Lactate in Sepsis: Much Maligned, but Not Quite the Evil Devil!

In the 2018 iteration of the Surviving Sepsis Guidelines, a 1-h bundle is recommended for expeditious resuscitation and management of severe sepsis. Serial lactate measurements are advocated to guide resuscitation with the aim to normalize levels. High lactate levels are considered to indicate tissue hypoperfusion in sepsis.1

Glucose metabolism

Aerobic pathway

Let us consider how lactate is generated. In the presence of an adequate supply of oxygen, aerobic metabolism occurs. Glucose is first converted to pyruvate, yielding two molecules of ATP. The pyruvate is then converted by pyruvate dehydrogenase to acetyl CoA (Fig. 1, red arrow). The acetyl CoA enters the tricarboxylic acid cycle (TCA) resulting in the formation of 36 molecules of ATP. If there is a lack of oxygen, the anaerobic pathway takes over. In this pathway, the first step, namely, the conversion of glucose to pyruvate occurs as previously, because oxygen is not required for this process. However, the next step, namely, the conversion of pyruvate to acetyl CoA, and subsequent entry into the TCA cannot happen in the absence of oxygen.

lactate-1.jpg

Fig. 1 Glucose metabolism. Red arrow: aerobic pathway through the TCA cycle. Green arrow: Due to enhanced aerobic glycolysis,  pyruvate accumulation occurs as the TCA pathway becomes saturated. The pyruvate is converted to lactate by lactate dehydrogenase 

Anaerobic pathway

What happens to the pyruvate that accumulates consequent to the failure of its conversion to acetyl CoA due to a lack of oxygen? Another enzyme, lactate dehydrogenase, takes over and converts the pyruvate to lactate (Fig. 1, green arrow). The lactate is then transported to the liver, where it is utilized in three different ways (Fig. 2): (1) Conversion to pyruvate by the same enzyme, lactate dehydrogenase, by a reverse process. The pyruvate generated by this process is converted to glucose by gluconeogenesis. The glucose thus produced goes back into circulation. The conversion of two molecules of pyruvate to one molecule of glucose consumes six molecules of ATP and hence is an energy expending process. (2) Conversion to glycogen, which may be converted to glucose for later use, and (3) Conversion to pyruvate, which re-enters the TCA under aerobic conditions to generate ATP. The excess lactate is also transported to the myocardium, where it is converted to pyruvate and enters the TCA cycle to yield ATP for the myocardial cells. Metabolism in the myocardial cells is always aerobic.

liver

Fig. 2 The lactate generated from pyruvate (green arrow, Fig. 1) is transported to the liver. It may be converted to glucose (gluconeogenesis),  to glycogen, or to pyruvate in the liver  

Lactate levels in sepsis

Why do lactate levels rise in sepsis? Is it because of reduced tissue oxygen delivery, and anaerobic metabolism of glucose? Tissue hypoxia due to impaired oxygen delivery is highly unlikely is sepsis. In most cases, there is preserved or increased cardiac output with adequate oxygen delivery. Lactate levels rise in sepsis, through entirely different mechanisms that are unrelated to tissue hypoxia. In sepsis, there is excessive stimulation of beta-2 receptors. This leads to accelerated aerobic metabolism of glucose. Increased aerobic metabolism of glucose leads to high levels of pyruvate. However, the pyruvate dehydrogenase pathway through to the TCA cycle gets overwhelmed due to the excessively high pyruvate levels. Consequently, the excess pyruvate gets converted to lactate by the lactate dehydrogenase enzyme. Hence, with an increase in aerobic metabolism of glucose, the lactate levels rise hand in hand. However, lactate production through this mechanism is not due to tissue hypoxia; it is entirely due to excessive aerobic metabolism of glucose, stimulated by beta 2 receptor-mediated release of epinephrine, a characteristic feature of sepsis. In fact, failure of lactate levels to rise in response to epinephrine infusion in shocked patients has been associated with increased mortality.Other mechanisms of lactate generation are also seen in sepsis, including excessive production in the lung due to ARDS and hepatic dysfunction leading to reduced utilization of lactate.

It has been clearly established that high lactate levels indicate more severe illness. Furthermore, increased lactate levels predict mortality.Hyperlactatemia without hypotension has been associated with significantly higher mortality compared to patients with hypotension and normal lactate levels.Be that as it may, will targeting resuscitative interventions with the lactate level as a therapeutic goal be appropriate? First, if the rise in lactate levels is unlikely to be due to oxygen debt, it would seem illogical to attempt to increase oxygen delivery with an eye on the lactate level. If a patient has improving blood pressures, urine output, and acid-base status, it defies logic to assume that continued measures aimed specifically at lactate levels would be beneficial.

The use of the term “lactate clearance” may also be flawed. Clearance is the volume of plasma from which a substance is completely removed per unit time. In a shocked patient, the lactate levels are more likely to fall due to reduced production; not from removal by metabolism. A falling lactate level is definitely more likely to be associated with survival; however, the rate of fall in lactate levels that may be associated with a better outcome is hard to define.5

The bottom line

  • Lactate levels rise in sepsis mainly because of catecholamine-mediated enhanced aerobic glycolysis.
  • Oxygen debt is uncommon in septic shock; hence “bundles” that target increased oxygen delivery are unlikely to help.
  • Lactate is an important metabolic fuel in shock. It is a substrate for the production of glucose and glycogen in the liver, and a source of aerobic generation of ATP for the myocardium.
  • A high lactate level is a strong predictor of mortality.
  • A fall in lactate levels carries a good prognosis; however, resuscitative interventions that target lactate levels are unlikely to be beneficial.
  • It is important not to view lactate levels in isolation; a holistic approach that addresses all the vital parameters that govern the circulatory status is essential.

 

References:

  1. Levy, M. M., Evans, L. E. & Rhodes, A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med.44, 925–928 (2018).
  2. Wutrich, Y. et al.Early increase in arterial lactate concentration under epinephrine infusion is associated with a better prognosis during shock. Shock Augusta Ga34, 4–9 (2010).
  3. Serum lactate as a predictor of mortality in patients with infection. – PubMed – NCBI. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17431582. (Accessed: 12th December 2018)
  4. Mortality is Greater in Septic Patients With Hyperlactatemia Than With Refractory Hypotension. – PubMed – NCBI. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28248722. (Accessed: 11th December 2018)
  5. Vincent, J.-L., Quintairos e Silva, A., Couto, L. & Taccone, F. S. The value of blood lactate kinetics in critically ill patients: a systematic review. Crit. Care20, (2016).

 

 

 

 

 

 

Noninvasive Ventilation in Severe Community-Acquired Pneumonia​: To Do or Not to Do, That Is the Question!

 

Invasive mechanical ventilation may be complicated by ventilator-associated lung injury, ventilator-associated pneumonia, the need for sedation and muscle paralysis, and the possibility of airway-related problems. Noninvasive ventilation (NIV) is widely used by clinicians in community-acquired pneumonia (CAP), in the hope of avoiding intubation thereby improving clinical outcomes. Although the efficacy of NIV in patients with chronic obstructive airways disease (COPD) with pneumonia is reasonably well established, the evidence for its use in non-COPD patients is less clear. We are currently faced with an epidemic of viral pneumonia in many parts of India; would it be appropriate to offer a trial of NIV to some of these patients?

In an early observational study of patients with CAP and acute respiratory failure, a high intubation rate (66%) was observed, although there was an initial improvement in the PaO2/FiO2ratios.A large, registry-based cohort study was carried out during the 2009 H1N1 pandemic from 35 intensive care units in Argentina. NIV use carried a survival of 43/64 patients (67%) in this study, significantly higher than those who underwent invasive ventilation.The authors speculated that the improved survival observed with NIV may have been due to a lower severity of illness at baseline. In our series of 31 patients during the 2009 H1N1 pandemic, noninvasive ventilation was initially carried out in eight patients; four patients failed and subsequently underwent invasive ventilation.Several early studies suggest worse outcomes with NIV in acute hypoxemic respiratory failure, including CAP.More recent studies, some using a helmet device, suggest benefit with NIV use.5,6 Elderly, immunocompromised patients with CAP were shown to have a better 90-d survival with NIV use in a retrospective cohort study.7

Against the background of this fairly dodgy evidence, where do we stand in relation to NIV use in severe CAP with acute hypoxemic respiratory failure? Unfortunately, there are no robust, controlled studies that can guide us in deciding whether to resort to NIV as an initial line of therapy. Should we give a trial of NIV or just carry on with intubation and invasive ventilation in patients who present with CAP and acute hypoxemic respiratory failure? Are there reliable predictors of NIV failure that can help decision making?

In a prospective observational study of 64 patients with CAP, NIV was successful in 28 (44%). On multivariate analysis, a decrease in the oxygenation index (mean airway pressure × FIO2 × 100/PaO2) by 1.2 or more and an increase in the PaO2/FiO2ratio by 42.2 or more predicted NIV success. Furthermore, on ROC curve analysis, a pH of more than 7.38 and a respiratory rate of less than 27/min were also predictive of successful NIV use.In another prospective study of 184 patients with CAP, NIV failed more often in patients without previous cardiac or respiratory disease compared to those who had comorbidities. Radiological worsening and higher SOFA scores also predicted NIV failure. After an NIV trial of 1 h, an increase in heart rate, a fall in the PaO2/FiO2ratio, and lower bicarbonate levels were independent predictors of failure.In another retrospective cohort study of 209 patients, NIV failure occurred in 90 of 117 patients (77%); patients who failed NIV had a significantly higher mortality compared to those who succeeded. On multivariate analysis, higher APACHE scores and the requirement for vasopressors at 2 h were associated with NIV failure.10

I am sure you would agree that the situation is far from clear-cut. We have been mortified by lack of success with NIV in a handful of patients in our unit during this flu season. With the limited observational evidence we have, I would highlight the following points to ponder on before embarking upon an NIV trial in patients with CAP and acute hypoxemic respiratory failure.

  1. It is crucial to identify patients who are likely to benefit from NIV.
  2. Patients who have no significant comorbidities are more likely to failNIV (counterintuitive as it may seem).
  3. The higher the baseline severity of illness, the lower the likelihood of NIV success.
  4. Failure to improve physiological parameters, including the respiratory rate, P/F ratio, oxygenation index, and bicarbonate levels within the first few hours is likely to result in failure.
  5. Radiological worsening in the first 24 hours calls for invasive ventilation.
  6. It is important to recognize early signs of failure and resort to invasive ventilation expeditiously.

 

Please feel free to offer your valuable comments and input.

References:

  1. Jolliet, P., Abajo, B., Pasquina, P. & Chevrolet, J. C. Non-invasive pressure support ventilation in severe community-acquired pneumonia. Intensive Care Med.27, 812–821 (2001).
  2. Estenssoro, E. et al.Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation. Am. J. Respir. Crit. Care Med.182, 41–48 (2010).
  3. Chacko, J., Gagan, B., Ashok, E., Radha, M. & Hemanth, H. V. Critically ill patients with 2009 H1N1 infection in an Indian ICU. Indian J. Crit. Care Med. Peer-Rev. Off. Publ. Indian Soc. Crit. Care Med.14, 77–82 (2010).
  4. Honrubia, T. et al.Noninvasive vs conventional mechanical ventilation in acute respiratory failure: a multicenter, randomized controlled trial. Chest128, 3916–3924 (2005).
  5. Cosentini, R. et al.Helmet continuous positive airway pressure vs oxygen therapy to improve oxygenation in community-acquired pneumonia: a randomized, controlled trial. Chest138, 114–120 (2010).
  6. Brambilla, A. M. et al.Non-invasive positive pressure ventilation in pneumonia outside Intensive Care Unit: An Italian multicenter observational study. Eur. J. Intern. Med.(2018). doi:10.1016/j.ejim.2018.09.025
  7. Johnson, C. S., Frei, C. R., Metersky, M. L., Anzueto, A. R. & Mortensen, E. M. Non-invasive mechanical ventilation and mortality in elderly immunocompromised patients hospitalized with pneumonia: a retrospective cohort study. BMC Pulm. Med.14, (2014).
  8. Carron, M., Freo, U., Zorzi, M. & Ori, C. Predictors of failure of noninvasive ventilation in patients with severe community-acquired pneumonia. J. Crit. Care25, 540.e9–14 (2010).
  9. Carrillo, A. et al.Non-invasive ventilation in community-acquired pneumonia and severe acute respiratory failure. Intensive Care Med.38, 458–466 (2012).
  10. Murad, A., Li, P. Z., Dial, S. & Shahin, J. The role of noninvasive positive pressure ventilation in community-acquired pneumonia. J. Crit. Care30, 49–54 (2015).

 

 

 

Is normal saline really worth its salt​?

 

The quest for suitable intravenous fluids began with the cholera pandemic of the 1830s. The deadly disease was characterized by repeated evacuation of large volumes of a rice-water-like fluid leading to severe dehydration among those afflicted. It spread from India to South East Asia and the Middle East, then towards Russia and the rest of Europe killing thousands of people along the way. Latta, a Scottish physician, concerned by the loss of huge volumes of fluid from the body, suggested replenishment with a “salt” solution. This solution was administered rectally first, and later, intravenously, with a profound effect on those affected. Several decades later, a Dutch scientist, Hamburger, suggested that the concentration of salt in the human body was 0.9%. He proposed that an identical concentration of salt would be “normal” and physiologically appropriate. From this early, humble beginning, “normal” saline percolated down generations of physicians and became deeply entrenched into contemporary clinical practice. Yes, normal saline has been, by far, the most commonly prescribed intravenous fluid for nearly two centuries.

Is normal saline really physiological as Hamburger believed?

The sodium and chloride levels of normal saline are markedly different from serum levels. Normal saline is acidic (pH: 5.4) and contains 154 mmol/L each of sodium and chloride. Compared to serum levels, the Na+level in normal saline is approximately 10% higher, and even more importantly, the chloride level is almost 50% higher.

Does normal saline cause acidosis? According to Stewart’s hypothesis, the pH of any fluid is dependent only on three factors, including the PCOlevel, the content of non-volatile acid (albumin and phosphate), and most importantly, the strong ion difference (SID). SID is the difference between the fully dissociated cations and anions. Thus, SID = Strong cations (Na+, K+, Ca++, and Mg++) – Strong anions (Cl, lactate, ketoacids, and organic anions). The normal SID is 40 mmol/L; a lower SID which may occur with a relative increase in the strong anions, leading to a lower pH (acidosis). The pH increases when the SID is higher (alkalosis). When normal saline is infused, both Na+and the Cllevels rise. However, the increase in Clis much higher than the increase in Na+. This is because the Cllevel in normal saline is almost 50% higher than the serum level, compared to the minimal difference in Na+levels. Hence, the infusion of normal saline results in a relative increase in the Cllevels with a reduction in the SID, leading to acidosis.

Normal saline and the kidneys

The excessive Clcontent of the fluid filtered through the glomeruli is sensed by the macula densa, a group of specialized cells located at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule. The Clsignal is transmitted to the afferent arteriole, which is in close contact with the macula densa. This leads to vasoconstriction of the afferent arteriole, a drop in the perfusion pressure in the glomeruli, and reduced glomerular filtration (Fig. 1).

macula

Fig. 1: The macula densa senses a high concentration of chloride in the filtered fluid and signals vasoconstriction in the afferent arteriole, thus reducing the glomerular filtration rate (From: Li, Heng, Shi-ren Sun, John Q. Yap, Jiang-hua Chen, and Qi Qian. 2016. 0.9% Saline Is Neither Normal nor Physiological. Journal of Zhejiang University-SCIENCE B 17(3): 181–187)

Normal saline and potassium levels

Many clinicians believe that it may be safer to infuse normal saline compared to Ringer Lactate in patients with high potassium levels. This is based on the assumption that, Ringer Lactate, with a K+ concentration of 4.0 mmol/L, may exacerbate hyperkalemia. However, this assumption is largely incorrect; the acidosis arising from normal saline infusion leads to a shift of Kfrom the intracellular to the extracellular compartment with an increase in the serum K+ levels. Several clinical studies have confirmed higher potassium levels with the infusion of normal saline compared to Ringer’s lactate (Weinberg et al. 2017).

Does the use of normal saline as a resuscitation fluid lead to clinical harm?

It is somewhat bewildering that the ubiquitous use of normal saline remained unquestioned for more than a century. Beginning from the 1980s, concerns were raised regarding the high Clcontent in normal saline and the possibility of consequent renal injury. Clinical investigation into possible harm commenced much later, with several observational studies suggesting a detrimental effect (Raghunathan et al. 2015; Shaw et al. 2012).

In a sequential pilot study that compared 6 months each of a chloride-liberal vs. chloride-restricted intravenous fluid, the incidence of acute kidney injury (AKI) and the need for renal replacement therapy were significantly lower during the chloride-restricted period (Yunos et al. 2012). The SPLIT study was a double-blind, cluster-randomized, crossover study that compared 0.9% saline with Plasma-Lyte 148 (Young et al. 2015). There was no significant difference in the incidence of AKI, the need for renal replacement therapy, and in-hospital mortality between groups. However, this study was aimed primarily to evaluate the feasibility and assess sample size for future studies. The study was meant to be conducted over a specific period of time with no fixed sample size. No power calculation was made considering the lack of previous randomized controlled trials.

Two large randomized controlled trials were conducted at the Vanderbilt University Medical Centre comparing normal saline Vs balanced crystalloids (Ringer’s solution or Plasma Lyte A) and published earlier this year (Self et al. 2018; Semler et al. 2018). The SMART study was carried out in five intensive care units. Patients were randomly assigned to receive one of the two types of fluid on alternate months. The primary composite outcome was one or more major kidney events during 30 days (MAKE-30) of follow-up. The MAKE-30 criteria included mortality, the requirement for renal replacement therapy, and a rise in creatinine to twice the baseline or more in 30 days. The composite outcome was significantly less with balanced crystalloids compared to normal saline (14.3 vs 15.4%; p = 0.04). The SALT-ED study was conducted on non-critically ill patients presenting to the emergency department and admitted to the wards. Using a similar design, this study also revealed a more favorable composite outcome (4.7 vs. 5.6%; p = 0.01). Subgroup analysis suggested that the impact of using balanced crystalloids was more pronounced in patients who received larger volumes of fluid and those with sepsis.

The question of whether balanced crystalloids is preferable to normal saline may be far from unequivocally answered as yet. However, we know today that the centuries-old practice of unrestricted use of normal saline may lead to unfavorable clinical outcomes. Balanced crystalloids, including Ringer’s lactate and Plasma Lyte, offer possible safer alternatives, especially if large volume resuscitation is required. It is also pertinent to point out that a perceptible outcome difference based on the choice of fluid may be largely confined to the most severely ill patients. An 8800-patient randomized controlled trial comparing normal saline vs. Plasma Lyte 148 (the PLUS study) is currently in progress across multiple ICUs in Australia and New Zealand and may add substantially to our body of knowledge. In our practice, we confine to Ringer Lactate for most of our patients who need fluid resuscitation. The findings of SMART and SALT-ED have only strengthened our bias.

References:

Raghunathan, Karthik, Anthony Bonavia, Brian H. Nathanson, et al. 2015.Association between Initial Fluid Choice and Subsequent In-Hospital Mortality during the Resuscitation of Adults with Septic Shock. Anesthesiology 123(6): 1385–1393.

Self, Wesley H., Matthew W. Semler, Jonathan P. Wanderer, et al. 2018.   Balanced Crystalloids versus Saline in Noncritically Ill Adults. The New England Journal of Medicine 378(9): 819–828.

Semler, Matthew W., Wesley H. Self, Jonathan P. Wanderer, et al. 2018.   Balanced Crystalloids versus Saline in Critically Ill Adults. The New England Journal of Medicine 378(9): 829–839.

Shaw, Andrew D., Sean M. Bagshaw, Stuart L. Goldstein, et al. 2012.        Major Complications, Mortality, and Resource Utilization after Open Abdominal Surgery: 0.9% Saline Compared to Plasma-Lyte. Annals of Surgery 255(5): 821–829.

Weinberg, L., L. Harris, R. Bellomo, et al. 2017.      Effects of Intraoperative and Early Postoperative Normal Saline or Plasma-Lyte 148® on Hyperkalaemia in Deceased Donor Renal Transplantation: A Double-Blind Randomized Trial. British Journal of Anaesthesia 119(4): 606–615.

Young, Paul, Michael Bailey, Richard Beasley, et al. 2015.Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA 314(16): 1701–1710.

Yunos, Nor’azim Mohd, Rinaldo Bellomo, Colin Hegarty, et al. 2012.        Association between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults. JAMA 308(15): 1566–1572.

 

 

 

 

The hypoxic drive – an urban legend?

It is not unusual to see physicians painstakingly titrate oxygen flows with elaborate precision, especially in CO2 retaining patients with chronic obstructive pulmonary disease (COPD). I have occasionally come across novice ICU trainees cease oxygen therapy in dyspneic patients ostensibly to stimulate the hypoxic drive. The driving principle behind this line of thinking is the tradition-borne belief that supplemental oxygen may inhibit the hypoxic drive and lead to hypoventilation and rise in PCO2 levels. How important is the contribution of the hypoxic drive in patients with respiratory failure, especially among those with hypercapnia? Does supplemental oxygen really suppress ventilation in spontaneously breathing patients with COPD and lead to a rise in CO2 levels?

Aubier et al. studied 22 spontaneously breathing patients with acute exacerbation of COPD.They measured minute ventilation and performed arterial blood gases analysis, initially on room air, and subsequently while breathing pure oxygen through a Douglas bag. The minute ventilation dropped in the first few minutes but recovered rapidly to near baseline levels at approximately 10 minutes after oxygen administration. However, the CO2 levels continued to rise (Fig. 1). Clearly, hypoventilation was not the mechanism behind the rise in PCOin these patients.

Presentation3

Fig. 1 Minute ventilation (VE) decreased transiently after oxygen administration but recovered to baseline levels. The PCO2 levels continued to rise even after ventilation had recovered (From Abdo WF, Heunks LMA: Oxygen-induced hypercapnia in COPD: myths and facts. Critical Care 2012; 16:323)

Hypoxic pulmonary vasoconstriction and effect on PCO2levels

If oxygen therapy does not cause hypoventilation, what may be the mechanism behind the rise in CO2 levels? In chronic lung disease, blood flow through the lung is redistributed by hypoxia-induced vasoconstriction of the pulmonary vasculature. Blood vessels in regions of the lung that are poorly ventilated become constricted to match perfusion to ventilation and prevent shunting (flow of blood through the lungs without gas exchange). Supplemental oxygen results in an increase in the oxygen level within alveoli that are poorly ventilated with the abolition of hypoxia-induced vasoconstriction. This leads to a redistribution of blood flow from the relatively better ventilated to less ventilated regions of the lung. In effect, this results in an increase in perfusion relative to ventilation (low V/Q) in under-ventilated areas of the lung while the reverse occurs in the relatively well-ventilated areas of the lung (increase in alveolar dead space). Both these mechanisms may contribute to the rise in the alveolar and arterial COlevels.

The Haldane effect

About 10% of CO2 is carried in the blood as carbamino compounds, especially in combination with hemoglobin, as carbaminohemoglobin. Hemoglobin combines more avidly with CO2 when it is in the deoxygenated form. Thus, in the lung, as the hemoglobin takes up oxygen, it gives up the COby the Haldane effect. The CO2 is normally flushed out by ventilation. However, in a damaged lung, when the ventilation is inadequate, CO2 cannot be washed out adequately. The extra CO2 released from hemoglobin dissolves in the plasma with a rise in the PCO2 levels.

The bottom line

It is abundantly clear that the rise in CO2 levels seen in COPD patients with oxygen therapy is unrelated to the abolition of the “hypoxic drive” as was conventionally believed. The inhibition of ventilation is transient and insignificant; the PCO2 levels rise through other mechanisms. Theories and hypotheses apart, the bottom line is that supplemental oxygen should never be denied to hypoxic patients. The chances of death due to uncorrected hypoxia is overwhelmingly higher than possible harm from the administration of supplemental oxygen. Needless to add, most patients, regardless of their COlevels, do not need an oxygen saturation of more than 92%. Increasing the FiO2 aiming for much higher levels of oxygenation is not appropriate under most circumstances; less is more, so sayeth the wise intensivist!

References:

  1. Aubier M, Murciano D, Milic-Emili J, Touaty E, Daghfous J, Pariente R, et al. Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis 1980; 122:747-754.

 

 

 

Peripheral Venous Cannulation Under Ultrasonographic Guidance

Most of us routinely insert central venous catheters under real-time ultrasound guidance. The technique is time-tested, and there is robust evidence that it is safer and more reliable compared to the landmark-based approach. However, peripheral venous access can, at times, be even more challenging in critically ill patients. Quite often, access may be difficult due to thrombophlebitis or edema. It is not unusual for poorly experienced operators to struggle with the insertion of peripheral IV lines causing avoidable pain and discomfort to the patient. Would ultrasonography enable visualization of veins that are invisible to the naked eye and enable ease of insertion?

The importance of using an effective tourniquet cannot be overemphasized for ultrasound-guided cannulation of peripheral veins. Many monitors have a built-in, sustained, cuff inflation mechanism on the NIBP module to enable venipuncture. The other option is to inflate a manual blood pressure cuff to slightly lower than the systolic blood pressure. A high-frequency linear probe is most suited to visualize peripheral veins. The initial scan may be on the short axis view just distal to the cubital fossa, where the cannula will not get bent or displaced with arm movement. If veins are not readily visible at this location, move the probe distally along the forearm.

Once you see a vessel of reasonable size, you need to ensure that it is, in fact, a vein. This may occasionally be more difficult than it may seem. If the inflation pressure is too high,  arteries may be compressed on minimal probe pressure, making the distinction difficult. Pulse wave Doppler helps to distinguish between arteries and veins but may not be absolutely confirmatory if the inflation pressure is set close to the systolic pressure. However, a good way to differentiate is using what I call the “deflation test.” When the cuff is deflated, the artery becomes more prominent, while the vein collapses.

I would strongly recommend cannulation in the long axis view, using an in-plane technique. This enables precise guidance; besides, it is possible to visualize the cannula from the site of puncture all along the soft tissue through to the vein. The stylet of the cannula projects beyond the plastic tip by about a millimeter. With the in-plane technique, it is possible to ensure that the cannula is also within the vein (not just the stylet) and guide it along under vision, without transfixing the vein. This prevents the possibility of the stylet being inside the vein while the cannula lies outside.

The first step is to search for a suitable vein in the short axis view (Fig 1).

short_axis

Fig 1. Short axis view. A: Artery; V: Vein

Once you identify an optimally sized vein, the probe is turned around to obtain a long axis view of the target vein (Fig 2). A sufficiently good length of the vein, without tortuosity, should be visible to enable ease of insertion.

Slide3

Fig 2. Long axis view of the vein

In practice, the cannula is inserted just distal to the probe in the long axis to enable an in-plane technique (Fig 3).insertion.jpg

Fig 3. The direction of insertion of the cannula on the long axis view

Puncture the skin and look for movement on the ultrasonographic image; pass the cannula a millimeter at a time and follow it right from under the skin through to the vein (Fig 4).

insidevein

Fig 4. The cannula (arrow) is seen within the vein on the long axis

Do ensure that you do not lose sight of the cannula at any time. At times, the cannula may seem to be in the vein, when it actually lies outside. This can be prevented by ensuring indentation of the wall of the vein as it makes contact.

How do you confirm that the cannula is in the vein? You could view the cannula inside the lumen on the long axis. However, the definitive method is by performing a bubble test with 10-20 ml of saline (Fig 5).

bubble

Fig 5. The bubble test. Opacification is seen within the right ventricle (RV)

The bubble test is carried out by rapid injection of 20-30 ml of saline into the IV line while watching for echocardiographic opacification of the right atrium and the ventricle. Do not forget to record the clip; it helps to review the loop if the opacification is not clear-cut on the initial view.

 

 

Is Doppler-based calculation of pulmonary artery pressure valid in critically ill patients on mechanical ventilation?

Pulmonary artery pressure (PAP) is an important parameter in mechanically ventilated patients. In cardiology practice, the pulmonary artery systolic pressure (PASP) is measured by transthoracic echocardiography by continuous wave Doppler interrogation of the tricuspid regurgitation (TR) jet. The measurement is based on the following equations:

Tricuspid pressure gradient (Right ventricular systolic pressure – right atrial pressure) =4V(where V = maximal velocity of the TR jet)

Right ventricular systolic pressure (RVSP) = Tricuspid gradient + CVP. The RVSP is assumed to be identical to the pulmonary artery systolic pressure (PASP).

If the CVP is not measured, conventionally, 10 mm Hg is added to the tricuspid gradient to obtain the PASP. This method of measurement of PASP has been validated in spontaneously breathing patients in cardiology practice. However, the question remains, would it be valid in patients on positive pressure ventilation and PEEP? The evidence so far has been inconclusive.

In a single-center study from France, published online first in the Critical Care Medicine, the investigators assessed the reliability of Doppler-derived PAP measurements compared to invasive measurements using a pulmonary artery catheter in mechanically ventilated patients (Mercado et al., 2018). The PASP was calculated by two formulas (1) PASP = tricuspid pressure gradient + CVP and (2) PASP = tricuspid pressure gradient + 10 mm Hg. The mean PAP was calculated (1) using the isovolemic relaxation time and (2) using the Chemla equation: 0.61 × PASP + 2. The Doppler-based calculations were compared with direct measurements from a pulmonary artery catheter.

The PASP calculated by adding the CVP to the tricuspid pressure gradient correlated best with invasive PASP measured using a pulmonary artery catheter, with a Spearman correlation coefficient of 0.87. When pulmonary artery hypertension was defined as a mean PAP more than 25 mm Hg, a PASP of more than 39 mm Hg, derived using this method, revealed 100% sensitivity and specificity. The mean PAP calculated using the Chemla equation showed a similar correlation (0.87) with invasive measurements. A cut-off value of 26 mm Hg revealed a sensitivity and specificity of 100% for the diagnosis of pulmonary hypertension, defined as mean PAP > 25 mm Hg by invasive measurement. When the PASP was calculated by adding 10 mm Hg to the tricuspid pressure gradient, the correlation coefficient was 0.79 on comparison with invasive measurements from a pulmonary artery catheter.

This study validates TR jet-based pulmonary artery pressure measurements in critically ill patients, who are on mechanical ventilation. The most precise method, with the best correlation, was by addition of the CVP to the tricuspid gradient. However, if the central venous pressure is not available, adding 10 mm Hg to the tricuspid gradient would be a close approximation. This study also showed that contrary to widely held belief, the maximal or minimal diameter of the inferior vena cava nor the variation in diameter bore no correlation with invasively measured CVP.

This study firmly establishes the precision of continuous-wave Doppler-derived assessment of pulmonary artery pressures in mechanically ventilated patients in the intensive care unit. However, a tricuspid regurgitation jet may not be evident in some patients to enable measurement of the gradient. In the present study, the authors report that a measurable jet was present in 60% of patients. Besides, an optimal 4-chamber view, with proper alignment of the Doppler cursor with the axis of the regurgitant flow may not be possible to obtain in some patients.

References:

Mercado, P., Maizel, J., Beyls, C., Kontar, L., Orde, S., Huang, S., Slama, M. (2018). Reassessment of the Accuracy of Cardiac Doppler Pulmonary Artery Pressure Measurements in Ventilated ICU Patients: A Simultaneous Doppler-Catheterization Study. Critical Care Medicine, Online First. https://doi.org/10.1097/CCM.0000000000003422

 

 

 

 

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.

 

 

 

 

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.