Do Procalcitonin Levels Help Guide Antibiotic Therapy in Acute Exacerbation of Chronic Obstructive Airway Disease?

 

There has been a growing interest regarding the utility of procalcitonin to guide appropriate initiation and duration of antibiotic therapy in critically ill patients. Two randomized controlled studies in critically ill patients suspected to have bacterial infections arrived at disparate conclusions (De Jong et al. 2016; Bouadma et al. 2010).

In patients presenting with acute exacerbation of chronic obstructive pulmonary disease (COPD), it is often difficult to clinically ascertain whether bacterial infection is the precipitating factor. Previous studies that evaluated the utility of procalcitonin in this setting involved less severely ill patients, with relatively few who required treatment in the intensive care unit. Against this background, Daubin et al. carried out a multicentre randomized controlled study in the intensive care unit of 11 hospitals in France to investigate the utility of procalcitonin-guided antibiotic therapy in acute exacerbations of COPD (Daubin et al. 2018).

The authors hypothesized that (1) procalcitonin-guided treatment would reduce antibiotic exposure and (2) mortality will not be different with a lower antibiotic exposure. To demonstrate non-inferiority, a cut off of 12% was considered as the excess mortality permissible with procalcitonin guidance.

Procalcitonin levels were measured in all patients at inclusion, 6 hours later, and on days 1, 3, and 5 after inclusion. In the intervention group, the initiation and duration of antibiotic therapy followed an algorithm based on procalcitonin levels. In the control group, antibiotic therapy was commenced and continued for an appropriate duration based on clinician judgment.

The primary endpoint was mortality at 3 months. At the end of this period, 30 patients (20%) died in the procalcitonin arm compared to 21 (14%) in the control arm, with a confidence interval of −0.3 to 13.5 %. As the upper limit of the confidence interval exceeded the pre-determined cut off of 12% mortality, the study failed to establish non-inferiority of procalcitonin-guided therapy. Mortality with procalcitonin-guided therapy was significantly higher in patients who were not on antibiotics at inclusion. Besides, there was no difference in secondary endpoints including the requirement for vasopressor or dialytic support, the incidence of acute respiratory distress syndrome, ICU-acquired pneumonia or other infections, and multiorgan failure. The duration ventilation, ICU and hospital stay were also not significantly different between groups.

In contrast to previous studies in acute exacerbation of COPD that showed reduced antibiotic usage with procalcitonin guidance, the present study included patients with a relatively higher severity of illness; 87% of patients required non-invasive or invasive mechanical ventilation. Vasopressor support was required in 17.2% of patients, while 5.6% of patients underwent dialysis. The number of patients who received antibiotics was significantly less in the procalcitonin group throughout the first 6 days of the study. This may suggest that procalcitonin levels may have been falsely low and failed to identify infection in some patients.

There were more patients on home oxygen and non-invasive ventilation in the procalcitonin group, which may indicate a more severe illness that may have contributed to mortality. There is no data available on the time to commencement of antibiotics in either group, which may also have affected outcomes.

The bottom line is that in critically ill patients with acute exacerbation of COPD, procalcitonin guidance may fail to identify patients who may have bacterial infection as the precipitating cause. Early antibiotics based on clinical judgment may be more appropriate in such patients. I must confess that I am not a procalcitonin fan; the results of this study is no surprise to me. Our practice of initiation and continuance of antibiotic treatment based on clinician judgment shall remain unchanged.

References:

  1. Bouadma, Lila, Charles-Edouard Luyt, Florence Tubach, Christophe Cracco, Antonio Alvarez, Carole Schwebel, Frédérique Schortgen, et al. 2010. “Use of Procalcitonin to Reduce Patients’ Exposure to Antibiotics in Intensive Care Units (PRORATA Trial): A Multicentre Randomised Controlled Trial.” Lancet (London, England)375 (9713): 463–74. https://doi.org/10.1016/S0140-6736(09)61879-1.
  2. Daubin, Cédric, Xavier Valette, Fabrice Thiollière, Jean-Paul Mira, Pascal Hazera, Djillali Annane, Vincent Labbe, et al. 2018. “Procalcitonin Algorithm to Guide Initial Antibiotic Therapy in Acute Exacerbations of COPD Admitted to the ICU: A Randomized Multicenter Study.” Intensive Care Medicine44 (4): 428–37. https://doi.org/10.1007/s00134-018-5141-9.
  3. Jong, Evelien de, Jos A. van Oers, Albertus Beishuizen, Piet Vos, Wytze J. Vermeijden, Lenneke E. Haas, Bert G. Loef, et al. 2016. “Efficacy and Safety of Procalcitonin Guidance in Reducing the Duration of Antibiotic Treatment in Critically Ill Patients: A Randomised, Controlled, Open-Label Trial.” The Lancet. Infectious Diseases16 (7): 819–27. https://doi.org/10.1016/S1473-3099(16)00053-0.

 

 

 

 

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Journal Critique

Effect of Thiamine Administration on Lactate Clearance and Mortality in Patients With Septic Shock

Woolum JA. Crit Care Med 2018; 46:1747–1752

doi: 10.1097/CCM.0000000000003311

 

Clinical Question: Does the administration of thiamine lead to more rapid lactate clearance and improved clinical outcomes in patients with septic shock?

Background: Septic shock is characterized by a hypermetabolic state that resembles thiamine deficiency. Thiamine deficiency is common in critically ill patients. A previous pilot randomized controlled trial had shown significantly lower lactate levels and improved mortality over time in patients with septic shock who were thiamine deficient.

Design: Retrospective, matched cohort study, based on data collected from electronic medical records. Regression analysis was performed with mortality as competing event (if the patient died with a lactate level of more than 2 mmol/l, clearance was considered not achieved). Three models were constructed: (1) with lactate levels alone, (2) after adjustment for age, sex, and race, and (3) with age, sex, race, and other likely factors that influence mortality and lactate clearance. A Cox proportional hazards model was constructed along the same lines for 28-day mortality.

Setting: A single academic center in the US. The study covered a 4-year period between January 1, 2013, and January 1, 2017.

Population: An electronic medical database was queried based on the diagnostic code for septic shock according to 9thor 10thedition of the International Classification of Diseases (ICD).

Inclusion criteria:

  • Patients who were coded as septic shock on the electronic medical database
  • 18 years and older
  • Admission to medical or surgical services

Exclusion criteria:

  • Less than 18 years of age
  • Septic shock not present at admission

After validation using the Sepsis-3 criteria, 1049 patients were included out of the 2270 patients who were initially screened. Out of this cohort, 123 patients who received thiamine were matched with 246 patients who did not.

Intervention: Intravenous administration of thiamine in any dose within the first 24 hours of hospital admission.

Control: Patients who received thiamine were matched with a cohort who did not receive thiamine in a 1:2 ratio.

Outcomes:

Primary outcome: Patients who were administered intravenous thiamine in the first 24 hours of hospital admission had more rapid lactate clearance. All three regression models revealed improved lactate clearance with thiamine administration. The subdistribution hazard ratios in the three models ranged between 1.292–1.339. The effect of thiamine on lactate clearance was significantly more in female patients on a gender-based interaction model.

Secondary outcomes: Thiamine was found to significantly reduce 28-day mortality on the three Cox’s proportional hazards models. Similar to lactate clearance, the benefit was more evident in female patients. There was no significant difference in other secondary outcomes including change in SOFA scores on day 5 compared to baseline, vasopressor-free days, ventilator-free days, ICU-free days, incidence of AKI, and the requirement for renal replacement therapy.

Authors’ conclusions:

In patients with septic shock, intravenous thiamine, administered within 24 hours of ICU admission resulted in more rapid lactate clearance and a significantly reduced 28-day mortality.

Strengths:

  • This is the largest study so far to evaluate the effect of thiamine on lactate clearance and mortality in patients with patients with septic shock.
  • Matching was carried out between patients who had thiamine and those who did not.
  • Regression analysis was performed with mortality as the competing event.

Weaknesses:  

  • This a retrospective observational study based on data derived from electronic medical records. Although matching was carried out between patients who received thiamine and those who did not, there may be confounders that have not been accounted for.
  • The dose of thiamine was variable and ranged between 100–500 mg per day.
  • Thiamine levels were not measured; it is unclear whether the benefit may be related to thiamine deficiency.
  • Lactate measurements were presumably carried out at random intervals; this may have led to miscalculation of time to lactate clearance.
  • The mortality of the cohort was high compared to contemporaneous studies (54%) which the authors attribute to a relatively large number of patients with cirrhosis.

My take:

This study adds to the growing body of evidence that intravenous thiamine may improve outcomes in patients with sepsis and septic shock. However, no prospective, controlled trial has evaluated the effect of thiamine in sepsis. In my opinion, given that harmful effects are unlikely, intravenous thiamine may be considered in critically ill patients with sepsis.

References

 

 

 

 

 

 

Hemodyanamic monitoring of the future

Several years ago, when the dinosaurs among us were in training, we used to look upon each pulmonary artery catheter that we inserted with a sense of pride and fulfillment​. Thankfully, the era of inflating balloons with the pulmonary artery, measurement of wedge pressures, and serial cold saline injections to measure cardiac output seem to be drawing to a close. Arterial lines are often inserted more for convenience than for precisely titrated therapeutic interventions. There is increasing realization that the central venous pressure may be just a ballpark number that may not reflect the preload to the heart that it is assumed to represent. Perhaps we need to look at technological refinement that will enable us to obtain maximal information with minimal invasion.

Non-invasive, continuous blood pressure measurements with display of an arterial waveform is possible today by the finger clamp and the applanation techniques. The former uses a finger cuff with inflation-deflation cycles to maintain the finger volume constant, while the counterpressure applied is reconstructed to obtain arterial blood pressures (Fig. 1). In the applanation technique, a miniaturized transducer placed on the surface exerts pressure on an artery and enables direct pressure measurement. Much work needs to be done to validate measurements using these techniques; however, it seems likely that reliable, continuous, non-invasive blood pressure measurements may be extensively available in the near future.

FINGER

Fig. 1 The finger clamp method of continous blood pressure measurement

Lack of adequate windows, especially in ventilated patients can be a frustrating experience for the intensivist by the bedside. There are major limitations to performing repeated transesophageal echocardiographic examinations in critically ill patients. However, a miniaturized probe, no bigger than a nasogastric tube, has been introduced that can be placed in the esophagus for repeated examination over a period of 72 hours. Three standard views are utilized, including the mid-esophageal  4-chamber view, the transgastric short axis view, and the superior vena caval view to enable assessment of volume responsiveness, size and function of the ventricles, assessment of valvular function, and detection of pericardial effusion (Fig. 2)

hTEE.

Fig. 2 Hemodynamic transesophageal echocardiography using a miniaturized probe

Despite the debate surrounding the use of lactate levels as a guide to the efficacy of resuscitation, it is well-established that persisting, high lactate levels are associated with increased mortality. Continuous, real-time measurement of lactate levels may help assess the trajectory of illness, especially in critically ill, septic patients. Using a 5-lumen central venous catheter, with saline infusion as a microdialysate, continuous measurement of lactate levels can be carried out, with values displayed in a graphic format (Fig. 3). The direction of the lactate curve may help guide therapy and assess progress in septic patients.

lact.jpg

Fig. 3 Continous lactate monitoring by microdialysis

The time to embrace non- or less invasive techniques of hemodynamic monitoring is probably overdue. Technological refinement, would, hopefully allow us in the near future to extract maximal information from our patients to tailor appropriate intervention with the least risk of damage.

 

Corticosteroids in H1N1 pneumonia – damned if you do, and damned if you don’t?

 

We are in the middle of yet another H1N1 epidemic in India. Karnataka has been particularly affected, with several new cases being reported every day. Several deaths have been reported so far, and the toll is likely to mount in the days to come. The current epidemic shares several common features with the global pandemic of 2009, with predominance in young adults and dense lung infiltrates leading to severe problems with gas exchange. Several rescue interventions have been resorted to, including the use of extracorporeal membrane oxygenation with a view to tide over the crisis until natural healing occurs.

Against this background, we reconsider the use of corticosteroids – considered savior by many and maligned by others in many different clinical situations. Several anecdotal reports of dramatic improvement were noted with corticosteroid therapy during the 2009 epidemic; subsequently, many observational studies have been published with no clear-cut answers; however, some studies suggest worse outcomes with the use of corticosteroids. To my knowledge, there has been no robust, prospective controlled study that has addressed this question. The World Health Organization is reasonably categorical in its H1N1 treatment guidelines, suggesting that “Patients who have severe or progressive clinical illness, including viral pneumonitis, respiratory failure, and ARDS due to influenza virus infection, should not be given systemic corticosteroids unless indicated for other reasons or as part of an approved research protocol”.

I tried to pool the limited data available so far, through a PubMed search using a combination of search terms including “corticosteroids and H1N1”, “steroids and H1N1”, “methylprednisonlone and H1N1”, “hydrocortisone and H1N1”, and “dexamethasone and H1N1”. I retrieved nine studies that analyzed mortality as the endpoint. I chose mortality for the longest period reported in each study as the outcome. This is what I found.

Fig 1. Pooled data on mortality from nine observational studies with the use of corticosteroids in H1N1 infection

Screen Shot 2018-10-14 at 5.55.41 PM 

The pooled data from these observational studies seem to suggest that the use of corticosteroids use in H1N1 infection may lead to increased mortality. Two previous meta-analyses have also reported similar results. (1,2)

However, how much importance do we attach pooled data in a clinical situation fraught with poor outcomes with conventional measures? We have also seen a dramatic improvement on the odd occasion with steroids when we were with our backs to the wall. Several important questions remain unanswered especially when data is pooled across heterogeneous patient populations. Specifically, would steroids be helpful in 1) the most severe forms of the disease 2) would the timing matter – early vs. late? 3) Is there a preferred corticosteroid preparation (methylprednisolone vs. hydrocortisone)? 4) Would corticosteroids improve outcomes in severe ARDS due to H1N1 infection?

Unfortunately, these questions are difficult to answer; it is an onerous if not impossible task to prospectively study specific patient populations who are likely to benefit from corticosteroid administration. Perhaps, when faced with similar difficult clinical situations when a clear-cut answer is not forthcoming, we should continue to have equipoise and keep an open mind.

Have you been taking your flu booster shots?

References:

  1. Zhang Y, Sun W, Svendsen ER, Tang S, MacIntyre RC, Yang P, et al. Do corticosteroids reduce the mortality of influenza A (H1N1) infection? A meta-analysis. Crit Care. 2015;19(1):46.
  2. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam JS, Lim WS. Effect of Corticosteroid Therapy on Influenza-Related Mortality: A Systematic Review and Meta-analysis. J Infect Dis. 2015 Jul 15;212(2):183–94.

 

Contentious Use of Corticosteroids in The Critically Ill

 

There is a long-drawn-out history with the use of corticosteroids in septic shock. In the 1980s, methylprednisolone was used in industrial strengths as a short course treatment, with predictably poor results.[1]After several studies that suggested poor outcomes in septic shock, the use of corticosteroids slowly faded away. However, in the 1990s, there was a rekindling of interest with the use of corticosteroids in lower, more physiological doses, as replacement therapy, considering the possibility of “relative adrenal insufficiency” in septic shock. Three adequately powered randomized controlled trials have been published with the use of “physiological” dose corticosteroids in septic shock (Annane et al.[2], Corticus[3], and ADRENAL[4]). A pooled analysis of these three studies does not demonstrate improved survival with the use of corticosteroids in septic shock.

 

Fig 1. A pooled analysis of studies on mortality with the use of corticosteroids in septic shock 

However, earlier shock reversal seems likely with the use of corticosteroids, as evidenced in most of the studies. The ADRENAL trial also revealed marginally lower ventilation days with corticosteroid use (6 vs. 7 days) with the initial episode of mechanical ventilation; however, there was no difference between groups with days alive and free of ventilation.

Severe acute respiratory distress syndrome (ARDS) may follow several acute illnesses, including sepsis, trauma, and acute pancreatitis. Corticosteroids are often used in patients who continue to remain hypoxic after optimization of mechanical ventilation. Meduri et al. carried out two RCTs,[5],[6]with 1:2 randomization. Both studies seemed to favor the use of corticosteroids, with improved lung injury scores, improved oxygenation, and less time on ventilation. However, the results of the ARDSnet study of 180 patients with ARDS was different.[7] Although steroid use was associated with improved P/F ratios and other parameters of respiratory physiology, there was no difference in the 60 or 180-day mortality. A pooled analysis of these three trials and a recent RCT does not show any survival advantage with the use of corticosteroids in ARDS

fig 2.jpg

Fig 2. A pooled analysis of studies on mortality with the use of corticosteroids in ARDS

Are corticosteroids beneficial in community-acquired pneumonia (CAP)? One of the early studies on critically ill patients revealed improved P/F ratios, earlier resolution of shock, shorter hospital stay, and improved mortality.[8]Subsequently, there have been several small RCTs that evaluated the possible beneficial effect of corticosteroids in CAP[9],[10],[11],[12],[13],[14]. Most of these studies have been performed on patients with a low severity of illness, and low mortality. A pooled analysis of all studies carried out after 2005 suggests a mortality benefit with the use of corticosteroids (Fig 3). 

fig 3

Fig 3. A pooled analysis of studies on mortality with the use of corticosteroids in community-acquired pneumonia 

However, several questions remain unanswered. Viral pneumonias are notorious to lead to a severe disease with profound impairment of oxygenation on occasions. We are seeing a resurgence of severe H1N1 pneumonia after several years in India. Would corticosteroids be of benefit in these patients? There are no robust data available to guide us in this situation. The limited evidence available so far seems to suggest that corticosteroids may have either have no effect or even be harmful in viral pneumonias.

References

[1] Veterans Administration Systemic Sepsis Cooperative Study Group, Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis.  N Engl J Med (1987);317659- 665

[2] Annane D1Sébille VCharpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.JAMA. 2002 Aug 21;288(7):862-71.

[3] Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. New England Journal of Medicine. 2008 Jan 10;358(2):111.

[4] Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C. Adjunctive glucocorticoid therapy in patients with septic shock. New England Journal of Medicine. 2018 Mar 1;378(9):797-808.

[5] Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. Jama. 1998 Jul 8;280(2):159-65.

[6] Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007 Apr 1;131(4):954-63.

[7] National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. New England Journal of Medicine. 2006 Apr 20;354(16):1671-84.

[8] Confalonieri M, Urbino R, Potena A, et al.  Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med. 2005 Feb 1;171(3):242-8.

[9] Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial. The Lancet. 2015 Apr 18;385(9977):1511-8.

[10] Fernández-Serrano S, Dorca J, Garcia-Vidal C, et al. Effect of corticosteroids on the clinical course of community-acquired pneumonia: a randomized controlled trial. Critical Care. 2011 Apr;15(2):R96.

[11] Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. The Lancet. 2011 Jun 11;377(9782):2023-30.

[12] Sabry NA, Omar EE. Corticosteroids and ICU course of community acquired pneumonia in Egyptian settings. Pharmacology & Pharmacy. 2011 Apr 25;2(02):73.

[13] Snijders D, Daniels JM, de Graaff CS, et al. Efficacy of corticosteroids in community-acquired pneumonia: a randomized double-blinded clinical trial. American journal of respiratory and critical care medicine. 2010 May 1;181(9):975-82.

[14] Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. Jama. 2015 Feb 17;313(7):677-86.

 

Extracorporeal Membrane Oxygenation (ECMO) for Acute Respiratory Failure – the EOLIA Study

 

Extracorporeal membrane oxygenation (ECMO) is being increasingly used in acute respiratory failure. It is employed as a rescue intervention when conventional measures including titration of PEEP and prone positioning fail to achieve the desired effect. Historically, two randomized controlled trials (RCTs) had failed to demonstrate efficacy; however, these studies were performed several decades ago, when ECMO techniques were less refined. The CESAR study, performed many years later, demonstrated a significant improvement in the primary outcome of death or disability at six months in ECMO treated-patients. This study used devices with roller pumps, in contrast to the centrifugal pumps that are currently the preferred technique.

Combes et al., in their RCT, compared ECMO with conventional care in severely hypoxic patients with acute respiratory distress syndrome (ARDS). Patients in the control group could crossover to ECMO in case of severe, refractory hypoxemia. They found no significant difference in the primary endpoint of 60-day mortality. The secondary endpoint was treatment failure at 60 days: mortality in the ECMO group, and mortality or crossover to ECMO in the control group. The secondary endpoint was significantly more favorable with ECMO.

It may not be prudent to reject ECMO therapy in acute respiratory failure based on the findings of this study. To begin with, the investigators assumed improved survival by 20% with ECMO. This was based on two previously published studies- the PEEP study by Mercat et al. and the CESAR trial. However, such a large effect size entailed a small sample size, increasing the likelihood of a type II error. Clearly, it would have been unethical to decline ECMO to patients who were dying of hypoxia; however, crossover from the control to the intervention arm also makes the results of the study difficult to interpret.

Thirty-five patients who developed refractory hypoxemia in the control group were crossed over to receive ECMO. At the time of crossover, the median P/F ratio was 51, and the median Saowas 77%. Many of these patients were on the verge of severe cardiovascular failure; nine patients suffered cardiac arrest prior to initiation of ECMO and seven underwent veno-arterial ECMO. None of these patients may be expected to survive with continued conventional care; however, the use of ECMO resulted in 60-day survival in 15 of 35 (43%) patients. Another weakness of this study is the large number (72%) of potentially eligible patients who were excluded; 166 (16%) were excluded because they were already on ECMO. Blinding is not feasible in a study of ECMO; however, investigator bias cannot be excluded.

Perhaps the inclusion criteria for ECMO initiation also need to be considered. In our practice, we would probably not consider ECMO in a patient with a P/F ratio of 80 for six hours, particularly if there is an improving trend. Nor would I be too keen with a PCO2 of 60 mm Hg and pH of 7.25 for 6 hours. Only 62% of patients who underwent ECMO were prone ventilated; in our practice, we would attempt prone ventilation almost always before we consider ECMO.

At the end of the day, it may well be difficult to definitely prove the efficacy of ECMO against conventional care in a randomized controlled trial. First, it may be unethical to withhold ECMO in patients who are dying of hypoxia; approval for such a trial may be denied by most ethics committees. Second, to generate a sufficient sample size to demonstrate a clear effect in patients with refractory hypoxemia may take an inordinately long period. This multicentric study took nearly six years to recruit 249 patients. Therefore, I feel, given the current level of evidence, it may be appropriate to initiate ECMO based more on clinical judgment and local feasibility.

 

 

 

 

The Sepsis Scenario in India

The World Sepsis Day is held on the 13th of September every year. We held a meeting of local intensive care physicians in Bangalore the other day to mark the occasion. It offered us an opportunity to reflect upon where we stand and the progress we have made over the years in battling this deadly affliction, that kills approximately 6 million people across the globe every year. It is sobering to realize that this number may well be an underestimate because most epidemiological studies do not include “middle” and “low income” countries. While the number of hospital admissions for myocardial infarction and stroke have decreased over the years, there has been a steady increase in patients who require hospitalization for sepsis. Several magic bullets have been tried and fallen by the wayside in our quest to combat sepsis.

In contrast to global epidemiology, there are several infectious diseases that are peculiar to and widely prevalent in India, including malaria, dengue, leptospirosis, typhoid, and tuberculosis. We have a paucity of country-specific epidemiological information on the incidence of and outcomes from sepsis-related illnesses from India. Multicentric studies from critical care units across the country would definitely offer us a plethora of information on the types of diseases, complications, and outcomes in critically ill patients with sepsis, from an Indian perspective. I am sure it will pave the way to enable us to deliver improved care to our patients.

Do we need to combine meropenem with colistin in multidrug-resistant infections?

Colistin is often used as combination therapy in multidrug-resistant infections. The antibiotics used in combination with colistin include meropenem, rifampicin, and minocycline. Combination therapy is favored for several theoretical reasons. Colistin levels in the lung have often resulted in subtherapeutic levels in animal models. Heteroresistance, a phenomenon by which subsets of bacteria may be resistant, even though in vitro testing suggests otherwise, may occur with colistin monotherapy. Heteroresistance may lead to the proliferation of a fully resistant strain during the course of treatment. Antibiotic synergism has also been proposed to explain the benefits of combination therapy with colistin. Furthermore, some studies suggest poor rates of clinical cure with colistin monotherapy. (1)

Paul et al. in a multicenter randomized controlled trial, compared combination therapy with colistin and meropenem with monotherapy using colistin alone in carbapenem-resistant gram-negative infections. (2) A total of 406 patients were included, with 198 in the monotherapy group and 208 with combination therapy. The groups were well matched at baseline; 65% of patients were ventilated, while 18% required hemodynamic support, and 6.4% required renal replacement therapy. The median SOFA score was 6, with an overall mortality of 44%. The most common infection was ventilator-associated pneumonia (VAP), followed by bacteremia, and urosepsis. About 36% of infections were ICU-acquired. The most common pathogen, by far, was Acinetobacter Baumannii.

The primary outcome was “clinical success” of therapy at 14 days, which required all the following criteria: 1. Survival; 2. Systolic blood pressure > 90 mm Hg without vasopressors; 3. Improved or stable SOFA score; 4. Stable or improved P/F ratio in patients with VAP; 5. No growth in blood culture on day 14 for patients with bacteremia. Clinical failure rates were high and similar in both groups; failure of therapy was seen in 156/198 (79%) of patients with monotherapy and 152/208 (73%) with combination therapy. There was no difference in all-cause mortality between groups at 14 and 28 days. There was a lower incidence of AKI on day 14 with combination therapy, in patients with “injury” and “failure” on the RIFLE classification. Clinical failure was lower in ventilator-associated pneumonia, hospital-acquired pneumonia, and bloodstream infection, although the difference was not statistically significant.

This study aimed to answer an important question that we ask in patients with multidrug-resistant infections with in vitro sensitivity to colistin and resistance to meropenem. Hitherto, the general policy in most units has been to combine both, although there was no robust evidence to support the efficacy of such a combination. This study had several limitations, including the use of a composite outcome with short-term (14-day) mortality as one of the components. The overwhelming majority of infections were caused by A.Baumannii, which naturally raises a question about applicability to other organisms. There was considerable heterogeneity in the site of infections. Would the results apply to specific infections such as VAP, given that colistin has poor penetration into lung tissue? Therapeutic drug monitoring was not performed; it may have been interesting to know if adequate drug levels were achieved, especially with colistin.

However, based on this study, I feel that we should strongly consider using colistin as monotherapy if in vitro resistance to meropenem is noted. Antibiotic synergism is at best, hypothetical, especially when resistance has been demonstrated in vitro. Furthermore, in our setting, the manifold escalation of the cost of care with combination therapy should also be a deterrent. The findings of a retrospective observational study from an oncological unit in India, that showed no change in crude mortality with a carbapenem-colistin combination compared to colistin alone, lends further support to monotherapy. (3)

References:

  1. Parchem NL, Bauer KA, Cook CH, Mangino JE, Jones CD, Porter K, et al. Colistin combination therapy improves microbiologic cure in critically ill patients with multi-drug resistant gram-negative pneumonia. Eur J Clin Microbiol Infect Dis. 2016 Sep;35(9):1433–9.
  2. Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018 Apr;18(4):391–400.
  3. Ghafur A, Devarajan V, Raja T, Easow J, Raja MA, Sreenivas S, et al. Monotherapy versus combination therapy against nonbacteremic carbapenem-resistant gram-negative infections: a retrospective observational study. Indian J Crit Care Med. 2017 Dec 1;21(12):825.

The BICAR study – does bicarbonate therapy help in metabolic acidosis?

In the BICAR-ICU study Jaber et al. randomized critically ill patients with metabolic acidosis with pH less than 7.2 and bicarbonate less than 22 mmol/L to receive 4.2% bicarbonate, targeting a pH of 7.3. They compared outcomes with a control group that did not receive bicarbonate.

Three hundred and eighty-nine patients were enrolled, with 195 in the bicarbonate group and 194 in the control group. The primary outcome, a composite of death at 28 days and at least a single organ failure on day 7, was not significantly different. However, the composite outcome was significantly lower in a pre-specified subgroup of patients with an AKIN score of 2 or 3. Besides, the 28-day survival and the presence of at least a single organ dysfunction on day 7 (the individual components of the composite primary outcome) were also significantly lower in this subgroup. The requirement for renal replacement therapy (RRT), based on pre-specified criteria, was also significantly lower in patients who received bicarbonate therapy.

This is indeed an interesting addition to the scarce body of knowledge that addresses the benefit of bicarbonate therapy in metabolic acidosis due to causes other than loss of alkali from the body. Conventional wisdom advocates treatment of the underlying cause in lactic acidosis, in contrast to correction of pH to a pre-set level. The generally held view is that administration of bicarbonate could lead to a release of CO2 and worsening of intracellular acidosis. Does this study challenge tradition-borne practice and suggest a benefit from bicarbonate therapy to correct the pH in metabolic acidosis?

There are several obvious limitations to appropriate interpretation of this study, some of them pointed out by the authors themselves. Composite primary outcomes have often been problematic to interpret; this study is no exception. How does 28-day survival add up with the presence of a single organ failure of day 7? Among the eligible patients, 58% were excluded; a significant proportion (20%) because they had already received bicarbonate therapy. The overall mortality of the cohort was 49%, largely explained by the high baseline severity, with a SAPS of 60. Only 60% of patients who received bicarbonate attained the set pH target of 7.3 by 48 hours. If the intention of correction of acidosis was not achieved in the majority of patients what may be the putative mechanism by which bicarbonate exerts a beneficial effect? The other major limitation of this study is that 47/194 (24%) of patients in the control group were administered bicarbonate therapy, leading to a major problem with the interpretation of intention to treat analysis.

It is interesting to note that overall, the requirement for RRT (based on prespecified criteria) was lower in the bicarbonate-treated group. The requirement for RRT was also lower in the subgroup of patients with an AKIN score of 2-3. Do we conclude that the improved 28-day survival among bicarbonate-treated patients in this subgroup may have been due to adverse outcomes resulting from RRT in the control group? This seems unlikely. The study was unblinded, which could also have led to bias; no placebo was employed because administration of a significant volume of any type of placebo fluid may have led to electrolyte abnormalities. Another point that I would raise is the difference in the composite outcome that was assumed to calculate power. I cannot recall a major study in recent times that assumed such a big difference (15%) in the primary outcome. The larger the assumed outcome difference, the smaller the sample size and the higher the propensity for a type I error.

Overall, I feel it is an interesting study which suggests improved outcomes in critically ill patients with AKI and metabolic acidosis from bicarbonate therapy. I do feel that there may be several critical care physicians in India who follow a similar approach in the hope of delaying RRT or avoiding it altogether. Perhaps we should consider a controlled study that specifically addresses patients with severe AKI and metabolic acidosis to seek a possible outcome benefit. I feel, the primary outcome of such a study should be 90-day mortality, which seems to be a more appropriate benchmark in this stone age.

 

 

 

Platelet transfusion in Dengue Fever

Following the monsoon rains, we see several cases of Dengue in our ICUs. Many of these patients develop severe thrombocytopenia, with the counts often dropping below 20,000. I feel most clinicians would strongly consider prophylactic platelet transfusion (without any evidence of clinical bleeding) when the count drops to between 10–20,000. However, there is a reasonably sound body of knowledge which suggests that prophylactic platelet transfusions using arbitrary thresholds may not have any favorable effect. There are several retrospective studies and two randomized controlled studies that have clearly shown that there is no reduction in the incidence of bleeding with platelet transfusion using such arbitrary thresholds. Indeed, even the platelet counts do not seem to rise significantly following transfusion. In fact, there is a possibility of potential harm with transfusion of platelets in this manner.

In two pediatric studies, it has been shown that ADAMTS-13 levels may be relatively low in Dengue,  compared to Von Willebrand factor (VWF) levels. This may result in increased platelet adhesion to VWF multimers, and endothelial sequestration. Sequestrated platelets may lead to impaired microcirculatory flow and organ dysfunction (through a pathophysiological mechanism similar to TTP). Hence, it is possible that prophylactic platelet transfusion may cause harm by increased endothelial sequestration and worsening organ function. Furthermore, the harmful effects of transfusion, including transfusion-associated lung injury (TRALI) and fluid overload may have an adverse impact on clinical outcomes.

How do we offset the possible harm from platelet transfusion in Dengue? Clearly, if the ADAMTS-13 levels are low, there may be a compelling reason to replenish it using fresh frozen plasma, prior to transfusion of platelets. Cryo-reduced plasma, which is FFP from which cryoprecipitate has been removed is another rich source of ADAMTS-13. Recombinant ADAMTS-13 is also currently available.

Although based on a well-founded hypothesis, no clinical studies have been done to test the benefit of replenishing ADAMTS-13 levels in Dengue prior to platelet transfusions. I strongly feel we could undertake a multicentric study to assess clinical outcomes with such an intervention. The clinical outcomes to consider may include a rise in platelet counts to a sustained level and clinical bleeding with and without ADAMTS-13 supplementation with any of the aforementioned products.