated as early supportive therapy in mild hypoxemic respiratory failure. However, there is concern regarding a high level of aerosolization and disease transmission with this modality of treatment. It may be advisable to use relatively low flows (20–30 l/min) to prevent excessive aerosolization. In a simulator-based study, exhaled air dispersion with HFNC therapy was limited with an adequate cannula fit (7). The patient may don a surgical mask over the nasal cannula to reduce the risk of excessive dissemination of aerosol. Close monitoring must be carried out during HFNC therapy, and early intubation should be considered in case of deterioration. 

Anecdotal reports suggest a slightly unusual clinical picture among patients with COVID-19-related acute respiratory distress syndrome (ARDS). This is characterized by a relative lack of subjective discomfort in the presence of hypoxemia, preserved lung compliance, and a favorable response to prone ventilation, suggesting progressively large areas of alveolar collapse. The use of NIV, particularly continuous positive airway pressure (CPAP) may have positive effects in this situation by maintaining high mean airway pressures. NIV may be particularly considered in patients with associated chronic obstructive pulmonary disease. An appropriate expiratory port filter may be attached to single-limb non-invasive ventilation devices to reduce the risk of aerosol transmission (8). Both HFNC and NIV are ideally used in negative pressure areas to reduce the risk of transmission. 

CT imaging

Patients with COVID-19 disease have shown characteristic features on CT imaging that may help with early diagnosis and evaluation of disease progression. Peripheral and subpleural ground-glass opacities (GGO) are one of the common features. The GGO may be unilateral or bilateral (9). Thickening of interlobular septa and intralobular lines against a background of GGO may result in a typical “crazy paving” pattern. Patchy consolidation, air bronchograms, pleural thickening, and sub-pleural curvilinear lines are other CT features among patients with COVID-19 pneumonia (Fig. 1) (10).

Fig 1. Chest CT in COVID-19 pneumonia, showing peripheral reticular pattern and ground-glass opacities

Chest CT imaging may allow early, reliable diagnosis in patients presenting with COVID-19 pneumonia compared to RT-PCR. Ai et al. studied 1014 patients who underwent CT imaging and RT-PCR testing during a 1-month period in Wuhan, China. Among patients suspected of COVID-19 disease, RT-PCR was positive in 601/1014 (59%), while CT imaging was diagnostic in 888/1014 (88%) patients. When RT-PCR was used as the reference, chest CT revealed a sensitivity of 97%. Among 308 patients with negative RT-PCR and a diagnostic CT scan, 147 (48%) were considered to be highly likely, and 103 (33%) patients were considered to have probable COVID-19 disease (11). When serial RT-PCR and CT scans were analyzed, 60–93% of patients had an initial diagnostic CT, prior to positive RT–PCR test results. 

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in COVID-19

Do ACE inhibitors and ARBs help or harm? 

It has been shown that COVID-19 uses the ACE2 receptor to gain access into cells (12). This has led to the hypothesis ACE inhibitors and ARBs may upregulate ACE2 expression, leading to increased predisposition to COVID-19 infection. However, according to Perico et al., the entry of the virus into the cell is a complex, tightly regulated process involving several steps. Besides, ARBs and angiotensin II compete for the same receptor; this may result in an increase in the release of angiotensin. An increase in angiotensin II levels leads to enhanced binding to the catalytic site of ACE2 receptors. An increase in binding may lead to a structural change in the ACE2 receptor that may inhibit the binding of the virus to the receptor and prevent cellular entry (13). This has led to the suggestion that ARBs may, in fact, reduce the extent of lung damage in patients with COVID-19 disease. Considering the conflicting theories and lack of clinical data, most guidelines, including those of the American College of Cardiology recommend the continued administration of ARBs and ACE inhibitors among patients who are currently on treatment (14). 


  1. The primary mode of COVID-19 spread is through droplets and fomites; however, it is plausible that aerosol transmission may also occur. Hence, healthcare workers need to take appropriate precautions with the use of appropriate personal protective equipment.
  2. There is an ongoing debate regarding the efficacy of hydroxychloroquine in the treatment of COVID-19 disease; based on the limited data available, no definitive conclusions can be drawn.
  3. There may be a role for the use of HFNC and NIV (especially CPAP), albeit with a marginally increased risk of aerosolization and disease transmission.  
  4. CT imaging appears to be a sensitive diagnostic modality, especially during the early stage of the disease. Early diagnosis may enable transmission control measures. 
  5. There are conflicting hypotheses regarding the impact of ACE inhibitors and ARBs on viral entry into cells and disease causation. Patients who are already on these drugs are advised to continue treatment. 
  6. There is ongoing research on several treatment modalities, which may help guide treatment in the near future. 


1.         van Doremalen N, Bushmaker T, Morris DH, Holbrook MG, Gamble A, Williamson BN, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020 Mar 17;NEJMc2004973. 

2.         Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005 Aug 22;2:69. 

3.         Golden EB, Cho H-Y, Hofman FM, Louie SG, Schönthal AH, Chen TC. Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors. Neurosurg Focus. 2015 Mar;38(3):E12. 

4.         43f8625d4dc74e42bbcf24795de1c77c.pdf [Internet]. [cited 2020 Mar 26]. Available from:

5.         Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar;105949. 

6.         Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 Mar 18;NEJMoa2001282. 

7.         Hui DS, Chow BK, Lo T, Tsang OTY, Ko FW, Ng SS, et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks. Eur Respir J. 2019 Apr;53(4):1802339. 

8.         COVID-19: How to safely optimize NIV therapy [Internet]. Philips. [cited 2020 Mar 26]. Available from:

9.         Chung M, Bernheim A, Mei X, Zhang N, Huang M, Zeng X, et al. CT Imaging Features of 2019 Novel Coronavirus (2019-nCoV). Radiology. 2020;295(1):202–7. 

10.       Ye Z, Zhang Y, Wang Y, Huang Z, Song B. Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review. Eur Radiol [Internet]. 2020 Mar 19 [cited 2020 Mar 26]; Available from:

11.       Ai T, Yang Z, Hou H, Zhan C, Chen C, Lv W, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020 Feb 26;200642. 

12.       Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270–3. 

13.       Perico L, Benigni A, Remuzzi G. Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade. Nephron. 2020 Mar 23;1–9.

14.       HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19 [Internet]. American College of Cardiology. [cited 2020 Mar 26]. Available from:

Management of the critically ill patient with COVID-19 disease

COVID-19 disease has spread far and wide across the globe. At the time of writing, more than 225,000 patients have been affected, leading to more than 9,300 deaths (1). The number of seriously ill patients who require intensive care is likely to increase, requiring several-fold increase in the requirement for caregivers and equipment. The clinical management strategy of infected patients is evolving, and encompasses several treatment modalities, including mechanical ventilation and support of vital organs. This review attempts to summarize the intensive care management of critically ill patients with COVID-19 based on the evidence available and experience from previous epidemics of viral pneumonias. 


Considering the high risk of transmission, patients with COVID-19 disease should be preferably cared for in single, negative pressure rooms. In case of non-availability of single, negative pressure rooms, standard single rooms are preferred. If the patient load is high and the above options are exhausted, the next suitable alternative is to cohort COVID-19 patients to a multi-bed area, which is physically separate from other patients. A distance of at least 2 meters should be maintained between patients. Each location should have an ante-room earmarked for staff preparation, including donning and doffing of personal protective equipment (PPE).


As part of advance planning, staff members who would be involved with the care of COVID-19 patients should be identified. The “clean” and “isolated” teams of healthcare workers should be segregated, with back-up personnel to stand-in if shortages arise. Staff members who care for COVID-19 patients should wear clean surgical scrubs and provided with provision to shower at the end of the shift. Strong consideration should be given to allow a break of 1-2 weeks after a 1-week period of regular duty to members of the isolation team. Healthcare workers should be instructed to report any untoward symptoms early and their temperature should be checked twice a day. 

Clinical management 

The presence of pneumonic infiltrates on imaging is one of early features of severe COVID-19 disease.  In a study of 99 patients from the Jintinyan Hospital in China, 74 (75%) patients had evidence of bilateral pneumonia,  while multiple mottling  or ground-glass opacities on CT imaging was seen in 14 (14%) patients (2). The management of COVID-19 pneumonia is similar to that of other viral pneumonias based on the information available until now. 

Acute respiratory distress syndrome is seen typically seen in severe disease. 

High-flow nasal oxygen

In resource-limited situations, high-flow nasal oxygen may be initiated as early supportive therapy. However, there is a risk associated with a high level of aerosolization and disease transmission with this modality of treatment. It may be advisable to use relatively low flows (20­–30 l/min) to prevent excessive aerosolization. The patient may don a surgical mask to reduce the risk of excessive dissemination of aerosol.

Non-invasive ventilation 

Should we use non-invasive ventilation (NIV) as the initial modality of ventilatory support in patients with COVID-19 disease? Among patients with the Middle East respiratory syndrome, NIV failure rate was very high. In an observational study, 92.4% of patients who were initially managed with NIV required invasive mechanical ventilation. Besides, there was no difference in the 90-d mortality between patients who received NIV initially and those who were invasively ventilated at the outset (3). Furthermore, emergent intubation with poor preparation following failed NIV carries an increased risk of disease transmission due to a failure to follow appropriate precautions. The Australia and New Zealand Intensive Care Society (ANZICS) recommends against the use of NIV in COVID-19 infected patients (4). 

When to intubate?    

There is an absence of robust information on how to decide on the appropriate time to intubate and commence invasive mechanical ventilation among patients with severe disease. It is better to be prepared and consider early intubation if there is a lack of improvement or worsening with conventional oxygen, NIV, or high-flow nasal oxygen within an hour of commencement of therapy (5). 

Intubation protocol 

Considering the high likelihood of transmission of infection to healthcare workers, intubation of patients with COVID-19 disease must be carefully planned and carried out with utmost precautions. It is highly desirable to perform intubations in a negative pressure room; if this is not feasible, a single isolation room is preferred. It is important to create a checklist of items required and ensure readiness before commencement of the procedure. Do ensure that the intubation plan is communicated to the whole team prior to commencement. If in doubt, it is appropriate to perform intubation early during the clinical course. Emergency intubations may carry additional risk to staff from the likelihood of inadequate donning of personal protective equipment (PPE) besides subjecting a severely hypoxic patient to the risks associated with unplanned intubation. 

Intubation should be carried out in a well-planned manner. All essential equipment must be in full readiness prior to commencement of the procedure. All staff involved must don adequate PPE including water-resistant gowns, gloves, fit-tested N95 masks or higher, goggle or face shields, and cap. Not more than three healthcare personnel should be by the bedside to carry out intubation. One staff member should administer medications while the other assists with intubation and monitors the patient during the procedure. The person who performs the intubation must be the most experienced with airway management in the team. A vasopressor infusion (e.g., noradrenaline, 4 mg/50 ml) must be set up and ready to infuse in case of hypotension after the administration of anesthetic agents. Preoxygenation is carried out using a bag-mask system to ensure maximal oxygen saturation prior to the administration of anesthetic drugs. The mask must be held tightly across the face with both hands to reduce air leak and aerosol generation. Do not attempt positive pressure ventilation with bag and mask if possible; if considered absolutely necessary, the assistant carries out insufflations while the intubator ensures an effective seal with the mask.  

Once the patient is adequately sedated, suxamethonium 1.5 mg/kg or rocuronium 1.2 mg/kg is administered for muscle relaxation. Adequate muscle relaxation must be ensured before laryngoscopy is attempted.  A video laryngoscope is preferred if the operator is skilled, as it reduces the proximity of the operator to the airway compared to direct laryngoscopy. 

It is important to place the tube correctly without undue delay; failed attempts are associated with increased risks of transmission of infection to staff. Ventilation must not be attempted before cuff inflation as this may cause a significant leak around the cuff and contamination. Closed suction must be employed to prevent the spread of aerosol. Samples for virology studies may be drawn during suctioning. Careful doffing of personal protective equipment is carried out after the procedure.

Ventilation strategies 

Based on available evidence, a low-tidal volume, lung-protective ventilation strategy is recommended for patients with COVID-19 pneumonia. Retrospective data suggests that ventilation strategies targeting driving pressure may be appropriate in patients with ARDS (6). The initial management of patients who are difficult to ventilate includes the use of deep sedation and muscle relaxants as appropriate. Initial clinical experience suggests that there is rapid improvement in the P/F ratio with initiation of mechanical ventilation, with the use of high levels of PEEP and recruitment maneuvers. Prone ventilation has also been extensively employed; early experience suggests rapid improvement in oxygenation. Extra-corporeal membrane oxygenation has been performed on a limited scale in some centers, but no data is currently available regarding clinical outcomes. A fluid-restrictive strategy is appropriate among patients who are not in shock; diuretic therapy may be considered to remove excessive fluid and aim for a negative balance. 

Extra-pulmonary organ failure

Besides pneumonia and ARDS, multiorgan failure has been frequently reported in patients with COVID-19 disease. This includes myocardial involvement, hepatic, and renal dysfunction. In a retrospective, observational study from China, there was evidence of cardiac injury (29%), hepatic dysfunction (29%), and acute kidney injury (23%) among 710 patients admitted to the Jinyintan Hospital in Wuhan. Renal replacement therapy was performed in 17% of patients with severe illness (7).


According to the guidelines of the World Health Organization (WHO) and the Center for Disease Control (CDC), corticosteroids are not recommended in patients with COVID-19 diseases (1,8). Corticosteroid use was associated with higher mortality and delay in viral clearance among patients with MERS-CoV infection. In severe acute respiratory distress syndrome (SARS) lack of benefit with corticosteroids has been demonstrated; besides, there may be short and long-term harmful effects including the requirement for mechanical ventilation, vasopressors, and renal replacement therapy (9). It is likely that the impact of corticosteroids in COVID-19 disease may also be similar. 

Anti-viral therapy under investigation

Several anti-viral drugs are being used as part of the treatment strategy in COVID-19 pneumonia in several countries. Apart from anecdotal information, there is no controlled data that supports the use of specific antiviral therapy. 


Both chloroquine and hydroxychloroquine have been shown to have anti-viral activity in vitro against SARS-CoV-2; hydroxychloroquine may be more potent (10). Several clinical trials are in progress, but it is unclear whether these drugs may exhibit anti-viral activity and improve clinical outcomes in COVID-19 disease. 


A novel nucleotide analogue, remdesivir has revealed in vitro activity against coronaviruses including SARS-CoV-2 and MERS-CoV. Besides, anti-viral activity has also been observed in animal studies. Although used sporadically in several patients across the globe, the clinical efficacy of remdesivir in COVID-19 disease is unknown. Several randomized controlled studies are currently in progress.


This protease receptor drug combination is used in retroviral infection and has been demonstrated to have in vitro activity against SARS-CoV. Animal data also suggest efficacy. There are several case reports of the use of this combination in COVID-19 disease. Young et al. reported use among five hypoxemic patients with COVID-19 disease in Singapore. Among these, three patients revealed improvement in oxygenation and two had viral clearance from the nasopharynx within two days of commencement of treatment. The condition of two patients worsened and one required intubation and ventilation. Both these patients exhibited viral carriage in the nasopharynx throughout their stay in the ICU. Adverse effects included gastrointestinal symptoms and abnormal liver function tests (11). 

In a recently published randomized controlled trial, Cao et al. evaluated the efficacy of the lopinavir-ritonavir combination among patients with an oxygen saturation of less than 94% while breathing room air or P/F ratio of less than 300 mm Hg. The primary endpoint was the time interval from randomization to improvement by two points on a seven-category scale or hospital discharge, whichever occurred earlier. There was no difference between the anti-viral combination and standard care in the primary outcome. No significant difference was observed in the 28-d mortality between groups. Besides, there was no difference in the number of patients with detectable viral RNA at different points of time during the course of treatment. This study suggests that the lopinavir-ritonavir combination may not improve clinical outcomes or reduce viral shedding in patients with COVID-19 disease. 


The interleukin-6 (IL-6) pathway may mediate the intensive inflammatory response that occurs in the lungs of critically ill patients with COVID-19 disease. Tocilizumab, an IL-6 inhibitor may have a beneficial effect among such patients. The guidelines of the National Health Commission in China recommends the use of tocilizumab, and is being currently evaluated in a clinical trial (12). 


  • Considering the likelihood of an increasing number of critically ill patients, it is important to identify appropriate care locations. Negative pressure isolation rooms are preferred; if this is not feasible, single isolation rooms are the next best option. 
  • A team of staff members needs to be identified and offered training in the management of COVID-19 patients as part of the initial plan. 
  • Initial supportive measures include oxygen therapy; if no improvement is observed or the patient deteriorates, early intubation must be considered. High flow nasal oxygen and NIV must be used judiciously considering the increased risk of aerosol generation and possible disease transmission.
  • Conventional ventilation strategies including the use of low tidal volumes and titration of PEEP levels may be followed; prone ventilation may help improve oxygenation.
  • Extrapulmonary organ failure including shock and acute kidney injury may occur and require appropriate levels of support.
  • Corticosteroids are generally not indicated in COVID-19 disease; several virus-specific treatment modalities are currently being evaluated in clinical trials


1.         Coronavirus Update (Live): 107,490 Cases and 3,652 Deaths from COVID-19 Wuhan China Virus Outbreak – Worldometer [Internet]. [cited 2020 Mar 8]. Available from:

2.         Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020 Feb;395(10223):507–13. 

3.         Alraddadi BM, Qushmaq I, Al-Hameed FM, Mandourah Y, Almekhlafi GA, Jose J, et al. Noninvasive ventilation in critically ill patients with the Middle East respiratory syndrome. Influenza Other Respir Viruses. 2019;13(4):382–90. 

4.         ANZICS-COVID-19-Guidelines-Version-1.pdf.

5.         Jin Y-H, Cai L, Cheng Z-S, Cheng H, Deng T, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020 Dec;7(1):4. 

6.         Amato MBP, Meade MO, Slutsky AS, Brochard L, Costa ELV, Schoenfeld DA, et al. Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. N Engl J Med. 2015 Feb 19;372(8):747–55. 

7.         Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 Feb;S2213260020300795. 

8.         CDC. Coronavirus Disease 2019 (COVID-19) [Internet]. Centers for Disease Control and Prevention. 2020 [cited 2020 Mar 19]. Available from:

9.         Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet. 2020 Feb 15;395(10223):473–5. 

10.       Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis Off Publ Infect Dis Soc Am. 2020 Mar 9; 

11.       Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA [Internet]. 2020 Mar 3 [cited 2020 Mar 8]; Available from:

12.       China approves use of Roche drug in battle against coronavirus complications – Reuters [Internet]. [cited 2020 Mar 19]. Available from:

Coronavirus disease 2019 (COVID-19) update for critical care physicians

Beginning from December 8, 2019, several cases of pneumonia of unknown origin were reported from Wuhan, the capital of the Chinese province of Hubei. The initial cluster of cases was traced to the Huanan live animal and seafood market. The causative pathogen has hence been identified as an enveloped RNA beta coronavirus with genealogical similarity to the SARS coronavirus and named SARS-CoV-2. Initial reports from Wuhan pointed towards an atypical pneumonia and was termed coronavirus disease 2019 (COVID-2019). At the time of writing, COVID-19 has afflicted 107,691 patients across 98 countries and has caused 3,661 deaths. Thirty-nine cases have been reported in India so far, from Delhi (NCR), Uttar Pradesh, Telangana, Rajasthan, and Kerala (1). 

Mode of transmission

The primary mode of COVID-19 transmission is through respiratory droplets generated when an infected person coughs, sneezes, or talks. Droplets that settle on the eyes, nose, or mouth of a person in close proximity leads to the transmission of infection. Transmission can also occur by touching the face with contaminated hands. Respiratory droplets do not remain suspended in the air for long; hence, a distance of six feet away from an infected person may be considered safe (2). Coronaviruses may contaminate metal, glass, or plastic surfaces that may remain infective for several days. Contact with such contaminated surfaces (fomites) and subsequent transfer to the face by touch may also be an important mode of transmission. 

Airborne transmission, distinct from droplet infection, is characterized by viruses that drift through the air. It is unclear if airborne transmission occurs with COVID-19 infection. The possibility of airborne transmission requires the use of additional protective measures, including N95 masks.   

R0, pronounced R-naught, is the basic reproduction number and indicates the transmissibility of a disease when special quarantining or isolation measures are not undertaken. In simple terms, R0 indicates the number of people to whom an afflicted person can transmit the infection. From preliminary analysis, the R0 for COVID-19 has been estimated to be between 2.2 and 3.6 (3). The capability to transmit infection can be highly variable between individuals. There are some infected individuals who are capable of transmitting the disease to a much larger number of people than most others (high R0). Such individuals with a high potential for transmission are called “super-spreaders”. 

Patient screening and triage

Patients who present with fever and respiratory symptoms with an epidemiological link to COVID-19 should carry a high index of suspicion for the disease. The epidemiological link may involve (a) travel to an area that experienced an outbreak, (b) close contact with an individual with confirmed or high risk of infection, or (c) close contact with an individual with respiratory symptoms who had been in a geographic location that witnessed an outbreak within a 14-day period prior to the onset of symptoms. Fever may not be a presenting symptom in all cases. Patients who present with bilateral pneumonia with the risk factors mentioned above carry a high index of suspicion even in the absence of fever. As the geographic area of involvement is expanding, clinicians need to keep themselves updated on the list of affected countries and territories. Following several generations of spread with a country, local transmission of disease occurs, and patients may present with no history of travel to a location with a known outbreak.

Critically ill patients may present to the emergency department from the community or by inter-hospital transfer to the intensive care unit. In such instances, a detailed enquiry should be carried out to ensure appropriate screening and infection control precautions should be followed. 

Infection control measures 


Although the predominant mode of transmission of COVID-19 disease appears to be through droplet and contact with respiratory secretions, airborne transmission may occur, and appropriate precautions are recommended in high-risk situations, especially when treating patients who are critically ill. The use of high-flow nasal oxygen, nebulizers, non-invasive ventilation, bag-mask ventilation, the performance of laryngoscopy and endotracheal intubation are likely to generate aerosols, that may predispose to transmission of the virus. 

Considering the uncertainty regarding airborne transmission, isolation rooms with negative pressure and frequent air exchanges are advisable for suspected cases. If sufficient airborne isolation areas are unavailable, patients should be accommodated in single rooms behind closed doors. Anterooms to enable caregivers to put on (don) and remove (doff) personal protective equipment (PPE) should also be available. 

Personal protective equipment

Healthcare workers who care for critically ill patients with suspected or confirmed COVID-19 disease must use PPE. Operating room scrubs or full coveralls should form the first layer of protection beneath PPE. The PPE must include fluid-resistant gowns and gloves, goggles with side protection, hair covers or hoods, and fit-tested N95 respirator masks. Caregivers should also wear disposable shoe covers or water-resistant shoes that can be decontaminated. Doffing of PPE should be carried out carefully, with diligent hand hygiene after removal. A powered air-purifying respirator (PAPR) is often recommended and may offer greater protection compared to N95 masks. It consists of a respirator worn as a hood; it draws in and filters potentially contaminated ambient air, and delivers clean, decontaminated air to the user through the hood. 

High flow nasal oxygen, non-invasive ventilation, and nebulizer use 

Droplet and aerosol spread may occur during therapeutic interventions among patients with COVID-19 disease. When administering oxygen through nasal prongs, the patient’s face may be covered with a surgical mask to prevent droplet spread. The use of a high-flow nasal cannula may lead to aerosol generation; hence, it should be used only in locations that provide airborne isolation. Nebulized medications are best avoided due to the possibility of aerosol generation; metered-dose inhalers may be used as an alternative. Although a few patients in hypoxemic respiratory failure may be managed with NIV, extensive disease transmission may occur over a wide area, as noted during the severe acute respiratory syndrome (SARS) epidemic (4). Besides, NIV use may delay intubation leading to patient deterioration and inadequate donning of PPE during emergent intubation.  As a general rule, high-flow nasal cannulae and NIV should be used sparingly, and never outside a suitable location with droplet and airborne isolation.  

The experience so far

Several retrospective observational studies have been reported from China since the outbreak of COVID-19 disease from late December 2019. These studies offer insight regarding the presenting symptoms, clinical and radiological features, progression, and outcomes of patients with COVID-19 disease. 

Chen et al. retrospectively evaluated 99 patients with COVID-19 admitted to the Jin Yin-tan Hospital in Wuhan, the epicenter of the novel coronavirus outbreak, between January 1 to January 20, 2020. The diagnosis of COVID-19 disease was confirmed by real-time RT-PCR, and evaluation of epidemiological, demographic, clinical, and radiological features, and laboratory data were performed. Patients were followed up until Jan 25, 2020. The mean patient age was 55·5 years (SD 13·1) with a male predominance (67%). Fever and cough were the most common symptoms, followed by breathing difficulty. Chest radiography and CT imaging revealed bilateral pneumonia in 75% of patients; unilateral pneumonic infiltrates were seen in others. Extensive mottling and ground-glass opacities were the predominant features on imaging. Acute respiratory distress syndrome (ARDS) occurred in 17% of patients, acute kidney injury in 3%, and septic shock in 4% of patients. The majority of patients required supplemental oxygen therapy (75%). NIV was applied in 13%, and invasive mechanical ventilation was carried out in 4% of patients. Continuous renal replacement therapy was performed in 9%, and extracorporeal membrane oxygenation (ECMO) in 3% of patients. Eleven patients (11%) had died at the time of follow up on January 25, 2020, all from ARDS and multiorgan failure (5). 

Guan et al. retrospectively analyzed the medical records of 1099 patients (outpatients and inpatients) with laboratory-confirmed COVID-19 from 552 hospitals in China between December 11, 2019, and January 29, 2020. The diagnosis was confirmed by RT-PCR assay of nasal and pharyngeal swabs. The primary composite endpoint of admission to ICU, mechanical ventilation, or death occurred in 67 patients (6.1%). Among the components of the primary outcome, 5% of patients required ICU admission, and 2.3% required invasive mechanical ventilation, with an overall mortality of 1.4%. Among all the patients, the cumulative risk of the composite endpoint was 3.6%; among those with severe disease, the cumulative risk was 20.6%. Invasive mechanical ventilation was required in 14% of patients with severe disease; NIV was required in 32.4% of patients with severe disease. ECMO was carried out in 5 patients. The median hospital length of stay was 12 (10–14) days (6).  

Forty-one hospitalized patients were evaluated in a retrospective study of patients with confirmed COVID-19 infection at the Jin Yin-tan Hospital in Wuhan, China. Data were collected between December 16, 2019, to January 2, 2020. The median age of patients was 49 years, with male preponderance (73%). Thirty-two percent of patients had underlying co-morbidities. Fever was the most common symptom at disease onset, followed by cough, myalgia, and fatigue. Fifty-five percent of patients developed dyspnea; all patients had evidence of pneumonia on CT imaging. Lymphopenia was another common finding (63%). Twelve patients (29%) developed ARDS, five (12%) showed signs of acute cardiac injury, and five (12%) patients developed secondary infections.  Four patients (10%) required ICU admission. Six patients (15%) had died by the time of last follow up on January 2, 2020 (7). 

Yang et al. evaluated 52 critically ill patients among 710 patients with COVID-19 pneumonia admitted to the ICU of Jin Yin-tan hospital in Wuhan between late December, 2019, and January, 2020. They compared data between survivors and non-survivors. The mean age of patients was 59·7 (SD 13·3) with male predominance (67%). Thirty-two (61.5%) patients had died by day 28; the median time interval between ICU admission and death was 7 (3–11) days. Non-survivors were older, had a higher incidence of ARDS, and received NIV or invasive ventilation more often than survivors. Organ dysfunction was common, including ARDS (67%), acute kidney injury (23%), hepatic dysfunction (29%), and acute myocardial dysfunction (23%) (8). 

The Chinese Center for Disease Control and Prevention has published the largest case series of COVID-19 disease in mainland China until February 11, 2020, including 72,314 patients. Among these patients, 44, 672 (62%) were confirmed COVID-19 disease by viral nucleic acid test on throat swab samples. Most patients were aged between 30–79 years (87%). Mild disease with no pneumonia or mild pneumonia was observed in the majority of patients (81%). Severe disease occurred in 14% of patients; 5% of patients were critically ill with respiratory failure, septic shock, and multiorgan dysfunction. Among the 44, 672 confirmed cases, 1023 patients died (case fatality rate: 2.3%). The case fatality rate among patients 70–79 years was much higher (8%); no deaths were reported among children aged less than 9 years. Critically ill patients had a high case fatality rate of 49%. Patients with underlying co-morbidities had a higher mortality. Among the confirmed cases, 1716 were healthcare workers (3.8%); 14.8% developed severe disease, and five had died until February 11, 2020. 


Beginning late 2019, a novel coronavirus led to the global outbreak of an acute respiratory illness, currently designated as COVID-19 disease. Rapid spread has occurred across several geographical locations within the first few weeks. Typical initial symptoms include fever, cough, and breathlessness. A large number of patients develop pneumonic infiltrates. The disease appears to mainly affect adults between the age of 30–79 years, with a male preponderance. The large majority of patients appear to develop mild disease, and the overall mortality appears to be low (2–3%). However, a high mortality of up to 49% has been observed among critically ill patients who develop multiorgan failure. 

Healthcare workers are at high risk of acquiring the infection; appropriate infection control measures are crucial in reducing disease transmission. Screening, triage, and isolation of patients are important among those with confirmed disease and at high risk of infection. Treatment is mainly supportive;  home management and isolation may be a viable option in patients with mild disease. 


1.         Coronavirus Update (Live): 107,490 Cases and 3,652 Deaths from COVID-19 Wuhan China Virus Outbreak – Worldometer [Internet]. [cited 2020 Mar 8]. Available from:

2.         Del Rio C, Malani PN. COVID-19-New Insights on a Rapidly Changing Epidemic. JAMA. 2020 Feb 28; 

3.         Zhao S, Lin Q, Ran J, Musa SS, Yang G, Wang W, et al. Preliminary estimation of the basic reproduction number of novel coronavirus (2019-nCoV) in China, from 2019 to 2020: A data-driven analysis in the early phase of the outbreak. Int J Infect Dis IJID Off Publ Int Soc Infect Dis. 2020 Jan 30;92:214–7. 

4.         Li Y, Huang X, Yu ITS, Wong TW, Qian H. Role of air distribution in SARS transmission during the largest nosocomial outbreak in Hong Kong. Indoor Air. 2005 Apr;15(2):83–95. 

5.         Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet. 2020 Feb;395(10223):507–13. 

6.         Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28;NEJMoa2002032. 

7.         Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020 Feb;395(10223):497–506. 

8.         Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 Feb;S2213260020300795. 

Oxygen: the elixir of life or a double-edged sword?

Our planet was born approximately 4.8 billion years ago. A billion years later, the oxygen levels began to rise on the earth’s atmosphere. With the rise in oxygen levels, the first signs of life also appeared on the face of the earth. However, it took several billion years before Joseph Priestly (1774) identified oxygen as the life-giving, life-sustaining gas present on the atmosphere of the earth. A century later, oxygen therapy was used for the first time by George Holzapple as part of the treatment for pneumonia. A decade later, Lorraine Smith described acute lung toxicity due to oxygen; he noted that the toxic effects of oxygen were related to oxygen levels in the blood. 

How do we reconcile with the adverse effects of oxygen therapy, first described 125 years ago by Lorraine Smith? 

What is hyperoxia?

Hyperoxia represents the exposure of cells, tissues, and organs to higher than normal levels of partial pressure of oxygen. Conventionally, a liberal approach to oxygen therapy is followed by most clinicians, mainly as a precaution against avoiding low PaO2 levels. Besides, high oxygen levels are difficult to monitor, mainly because pulse oximetry does not help in recognizing hyperoxia. In an observational cohort study, the mean time-weighted PaO2 was 144 mm Hg in a mixed medical-surgical ICU during the first 7 days of mechanical ventilation and >80 mm Hg during 80% of the duration of mechanical ventilation (1). There is no clear definition of hyperoxia, although a PaO2 higher than 120 mm Hg has been considered to represent mild hyperoxia, and levels higher than 200 mm Hg as severe hyperoxia. 

What are the physiological consequences of hyperoxia?

The first evidence of harm from excessive oxygen was described by Lorraine Smith, who described acute lung toxicity. The oxygen molecule has the unique property of acting as an “electron acceptor”. The newly accepted electrons, however, remain unpaired. These molecules with unpaired electrons are called oxygen free radicals, and when they participate in biological reactions, they are termed reactive oxygen species (ROS). ROS play an important physiological role in the removal of mutated or otherwise damaged cells through a process called apoptosis, to enable the generation of new cells. However, excessive oxygen levels result in increased levels of ROS. Anti-oxidants, including superoxide dismutase, catalase, vitamin C and E, which normally scavenge excessive ROS are rapidly overwhelmed. This results in the uncontrolled killing of normal cells by the ROS. Consequently, harmful effects become manifest in different organs. 


One of the early effects of hyperoxia in the lung is the loss of ciliary activity, leading to tracheobronchitis. This is characterized by substernal distress, cough, and dyspnea. High FiOlevels also lead to alveolar collapse, as the oxygen gets rapidly absorbed. However, the presence of nitrogen in the alveoli exerts a “splinting” effect and maintains them open. High FiO2 levels induce changes in the lung that are indistinguishable from changes that occur in acute respiratory distress syndrome.

Vasoconstrictor effect

Oxygen acts as an inhibitor of nitric oxide, which is a naturally occurring vasodilator. This results in a vasoconstrictor effect due to high levels of oxygen, compromising blood flow to the vital organs. Coronary vasoconstriction may ensure, leading to acute myocardial ischemia. 

Control of breathing 

The administration of high FiO2 is often associated with the development of hypercapnia, particularly in patients with acute exacerbation of chronic obstructive pulmonary disease (COPD). This effect has been conventionally attributed to the abolition of the respiratory drive. However, this is unlikely to be the mechanism for the hypercapnia as minute ventilation has been found to be unaffected with oxygen therapy among patients with acute exacerbation of COPD. A more likely explanation for the hypercapnia is the inhibition of hypoxic pulmonary vasoconstriction. The inhaled oxygen leads to vasodilatation of hypoxic regions of the lung, with the diversion of blood flow away from better-ventilated regions. 

What does clinical evidence suggest in real-world practice?

We administer supplemental oxygen to most patients with acute myocardial infarction. In fact, oxygen is part of the MONA therapy (morphine, oxygen, nitrates, and aspirin) recommended by many guidelines. However, does the administration of supplemental oxygen to normoxic patients with ST-elevation myocardial infarction (STEMI) lead to any clinical benefit? 

The AVOID study was conducted by the paramedic services in Melbourne, Australia. Patients with STEMI, who were normoxic with a baseline oxygen saturation of >94%, were included in this study. Supplemental oxygen at 8L/min was administered in the intervention group; the control group received no supplemental oxygen. In this randomized controlled study, the administration of supplemental oxygen to normoxic patients with STEMI revealed no beneficial effects. In contrast, an increase in infarct size at 6 months on magnetic resonance imaging,  recurrent myocardial infarction, and an increase in the incidence of arrhythmias were noted with supplemental oxygen (2). 

How about the effect of oxygen levels on mechanically ventilated patients in the intensive care unit? The OXYGEN-ICU study was a single-center randomized controlled trial conducted in a medical-surgical ICU in Italy, among patients who were expected to stay in the ICU for longer than 72 hours. In the restrictive oxygen arm, the target PaO2 level was between 70–100 mm Hg; in the liberal (conventional) arm, standard ICU practice was followed, with the PaO2 levels allowed to rise to a maximum of 150 mm Hg, and saturation levels were maintained between 97–100%. This study revealed significantly higher ICU mortality in the liberal oxygen arm; besides, there was a higher incidence of shock, liver failure, and bacteremia with liberal oxygen therapy (3). 

Mechanically ventilated patients expected to be on ventilation beyond the day of recruitment were included in the multicentric, ICU-ROX study, conducted by the ANZICS-CTG. In the restrictive arm, the oxygen saturation was maintained between 91–96%. An alarm was triggered if the saturation touched 97%, and the FiOlevels were turned down rapidly to the target level. The FiO2 levels could be reduced to 0.21 if the target saturation levels were met. In the more liberal arm (usual care), no specific measures were taken to limit FiO2 levels, with the saturation maintained between 91–100%. In this study, there was no significant difference between groups in the number of ventilator-free days at day 28; the 90- and 180-day mortality were also not significantly different. On subgroup analysis, possible harmful effects were observed with liberal oxygen therapy among patients with hypoxic-ischemic encephalopathy (HIE). Patients with HIE who received liberal oxygen therapy had fewer ventilator-free days, higher 180-day mortality, and a higher incidence of adverse outcomes on the Glasgow Outcome Scale at 180 days. A subsequent post-hoc analysis of septic patients revealed a trend to improved 90-day survival among septic patients who received a more liberal oxygen therapy (4). However, these findings can only be considered hypothesis-generating and needs to be addressed in future controlled studies. 

A multicentric French study compared two levels of oxygen therapy among mechanically ventilated patients with septic shock. In the liberal group, an FiO2 of 1.0 was maintained for the first 24 hours, while the oxygen saturation was maintained 88–95% in the restrictive group. Predictably, this study was stopped prematurely due to concerns with safety with the use of 100% oxygen. The 28-day mortality was higher among patients who received 100% oxygen at the time of stopping. Besides, there was a significant increase in the overall incidence of serious adverse events with 100% oxygen administration. The incidence of ICU-acquired weakness was twice as high, and the incidence of atelectasis was also significantly higher (5). 

The bottom line 

  • Robust clinical evidence suggests that excessive oxygen may be associated with adverse consequences, including increased mortality. 
  • The safe levels of oxygen are unclear; this may vary according to the underlying condition. Patients with hypoxic-ischemic encephalopathy may be particularly vulnerable to the adverse effects of excessive oxygen.
  • Among mechanically ventilated patients, aiming for a saturation level of 91–96% may be appropriate under most clinical circumstances.
  • It is appropriate to turn down the FiO2 levels to target saturation levels, in contrast to setting arbitrary lower limits of FiO2.
  • Oxygen must be considered as a drug, with adverse effects associated with injudicious use. 
  • A target saturation level must be prescribed, and the FiO2 levels should be appropriately titrated among critically ill patients.


1.         Panwar R, Capellier G, Schmutz N, Davies A, Cooper DJ, Bailey M, et al. Current Oxygenation Practice in Ventilated Patients—An Observational Cohort Study. Anaesth Intensive Care. 2013 Jul;41(4):505–14. 

2.         Stub D, Smith K, Bernard S, Nehme Z, Stephenson M, Bray JE, et al. Air Versus Oxygen in ST-Segment–Elevation Myocardial Infarction. :8. 

3.         Girardis M, Busani S, Damiani E, Donati A, Rinaldi L, Marudi A, et al. Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016 Oct 18;316(15):1583–9. 

4.         Young P, Mackle D, Bellomo R, Bailey M, Beasley R, Deane A, et al. Conservative oxygen therapy for mechanically ventilated adults with sepsis: a post hoc analysis of data from the intensive care unit randomized trial comparing two approaches to oxygen therapy (ICU-ROX). Intensive Care Med. 2020;46(1):17–26. 

5.         Asfar P, Schortgen F, Boisramé-Helms J, Charpentier J, Guérot E, Megarbane B, et al. Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med. 2017 Mar;5(3):180–90. 

Getting rid of excess fluid: the strategy of de-resuscitation

The use of intravenous fluid therapy is ubiquitous among critically ill patients to optimize tissue perfusion and oxygen delivery. Apart from intravenous fluids administered during initial resuscitation, fluid accumulation occurs from nutrition, maintenance fluids, and diluents used for intravenous drug therapy. An aggressive resuscitation strategy may be appropriate during the “ebb” phase of septic shock, characterized by widespread vasodilatation, intravascular hypovolemia, and capillary leak, leading to extravasation of fluid into the interstitial compartment. Typically, the “ebb” phase is followed by the “flow” phase, during which the body tries to eliminate excess fluid. However, normal physiological mechanisms may be overwhelmed, especially with the onset of acute kidney injury. In this situation, should we consider a “de-resuscitation” strategy aimed at the active removal of excess fluid? 

Adverse consequences of fluid overload

Excessive fluid accumulation may be the harbinger of multiorgan dysfunction (1). Interstitial and intra-alveolar edema in the lung may lead to delayed weaning and prolongation of the duration of ventilator support. A rise in the venous pressure may impair renal blood flow, trigger interstitial edema, and result in compromised renal function. Myocardial edema may occur, leading to systolic and diastolic dysfunction. As the intra-abdominal pressure rises due to excessive gastrointestinal fluid accumulation, abdominal perfusion may be compromised. This may trigger increased intestinal permeability and bacterial translocation from the gut. The potential harm arising from injudicious fluid administration has been equated to adverse effects arising from inappropriate drug dosing (1). 

What is de-resuscitation? 

Among patients who respond to initial therapeutic interventions, shock resolution and circulatory stabilization typically occurs. By this time, a large positive fluid balance occurs among critically ill patients, particularly among those with sepsis. In a secondary analysis of the Vasopressin in Septic Shock Trial (VASST), the mean positive fluid balance was 4.2 L at 12 hours and 11.0 L on the 4th day of enrollment (2). It is important to take stock of the net fluid balance after the initial phase of resuscitation. The extent of fluid accumulation may be calculated using the formula (3): 

[Cumulative fluid balance (liters) / baseline body weight (kg)] × 100

A fluid accumulation of more than 10% has been shown to be associated with poor clinical outcomes (3).  During the “flow” phase, the body attempts to dispose of the accumulated fluid. Therapeutic fluid removal, using diuretics and ultrafiltration with renal replacement therapy, may be appropriate measures during this stage. Aggressive interventions to remove fluid may be combined with a fluid-restrictive strategy. 

What is the evidence to support a de-resuscitative strategy? 

Fluids administered during the early resuscitation phase may constitute only a small fraction of the fluid accumulated over time. A retrospective analysis was performed to evaluate the volume of fluids administered to 14,654 critically ill patients. In this study, maintenance and replacement fluids constituted 24.7% of the daily fluid administered, compared to only 6.5% of resuscitation fluids. Significant volumes of fluid (32.6% of the daily volume administered) were administered as diluents for intravenous or other medication (4). 

Silversides et al. conducted a retrospective observational study across 10 ICUs in the United Kingdom and Canada to identify outcomes with de-resuscitative strategies and risk factors for positive fluid balance among critically ill patients. Four-hundred adult patients who underwent mechanical ventilation for a minimum period of 24 hours were included. Over the first 1–3 days, a positive fluid balance occurred in 87.3% of patients. Medications represented the largest volume of fluid administered (34.5%). The volume of bolus (26.5%) and maintenance fluids (24.4%) were lower compared to fluids administered as medication. A negative balance was observed on day 3 in 123 patients; a spontaneous negative balance, without the use of diuretics or ultrafiltration, occurred in 70 (56.9%) patients and was associated with lower 30-day mortality. De-resuscitative measures were employed in 52.3% of all patients, most frequently on the 2nd or 3rd day. On multivariate logistic regression, the fluid balance on day 3 was an independent predictor of 30-day mortality. A negative fluid balance achieved using active de-resuscitative measures, including frusemide administration and fluid removal using continuous renal replacement therapy, was associated with lower mortality (5). 

A meta-analysis of 11 randomized controlled studies, including 2051 adults and children, was performed by Silversides et al. The study included patients with acute respiratory distress syndrome, sepsis, or the systemic inflammatory response syndrome (SIRS). Compared to a liberal approach, the authors found no significant difference in mortality reported at the longest time point between a conservative or de-resuscitative fluid management strategy. However, there was an increase in ventilator-free days and reduced length of stay in the ICU with a conservative or de-resuscitative approach (6). 

The FFAKI-trial was a pilot randomized controlled trial that tested the feasibility of forced fluid removal compared to standard care among critically ill patients who were at moderate to high risk of acute kidney injury with more than 10% fluid accumulation. Active de-resuscitation was carried out with a bolus dose of furosemide, 40 mg, followed by a continuous infusion of up to 40 mg/hour or fluid removal using renal replacement therapy. The investigators aimed for a net negative fluid balance of >1 ml/kg/hour (ideal body weight) with a target cumulative fluid balance of less than 1000 ml from the time of ICU admission. The recruitment rate was low, with only 23 included among 1144 patients who were screened. Despite the small sample size, a conspicuous reduction in the cumulative fluid balance was observed with active de-resuscitative measures at 5 days after randomization. The mean difference in the cumulative balance between groups was 5,814 ml (95% CI 2063 to 9565, P = .003). Although not powered to evaluate clinical outcomes, no adverse effects were noted with forced fluid removal in this pilot study (7).  

A combination of high PEEP, small volume resuscitation with 20% albumin, and diuretic treatment with furosemide (described as “PAL-treatment”) was evaluated among patients with acute lung injury by Cordemans et al., in a retrospective case-control study. The PEEP level (cm of H2O) was set at the level of the intra-abdominal pressure (mm of Hg). This strategy resulted in a lower extravascular lung water index, intra-abdominal pressure, and cumulative fluid balance compared to control patients. The use of the PAL strategy resulted in a shorter duration of mechanical ventilation and ICU stay. The 28-day mortality was also lower with this approach (8). 

Possible harm from a de-resuscitative strategy? 

The question of choosing the optimal time to commence de-resuscitation can be challenging. Fluid overload may be difficult to recognize in the clinical setting. The central venous pressure is a relatively ineffectual parameter; bedside echocardiography to assess fluid responsiveness vs. overload may not always be practicable due to suboptimal windows among ventilated patients. The clinician may often face the conundrum of when to resort to de-resuscitative measures after the initial stabilization of the hemodynamic status. In a secondary analysis of the Randomized Evaluation of Normal vs. Augmented Level of Renal Replacement Therapy (RENAL) trial, net ultrafiltration of more than 1.75 ml/kg/hour was associated with lower 90-day survival compared to ultrafiltration rates of less than 1.01 ml/kg/hour (9). Clearly, more robust evidence from controlled trials is required before the routine adoption of aggressive de-resuscitative measures. 

The bottom line 

  • A net positive fluid balance after the initial phase of resuscitation (the “ebb” phase) is strongly associated with mortality.
  • Positive fluid balance is an inherently modifiable risk factor that leads to adverse outcomes in critically ill patients. 
  • After the resuscitation phase, it is appropriate to adopt a conservative fluid strategy and consider active measures of de-resuscitation, including the use of diuretics and fluid removal using renal replacement therapy. 
  • It may be prudent to aim for a zero or negative balance by day 3 among patients in whom hemodynamic stabilization has been achieved.  
  • The routine administration of maintenance intravenous fluids to critically ill patients must be strongly discouraged. Besides, the volume of diluents used for intravenous drug administration should also be restricted to the minimum volume possible.  


1.         Malbrain MLNG, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Dec;46(5):361–80. 

2.         Boyd JH, Forbes J, Nakada T, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011 Feb;39(2):259–65. 

3.         O’Connor ME, Prowle JR. Fluid Overload. Crit Care Clin. 2015 Oct;31(4):803–21. 

4.         Van Regenmortel N, Verbrugghe W, Roelant E, Van den Wyngaert T, Jorens PG. Maintenance fluid therapy and fluid creep impose more significant fluid, sodium, and chloride burdens than resuscitation fluids in critically ill patients: a retrospective study in a tertiary mixed ICU population. Intensive Care Med. 2018 Apr;44(4):409–17. 

5.         Silversides JA, Fitzgerald E, Manickavasagam US, Lapinsky SE, Nisenbaum R, Hemmings N, et al. Deresuscitation of Patients With Iatrogenic Fluid Overload Is Associated With Reduced Mortality in Critical Illness. Crit Care Med. 2018;46(10):1600–7. 

6.         Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, et al. Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med. 2017 Feb;43(2):155–70. 

7.         Berthelsen RE, Perner A, Jensen AK, Rasmussen BS, Jensen JU, Wiis J, et al. Forced fluid removal in intensive care patients with acute kidney injury: The randomised FFAKI feasibility trial. Acta Anaesthesiol Scand. 2018;62(7):936–44. 

8.         Cordemans C, De Laet I, Van Regenmortel N, Schoonheydt K, Dits H, Martin G, et al. Aiming for a negative fluid balance in patients with acute lung injury and increased intra-abdominal pressure: a pilot study looking at the effects of PAL-treatment. Ann Intensive Care. 2012 Jul 5;2 Suppl 1:S15. 

9.         Murugan R, Kerti SJ, Chang C-CH, Gallagher M, Clermont G, Palevsky PM, et al. Association of Net Ultrafiltration Rate With Mortality Among Critically Ill Adults With Acute Kidney Injury Receiving Continuous Venovenous Hemodiafiltration: A Secondary Analysis of the Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy Trial. JAMA Netw Open. 2019 05;2(6):e195418. 

Hypercapnia during ARDS ventilation: testing the limits of permissibility

From the 1990s, lung-protective ventilation using low tidal volumes and limitation of plateau pressures emerged as a pivotal strategy in patients with acute respiratory failure, especially with acute respiratory distress syndrome (ARDS), who undergo mechanical ventilation (1). Amato et al., in a landmark study, titrated positive end-expiratory pressures (PEEP) levels to higher than the lower inflection point of the pressure-volume curve, with tidal volumes of less than 6 ml/kg and driving pressures of less than 20 cm of H2O in patients with ARDS. On the pressure-controlled mode of ventilator support, they allowed permissive hypercapnia as part of a lung-protective strategy. This strategy resulted in higher PCO2 values compared to the control arm that used a tidal volume of 12 ml/kg (55 vs. 38 mm Hg). However, the lung-protective strategy led to a significantly lower 28-day mortality, less barotrauma, and a higher rate of successful weaning from mechanical ventilation (2). The use of a low tidal volume strategy was further bolstered by the ARMA trial and widely accepted as the optimal approach to ventilation in patients with ARDS (3). 

Is hypercapnia protective? 

Clearly, a lung-protective ventilation strategy using low tidal volumes often results in hypercapnia among patients with ARDS. However, the effect of hypercapnia and respiratory acidosis remains unclear. Hypercapnia and respiratory acidosis have even been postulated to offer possible beneficial effects in ARDS through down-regulation of pro-inflammatory mediators in experimental studies. In experimental animal models, hypercapnia has been shown to reduce the severity of ventilator-induced lung injury (4,5). Kregenow et al. evaluated the effect of hypercapnic respiratory acidosis by performing a secondary analysis of data from the ARDS Network trial that compared tidal volumes of 6 vs.12 ml/kg. They observed a reduction in mortality among patients with hypercapnic respiratory acidosis who were randomized to receive a tidal volume of 12 ml/kg of predicted body weight. The investigators suggested that hypercapnic respiratory acidosis may ameliorate the injurious effects of high tidal volume ventilation in patients with ARDS (6). 

Adverse effects of hypercapnia 

The putative beneficial effects of hypercapnia have not been substantiated in clinical studies. Hypercapnic acidosis has been shown to inhibit adaptive immune responses through suppression of neutrophil and macrophage migration and impaired phagocytosis (7). Acute hypercapnia may also trigger a rise in pulmonary artery pressures and right ventricular dysfunction, leading to acute cor pulmonale (8). Besides, hypercapnia may result in increased tissue susceptibility to infection. In-hospital mortality was significantly higher among hypercapnic patients with community-acquired pneumonia in an observational study (9). Furthermore, high carbon dioxide levels may impair left ventricular contractility due to intracellular acidosis (10). 

Evidence of harm from hypercapnia 

Nin et al. analyzed data from 18,302 patients with ARDS from three international observational studies who underwent invasive mechanical ventilation for more than 24 hours or developed ARDS after 24 hours of mechanical ventilation. On multivariate analysis, they observed a significantly higher mortality among patients with a maximum PaCOlevel of more than 50 mm Hg (defined as “severe” hypercapnia) during the first 48 hours of ventilation compared to those with a maximum PaCOlevel of less than 50 mm Hg. After adjusting for baseline characteristics, an independent association was observed between severe hypercapnia and ICU mortality. Furthermore, the incidence of complications and organ dysfunction, including barotrauma, renal and cardiovascular dysfunction, were more common among hypercapnic patients. ICU mortality was also significantly higher among patients who received a tidal volume of more than 8 ml/kg (11).  

Tiruvoipati et al. collated data from the Australian and New Zealand Intensive Care Society (ANZICS) database in patients who were mechanically ventilated over a 14-year period. Adult patients who received mechanical ventilation during the first 24 hours of ICU stay were included.  Patients were divided into three groups – with normal pH and PCO2, compensated hypercapnia, and hypercapnic acidosis. The study comprised of 252,812 patients including 110,104 with normal pH and normal PCO2, 20,643 with compensated hypercapnia, and 122,245 with hypercapnic acidosis (12). 

On multivariate analysis, a significantly higher mortality was observed among patients with compensated hypercapnia and hypercapnic acidosis compared to patients with normocapnia and normal pH levels. The mortality difference was unrelated to the P/F ratio. Among patients with compensated hypercapnia, the mortality increased with increasing PCO2 levels up to 65 mm Hg; a further rise in PCOrevealed a trend towards lower mortality. However, in patients with hypercapnic acidosis, the mortality plateaued after a peak PCOlevel of  65 mm Hg. The authors hypothesized that the variable influence of hypercapnia on the arteriolar myogenic tone and consequent modulation of the microcirculation might contribute to this plateau effect (12). 

Is extracorporeal COremoval the future of ARDS ventilation? 

The SUPERNOVA study assessed the feasibility of extracorporeal carbon dioxide removal (ECCO2R) combined with ultra-low tidal volume (4 ml/kg) ventilation among patients with moderate ARDS. Among the 95 patients who were enrolled, ultra-protective settings were achieved in 82% by 24 hours; the PCO2 levels rose by less than 20% of baseline levels, and the arterial pH remained > 7.30 (13). A randomized controlled trial is currently in progress to evaluate the benefit of ECCO2R combined with tidal volumes equal to or less than 3 ml/kg, compared to standard care, using tidal volumes of 6 ml/kg (14). 

The bottom line 

  • The concept of permissive hypercapnia evolved with the use of low tidal volume ventilation strategies.
  • High COlevels were considered to be harmless or even protective; however, clinical evidence suggests worse clinical outcomes among hypercapnic patients with ARDS.
  • It may be appropriate to aim for PCO2 levels of less than 50 mm Hg in patients with ARDS who are mechanically ventilated (12,15).
  • A strategy of “ultra” low tidal volume ventilation combined with extracorporeal carbon dioxide removal is currently being evaluated in a randomized controlled trial.


1.         Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med. 1990;16(6):372–7. 

2.         Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998 Feb 5;338(6):347–54. 

3.         Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 04;342(18):1301–8. 

4.         Sinclair SE, Kregenow DA, Lamm WJE, Starr IR, Chi EY, Hlastala MP. Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med. 2002 Aug 1;166(3):403–8. 

5.         Broccard AF, Hotchkiss JR, Vannay C, Markert M, Sauty A, Feihl F, et al. Protective effects of hypercapnic acidosis on ventilator-induced lung injury. Am J Respir Crit Care Med. 2001 Sep 1;164(5):802–6. 

6.         Kregenow DA, Rubenfeld GD, Hudson LD, Swenson ER. Hypercapnic acidosis and mortality in acute lung injury*: Crit Care Med. 2006 Jan;34(1):1–7. 

7.         Coakley RJ, Taggart C, Greene C, McElvaney NG, O’Neill SJ. Ambient pCO2 modulates intracellular pH, intracellular oxidant generation, and interleukin-8 secretion in human neutrophils. J Leukoc Biol. 2002 Apr;71(4):603–10. 

8.         Jardin F, Dubourg O, Bourdarias JP. Echocardiographic pattern of acute cor pulmonale. Chest. 1997 Jan;111(1):209–17. 

9.         Sin DD, Man SFP, Marrie TJ. Arterial carbon dioxide tension on admission as a marker of in-hospital mortality in community-acquired pneumonia. Am J Med. 2005 Feb;118(2):145–50. 

10.       Jerusalem E, Starling EH. On the significance of carbon dioxide for the heart beat. J Physiol. 1910 May 13;40(4):279–94. 

11.       for the VENTILA Group, Nin N, Muriel A, Peñuelas O, Brochard L, Lorente JA, et al. Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome. Intensive Care Med. 2017 Feb;43(2):200–8. 

12.       Tiruvoipati R, Pilcher D, Buscher H, Botha J, Bailey M. Effects of Hypercapnia and Hypercapnic Acidosis on Hospital Mortality in Mechanically Ventilated Patients*: Crit Care Med. 2017 Jul;45(7):e649–56. 

13.       Combes A, Fanelli V, Pham T, Ranieri VM, European Society of Intensive Care Medicine Trials Group and the “Strategy of Ultra-Protective lung ventilation with Extracorporeal CO2 Removal for New-Onset moderate to severe ARDS” (SUPERNOVA) investigators. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study. Intensive Care Med. 2019;45(5):592–600. 

14.       McNamee JJ, Gillies MA, Barrett NA, Agus AM, Beale R, Bentley A, et al. pRotective vEntilation with veno-venouS lung assisT in respiratory failure: A protocol for a multicentre randomised controlled trial of extracorporeal carbon dioxide removal in patients with acute hypoxaemic respiratory failure. J Intensive Care Soc. 2017 May;18(2):159–69. 

15.       Repessé X, Vieillard-Baron A. Hypercapnia during acute respiratory distress syndrome: the tree that hides the forest! J Thorac Dis. 2017 Jun 13;9(6):1420-1425–1425. 

Lung protective ventilation: targeting tidal volume and plateau pressure vs. driving pressure

The acute respiratory distress syndrome (ARDS) constitutes 23.4% of mechanically ventilated patients (1). Prevention of ventilator-induced lung injury has typically revolved around the use of tidal volumes of 5–8 ml/kg of predicted body weight and limitation of plateau pressures to 30 cm H2O. However, the lung available for ventilation is significantly reduced and highly variable in patients with ARDS. Hence, the use of tidal volumes based on the predicted body weight leads to variable lung stress, proportionate to the extent of lung involvement. 

What is driving pressure?

The airway driving pressure represents the stress applied to the lungs. It is measured at the bedside as the difference between the plateau pressure (Pplat) and the positive end-expiratory pressure (PEEP). It effectively denotes the tidal volume tailored to lung compliance. 

Driving pressure = Pplat – PEEP

Compliance = tidal volume/Pplat – PEEP

Thus, Pplat – PEEP (driving pressure) = tidal volume/compliance 

Hence, targeting the driving pressure effectively titrates tidal volume based on lung compliance in contrast to the predicted body weight. Considering the relatively small size of the functional lung in ARDS, tidal volumes titrated to the lung available for ventilation, represented by compliance, maybe physiologically more appropriate. The driving pressure is expected to be high in a poorly recruited lung at low levels of PEEP; it will also rise if the applied PEEP is too high, with overdistension of the lungs. In other words, there is an optimal level of PEEP at which the driving pressure is lowest for a given tidal volume, wherein the lung compliance is optimal. The application of an ideal level of PEEP may be expected to result in optimal lung recruitment, and thus, reduce driving pressures. 

Driving pressure and clinical outcomes

Studies on animal models have shown that tissue damage may be more dependent on the amplitude of cyclical stretch in contrast to the level of maximal stretch (2). Lung tissue may withstand sustained stretching without injury. Driving pressures of less than 20 cm H2O  was employed as part of a lung-protective strategy that resulted in a significantly lower 28-d mortality in an early randomized controlled trial (3). 

Amato et al. retrospectively analyzed data from 3562 patients from nine randomized controlled trials using multilevel mediation analysis. In this study, the driving pressure was the strongest predictor of survival. The important findings of this study were: 1. For similar PEEP levels, mortality was higher with increasing driving pressures. 2. When the driving pressure remained constant, an increase in the PEEP level did not result in higher mortality, despite higher plateau pressures. 3. Importantly, at similar plateau pressure levels, the mortality decreased with lower driving pressures. This was probably because increasing PEEP levels improved lung recruitment and compliance, thereby allowing lower driving pressures for similar tidal volumes (4). 

A meta-analysis of four studies, including 3,252 patients, revealed significantly higher mortality with higher driving pressures. The median (IQR) upper limit of driving pressure in this meta-analysis was 15 (14–16) cm H2O. A sensitivity analysis of three studies that used similar driving pressure limits (13–15 cm H2O) also revealed a similar effect on mortality (5).  A hospital-based registry study analyzed patients who underwent non-cardiothoracic surgery under general anesthesia with endotracheal intubation. On multivariable regression analysis, lung-protective ventilation was associated with a reduced risk of respiratory complications in the postoperative period. Driving pressure had a dose-dependent association with postoperative pulmonary complications in this study (6).  

Transpulmonary driving pressure

The transpulmonary driving pressure is the difference between the end-inspiratory and end-expiratory transpulmonary pressures. The transpulmonary driving pressure directly correlates with stress on the lung alone; it removes the variable impact of chest-wall compliance. 

Transpulmonary driving pressure = (Pplat – PEEP) – (end-inspiratory – end-expiratory esophageal pressure) 

Estimation of pleural pressure is required to measure transpulmonary pressure, which requires the measurement of esophageal pressure. The airway driving pressure is relatively simple to measure, based on readily available ventilation parameters and correlates with the transpulmonary driving pressure. 

Future perspectives

In a retrospective observational study of patients ventilated using a tidal volume-based protocol, 60% of patients received a driving pressure exceeding the suggested upper limit of 15 cm of H2O at the time of commencement of ventilator support (7). Targeting driving pressure is based on a strong physiological rationale and supported by clinical evidence. However, the safe range of driving pressures is currently unclear. Besides, the impact of driving pressure in the presence of spontaneous breathing efforts is also unknown. Controlled studies are required in the future to compare the conventional tidal volume and Pplat based strategies with a driving pressure-based strategy. 

The bottom line 

  • Optimization of ventilatory support is important to prevent ventilation-induced lung injury; the use of a low tidal volume strategy with limitation of plateau pressures has been conventionally considered to be the most effective strategy.
  • Considering the limited and highly variable volume of the ventilatable lung in patients with ARDS, the use of tidal volumes based on predicted body weight may not be optimal.
  • The driving pressure is based on a sound physiological rationale and targets tidal volumes based on lung compliance, in contrast to predicted body weight. 
  • A driving pressure of 15 cm of H2O has been suggested as a reasonable target, with an upper Pplat limit of 40 cm of H2O, largely based on observational studies (4). 
  • The transpulmonary driving pressure may more precisely represent lung stress; however, the airway driving pressure is easier to measure by the bedside and maybe a reasonable surrogate.
  • Controlled studies are required to confirm the beneficial effect of a driving pressure-based ventilator strategy in patients with ARDS. 


1.         Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788–800.

2.         Tschumperlin DJ, Oswari J, Margulies AS. Deformation-induced injury of alveolar epithelial cells. Effect of frequency, duration, and amplitude. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):357–62.

3.         Passos AMB, Valente BCS, Machado MD, Borges MR, Paula SG, Geraldo L-F, et al. Effect of a Protective-Ventilation Strategy on Mortality in the Acute Respiratory Distress Syndrome. N Engl J Med. 1998;8. 

4.         Amato MBP, Meade MO, Slutsky AS, Brochard L, Costa ELV, Schoenfeld DA, et al. Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. N Engl J Med. 2015 Feb 19;372(8):747–55.

5.         Aoyama H, Pettenuzzo T, Aoyama K, Pinto R, Englesakis M, Fan E. Association of Driving Pressure With Mortality Among Ventilated Patients With Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis*. Crit Care Med. 2018 Feb;46(2):300–6. 

6.         Ladha K, Vidal Melo MF, McLean DJ, Wanderer JP, Grabitz SD, Kurth T, et al. Intraoperative protective mechanical ventilation and risk of postoperative respiratory complications: hospital based registry study. BMJ. 2015 Jul 14;351:h3646. 

7.         Baldomero AK, Skarda PK, Marini JJ. Driving Pressure: Defining the Range. Respir Care. 2019 Aug;64(8):883–9. 

Thrombolysis for acute pulmonary embolism: one size may not fit all!

Thrombolytic agents lead to the activation of plasminogen to plasmin, resulting in accelerated clot lysis. They have been used in a variety of thrombotic disorders, including acute pulmonary embolism (PE). Thrombolytic therapy in acute PE has been clearly established to improve arterial oxygenation, reduce pulmonary artery pressure, and results in resolution of filling defects on the perfusion scan.1 However, thrombolysis carries a relatively increased risk of life-threatening hemorrhagic events compared to anticoagulation alone. How do we decide upon when may thrombolytic therapy be more appropriate compared to anticoagulation alone in patients with acute pulmonary embolism? 

Early, benchmark studies

Several early randomized controlled trials have evaluated the efficacy of thrombolytic therapy in acute pulmonary embolism.2,3 Most of these early studies used streptokinase and demonstrated a consistent mortality benefit with thrombolytic therapy compared to anticoagulation alone. In a subgroup of patients with massive PE, a meta-analysis that included these benchmark studies demonstrated that systemic thrombolytic therapy significantly reduced the composite endpoint of death and recurrent PE.4

Thrombolysis in hypotensive patients

There is a general consensus that thrombolytic therapy is beneficial in patients with acute PE who are hemodynamically unstable. Thrombolytic therapy may also be appropriate in patients who become hemodynamically unstable following an initial period of stability after the commencement of anticoagulant therapy. There are several early studies that compared thrombolysis with anticoagulation alone in patients with acute pulmonary embolism;  these studies demonstrated a consistent benefit with thrombolytic therapy. A recent meta-analysis enrolled patients with acute PE from prospective registries. Among the 1574 patients included in this meta-analysis, the authors found a significant association between hemodynamic instability and short-term all-cause and pulmonary embolism-related mortality. Thrombolytic therapy was associated with lower short term mortality among patients who were hemodynamically unstable.5 Based on available evidence, there is a strong indication for thrombolytic therapy in patients with acute PE who are hypotensive and do not have an increased risk of bleeding. 

Thrombolysis in patients without hypotension

In contrast to patients with acute PE who present with hemodynamic instability, the administration of thrombolytic agents in patients with stable blood pressure is contentious. The Pulmonary Embolism Thrombolysis (PEITHO) trial investigated the effect of a single dose tenecteplase and heparin compared with with heparin alone in acute PE. This study enrolled normotensive patients with right ventricular dysfunction and evidence of myocardial injury suggested by positive cardiac troponin I or troponin T levels. The primary composite outcome of all-cause mortality or hemodynamic decompensation within 7 days of randomization was significantly lower among patients who received the tenecteplase-heparin combination compared to heparin alone. The incidence of extracranial hemorrhage and hemorrhagic stroke was significantly higher among patients who received tenecteplase. Furthermore, rescue thrombolytic therapy seemed to benefit patients who became hemodynamically unstable after initial treatment with anticoagulation alone.6

Kline et al. performed a randomized controlled trial, including 83 patients with acute PE across eight centers in the US. Patients were normotensive, with evidence of right ventricular strain on echocardiography or the presence of elevated levels of biomarkers. Patients received tenecteplase combined with low molecular weight or unfractionated heparin or anticoagulation alone. The primary composite outcome included death, circulatory shock, the requirement for intubation, major bleeding within 5 days, recurrent pulmonary embolism, or an adverse SF36 Physical Component Summary score at 90 days. The composite primary outcome was significantly worse in patients who received anticoagulation alone. This study suggested that thrombolytic therapy with tenecteplase leads to improved clinical outcomes in normotensive patients with submassive pulmonary embolism.

These studies suggest that among patients with acute PE who are not hypotensive, the decision to thrombolyze needs to be individualized. Thrombolytic therapy may benefit patients with submassive PE who develop severe or worsening right ventricular dysfunction and an increase in cardiac biomarkers.

Thrombolysis during cardiopulmonary resuscitation

Does thrombolysis improve outcomes during cardiopulmonary resuscitation? In a retrospective study, acute PE was found to be the underlying cause of cardiac arrest in 4.8% of patients. Return of spontaneous circulation was significantly higher among those who received thrombolytic therapy with tissue plasminogen activator (tPA) compared to those who did not.7 In another retrospective study, patients with cardiac arrest and pulseless electrical activity due to massive PE were administered 50 mg of tPA as an intravenous bolus. Return of spontaneous circulation was observed in all except one of 23 patients who underwent thrombolytic therapy. Besides, a significant reduction in the right ventricular size and pulmonary artery pressure were also observed.8

Abu-Laban et al. randomized patients who suffered cardiac arrest with pulseless electrical activity as the presenting rhythm to receive 100 mg tPA or placebo. There was no difference in the number of patients who had return of spontaneous circulation; only one patient in the study cohort survived to hospital discharge.9

In light of the equivocal evidence, the administration of thrombolytic agents cannot be routinely recommended as part of therapy during cardiopulmonary resuscitation. 

Specific agents, dosing strategies

Recombinant tPA, streptokinase, and recombinant human urokinase have been the most studied thrombolytic agents in acute PE. Tenecteplase and reteplase have also been used in acute pulmonary embolism. Fibrin specific agents bind preferentially to clot-bound plasminogen. Although the superiority of one agent over the other has not been established in acute PE, fibrin specific agents are commonly preferred (Table 1). Thrombolytic therapy is typically administered as an intravenous infusion through a peripheral IV line. Anticoagulant therapy is discontinued during the administration of the thrombolytic agent and commenced when clot lysis occurs and the APTT is less than twice the upper limit of normal. 

Table 1. The dose of commonly used fibrin specific thrombolytic agents in acute PE

Alteplase 100 mg IV over 2 hours
Reteplase 10 units IV bolus, two doses, 30 minutes apart 
Tenecteplase  Less than 60 kg: 30 mg 
60–70 kg: 35 mg
70–80 kg: 40 mg
80–90 kg: 45 mg
More than 90 kg: 50 mg 

Catheter-directed treatment with or without thrombolysis may be appropriate in patients with a high risk of bleeding, when death seems imminent before thrombolytic therapy can take effect, and as rescue therapy after failure of systemic thrombolysis. 

Low-dose thrombolysis

The MOPETT trial addressed the benefit of low-dose thrombolytic therapy in patients with moderate PE (clinical features of PE with more than 70% involvement of 2 or more lobar or main pulmonary arteries on CT-pulmonary angiogram or a high probability ventilation/perfusion scan showing ventilation/perfusion mismatch in 2 or more lobes). Patients were randomized to receive heparin alone or in combination with low-dose tPA. The dose of tPA was 50% of the conventionally accepted dose. Low-dose thrombolytic therapy resulted in a lower incidence of pulmonary hypertension, lower pulmonary systolic pressures, and a more rapid resolution of pulmonary hypertension, with similar rates of bleeding.10 Kiser et al. performed a retrospective cohort study among patients who received half dose (50 mg) compared to a full dose of alteplase. Propensity matching was carried out to eliminate confounders and hospital-level clustering. The use of half dose alteplase did not result in a significant difference in mortality or the incidence of major bleeding; however, escalation of therapy was more often required with the lower dose.11  The use of reduced-dose thrombolytic therapy requires more robust evidence of efficacy before it can be recommended as a routine treatment modality. 

The bottom line

  • In hypotensive patients with acute PE, without an increase in the risk of bleeding, there is robust evidence to support thrombolytic therapy. 
  • Among patients who are not hypotensive, the decision to thrombolyze needs to be individualized. Thrombolytic therapy may benefit in patients with submassive PE with severe or worsening right ventricular dysfunction and an increase in cardiac biomarkers. It may also be appropriate to administer thrombolytic therapy among patients who remain normotensive but deteriorate otherwise after the commencement of anticoagulant therapy.
  • Patients with acute PE who remain normotensive following cardiopulmonary resuscitation may also benefit from thrombolytic therapy. 
  • Extensive clot burden or the presence of a free-floating thrombus in the right atrium or ventricle are unsubstantiated, but possibly beneficial indications for thrombolysis.
  • It may be reasonable to consider thrombolytic agents in patients who develop recurrent PE while on anticoagulant therapy. 


1.         Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026

2.         Jerjes-Sanchez  null, Ramírez-Rivera  null, de Lourdes García M  null, et al. Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis. 1995;2(3):227-229. doi:10.1007/bf01062714

3.         Ly B, Arnesen H, Eie H, Hol R. A controlled clinical trial of streptokinase and heparin in the treatment of major pulmonary embolism. Acta Med Scand. 1978;203(6):465-470. doi:10.1111/j.0954-6820.1978.tb14909.x

4.         Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004;110(6):744-749. doi:10.1161/01.CIR.0000137826.09715.9C

5.         Quezada CA, Bikdeli B, Barrios D, et al. Meta-analysis of prevalence and short-term prognosis of hemodynamically unstable patients with symptomatic acute pulmonary embolism. Am J Cardiol. 2019;123(4):684-689. doi:10.1016/j.amjcard.2018.11.009

6.         Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. doi:10.1056/NEJMoa1302097

7.         Kürkciyan I, Meron G, Sterz F, et al. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. Arch Intern Med. 2000;160(10):1529-1535. doi:10.1001/archinte.160.10.1529

8.         Sharifi M, Berger J, Beeston P, et al. Pulseless electrical activity in pulmonary embolism treated with thrombolysis (from the “PEAPETT” study). Am J Emerg Med. 2016;34(10):1963-1967. doi:10.1016/j.ajem.2016.06.094

9.         Abu-Laban RB, Christenson JM, Innes GD, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med. 2002;346(20):1522-1528. doi:10.1056/NEJMoa012885

10.       Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277. doi:10.1016/j.amjcard.2012.09.027

11.       Kiser TH, Burnham EL, Clark B, et al. Half-Dose Versus Full-Dose Alteplase for Treatment of Pulmonary Embolism*: Crit Care Med. 2018;46(10):1617-1625. doi:10.1097/CCM.0000000000003288

When rising intra-abdominal pressure turns silent killer: the abdominal compartment syndrome

The spectrum of clinical disorders arising from raised intra-abdominal pressure (IAP) was recognized from the 19thcentury onwards. Abdominal compartment syndrome (ACS) was first described three decades ago among four patients who underwent surgery for ruptured abdominal aortic aneurysm. ACS manifested within the first 24 hours postoperatively with massive abdominal distension and was characterized by rising ventilation pressures, central venous pressure, and oliguria.1 There is increasing awareness among clinicians that ACS may be the underlying cause for impaired cardiac output, renal function, and lead to metabolic acidosis. A high index of suspicion is called for as the consequences of ACS may be easily mistaken for hypovolemia; continued fluid resuscitation results in worsening of the clinical state. 

Retrospective studies have reported the presence of intra-abdominal hypertension (IAH) in 38–45% of adult critically ill patients.2 In a recent multicentric study of 491 mixed critically ill patients, IAH occurred in 34.0% of patients day 1 of ICU admission and in 48.9% of patients during the entire study period.3

Pathophysiology, causes, and risk factors 

The volume of the intra-abdominal compartment may increase due to fluid, air, tissue edema, or the presence of a solid tumor. As the intra-abdominal volume rises, the elastic recoil of the abdominal wall tends to mitigate any rise in pressure. However, the IAP rises steeply once compensatory mechanisms fail. Thus, ACS may occur due to an increase in the intra-abdominal volume, decreased compliance of the abdominal wall, or a combination of both mechanisms. Massive crystalloid fluid resuscitation and a positive fluid balance are being increasingly recognized as a trigger for raised IAP, probably due to visceral edema leading to an increase in the intra-abdominal volume.4 Tense ascites, hemoperitoneum, acute pancreatitis, and unrelieved ileus are common etiological factors for the development of ACS. Blunt trauma, sepsis, and massive blood transfusion can also trigger the development of ACS. 


The World Society of Abdominal Compartment Syndrome (WSACS) has formulated definitions and practice guidelines for IAP and ACS. IAH is defined as a sustained rise in IAP of higher than 12 mm Hg. IAH is classified into four grades of severity (Table 1). ACS is defined as a sustained rise in IAP greater than 20 mm Hg with or without an abdominal perfusion pressure (mean arterial pressure – IAP) less than 60 mm Hg and accompanied by end-organ dysfunction.5

Grade of intra-abdominal hypertensionIntra-abdominal pressure (mm Hg)
Grade I 12–15
Grade II16–20
Grade III21–25
Grade IV> 25

Table 1. The WSACS classification of intra-abdominal hypertension based on severity 

Organ dysfunction in ACS

IAH can impair the function of both ventricles and reduce cardiac output. There is an increase in the central venous and pulmonary artery pressures. Besides, the systemic vascular resistance rises, with an increase in the left ventricular afterload. The respiratory function is compromised, with the requirement for increased ventilation pressures. There is a reduction in the functional residual capacity, with impaired gas exchange, leading to hypoxia and hypercarbia. There may be a profound drop in the pH due to a combination of respiratory and metabolic acidosis. Increased IAP leads to compression of the renal parenchyma; furthermore, the renal blood flow decreases due to a fall in the cardiac output. The activation of the renin-angiotensin system results in salt and water retention. Oliguria in spite of the administration of fluids is a key early feature of ACS. IAH can lead to compromise of intestinal mucosal blood flow. This may precipitate gut ischemia and lead to translocation of bacteria, resulting in systemic sepsis. An increase in IAP leads to upward displacement of the diaphragm, with an increase in the intrathoracic and jugular venous pressures. The rise in jugular venous pressure impedes venous return from the brain and may precipitate severe intracranial hypertension in patients with traumatic brain injury.  

Measurement of IAP

Clinical examination alone is poorly sensitive in diagnosing IAH.6 Measurement of the intravesical pressure is the standard method followed to measure IAP. The urinary catheter is connected to a 3-way stopcock and transduced at the level of the midaxillary line. The intravesical pressure is measured after instillation of 20 ml of normal saline into the urinary bladder. A larger volume of normal saline may lead to erroneously high readings. There are commercially available kits that reduce the possibility of technical errors; however, a needle inserted into the sampling port of the urinary catheter is easy to use and usually allows accurate measurement of the intravesical pressure. 

Treatment of IAH 

Unrelieved, severe IAH has been shown to be an independent predictor of 28- and 90-day mortality among critically ill patients.3 Hence, it is important to monitor IAP in patients at risk and resort to early corrective intervention. Figure 1 illustrates a step-wise approach to the management of unrelieved IAH leading to ACS. 

Figure 1. A stepwise approach to the management of IAH and ACS


The abdominal perfusion pressure predicted survival from IAH and ACS and was found to be a useful endpoint of resuscitation in a retrospective observational study.7 However, abdominal perfusion pressure-based resuscitation has not been clinically validated. Evacuation of abdominal contents by gastric drainage, rectal tube insertion, and administration of enema may have a mitigating effect on IAH. The commonly recommended head-up position in ventilated patients may worsen IAH; hence, it may be appropriate to assume a reverse Trendelenburg position. The administration of analgesics, sedative medication, and neuromuscular blockade may offer temporary respite while the underlying problem is addressed. Large-volume paracentesis may also contribute significantly to a reduction in the IAP. It is important not to over-resuscitate patients who may have ACS; judicious use of diuretics may help de-resuscitate patients who are fluid overloaded, and reduce IAP.8 If renal function is compromised, fluid removal by ultrafiltration may be required.  


If medical therapies fail, surgical decompression with open abdomen must be carried out expeditiously. Surgical decompression combined with suction drainage may lead to a reduced incidence of septic complications and improve clinical outcomes.9 Managing a patient with open abdomen may be complicated by excessive protein loss, fistula formation, hemorrhage, and infection. Ventral hernias may also develop in the long-term.10 A patch closure is commonly resorted to for temporary closure of an open abdomen (Figure 2). The patch is interposed between facial edges and gradually approximated as the IAP resolves. The negative pressure vacuum system applies an airtight seal around the edges of the wound while suction is applied. This enables drainage of fluid and maintains tension on the facial edges and enables healing. It is preferable to close an open abdomen within 48 h. Maintaining an open abdomen for a longer duration may be required, while repeated surgical interventions are carried out. 

Figure 2. Decompressive laparotomy and open abdomen with mesh closure in a patient with necrotising pancreatitis

The bottom line

  • IAH is common in critically ill patients and is an independent predictor of mortality. 
  • Clinical examination is poorly sensitive for the diagnosis of IAH; intravesical pressure reflects IAP with reasonable accuracy. 
  • Common etiological factors for IAH and ACS include overexuberant fluid resuscitation, tense ascites, hemoperitoneum, acute pancreatitis, unrelieved ileus, blunt abdominal trauma, and sepsis.
  • Unrelieved IAH triggers organ failure, leading to ACS.
  • Early detection of IAH with an expeditious, stepwise approach is necessary to relieve rising IAP; unrelieved IAH with ACS requires surgical decompression and maintenance of an open abdomen.


1.         Fietsam R, Villalba M, Glover JL, Clark K. Intra-abdominal compartment syndrome as a complication of ruptured abdominal aortic aneurysm repair. Am Surg. 1989;55(6):396-402.

2.         Murphy PB, Parry NG, Sela N, Leslie K, Vogt K, Ball I. Intra-abdominal hypertension is more common than previously thought: A prospective study in a mixed medical-surgical ICU. Crit Care Med. 2018;46(6):958-964. doi:10.1097/CCM.0000000000003122

3.         Reintam Blaser A, Regli A, De Keulenaer B, et al. Incidence, risk Factors, and outcomes of intra-abdominal hypertension in critically ill patients—a prospective multicenter study (IROI Study): Crit Care Med. 2019;47(4):535-542. doi:10.1097/CCM.0000000000003623

4.         Malbrain MLNG, Chiumello D, Cesana BM, et al. A systematic review and individual patient data meta-analysis on intra-abdominal hypertension in critically ill patients: the wake-up project. World initiative on Abdominal Hypertension Epidemiology, a Unifying Project (WAKE-Up!). Minerva Anestesiol. 2014;80(3):293-306.

5.         Kirkpatrick AW, Roberts DJ, De Waele J, et al. Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome. Intensive Care Med. 2013;39(7):1190-1206. doi:10.1007/s00134-013-2906-z

6.         Al-Dorzi HM, Tamim HM, Rishu AH, Aljumah A, Arabi YM. Intra-abdominal pressure and abdominal perfusion pressure in cirrhotic patients with septic shock. Ann Intensive Care. 2012;2 Suppl 1:S4. doi:10.1186/2110-5820-2-S1-S4

7.         Cheatham ML, White MW, Sagraves SG, Johnson JL, Block EF. Abdominal perfusion pressure: a superior parameter in the assessment of intra-abdominal hypertension. J Trauma. 2000;49(4):621-626; discussion 626-627. doi:10.1097/00005373-200010000-00008

8.         Malbrain MLNG, Marik PE, Witters I, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014;46(5):361-380. doi:10.5603/AIT.2014.0060

9.         Cheatham ML, Demetriades D, Fabian TC, et al. Prospective study examining clinical outcomes associated with a negative pressure wound therapy system and Barker’s vacuum packing technique. World J Surg. 2013;37(9):2018-2030. doi:10.1007/s00268-013-2080-z

10.       Sugrue M. Abdominal compartment syndrome and the open abdomen: any unresolved issues? Curr Opin Crit Care. 2017;23(1):73-78. doi:10.1097/MCC.0000000000000371

Does intracranial pressure monitoring help in patients with severe traumatic brain injury?

One of the guiding principles in the management of traumatic brain injury (TBI) is based on the Munro-Kellie doctrine. According to this principle, the volume of the intracranial compartment is fixed and comprises of the brain parenchyma (80%), intracranial blood volume (10%), and the cerebrospinal fluid volume (10%). An increase in the intracranial volume is compensated to a limited extent by a shift of the cerebrospinal fluid out of the intracranial compartment. However, beyond a certain threshold level of increase in the intracranial volume, compensatory mechanisms fail, and the intracranial pressure (ICP) begins to rise steeply. The rise in ICP compresses the brain parenchyma, leading to a drop in the cerebral perfusion pressure (CPP). 

CPP = Mean arterial pressure (MAP) – ICP 

If the ICP continues to rise unabated, cerebral perfusion is compromised, leading to secondary brain injury, which is usually fatal. 

Early studies, ICP thresholds

Lundberg et al. first reported the use of an intraventricular catheter connected to a strain gauge transducer for the continuous measurement ICP  in 30 patients with TBI. They proposed that continuous ICP measurement offers a more rational basis to optimize interventions in TBI.1 More than a decade later, Miller et al., in their series of 160 patients, suggested that an ICP higher than a threshold level of 20 mm Hg led to poor outcomes after TBI. They proposed that ICP measurement needs to be considered as part of the management protocol for severe TBI.2  In another early landmark study of patients with intracranial hematoma, clinical features were not helpful in predicting the requirement for surgical intervention; however, an ICP of more than 20 mm Hg was associated with deterioration of the neurological status and the requirement for surgical intervention.3

Advantages and disadvantages of ICP monitoring 

ICP monitoring enables CPP-targeted therapeutic interventions. Severe TBI requires controlled ventilation with sedatives, and muscle relaxants for ICP control. Meaningful clinical assessment is often not feasible in this setting. Repeated interruption of sedation at regular intervals to enable clinical assessment may be detrimental in patients with intracranial hypertension. An increase in the ICP alerts the clinician to possible neurological deterioration that may call for re-imaging or surgical intervention. An intraparenchymal catheter is relatively easy to insert and reasonably safe; besides, staff familiarity with this modality of monitoring may improve the level of care. 

However, paradoxically, aggressive interventions to normalize ICP, including the excessive use of mannitol and hypertonic saline in elderly patients, with compromised cardiovascular and renal function, may lead to harm. Decompressive craniectomy aimed at alleviating intracranial hypertension may also lead to poor functional outcomes in patients with TBI.4 Although ICP monitoring is recommended by the Brain Trauma Foundation guidelines, in the Trauma Quality Improvement Program database study that included 13,188 patients, only 11.5% of eligible patients underwent ICP monitoring. This finding probably suggests ambivalence among neurosurgeons regarding the efficacy of ICP monitoring in the setting of severe TBI.5

What is the evidence for the usefulness of ICP monitoring? 

ICP monitoring is commonly used to titrate interventions including osmotherapy, optimize sedation and ventilator management, and for decision making regarding surgical intervention such as decompressive craniectomy. Most of the information available regarding the efficacy of ICP monitoring and its impact on clinical outcomes is based on observational studies. 

The relationship between ICP monitoring and mortality was evaluated among centers participating in the American College of Surgeons Trauma Quality Improvement Program (TQIP). After adjustment for possible confounders, mortality was significantly lower in patients who underwent ICP-guided management. Besides, centers that performed ICP monitoring more often revealed lower mortality.6 A 2-year observational study was performed in patients with severe TBI (GCS of 8 or less) from 14 trauma centers in the US. In-hospital mortality was evaluated after adjusting for confounders using propensity score matching. On both unadjusted and propensity-matched analysis, ICP-based care resulted in a significantly lower in-hospital mortality compared to patients who did not receive ICP monitoring.7  

However, other studies have revealed conflicting results. In a two-center Dutch study, one of the study centers used therapeutic interventions based on clinical features and computed tomography (CT) findings. The other study center utilized interventions to maintain an ICP of less than 20 mm Hg and CPP of more than 70 mm Hg. The Glasgow outcome score was used to assess functional outcomes after 12 months. After adjustment for confounders, there was no difference in functional outcomes between centers. The median duration of ventilator support was significantly lower among patients who did not undergo ICP-based management.8 A large US  National Trauma Databank (NTDB) study compared patients with TBI who underwent ICP monitoring with those who did not. Patients with blunt TBI with a GCS of 8 or less, with an abnormal brain CT scan, and ICU stay of 3 days or more were included. On multivariate analysis, after adjustment for possible confounders, ICP monitoring resulted in a 45% reduction in survival.9  

In a study based on the Trauma Quality Improvement Program (TQIP) database, the investigators assessed compliance with the BTF guidelines for ICP monitoring and the impact of ICP monitoring on clinical outcomes. The study included patients with isolated TBI with a GCS of less than 9 and a score of 3 or more on the head Abbreviated Injury Scale (AIS). This study included 13,188 patients. ICP monitoring was carried out only in 11.5% of eligible patients. Overall, no mortality benefit was discernible among patients who underwent ICP monitoring. Placement of an ICP monitor was an independent predictor of overall complications, infectious complications, and was associated with poor functional outcomes. In the subgroup of patients with the most severe injuries according to the AIS, ICP monitoring was an independent predictor of mortality.5

The only randomized controlled trial comparing ICP-based vs. clinical assessment and imaging-based management was conducted in 324 patients who had suffered severe TBI. The study was conducted across six centers in Bolivia and Ecuador. The composite primary outcome included the duration of survival, the level and duration of impairment of conscious level, the functional status at 3 and 6 months, and the neuropsychological state at 6 months. There was no significant difference in the composite primary outcome between groups. The 6-month mortality and the median duration of ICU stay were also similar in both groups. The duration of cerebral protective therapy was longer in the clinical assessment and imaging-based group; the incidence of adverse events was similar in both groups. Thus, ICP-guided management of severe TBI was not superior to clinical assessment and imaging-based management in this study.10 This study has evoked intense debate and may need to be interpreted against the background of a clinical setting in which ICP monitoring may not be the standard of care. 

The bottom line

  • ICP monitoring-based care in severe TBI remains contentious with conflicting results from observational studies.
  • The only randomized controlled trial on this topic did not demonstrate any clinical outcome benefit with ICP monitoring-based care compared to clinical examination and CT imaging-based care; however, the generalizability of this study remains uncertain.
  • Patients with severe TBI require controlled ventilation with sedatives and muscle relaxants as part of neuroprotective therapy; clinical assessment is often not feasible in such patients. Continuous ICP monitoring enables early detection of neurological deterioration.  
  • There is persisting uncertainty regarding the usefulness of ICP monitoring in patients with severe TBI. Equipoise needs to be maintained on this unresolved issue until more robust evidence is available. 


1.         Lundberg N, Troupp H, Lorin H. Continuous Recording of the Ventricular-Fluid Pressure in Patients with Severe Acute Traumatic Brain Injury. J Neurosurg. 1965;22(6):581-590. doi:10.3171/jns.1965.22.6.0581

2.         Miller JD, Becker DP, Ward JD, Sullivan HG, Adams WE, Rosner MJ. Significance of intracranial hypertension in severe head injury. J Neurosurg. 1977;47(4):503-516. doi:10.3171/jns.1977.47.4.0503

3.         Gallbraith S, Teasdale G. Predicting the need for operation in the patient with an occult traumatic intracranial hematoma. J Neurosurg. 1981;55(1):75-81. doi:10.3171/jns.1981.55.1.0075

4.         Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011;364(16):1493-1502. doi:10.1056/NEJMoa1102077

5.         Aiolfi A, Benjamin E, Khor D, Inaba K, Lam L, Demetriades D. Brain Trauma Foundation Guidelines for Intracranial Pressure Monitoring: Compliance and Effect on Outcome. World J Surg. 2017;41(6):1543-1549. doi:10.1007/s00268-017-3898-6

6.         Alali AS, Fowler RA, Mainprize TG, et al. Intracranial pressure monitoring in severe traumatic brain injury: results from the American College of Surgeons Trauma Quality Improvement Program. J Neurotrauma. 2013;30(20):1737-1746. doi:10.1089/neu.2012.2802

7.         Dawes AJ, Sacks GD, Cryer HG, et al. Intracranial pressure monitoring and inpatient mortality in severe traumatic brain injury: A propensity score-matched analysis. J Trauma Acute Care Surg. 2015;78(3):492-501; discussion 501-502. doi:10.1097/TA.0000000000000559

8.         Cremer OL, van Dijk GW, van Wensen E, et al. Effect of intracranial pressure monitoring and targeted intensive care on functional outcome after severe head injury. Crit Care Med. 2005;33(10):2207-2213. doi:10.1097/01.ccm.0000181300.99078.b5

9.         Shafi S, Diaz-Arrastia R, Madden C, Gentilello L. Intracranial pressure monitoring in brain-injured patients is associated with worsening of survival. J Trauma. 2008;64(2):335-340. doi:10.1097/TA.0b013e31815dd017

10.       Chesnut RM, Temkin N, Carney N, et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med. 2012;367(26):2471-2481. doi:10.1056/NEJMoa1207363

Circulatory support in septic shock: looking beyond catecholamines

Why look for alternatives for the circulatory support of septic patients? 

Vasopressor therapy in patients with septic shock has centered around the use of noradrenaline titrated to a target mean arterial pressure. The surviving sepsis guidelines recommend noradrenaline as the first-line vasopressor in sepsis.1 Noradrenaline increases venous return and the left ventricular end-diastolic volume by venoconstriction and mobilization of the “unstressed” volume from the splanchnic circulation. It increases myocardial contractility though beta-1 adrenergic receptor stimulation. The cardiac output and blood pressure increase, with no increase in the heart rate. In contrast to adrenaline, noradrenaline has no significant effect on the beta-2 adrenergic receptors, and hence, there is no rise in the lactate levels. Several clinical studies have been carried out comparing noradrenaline with dopamine, adrenaline, and vasopressin alone and in combination. These studies have clearly established that noradrenaline is equally efficacious or superior in the hemodynamic support of patients with septic shock.

Circulatory support using catecholamines is not entirely benign; several non-hemodynamic effects may adversely affect clinical outcomes. These include a hypermetabolic state characterized by hyperglycemia, hyperlactatemia, and an increase in the tissue oxygen demand. Catecholamines may cause mitochondrial uncoupling and lead to exacerbation of oxidative stress. Besides, they may exert a significant immunosuppressive effect, increasing the likelihood of secondary infections.2 There is increasing concern that high doses of catecholamine support may adversely impact clinical outcomes. In a retrospective observational study, a noradrenaline dose of more than 1mcg/kg/min was the strongest independent predictor of mortality on multidimensional logistic regression analysis.3 Considering the possible deleterious effects of high-dose noradrenaline, there is an increased focus on “decatecholaminization” using non-catecholamine-based circulatory support.4 Let us consider the non-catecholamine pharmacological agents that have been evaluated in patients with septic shock. 


A relative vasopressin deficiency may occur in septic shock. Exogenous vasopressin administration leads to vasoconstriction by its action on the non-adrenergic, V1 receptors located in the vascular endothelium. This leads to increased blood pressure, less requirement for noradrenaline, and possible inhibition of cytokine production. The VAAST study did not show any change in mortality in patients with septic shock with vasopressin use; however, it was associated with lower 28-d mortality among patients with less severe shock, who were on less than 15 mcg/min of noradrenaline infusion.5 Vasopressin use in vasoplegic shock following cardiac surgery may be associated with a lower incidence of atrial fibrillation compared to noradrenaline.6

In a factorial double-blind, randomized clinical trial with the use of noradrenaline, vasopressin, and hydrocortisone in septic shock, early vasopressin administration had no effect on the kidney failure-free days compared to noradrenaline.7Although frequently used in combination with noradrenaline and hydrocortisone, there is no firm evidence that vasopressin improves clinical outcomes in patients with septic shock. 


Besides its effect on the V1 receptors resulting in an increase in the vascular tone, vasopressin stimulates the V2 receptors located in the basolateral membrane of the collecting tubules of the kidneys. This may lead to fluid retention, release of procoagulant factors including Von Willebrand factor and factor VIII, leading to thrombosis. Furthermore, nitric oxide release may lead to vasodilatation. Selepressin is a novel, selective vasopressin V1a receptor agonist that may be devoid of many of the adverse effects related to vasopressin. In a phase IIa randomized controlled trial in patients with septic shock, selepressin in a dose of 2.5 ng/kg/minute resulted in rapid weaning down and cessation of noradrenaline. Furthermore, it reduced the duration of mechanical ventilation and the cumulative fluid balance over the study period.8 A recent phase 2b/3 randomized controlled trial compared three dosing regimens of selepressin with placebo. There was no difference noted in the primary endpoint of ventilator or vasopressor-free days at day 40 with the use of selepressin. The 90-d mortality, intensive care-free days, and the requirement for renal replacement therapy at 30 days were also not different compared to placebo. Future research is required to evaluate the appropriate dose of selepressin and assess patient-centred outcomes in adequately powered, controlled studies. 

Angiotensin II

Angiotensin II is the biologically active component of the renin-angiotensin system. It acts on two receptor subtypes, AT1 and AT2. The physiological effects leading to vasoconstriction, retention of water and sodium, and release of aldosterone and vasopressin are mediated through the AT1 receptors.  The ATHOS-3 trial evaluated the effect of angiotensin II in patients with vasodilatory shock in a placebo-controlled randomized controlled trial. The primary endpoint was an increase in the mean arterial pressure by at least 10 mm Hg or to a minimum level of 75 mm Hg, without any increase in the background vasopressor dose at 3 h after commencement of infusion. A significantly higher number of patients achieved the target MAP compared to placebo. The mean improvement in the cardiovascular SOFA score was also significantly higher with angiotensin II.9 The data from this study led to the approval of angiotensin II in septic shock by the Food and Drug Administration in the USA and the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP).


The use of corticosteroids as adjunctive therapy in septic shock has captivated intensive care physicians for over five decades. The concept of corticosteroid insufficiency related to critical illness (CIRCI) has arisen more recently. CIRCI is based on the hypothesis that even maximal stimulation of the hypothalamic-pituitary-adrenal axis in disease states such as sepsis results in insufficient corticosteroid levels. Besides, there may be tissue resistance to corticosteroids in the presence of sepsis. The ADRENAL trial is the largest randomized controlled trial that compared hydrocortisone infusion at 200 mg/day to placebo in patients with septic shock. No difference was observed in the 90-d mortality, the primary outcome, for which the study was powered. However, hydrocortisone reduced the median time to shock resolution, the median time to initial discontinuation of mechanical ventilation, the median time to ICU discharge, and the requirement for blood transfusion.10 The APROCCHSS trial evaluated the efficacy of a combination of hydrocortisone and fludrocortisone in patients with septic shock. In contrast to ADRENAL, a statistically significant difference was observed in the 90-d mortality, which was the primary endpoint. The all-cause mortality at ICU and hospital discharge, and at 180 days, were also significantly lower among corticosteroid-treated patients. Earlier shock reversal was also observed; there were more patients alive and off vasopressor support at 28 days with corticosteroids.11 In light of the available evidence, it may be appropriate to consider the administration of corticosteroids in patients with refractory septic shock.

Methylene blue 

Vasodilatory shock is mediated by excessive production of nitric oxide (NO) and cyclic GMP. Methylene blue inhibits the effects of endothelial NO and may act as a NO scavenger, thereby offsetting its vasodilator effect. Thus, it may be useful in clinical states characterized by extreme vasodilation, including post-cardiopulmonary bypass, septic shock, drug toxicity, and anaphylactic reactions. In a systematic review of mostly observational studies, Kwok et al. observed that methylene blue resulted in an increase in the systemic vascular resistance and the mean arterial pressure with a decrease in the requirement for vasopressors.12 However, there is no robust evidence from controlled studies that support its clinical efficacy in septic shock. 

Vitamins for circulatory support

Vitamin C (ascorbic acid) is a cofactor for the enzymes required for the synthesis of endogenous vasopressin and noradrenaline. A relative or absolute deficiency of Vitamin C may exist in septic patients, resulting in depletion of endogenous noradrenaline and vasopressin. Besides, vitamin C is a powerful antioxidant end effectively scavenges oxygen free radicals and replenishes cellular antioxidants. Thiamine (vitamin B1) is a cofactor for the enzyme pyruvate dehydrogenase that converts pyruvate to acetyl-coA and entry in to the Kreb’s cycle. If thiamine levels are deficient, conversion of pyruvate to acetyl-coA does not occur, with shift to anerobic metabolism and an increase in the lactate levels. Thiamine deficiency is common in septic patients and may lead to increased mortality.13 Marik et al. conducted a retrospective, before-after study to evaluate the effect of a combination of vitamin 1.5 g 6 hourly, hydrocortisone 50 mg 6 hourly, and thiamine 200 mg twice daily among patients with severe sepsis or septic shock. The hospital mortality was significantly lower with this combination compared to a historical control group. The mean duration of vasopressor therapy and the requirement for renal replacement therapy was also significantly lower in the treatment group. A multicentre, randomized controlled trial is currently recruiting patients to evaluate the efficacy of this cocktail in patients with septic shock.14

The bottom line 

  • Noradrenaline is the time-tested and the most widely recommended vasopressor agent in septic shock.
  • However, considering the adverse effects of catecholamine-based circulatory support, it may be appropriate to pursue alternative therapies, especially as a rescue intervention in septic shock.
  • Vasopressin has been evaluated in randomized controlled trials and found to be effective in maintaining blood pressure; however, improved clinical outcomes have not been demonstrated. 
  • Selepressin, V1A-selective vasopressin analog has undergone preliminary clinical studies and found to result in more rapid weaning down of noradrenaline support and reduced cumulative fluid balance. 
  • Angiotensin II has been shown to be effective in attaining the target mean arterial pressure with improvement in cardiovascular SOFA scores. 
  • Based on the findings of two recent randomized controlled trials, corticosteroids administration appears to improve outcomes in refractory septic shock.
  • The combination of thiamine, vitamin C, and hydrocortisone has been shown to improve outcomes in septic shock in an observational study; the results of a randomized controlled study are awaited. 


1.         Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377. doi:10.1007/s00134-017-4683-6

2.         Hartmann C, Radermacher P, Wepler M, Nußbaum B. Non-Hemodynamic Effects of Catecholamines. Shock Augusta Ga. 2017;48(4):390-400. doi:10.1097/SHK.0000000000000879

3.         Martin C, Medam S, Antonini F, et al. NOREPINEPHRINE: NOT TOO MUCH, TOO LONG. Shock. 2015;44(4):305-309. doi:10.1097/SHK.0000000000000426

4.         Singer M, Matthay MA. Clinical review: Thinking outside the box–an iconoclastic view of current practice. Crit Care Lond Engl. 2011;15(4):225. doi:10.1186/cc10245

5.         Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877-887. doi:10.1056/NEJMoa067373

6.         Hajjar LA, Vincent JL, Barbosa Gomes Galas FR, et al. Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: The VANCS Randomized Controlled Trial. Anesthesiology. 2017;126(1):85-93. doi:10.1097/ALN.0000000000001434

7.         Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.10485

8.         Russell JA, Vincent J-L, Kjølbye AL, et al. Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients. Crit Care. 2017;21(1):213. doi:10.1186/s13054-017-1798-7

9.         Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017;377(5):419-430. doi:10.1056/NEJMoa1704154

10.       Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. doi:10.1056/NEJMoa1705835

11.       Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818. doi:10.1056/NEJMoa1705716

12.       Kwok ESH, Howes D. Use of methylene blue in sepsis: a systematic review. J Intensive Care Med. 2006;21(6):359-363. doi:10.1177/0885066606290671

13.       Donnino MW, Andersen LW, Chase M, et al. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016;44(2):360-367. doi:10.1097/CCM.0000000000001572

14.       Fujii T, Udy AA, Deane AM, et al. Vitamin C, Hydrocortisone and Thiamine in Patients with Septic Shock (VITAMINS) trial: study protocol and statistical analysis plan. Crit Care Resusc J Australas Acad Crit Care Med. 2019;21(2):119-125.

Knowing when to stop: shorter duration of antibiotic therapy in the critically ill

Inappropriately prolonged use of antibiotics has several deleterious effects in critically ill patients. Injudicious administration of broad-spectrum antibiotics for an extended period may lead to new-onset infections with resistant organisms due to selective pressure. Besides adding to the cost of care, drug-related adverse effects resulting from prolonged use may also impact clinical outcomes. Let us consider the evidence behind the use of a short-duration antibiotic strategy in the treatment of infections commonly encountered in the critically ill. 

Empirical treatment for ventilator-associated pneumonia

Despite a surfeit of scoring systems and diagnostic criteria, the precise identification of ventilator-associated pneumonia (VAP) remains elusive. Early commencement of empirical antibiotic therapy is often necessary depending on the level of clinical suspicion. Singh et al. studied patients with a low likelihood of VAP, with a clinical pulmonary infection score (CPIS) <= 6. In the experimental group, patients received 3 days of ciprofloxacin followed by cessation of treatment if the CPIS remained <= 6. In the standard therapy group, the choice and duration of treatment were left to physician judgment. The 30-d mortality and ICU length of stay were not different between groups; antibiotic resistance and the incidence of superinfections were higher in the standard therapy group.1 In a recent observational study, patients suspected to have VAP, but on stable ventilator settings (FiO2 <= 0.4 and PEEP <= 5 cm H2O) received 1–3 days vs. > 3 days of antibiotic treatment. There was no difference in the time to extubation, death while on ventilation, time to hospital discharge, and death in hospital between groups.2

These studies support the early discontinuation of empirical antibiotic therapy in patients who are suspected to have VAP but remain clinically stable. In many of these patients, radiographic infiltrates may have been due to non-infectious causes, and antibiotic treatment may not have been necessary. 

Treatment of confirmed ventilator-associated pneumonia

What may the optimal duration of antibiotic therapy for microbiologically confirmed VAP? In a benchmark trial, Chastre et al.  compared 8 vs.15 days of treatment among patients with positive cultures of bronchoscopic specimens and underwent initial appropriate empirical antibiotic cover. A shorter duration of treatment did not result in increased 28-d mortality nor an increased incidence of recurrent infections. The incidence of recurrent infection with multidrug-resistant organisms was less with a shorter duration of treatment. Recurrent infection was more with a shorter duration of treatment in patients who had infection with non-fermenting gram-negative bacilli, including Pseudomonas aeruginosa.3 In another randomized controlled trial, among patients with early-onset VAP (between 24 h to 8 days of ventilation), there was no difference in the clinical cure rates, and mortality at 21 and 90 days with 8-day compared to 15-day antibiotic treatment.4 Based on available evidence, a prolonged course of antibiotic treatment may be unnecessary in microbiologically confirmed VAP, except in case of infection with non-fermenting gram-negative bacilli. 

Community-acquired pneumonia 

Severe community-acquired pneumonia (CAP) often leads to sepsis and multiorgan failure. Dual antibiotic therapy with a third-generation cephalosporin combined with a macrolide or fluoroquinolone is recommended, although the optimal duration of treatment is uncertain. In a Spanish multicentric study, Uranga et al. randomized patients with moderate to severe CAP on day 5 of treatment. In the intervention group, antibiotics were ceased at 5 days if the body temperature was =< 37.8 C or less for 48 h and patients were clinically stable; in the control group, the duration of antibiotic therapy was left to physician judgment. The clinical success rate was comparable at days 10 and 30, suggesting that a shorter duration of antibiotic therapy based on clinical stability is safe and effective in patients with CAP.5 A multicentric Italian study compared cessation of antibiotics 48 h after attaining clinical stability with a physician-determined duration of treatment. This study was stopped early on interim analysis due to an apparent increase in early treatment failure and 30-d mortality in the experimental group. The Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) recommend a minimum of 5 days antibiotic treatment for CAP. A longer duration of treatment may be required in case of extrapulmonary infection, infection due to Pseudomonas aeruginosa or unusual organisms (e.g., Burkholderia pseudomallei), and in the presence of necrotizing pneumonia, empyema, or lung abscess.6


Bacteremia occurs in 15% of critically ill patients commonly due to pneumonia, urosepsis, intra-abdominal infections, and catheter-related bloodstream infections and carries a high mortality. In a Canadian retrospective cohort study, the median duration of antibiotic treatment in bacteremia was 14 days (interquartile range, 9–17.5). Most pathogens, except coagulase-negative staphylococcus aureus, were treated for a relatively long duration. Urosepsis was often treated for a shorter duration; unknown primary foci were associated with a longer duration of treatment.7 In a meta-analysis of 13 studies, including 227 patients with bacteremia, no difference was observed in clinical and microbiological cure rates, and survival with 5–7 days compared to 7–21 days of antibiotic treatment. The BALANCE randomized controlled trial comparing 7 vs. 15 days treatment for bloodstream infections in the critically ill is currently recruiting patients,8 following successful completion of a pilot feasibility study.9

Intra-abdominal infections

The management of severe intra-abdominal infection involves initial resuscitation, source control, and antimicrobial therapy. Conventionally, antibiotics are administered for 7–14 days after source control; however, a shorter duration of treatment may be safe and effective. In a recent randomized controlled trial, patients with complicated intra-abdominal infection were randomized to receive antibiotics for 2 days after resolution of fever and ileus and normalization of the leukocyte count; this was compared to an experimental group who received antibiotics for 4 ± 1 calendar days after source control. There was no difference in the composite primary outcome of surgical site infection, recurrent intra-abdominal infection, or 30-d mortality between groups. The duration of antibiotic therapy was significantly less in the experimental group.10 Antibiotic therapy for 8 vs. 15 days was compared among critically ill patients with postoperative intra-abdominal infections in a randomized controlled trial. The 45-d mortality, ICU and hospital length of stay, emergence of multidrug-resistant bacteria, and re-exploration rates were similar in both study groups.11 These studies suggest that a shorter duration of antibiotic therapy is efficacious once source control has been achieved in critically ill patients with intra-abdominal infections. 

Urinary infections

The optimal duration of antimicrobial treatment in patients with urosepsis, including pyelonephritis is uncertain. Eliakim-Raz et al. performed a meta-analysis of 10 randomized controlled trials, including 2,515 patients with acute pyelonephritis. Antibiotic therapy for 7 days or less was compared with a longer duration of treatment. There was no difference in clinical or microbiological failure during the follow-up period, including among patients who had bacteremia. Microbiological failure occurred more commonly with a shorter duration of treatment in a small subgroup of patients with urogenital abnormalities.12 This study suggests that a 7-d course of antibiotics is appropriate in most patients with urosepsis due to acute pyelonephritis. 

When is a longer duration of treatment required? 

There are some infections that demand longer-term antibiotics, including infective endocarditis and bone and joint infections. Infection related to prosthetic material also require prolonged treatment. VAP with non-fermenting gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumanni, and Stenotrophomonas maltophilia also require a longer duration of antimicrobial treatment. Bacteremia with Staphylococcus aureus may require more than 2 weeks of antibiotic treatment. Recurrent bacteremia or deep-seated infection with shorter courses of antibiotics would also require a longer than a conventional period of treatment. In candidemia, although guidelines suggest 2 weeks of treatment after blood cultures become negative, there is no strong evidence to support this recommendation. Augmented renal clearance, observed in younger patients with less severe illness, may lead to enhanced renal elimination of antibiotics, including beta-lactams, and may require more prolonged treatment.  

Biomarkers to guide the duration of antibiotic treatment

C-reactive protein had been conventionally used to evaluate the efficacy and guide the duration of antibiotic treatment. Procalcitonin has been extensively evaluated to guide therapy in various infective illnesses. A meta-analysis13 and a randomized controlled trial14 have supported the use of procalcitonin as a tool to guide the duration of antimicrobial therapy. However, at the end of the day, the decision to cease antibiotic therapy needs to be based on the clinical picture and microbiological data, perhaps in combination with biomarker levels. Table 1 depicts the suggested duration of antibiotic therapy for common infections among critically ill patients.15   

Table 1. Suggested duration of antibiotic therapy for common infections in critically ill patients 

DurationType of infection
5–7 daysEarly VAP with susceptible pathogens, bacteremia with coagulase-negative Staphylococcus aureus, urinary tract infections. 
7–10 daysBloodstream infection with gram-negative bacteria, anaerobes, and Enterococcus spp; meningitis, community-acquired pneumonia 
14 days or more VAP with non-fermenting gram-negative bacilli, candida bloodstream infections, Staphylococcus aureus bloodstream infections, nosocomial meningitis

The bottom line

  • Inappropriately prolonged use of antibiotics can adversely impact clinical outcomes, including new-onset infections with multidrug-resistant organisms.
  • In clinical situations with a high index of suspicion for an infective illness, it is reasonable to commence empirical antibiotics. However, the appropriateness of continued antibiotic therapy must be reconsidered early if a non-infectious etiology seems more likely.  
  • There is robust evidence that a short duration of antibiotic treatment is appropriate in VAP, except in case of infection with non-fermenting gram-negative bacilli. 
  • The clinical situation and microbiological data should guide the duration of antibiotic therapy; biomarkers may support the decision-making process.
  • Besides the adverse impact on clinical outcomes, unnecessarily prolonged antibiotic treatment adds to the overall cost of care. 


1.         Singh N, Rogers P, Atwood CW, et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription: Infect Dis Clin Pract. 2001;10(4):230. doi:10.1097/00019048-200105000-00015

2.         Klompas M, Li L, Menchaca JT, Gruber S, for the CDC Prevention Epicenters Program. Ultra short course antibiotics for patients with suspected ventilator-associated pneumonia but minimal and stable ventilator settings. Clin Infect Dis. December 2016:ciw870. doi:10.1093/cid/ciw870

3.         Chastre J, Wolff M, Fagon J-Y, et al. Comparison of 8 vs 15 Days of Antibiotic Therapy for Ventilator-Associated Pneumonia in Adults: A Randomized Trial. JAMA. 2003;290(19):2588. doi:10.1001/jama.290.19.2588

4.         Capellier G, Mockly H, Charpentier C, et al. Early-Onset Ventilator-Associated Pneumonia in Adults Randomized Clinical Trial: Comparison of 8 versus 15 Days of Antibiotic Treatment. Spellberg B, ed. PLoS ONE. 2012;7(8):e41290. doi:10.1371/journal.pone.0041290

5.         Uranga A, España PP, Bilbao A, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2016;176(9):1257. doi:10.1001/jamainternmed.2016.3633

6.         Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis Off Publ Infect Dis Soc Am. 2007;44 Suppl 2:S27-72. doi:10.1086/511159

7.         Daneman N, Rishu AH, Xiong W, et al. Duration of Antimicrobial Treatment for Bacteremia in Canadian Critically Ill Patients: Crit Care Med. 2016;44(2):256-264. doi:10.1097/CCM.0000000000001393

8.         Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness – Full Text View – Accessed October 17, 2019.

9.         Daneman N, Rishu AH, et al. on behalf of the Canadian Critical Care Trials Group. Seven versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: a pilot randomized clinical trial. Trials. 2018;19(1):111. doi:10.1186/s13063-018-2474-1

10.       Sawyer RG, Claridge JA, Nathens AB, et al. Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection. N Engl J Med. 2015;372(21):1996-2005. doi:10.1056/NEJMoa1411162

11.       Montravers P, Tubach F, et al., for the DURAPOP Trial Group. Short-course antibiotic therapy for critically ill patients treated for postoperative intra-abdominal infection: the DURAPOP randomised clinical trial. Intensive Care Med. 2018;44(3):300-310. doi:10.1007/s00134-018-5088-x

12.       Eliakim-Raz N, Yahav D, Paul M, Leibovici L. Duration of antibiotic treatment for acute pyelonephritis and septic urinary tract infection— 7 days or less versus longer treatment: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2013;68(10):2183-2191. doi:10.1093/jac/dkt177

13.       Prkno A, Wacker C, Brunkhorst FM, Schlattmann P. Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock – a systematic review and meta-analysis. Crit Care. 2013;17(6):R291. doi:10.1186/cc13157

14.       de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-827. doi:10.1016/S1473-3099(16)00053-0

15.       Garnacho-Montero J, Arenzana-Seisdedos A, De Waele J, Kollef MH. To which extent can we decrease antibiotic duration in critically ill patients? Expert Rev Clin Pharmacol. 2017;10(11):1215-1223. doi:10.1080/17512433.2017.1369879

Early invasive ventilation as a lung-protective strategy in acute hypoxemic respiratory failure

High spontaneous respiratory drive in acute hypoxemic respiratory failure 

There is increasing concern that continued vigorous spontaneous respiratory efforts may be harmful in the presence of severe lung injury. The adverse impact of using high tidal volumes during invasive mechanical ventilation is well known. The swings in transpulmonary pressure (airway pressure – pleural pressure), representing lung stress, are comparable with spontaneous, controlled, or partially supported breathing when similar tidal volumes are delivered.1 Thus, high tidal volumes may be equally injurious with spontaneous or assisted breaths compared to controlled breaths. Patients with de novo acute hypoxemic respiratory failure (AHRF) may have a strong respiratory drive, leading to the generation of large spontaneous tidal volumes. 

How does a high spontaneous respiratory drive cause harm?

Besides the adverse effects related to high transpulmonary pressures, the alveolar pressure may drop significantly lower than the end-expiratory pressure during spontaneous breathing. The intravascular pressure within the pulmonary blood vessels decreases proportionally; however, the pleural pressure decreases to a greater extent, thus, increasing the transmural pulmonary vascular pressure. The increase in the transmural pulmonary vascular pressure combined with increased capillary permeability results in leakage of fluid from within the capillaries and may lead to pulmonary edema. These changes may be similar to the pathophysiology of negative-pressure pulmonary edema, characterized by high airway resistance, leading to the a precipitous drop in the airway and alveolar pressures.2 In patients with injured lungs, there may be regional variations in transpulmonary pressures. This may lead to movement of air from the non-dependent to dependent areas of the lung during the early inspiratory phase of spontaneous respiratory efforts (the pendulluft phenomenon). Overstretch injury to the dependent lung may occur due to this phenomenon.3 The adverse consequences arising from a continued high respiratory drive have been termed patient self-inflicted lung injury (P-SILI).4

Use of NIV in AHRF

The use of non-invasive ventilation (NIV) as the initial modality of ventilatory support has increased several-fold over the years. There is well-established evidence for the benefit of NIV use in acute respiratory failure due to exacerbation of chronic obstructive pulmonary disease and in cardiogenic pulmonary edema. However, improved outcomes with NIV use in patients with AHRF with no pre-existing cardiopulmonary disease (de novo acute respiratory failure) is less certain. 

From a physiological perspective, there appears to be a strong rationale for the application of NIV in AHRF. Oxygenation may improve with alveolar recruitment, and the work of breathing may improve, thereby ameliorating the subjective feeling of dyspnea. These positive effects may avoid the need for intubation and invasive ventilation, and thus, improve clinical outcomes. However, there is increasing concern regarding possible harm from NIV use in AHRF, especially in pneumonia and acute respiratory distress syndrome (ARDS). Bellani et al. performed a sub-analysis of the LUNG-SAFE study, a large observational study that evaluated the management of patients with ARDS. NIV failure was strongly correlated with the severity of ARDS. Furthermore, on propensity-matched analysis, among patients with a PaO2/FiO2 ratio <150, ICU mortality was higher with NIV compared to invasive mechanical ventilation. The magnitude of the decrease in the PaO2/FiO2 ratio between days 1 and 2 was an independent predictor of mortality on multivariate analysis.5 In the FLORALI study that compared high-flow nasal oxygen with NIV or standard oxygen therapy through a non-rebreather face mask in patients with AHRF, 58% of patients failed NIV and required intubation by 28 days.6

Possible reasons for NIV failure in AHRF

Evidence from observational studies suggests that failure of NIV, followed by invasive ventilation, is associated with worse clinical outcomes, including higher overall mortality.7,8 

The apparent adverse impact of NIV may be a confounding effect related to higher underlying severity of illness. The transient salutary effects of NIV on gas exchange and the subjective feeling of dyspnea could delay intubation when the underlying disease process may actually be worsening.  It is also possible that interruption of NIV, even for short periods of time, may offset alveolar recruitment and reduction in the work of breathing, leading to worsening of the clinical situation. 

Does the use of analgesic and sedative agents as adjunctive treatment lead to NIV failure? Muriel et al. evaluated 842 patients who underwent NIV in a multicentric study. Analgesics or sedative use alone was not associated with NIV failure; however, the combined use of both analgesics and sedatives was significantly associated with failure of NIV. On multivariate analysis, the 28-d mortality was also higher with combined analgesic and sedative use.9

In patients with an increased respiratory drive, it may be impossible to limit tidal volumes within the “lung-protective” range during NIV use. Carteaux et al., in a prospective observational study, evaluated 62 patients who underwent NIV for AHRF. An algorithmic approach was utilized to limit the tidal volume to 6–8 ml/kg of ideal body weight. However, the tidal volume delivered was higher across all NIV sessions (median tidal volume, 9.8 ml/kg; interquartile range, 8.1–11.1 ml/kg). The tidal volume was significantly higher in patients who failed NIV and required intubation, compared to those who succeeded [10.6 ml/kg (9.6–12.0) vs. 8.5 ml/kg (7.6–10.2)]. A threshold tidal volume of 9.5 ml/kg was the most accurate predictor of NIV failure with 82% sensitivity, and 87% specificity.10

Early invasive ventilation as a part of a lung-protective strategy

Identification of patients who may benefit from early invasive ventilation as part of a lung-protective strategy is crucial, to prevent possible harm from P-SILI due to enhanced respiratory drive. Abolition of spontaneous respiratory efforts with the use of neuromuscular blockers has been shown to reduce the pro-inflammatory response in patients with ARDS.11 The use of continuous neuromuscular blockade with cis-atracurium during the first 48 h of mechanical ventilation was evaluated in the ACURASYS study. The adjusted 90-d mortality, the primary outcome, was significantly lower with continuous neuromuscular blockade compared to the control group.12 These studies reinforce the possibililty of improved outcomes with a fully controlled ventilator strategy in severe ARDS.  

The strategy of mechanical ventilation has been refined in the past two decades with emphasis on lung-protective strategies, including the use of low tidal volumes, and increasing focus on optimizing transpulmonary and driving pressures (driving pressure = Pplat – PEEP). In this context, the important question arises whether persistence with NIV or other assisted modes of ventilation could lead to harm, compared with a strategy of early intubation, and controlled, lung-protective mechanical ventilation in patients with AHRF. Importantly, the crucial question regarding the appropriate timing of invasive ventilation needs to be investigated, considering the evidence of poor outcomes with NIV failure in AHRF. 

The bottom line 

  • Continued vigorous spontaneous respiratory efforts may lead to harm in the injured lung.
  • Although there is a sound physiological rationale for NIV use in AHRF, adverse clinical outcomes are becoming increasingly evident, especially in patients with ARDS.
  • NIV failure and the generation of high tidal volumes during NIV have been associated with poor outcomes.
  • A PaO2/FiOratio of <150 and the combined use of sedatives and analgesics are risk factors for NIV failure.
  • Early invasive ventilation using a lung-protective strategy combined with the use of neuromuscular blockade in the initial phase of ventilation may lead to improved outcomes. 


1.         Bellani G, Grasselli G, Teggia-Droghi M, et al. Do spontaneous and mechanical breathing have similar effects on average transpulmonary and alveolar pressure? A clinical crossover study. Crit Care. 2016;20. doi:10.1186/s13054-016-1290-9

2.         Bhattacharya M, Kallet RH, Ware LB, Matthay MA. Negative-Pressure Pulmonary Edema. Chest. 2016;150(4):927-933. doi:10.1016/j.chest.2016.03.043

3.         Yoshida T, Torsani V, Gomes S, et al. Spontaneous effort causes occult pendelluft during mechanical ventilation. Am J Respir Crit Care Med. 2013;188(12):1420-1427. doi:10.1164/rccm.201303-0539OC

4.         Brochard L, Slutsky A, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med. 2017;195(4):438-442. doi:10.1164/rccm.201605-1081CP

5.         Bellani G, Laffey JG, Pham T, et al. Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study. Am J Respir Crit Care Med. 2017;195(1):67-77. doi:10.1164/rccm.201606-1306OC

6.         Frat J-P, Thille AW, Mercat A, et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N Engl J Med. 2015;372(23):2185-2196. doi:10.1056/NEJMoa1503326

7.         Demoule A, Girou E, Richard J-C, Taille S, Brochard L. Benefits and risks of success or failure of noninvasive ventilation. Intensive Care Med. 2006;32(11):1756-1765. doi:10.1007/s00134-006-0324-1

8.         Schnell D, Timsit J-F, Darmon M, et al. Noninvasive mechanical ventilation in acute respiratory failure: trends in use and outcomes. Intensive Care Med. 2014;40(4):582-591. doi:10.1007/s00134-014-3222-y

9.         Muriel A, Peñuelas O, Frutos-Vivar F, et al. Impact of sedation and analgesia during noninvasive positive pressure ventilation on outcome: a marginal structural model causal analysis. Intensive Care Med. 2015;41(9):1586-1600. doi:10.1007/s00134-015-3854-6

10.       Carteaux G, Millán-Guilarte T, De Prost N, et al. Failure of Noninvasive Ventilation for De Novo Acute Hypoxemic Respiratory Failure: Role of Tidal Volume*. Crit Care Med. 2016;44(2):282-290. doi:10.1097/CCM.0000000000001379

11.       Forel J-M, Roch A, Marin V, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749-2757. doi:10.1097/01.CCM.0000239435.87433.0D

12.       Papazian L, Forel J-M, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. doi:10.1056/NEJMoa1005372

Augmented renal clearance: when supranormal renal function may cause harm

What is augmented renal clearance? 

Augmented renal clearance (ARC) is the phenomenon of enhanced renal function in critically ill patients. ARC is characterized by a higher than predicted increase in the renal elimination of solutes. It occurs due to an increase in glomerular filtration and altered renal tubular function, usually manifest as an increase in the creatinine clearance. ARC leads to increased clearance of drugs excreted through the kidneys resulting in suboptimal concentrations of important medications, including antibiotics, and may lead to treatment failure. This phenomenon was first described more than 40 years ago in burns patients who were observed to have higher than normal creatinine clearance, leading to a reduction in the half-life of intravenously administered tobramycin.1


Currently, ARC is defined as an increase in creatinine clearance above 130 ml/min/1.73 cm2. It is considered clinically significant at a level of more than 150 ml/min/1.73 m2 in female and more than 160 ml/min/1.73m2 in male subjects.2 ARC may occur in 20–65% of critically ill patients.3

Risk factors, pathophysiological mechanisms

The systemic inflammatory reaction that occurs in critically ill patients, secondary to major trauma, burns, sepsis, and following major surgery could play an important role in triggering ARC. The release of inflammatory mediators lead to systemic vasodilatation, with a reduction in the systemic vascular resistance, leading to an increase in the cardiac output; an increase in the renal blood flow and the glomerular filtration rate (GFR) ensues. Fluid resuscitation and the use of vasopressor medication may also increase the GFR, leading to ARC.4 Another factor that may play an important role in ARC is the functional reserve of the kidney, which enables an increase in the GFR in response to critical illness. The functional reserve is higher in younger subjects, who have a greater propensity to the development of ARC.5 ARC is frequently observed in neurocritical care, including patients with traumatic brain injury and subarachnoid haemorrhage; contributing factors may be the use of osmotherapy for raised intracranial pressure and vasopressors to maintain the cerebral perfusion pressure. Younger age group (34–50 y), polytrauma, and lower severity of illness are common risk factors for ARC.3      

How do you diagnose ARC? 

The commonly used equations for the calculation of GFR, including the Cockcroft–Gault and the Modification of Diet in Renal Disease equations are inaccurate in estimating GFR, and may under or overestimate measured values of creatinine clearance (CrCl).6,7 Hence, measurement of urinary CrCl is more appropriate in the diagnosis of ARC. Although an 8–24 h urine collection is conventionally followed, a 2 h urine collection may be adequate in most circumstances. 

CrCl = urinary creatinine (mg/dl)x collected urinary volume (ml) x 1.73/serum creatinine x collection time in min xbody surface area

Body surface area = square root of [height (cm) x weight (kg)/3600]

Scoring systems to identify risk factors ARC 

Various scoring systems have been proposed for the early recognition of ARC. The ARC scoring system is based on age < 50 years, presence of trauma, and a SOFA score ≤ 4 as predictive criteria.5 It has been shown to have 100% sensitivity and 71% specificity for identifying patients with ARC, based on pharmacokinetic data after piperacillin/tazobactam administration in critically ill patients.8 The ARCTIC scoring system, that does not include the SOFA score, has been developed to identify ARC in trauma patients, and shown to have a sensitivity of 84% and specificity of 68% in identifying ARC.9 (Table. 1)

Table 1. Scoring systems for the early identification of ARC 

 ARC scoring system ARCTIC scoring system 
Criteria Age 50 or less: 6 pointsTrauma: 3 pointsSOFA < 4: 1 pointS. creat 0.7 mg/dl: 3 pointsMale gender: 2 pointsAge <56: 4 pointsAge 56–75: 3 points
Risk for ARC 0–6 points: low risk 7–10 points: high risk <6 points: low risk>6 points: high risk

What is the impact of ARC on drug clearance in critically ill patients? 

Enhanced renal elimination leads to a reduction in the half-life and reduced effectiveness of several antibiotics in common use among critically ill patients. ARC may lead to increased elimination of beta-lactam antibiotics, including penicillins and cephalosporins. Beta-lactams exhibit time-dependent killing, with their efficacy contingent on the duration for which the serum level of the drug is above the minimum inhibitory concentration. There may be a strong rationale for the administration of beta-lactams as a continuous infusion is patients with ARC.10 Continuous administration may be particularly relevant as therapeutic drug level monitoring of beta-lactams is rarely carried out in clinical practice.  

Therapeutic drug levels may be poorly achieved with carbapenems in the presence of ARC. Extended infusions of 2 g over 3 h after an initial loading dose of 2 g over 30 min may facilitate the attainment of appropriate serum levels of meropenem. Vancomycin is a hydrophilic drug, and 80­–90% is excreted unchanged by the kidneys. Target trough levels of vancomycin are difficult to achieve with conventional dosing in the presence of ARC.11 An initial loading dose of 25–30 mg/kg followed by 45 mg/kg/day in three divided doses or as a continuous infusion along with therapeutic drug level monitoring is recommended. Aminoglycosides and fluoroquinolones are also primarily eliminated by the kidneys and need adjustment of dosing in the presence of ARC. Apart from antibiotics, levetiracetam clearance is higher among the neurocritical care patient population. Besides, patients with ARC may have a shorter duration of action of enoxaparin. Table 2 summarizes recommended dosing for drugs significantly impacted by ARC.12    

Table 2. Suggested intravenous dosing for drugs that are significantly impacted by ARC12

Drug Suggested IV dose 
Meropenem Bolus: 2 g over 30 min, followed by 2 g/8 h, administered over 3 h
VancomycinLoading dose: 25–30 mg/kg; maintenance: 45 mg/kg/d, as continuous infusion or divided into 3 doses. Therapeutic drug level monitoring recommended. Maintain level 10–20 mg/l 
Piperacillin/tazobactam4.5 g/6h, as extended infusion over 4 h
Levofloxacin 750–1000 mg 24 hourly
Levetiracetam 1000 mg 8 hourly

The bottom line 

  • ARC is characterized by an enhanced rate of drug elimination by the kidneys and may result in suboptimal drug levels and treatment failure, particularly during antibiotic administration.
  • ARC is commonly seen in young patients with relatively low severity of illness. It is associated with sepsis, trauma, burns, and after major surgery. 
  • Estimation of the glomerular filtration rate based on standard equations may be imprecise in the critical care setting and fail to identify patients with ARC. Measurement of urinary creatinine clearance is more appropriate. 
  • Adjustment of dose to compensate for enhanced renal elimination is required with many antibiotics commonly used in the critically ill. Therapeutic drug monitoring should be carried out if feasible. 


1.         Loirat P, Rohan J, Baillet A, Beaufils F, David R, Chapman A. Increased glomerular filtration rate in patients with major burns and its effect on the pharmacokinetics of tobramycin. N Engl J Med. 1978;299(17):915-919. doi:10.1056/NEJM197810262991703

2.        Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010;49(1):1-16. doi:10.2165/11318140-000000000-00000

3.        Bilbao-Meseguer I, Rodríguez-Gascón A, Barrasa H, Isla A, Solinís MÁ. Augmented Renal Clearance in Critically Ill Patients: A Systematic Review. Clin Pharmacokinet. 2018;57(9):1107-1121. doi:10.1007/s40262-018-0636-7

4.        Udy AA, Jarrett P, Lassig-Smith M, et al. Augmented Renal Clearance in Traumatic Brain Injury: A Single-Center Observational Study of Atrial Natriuretic Peptide, Cardiac Output, and Creatinine Clearance. J Neurotrauma. 2017;34(1):137-144. doi:10.1089/neu.2015.4328

5.        Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Crit Care Lond Engl. 2013;17(1):R35. doi:10.1186/cc12544

6.        Baptista JP, Udy AA, Sousa E, et al. A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Crit Care Lond Engl. 2011;15(3):R139. doi:10.1186/cc10262

7.        Grootaert V, Willems L, Debaveye Y, Meyfroidt G, Spriet I. Augmented renal clearance in the critically ill: how to assess kidney function. Ann Pharmacother. 2012;46(7-8):952-959. doi:10.1345/aph.1Q708

8.        Akers KS, Niece KL, Chung KK, Cannon JW, Cota JM, Murray CK. Modified Augmented Renal Clearance score predicts rapid piperacillin and tazobactam clearance in critically ill surgery and trauma patients. J Trauma Acute Care Surg. 2014;77(3 Suppl 2):S163-170. doi:10.1097/TA.0000000000000191

9.        Barletta JF, Mangram AJ, Byrne M, et al. Identifying augmented renal clearance in trauma patients: Validation of the Augmented Renal Clearance in Trauma Intensive Care scoring system. J Trauma Acute Care Surg. 2017;82(4):665-671. doi:10.1097/TA.0000000000001387

10.      Roberts JA, Lipman J. Optimal doripenem dosing simulations in critically ill nosocomial pneumonia patients with obesity, augmented renal clearance, and decreased bacterial susceptibility. Crit Care Med. 2013;41(2):489-495. doi:10.1097/CCM.0b013e31826ab4c4

11.      Campassi ML, Gonzalez MC, Masevicius FD, et al. [Augmented renal clearance in critically ill patients: incidence, associated factors and effects on vancomycin treatment]. Rev Bras Ter Intensiva. 2014;26(1):13-20.

12.      Mahmoud S, Shen C. Augmented Renal Clearance in Critical Illness: An Important Consideration in Drug Dosing. Pharmaceutics. 2017;9(4):36. doi:10.3390/pharmaceutics9030036

What may be the ideal nutritional strategy in acute pancreatitis?


Acute pancreatitis runs a relatively mild course in most patients and responds rapidly to supportive therapy, including adequate pain relief, intravenous fluids, and oral intake when feasible. However, the severe form of the disease is characterized by organ failures and leads to a protracted and often complicated clinical course. Nutritional support is crucial and can be challenging to the bedside intensive care physician. The optimal nutritional strategy in acute pancreatitis has been intensely debated, with a distinct change in paradigms over the years. 

How early to feed?

In mild acute pancreatitis, intravenous hydration alone may be adequate, because rapid recovery is common, and oral intake is possible within a week. However, in moderate to severe acute pancreatitis, nutritional support is usually required as early oral intake is usually not possible. 

Mild disease

Conventionally, it was widely believed that enteral feeding may lead to worsening of pain and exacerbate acute pancreatitis. Gastric feeding may stimulate the release of pancreatic enzymes, worsen autodigestion, and aggravate the disease process. Hence, conventional management has been to place patients on strict bowel rest and use parenteral nutrition to bypass the stimulatory effects of oral feeding. Current evidence suggests a low-fat diet is safe and well-tolerated in most patients with acute pancreatitis. Hence, oral nutrition is advisable as tolerated when abdominal pain eases off, and there is a subjective feeling of hunger, regardless of complete resolution of pain and normalization of pancreatic enzyme levels.

Moderate to severe disease

Severe pancreatitis leads to reduced contractility of the small bowel leading to bacterial overgrowth. Besides, reduced splanchnic blood flow increases intestinal permeability. Early commencement of enteral nutrition may have a trophic effect on gut wall integrity and may help reduce the inflammatory response. In the PYTHON trial, patients predicted to have severe acute pancreatitis were randomized to receive either early enteral nutrition through a nasoenteral feeding tube within 24 hours after presentation to the emergency department or placed on a nil-per-mouth regime for 72 hours followed by an oral diet. If oral intake was insufficient after this period, a feeding tube was inserted, and enteral nutrition commenced. The primary endpoint was a composite of major infection (infected pancreatic necrosis, bacteremia, or pneumonia) or death during 6 months of follow-up. There was no difference in these outcomes between the two groups (30% in the early vs. 27% in the later feeding group).1

A recent systematic review of 11 randomized controlled trials (RCT) compared early vs. delayed feeding in acute pancreatitis.2 This review suggested a reduced hospital length of stay with early enteral nutrition. None of the included studies showed a significant increase in the incidence of adverse events or worsening of symptoms with early feeding, regardless of disease severity.

Enteral vs. parenteral nutrition

Previously, parenteral nutrition was administered routinely in acute pancreatitis to prevent pancreatic stimulation. The traditional belief was that nutrition delivered proximal to the ligament of Treitz would stimulate the pancreas and worsen the severity of acute pancreatitis. Hence, parenteral nutrition seemed ideal for adequate nutritional support in acute pancreatitis.

Enteral feeding may have immunomodulating effects, including preservation of the integrity of the gut mucosa; it may also stimulate intestinal motility, thereby reducing bacterial overgrowth. Besides, enteral feeding may also enhance splanchnic blood flow. All these may reduce bacterial translocation from the gut, which is one of the key factors that lead to infection in acute pancreatitis. Although there is no strong corroboratory evidence, enteral nutrition may prevent infection of the necrosis and reduce mortality.

Two major RCTs have been carried comparing enteral with total parenteral nutrition. Wu et al., in a randomized controlled trial of 208 patients, showed a lower incidence of organ failure, infected necrosis, surgical intervention, and mortality with enteral nutrition.3 A smaller RCT of 70 patients also showed a lower incidence of infected necrosis, reduced organ failures, and lower mortality with enteral compared to parenteral nutrition.4 Three recent meta-analyses have also concluded that enteral nutrition significantly reduces infections, organ failure, and mortality in patients with acute pancreatitis compared with parenteral nutrition.5–7 Meta-analyses are limited by heterogeneous patient groups; inclusion of patients with mild disease may have resulted in reduced mortality. Despite these limitations, early enteral nutrition is recommended in acute pancreatitis; total parenteral nutrition is indicated only if enteral nutrition is not tolerated.  

Nasojejunal vs. nasogastric feeding

Placement of a feeding tube beyond the ligament of Treitz is considered to reduce the risk of reflux of feeds back into the stomach and prevent stimulation of pancreatic enzyme release. However, it has been shown that pancreatic stimulation may be preventable only when enteral nutrition is given in the mid-distal jejunum.8 Three trials compared nasojejunal with nasogastric nutrition in patients with severe acute pancreatitis.9–11 These studies suggested that nasogastric feeding may be easier, well-tolerated, and equally efficacious as nasojejunal feeding. Infectious complications and duration of stay in hospital were also comparable. There was no difference in pain on refeeding, intestinal permeability, and endotoxemia. These studies were limited by small sample sizes, and included patients at different stages of the disease, with varying severity. A meta-analysis of these three randomized trials showed no differences in mortality, the incidence of tracheal aspiration, and attainment of calorie targets between the two groups.12

Although the quality of the evidence is limited, when tolerated, nasogastric nutrition appears to be safe. When nasogastric nutrition is not tolerated, or when the caloric requirement cannot be attained, nasojejunal feeding beyond the ligament of Treitz is recommended.

Nutritional supplements


Probiotic bacteria may prevent infectious complications by inhibiting the overgrowth of pathogenic bacteria in the small bowel, restoration of gastrointestinal barrier function, and immune modulation. Hence, probiotic administration may potentially prevent pancreatic and extra-pancreatic bacterial infections. This was particularly of interest following the failure of prophylactic antibiotic therapy to prevent infections. 

The PROPATRIA trial compared probiotic prophylaxis using six different strains of freeze-dried, viable bacteria with placebo in 298 patients who were predicted to have severe acute pancreatitis.13 No difference was observed in the incidence of infectious complications. Besides, there was a significant increase in mortality with the use of probiotics. Nine patients suffered non-occlusive mesenteric ischemia in the probiotic group compared to none in the placebo group. A subsequent retrospective study used the same type of probiotics in patients with acute pancreatitis without organ failure.14 This study revealed no evidence of benefit or harm, suggesting that the harmful effects of probiotics may occur in patients with evidence of organ failure. Based on these findings, the current recommendation is against the use of probiotics in acute pancreatitis. 

Other supplements

The use of glutamine and omega-3 fatty acids are not recommended in acute pancreatitis. Vitamin C, N-acetylcysteine, and selenium administration have also shown no benefit. Although antioxidant vitamins, including Vitamin C, could theoretically attenuate the inflammatory reaction, no clinical benefit has been demonstrated in acute pancreatitis. 

The bottom line 

  • In mild acute pancreatitis, intravenous hydration alone may suffice if oral intake is not feasible due to pain or intolerance. A low-fat diet is usually possible within a week once symptoms begin to subside.
  • In severe disease, nutritional support is essential; early enteral nutrition is recommended, although the optimal timing of commencement is uncertain. 
  • Nasogastric feeding may be as efficacious as feeding through the nasojejunal route; the latter is preferred if there is intolerance to gastric feeds.
  • Enteral nutrition is always preferred compared to total parenteral nutrition; prolonged paralytic ileus may be an indication for parenteral nutritional support. 
  • Nutritional supplements, including probiotics, glutamine, omega-3 fatty acids, and Vitamin C have not been shown to be useful.    


1.        Bakker OJ, van Brunschot S, van Santvoort HC, et al. Early versus On-Demand Nasoenteric Tube Feeding in Acute Pancreatitis. N Engl J Med. 2014;371(21):1983-1993. doi:10.1056/NEJMoa1404393

2.         Vaughn VM, Shuster D, Rogers MAM, et al. Early Versus Delayed Feeding in Patients With Acute Pancreatitis: A Systematic Review. Ann Intern Med. 2017;166(12):883. doi:10.7326/M16-2533

3.         Wu X-M, Ji K-Q, Wang H-Y, Li G-F, Zang B, Chen W-M. Total Enteral Nutrition in Prevention of Pancreatic Necrotic Infection in Severe Acute Pancreatitis: Pancreas. 2010;39(2):248-251. doi:10.1097/MPA.0b013e3181bd6370

4.         Petrov MS, Kukosh MV, Emelyanov NV. A Randomized Controlled Trial of Enteral versus Parenteral Feeding in Patients with Predicted Severe Acute Pancreatitis Shows a Significant Reduction in Mortality and in Infected Pancreatic Complications with Total Enteral Nutrition. Dig Surg. 2006;23(5-6):336-345. doi:10.1159/000097949

5.         Yi F, Ge L, Zhao J, et al. Meta-analysis: Total Parenteral Nutrition Versus Total Enteral Nutrition in Predicted Severe Acute Pancreatitis. Intern Med. 2012;51(6):523-530. doi:10.2169/internalmedicine.51.6685

6.         Al-Omran M, AlBalawi ZH, Tashkandi MF, Al-Ansary LA. Enteral versus parenteral nutrition for acute pancreatitis. 2010:44.

7.         Petrov MS, van Santvoort HC, Besselink MGH, van der Heijden GJMG, Windsor JA, Gooszen HG. Enteral nutrition and the risk of mortality and infectious complications in patients with severe acute pancreatitis: a meta-analysis of randomized trials. Arch Surg Chic Ill 1960. 2008;143(11):1111-1117. doi:10.1001/archsurg.143.11.1111

8.         Vu MK, van der Veek PP, Frölich M, et al. Does jejunal feeding activate exocrine pancreatic secretion? Eur J Clin Invest. 1999;29(12):1053-1059. doi:10.1046/j.1365-2362.1999.00576.x

9.         Eatock FC, Chong P, Menezes N, et al. A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gastroenterol. 2005;100(2):432-439. doi:10.1111/j.1572-0241.2005.40587.x

10.       Kumar A, Singh N, Prakash S, Saraya A, Joshi YK. Early enteral nutrition in severe acute pancreatitis: a prospective randomized controlled trial comparing nasojejunal and nasogastric routes. J Clin Gastroenterol. 2006;40(5):431-434. doi:10.1097/00004836-200605000-00013

11.       Singh N, Sharma B, Sharma M, et al. Evaluation of Early Enteral Feeding Through Nasogastric and Nasojejunal Tube in Severe Acute Pancreatitis: A Noninferiority Randomized Controlled Trial. Pancreas. 2012;41(1):153-159. doi:10.1097/MPA.0b013e318221c4a8

12.       Chang Y, Fu H, Xiao Y, Liu J. Nasogastric or nasojejunal feeding in predicted severe acute pancreatitis: a meta-analysis. Crit Care Lond Engl. 2013;17(3):R118. doi:10.1186/cc12790

13.       Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2008;371(9613):651-659. doi:10.1016/S0140-6736(08)60207-X

14.       van Baal MC, Kohout P, Besselink MG, et al. Probiotic treatment with Probioflora in patients with predicted severe acute pancreatitis without organ failure. Pancreatology. 2012;12(5):458-462. doi:10.1016/j.pan.2012.08.004

Contentious topics in the management of severe acute pancreatitis


Acute pancreatitis results from an intense inflammatory reaction resulting most commonly from excessive alcoholism or the presence of gall stones. It runs a relatively mild course in most patients and responds rapidly to supportive therapy including adequate pain relief, intravenous fluids, and oral intake when feasible. However, the severe form of the disease occurs in 20-30% of patients, characterized by organ failures, and leads to a protracted and often complicated clinical course.1 The management of the critically ill patient with severe acute pancreatitis (SAP) has evolved over the years; however, several contentious issues remain, especially in the high-risk group of patients. 

Classification of severity

Although the revised Atlanta Classification is widely accepted, no single classification system has been demonstrated to accurately predict the development of organ failures, infected necrosis, or other important clinical outcomes in SAP. According to this classification, mild acute pancreatitis is defined as uncomplicated pancreatitis without organ failures. The presence of organ failure for a period of less than 48 h or local complications represents moderately severe acute pancreatitis. SAP is defined as the presence of organ failure for more than 48 h. The APACHE II score was shown to have a high sensitivity for the prediction of necrosis, organ failures, and the requirement for ICU admission.2 In the real world, severity scoring systems may be of limited value in predicting clinical outcomes. Furthermore, the decision for focused care in the ICU is largely based on the current clinical situation, and not on predicted outcomes. 

Therapeutic modalities 

Intravenous fluids

Extensive third space fluid sequestration can lead to hypovolemia in SAP. Hypovolemia can result in global circulatory impairment and provoke organ failures; besides, it can also compromise microcirculatory flow within the pancreas and trigger pancreatic and peripancreatic necrosis. However, high-volume fluid resuscitation may be detrimental and lead to fluid overload, pulmonary edema, and abdominal compartment syndrome (ACS). Aggressive resuscitation with 10 to 15 ml/kg/h within the first 72 h of disease onset was associated with increased requirement for ventilator support, development of ACS, sepsis, and higher mortality as compared to a modest resuscitative strategy of 5 to 10 ml/kg/h. The choice of crystalloid fluid between normal saline and Ringer’s lactate is widely debated in the critically ill, with no definitive conclusions. A recent randomized controlled trial (RCT) of 40 patients suggested a lower inflammatory response based on the SIRS criteria and C-reactive protein levels at 24, 48, and 72 h using Ringer’s lactate compared to normal saline as the resuscitation fluid in patients with SAP.3

Nutritional support 

Patients with SAP require nutritional support for an extended period, usually, for 6–8 weeks. Total parenteral nutrition was recommended previously, based on the presumption that enteral feeding may stimulate pancreatic and intestinal secretions, worsening the inflammatory process. However, withholding enteral feeds leads to gut mucosal atrophy, translocation of bacteria from the intestines, and endotoxin release. This may lead to an increased propensity for infection within the necrotic pancreas. In a meta-analysis of 381 patients from eight RCTs, enteral nutrition was associated with lower mortality, a lower incidence of infectious complications, reduced organ failures, and less requirement for surgical intervention compared to parenteral nutrition. Most patients may be fed by the nasogastric route. Enteral nutrition is well usually well-tolerated by the nasogastric route with no recurrence of pain or feeding intolerance in patients with SAP. A recent meta-analysis revealed no difference in the delivery of 75% of nutritional targets with nasogastric compared to nasojejunal feeding; the requirement for total parenteral nutrition was also no different.4

Prophylactic antibiotics

Antibiotic therapy is not indicated in acute pancreatitis in the absence of infection. Prophylactic antibiotic therapy does not prevent infection in sterile necrosis; besides, it does not influence the incidence of organ failures, mortality, and duration of stay in hospital.5 Infection of the necrotic pancreatic or peripancreatic tissues generally occurs after 10 days of disease onset. Appropriate antibiotic therapy is indicated in the presence of pancreatic or non-pancreatic infections. Infection of pancreatic or peripancreatic collections is strongly suggested by the presence of gas on a contrast-enhanced CT scan, or by positive culture from fine-needle aspiration (FNA). FNA and culture, though recommended, has a low sensitivity for the diagnosis of infection, and generally not utilized by most physicians.6 Carbapenems, fluoroquinolones, and metronidazole achieve high concentrations in infected pancreatic tissue and are generally recommended. Fungal infections are common in patients with infected necrosis and pseudocyst formation. Prolonged therapy with multiple broad-spectrum antibiotics predisposes to fungal infections in SAP. 

The role of endoscopic retrograde cholangiopancreatography in SAP

Gall stones may obstruct the sphincter of Oddi impeding biliary drainage; this results in back pressure within the pancreatic duct and stimulates enzyme release, with the potential to worsen the inflammatory response. Endoscopic retrograde cholangiopancreatography (ERCP) directed sphincterotomy and stone extraction is appropriate within 24–48 h of disease onset in patients with cholangitis or in the presence of unrelieved biliary obstruction. Although a mortality benefit has not been demonstrated in patients who undergo early ERCP, it may lead to a more rapid recovery and reduced hospital stay.7

Triglyceride lowering therapies

Hypertriglyceridemia is the third commonest cause of acute pancreatitis worldwide; an appropriate treatment plan is crucial. Specific therapy in the acute phase includes insulin, heparin, high volumehemofiltration, and plasmapheresis with albumin replacement. Treatment should be continued aiming for serum triglyceride levels of <500 mg/dl. Oral lipid-lowering therapy with fibrates is recommended when oral intake is feasible.

Abdominal compartment syndrome

The intra-abdominal pressure (IAP) may rise in SAP due to aggressive fluid resuscitation, leaky capillaries, pancreatic and peripancreatic edema, hemorrhage, necrosis, and generalized ileus. Measurement of IAP is important, as clinical assessment is often fallacious. Bladder pressure is well established as the surrogate of IAP and transduced at the point of intersection between the midaxillary line and the iliac crest. Abdominal compartment syndrome is diagnosed when there is a sustained rise in IAP over 20 mm Hg or an abdominal perfusion pressure (mean arterial pressure-intra-abdominal pressure) below 60 mm Hg accompanied by the onset of new organ failure. The kidneys are often initially affected, followed by circulatory and respiratory impairment. It is crucial to recognize ACS early and initiate measures to reduce IAP. These include using a judicious resuscitative strategy, abdominal fluid drainage, and evacuation of intraluminal contents. Administration of intravenous diuretics and fluid removal by continuous renal replacement therapies may also help reduce IAP. 

Interventional strategies 

Intervention is often required in the presence of infected pancreatic or peripancreatic necrosis. Interventional strategies have undergone a paradigm shift in recent years; minimally invasive surgical and endoscopic approaches have largely supplanted the traditional open approach. Drainage or necrosectomy may not be required in a minority of patients with infected necrosis if they remain clinically stable on antibiotic therapy.8 The first step in patients who require intervention is either endoscopic transluminal drainage (ETD) or CT or ultrasound-guided percutaneous drainage, usually through the retroperitoneal route. This is followed by endoscopic or minimally invasive surgical necrosectomy as appropriate. A minimally invasive approach has not been shown to reduce mortality compared to open necrosectomy in RCTs. However, a recent pooled analysis of 1980 patients from 15 study cohorts showed reduced overall mortality with endoscopic and minimally invasive surgical compared to open necrosectomy. Following propensity score matching and risk stratification, the mortality benefit was evident in the high and very high-risk category of patients.9 Endoscopic ultrasonography is currently preferred for transluminal drainage as collections can be directly visualized and drained regardless of the presence of a visible gastric bulge. Color doppler allows visualization and avoidance of blood vessels, adding to safety. Forward-viewing endoscopes allow irrigation and debridement of necrotic material using a combination of balloons, snares, nets, and other accessories.10

Centrally located and lesser sac collections may be drained through the endoscopic route; however, collections in the flanks, and deep pelvic collections may require image-guided percutaneous catheter drainage. This may later be followed up later by sinus tract endoscopy or video-assisted retroperitoneal debridement. A step-up approach to necrotizing SAP is depicted in Fig 1. An open surgical approach may be required in case of perforated viscus, to relieve refractory ACS, if ischemic bowel is suspected, or with failure of a step-up approach. 

Fig 1. A step-up approach to interventions in acute necrotizing pancreatitis

The bottom line 

  • SAP often leads to a complicated clinical course and carries significant mortality.
  • Although several severity classifications have been described, they have limited value in predicting hardcore clinical outcomes. 
  • A judicious approach to fluid resuscitation with crystalloids is warranted in the early phase of resuscitation; Ringer’s lactate solution may be preferable to normal saline as the resuscitation fluid.
  • Enteral nutrition within the first 48 h of disease onset may help to preserve the integrity of the gut mucosa and reduce the incidence of infective complications.
  • Prophylactic antibiotic use is not beneficial in SAP; in contrast, it may lead to overgrowth with resistant organisms. 
  • ERCP and sphincterotomy within the first 48 h may be appropriate in patients with gall stone-related pancreatitis. 
  • Contrary to the traditional open approach, a minimally invasive step-up strategy with endoscopic and percutaneous drainage as the first step is currently preferred. This may be followed later by minimally invasive surgical or endoscopic necrosectomy as appropriate.  


1.         Santvoort HC van, Bakker OJ, Bollen TL, et al. A Conservative and Minimally Invasive Approach to Necrotizing Pancreatitis Improves Outcome. Gastroenterology. 2011;141(4):1254-1263. doi:10.1053/j.gastro.2011.06.073

2.         Kumar AH, Griwan MS. A comparison of APACHE II, BISAP, Ranson’s score and modified CTSI in predicting the severity of acute pancreatitis based on the 2012 revised Atlanta Classification. Gastroenterol Rep. 2018;6(2):127. doi:10.1093/gastro/gox029

3.         al de-ME et. Fluid resuscitation with lactated Ringer’s solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial. – PubMed – NCBI. Accessed September 5, 2019.

4.         Yi F, Ge L, Zhao J, et al. Meta-analysis: Total Parenteral Nutrition Versus Total Enteral Nutrition in Predicted Severe Acute Pancreatitis. Intern Med. 2012;51(6):523-530. doi:10.2169/internalmedicine.51.6685

5.         Lim CLL, Lee W, Liew YX, Tang SSL, Chlebicki MP, Kwa AL-H. Role of Antibiotic Prophylaxis in Necrotizing Pancreatitis: A Meta-Analysis. J Gastrointest Surg. 2015;19(3):480-491. doi:10.1007/s11605-014-2662-6

6.         Grinsven J van, Brunschot S van, Bakker OJ, et al. Diagnostic strategy and timing of intervention in infected necrotizing pancreatitis: an international expert survey and case vignette study. HPB. 2016;18(1):49-56. doi:10.1016/j.hpb.2015.07.003

7.         Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN. Initial Medical Treatment of Acute Pancreatitis: American Gastroenterological Association Institute Technical Review. Gastroenterology. 2018;154(4):1103-1139. doi:10.1053/j.gastro.2018.01.031

8.         Runzi M, Niebel W, Goebell H, Gerken G, Layer P. Severe acute pancreatitis: nonsurgical treatment of infected necroses.Pancreas. 2005;30(3):195-199.

9.         van Brunschot S, Hollemans RA, Bakker OJ, et al. Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients. Gut. 2018;67(4):697-706. doi:10.1136/gutjnl-2016-313341

10.       Arvanitakis M, Dumonceau J-M, Albert J, et al. Endoscopic management of acute necrotizing pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) evidence-based multidisciplinary guidelines. Endoscopy. 2018;50(5):524-546. doi:10.1055/a-0588-5365

Intra-aortic balloon counterpulsation in critically ill patients

More than half a century ago, Kantrowitz et al. first described the use of an “intra-aortic cardiac assistance system” using a balloon-tipped catheter inserted into the descending thoracic aorta.1 They described two patients who developed cardiogenic shock after acute myocardial infarction. The blood pressure remained low, followed by anuria, in spite of high-dose vasopressor therapy. Following intra-aortic balloon counterpulsation, there was a perceptible improvement in the hemodynamic status in both patients. The first patient continued to improve, was weaned off balloon support, and made a complete recovery. However, the second patient developed recurrent ventricular fibrillation, rendering balloon counterpulsation ineffective. Since then, there have been major technological advances in the field of mechanical support, ranging from percutaneous left ventricular assist devices to the total artificial heart. However, from its humble beginnings, the intra-aortic balloon pump (IABP) has remained the most frequently used mechanical support device.  

How does IABP work? 

The IABP is a double-lumen, balloon-tipped catheter, usually inserted through a sheath placed in the femoral artery. A sheathless technique is preferred in patients with peripheral vascular disease. The catheter tip is positioned in the descending thoracic aorta immediately distal to the left subclavian artery. One lumen is connected to the balloon, allowing back and forth movement of helium gas, while the other lumen is used for flushing the catheter and transduce aortic pressure. The balloon inflates during diastole leading to augmentation of aortic root and coronary artery pressures, thus improving coronary perfusion; it rapidly deflates in systole enabling reduction of afterload with a decrease in systolic pressures. (Figure 1) The inflation-deflation sequence is timed with the arterial waveform or the EKG trace to synchronize with the cardiac cycle. Besides improving coronary blood flow and oxygen supply to the myocardium, IABP support results in a reduction of the left ventricular wall stress and afterload with a decrease in the myocardial oxygen consumption. The stroke volume and cardiac output increase, with an improvement in organ perfusion. 

Figure 1. The tip of the catheter is positioned immediately distal to the left subclavian artery. The balloon inflates in diastole and deflates in systole

When is IABP support useful?

The classical indications for the use of IABP support include acute myocardial infarction with cardiogenic shock, as an adjunct to high-risk percutaneous coronary intervention, preoperative stabilization prior to coronary artery bypass surgery, and for continued support in the postoperative period. Less conventional indications include stabilization of left main disease, and as a bridge to cardiac transplantation. It may also be effective in the management of mechanical complications of myocardial infarction, such as acute mitral regurgitation and ventricular septal defect. Patients with intractable arrhythmia and heart failure refractory to medical therapy may also benefit.  

IABP is generally contraindicated in the presence of aortic regurgitation as it may increase retrograde flow during balloon inflation through a leaky valve. It is also contraindicated in aortic dissection or aneurysm and in the presence of severe coagulopathy. In patients with severe peripheral vascular disease, it may lead to ischemia of the limb. 

What is the evidence? 

Acute myocardial infarction with cardiogenic shock

Early retrospective and registry-based studies seemed to suggest improved survival with a combination of thrombolytic therapy and IABP in patients with cardiogenic shock after acute myocardial infarction.2

The IABP-SHOCK II is the only large RCT addressing the efficacy of IABP in patients with acute myocardial infarction and cardiogenic shock who undergo early revascularization.3 In this multicentric German study, 600 patients who were planned to undergo early PCI or emergency coronary artery bypass surgery were randomized to receive IABP support either before or immediately following the intervention, based on physician judgment. More than 95% of patients in both groups underwent PCI; about 3% of patients underwent emergency coronary artery bypass surgery. No significant difference was observed in the 30-d all-cause mortality, the primary outcome. The study had several limitations, including the selection of patients with relatively mild shock, and exclusion of patients with mechanical complications of myocardial infarction. IABP was inserted after revascularization in the majority (87%) of patients, which failed to evaluate the possible benefit of early hemodynamic stabilization in cardiogenic shock. A relatively large number of patients in the control group (10%) crossed over and underwent IABP insertion, which may have masked a possible benefit from IABP support on intention-to-treat analysis. The question of IABP efficacy in more severe forms of cardiogenic shock after acute myocardial infarction remains unanswered. 

A more recent meta-analysis of 13 observational and four randomized controlled trials (RCT) of patients with acute myocardial infarction complicated by cardiogenic shock revealed no overall difference in hospital mortality.4 However, mortality was significantly lower among patients who received thrombolysis combined with IABP. In contrast, patients who received PCI and IABP support had significantly increased mortality.  

Acute myocardial infarction without cardiogenic shock

Considering the potential improvement in coronary perfusion resulting from aortic counterpulsation, would IABP insertion reduce infarct size and improve clinical outcomes in patients with acute myocardial infarction without cardiogenic shock? This question was addressed in an RCT involving 337 patients in a multicentric study.5 IABP was inserted prior to PCI and continued for at least 12 h in the intervention group; patients in the control group received PCI alone. The infarct size was assessed using cardiac magnetic resonance imaging and expressed as a percentage of the total mass of the left ventricle. No significant difference was noted in the infarct size between patients who received IABP compared to those who did not. Besides, there was no significant difference in secondary outcomes, including major vascular or bleeding complications, transfusion requirements, and  6 m mortality. This study clearly demonstrated the lack of benefit of balloon counterpulsation in patients with acute myocardial infarction, without cardiogenic shock. 

IABP before high-risk PCI

Observational studies have revealed improvement in clinical outcomes with elective IABP insertion prior to high-risk PCI. The BCIS 1 study was carried out to address this question. This multicentre RCT was conducted across 17 tertiary cardiac centers in the UK.6 The study included 301 patients with a left ventricular ejection fraction of less than 30% and extensive coronary artery disease. IABP was inserted before PCI in the intervention group. The primary endpoint of major cardiac and cardiovascular events (MACCE) including death, acute myocardial infarction, cerebrovascular event, or requirement for repeat revascularization at hospital discharge was not significantly different between groups. The 6 m all-cause mortality was similar in both groups. At 5 y follow-up, there was significantly less mortality in the IABP group; however, the study was not powered to determine long term mortality. The mechanism of long term benefit in the absence of any difference in the short term mortality also remains unclear. 

Coronary artery bypass surgery

Balloon counterpulsation is frequently used to stabilize patients before they undergo coronary artery bypass surgery, and for continued hemodynamic support in the postoperative period. Qui et al. prospectively evaluated the efficacy of pre vs. postoperative IABP insertion in patients with severe left ventricular dysfunction who underwent off-pump coronary artery.7 Patients who underwent preoperative IABP had a significantly lower in-hospital mortality, and reduced incidence of low cardiac output, malignant arrhythmias, and acute renal failure in the postoperative period. 

A Cochrane meta-analysis evaluated data from 255 patients in six randomized controlled trials;8 132 patients underwent balloon counterpulsation. In-hospital mortality was significantly lower with balloon counterpulsation. A postoperative low cardiac output syndrome was more common among patients who did not receive IABP support. A high crossover rate (51%) to balloon counterpulsation was noted. A recent meta-analysis confirmed these findings.9 Considering the poor outcomes in patients who undergo IABP support as a late intervention,10 preoperative stabilization may be appropriate in high-risk patients undergoing coronary artery bypass surgery.  

The bottom line

  • Balloon counterpulsation remains the most frequently used device for mechanical circulatory support.
  • Although the SHOCK II trial showed a lack of clinical benefit in patients with acute myocardial infarction and cardiogenic shock, IABP support may continue to play a role in patients with more severe degrees of shock.
  • Mechanical support with IABP may not significantly impact infarct size or clinical outcomes in hemodynamically stable patients with acute myocardial infarction.
  • The use of IABP as a supportive measure before high-risk PCI has not been shown to affect major cardiac and cardiovascular events. 
  • Balloon counterpulsation may have a crucial role in the stabilization of high-risk patients prior to coronary artery bypass surgery and continued support in the postoperative period.


1.        Tj S, Butner N, Sherman L. Initial Clinical Experience With Intraaortic Balloon Pumping in Cardiogenic Shock. :6.

2.         Sanborn TA, Sleeper LA, Bates ER, et al. Impact of thrombolysis, intra-aortic balloon pump counterpulsation, and their combination in cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? J Am Coll Cardiol. 2000;36(3 Suppl A):1123-1129. doi:10.1016/s0735-1097(00)00875-5

3.         Thiele H, Zeymer U, Neumann F-J, et al. Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock. N Engl J Med. 2012;367(14):1287-1296. doi:10.1056/NEJMoa1208410

4.         Romeo F, Acconcia MC, Sergi D, et al. The outcome of intra-aortic balloon pump support in acute myocardial infarction complicated by cardiogenic shock according to the type of revascularization: A comprehensive meta-analysis. Am Heart J. 2013;165(5):679-692. doi:10.1016/j.ahj.2013.02.020

5.         Patel MR, Smalling RW, Thiele H, et al. Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI randomized trial. JAMA. 2011;306(12):1329-1337. doi:10.1001/jama.2011.1280

6.         Perera D. Elective Intra-aortic Balloon Counterpulsation During High-Risk Percutaneous Coronary InterventionA Randomized Controlled Trial. JAMA. 2010;304(8):867. doi:10.1001/jama.2010.1190

7.         Qiu Z, Chen X, Xu M, et al. Evaluation of preoperative intra-aortic balloon pump in coronary patients with severe left ventricular dysfunction undergoing OPCAB surgery: early and mid-term outcomes. J Cardiothorac Surg. 2009;4(1):39. doi:10.1186/1749-8090-4-39

8.         Theologou T, Bashir M, Rengarajan A, et al. Preoperative intra aortic balloon pumps in patients undergoing coronary artery bypass grafting. Cochrane Database Syst Rev. 2011;(1):CD004472. doi:10.1002/14651858.CD004472.pub3

9.         Deppe A-C, Weber C, Liakopoulos OJ, et al. Preoperative intra-aortic balloon pump use in high-risk patients prior to coronary artery bypass graft surgery decreases the risk for morbidity and mortality-A meta-analysis of 9,212 patients. J Card Surg. 2017;32(3):177-185. doi:10.1111/jocs.13114

10.       Böning A, Buschbeck S, Roth P, et al. IABP before cardiac surgery: clinical benefit compared to intraoperative implantation. Perfusion. 2013;28(2):103-108. doi:10.1177/0267659112471577

Corticosteroids in septic shock: to do or not to do, that is the question

The rationale for the administration of corticosteroids in septic shock 

The use of corticosteroids as adjunctive therapy in septic shock has captivated intensive care physicians for over five decades. Many of the early studies used industrial doses of synthetic glucocorticoids, and predictably, led to poor clinical outcomes. The concept of corticosteroid insufficiency related to critical illness (CIRCI) has arisen more recently. CIRCI is based on the hypothesis that even maximal stimulation of the hypothalamic-pituitary-adrenal axis in disease states such as sepsis results in insufficient corticosteroid levels. Besides, there may be tissue resistance to corticosteroids in the presence of sepsis. Based on this theory, the use of more physiological doses of corticosteroids as adjuvant therapy in sepsis was conceptualized, with several small randomized controlled studies (RCTs) demonstrating improvement in hemodynamic parameters, and a trend to improved survival.1,2 Many large RCTs have been carried out since then, evaluating the effect of low-dose corticosteroids to replenish insufficient endogenous activity. What does the current evidence suggest regarding the efficacy of corticosteroids in septic shock? 

Earlier randomized controlled trials

Annane et al. conducted the first, adequately powered RCT to evaluate the usefulness of corticosteroids in septic shock. The combination of intravenous hydrocortisone 50 mg every 6 hours and fludrocortisone 50 μg tablet once daily were administered for a week and compared with placebo. A short corticotrophin test was performed in all patients to test adrenal function. Patients with a rise in cortisol level of less than 9 μg/dl in response to corticotrophin were considered as “non-responders”. The 28-d survival, the primary outcome, was significantly higher among non-responders; this suggested that exogenous administration of corticosteroids led to improved survival in patients with relative adrenal insufficiency. The time to cessation of vasopressors was also significantly less among non-responders who were treated with corticosteroids.3 This was followed by the CORTICUS trial, which included 499 patients; in this study, intravenous hydrocortisone alone was administered as adjunctive therapy (not in combination with fludrocortisone) and compared with placebo.4 No difference was observed in the 28-d mortality in this study; however, a reduced time to shock reversal was noted in corticosteroid-treated patients. The patients in the CORTICUS trial were less severely ill, compared to the Annane et al. study, with relatively fewer patients who fulfilled the criteria for septic shock. 

Recent randomized controlled trials 

Considering the contrasting results of these two studies, the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) study was carried out by the Australian-New Zealand Intensive Care Society Clinical Trials Group.5 The largest RCT to address this question, the ADRENAL study recruited 3800 patients involving 69 medical–surgical ICUs in Australia, the United Kingdom, New Zealand, Saudi Arabia, and Denmark. Patients were intubated or on non-invasive ventilation and on vasopressor therapy for  more than 4 h at randomization. In the intervention arm, hydrocortisone was administered as an intravenous infusion of 200 mg/d for 7 d or until death or discharge from the ICU. No difference was observed in the 90-d mortality, the primary outcome, for which the study was powered. Among the secondary outcomes, the investigators observed a significant difference in the median time to shock resolution, the median time to initial of discontinuation of mechanical ventilation, the median time to ICU discharge, and the number of patients who received a blood transfusion. The 28-d mortality, shock recurrence, use of renal replacement therapy, number of days alive and out of ICU, the median time to hospital discharge, and the number of days alive and out of hospital were not different between groups. 

The combination of hydrocortisone, 50 mg/kg intravenously and 50 μg fludrocortisone once daily was evaluated in a recent French multicentric study (APROCCHSS) among patients with septic shock who were on vasopressor therapy for at least 6 hours.6 The study was originally designed to assess the efficacy of the combination of drotrecogin alfa and corticosteroids. However, during the course of the study, drotrecogin alfa was withdrawn from the market; thereafter, the study was continued with corticosteroids alone and compared with placebo. In contrast to ADRENAL, a statistically significant difference was observed in the 90-d mortality, which was the primary endpoint. The all-cause mortality at ICU and hospital discharge, and at 180 days were also significantly lower among corticosteroid-treated patients. Earlier shock reversal was also observed; there were more patients alive and off vasopressor support at 28 d with corticosteroids. 

APROCCHSS vs. ADRENAL: Why the difference? 

A relatively large number of patients were excluded in the ADRENAL trial; 21,818 patients were screened, out of which 8,263patients were excluded. Exclusion of a large number of subjects may represent a bias in RCTs. In contrast, in the APROCCHSS trial, 1,671 patients with septic shock were screened, and 1,241 patients were included in the study. Patients in the APROCCHSS trial may have been more severely ill. They were on higher doses of noradrenaline, had higher lactate levels, and renal replacement therapy was more frequent, all suggesting more severe illness at baseline. In the ADRENAL study, patients were enrolled later compared to APROCCHSS, suggesting that earlier administration of corticosteroids may be more efficacious. Administration of hydrocortisone as an infusion may not be optimal, considering that achievement of adequate blood levels may be delayed without an initial bolus. Furthermore, it may be illogical to administer hydrocortisone as an infusion considering its relatively long half-life (8–12 h). Did fludrocortisone make a difference to the final outcome? It is difficult to answer this question based on the current level of evidence. Vasopressin use was much more common in the ADRENAL trial; however, the impact of a combination of vasopressin and corticosteroids needs detailed evaluation in patients with septic shock.  

The bottom line

  • There is a strong physiological rationale for the use of corticosteroids as adjunctive treatment in septic shock.
  • All major randomized controlled studies that evaluated the use of corticosteroids in septic shock have shown earlier shock reversal and more rapid weaning down of vasopressors.
  • Corticosteroid administration may lead to a shorter duration of mechanical ventilation and length of stay in the intensive care unit.
  • In the light of the available evidence, it may be appropriate to consider administration of corticosteroids in patients with septic shock.
  • Future studies need to be designed to evaluate whether 1) corticosteroids are more efficacious in the more severely ill and 2) addition of a fludrocortisone would make a difference.


1.         Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26(4):645-650. doi:10.1097/00003246-199804000-00010

2.         Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27(4):723-732. doi:10.1097/00003246-199904000-00025

3.         Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-871. doi:10.1001/jama.288.7.862

4.         Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111-124. doi:10.1056/NEJMoa071366

5.         Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808. doi:10.1056/NEJMoa1705835

6.         Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809-818. doi:10.1056/NEJMoa1705716

The challenge of fluid therapy in sepsis: when less is more

Administration of fluid boluses is considered to be one of the cornerstones of sepsis resuscitation. The surviving sepsis guidelines continue to ardently recommend a fluid bolus of 30 ml/kg within 3 h of presentation to hospital in patients who are hypotensive and considered to have sepsis.1 Let us consider the physiological rationale behind fluid administration in patients with sepsis and hypotension. 

The physiological rationale behind fluid resuscitation 

Fluid resuscitation is based on the Starling curve that correlates preload with stroke volume. The early, ascending part of the curve represents fluid responsiveness; if the preload is increased along this part of the curve, the stroke volume increases. The increase in stroke volume plateaus off towards the latter part of the curve, with no further increase in stroke volume with an additional increase in the preload. Based on this physiological response, bolus fluids are administered, with an expectation that the stroke volume would increase and improve blood flow to the vital organs. However, there are two important considerations with this approach. First, echocardiography based studies have demonstrated that up to 50% of normal subjects may also be fluid responsive;2 second, the stroke volume is normal or high in most patients with sepsis and it may seem counter-intuitive to attempt to increase it further by increasing the preload. Indeed, studies aimed at increasing the cardiac output and oxygen delivery to “supranormal” targets have uniformly demonstrated a lack of benefit or possible harm using this strategy.3

How much fluid, for how long? 

Among patients with sepsis, only 5% of a crystalloid solution may remain in the circulation after an hour of infusion.4 This corroborates with the transient improvement in hemodynamic parameters observed after bolus fluid therapy in septic patients. Hence, the question arises, considering the lack of sustained improvement, how often could fluid boluses be repeated? Inevitably, excessive fluid administration leads to the breakdown of the endothelial glycocalyceal barrier and tissue edema, with impaired organ function. Furthermore, fluid resuscitation may also lead to reduced systemic vascular resistance5 and reduce perfusion pressure to vital organs. There is provocative evidence from a human volunteer study suggesting that an increase in mean arterial pressure may be more related to the temperature of the fluid, compared to the volume administered; administration of intravenous fluid at room temperature (22°C) resulted in a higher mean arterial pressure compared to fluid that was warmed to 38°C.6

Fluid administration, increasing venous pressures, and effects on organ perfusion 

The central venous pressure (CVP) has been recommended to guide intravenous fluid therapy in septic patients. Blood flow to the vital organs is determined by the difference between mean arterial pressure, the upstream pressure, and venous pressure, the downstream pressure. An inappropriate rise in CVP may thus compromise organ perfusion, besides reducing venous return. In fact, the venous pressure may be a more decisive factor that determines organ perfusion. A drop in MAP within the autoregulatory range may not compromise organ perfusion. However, capillary blood flow may be solely determined by venous pressures within the autoregulatory range of arterial pressures.7  

Effect of fluid boluses on cardiac function

Sepsis is generally characterized by a preserved or higher than normal cardiac output. Left ventricular systolic function is usually well maintained; however, there is increasing evidence of significant diastolic dysfunction in septic patients.8 Aggressive fluid resuscitation in patients with impaired diastolic dysfunction leads to raised systemic venous and pulmonary artery pressures, with no significant increase in the stroke volume. Furthermore, excessive fluid resuscitation may exacerbate and perpetuate diastolic dysfunction. 

What is the clinical evidence? 

Measurement of the stroke volume by echocardiography demonstrated fluid responsiveness following 500 ml of a crystalloid solution in only 53% of patients with septic shock.9  A study of over 3000 children with severe sepsis revealed convincing evidence of significantly higher 48 h mortality with the use of bolus intravenous fluid compared to maintenance fluids alone as part of the initial resuscitation strategy.10 In a Zambian study among patients with sepsis and hypotension, early resuscitation with bolus intravenous fluid, vasopressors, and blood transfusion was compared with usual care based on clinician judgment. The intervention group received significantly more intravenous fluid in the first 6 h; however, in-hospital mortality was significantly lower among patients who received treatment based on clinician judgment.11 The CLASSIC study randomized patients with septic shock to receive fluid boluses until circulatory parameters continued to improve or a restrictive strategy with the administration of bolus fluid only if signs of severe hypoperfusion were present. In the fluid-restrictive group, the incidence of worsening of acute kidney injury was significantly less common.12

What may be a more optimal strategy? 

Conventional measures, including CVP, inferior vena caval diameter variation, and central venous oxygen saturation have limited value in the assessment of fluid responsiveness. The passive leg raising test (PLR) coupled with stroke volume monitoring may be more efficacious and safer compared to the administration of bolus fluid as a “challenge dose”. When performed optimally, the PLR mobilizes approximately 300 ml of blood from the peripheral to the central compartment. A change in stroke volume by this intervention may be conveniently evaluated by measuring the velocity-time integral by bedside transthoracic echocardiography. Unlike administration of a fluid bolus, any effect on the hemodynamic status is completely reversed on reassuming the horizontal position of the legs. PLR-induced increase in cardiac output has been shown to be highly predictive of fluid responsiveness in a meta-analysis.13 The importance of reassessment of fluid responsiveness needs to be emphasized prior to the administration of repeated fluid boluses. If fluid responsiveness cannot be reliably assessed, a mini-fluid challenge with 200-500 ml of fluid over 30 min may be much safer compared to larger boluses of 30 ml/kg.14

Early use of vasopressors

Alpha-1 agonists including norepinephrine, at low doses, result in venoconstriction earlier than arterial constriction. Venoconstriction mobilizes unstressed blood volume from the skin and the splanchnic circulation, leading to increased preload and cardiac output. Besides, norepinephrine effectively produces arterial constriction, reversing the vasodilation-induced hypotension among patients with septic shock. Intuitively, a restricted fluid strategy combined with early vasopressor therapy, may be more appropriate in septic shock, characterized by intense vasodilation. Such an approach needs future studies to evaluate clinical outcomes, compared to a fluids-first strategy. 

The bottom line: 

  • Empirical, large volume fluid boluses during resuscitation of septic patients may be ineffective and lead to harm.
  • The hemodynamic effect of bolus fluid administration is usually transient; repeated boluses lead to tissue edema and impaired organ function.
  • Excessive fluid administration has been shown to cause increased mortality compared to a fluid-restrictive strategy.
  • The passive leg raising test combined with echocardiographic assessment of the stroke volume may be a safer, more effective method of evaluating fluid-responsiveness compared to repeated fluid challenges.
  • Early use of vasopressors such as noradrenaline combined with restricted fluid resuscitation may be a more optimal strategy among septic patients. 


1.         Jozwiak M, Monnet X, Teboul J-L. Implementing sepsis bundles. Ann Transl Med. 2016;4(17). doi:10.21037/atm.2016.08.60

2.         Alves DR. Is Fluid Responsiveness A Normal State in Human Beings? A Study in Volunteers. 2016;2017(01):5.

3.         Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994;330(24):1717-1722. doi:10.1056/NEJM199406163302404

4.         Bark BP, Öberg CM, Grände P-O. Plasma volume expansion by 0.9% NaCl during sepsis/systemic inflammatory response syndrome, after hemorrhage, and during a normal state. Shock Augusta Ga. 2013;40(1):59-64. doi:10.1097/SHK.0b013e3182986a62

5.         Pierrakos C, Velissaris D, Scolletta S, Heenen S, De Backer D, Vincent J-L. Can changes in arterial pressure be used to detect changes in cardiac index during fluid challenge in patients with septic shock? Intensive Care Med. 2012;38(3):422-428. doi:10.1007/s00134-011-2457-0

6.         Wall O, Ehrenberg L, Joelsson-Alm E, et al. Haemodynamic effects of cold versus warm fluid bolus in healthy volunteers: A randomised crossover trial. Crit Care Resusc J Australas Acad Crit Care Med. 2018;20(4):277-284.

7.         Vellinga NA, Ince C, Boerma EC. Elevated central venous pressure is associated with impairment of microcirculatory blood flow in sepsis: A hypothesis generating post hoc analysis. BMC Anesthesiol. 2013;13:17. doi:10.1186/1471-2253-13-17

8.         Sanfilippo F, Corredor C, Fletcher N, et al. Diastolic dysfunction and mortality in septic patients: A systematic review and meta-analysis. Intensive Care Med. 2015;41(6):1004-1013. doi:10.1007/s00134-015-3748-7

9.         AzuRea Group, Roger C, Zieleskiewicz L, et al. Time course of fluid responsiveness in sepsis: The fluid challenge revisiting (FCREV) study. Crit Care. 2019;23(1):179. doi:10.1186/s13054-019-2448-z

10.       Maitland K, Kiguli S, Opoka RO, et al. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011;364(26):2483-2495. doi:10.1056/NEJMoa1101549

11.       Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA. 2017;318(13):1233-1240. doi:10.1001/jama.2017.10913

12.       Hjortrup PB, Haase N, Bundgaard H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: The CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016;42(11):1695-1705. doi:10.1007/s00134-016-4500-7

13.       Cavallaro F, Sandroni C, Marano C, et al. Diagnostic accuracy of passive leg raising for prediction of fluid responsiveness in adults: Systematic review and meta-analysis of clinical studies. Intensive Care Med. 2010;36(9):1475-1483. doi:10.1007/s00134-010-1929-y

14.       Nunes TSO, Ladeira RT, Bafi AT, de Azevedo LCP, Machado FR, Freitas FGR. Duration of hemodynamic effects of crystalloids in patients with circulatory shock after initial resuscitation. Ann Intensive Care. 2014;4:25. doi:10.1186/s13613-014-0025-9

The ART of lung recruitment maneuvers

The physiologic rationale

ARDS is a heterogeneous disease process, characterized by a mix of relatively normal, collapsed, fluid-filled, and consolidated alveoli. The functional lung tissue is relatively small, and has been described as the “baby lung” (Fig 1). Cyclical opening and closure of collapsed alveoli leads to shear stress at alveolar interphases and leads to ventilator-induced lung injury (VILI). Ventilation with low tidal volumes may prevent overdistension; however, it cannot prevent cyclical opening and closure of collapsed alveoli. There may be collapsed, potentially aeratable units in patients with ARDS that may require higher opening pressures compared to the airway pressures attained during tidal ventilation. Recruitment maneuvers (RMs) aim to open collapsed alveoli with a sustained increase in airway pressure. Following this, an appropriate level of PEEP is applied to keep the lungs open. Through the use of this strategy, we aim to open up alveoli that are potentially “recruitable”. Keeping them open will hopefully, prevent damage resulting from cyclical opening and closure. Furthermore, as collapsed alveoli open, oxygenation may improve. 

Fig 1. CT image of a typically heterogenous ARDS lung. The dependent areas are densely consolidated with a relatively small volume of non-dependent, normal lung (the “baby” lung).

When to perform RMs?

There is scant evidence to support appropriate indications to perform RMs. RMs are generally resorted to in patients with moderate to severe hypoxemia with a P/F ratio of less than 150 as a rescue intervention. RMs may be indicated only in the early stage of ARDS (within the first 5 days). RMs may also be effective in enhancing recruitment of dorsal areas of the lung during prone ventilation. 

Performing an RM involves a transient increase in intrathoracic pressure. A rise in the intrathoracic pressure may lead to reduced venous return and preload, with a fall in cardiac output and cause hypotension. Hence, it is important to assess volume responsiveness prior to an RM and infuse intravenous fluids if appropriate. A rise in intrathoracic pressure also increases pulmonary artery pressures and the afterload to the right ventricle (RV). Excessive afterload may precipitate RV dysfunction and hemodynamic instability. RV dysfunction may be monitored in real time by bedside transthoracic echocardiography. Application of excessive pressure may be harmful in patients with chronic obstructive pulmonary disease and emphysema; the risk of inducing a pneumothorax is increased in these patients. Clearly, in a patient with a pre-existing pneumothorax or bronchopleural fistula, RMs are contraindicated. Any significant rise in the intrathoracic pressure may be transmitted to the intracranial compartment; hence, RMs may be inadvisable in patients with raised intracranial pressure, including traumatic brain injury. Importantly, it is inadvisable to attempt RM in patients in the late phase of ARDS (more than 5–7 days). At this stage of ARDS, the potential for recruitment is low due to the onset fibrotic changes.

How to perform RMs

There are different methods of performing RMs. The most commonly used method until recently was the sustained inflation method, wherein a pressure of 30–40 cm of H2O is applied for 30–40 seconds in the CPAP mode.1 However, this method may not be the most optimal method of applying an RM. In contrast to sustained pressure, multiple cycles of tidal ventilation may be required after an increase of PEEP before the functional residual capacity increases and stabilizes at a particular level.2 Hence, the time over which pressure is sustained may be a less important factor in recruitment compared to the level of applied pressure. The efficacy of recruitment fades over the duration for which it is applied; an arbitrary duration of 30–40 seconds may be too lengthy and lead to a higher incidence of complications, particularly, increased right ventricular afterload and hemodynamic instability leading to hypotension.2

A more optimal method may be the “staircase” method of performing an RM. On the pressure controlled ventilation mode, the PEEP level is increased in a stepwise manner. The inspiratory pressure is set at 15 cm of H2O above the PEEP level. The PEEP level is increased to 20, 30, and 40 cm H2O. At each step, the PEEP level is sustained for 2 min, while the change in oxygen saturation is observed and blood pressure is continuously monitored. After a maximum inspiratory pressure around 55 cm H2O is reached, the PEEP level is titrated backwards at 3 min intervals in a stepwise manner, by 2.5 cm of H2O at each step to a minimum of 15 cm H2O or until a decrease in oxygen saturation by 1–2% is observed. This is defined as the decruitment point. A “re-recruitment” maneuver is then performed, followed by setting the PEEP at 2.5 cmH2O above the de-recruitment point.3

What is the evidence?

There have been about seven RCTs that have addressed the use of RMs in patients with ARDS. Most of these have used a higher PEEP level as a co-intervention; hence, it is difficult to evaluate the effect of RMs alone. RMs have generally shown to improve the P/F ratio; however, the effect appears to be transient. One of the studies that used RMs without co-interventions included 110 patients in which all subjects received a low tidal volume strategy of 6–8 ml/kg of the predicted body weight.4 RM was performed by a sustained inflation maneuver of 40 cm H2O maintained for 40 seconds, conducted every eight hours for the first five days. This study showed significantly improved ICU mortality and ventilation-free days; however, there was no difference in hospital or 28-day mortality. No significant hemodynamic instability or barotrauma were noted. 

The latest RCT that addressed the effect of RMs was the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART).5 The control group received PEEP and FiO2 titrated according to ARDS-net table. The intervention group received the following interventions in a stepwise manner:

  1. Pressure controlled ventilation with a driving pressure (delta p) of 15 cm H2O
  2. PEEP of 25 cm H2O for 1 min, 35 cm H2O for 1 min, and 45 cm H2O for 2 min (reduced to 25-30-35 for 1 min each, starting with the 556thof 1010 patients, as three patients suffered cardiac arrest with the higher pressures)
  3. Volume controlled ventilation with PEEP of 23 
  4. Decrease PEEP by 3 cm H2O at each step; 4 min at each decremental level of PEEP (changed to 3 min at each level); down to a minimum of 11 cm H2O) 
  5. Measure compliance at each step
  6. PEEP with the best compliance + 2 cm H2O was set (optimal PEEP)
  7. Switch to PCV again, another one-step, 2 min recruitment: PEEP 45 cm H2O, (changed to 35) delta p 15 cm H2O. 
  8. Following the RM and PEEP titration, the tidal volume was maintained between 4–6 ml/kg predicted body weight to keep plateau pressure ≤ 30 cm H2O. 

Outcomes were significantly worse in the recruitment group. The primary outcome, 28-day mortality, was significantly higher in the recruitment group. Six-month mortality was higher with RMs; ventilator-free days at 28 days was more in the control arm. The incidence of barotrauma, including pneumothorax, was also significantly higher with RMs.

Our practice

We do not perform RMs routinely for patients with moderate to severe ARDS in our practice. In patients with a low P/F ratio, we perform upward titration of PEEP. In the pressure-controlled mode, we increase the PEEP in a step-wise manner, with increments of about 5 cm of H2O at a time, to a maximum level of 15–20 cm of H2O. The driving pressure is held constant. We evaluate the patient at each incremental level of PEEP for at least 10–15 minutes. The compliance and oxygen saturation are monitored closely at each level of PEEP; we select a final PEEP level that we feel offers the best compliance. An improvement in oxygen saturation with incremental PEEP would also suggest “recruitability”. 

The bottom line 

  1. The use of high plateau pressures of up to 60 cm of H2O, even for brief periods, may lead to adverse outcomes, if used as a routine intervention in patients with moderate to severe ARDS. The poor outcomes including three instances of cardiac arrest and significantly higher barotrauma in the intervention group in the ART trial clearly demonstrated this.
  2. The efficacy of RMs may depend on the extent of “recruitability”. If RMs are performed on lungs that are non-recruitable, it may lead to harm.
  3. Improvements in compliance, oxygen saturation, and driving pressures are commonly employed to evaluate the efficacy of RMs; however, it is unclear whether these parameters are sufficiently predictive of recruitability.
  4. Future research is necessary to evaluate more optimal tools to assess recruitability. Lung ultrasound needs to be investigated as a possible option to evaluate the efficacy of RMs.  


1.         Passos AMB, Valente BCS, Machado MD, et al. Effect of a Protective-Ventilation Strategy on Mortality in the Acute Respiratory Distress Syndrome. N Engl J Med. 1998:8.

2.         Marini JJ. Recruitment by sustained inflation: time for a change. Intensive Care Med. 2011;37(10):1572-1574. doi:10.1007/s00134-011-2329-7

3.         Hodgson C, Cooper DJ, Arabi Y, et al. Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure (PHARLAP): a protocol for a phase 2 trial in patients with acute respiratory distress syndrome. Crit Care Resusc J Australas Acad Crit Care Med. 2018;20(2):139-149.

4.         Xi X-M, Jiang L, Zhu B, RM group. Clinical efficacy and safety of recruitment maneuver in patients with acute respiratory distress syndrome using low tidal volume ventilation: a multicenter randomized controlled clinical trial. Chin Med J (Engl). 2010;123(21):3100-3105.

5.         Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, et al. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017;318(14):1335. doi:10.1001/jama.2017.14171

Blood glucose control in the critically ill: hitting the sweet spot

Control of blood glucose levels among critically ill patients continues to evoke intense attention. Van den Berghe et al., in a landmark study, demonstrated that maintaining blood glucose levels within a narrow range, between 80–110 mg/dl may improve clinical outcomes, including ICU and hospital mortality among patients admitted to a surgical ICU.1 In a similar study of medical patients that followed, there was no difference in hospital mortality in patients who received intensive insulin therapy. However, there was a lower incidence of acute kidney injury, more rapid weaning from mechanical ventilation, and earlier discharge from ICU and hospital.2

Subsequent randomized controlled trials failed to reproduce the findings of these early studies, with reports of undesirable levels of hypoglycemia associated with tight glucose control. The NICE-SUGAR study, in a group of mixed ICU patients, revealed increased mortality with tight glucose control, mostly attributable to hypoglycemic episodes.3 Let us examine the current understanding of the importance of control of blood glucose levels in critically ill patients.   

Probable reasons for contrasting results 

Could it be possible that the conflicting results in major randomized controlled trials were related to the blood glucose targets aimed for? In the Leuven studies, insulin infusion was commenced when the blood glucose level exceeded 215 mg/dl in the control arm, while in the NICE-SUGAR study, insulin therapy was initiated at a blood glucose level higher than 180 mg/dl. In fact, blood glucose levels were higher in the control arm of the Leuven studies compared to the NICE-SUGAR study. One could argue that the lower blood glucose levels in the control arm of the NICE-SUGAR study may be the optimal range and further lowering of glucose levels may, in fact, lead to harm. One could hypothesize a “U” shaped curve of mortality depending on blood glucose levels. The mortality may reduce with lowering blood glucose up to a certain threshold level; a further decrease in levels may increase mortality. Blood glucose levels were measured on arterial blood samples, using blood gas analyzers in the Leuven studies. In the NICE-SUGAR study, arterial, venous, or capillary glucose levels were measured, depending on the circumstances. Could possible inaccuracies with measurement have led to suboptimal insulin dosing and a higher incidence of hypoglycemia? Furthermore, unlike in the NICE-SUGAR study, early parenteral nutrition was administered in the Leuven studies. Early parenteral nutrition may have resulted in higher blood glucose levels and offered protection against hypoglycemia. Bolus doses of insulin were allowed in the NICE-SUGAR study; this may also have contributed to a higher incidence of hypoglycemia. 

Glycemic variability and time in the target range 

The mean glucose levels over a finite period of time may remain in the target range; however, significant fluctuations may occur over the same period. The frequency (number of times the blood glucose levels are outside the target range) and the magnitude of variability (the degree of change of glucose levels outside the target range) may have an impact. Egi et al. studied the variability of glucose levels in 7,049 critically ill patients. Both higher mean blood glucose levels and a wider standard deviation from the mean were significantly associated with intensive care and hospital mortality. The standard deviation of glucose levels remained an independent predictor of ICU, and hospital mortality.4 A subsequent retrospective cohort review reinforced the importance of glycemic variability. In this study among mixed medical-surgical ICU patients, there was a step-wise increase in mortality with an increase in the standard deviation of blood glucose levels.5 

The time in the target range (TiTR) describes the period of time during which the blood glucose levels remain within the acceptable range expressed as a percentage of the total time. In a study of postoperative cardiac surgical patients, TiTR more than 80% was associated with a significantly lower incidence of atrial fibrillation, shorter duration of mechanical ventilation and ICU stay, and a lower incidence of postoperative wound infection.6 In a retrospective analysis, Krinsley et al. examined the relationship between TiTR and mortality in a mixed medical-surgical ICU. In non-diabetic patients, mortality was significantly higher with the TiTR less than 80%. However, the association between TiTR and mortality was not significant in patients with pre-existing diabetes.7

In a multicentric, retrospective analysis of prospectively collected data, maintenance of blood glucose levels between 80–140 mg/dl among non-diabetic patients was independently associated with lower mortality and higher levels with an increased risk of mortality. In contrast, mortality was higher with a blood glucose range between 80–110 mg/dl compared to a higher target range of 110–180 mg/dl among diabetic patients.8 Several other studies also point to a “diabetes paradox” in critically ill patients, with no significant increase in mortality associated with pre-existing, insulin-treated diabetes mellitus.9,10 Chronic hyperglycemia, as seen in diabetic patients, may lead to cellular conditioning that may protect against episodes of acute glycemia.11 Absence of such preconditioning may lead to poor tolerance of hyperglycemic episodes in non-diabetic patients. Hence, it may be reasonable to assume that tighter control of blood glucose levels may be more important in non-diabetic patients.

Is glycosylated hemoglobin (HBA1c) estimation useful in the critically ill?

There may be a marked difference in clinical outcomes with the maintenance of blood glucose levels within a narrow range between diabetic and non-diabetic critically ill patients. Would the estimation of HBA1c be of value to evaluate the degree of blood glucose control prior to the acute illness and titrate control of blood glucose levels? In a retrospective, observational study, among patients with HBA1c levels higher than 7%, a time-weighted glucose level of more than 180 mg/dl resulted in lower mortality. These findings suggest that among patients with poor metabolic control preceding critical illness, there was greater survival when blood glucose levels were maintained at higher levels; in contrast, survival was lower when euglycemic levels were targeted.12 These findings have been corroborated in a recent before-after interventional trial which aimed for target blood glucose levels of 80–140 mg/dl for patients with HBA1c below 7% and 110–160 mg/dl for those with HBA1c above 7%. In diabetic patients with HBA1c above 7%, higher target blood glucose levels between 110–160 mg/dl resulted in lower mortality.13

What blood glucose levels do we aim for among critically ill patients? 

Similar to most other areas of medical practice, one size may not fit all with control of blood glucose among the critically ill. Patients exposed to chronic hyperglycemia and those who were normoglycemic in the premorbid period may require different blood glucose targets when they develop an acute illness. Diabetic patients who have adequately controlled blood glucose levels may also differ from those with poor metabolic control. Based on the best evidence available, blood glucose levels between 140–200 mg/dl for non-diabetics and diabetic patients with HbA1c less than 7% may be targeted; a higher level of 160–220 mg/dl for diabetics with HbA1c more than 7% may be appropriate.14

The future

The current practice of measuring blood glucose levels at fixed intervals is less than ideal. Near real-time blood glucose monitoring with closed-loop control has been reported using different algorithms. Clearly, the utilization of such systems will pave the way for maintenance of blood glucose level within a narrow therapeutic range without the risk of wide fluctuations. Interstitial and intravascular sensors have been tested; however, the accuracy of many of these devices do not meet the requisite standards, with no approval from regulators for use in critically ill patients. However, near real-time glucose monitoring with closed-loop control holds the promise to enable maintenance of blood glucose levels within the targeted range, without the risk of hypoglycemia. 

The bottom line

  • Aiming to maintain blood glucose levels in a narrow therapeutic range may lead to an increased incidence of hypoglycemia and poor outcomes. 
  • Glycemic variability and time spent in the therapeutic range may impact clinical outcomes.  
  • Patients with pre-existing high blood glucose levels may tolerate the lower range of blood glucose levels poorly.
  • Diabetic patients with adequate glucose control and non-diabetics may require lower blood glucose targets. 
  • Near real-time measurement of blood glucose levels and closed-loop control holds promise in maintaining levels within a narrow therapeutic range.


1.         van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-1367. doi:10.1056/NEJMoa011300

2.        Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-461. doi:10.1056/NEJMoa052521

3.        NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. doi:10.1056/NEJMoa0810625

4.        Egi M, Bellomo R, Stachowski E, French CJ, Hart G. Variability of blood glucose concentration and short-term mortality in critically ill patients. Anesthesiology. 2006;105(2):244-252.

5.        Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008;36(11):3008-3013. doi:10.1097/CCM.0b013e31818b38d2

6.        Omar AS, Salama A, Allam M, et al. Association of time in blood glucose range with outcomes following cardiac surgery. BMC Anesthesiol. 2015;15:14. doi:10.1186/1471-2253-15-14

7.        Krinsley JS, Preiser J-C. Time in blood glucose range 70 to 140 mg/dl >80% is strongly associated with increased survival in non-diabetic critically ill adults. Crit Care Lond Engl. 2015;19:179. doi:10.1186/s13054-015-0908-7

8.        Krinsley JS, Egi M, Kiss A, et al. Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study. Crit Care Lond Engl. 2013;17(2):R37. doi:10.1186/cc12547

9.        Vincent J-L, Preiser J-C, Sprung CL, Moreno R, Sakr Y. Insulin-treated diabetes is not associated with increased mortality in critically ill patients. Crit Care Lond Engl. 2010;14(1):R12. doi:10.1186/cc8866

10.      Graham BB, Keniston A, Gajic O, Trillo Alvarez CA, Medvedev S, Douglas IS. Diabetes mellitus does not adversely affect outcomes from a critical illness. Crit Care Med. 2010;38(1):16-24. doi:10.1097/CCM.0b013e3181b9eaa5

11.      Klip A, Tsakiridis T, Marette A, Ortiz PA. Regulation of expression of glucose transporters by glucose: a review of studies in vivo and in cell cultures. FASEB J Off Publ Fed Am Soc Exp Biol. 1994;8(1):43-53. doi:10.1096/fasebj.8.1.8299889

12.      Egi M, Bellomo R, Stachowski E, et al. The interaction of chronic and acute glycemia with mortality in critically ill patients with diabetes. Crit Care Med. 2011;39(1):105-111. doi:10.1097/CCM.0b013e3181feb5ea

13.      Krinsley JS, Preiser J-C, Hirsch IB. Safety and efficacy of personalized glycemic control in critically ill patients: a 2-year before and after interventional trial. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2017;23(3):318-330. doi:10.4158/EP161532.OR

14.      Marik PE, Egi M. Treatment thresholds for hyperglycemia in critically ill patients with and without diabetes. Intensive Care Med. 2014;40(7):1049-1051. doi:10.1007/s00134-014-3344-2

Multidrug-resistant gram-negative bacteria: new therapeutic options

Following the discovery of penicillin in 1928, and its widespread use in clinical practice from the 1940s, several new antibiotic classes were introduced. Vancomycin was introduced in 1958, followed by the cephalosporins, beta-lactamase inhibitors, and quinolones. However, since the introduction of carbapenems in the 1980s, no new class of antibiotic has been added to our therapeutic armamentarium. Multidrug-resistant bacteria have, in the meantime, multiplied across the globe by several fold. There has been an ever-increasing problem with multidrug-resistant gram-negative bacteria (MDR-GNB) in critically ill patients. Different types of beta-lactamases are produced by GNB rendering them resistant to commonly available antibiotics (Table 1). Considering the lack of new agents to combat these organisms, several older antibiotics, including colistin, and fosfomycin, have found renewed utility in critically ill patients across the globe. Combination of drugs with reduced sensitivity have also been resorted to in the face of lack of availability of more effective therapy. However, infection with carbapenem-resistant Enterobacteriaceae, Ps. aeruginosa, and A.baumanni continue to wreak havoc among the critically ill. Several newer antibiotics have undergone clinical evaluation and introduced into clinical practice recently, with increased potency against MDR-GNB. Let us consider some of the newer drugs and their clinical efficacy based on the best available evidence. 

Table 1. The Ambler classification of beta-lactamases

Beta-lactamase typeCharacteristics
Class APenicllinases, narrow and extended- spectrum beta-lactamases, carbapenemases including Klebsiella pneumoniae carbapenemase (KPC) 
Class B Metallo-beta-lactamases
Class CCephalosporinases
Class D Oxa-type enzymes 


Ceftolozane is a third-generation cephalosporin with a distinctive side-chain that confers it with enhanced efficacy against penicillin-binding proteins. Ceftolozane has a much lower minimum inhibitory concentration (MIC) against Ps. aeruginosa compared to ceftazidime, imipenem, and ciprofloxacin. The addition of tazobactam enables inhibition of Amp C and extended-spectrum beta-lactamases (ESBLs). Following the ASPECT-cIAI1 and ASPECT-cUTI2trials, ceftolozane/tazobactam has been approved for clinical use in complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). Ceftolozane/tazobactam may be efficacious against infections caused by carbapenem-resistant P. aeruginosa. It may also have a future role against ESBL producing Enterobacteriaceae. A recently completed randomized controlled trial compared 3 g cefotzolane/tazobactam with 1 g meropenem in patients with ventilator-associated pneumonia (VAP), for a period of 8–14 days. Clinical cure and microbiological eradication rates were comparable between the two agents in this non-inferiority trial. This combination may be a viable treatment option in VAP caused by gram-negative organisms.3


Avibactam is a non-beta-lactam type of beta-lactamase inhibitor that offers protection against class A and C beta-lactamases when used in combination with ceftazidime, a third-generation cephalosporin. Ceftazideme-avibactam is effective against most carbapenemase and OXA-48 producers, including Klebsiella pneumoniae carbapenemase (KPC). However, it is not effective against class B beta-lactamases, including metallo-lactamases. In a randomized, controlled study in patients with cUTI, the ceftazidime/avibactam combination was non-inferior to doripenem for the primary endpoints of clinical and microbiological cure.4 Ceftazidime/avibactam combined with metronidazole was non-inferior to meropenem in cIAI in another randomized controlled trial.5


Vaborbactam is a novel beta-lactamase inhibitor which has no intrinsic antibacterial activity; however, it inhibits beta-lactamases that neutralize meropenem. The meropenem/vaborbactam combination has a potent effect against type A beta-lactamases, including KPC. In the TANGO-I trial, meropenem/vaborbactam was shown to be superior to piperacillin/tazobactam in cUTI, including acute pyelonephritis. The meropenem/vaborbactam combination was also compared with the best available alternative therapy in carbapenem-resistant Enterobacteriaceae infections.6 The infections included cUTIs, hospital and community-acquired pneumonia, and bacteremia. The study was stopped early due to demonstrated superiority of meropenem/vaborbactam therapy. However, meropenem/vaborbactam may not be effective against OXA-type carbapenemase producing A. baumanni and P. aeruginosa that acquire resistance by porin changes and efflux mechanisms. The European Medical Agency has currently approved meropenem/vaborbactam in the treatment of cUTI, c-IAI, hospital-acquired pneumonia (HAP), VAP, and other infections due to aerobic gram-negative organisms. 


Plazomicin is a new aminoglycoside that shares a common mechanism of action by inhibition of bacterial protein synthesis. Similar to other aminoglycosides, lung penetration is poor and elimination is through the kidneys. It has good in vitro activity against carbapenem resistant Enterobacteriaceae; however, the efficacy is much less against carbapenem-resistant A. baumanni and P. aeruginosa. In the phase 3 EPIC trial, plazomicin was demonstrated to be superior to meropenem in c-UTI.7 Plazomicin and colistin were compared in combination with other drugs in the treatment of blood stream infections, HAP, and VAP. All-cause mortality with combination therapy, including plazomicin was lower compared to combination therapy with colistin.3 Plazomicin may be a therapeutic option in resistant gram-negative infections in combination with meropenem, colistin, or fosfomycin.  


Eravacycline is a novel derivative of tigecycline with a broader spectrum of activity. It is not susceptible to beta-lactamases and efflux channel mechanisms that confer resistance to GNBs. In vitro studies have demonstrated a wide spectrum of activity against GNB, except Ps. aeruginosa and Burkholderia cenocepacia. Particularly noteworthy is the superior efficacy against carbapenem-resistant A. baumanni. In a randomized controlled trial, eravacycline was compared with ertapenem in cIAI. Clinical cure was comparable with both drugs, establishing non-inferiority compared to ertapenem.8 In cUTI, eravacycline did not achieve non-inferiority compared to levofloxacin and ertapenem.9 Eravacycline has a high bioavailability on oral administration, enabling switch from  intravenous to oral therapy if appropriate. 

The bottom line

  • In the face of increasingly resistant GNB, the antibiotic cupboard appears relatively bare. The aforementioned drugs have been approved by the FDA for use against MDR-GNB.
  • The newly available agents are derivatives of existing class of antibiotics; no new class of antibiotic has been introduced into clinical practice in more than three decades.
  • It is of utmost importance to use these drugs only when there is no viable alternative; bacteria evolve over time and develop resistance following exposure to newer antibiotics.


1.         Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/Tazobactam Plus Metronidazole for Complicated Intra-abdominal Infections in an Era of Multidrug Resistance: Results From a Randomized, Double-Blind, Phase 3 Trial (ASPECT-cIAI). Clin Infect Dis Off Publ Infect Dis Soc Am. 2015;60(10):1462-1471. doi:10.1093/cid/civ097

2.        Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet Lond Engl. 2015;385(9981):1949-1956. doi:10.1016/S0140-6736(14)62220-0

3.        Koulenti D, Song A, Ellingboe A, et al. Infections by multidrug-resistant Gram-negative Bacteria: What’s new in our arsenal and what’s in the pipeline? Int J Antimicrob Agents. 2019;53(3):211-224. doi:10.1016/j.ijantimicag.2018.10.011

4.        Wagenlehner FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam Versus Doripenem for the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis: RECAPTURE, a Phase 3 Randomized Trial Program. Clin Infect Dis Off Publ Infect Dis Soc Am. 2016;63(6):754-762. doi:10.1093/cid/ciw378

5.        Qin X, Tran BG, Kim MJ, et al. A randomised, double-blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra-abdominal infections in hospitalised adults in Asia. Int J Antimicrob Agents. 2017;49(5):579-588. doi:10.1016/j.ijantimicag.2017.01.010

6.        Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and Safety of Meropenem-Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial. Infect Dis Ther. 2018;7(4):439-455. doi:10.1007/s40121-018-0214-1

7.        Wagenlehner FME, Cloutier DJ, Komirenko AS, et al. Once-Daily Plazomicin for Complicated Urinary Tract Infections. N Engl J Med. 2019;380(8):729-740. doi:10.1056/NEJMoa1801467

8.        Solomkin J, Evans D, Slepavicius A, et al. Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) Trial: A Randomized Clinical Trial. JAMA Surg. 2017;152(3):224-232. doi:10.1001/jamasurg.2016.4237

9.        Bassetti M, Peghin M, Vena A, Giacobbe DR. Treatment of Infections Due to MDR Gram-Negative Bacteria. Front Med. 2019;6:74. doi:10.3389/fmed.2019.00074

Ventilator-associated events: are we losing the plot?

Hospital-acquired infections are generally considered preventable and used as a quality assessment tool in health care by regulatory bodies. Ventilator-associated pneumonia (VAP) is one of the quality indicators employed by accreditation bodies, including the National Accreditation Board for Hospitals and Healthcare Providers (NABH) in India. It is not unusual for hospital administrators and ICU staff, in particular, to dedicate considerable time and effort to ensure compliance to the satisfaction of the assessors involved with accreditation. Increasing emphasis is placed on the new definitions and surveillance methodology in the pursuit of evaluating the incidence of VAP.  

The new approach to surveillance

Let us consider the changes that have evolved over the past few years in the surveillance of VAP in critically ill patients. VAP Surveillance and public reporting commenced in the US several years ago, at the behest of the  Center for Disease Control and Prevention (CDC) and the National Healthcare Safety Network (NHSN). An inexplicable decline in the incidence of VAP was observed with the commencement of surveillance. The most likely reason for the steep decline may have arisen from biased interpretation and reporting by hospitals faced with unwelcome consequences related to a high incidence. The highly subjective criteria employed for the diagnosis of VAP may have led to bias and underreporting. Against this background, the CDC, along with the Critical Care Societies Collaborative, attempted to develop a more objective and credible definition of VAP.1 A three-tiered algorithmic approach was introduced under the broad category of ventilator-associated events (VAE). The first step was defined as ventilator-associated conditions (VAC), followed by infection-related, ventilator-associated conditions (IVAC), and finally, possible or probable VAP(Fig. 1). Radiological confirmation of consolidation was not considered as an essential requirement for the diagnosis of VAP considering its lack of specificity. 

Fig 1. The new ventilator-associated events (VAE) algorithm. VAC: ventilator-associated conditions; IVAC: infected ventilator-associated conditions; VAP: ventilator-associated pneumonia

Problems with the new approach

The step-wise approach requires stable or decreasing FiOand PEEP levels for two calendar days. A sustained FiOincrease by more than 0.2 or an increase of PEEP by more than 3 cm of H2O for at least two consecutive days must follow the period of stability before a diagnosis of IVAC or VAP can be considered. However, a pre-defined period of stable oxygenation may not occur in patients with worsening lung disease at the outset, such as pneumonia or acute respiratory distress syndrome (ARDS). Furthermore, VAP can clearly occur without a sustained period of diminished oxygenation requiring an increase of FiOor PEEP.2 Although the new definitions were intended to add objectivity to VAP surveillance, they have not been validated by clinical evidence. 

What does the evidence suggest? 

A Dutch cohort study revealed that the VAE algorithm could identify only 32% of patients with VAP, diagnosed by prospective surveillance.3 In another retrospective study that evaluated 165 episodes of VAP diagnosed according to the conventional definition, only 12.1% were identified as probable VAP and 1.2% as possible VAP based on the new diagnostic algorithm.4 Clearly, the new definitions are poorly sensitive to the diagnosis of VAP; besides, worsening of oxygenation is often due to non-infective conditions such as cardiogenic pulmonary edema, ARDS, and atelectasis. Furthermore, some episodes of VAP may be missed out by the exclusion of radiological findings from the VAE algorithm. Fan et al. performed a meta-analysis of 61,489 patients from 18 studies to evaluate consistency between surveillance using conventional VAP criteria and the VAE algorithm. The VAE algorithm underestimated the true incidence of VAP as diagnosed by conventional criteria, with a pooled sensitivity and positive predictive value of less than 50%.5

The new algorithm as a quality indicator

The creators of the VAE algorithm argue that it is meant solely for surveillance and not for clinical management of patients. However, it appears to be an imperfect screening tool and lacks sensitivity for the diagnosis of VAP based on the clinical evidence available. The new algorithm is clearly ineffective in the early identification of mechanical ventilation-related complications by focussing solely on deterioration of oxygenation. 

In India, if you seek NABH accreditation, toeing the CDC line with the VAE algorithm appears to be a key ICU quality indicator. Hospitals take great pains to furnish VAE data to the satisfaction of NABH assessors who are often far removed from the real world of bedside clinical practice. Besides, there is often an irrational expectation to seek a “root cause” for everything under the sun and corrective action that will “eliminate” the problem, with little realization that many of the common complications of clinical medicine may not be entirely preventable. 

The bottom line

  • The new algorithm-based surveillance defines VAE as sustained deterioration in oxygenation after a period of stability; the new definitions were meant to add more objectivity to VAP surveillance. 
  • Lack of sensitivity to diagnose VAP is one of the main drawbacks of the new algorithm; many patients who develop VAP do not experience stable oxygenation followed by sustained deterioration. 
  • Absence of radiological correlation may also lead to underestimation of the true incidence of VAP.
  • The validity of the new algorithm has not been established in clinical studies.
  • Regulatory bodies need to be mindful of the relative lack of evidence to support the VAE algorithm-based surveillance methodology as a quality assessment tool. 


1.         Magill SS, Klompas M, Balk R, et al. Executive summary: Developing a new, national approach to surveillance for ventilator-associated events. Ann Am Thorac Soc. 2013;10(6):S220-223. doi:10.1513/AnnalsATS.201309-314OT

2.         Lilly CM, Landry KE, Sood RN, et al. Prevalence and test characteristics of national health safety network ventilator-associated events. Crit Care Med. 2014;42(9):2019-2028. doi:10.1097/CCM.0000000000000396

3.         Klein Klouwenberg PMC, van Mourik MSM, Ong DSY, et al. Electronic implementation of a novel surveillance paradigm for ventilator-associated events. Feasibility and validation. Am J Respir Crit Care Med. 2014;189(8):947-955. doi:10.1164/rccm.201307-1376OC

4.         Chang H-C, Chen C-M, Kung S-C, Wang C-M, Liu W-L, Lai C-C. Differences between novel and conventional surveillance paradigms of ventilator-associated pneumonia. Am J Infect Control. 2015;43(2):133-136. doi:10.1016/j.ajic.2014.10.029

5.         Fan Y, Gao F, Wu Y, Zhang J, Zhu M, Xiong L. Does ventilator-associated event surveillance detect ventilator-associated pneumonia in intensive care units? A systematic review and meta-analysis. Crit Care. 2016;20(1):338. doi:10.1186/s13054-016-1506-z

Oxygen : the elixir of life or the kiss of death?

The administration of supplemental oxygen is ubiquitous in medical practice, especially among critically ill patients. Hyperoxia is fairly common during oxygen therapy, and generally considered to be less deleterious than the potential harm that may arise from hypoxia. However, there has been an increased understanding of the detrimental effects of hyperoxia in recent times. How does the clinician balance the lifesaving effect of oxygen therapy while minimizing possible harm? 

Hypoxemia and compensatory mechanisms

A PaO2 level of less than 60 mm Hg is generally considered to be the lower limit of acceptable oxygenation. Several adaptive mechanisms are triggered in the presence of hypoxia. Downregulation of mitochondrial uncoupling has been demonstrated in human volunteers; hypoxia may enable more efficient ATP generation and mitochondrial protection.1 The release of hypoxia-inducible factors result in the activation of glycolytic enzymes leading to a preponderance of anerobic metabolism. Mitochondrial hibernation may occur, resulting in a reduction in the oxygen demand.2 Other compensatory mechanisms that enable acclimatization include hypoxic pulmonary vasoconstriction, increased cardiac output, polycythemia, and increased production of 2-3 diphosphoglycerate with a shift of the oxygen-dissociation curve to the right, enabling offloading of oxygen to the tissues.3

Potential harmful effects of hyperoxia

Hyperoxia results in the generation of reactive oxygen species (ROS). Excessive production of ROS resulting from high levels of oxygen may lead to cellular death by necrosis or apoptosis. Furthermore, ROS are the chief mediators of reperfusion injury. Hyperoxia has been well known to lead to pulmonary damage similar to acute respiratory distress syndrome, inhibition of mucociliary transport, and atelectasis. Supranormal arterial partial pressures of oxygen also lead to a fall in the cardiac output due to generalized vasoconstriction and increased afterload. Besides, coronary vasoconstriction may occur, and predispose to myocardial ischemia.4

Evidence of harm or lack of benefit from hyperoxia

In a randomized controlled study of normoxic patients with acute ST-elevation myocardial infarction (STEMI), supplemental oxygen at 8L/min was compared to no oxygen therapy. Recurrent myocardial infarction was significantly more common in the supplemental oxygen group; besides, there was an increase in the incidence of cardiac arrhythmias with oxygen supplementation. Infarct size assessed by cardiac magnetic resonance imaging (MRI) was significantly higher with oxygen therapy.5 In a similar study of normoxic patients with STEMI, supplemental oxygen was administered until the completion of percutaneous coronary intervention and compared to controls who received no supplemental oxygen. No difference was observed in the myocardial salvage index assessed by cardiac MRI or in the infarct size.6 These studies suggest that supplemental oxygen therapy in normoxic patients with acute myocardial infarction offers no benefit and may be potentially harmful. 

Does supplemental oxygen improve outcomes in acute stroke patients who are not hypoxic? Patients with acute stroke were randomized to receive continuous supplemental oxygen for 72 h, nocturnal oxygen only for three consecutive nights, or no oxygen in the Stroke Oxygen Study.7 No significant difference was observed in death or disability at 3 months, assessed using the modified Rankin score. 

The association between supranormal oxygen levels and in-hospital mortality was examined in a multicenter cohort study among survivors of cardiac arrest. A PaO2 level of > 300 mm Hg carried a significantly higher in-hospital mortality compared to 60–300 mm Hg or < 60 mm Hg.8 This study suggests that supranormal oxygen levels may worsen reperfusion injury following cardiac arrest. 

Three contemporaneous studies have compared a conservative to a more liberal oxygenation target in mechanically ventilated patients. The Oxygen ICU study randomized mechanically ventilated patients targeting a PaOlevel between 70–100 mm or oxygen saturation (SpO2) of 94–98% in the conservative group.9 In the liberal group, PaO2 levels of up to 150 mm Hg was allowed, with an oxygen saturation between 97–100%. ICU mortality was significantly lower in the conservative group (25% vs. 44%, p = 0.01). Panwar et al. studied patients who were likely to require mechanical ventilation for more than 24 h.10 In the conservative group, the target SpO2 was 88–92% compared to more than 96% in the liberal group. No significant differences were observed in new onset organ dysfunction, intensive care or 90-day mortality between groups.

An observational cohort study involving three Dutch ICUs assessed the association between predefined metrics of hypoxia and clinical outcomes.11 Mild hyperoxia was defined as a PaOranging between 120 to 200 mm of Hg and severe hyperoxia as a PaOmore than 200 mm Hg. Logistic regression analysis was performed with each metric of hyperoxia using specific thresholds. A significant association was observed between severe hyperoxia and mortality rates; ventilator-free days were also less in patients with hyperoxia. A linear relationship was seen between the duration of hyperoxia and hospital mortality. 

Permissive hypoxia 

A U-shaped relationship has been demonstrated between PaO2 and hospital mortality; the lowest mortality being between 110-150 mm Hg. Mortality was higher at a PaOof <67 mm Hg and >225 mm Hg.12 There has been increasing focus on “permissive” hypoxia, in patients who might suffer adverse outcomes from interventions aimed to maintain oxygenation in the physiological range. It is also important to consider lung injury resulting from high FiOlevels besides the harmful effects of systemic hypoxemia. Permissive hypoxia must ensure a favorable balance between oxygen consumption and delivery. The parameters that may help assess adequacy of oxygen delivery include lactate levels, central venous oxygen saturation (>70%), central venous to arterial PaCOdifference (<6 mm Hg), and the ratio between the central venous and arterial venous PaCO2difference and the arterial to central venous PaOdifference (<1.23).13 Clinical evidence to support permissive hypoxia is lacking; the threshold levels below which harm may ensue is unknown and likely to vary depending on age, the underlying clinical condition, and the chronicity of hypoxia. In practice, targeting lower values of PaO2 (55-80 mmHg) may be safer compared to the adverse outcomes that may ensue from efforts at maintaining normoxia. 

The bottom line

  • High levels of inspired oxygen and PaOhave been well established to cause harm. Aiming for physiological levels of oxygenation with injurious ventilatory strategies are likely to be counterproductive. 
  • Several damage-limiting compensatory mechanisms are triggered by hypoxia; however, hyperoxia may lead to unmitigated harmful effects. 
  • Supplemental oxygen therapy is not beneficial and may lead to adverse outcomes in normoxic patients with acute myocardial infarction and acute stroke. 
  • The is a growing body of evidence that supports the use of conservative targets for oxygenation in critically ill patients. 
  • Permissive hypoxia may be appropriate in selected patients; however, the safe thresholds for permissible oxygen levels are unknown. 


1.        Martin DS, Grocott MPW. Oxygen Therapy in Critical Illness: Precise Control of Arterial Oxygenation and Permissive Hypoxemia*. Crit Care Med. 2013;41(2):423-432. doi:10.1097/CCM.0b013e31826a44f6

2.         Schumacker PT. Hypoxia-inducible factor-1 (HIF-1). Crit Care Med. 2005;33(12 Suppl):S423-425.

3.         MacIntyre NR. Tissue Hypoxia: Implications for the Respiratory Clinician. Respir Care. 2014;59(10):1590-1596. doi:10.4187/respcare.03357

4.         Farquhar H, Weatherall M, Wijesinghe M, et al. Systematic review of studies of the effect of hyperoxia on coronary blood flow. Am Heart J. 2009;158(3):371-377. doi:10.1016/j.ahj.2009.05.037

5.         Stub D, Smith K, Bernard S, et al. Air Versus Oxygen in ST-Segment–Elevation Myocardial Infarction. :8.

6.         Khoshnood A, Carlsson M, Akbarzadeh M, et al. Effect of oxygen therapy on myocardial salvage in ST elevation myocardial infarction: the randomized SOCCER trial. Eur J Emerg Med Off J Eur Soc Emerg Med. 2018;25(2):78-84. doi:10.1097/MEJ.0000000000000431

7.         Roffe C, Nevatte T, Sim J, et al. Effect of Routine Low-Dose Oxygen Supplementation on Death and Disability in Adults With Acute Stroke: The Stroke Oxygen Study Randomized Clinical Trial. JAMA. 2017;318(12):1125. doi:10.1001/jama.2017.11463

8.         Kilgannon J. Hope, Jones Alan E., Parrillo Joseph E., et al. Relationship Between Supranormal Oxygen Tension and Outcome After Resuscitation From Cardiac Arrest.Circulation. 2011;123(23):2717-2722. doi:10.1161/CIRCULATIONAHA.110.001016

9.         Girardis M, Busani S, Damiani E, et al. Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016;316(15):1583. doi:10.1001/jama.2016.11993

10.       Panwar R, Hardie M, Bellomo R, et al. Conservative versus Liberal Oxygenation Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial. Am J Respir Crit Care Med. 2016;193(1):43-51. doi:10.1164/rccm.201505-1019OC

11.       Helmerhorst HJF, Arts DL, Schultz MJ, et al. Metrics of Arterial Hyperoxia and Associated Outcomes in Critical Care*: Crit Care Med. 2017;45(2):187-195. doi:10.1097/CCM.0000000000002084

12.       de Jonge E, Peelen L, Keijzers PJ, et al. Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients. Crit Care. 2008;12(6):R156. doi:10.1186/cc7150

13.       He H, Liu D, Long Y, Wang X. High central venous-to-arterial CO2 difference/arterial-central venous O2 difference ratio is associated with poor lactate clearance in septic patients after resuscitation. J Crit Care. 2016;31(1):76-81. doi:10.1016/j.jcrc.2015.10.017

Decompressive Craniectomy for Severe Traumatic Brain Injury: Does It Make Life Worth Living?

Severe traumatic brain injury (TBI) due to focal or diffuse lesions leads to raised intracranial pressure (ICP). The normal ICP is less than 15 mm Hg; if the ICP remains persistently high, cerebral perfusion is compromised. Unrelieved intracranial hypertension culminates in irreversible neurological deterioration leading to fatal brain herniations. Raised ICP may be controlled by surgical evacuation of focal lesions when feasible and medical therapy including head end elevation, sedation, ventilation to normocarbia, osmotherapy, induced hypothermia, and metabolic suppression using barbiturate infusion. In refractory intracranial hypertension, a decompressive craniectomy (DC) is being increasingly performed, involving removal of a large segment of the skull and opening of the underlying dura mater.

It makes physiological sense to perform DC; if excessive pressure within the skull squashes the brain and leads to fatal herniation, opening the skull to relieve the pressure seems intuitive. Historically, the pressure-relieving effect of DC has been well known. In 1901, Kocher proposed DC for patients with raised ICP following TBI, followed by sporadic use of this technique over the years. Following its established efficacy in acute ischemic stroke,there has been an upsurge of interest in DC for severe TBI with intractable intracranial hypertension in recent times.

How does it work?  

According to the Munro-Kellie hypothesis, the intracranial compartment in inelastic. Increase in volume of any of the intracranial contents (brain, blood, or cerebrospinal fluid), is compensated by a shift of the remaining contents out of the skull. However, when compensatory mechanisms fail, the ICP begins to rise. Opening the rigid skull allows room for the intracranial contents to expand, thus relieving pressure. Maintenance of ICP between 20–25 mm Hg improves outcomes following TBI.2,3

Technique of DC

DC is performed to reduce ICP and prevent brain herniation. Craniectomy must be extensive allowing enough room for the brain to expand. A unilateral frontotemporoparietal craniectomy is commonly carried out for a unilateral focal lesion. The incision is approximately 2 cm lateral to the midline to prevent injury to the superior sagittal sinus. The anteroposterior diameter of the bone flap must be more than 15 cm and descend down to the base of the temporal fossa to enable adequate decompression (Figure 1). Bifrontal craniectomy is performed for diffuse lesions with generalized cerebral edema. Through a bicoronal skin flap, a frontotemporal bone flap is removed including the bone over the superior sagittal sinus (Figure 2). The dura is opened after removal of the bone flap followed by augmentative duroplasty.


Does DC improve clinical outcomes?

Although relief of life-threatening intracranial hypertension may seem rational and intuitive, does it really improve clinical outcomes in TBI? Two randomized controlled studies have addressed this all-important question. The DECRA study recruited 155 patients with severe, diffuse TBI between 2002–2010.Patients with an ICP of more than 20 mm Hg for more than 15 min during a 1-h period, either continuously or intermittently, despite optimal first-tier medical management were enrolled. DC was performed within the first 72 h of injury in the study group, while standard medical care was continued in the control group. The surgical technique involved a bifrontotemporoparietal craniectomy with bilateral dural opening. Predictably, patients who underwent DC had significantly lower ICP compared to those who received standard medical management alone. The composite primary outcome comprised of death, vegetative state, or severe disability corresponding to a score of 1–4 on the extended Glasgow outcome scale (GOS-E). At 6-month follow-up, the composite unfavorableoutcome was significantly higher among patients who underwent DC compared to those who received standard medical therapy alone (70% vs. 51%). The study had several limitations including a higher number of patients with non-reactive pupils in the DC arm. The ICP threshold for DC was considered too low and out of tune with real-world care. Furthermore, bifrontal craniectomy without sectioning of the falx may not have been the most optimal DC technique. Notwithstanding these limitations, DECRA suggested that relief of ICP with DC may not translate to improved clinical outcomes.

The RESCUE-ICP study enrolled 398 patients with severe TBI between 2004–2014 who had an ICP of more than 25 mm Hg for 1–12 h in spite of stage I and II treatments.Patients were randomized to undergo DC or continued medical treatment, including barbiturate infusion. In contrast to the DECRA study, patients who had undergone evacuation of an intracranial hematoma were included if a craniectomy had not been performed previously. A large frontotemporoparietal DC was carried out for unilateral lesions and bifrontal DC was performed for diffuse lesions, based on the judgment of the operating surgeon. The primary outcome was assessed using the GOS-E at 6 months. Patients were followed up at for 24 months after randomization. In the DECRA study, a favorable outcome was defined as a score of 5 or higher on the GOS-E; however, in the RESCUE-ICP study, a score of 4 or higher was defined as a favorable outcome. (It is important to note this difference; a score of 4 on the GOS-E indicates that the patient is able to be alone at home, without assistance, for a period of up to 8 h). At 6 m follow-up, mortality was significantly lower with DC; however, there was a higher incidence of vegetative state, lower and upper severe disability compared to medical therapy. On sensitivity analysis, at 6 months, a favorable GOS-E (4 or higher) was not significantly different between patients who underwent DC and those who did not.

The RESCUE-ICP study suggests that DC improves survival at the expense of severely disabled life. However, the culture, beliefs, and values of the community may be crucial in determining what may be an acceptable level of functional ability. For instance, a GOS-E of 4 indicates the ability to be alone at home, but unable to travel or shop independently. Many patients and families may consider this an acceptable outcome, especially among the Indian population. Another important consideration is the validity of these studies in settings where ICP monitoring is not routine, with decision-making based primarily on clinical examination and CT imaging.

The bottom line

  • DC as a relatively early intervention does not improve outcomes; it improves survival as a later intervention when first and second stage medical therapies fail.
  • Improved survival with DC may result in a life with significant disability; however, the degree of acceptable disability varies among populations.
  • A considered, patient and family-centered decision is important in deciding the most optimal therapy.
  • A subset of patients may benefit from DC; it may be challenging to identify or study this subgroup in randomized controlled trials.



  1. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6(3):215-222. doi:10.1016/S1474-4422(07)70036-4
  2. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial pressure monitoring. J Neurotrauma. 2007;24 Suppl 1:S37-44. doi:10.1089/neu.2007.9990
  3. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. VIII. Intracranial pressure thresholds. J Neurotrauma. 2007;24 Suppl 1:S55-58. doi:10.1089/neu.2007.9988
  4. Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive Craniectomy in Diffuse Traumatic Brain Injury. N Engl J Med. 2011;364(16):1493-1502. doi:10.1056/NEJMoa1102077
  5. Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension. N Engl J Med. 2016;375(12):1119-1130. doi:10.1056/NEJMoa1605215


Damage control resuscitation: redefining trauma management



Many conventionally held dogmas in trauma resuscitation have been disproven in the past decade. Generous use of crystalloids during the early resuscitation phase of trauma, recommended by the Advanced Trauma Life Support Course, based on earlier studies, has been largely shown to be harmful. Coagulopathy was considered unlikely with up to transfusion of six units of packed red cells. Supplementation with plasma and platelets was thought to be unnecessary unless there was clinical or laboratory evidence of coagulopathy. However, we know today that trauma-induced endogenous coagulopathy occurs at the onset of shock; besides, conventional tests of clotting function are poorly sensitive in coagulopathy associated with trauma. There has been a major shift in the resuscitation strategy of major trauma over the years. One of the most important tenets that have emerged in the management of severe trauma has been damage control resuscitation.

Let us consider the key elements of damage control resuscitation in major trauma.

Recognition of the actively bleeding patient

Damage control resuscitation applies specifically to the patient who is actively bleeding. Hypovolemia from ongoing blood loss is compensated by vasoconstriction, with the maintenance of normal heart rates and blood pressures. However, a fall in cardiac output and compromised organ perfusion occurs in this compensated state. In this state of cryptic shock, hemodynamic parameters may appear normal; however, it is associated with increased mortality (1). The response to a fluid bolus may help identify patients who are actively bleeding. Patients who respond to a fluid bolus and continue to remain stable may not have ongoing bleeding; however, non-responders and transient responders are likely to be actively bleeding. In practice, a considered decision on the likelihood of ongoing bleed must be made based on the nature of injuries and the response to the initial administration of a fluid bolus. If ongoing bleeding is suspected, packed red cells are preferred over crystalloids as the initial bolus of fluid.

Cut down crystalloid use

Administration of large volumes of crystalloids leads to major adverse outcomes in severe trauma. Dilution of clotting factors commonly occurs, leading to the perpetuation of coagulopathy associated with major trauma. Hypothermia is another adverse effect of the administration of large volumes of crystalloids. The excessive use of normal saline may lead to metabolic acidosis. Abdominal compartment syndrome with multiorgan failure may be associated with overzealous crystalloid resuscitation. Delayed fluid resuscitation was studied in patients with penetrating injury to the torso, who presented with a pre-hospital systolic blood pressure of 90 mm Hg or less. Patients were randomized to receive pre-hospital standard resuscitation or delayed resuscitation after reaching the operating room. Hospital mortality was significantly less with delayed resuscitation; the duration of hospital stay was also shorter in the delayed resuscitation group (2).

Permissive hypotension

The key to damage control resuscitation is the prioritization of hemorrhage control over perfusion. The blood pressure is maintained at a low level to prevent hydrostatic disruption of the clot. The lowest blood pressure required to maintain coronary perfusion is targeted during damage control resuscitation. Considering that coronary flow occurs mainly during diastole, a diastolic pressure of 25–30 mm Hg may be the minimum target; this may be extrapolated to a systolic pressure target of 60–70 mm Hg (3). For practical purposes, the presence of a radial pulse may be a rough indicator of an adequate level of perfusion (4). Measurement of lactate levels and the base deficit also offers important information on the circulatory state. A drop in the end-tidal carbon dioxide (ETCO2) levels is closely associated with decreasing cardiac output. Continuous monitoring of ETCOmay be useful in monitoring the hemodynamic status in patients who are intubated and ventilated.

It is unclear whether a strategy of permissive hypotension is appropriate in hemorrhaging patients with traumatic brain injury (TBI). There is strong evidence to suggest that even transient hypotension may lead to worse outcomes in TBI (5). No definite recommendations are available in this situation; however, it may be appropriate to follow a hypotensive strategy if the predominant clinical problem is ongoing major bleeding. However, if TBI appears to be the dominant pathophysiology, adequate cerebral perfusion pressures must be maintained (3).

Hemostatic resuscitation

Coagulopathy occurs in trauma by two different mechanisms. An early, endogenous coagulopathy occurs due to activation of protein C, resulting in the cleaving of factors Va and VIIIa with reduced thrombin generation. Degradation of fibrinogen and excessive fibrinolytic activity also contributes to the early, endogenous coagulopathy. During the later phase, dilutional coagulopathy secondary to resuscitation further exacerbates impairment of clotting function. Dilutional coagulopathy may be prevented using a balanced transfusion regimen, by administering an equal ratio of red cells, plasma, and platelets. Protocols using a balanced transfusion strategy have been shown to reduce mortality and mortality. The PROPPR trial compared the efficacy of a 1:1:1 ratio of plasma, platelets, and RBCs with a 1:1:2 ratio; although there was no difference in the 24 h and 28 d mortality, there were a lower number of deaths due to exsanguination with a 1:1:1 strategy (6). Fibrinogen levels may drop in spite of a 1:1:1 resuscitation strategy; it is important to maintain levels >2g/L with cryoprecipitate or fibrinogen concentrate.

Tranexamic acid has been shown to reduce blood loss and mortality in bleeding trauma patients. The CRASH II trial revealed a mortality reduction of 15% in patients with exsanguinating hemorrhage. Tranexamic acid must be administered within 3 h of injury; the initial dose is 1 gm followed by a repeat dose of 1 gm infused over 8 h (7).

It is important to note that conventional parameters of clotting function, including APTT and INR are poorly sensitive for the coagulopathy associated with major trauma; besides, they can only be tested intermittently. Point of care testing of coagulation function with thromboelastography (TEG) is being increasingly used to monitor trauma-induced coagulopathy. It is possible to assess the entire coagulation cascade including platelet function with TEG.

The bottom line

  • The traditional strategy of liberal crystalloid resuscitation aimed at hemodynamic optimization leads to adverse outcomes in trauma patients with active bleeding.
  • In patients who are actively bleeding, resuscitation should ideally commence with blood products.
  • Damage control resuscitation prioritizes hemorrhage control over optimization of hemodynamic parameters; permissive hypotension is an important element of this strategy.
  • Hemostatic resuscitation involves the transfusion of plasma and platelets in a 1:1:1 ratio. Conventional tests of coagulation are poorly sensitive in major trauma.
  • Future research is required to evaluate hemodynamic targets during damage control resuscitation and the management of actively bleeding patients with traumatic brain injury.



  1. Meregalli A, Oliveira RP, Friedman G. Occult hypoperfusion is associated with increased mortality in hemodynamically stable, high-risk, surgical patients. Crit Care Lond Engl. 2004 Apr;8(2):R60-65.
  2. Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994 Oct 27;331(17):1105–9.
  3. Harris T, Davenport R, Mak M, Brohi K. The evolving science of trauma resuscitation. Emerg Med Clin North Am. 2018 Feb;36(1):85–106.
  4. Giannoudi M, Harwood P. Damage control resuscitation: lessons learned. Eur J Trauma Emerg Surg. 2016 Jun;42(3):273–82.
  5. Spaite DW, Hu C, Bobrow BJ, Chikani V, Sherrill D, Barnhart B, et al. Mortality and prehospital blood pressure in patients with major traumatic brain injury: Implications for the hypotension threshold. JAMA Surg. 2017 Apr 1;152(4):360–8.
  6. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 Ratio and mortality in patients with severe trauma: The PROPPR randomized clinical trial. JAMA. 2015 Feb 3;313(5):471–82.
  7. Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess Winch Engl. 2013 Mar;17(10):1–79.


The endothelial glycocalyx, the modified Starling principle, and rational fluid therapy

History has witnessed intense debates on the behavior of intravenously administered fluids in critically ill patients. The basic concepts of capillary permeability have changed in recent times. There has been an increasing understanding of the crucial role played by the glycocalyx that lines the endothelium on the behavior of intravenously administered fluids.

The Starling principle

According to the Starling principle, movement of fluid across the capillary barrier is driven by the difference in the hydrostatic and colloid osmotic pressures between the capillaries and the interstitial space. The higher hydrostatic pressure within the capillaries tends to drive fluid out to the interstitium; the higher colloid osmotic pressure of the plasma tends to retain fluid within the capillaries. Thus, according to the Starling principle, the filtered volume per unit area is as follows:

Jv/A = Lp [(Pc–Pis) – σ (πc–πis)] (Fig. 1)

fig 1 mod


Fig 1. The Starling principle that governs the net movement of fluid from the capillaries to the interstitium. The difference between the capillary and interstitial hydrostatic pressures (Pc–Pis) tends to drive fluid out; the difference in colloid osmotic pressures (πc–πis) tends to retain fluid within the capillary lumen. 

Jv/A: filtered volume per unit area; Lp: hydraulic conductance; Pc: capillary hydrostatic pressure; Pis: interstitial hydrostatic pressure; σ: osmotic reflection coefficient; πc: capillary colloid osmotic pressure; πis: interstitial colloid osmotic pressure

The endothelial glycocalyx layer

Recent changes in the understanding of vascular permeability have led to changes in the concepts that guide transendothelial fluid movement. The key to the revised concept is the presence of the glycocalyx layer that lines the lumen of the vascular endothelium. The existence of this layer was unknown at the time that Starling proposed his hypothesis.

The glycocalyx is composed of proteoglycans including syndecans and glypicans. Attached to the central core of the proteoglycans are glycosaminoglycan (GAG) side chains, including heparan, chondroitin, dermatan, and keratin. The endothelial glycocalyx plays a crucial role in regulating vascular permeability. Furthermore, it regulates coagulation, fibrinolysis, and modulates shear stress on the vasculature. The glycocalyx suffers damage in several types of critical illnesses including sepsis, trauma, and following major surgery. Besides, ischemia-reperfusion injury, hypervolemia, hyperglycemia, and hypernatremia are known to cause shedding of the glycocalyx layer. Damage to the glycocalyx results in increased vascular permeability, platelet aggregation, adhesion of leukocytes, and leads to a prothrombotic state, typically seen is sepsis.

Revisions to the Starling principle

Based on the pivotal function of the glycocalyx, several important modifications have been made to the Starling principle.

Capillary filtration is less than predicted by the Starling principle

It has been consistently observed that filtration out of the capillaries to the interstitial space is much less than predicted by the Starling principle. This phenomenon is due to the presence of the sub-glycocalyx layer, a protein-free layer between the glycocalyx and the endothelium. The absence of protein essentially means that the sub-glycocalyx layer has a negligible colloid osmotic pressure. Thus, the Starling equation for calculation of the filtered fluid needs to be revised; specifically, the force that opposes filtration is the difference between the capillary (πc) and sub-glycocalyx (πg) colloid osmotic pressures. Clearly, (πc – πg) is much higher than (πc – πis), thereby, reducing the filtered volume per unit area, Jv/A.

Jv/A = Lp [(Pc– Pis) – σ (πc – πg)] (Fig. 2)

Fig 2 mod


Fig 2. The modified Starling principle. The difference between the capillary and interstitial hydrostatic pressures (Pc–Pis) tends to drive fluid out; however, the force that tends to retain fluid within the capillaris is the difference in colloid osmotic pressure between the capillary and the subglycocalyx layer (πc – πg)

Jv/A: filtered volume per unit area; Lp: hydraulic conductance; Pc: capillary hydrostatic pressure; Pis: interstitial hydrostatic pressure; σ: osmotic reflection coefficient; πc: capillary colloid osmotic pressure; πg: colloid osmotic pressure of the glycocalyx 

In clinical practice, at normal or low levels of Pc, the filtered volume is similar during intravenous administration of both crystalloids and colloids. This explains why in recent studies, resuscitation volumes required to achieve hemodynamic endpoints were similar with both crystalloids and colloids. In two trials of critically ill patients, 100 ml of normal saline was comparable to 62–76 ml of human albumin (1)and 63–69 ml of pentastarch, a synthetic colloid (2).

At higher levels of Pc, more filtration occurs with crystalloids compared to colloids, resulting in more efficient filling of the intravascular compartment with colloids.

The interstitial COP is not a major determinant of filtered volume

The interstitial COP is higher than originally assumed and plays very little role in determining the filtration rate. The main driver of filtration is the transendothelial hydrostatic pressure difference and the difference in COP between the plasma and the sub-glycocalyx layer.

Under most circumstances, there is no reabsorption of fluid from the interstitium to the capillaries

According to the Starling principle, fluid is filtered from the arterial end of capillaries and reabsorbed from the venous end. However, under most circumstances, there is no reabsorption of fluid from the interstitium to the capillaries. On the contrary, the filtered fluid is absorbed by the lymphatic system. Reabsorption of fluid back into the capillaries does not occur because the driving force for filtration, Pc, is higher than the forces that oppose filtration [Pis + (πc – πis)] throughout the capillary system.

Pc > Pis + (πc – πis)

Transient fluid reabsorption of about 500 ml may occur from the interstitium to the capillaries, for about 15–30 min after a sudden decrease in Pc. This may occur due to rapid loss of intravascular volume, for instance, from hemorrhage. However, equilibrium is reached after a transient phase of reabsorption, followed by continued filtration.

In clinical practice, this implies that the administration of colloids does not result in reabsorption of fluid from the interstitium back into the intravascular compartment; resolution of tissue edema does not happen with colloid use. On the contrary, if the glycocalyx is damaged, colloids may leak out from the capillaries and worsen edema.

Measures that may protect the glycocalyx

Several studies have shown improved clinical outcomes when a higher ratio of fresh frozen plasma to packed red cells is administered during major transfusion (3). A more liberal use of fresh frozen plasma may thus help preserve the glycocalyx following major transfusion. Adverse clinical outcomes associated with overzealous fluid resuscitation have emerged from many recent trials (4,5). Hypervolemia due to aggressive resuscitation may lead to damage to the glycocalyx and increased vascular permeability. There has been an intense debate on the optimal degree of glycemic control among critically ill patients (6,7). Avoidance of hyperglycemia may be one of the important strategies that may preserve the glycocalyx. Hydrocortisone may preserve the glycocalyx by attenuating possible damage by inflammatory mediators, especially TNF-alpha (8). It is possible that the purported clinical benefits observed with corticosteroid use in sepsis may be related to a favorable effect on the glycocalyx. Volatile anesthetic agents, especially sevoflurane may conserve the glycocalyx in post-ischemic coronary artery beds and improve coronary flow (9).

The bottom line

  • The presumed superiority of colloid resuscitation based on the Starling principle is a flawed concept.
  • In critically ill patients, the glycocalyx layer suffers damage, leading to leakage of both colloids and crystalloids.
  • Transendothelial filtration of fluid occurs to a similar extent with both crystalloids and colloids at normal or low capillary pressures.
  • Filtration occurs throughout the capillary bed; reabsorption does not occur except transiently following acute hypovolemia.
  • Reabsorption of fluid from the interstitium to the intravascular compartment and resolution of edema does not occur with the infusion of colloids.
  • Maintenance of normovolemia and normoglycemia may protect the glycocalyx; hydrocortisone may attenuate damage to the glycocalyx in septic patients. The glycocalyx-preserving effect of fresh frozen plasma during major transfusion needs further investigation.



  1. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247–56.
  2. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008 Jan 10;358(2):125–39.
  3. Gonzalez EA, Moore FA, Holcomb JB, Miller CC, Kozar RA, Todd SR, et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma. 2007 Jan;62(1):112–9.
  4. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011 Jun 30;364(26):2483–95.
  5. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564–75.
  6. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive Insulin Therapy in Critically Ill Patients. N Engl J Med. 2001 Nov 8;345(19):1359–67.
  7. Intensive versus Conventional Glucose Control in Critically Ill Patients. N Engl J Med. 2009 Mar 26;360(13):1283–97.
  8. Chappell D, Hofmann-Kiefer K, Jacob M, Rehm M, Briegel J, Welsch U, et al. TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol. 2009 Jan;104(1):78–89.
  9. Annecke T, Chappell D, Chen C, Jacob M, Welsch U, Sommerhoff CP, et al. Sevoflurane preserves the endothelial glycocalyx against ischaemia-reperfusion injury. Br J Anaesth. 2010 Apr;104(4):414–21.





Fluid resuscitation in septic patients: Is it a case of “less is more”?


In patients with septic shock, one of the key initial interventions is fluid resuscitation. The Surviving Sepsis Guidelines recommend an initial volume of resuscitation of 30 ml/kg, followed by additional boluses guided by volume responsiveness (1). In fact, most patients with septic shock receive around 5 liters of fluid in the first few hours of resuscitation (2).

Septic shock is characterized by widespread vasodilatation of vascular beds leading to hypotension. Besides, intravascular fluid leaks into the interstitial space due to capillary endothelial dysfunction. Administration of intravenous fluid enables filling up of the intravascular compartment and compensates for the loss of fluid into the interstitial space. Fluid replenishment may also improve perfusion pressures to the vital organs.

However, do the putative benefits of targeted fluid resuscitation lead to improved clinical outcomes in septic patients?

The evidence behind fluid resuscitation

In a landmark study, Rivers at al. randomized patients presenting to the emergency department with severe sepsis or septic shock to a protocolized, early, goal-directed therapy (EGDT) or to clinician-guided resuscitation targets (3). In the study arm, the resuscitative interventions included fluid boluses of 500 ml of crystalloid every 30 min targeting a central venous pressure of 8–12 mm Hg and vasopressors to achieve a mean arterial pressure of 65 mm Hg. The central venous oxygen saturation (ScvO2) was monitored continuously using a special catheter; packed red cells were transfused if the ScvOdropped below 70%. If the ScvOremained low in spite of all the above measures, a dobutamine infusion was commenced aiming to improve the cardiac output. Patients who received goal-directed therapy had significantly larger volumes of fluid resuscitation in the first 6 h (5.0 L vs 3.5 L). In-hospital mortality, the primary endpoint, was significantly lower in patients who received goal-directed therapy (30.5 vs. 46.5%, p = 0.009).

Several subsequent studies seem to ratify the findings of this single-center study from an emergency department in the US (4). However, it remained unclear whether the improvement in clinical outcomes was related to the overall impact of a “bundled” approach or due to specific elements of the bundle. Particularly, were the favorable effects due to earlier recognition of sepsis and appropriate antibiotic administration? Indeed, a recent meta-analysis suggests that the favorable effect on mortality may be more likely due to earlier administration of appropriate antibiotics compared to the effects of fluid resuscitation or attainment of hemodynamic targets (5).

More than a decade after the original EGDT trial, three randomized controlled studies were published that compared EGDT with usual care. The ProCESS (6), ARISE (7), and ProMISe (8)studies did not find any difference in any clinical outcomes, including mortality, with the use of EGDT. The volume of fluids administered during the first 6 h of resuscitation was similar across all the groups in these studies. However, it is important to note that the volume of fluid received by all the groups in the first 6 h was less than in either arm of the original EGDT study.

 Can fluid resuscitation cause harm?

The Fluid Expansion as Supportive Therapy (FEAST) study was conducted among children in sub-Saharan Africa,  who presented with a severe febrile illness and signs of impaired perfusion. In this provocative three-armed study, fluid boluses of 20 to 40 ml of 5% albumin or normal saline solution were compared with a control group who received no bolus fluid (9). The 48 h mortality was significantly higher in children who received bolus fluids compared to those who did not (10.5% vs. 7.3%, p = 0.003). Interestingly, although shock resolution occurred more often in the bolus groups, improved blood pressures did not translate to better survival.

The mean cumulative positive fluid balance has ranged from 5–11 liters in the first week of illness in previous studies among septic patients (10). Several observational studies have reported increased mortality with a higher cumulative fluid balance. The Vasopressin in Septic Shock Trial (VAAST) revealed a doubling of mortality among patients with the highest cumulative fluid balance (10). The Sepsis Occurrence in Acutely Ill Patients (SOAP) study also revealed similar findings, with a 10% excess mortality for every liter of positive fluid balance at 72 hours (11).  A fluid-conservative strategy was evaluated during the first week of illness in patients with acute respiratory distress syndrome (12). The mean cumulative fluid balance was –136 ± 491 ml vs. 6992 ± 502 ml (p < 0.001) in the fluid-conservative and fluid-liberal groups. A fluid-conservative strategy resulted in significantly less duration of mechanical ventilation and ICU stay.

A fluid-restrictive approach

An alternative strategy to liberal fluid resuscitation would be to limit fluid administration and use vasopressors early to maintain perfusion pressures and preserve organ function. Excessive fluid administration may raise venous pressures, leading to a reduction in the perfusion pressure to vital organs. Vasopressors decrease the venous capacitance, thereby, effectively increasing the venous return and cardiac output without overloading vital organs with excessive fluid and tissue edema. A restrictive approach may be justified as the response to intravenous fluid boluses is often transient; furthermore, fluid accumulation occurs over time leading to organ dysfunction involving the lungs, kidneys, and the heart. Besides, the effect of a fluid bolus among patients in circulatory shock may be transient; further fluid boluses may not improve the hemodynamic status even among apparent fluid-responders (13).

A forthcoming multi-center randomized controlled trial (CLOVERS) aims to compare a conventional resuscitation strategy with a fluid-restrictive approach during the first 24 h in patients with septic shock. The liberal strategy will use conventional fluid therapy similar to the control arms of the ProCESS, ARISE, and ProMISe studies. The fluid-restrictive approach will involve early vasopressor administration with lower volumes of initial resuscitation fluid.

The bottom line

  • The landmark EGDT study and subsequent accumulated evidence has led to widespread adoption of targeted fluid resuscitation in septic patients.
  • Excessive fluid administration and a cumulative positive balance may lead to fluid overload, edema, and dysfunction of vital organs.
  • Recent evidence supports the possibility of clinical harm from overzealous fluid administration.
  • An alternative approach may be to restrict the volume of resuscitation fluid and use vasopressors early to maintain perfusion pressure to vital organs.
  • The optimal volume of initial fluid administration and hemodynamic targets remain unclear and require further studies.


  1. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018 Jun;44(6):925–8.
  2. Nguyen HB, Jaehne AK, Jayaprakash N, Semler MW, Hegab S, Yataco AC, et al. Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. Crit Care Lond Engl. 2016 Jul 1;20(1):160.
  3. Emanuel R, Bryant N, Suzanne H, Julie R, Alexandria M, Bernhard K, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med. 2001;10.
  4. Trzeciak S, Dellinger RP, Abate NL, Cowan RM, Stauss M, Kilgannon JH, et al. Translating research to clinical practice: a 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest. 2006 Feb;129(2):225–32.
  5. Kalil AC, Johnson DW, Lisco SJ, Sun J. Early Goal-Directed Therapy for Sepsis: A Novel Solution for Discordant Survival Outcomes in Clinical Trials. Crit Care Med. 2017 Apr;45(4):607–14.
  6. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683–93.
  7. ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496–506.
  8. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301–11.
  9. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011 Jun 30;364(26):2483–95.
  10. Boyd JH, Forbes J, Nakada T, Walley KR, Russell JA. Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality*. Crit Care Med. 2011 Feb 1;39(2):259–65.
  11. Vincent J-L, Sakr Y, Sprung C, Ranieri V, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: Results of the SOAP study*. Crit Care Med. 2006 Feb 1;34(2):344–53.
  12. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564–75.
  13. Nunes TSO, Ladeira RT, Bafi AT, de Azevedo LCP, Machado FR, Freitas FGR. Duration of hemodynamic effects of crystalloids in patients with circulatory shock after initial resuscitation. Ann Intensive Care [Internet]. 2014 Dec [cited 2019 Apr 6];4(1). Available from:







Renal Replacement Therapy in Acute Kidney Injury: It Is All About Timing!

Intensive care physicians often face the conundrum of deciding when to consider renal replacement therapy (RRT) in acute kidney injury (AKI). RRT may be commenced for the early correction of metabolic complications and prevention of volume overload. However, an early strategy may entail unnecessary therapy for some patients who might recover renal function otherwise. Even more concerning is the perpetuation of damage that may occur due to the hemodynamic instability that often accompanies RRT. The proximal tubules located at the corticomedullary junction are particularly vulnerable to ischemic insult. The partial pressure of oxygen at this region is less than 40 mm Hg, which increases the susceptibility of the tubular cells to RRT-induced damage (1) (Fig 1). Hence it is critically important to decide on the requirement for RRT and to initiate therapy at the optimal time.


Fig 1. The corticomedullary junction (marked in red) has a low partial pressure of oxygen (less than 40 mm Hg). The relatively low partial pressure of oxygen makes the proximal tubular cells vulnerable to ischemic insult that may occur during renal replacement therapy

Many of the older studies that support early RRT have been observational in nature (2); besides, the overall management of critically ill patients has changed considerably over the years. Hence, it is appropriate to reconsider the impact of the timing of RRT, particularly with new information available from the more recent randomized controlled studies.

The ELAIN study involved 231 postoperative patients (47% cardiac surgical) with AKI from a single center in Germany (3). The early group was randomized to receive RRT within 8 h of the diagnosis of AKI, KDIGO stage 2; the late group was randomized to undergo RRT within 12 hours of reaching KDIGO stage 3. Besides, at least one of the following conditions had to be present, including severe sepsis, catecholamine use, refractory fluid overload, and new-onset or worsening of non-renal organ dysfunction. All 112 patients randomized to the early group received RRT, compared to 108/119 patients in the late group. The 90-d mortality, the primary outcome, was significantly lower in the early group. Approximately 75% of all patients had evidence of fluid overload according to the pre-defined criteria. This raises the question of whether RRT may have been delayed among patients who had evidence of fluid overload but were randomized to the late group, leading to worse outcomes in this group of patients. Besides, the fragility index for the primary outcome was only 3 patients (the results would have been non-significant if 3 extra patients had suffered 90-day mortality in the early group). Besides, it is hard to explain a mortality benefit at 90 d, with no difference in the 28 and 60 d mortality.

Patients in KDIGO stage 3 were randomized to receive early or late RRT in the AKIKI study (4). In the early group, RRT was initiated immediately after randomization. In the late group, RRT was performed if any of the following criteria were present: K+> 6.0 mmol/l (> 5.5 mmol/l after corrective measures), BUN > 112 mg/dl, pH < 7.15, and acute pulmonary edema due to fluid overload. In the early group, 305/311 (98.1%) received RRT, while only 157/308 (51%) patients in the late group underwent RRT. There was no significant difference in mortality between groups on day 60, which was the primary outcome of the study. Thus, in the AKIKI study, nearly half of all patients who were randomized to the late group did not require RRT but did not suffer adverse outcomes.

The IDEAL-ICU investigators, in a multicentric French study, randomized patients in early-stage septic shock who were in the failure stage (stage F) of the RIFLE classification (5). The early group received RRT within 12 h of documentation of stage F; the late group underwent RRT after 48 h if renal recovery had not occurred in the meantime. The primary outcome was 90-d mortality. The study was stopped for futility after a second interim analysis. No difference was observed in the 90-d mortality between the early and late groups (58% vs. 54%, p = 0.38). In the late group, 38% of patients did not receive RRT.

The AKIKI and the IDEAL-ICU studies suggest that in the absence of life-threatening complications, a delayed strategy may be appropriate in most patients with AKI. Such a strategy may facilitate avoidance of RRT, with its associated complications. In fact, these studies reinforce the view that initiation of RRT should not be based on the AKI stage; it may be more appropriate to be guided by the presence of complications, including fluid overload and metabolic abnormalities. Furthermore, a strategy of watchful waiting may enhance the possibility of renal recovery. In contrast, RRT-related hemodynamic instability may lead to worsening or perpetuation of renal damage and adversely impact recovery.

It is also important to assess the trajectory of the underlying disease process and the presence of failure of other organs while considering RRT. If the patient is clinically improving with the resolution of other organ failures, perhaps a waiting strategy would be more appropriate. However, if the metabolic demands continue to remain high with a continued requirement for fluid resuscitation, it may be necessary to consider early RRT. In such situations, the metabolic and fluid demands far exceed the capacity of the kidney necessitating prompt supportive therapy. The “frusemide test” was used to identify patients who are likely to require renal replacement therapy in a previous study (6). It involves the administration intravenous frusemide, 1.0 mg/kg to frusemide-naïve patients and 1.5 mg/kg to those already on frusemide. A urine output of less than 200 ml in the ensuing 2 h was highly predictive of patients who required RRT.

The bottom line

  • Previous observational studies of AKI seemed to suggest that an early-RRT strategy may lead to more favorable clinical outcomes.
  • Recent randomized controlled trials reinforce the view that a delayed strategy may be appropriate in the absence of life-threatening complications of AKI.
  • Apart from the complications directly related to therapy, hemodynamic perturbations during RRT may adversely impact recovery of renal function.
  • The decision to perform RRT will also depend on the trajectory of the underlying illness and metabolic demand.
  • Fastidious conformance to physiological or biochemical parameters is unlikely to be helpful with the timing of initiation of RRT.
  • A holistic, individualized strategy based on clinical, physiological, and biochemical parameters is more likely to be beneficial compared to a “one-size-fits-all” approach.



  1. Gaudry S, Quenot J-P, Hertig A, Barbar SD, Hajage D, Ricard J-D, et al. Timing of Renal Replacement Therapy for Severe Acute Kidney Injury in Critically Ill Patients. Am J Respir Crit Care Med [Internet]. 2019 Feb 20 [cited 2019 Mar 21]; Available from:
  2. Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury. J Crit Care. 2009 Mar;24(1):129–40.
  3. Zarbock A, Kellum JA, Schmidt C, Van Aken H, Wempe C, Pavenstädt H, et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016 May 24;315(20):2190.
  4. Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Pons B, Boulet E, et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375(2):122–33.
  5. Barbar SD, Clere-Jehl R, Bourredjem A, Hernu R, Montini F, Bruyère R, et al. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018 Oct 11;379(15):1431–42.
  6. Lumlertgul N, Peerapornratana S, Trakarnvanich T, Pongsittisak W, Surasit K, Chuasuwan A, et al. Early versus standard initiation of renal replacement therapy in furosemide stress test non-responsive acute kidney injury patients (the FST trial). Crit Care Lond Engl. 2018 Apr 19;22(1):101.



Superbugs vs. superdrugs: are we waging a losing battle?


Intensive care units (ICUs) are the breeding grounds for resistant microorganisms. The use of invasive devices that breach physiological defensive barriers predispose to nosocomial infections in ICUs. A state of “immunoparalysis” often accompanies critical illness, including sepsis, trauma, and major surgery. Furthermore, therapy with powerful, broad-spectrum antibiotics, appropriate or otherwise, is common in the ICU, contributing to the preponderance of drug-resistant microorganisms.

The most frequently encountered resistant pathogens in the ICU include:

  • Carbapenem-resistant Enterobacteriaceae
  • Multidrug-resistant Pseudomonas aeruginosa, Acinetobacter spp, and Stenotrophomonas maltophilia
  • Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE)

In this review, we shall focus on resistant gram-negative pathogens that are commonly encountered in ICUs.

Carbapenemase-producing Enterobacteriaceae

The family of Enterobacteriaceae includes Escherichia coli, Klebsiella pneumoniae, and Enterobacter species, and commonly cause gram-negative bacteremia, intra-abdominal, and urinary tract infections. Infection with resistant Enterobacteriaceae results in poor clinical outcomes, including high mortality, in addition to the increased cost of care. Carbapenem resistance is conferred by the production of the hydrolyzing enzyme carbapenemase, an extended-spectrum beta-lactamase (ESBL). Carbapenemases are carried on genetic material including transposons and plasmids and transmitted extensively to other bacterial genera. Pseudomonas aeruginosa and Acinetobacter baumanni can also acquire carbapenem resistance through mechanisms other than carbapenemase production.

Beta-lactamases are classified based on the amino acid sequence into 4 types (Ambler classification).

  • Class A: Penicillinases, including Klebsiella pneumoniae carbapenemase (KPC). KPC confers resistance to most beta-lactams; besides, KPC can be transmitted from Klebsiella to other Enterobacteriaceae and Pseudomonas aeruginosa.
  • Class B: Metallo-beta-lactamases (MBL), including the New Delhi metallo-beta-lactamase (NDM-1). NDM-1-producing bacteria have been isolated from tap water and sewage effluents from New Delhi (1). Metallolactamases mediate resistance to all beta-lactamase inhibitors
  • Class C: Cephalosporinases
  • Class D: Oxacillinases, which hydrolyze oxacllin and hence referred to as OXA-type; some beta-lactamase inhibitors can neutralize them. Enterobacteriaceae and Acinetobacer baumanni are known to produce OXA-type carbapenemases.

Carbapenems are generally considered as the most effective therapy against resistant pathogens; however, there is an ever-increasing proliferation of carbapenem-resistant pathogens in ICUs all over the world. The mortality rate associated with carbapenem resistance may be 24–70% (2).

Faced with a daunting milieu of highly resistant, potentially lethal pathogens, what are our therapeutic options?  Several new antimicrobials have been added to our therapeutic armamentarium; besides some older antibiotics that have re-emerged as possible treatment options.

A common mechanism of resistance to carbapenem is through the production of Klebsiella pneumoniae carbapenemases (KPC). KPC is produced by several enterobacterial species; besides carbapenems, they confer resistance against penicillins, cephalosporins, and monobactams. Polymyxins, generally colistimethate (polymyxin E) is the preferred treatment for KPC-producing organisms if the isolate is sensitive. Polymyxins are often used in combination, usually with meropenem, if the minimum inhibitory concentration (MIC) for meropenem is less than 8–12 mcg/ml. Combination therapy with meropenem may not be superior to monotherapy with polymyxin if the MIC for meropenem is more than 16 mcg/ml (3). An emerging therapeutic option is the combination of ceftazidime, a third-generation cephalosporin with the novel beta-lactamase inhibitor, avibactam. Avibactam is more potent and active against a wider range of beta-lactamases including Amber class A, C, and D. The ceftazidime-avibactam combination was non-inferior to imipenem-cilastatin in complicated urinary tract infections, including acute pyelonephritis (4). In another study, a combination of ceftazidime-avibactam and metronidazole was shown to be equivalent to meropenem in the treatment of complicated intra-abdominal infections (5). This combination is an emerging therapeutic option for infections caused by carbapenemase-producing Enterobacteriaceae and has been approved by the FDA for the treatment of complicated urinary tract and intra-abdominal infections. The combination of meropenem with vaborbactam, another novel beta-lactamase inhibitor, may also be effective in the treatment of infection with KPC-producing organisms, although it requires further studies to establish clinical efficacy.

A polymyxin-based combination as described previously is generally preferred for metallo-lactamase producers. If the isolate is colistin resistant, the options are limited, as beta-lactamase inhibitors are ineffective against metallo-lactamases. However, ceftazidime-avibactam combined with aztreonam has been successfully used in this situation (6). This combination may have a synergistic effect as avibactam may inhibit beta-lactamases other than metallo-lactamases and enhance the effectiveness of aztreonam.

The new aminoglycoside antibiotic, plazomycin is another new antibiotic that may be useful in the treatment of carbapenemase-producing Enterobacteriaceae. Unaffected by carbapenemase, it is effective against beta-lactamase producing K. pneumoniae, E. coli, and Enterobacter species. However, it may be less effective against NDM-1 producers. Plazomycin was shown to be equally effective compared to levofloxacin in the treatment of complicated urinary tract infections (7). Besides, the nephrotoxic and ototoxic effects may be less compared to other aminoglycosides.


Intravenous fosfomycin has excellent penetration into tissues and body fluids including lungs, soft tissue, bone, urinary bladder, and the central nervous system. It has a broad spectrum of activity against gram-positive and gram-negative bacteria. The efficacy against carbapenemase-producing Enterobacteriaceae is variable. It is mainly used in urinary tract infections as it is excreted in the urine and works optimally in an acidic environment. There are anecdotal reports of its efficacy against NDM-1 producing Enterobacteriaceae (8). Fosfomycin is moderately effective against pseudomonas; however, Acinetobacter and anaerobic organisms are poorly susceptible. It is advisable to use fosfomycin as part of combination therapy as evidence for its efficacy as monotherapy is currently unclear.


Another re-emerging antibiotic, minocycline has evinced renewed interest in the treatment of multi-drug resistant infections. A tetracycline class of antibiotic, minocycline has been showed to be effective against infections caused by Acinetobacter baumanni. It has been successfully used in combination with colistin, meropenem, and aminoglycosides in carbapenem-resistant bloodstream infections caused by Klebsiella pneumoniae. It may result in higher serum levels compared to tigecycline; besides, it has relatively few side effects and carries the option of scaling down to oral therapy. The FDA has approved its use in urinary tract infections.

Pseudomonas aeruginosa and Acinetobacter baumanni resistant to carbapenems

Carbapenem-resistant A. baumannii and P. aeruginosa are usually resistant to all beta-lactams and fluoroquinolones. Polymyxins, usually colistimethate, are commonly used solely or in combination to treat multi-drug resistant infections due to these organisms. Besides, for ventilator-associated pneumonia and tracheobronchitis, aerosolized colistin may be administered. Aerosolized colistin has minimal systemic absorption and hence may be safely used in renal dysfunction. However, it is doubtful if aerosolized therapy alone is efficacious in lung infections.

Colistin resistance in A. baumanni and P. aeruginosa is bad news. Carbapenem-resistant A. baumanni may be susceptible to tigecycline; another option is eravacycline, the novel synthetic fluorocycline, which is 2–4 times more potent than tigecycline. Eravacycline was comparable to imipenem in the treatment of complicated intra-abdominal infections (9). Although sulbactam is another therapeutic option for multi-drug resistant A. baumanni, most isolates have reduced susceptibility. Ceftazidime-avibactam may not be effective against most isolates of carbapenem-resistant P. aeruginosa and A. baumanni. Aztreonam may be a potential therapeutic option against carbapenem-resistant P. aeruginosa; however, corroboratory clinical evidence regarding efficacy is lacking.

The bottom line

  • Carbapenemase-producing gram-negative pathogens pose an increasing threat worldwide and therapeutic options are limited. These organisms are resistant to most other classes of antibiotics. Among the most worrisome are KPC-producing pathogens.
  • The ceftazidime-avibactam combination is preferred for KPC-producing organisms.
  • Possible therapeutic options are re-emergent, older drugs, including colistin, fosfomycin, and minocycline; novel agents that may have an increasing role to play include ceftazidime-avibactam, plazomycin, and eravacycline.
  • The optimal dosing regimen is unclear with many of the newer drugs.
  • Metallo-lactamases, including NDM-1 have proliferated across ICUs in India.
  • Beta-lactamase inhibitors are largely ineffective against metallo-lactamase producing pathogens; colistin remains the preferred therapeutic option.
  • Although combination therapy is often preferred in resistant infections, there is no corroboratory clinical evidence.
  • Clinical studies are urgently required to adequately assess the efficacy of newer agents in the real world.



  1. Walsh TR, Weeks J, Livermore DM, Toleman MA. Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study. Lancet Infect Dis. 2011 May;11(5):355–62.
  2. Thaden JT, Pogue JM, Kaye KS. Role of newer and re-emerging older agents in the treatment of infections caused by carbapenem-resistant Enterobacteriaceae. Virulence. 2017 May 19;8(4):403–16.
  3. Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis Off Publ Infect Dis Soc Am. 2012 Oct;55(7):943–50.
  4. Vazquez JA, González Patzán LD, Stricklin D, Duttaroy DD, Kreidly Z, Lipka J, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded, randomized study. Curr Med Res Opin. 2012 Dec;28(12):1921-31
  5. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, et al. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis Off Publ Infect Dis Soc Am. 2016 01;62(11):1380–9.
  6. Shaw E, Rombauts A, Tubau F, Padullés A, Càmara J, Lozano T, et al. Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection. J Antimicrob Chemother. 2018 Apr 1;73(4):1104–6.
  7. Connolly LE, Riddle V, Cebrik D, Armstrong ES, Miller LG. A Multicenter, Randomized, Double-Blind, Phase 2 Study of the Efficacy and Safety of Plazomicin Compared with Levofloxacin in the Treatment of Complicated Urinary Tract Infection and Acute Pyelonephritis. Antimicrob Agents Chemother. 2018;62(4).
  8. Denis C, Poirel L, Carricajo A, Grattard F, Fascia P, Verhoeven P, et al. Nosocomial transmission of NDM-1-producing Escherichia coli within a non-endemic area in France. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2012 May;18(5):E128-130.
  9. Solomkin J, Evans D, Slepavicius A, Lee P, Marsh A, Tsai L, et al. Assessing the Efficacy and Safety of Eravacycline vs Ertapenem in Complicated Intra-abdominal Infections in the Investigating Gram-Negative Infections Treated With Eravacycline (IGNITE 1) Trial: A Randomized Clinical Trial. JAMA Surg. 2017 01;152(3):224–32.












Tidal volume and plateau pressure vs. driving pressure targeted ventilator management in ARDS


Mechanical ventilation in acute respiratory distress syndrome (ARDS) aims to maintain gas exchange and support respiratory muscles during the critical phase of illness. It is important to prevent possible harm from ventilation-induced lung injury (VILI) during this period. Limiting tidal volumes to 6 ml/kg of predicted body weight and plateau pressures to 30 cm of H2O are considered to be crucial in preventing VILI (1). However, ARDS is characterized by non-homogenous involvement of the lung; the extent of relatively normal lung available for ventilation is highly variable and has been conceptualized as the “baby lung”(2). Hence, a ventilation strategy targeting tidal volume based on the predicted body weight may result in hyperinflation of relatively normal lungs and lead to VILI (3).

Cyclic strain leads to mechanical stress and triggers VILI. The difference between the plateau pressure (Pplat) and PEEP, known as the driving pressure (ΔP) may be a surrogate for the degree of cyclic strain.

Driving pressure (ΔP) = Pplat – PEEP

Lung compliance (CRS) = ΔV/ ΔP

Hence, ΔP = ΔV/ CRS

As evident from this equation, to maintain a constant driving pressure, the tidal volume (ΔV) must decrease as the compliance decreases. Hence, the tidal volume will need to be adjusted based on compliance to control the driving pressure. Targeting tidal volume based on predicted body weight, on the contrary, may lead to excessive driving pressures and cause VILI.

Amato et al. re-analyzed data involving 3562 patients with ARDS from nine randomized controlled trials (4). A statistical methodology called multilevel mediation analysis was used to evaluate the impact of the driving pressure as an independent predictor of survival. Four parameters, including tidal volume, Pplat, PEEP, and driving pressure were tested for possible association with survival. Three important findings were observed. 1. For a constant level of PEEP, mortality increased as the driving pressure increased (Fig. 1); 2. A higher Pplat did not increase mortality if the driving pressure was maintained constant (Fig. 2); 3. Even with similar Pplat, the mortality decreased as the driving pressure decreased (Fig. 3) (for the same Pplat, the driving pressure becomes lower with an increase of PEEP). In simple terms, even if the Pplat rose, the mortality was higher only if driving pressure increased. Another interesting finding was that the tidal volume predicted survival only if it was adjusted for compliance. The tidal volume did not predict survival when adjusted for the predicted body weight.



Fig. 1 For a constant level of PEEP (red  bracket) the mortality increased with an increase of driving pressure (green bracket)



Fig. 2 A higher Pplat did not increase mortality if the driving pressure (green bracket) remained constant 



Fig 3. At constant Pplat, the mortality decreased with lower driving pressures (green bracket) (Figures adapted from Amato MBP, Meade MO, Slutsky AS, Brochard L, Costa ELV, Schoenfeld DA, et al. Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. N Engl J Med. 2015 Feb 19;372(8):747–55)

Aoyoma et al. performed a meta-analysis including secondary analyses of five randomized controlled and two observational studies to assess the mortality risk associated with high driving pressures (5). They found a significant association of higher driving pressures with increased mortality among patients with ARDS (RR, 1.44; 95% CI, 1.11–1.88). From a sensitivity analysis of three studies with similar driving pressure thresholds, the authors suggested a target driving pressure of 13–15 cm of H2O.

Lung stress (calculated from esophageal and airway pressures), driving pressure, and lung and chest wall elastance were studied in 150 patients with ARDS at PEEP levels of 5 and 15 cm H2O (6). At both PEEP levels, increasing driving pressures were significantly associated with lung stress. The optimal cutoff value of driving pressure was 15 cm of H2O to prevent significant lung stress.

The driving pressure may also be useful as a tool to titrate PEEP for optimizing lung recruitment. Lower driving pressures for a constant tidal volume with increasing levels of PEEP suggests improved compliance and potential for recruitment (7).

VILI may be conceptualized to occur from excessive mechanical power applied to the lung (8). The mechanical power may be directly related to the driving pressure; high tidal volumes probably contribute to the damage indirectly through an increase in driving pressures. The mechanical power applied to the lung may also be a function of the respiratory rate. The lack of benefit with high-frequency oscillation ventilation, despite minimal tidal excursions, may be related to the rate-related increase in mechanical power.

There are several caveats to the application of the concept of driving pressure to clinical practice. First, the driving pressure may be significant only within the range of airway pressures commonly employed in clinical practice (Pplat less than 40 and PEEP more than 5 cm of H2O). Second, measurement of Pplat and driving pressure in spontaneously breathing patients is unreliable; hence driving pressure-guided ventilation is applicable only in patients who do not have spontaneous breathing efforts. Third, most of the available data are based on secondary analysis from previous randomized controlled studies. Controlled studies comparing driving pressure-guided with tidal volume and Pplat-guided ventilatory management are required to validate the applicability of driving pressure in clinical practice; besides, optimal cutoff levels for driving pressure need to be defined.

The bottom line

  • A ventilatory strategy targeting tidal volume and plateau pressure may not prevent VILI.
  • Conventionally accepted limits for “low” tidal volume may lead to hyperinflation and injury to relatively normal lung regions in ARDS.
  • The driving pressure (Pplat – PEEP) may be a more significant determinant of the mechanical power applied to the lungs.
  • Secondary analysis of previous randomized controlled studies of ARDS suggests that a higher Pplat does not increase mortality at constant driving pressures.
  • Similarly, a lower driving pressure may reduce mortality for the same level of Pplat.
  • Based on the limited evidence available, a target driving pressure of 13-15 cm of H2O may be appropriate to prevent VILI.
  • Controlled studies are required to validate the superiority of driving pressure targeted ventilator management with a tidal volume and Pplat-guided approach.



  1. Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome. N Engl J Med. 2000 May 4;342(18):1301–8.
  2. Gattinoni L, Pesenti A. The concept of “baby lung.” Intensive Care Med. 2005 Jun;31(6):776–84.
  3. Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007 Jan 15;175(2):160–6.
  4. Amato MBP, Meade MO, Slutsky AS, Brochard L, Costa ELV, Schoenfeld DA, et al. Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. N Engl J Med. 2015 Feb 19;372(8):747–55.
  5. Aoyama H, Pettenuzzo T, Aoyama K, Pinto R, Englesakis M, Fan E. Association of Driving Pressure With Mortality Among Ventilated Patients With Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis*. Crit Care Med. 2018 Feb;46(2):300–6.
  6. Chiumello D, Carlesso E, Brioni M, Cressoni M. Airway driving pressure and lung stress in ARDS patients. Crit Care [Internet]. 2016 Aug 22 [cited 2019 Mar 4];20. Available from:
  7. Aoyama H, Yamada Y, Fan E. The future of driving pressure: a primary goal for mechanical ventilation? J Intensive Care [Internet]. 2018 Dec [cited 2019 Mar 4];6(1). Available from:
  8. Gattinoni L, Quintel M. How ARDS should be treated. Crit Care [Internet]. 2016 Dec [cited 2019 Mar 4];20(1). Available from:


The rocket science behind PEEP titration in ARDS


The acute respiratory distress syndrome (ARDS) was first described half a century ago by Ashbaugh et al. (1). They considered several therapeutic options to combat refractory hypoxemia and proposed that appropriate titration of positive end-expiratory pressure (PEEP) may be the sole effective intervention. Ever since the publication of this seminal paper, the pursuit of an adequate level of PEEP has never ceased to intrigue intensivists. Let us consider the physiology behind the application of PEEP and how it may be titrated to an ideal level.

Titration of PEEP to improve oxygenation

PEEP may be targeted to improve oxygenation; many intensivists aim for this easily discernible endpoint by the bedside. PEEP may also be used as part of an overall strategy aimed at lung protection. Conventionally, the inspiratory limb of the pressure-volume curve has been the focus of attention in an attempt to find the optimal pressure that will enable an open lung approach. However, lung recruitment is not confined to a single point such as the lower inflection point of the pressure-volume curve; it occurs throughout the inspiratory limb. The extent of lung recruitment increases with increasing inspiratory pressure. Thus, recruitment is essentially an inspiratory phenomenon. In contrast, PEEP is an expiratory phenomenon that prevents de-recruitment during the expiratory phase. Besides, it is important to note that for any level of airway pressure, the lung volume is higher during expiration compared to inspiration (Fig. 1). Hence, it may be more appropriate to titrate PEEP based on the deflation limb of the pressure-volume curve (2). Aiming for improvement in oxygenation as the sole target may also have several pitfalls. ARDS is a non-homogenous disease process; attempts to recruit non-ventilated regions of the lung invariably leads to overdistension of areas of the lung that are better ventilated. Overdistension may lead to a rise in the pulmonary artery and right ventricular pressures, leading to a fall in cardiac output. Any fall in cardiac output and impaired oxygen delivery may offset the advantage gained by improvement in arterial oxygen levels.


Fig 1. The pressure-volume curve of the lung. For a given level of pressure, the lung volume is higher during expiration compared to inspiration. Green arrow: Lower inflection point; red arrow: upper inflection point

Titration based on compliance

This method involves the upward titration of PEEP until the static compliance ceases to rise. Pintado et al. increased PEEP levels in a step-wise manner based on static compliance (3). The PEEP level that resulted in the highest static compliance was chosen in the intervention group. In the control group, PEEP was applied based on the FiO2, as recommended in the ARDS-net study. Patients who received best compliance-based PEEP levels had significantly more multiorgan dysfunction-free days. There were non-significant improvements in the PaO2/FiO2ratios in the initial 14 days of treatment and the 28-day mortality.

CT and ultrasound-guided lung recruitment

Would CT imaging help to assess recruitability and appropriate titration of PEEP? Cressoni et al. performed CT scans at PEEP levels of 5 and 45 cm of H2O and attempted to calculate the optimal level of PEEP (4). This theory assumes that PEEP constitutes the pressure required to elevate the chest wall and non-dependent lung that leads to compression and gravity-induced collapse of the dependent lung regions. However, no correlation could be found between CT-guided PEEP values and the extent of lung recruitment. Besides, repeated transfer of sick patients for CT makes this an unwelcome option. Repeated ultrasound imaging may also guide the clinician in choosing the appropriate level of PEEP. A progressive reduction in the extent of lung collapse with increasing PEEP is relatively easy to visualize by ultrasonography (Fig. 2). A significant limitation of this strategy may be the relative inability to view deeper regions of the lung by ultrasonography.


Fig 2. Ultrasonography-based titration of PEEP. Progressive recruitment of collapsed lung is seen from panel A to C

PEEP titration based on transpulmonary pressure

Maintenance of positive airway pressure alone may be insufficient to prevent alveolar collapse, especially at end-expiration. A higher pleural pressure compared to applied PEEP may lead to lung collapse. A non-compliant chest wall and increased intra-abdominal pressure may lead to variable pleural pressures in mechanically ventilated patients.

The distending pressure of the lung (which maintains the lung open) is the transpulmonary pressure:

Transpulmonary pressure = airway pressure – pleural pressure

The esophageal pressure is considered to be a reasonable surrogate of the pleural pressure. The transpulmonary pressure needs to be positive throughout the respiratory cycle to prevent derecruitment. Beitler et al. titrated PEEP levels to maintain the end-expiratory transpulmonary pressure equal to or higher than the esophageal pressure (between 0–6 cm H2O higher than the esophageal pressure) and compared it with PEEP settings based on a PEEP–FiOtable (5). The composite primary outcome of death and ventilation-free survival through day 28 did not differ significantly between groups. Pre-specified secondary outcomes, including 28-day mortality, ventilation-free days, and the need for rescue therapy were also not significantly different. Although titration of PEEP based on end-expiratory pleural pressures is based on strong physiological grounds, it requires further investigation for efficacy in severely hypoxic patients and during prone ventilation.

High vs. low PEEP

Three large randomized controlled studies have compared empirical high vs. low PEEP levels in patients with ARDS (6–8). The ARDS-net study used PEEP/FiO2tables for PEEP adjustment, while the ExPress study adopted a compliance-based PEEP strategy. None of these studies revealed a significant mortality benefit with the application of a higher PEEP level. Briel et al. performed a meta-analysis of the three studies (9). They observed that the treatment effect was variable and depended on the severity of ARDS, with a suggestion that a higher PEEP level may be beneficial in patients with more severe illness, with a PaO2/FiO2ratio < 200.

The bottom line

  • The holy grail of optimal PEEP lies in the grey area between maintenance of effective alveolar recruitment and the potential for harmful overdistension.
  • Strategies based solely on improving arterial oxygenation are unlikely to be beneficial; a more comprehensive lung-protective approach may be more appropriate.
  • Several methods have been studied to choose an optimal level of PEEP; however, no significant improvement in clinical outcomes have been demonstrated with any specific titration strategy.
  • Arbitrarily chosen higher levels of PEEP may not benefit in heterogeneous groups of ARDS patients; however, a higher PEEP may improve outcomes in patients with severe ARDS.
  • A ballpark PEEP level may be 5–10 cm of H2O in mild to moderate ARDS; a higher level of 15–20 cm of H2O may be more appropriate in severe ARDS.
  • Time-consuming and cumbersome techniques in the pursuit of titration of PEEP levels may not lead to a discernible benefit.



  1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet Lond Engl. 1967 Aug 12;2(7511):319–23.
  2. Gattinoni L, Carlesso E, Cressoni M. Selecting the ‘right’ positive end-expiratory pressure level: Curr Opin Crit Care. 2015 Feb;21(1):50–7.
  3. Pintado M-C, de Pablo R, Trascasa M, Milicua J-M, Rogero S, Daguerre M, et al. Individualized PEEP Setting in Subjects With ARDS: A Randomized Controlled Pilot Study. Respir Care. 2013 Sep 1;58(9):1416–23.
  4. Cressoni M, Chiumello D, Carlesso E, Chiurazzi C, Amini M, Brioni M, et al. Compressive forces and computed tomography-derived positive end-expiratory pressure in acute respiratory distress syndrome. Anesthesiology. 2014 Sep;121(3):572–81.
  5. Beitler JR, Sarge T, Banner-Goodspeed VM, Gong MN, Cook D, Novack V, et al. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure–Guided Strategy vs an Empirical High PEEP-F io2Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA [Internet]. 2019 Feb 18 [cited 2019 Feb 24]; Available from:
  6. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004 Jul 22;351(4):327–36.
  7. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, Laranjeira LN, Paisani D de M, Damiani LP, et al. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017 10;318(14):1335–45.
  8. Mercat A, Richard J-CM, Vielle B, Jaber S, Osman D, Diehl J-L, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008 Feb 13;299(6):646–55.
  9. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010 Mar 3;303(9):865–73.


High flow nasal oxygen therapy: A breath of fresh air?

Supplemental oxygen is conventionally delivered through nasal prongs or various types of masks. Although these devices increase the inspired oxygen concentration, they have significant limitations. The inability to generate adequate flows in patients who are dyspneic is a major drawback. Respiratory failure is characterized by high peak inspiratory flow rates ranging from 30–120 L/min (1). However, most conventional devices are limited to a maximum flow of 15 L/min, resulting in a significant mismatch between the peak inspiratory and delivered flows. The flow mismatch results in variable entrainment of atmospheric air and failure to deliver a constant FiO2.

Bubble humidifiers are commonly used to humidify the inspired gas. However, the humidification imparted by bubble humidifiers is negligible (2). Dry inspired gas, delivered at room temperature, results in reduced water content of the airway mucus. Lack of humidification and low temperature of supplemental oxygen impairs ciliary activity and inhibits mucus clearance (3). To make matters worse, many patients in respiratory failure are unable to cough forcefully, leading to retention of secretions. There has been increasing interest in the use of high flow nasal cannula (HFNC) to deliver optimally warmed and humified oxygen at high flows following an initial report by Dewan et al (4). Several commercially available devices are currently in use that can deliver fully conditioned gas at flows of up to 60 L/min, at a fixed FiO2. (Figure 1). These systems use a built-in flow generator and an air-oxygen blender that generates inspired gas flows at a pre-set FiO2.  A heated passover type of humidifier is utilized to ensure adequate humification. The pre-warmed, humidified gas mixture flows through a heated wire embedded, single limb corrugated tubing. The heated tubing prevents condensation of water and any significant drop in temperature of the inspired gas as it reaches the patient end. A soft, wide-bored nasal cannula is used to deliver the inspired gas.


Figure 1. A typical high-flow device with nasal cannula

How does HFNC deliver a constant FiO2?

The flow rates delivered by HFNC exceed the peak inspiratory flow rate of patients who are dyspneic. This minimizes atmospheric air entrainment and enables a constant, predictable FiO2.  Most devices allow a maximal gas flow of 60L/min, at a fixed FiO2 ranging between 0.21 to nearly 1.0.   

Does HFNC enable CO2 washout?          

High gas flows result in flushing out of CO2 from the nasopharynx with less rebreathing of dead space gas and improved alveolar ventilation (5). A lower partial pressure of carbon dioxide in the inspired gas mixture results in an increase in the FiO2 (6). As the alveolar ventilation improves, a lower respiratory rate and a greater sense of comfort ensue (7).

Does HFNC offer positive end-expiratory pressure?

HFNC generates positive pressure in the airways, directly proportional to the flow rate. In postoperative patients, the airway pressure increased with increasing inspiratory flow. Mean airway pressures with the mouth closed ranged from 1.52 ± 0.7, 2.21 ± 0.8, and 3.1 ± 1.2 cm H2O at flow rates of 40, 50, and 60 L/min respectively in postoperative patients (8). The low level of PEEP generated by HFNC may facilitate alveolar recruitment and an increase in the end-expiratory lung volume.

HFNC and airway resistance

The nasopharynx is a narrow part of the supraglottic airway that offers resistance to airflow. The application of positive pressure may splint and widen the airways during inspiration and reduce airway resistance. Furthermore, inspiratory gas flows that closely match the peak inspiratory flow may contribute to decreased inspiratory resistance. Both these mechanisms may contribute to a decrease in the resistive work of breathing (9).

The beneficial effects of humidification

Warming and humidification of the inspired gas involve an energy expenditure of 156 calories/min for a tidal volume of 500 ml at a respiratory rate of 12/min. Delivery of pre-conditioned gas conserves the energy thus expended and may reduce the metabolic cost of breathing. Furthermore, warming and humidification results in an improved sense of comfort and reduces resistance to breathing. Besides, optimal humidification adds to the aqueous content of the mucosal layer, thus improving ciliary activity and secretion clearance (10).

The aforementioned physiological effects of HFNC are clearly advantageous. However, do they translate to improved clinical outcomes in the real world?

Does HFNC help in patients with acute hypoxemic respiratory failure?  

Early studies with the use of HFNC in patients with acute hypoxemic respiratory failure have shown improvement in physiological endpoints including oxygenation and respiratory rate, besides increasing the level of comfort (5,11). The FLORALI study evaluated HFNC therapy in patients with acute hypoxic respiratory failure (12). In this three-armed randomized controlled study, HFNC was compared with non-invasive ventilation (NIV) and oxygen administered through a non-rebreather mask. There was no significant reduction in the requirement for endotracheal intubation and invasive ventilation with HFNC use. The overall intubation rate was lower than that assumed for power calculation; this may have led to a type II error. In patients who required intubation and mechanical ventilation, HFNC use resulted in more ventilator-free days and improved 90-day survival after adjusting for simplified acute physiology score II (SAPS II) scores. On post hoc analysis, a significantly lower rate of endotracheal intubation was noted in with PaO2/FiOratios of less than 200. This finding suggests that severely hypoxic patients may benefit with HFNC; however, this hypothesis needs validation. The 90-d mortality was lower in the HFNC group; however, being a secondary endpoint, the study was not powered to demonstrate a difference.

In a randomized controlled study (RCT) of postoperative patients who underwent cardiac surgery under cardiopulmonary bypass, HFNC was compared with standard oxygen therapy through a face mask or nasal prongs. There was no significant difference in the SpO2/FiOratios between groups on day 3 after enrolment. However, NHFC resulted in fewer episodes of desaturation. The number of patients requiring escalation of respiratory support was significantly lower in the HFNC group (13).

HFNC was used in patients with severe ARDS in a single center, 1-y observational study. The intubation rate was 40% in this study; failure of HFNC was associated with higher SAPS II scores, the presence of extra-pulmonary organ failures, a lower PaO2/FiOratio, and a higher respiratory rate (14).

Concerns have been raised regarding persistence with HFNC for too long with delayed intubation leading to adverse outcomes. In a propensity-matched, retrospective study, patients who required endotracheal intubation after failure of HFNC were analyzed. Delayed intubation after 48 hours of HFNC use was associated with significantly higher mortality compared to intubation within 48 hours (15).

Is HFNC beneficial as postextubation therapy?

Earlier studies showed improvement in physiological endpoints including heart rate, respiratory rate, and dyspnoea scores with postextubation use of HFNC (16). HFNC was compared with ventimask in a randomized controlled trial of patients with a PaO2/FiOratio of less than 300 prior to extubation (17). There were fewer episodes of desaturation with HFNC use. The need for NIV support and endotracheal intubation was also significantly less in patients who received HFNC. In patients who were at high risk of reintubation following cardiothoracic surgery, HFNC was compared to NIV delivered as bilevel positive airway pressure following extubation. There was no difference in treatment failure (reintubation, switch to the other treatment modality, or premature discontinuation of the study intervention) or intensive care mortality(18). HFNC was compared with standard oxygen therapy using nasal prongs or facemask after extubation in patients who underwent major abdominal surgery (19). The incidence of hypoxemia 1 h after extubation and after discontinuation of treatment was not different between groups. Pulmonary complications at 1 week after surgery were also similar. In a large, multicentre randomized controlled study, HFNC was compared with standard oxygen therapy following extubation among patients who were at low risk for reintubation (20). Reintubation within 72 h of extubation was significantly lower with HFNC (4.9% vs 12.2%, p = 0.004). Postextubation respiratory failure was also less common with HFNC.

Other uses

HFNC may be the preferred mode of support in terminally ill patients in whom endotracheal intubation and invasive ventilation may be inappropriate. In addition to an increased sense of comfort, HFNC perseveres the ability to communicate and allows oral intake. HFNC may be the ideal modality of continuous oxygen administration during attempts at intubation with better maintenance of oxygen saturation. It may also be useful to prevent desaturation in awake, spontaneously breathing patients who undergo bronchoscopy. 

The bottom line

  • HFNC delivers warmed and humified gases. As the delivered flow is higher than peak inspiratory flow rates, a constant FiOis achieved
  • The high flow rate enables maintenance of positive airway pressure in the nasopharynx with augmentation of the end-expiratory lung volume
  • The positive airway pressure distends the airways and reduces airway resistance
  • Improved physiological parameters have been consistently demonstrated with HFNC
  • HFNC may reduce the requirement for intubation and invasive mechanical ventilation in patients with low PaO2/FiOratios
  • Improvement in oxygenation, reduced requirement for NIV use and reintubation are possible advantages with postextubation HFNC use
  • As with any other form of respiratory support, persistence with HFNC in non-responders and delayed intubation may lead to adverse outcomes



  1. L’Her E, Deye N, Lellouche F, Taille S, Demoule A, Fraticelli A, et al. Physiologic effects of noninvasive ventilation during acute lung injury. Am J Respir Crit Care Med. 2005 Nov 1;172(9):1112–8.
  2. Chanques G, Constantin J-M, Sauter M, Jung B, Sebbane M, Verzilli D, et al. Discomfort associated with underhumidified high-flow oxygen therapy in critically ill patients. Intensive Care Med. 2009 Jun;35(6):996–1003.
  3. Kilgour E, Rankin N, Ryan S, Pack R. Mucociliary function deteriorates in the clinical range of inspired air temperature and humidity. Intensive Care Med. 2004 Jul;30(7):1491–4.
  4. Dewan NA, Bell CW. Effect of low flow and high flow oxygen delivery on exercise tolerance and sensation of dyspnea. A study comparing the transtracheal catheter and nasal prongs. Chest. 1994 Apr;105(4):1061–5.
  5. Sztrymf B, Messika J, Bertrand F, Hurel D, Leon R, Dreyfuss D, et al. Beneficial effects of humidified high flow nasal oxygen in critical care patients: a prospective pilot study. Intensive Care Med. 2011 Nov;37(11):1780–6.
  6. Spence CJT, Buchmann NA, Jermy MC. Unsteady flow in the nasal cavity with high flow therapy measured by stereoscopic PIV. Exp Fluids. 2012;52(3):569–579.
  7. Schmidt M, Banzett RB, Raux M, Morélot-Panzini C, Dangers L, Similowski T, et al. Unrecognized suffering in the ICU: addressing dyspnea in mechanically ventilated patients. Intensive Care Med. 2014 Jan;40(1):1–10.
  8. Ritchie JE, Williams AB, Gerard C, Hockey H. Evaluation of a humidified nasal high-flow oxygen system, using oxygraphy, capnography and measurement of upper airway pressures. Anaesth Intensive Care. 2011 Nov;39(6):1103–10.
  9. Ricard J-D. High flow nasal oxygen in acute respiratory failure. Minerva Anestesiol. 2012 Jul;78(7):836–41.
  10. Sim M a. B, Dean P, Kinsella J, Black R, Carter R, Hughes M. Performance of oxygen delivery devices when the breathing pattern of respiratory failure is simulated. Anaesthesia. 2008 Sep;63(9):938–40.
  11. Roca O, Riera J, Torres F, Masclans JR. High-flow oxygen therapy in acute respiratory failure. Respir Care. 2010 Apr;55(4):408–13.
  12. Frat J-P, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N Engl J Med. 2015 Jun 4;372(23):2185–96.
  13. Parke R, McGuinness S, Dixon R, Jull A. Open-label, phase II study of routine high-flow nasal oxygen therapy in cardiac surgical patients. Br J Anaesth. 2013 Aug 6;aet262.
  14. Messika J, Ben Ahmed K, Gaudry S, Miguel-Montanes R, Rafat C, Sztrymf B, et al. Use of High-Flow Nasal Cannula Oxygen Therapy in Subjects With ARDS: A 1-Year Observational Study. Respir Care. 2015 Feb;60(2):162–9.
  15. Kang BJ, Koh Y, Lim C-M, Huh JW, Baek S, Han M, et al. Failure of high-flow nasal cannula therapy may delay intubation and increase mortality. Intensive Care Med. 2015 Apr;41(4):623–32.
  16. Rittayamai N, Tscheikuna J, Rujiwit P. High-flow nasal cannula versus conventional oxygen therapy after endotracheal extubation: a randomized crossover physiologic study. Respir Care. 2014 Apr;59(4):485–90.
  17. Maggiore SM, Idone FA, Vaschetto R, Festa R, Cataldo A, Antonicelli F, et al. Nasal High-Flow versus Venturi Mask Oxygen Therapy after Extubation. Effects on Oxygenation, Comfort, and Clinical Outcome. Am J Respir Crit Care Med. 2014 Aug;190(3):282–8.
  18. Stéphan F, Barrucand B, Petit P, Rézaiguia-Delclaux S, Médard A, Delannoy B, et al. High-Flow Nasal Oxygen vs Noninvasive Positive Airway Pressure in Hypoxemic Patients After Cardiothoracic Surgery: A Randomized Clinical Trial. JAMA. 2015 Jun 16;313(23):2331–9.
  19. Futier E, Paugam-Burtz C, Godet T, Khoy-Ear L, Rozencwajg S, Delay J-M, et al. Effect of early postextubation high-flow nasal cannula vs conventional oxygen therapy on hypoxaemia in patients after major abdominal surgery: a French multicentre randomised controlled trial (OPERA). Intensive Care Med. 2016 Dec;42(12):1888–98.
  20. Hernández G, Vaquero C, González P, Subira C, Frutos-Vivar F, Rialp G, et al. Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial. JAMA. 2016 Apr 5;315(13):1354.



Early vasopressors or a fluid-liberal resuscitation strategy​ in sepsis-related hypotension?

Fluid resuscitation is the cornerstone of the established management of sepsis-related hypotension. Guidelines recommend an initial bolus of 30 ml/kg of crystalloids with administration of repeated boluses if the hemodynamic parameters continue to improve (1). The physiological rationale behind this approach is the extensive vasodilatation and capillary leak that characterize sepsis. Adequate intravascular volume expansion is considered to be the appropriate initial management, followed by the administration of vasopressors if severe hypotension persists. Rivers et al., in their landmark study, administered intravenous fluid boluses targeting central venous pressure; this resulted in a much larger volume of fluid being administered to the intervention group compared to controls during the initial hours of resuscitation (2). Subsequently, three randomized controlled studies further bolstered the “fluids first” approach; both control and intervention arms of these studies received similar volumes of fluid in the first few hours, suggesting that this approach has firmly entrenched into clinical practice over the years (3–5). However, a “fluid liberal” initial approach may have adverse consequences, with overfilling of the intravascular and interstitial compartments due to capillary leakage. Excessive fluid in the interstitial compartment may lead to tissue edema and precipitate organ failure (6). Furthermore, a central venous pressure targeted resuscitation strategy may result in increased venous pressures, thereby decreasing perfusion pressures in vital organs such as the kidneys (7). Is it time to re-evaluate the traditional fluid liberal resuscitation strategy considering the putative harm that may emanate from such an approach? Would it be appropriate to limit fluid resuscitation and administer vasopressors early in patients with sepsis? Such an approach may accelerate the process of resuscitation and result in a lower volume of fluids being administered.

In a study of African children with severe febrile illness and signs of impaired perfusion, an initial fluid bolus of normal saline or 5% albumin was compared to no bolus fluid. Intravenous maintenance fluid was administered to all children. Mortality at 48 h and 4 weeks was significantly lower in children who received no bolus fluid (8). Although this study was performed among children in resource-limited settings and may not be directly extrapolatable to adult practice, it underlines potential harm from excessive fluid resuscitation in the initial stage of sepsis.

Bai et al. conducted a retrospective cohort study on the timing of noradrenaline administration in patients with septic shock (9). They hypothesized that later administration of noradrenaline may lead to more prolonged hypotension resulting in impaired organ perfusion compared to early administration. Mortality at 28 days was significantly lower in patients who received noradrenaline within 2 h of the onset of septic shock compared with those who received it later. The mortality increased by 5.3% for every 1 h of delay in noradrenaline administration within the first 6 h of onset of septic shock. On multivariate logistic regression analysis, the time to noradrenaline administration was one of the independent predictors of mortality.

A multicentre randomized controlled study was conducted to assess the feasibility of a fluid-restrictive strategy after initial resuscitation. In the fluid-restricted group, after initial resuscitation, additional boluses were administered only if signs of severe hypoperfusion were noted. In the control group, continued boluses were administered if there was an improvement in hemodynamic parameters assessed using static or dynamic indices. Resuscitation volumes on day 5 and during ICU stay were the co-primary outcomes. The resuscitation volumes at both time points were significantly less with a restrictive strategy. The study was not powered to evaluate patient-centered outcomes; however, it suggested that a restricted fluid strategy was feasible among patients with septic shock.

In a recent randomized controlled study, noradrenaline was administrated in a dose of 0.05 mcg/kg/min within 1 hr of the diagnosis of septic shock (mean arterial pressure of less than 65 mm Hg and diagnosis of sepsis based on the Surviving Sepsis Guidelines) (10). The infusion was continued for a period of 24 h; the control group received a placebo infusion. Fluid resuscitation, antibiotic therapy, and organ support were based on physician discretion. If the mean arterial pressure remained below 65 mm Hg, open-label vasopressors were administered. The primary outcome was “shock control” at 6 h after the diagnosis of septic shock. Shock control was determined by a sustained mean arterial pressure of more than 65 mm Hg and evidence of adequate tissue perfusion, defined as a urine output of more than 0.5 ml/kg/h for 2 consecutive hours or a decrease in the serum lactate by more than 10% of the baseline levels. In this study, shock control after 6 h of initial resuscitation was significantly higher with early noradrenaline compared to placebo. The median time to noradrenaline administration was significantly less in the early noradrenaline group (93 vs. 192min; P<0.001). There was no difference in the 28-day and hospital mortality between groups. This study demonstrated that the early use of noradrenaline leads to more rapid attainment of resuscitation goals.

The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) study is a  multi-center randomized controlled trial that is currently recruiting patients (11). It aims to compare the impact of a restrictive fluid strategy with a liberal fluid strategy on the 90 d mortality. In the restricted fluids group, patients are randomized to receive noradrenaline after an initial fluid bolus of 1L; further boluses are administered as a rescue measure. In the fluid liberal group, repeated boluses of fluid are administered as the initial intervention; rescue noradrenaline is commenced only after either 5 L of fluid has been administered, signs of acute volume overload develop, or other predefined rescue criteria are met. The results of this study are eagerly awaited.


  • The conventional, guideline-based approach of the “fluids first” strategy may lead to excessive capillary leakage, interstitial edema, and impaired organ perfusion.
  • Early use of vasopressors may enable more rapid attainment of resuscitation goals and improved organ perfusion.
  • The optimal volume of fluid resuscitation prior to the commencement of vasopressors may be variable.
  • Clinical studies suggest that a fluid restricted resuscitation strategy with early use of vasopressors may improve outcomes.
  • Further prospective controlled studies are warranted to assess the impact of early vasopressor therapy in sepsis-related hypotension.



  1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304–77.
  2. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368–77.
  3. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683–93.
  4. ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496–506.
  5. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301–11.
  6. Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care. 2014;4:21.
  7. Legrand M, Dupuis C, Simon C, Gayat E, Mateo J, Lukaszewicz A-C, et al. Association between systemic hemodynamics and septic acute kidney injury in critically ill patients: a retrospective observational study. Crit Care Lond Engl. 2013 Nov 29;17(6):R278.
  8. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483–95.
  9. Bai X, Yu W, Ji W, Lin Z, Tan S, Duan K, et al. Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care Lond Engl. 2014 Oct 3;18(5):532.
  10. Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial. Am J Respir Crit Care Med [Internet]. 2019 Feb [cited 2019 Feb 7]; Available from:
  11. Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis – Full Text View – [Internet]. [cited 2019 Feb 8]. Available from:



When the most important muscle in the body fails…


The diaphragm is the principal muscle of respiration and is innervated by the phrenic nerves through the C3–C5 nerve roots. There is a high prevalence of diaphragmatic weakness among critically ill patients. No correlation seems to exist between weakness of the limbs and diaphragmatic weakness; in fact, diaphragmatic dysfunction may be twice as common as paresis of the limbs due to polyneuropathy or myopathy related to critical illness (1). Diaphragmatic dysfunction may be a stronger predictor of mortality than the severity of multiorgan failure among critically ill patients (2). Furthermore, weakness of the diaphragm is much harder to recognize compared to limb muscle weakness. Hence, it is important to have a high index of suspicion in patients who may be at risk of developing diaphragmatic dysfunction.

Clinical indicators

The possibility of diaphragmatic dysfunction must be considered in patients who seem to have recovered sufficiently from the underlying illness but fail repeated attempts to wean. Failure of adequate spontaneous ventilation in spite of reasonable lung mechanics and good gas exchange heightens the suspicion of diaphragmatic dysfunction. Paradoxical breathing, when the abdomen seems to get sucked in during inspiration and moves outwards during expiration is an important clinical indicator. The chest radiograph may show elevation of the diaphragm on one or both sides, depending on the extent of involvement.

The incidence of diaphragmatic dysfunction

The most sensitive test of diaphragmatic dysfunction is through magnetic stimulation of the phrenic nerves in the neck and measurement of the twitch pressure generated at the proximal end of the endotracheal tube. Using trans-diaphragmatic twitch pressure measurement, 34/43 (79%) patients developed diaphragmatic dysfunction during their stay in the ICU (3). Obviously, mild dysfunction may often be missed by clinical examination alone.

Ventilation (VIDD) and sepsis-induced diaphragmatic dysfunction (SIDD)

Both mechanical ventilation and sepsis can independently, and in combination, lead to signification diaphragmatic dysfunction. The degree of dysfunction may be closely related to the duration of mechanical ventilation. Histopathological examination of the diaphragm was carried out in brain dead organ donors who were on mechanical ventilation for 18–79 h and compared with patients who underwent 2–3 h of ventilation during thoracotomy for lung cancer. Inactivity of the diaphragm combined with mechanical ventilation resulted in marked atrophy of myofibers compared to controls (4). Activation of oxidative stress appears to be the trigger for VIDD. The generation of reactive oxygen species appears to initiate oxidative stress, resulting in DNA fragmentation and proteolysis leading to impairment of diaphragmatic contractility.

Ultrasonography- a simple bedside tool to identify diaphragmatic dysfunction

The identification of diaphragmatic dysfunction by the bedside may be reliably carried out by ultrasonography. Two parameters are used to assess diaphragmatic function: (1) diaphragmatic thickening during a maximal inspiratory effort (thickening fraction) and (2) amplitude of diaphragmatic excursion during tidal breathing.

Diaphragmatic excursion

A low frequency (2–5 MHz) curvilinear probe is placed in the subcostal region between the midclavicular and anterior axillary lines using the liver or the spleen as the acoustic window. Once the diaphragm is visualized, the M-mode cursor is positioned perpendicular to the posterior aspect of the diaphragm and the excursion is measured (Fig 1). A distance of excursion of less than 1 cm during quiet breathing or paradoxical movement (cranial movement on inspiration) is indicative of diaphragmatic weakness (5).

fig 1

Fig 1. Measurement of diaphragmatic excursion on M-mode view using a 5 MHz curvilinear transducer. The M-mode cursor is positioned perpendicular to the posterior aspect of the diaphragm. The amplitude of excursion measured in this image is 3.15 cm (double-headed arrow)

Thickening fraction

To assess thickening during inspiration, a high frequency (8–12 mHz) linear probe is used. The probe is placed between the 7–9thintercostal spaces in the midaxillary line. The diaphragm is seen as a non-echogenic zone sandwiched between the diaphragmatic pleura and the peritoneum. Thickness is measured at end-inspiration and end-expiration (Fig 2). The thickening fraction is calculated using the formula: Thickness at end-inspiration (maximal thickness) – thickness at end-expiration/thickness at end-inspiration. A thickening fraction of less than 20% is suggestive of diaphragmatic dysfunction (6).

Fig 2

Fig 2. Ultrasonographic imaging of the diaphragm using a 12 MHz linear probe. The diaphragm is seen as a hypoechoic zone between the pleura and the peritoneum, seen as hyperechoic lines. The image on the left shows thickness at end-expiration (green line); the image on the right shows thickness at end-inspiration (orange line). Thickening fraction = End-expiratory thickness – End inspiratory thickness/End-expiratory thickness

Prevention and treatment of diaphragmatic dysfunction

Maintenance of spontaneous respiratory effort during mechanical ventilation is the key to prevention of diaphragmatic dysfunction. Clearly, this strategy may be counterproductive and harmful in patients with a pronounced respiratory drive, particularly in severe acute respiratory distress syndrome. Modest use of sedatives and muscle relaxants for a limited duration is appropriate to during the initial period of mechanical ventilation. However, regular interruption of muscle relaxants and sedation should be carried out to assess the respiratory drive with a view to allowing spontaneous respiratory efforts as early as possible. Electrolyte abnormalities, including hypocalcemia, hypomagnesemia, and hypophosphatemia are well known to provoke or worsen diaphragmatic weakness; levels must be estimated regularly and maintained within the normal range. Endocrine abnormalities, especially myxedema is known to cause muscle weakness and must be considered in patients with diaphragmatic dysfunction. There is emerging interest in improving diaphragmatic function by phosphodiesterase inhibition using theophylline and with the use of levosimendan, a calcium sensitizer. Phrenic nerve stimulation and antagonization of oxidative stress using antioxidants including vitamin C and E may be therapeutic modalities for the future.


  • Diaphragmatic dysfunction is common among critically ill patients and may often be unrecognized.
  • Diaphragmatic dysfunction leads to adverse clinical outcomes including mortality.
  • Mechanical ventilation and sepsis are independent triggers of diaphragmatic dysfunction and may potentiate each other in combination.
  • It is important to have a high index of suspicion in patients at risk of diaphragmatic dysfunction.
  •  Ultrasonography is a simple and sensitive tool to diagnose diaphragmatic dysfunction by the bedside in critically ill patients.
  • Maintenance of spontaneous respiratory efforts in mechanically ventilated patients with limited use of sedatives and muscle relaxants may prevent diaphragmatic dysfunction.
  • Electrolyte and endocrine abnormalities must be sought for and corrected.



  1. Dres M, Dubé B-P, Mayaux J, Delemazure J, Reuter D, Brochard L, et al. Coexistence and Impact of Limb Muscle and Diaphragm Weakness at Time of Liberation from Mechanical Ventilation in Medical Intensive Care Unit Patients. Am J Respir Crit Care Med. 2017 01;195(1):57–66.
  2. Supinski GS, Westgate P, Callahan LA. Correlation of maximal inspiratory pressure to transdiaphragmatic twitch pressure in intensive care unit patients. Crit Care. 2016 Mar 23;20(1):77.
  3. Demoule A, Molinari N, Jung B, Prodanovic H, Chanques G, Matecki S, et al. Patterns of diaphragm function in critically ill patients receiving prolonged mechanical ventilation: a prospective longitudinal study. Ann Intensive Care. 2016;6:75. Available from:
  4. Levine S, Budak MT, Sonnad S, Shrager JB. Rapid Disuse Atrophy of Diaphragm Fibers in Mechanically Ventilated Humans. N Engl J Med. 2008;9.
  5. Kim WY, Suh HJ, Hong S-B, Koh Y, Lim C-M. Diaphragm dysfunction assessed by ultrasonography: influence on weaning from mechanical ventilation. Crit Care Med. 2011 Dec;39(12):2627–30.
  6. Gottesman E, McCool FD. Ultrasound evaluation of the paralyzed diaphragm. Am J Respir Crit Care Med. 1997 May;155(5):1570–4.


Does pantoprazolization prevent gastrointestinal bleeding in critically ill patients?


The efficacy of acid suppression in the prevention of stress ulcers using antacids was first investigated more than four decades ago among burns patients (1). Many different classes of acid suppressant medication have evolved since then, but their utility in the prevention of stress ulcers in critically ill patients remains unresolved. It has been hypothesized that stress ulcers may be more related to impaired mucosal blood flow and ischemia reperfusion-related injury; hence, in contrast to peptic ulceration, the evolution and propagation of such ulcers may be less related to gastric acidity.

The reported incidence of clinically important gastrointestinal bleeding is variable and probably related to the heterogeneity among patient populations studied, non-uniform definitions, and the lack of distinction between true stress ulceration and other unrelated causes of bleeding. Although not approved by the Food and Drug Administration for this indication, proton pump inhibitors (PPIs) are among the most common medications administered to critically ill (2) and perhaps to all hospitalized patients. In a study from two Australian ICUs, acid suppressant medication was inappropriately continued in 63% of patients after ICU and in 39% of patients after hospital discharge (3).

Most of the current recommendations regarding stress ulcer prophylaxis are based on results from studies and risk factors identified several decades ago. Changes in clinical practice, particularly with the increased emphasis on expeditious resuscitation and early commencement of enteral nutrition may have reduced the risk of stress ulceration and clinically important bleeding in the ICU. Do we need to rethink and modify our approach with the use of acid suppressant medication in the light of more contemporaneous evidence?

Harmful effects of acid suppression

A cohort study of patients on mechanical ventilation for more than 24 hours compared the use of PPI with H2 receptor antagonists (H2RA). After propensity-matched multivariate analysis, PPIs were associated with a significantly higher incidence of pneumonia and C. difficile infection; surprisingly, the incidence of gastrointestinal hemorrhage was also higher with PPI use (4). A recent meta-analysis investigated the risk of C. difficile infection associated with the use of PPIs. Among the 23 observational studies included, 10,307 cases of C. difficile infection were observed, with a significantly higher incidence with the use of PPIs (5). There is concern regarding adverse cardiovascular events associated with the use of PPIs. In a cohort study of 56,406 patients from Denmark, PPI use was associated with a significantly increased risk of cardiovascular death and readmission to hospital with myocardial infarction or stroke (hazard ratio: 1.29; CI, 1.21 to 1.37) (6). Among 244,679 subjects who underwent elective gastroscopy, there was a dose-related increase in the risk of first-time ischemic stroke with PPI use. No such association was observed with the use of H2RAs (7). Concern has also been raised regarding thrombocytopenia in patients with upper gastrointestinal bleeding who are treated with continuous infusions of PPIs (8).

Early enteral nutrition as prophylaxis

Continuous enteral feeds may be more effective at maintaining a higher gastric pH (above 3.5) compared to PPIs and H2RAs. In a randomized controlled trial (RCT), intravenous pantoprazole was compared to placebo in 214 mixed medical-surgical patients on mechanical ventilation who were expected to be commenced on enteral nutrition within 48 hours of ICU admission. No clinically significant gastrointestinal bleeding was observed in either group of patients (9). In a similar RCT of critically ill patients on mechanical ventilation who were expected to receive enteral nutrition within the first 24 hours of ICU admission, there was no overt or significant gastrointestinal bleeding with intravenous pantoprazole administration compared to placebo (10).

The SUP-ICU trial investigated the effects of intravenous pantoprazole in critically ill adult patients at high risk of gastrointestinal bleeding (11). The study was conducted across 33 ICUs in six countries between January 2016 to October 2017. In this randomized controlled trial, 3298 patients were enrolled to receive intravenous pantoprazole or placebo. The primary outcome, which the study was powered for, was the 90-d mortality. There was no significant mortality difference between pantoprazole (31.1%) and placebo (30.4%). The secondary outcome, a composite endpoint of gastrointestinal bleeding, pneumonia, C. difficile infection, and acute myocardial ischemia, was not different between groups. Clinically important bleeding was lower with pantoprazole compared to placebo (2.5 vs. 4%); the significance of this finding was not evaluated, as no adjustments were made for multiple comparisons. The power calculation of this study may have been flawed because it was based on a previous report that revealed no increase of mortality secondary to gastrointestinal bleeding. The composite secondary endpoint has also not been evaluated previously. The source of bleeding was not confirmed endoscopically, to differentiate from causes other than stress ulceration. Besides, there was no information on whether enteral nutrition had been established at baseline. This study confirms that the overall incidence of gastrointestinal bleeding is very low in today’s world (3.3% overall); adequately powered studies to prove a difference in the incidence may be difficult to carry out in practice.

The bottom line

  • With an increased focus on early resuscitation, the incidence of clinically important gastrointestinal bleeding has probably decreased compared to previous reports.
  • Widespread use of acid-suppressant medication has been linked to several adverse effects, including pneumonia, C. difficile infection, and cardiovascular events in critically ill patients.
  • Routine use of stress ulcer prophylaxis may be unnecessary in patients who can be initiated on early enteral nutrition within the first 24–48 hours.
  • Risk factors identified in earlier studies, including mechanical ventilation for more than 48 hours, may not necessitate routine prophylaxis.
  • Future studies should be directed towards identification of patients who may be truly “at risk” for stress ulcer-related bleeding.



  1. McAlhany JC, Colmic L, Czaja AJ, Pruitt BA. Antacid control of complications from acute gastroduodenal disease after burns. J Trauma. 1976 Aug;16(08):645–8.
  2. Barletta JF, Lat I, Micek ST, Cohen H, Olsen KM, Haas CE, et al. Off-label use of gastrointestinal medications in the intensive care unit. J Intensive Care Med. 2015 May;30(4):217–25.
  3. Farley KJ, Barned KL, Crozier TM. Inappropriate continuation of stress ulcer prophylaxis beyond the intensive care setting. Crit Care Resusc J Australas Acad Crit Care Med. 2013 Jun;15(2):147–51.
  4. MacLaren R, Reynolds PM, Allen RR. Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern Med. 2014 Apr;174(4):564–74.
  5. Arriola V, Tischendorf J, Musuuza J, Barker A, Rozelle JW, Safdar N. Assessing the Risk of Hospital-Acquired Clostridium Difficile Infection With Proton Pump Inhibitor Use: A Meta-Analysis. Infect Control Hosp Epidemiol. 2016;37(12):1408–17.
  6. Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010 Sep 21;153(6):378–86.
  7. Sehested Thomas S, Fosbøl Emil L, Hansen Peter W, Charlot Mette G, Torp-Pedersen Christian, Gislason Gunnar H. Abstract 18462: Proton Pump Inhibitor Use Increases the Associated Risk of First-Time Ischemic Stroke. A Nationwide Cohort Study. Circulation. 2016 Nov 11;134(suppl_1):A18462–A18462.
  8. Binnetoğlu E, Akbal E, Şen H, Güneş F, Erbağ G, Aşık M, et al. Pantoprazole-induced thrombocytopenia in patients with upper gastrointestinal bleeding. Platelets. 2015;26(1):10–2.
  9. Selvanderan SP, Summers MJ, Finnis ME, Plummer MP, Abdelhamid YA, Anderson MB, et al. Pantoprazole or Placebo for Stress Ulcer Prophylaxis (pop-up): Randomized Double-blind Exploratory Study*. Crit Care Med. 2016 Oct 1;44(10):1842–50.
  10. El-Kersh K, Jalil B, McClave SA, Cavallazzi R, Guardiola J, Guilkey K, et al. Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study. J Crit Care. 2018 Feb;43:108–13.
  11. Krag M, Marker S, Perner A, Wetterslev J, Wise MP, Schefold JC, et al. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. N Engl J Med. 2018 Dec 6;379(23):2199–208.