ICU literature review

No significant RCTs to analyse this week
 However, some very good reviews

1. A state of the art review on optimal practices to prevent, recognize, and manage complications associated with intravascular devices in the critically ill.
Timsit, JF., Rupp, M., Bouza, E. et al. Intensive Care Med (2018) 44: 742
2. Diagnostic workup, etiologies and management of acute right ventricle failure
Vieillard-Baron, A., Naeije, R., Haddad, F. et al. Intensive Care Med (2018) 44: 774.

3. Expert statement for the management of hypovolemia in sepsis.
Perner, A., Cecconi, M., Cronhjort, M. et al. Intensive Care Med (2018) 44: 791

Review on the Eolia trial - posted by Dr Ketan Kargirwar

Clinical Question ▪ In patients with severe ARDS, does the early initiation of Extracorporeal Membrane Oxygenation (ECMO), compared to standard care, improve mortality at day 60.

Highlight of Trial
 ▪ The trial was conducted with sequential design methodology according to the triangular test.
 ▪ Triangular test designs have the advantage of allowing a study to be stopped early either for efficacy or for futility.
 ▪ The stopping rules were defined prior to the commencement of the trial. The trial could be stopped due to: ▪ Safety ▪ Efficacy ▪ Futility (ie unlikely to reach a definitive result)
▪ The data safety monitoring board (DSMB) recommended stopping the trial after the 4th interim analysis 249/331 (75% of planned recruitment) when it met the predefined stopping rules for futility. ▪ A post hoc rank preserving structural failure time analysis was performed to adjust for high rate of crossover in the control group in the estimation of the “actual and unbiased” ECMO effect on survival.

Outcome
 ▪ Primary outcome: No statistical difference in mortality at day 60 ▪ ECMO group 44/124 (35%) vs Control group 57/125 (46%) ▪ Relative risk, 0.76; 95% confidence interval [CI], 0.55 to 1.04; P=0.09 ▪

▪ Secondary outcomes: ▪ Compared to control group, the ECMO group had:
▪ Lower relative risk of treatment failure 0.62 (95% CI, 0.47 to 0.82; P<0.001) ▪ Treatment failure was defined as death by day 60 in patients in the ECMO group, and as crossover to ECMO or death in patients in the control group
 ▪ Lower risk of Renal replacement therapy (RRT) at day 60 (50 vs. 32 days; median difference, 18 days; 95% CI, 0 to 51)
 ▪ Underwent less proning (59 vs. 46 days; median difference, 13 days; 95% CI, 5 to 59)
 ▪ Cross over to ECMO occurred in 35/125 (28%) of control patients ▪ Occurred at median 4 days (IQR 1 to 7) ▪ Median PaO2:FiO2 51 mmHg (IQR 46 to 61), median SaO2 77% (IQR 74 to 87), median lactate was 3.2 mmol/L (1.5-6.2) ▪ 9 patients had cardiac arrest, 7 had right heart failure, 11 received RRT ▪ 7 underwent venoarterial (VA) ECMO (and 6 had E-CPR)
▪ 60 day mortality was higher in cross over patients than rest of controls: 20/35 (57%) in cross over patients vs 90 (41%) in remaining cross over patients ▪ The hazard ratio for death within 60 days, for the ECMO group compared to controls after adjusting for selective crossover with the rank-preserving structural failure time analysis, was 0.51 (95% CI, 0.24 to 1.02; P=0.055) ▪

Weaknesses ▪ Underpowered to answer the trial question.
▪ Trial was stopped early at 249/331 (75% of recruitment) due to predefined futility rules (ie unlikely to get a definitive result.
▪ Initial power calculation was based on a 60% mortality in the control group, which became clear was inflated compared to the actual mortality rate in the controls of 46%.
 ▪ A 20% absolute risk reduction sets a very large requirement for a single ICU intervention, increasing the risk of a falsely negative trial (CESAR, published in 2009, had a ARR of 16%)
 ▪ High cross over rate of controls
▪ The 28% cross over rate resulted a reduction of separation between the two arms, and diluted the ECMO treatment effect. This potentially impacted the trial in the following ways:
 ▪ The cross over complicates the interpretation of the two arms in an intention to treat analysis.
▪ It also introduces a potential bias against the ECMO group in the secondary risk of treatment failure analysis, as ECMO was initiated much later and in sicker patients than the rest of the controls
▪ Despite the use of objective criteria, the decision to crossover controls to ECMO was ultimately at the discretion of unblinded treating clinicians
 ▪ Equipoise – high cross over rate raises the question whether some clinicians had clinical equipoise ▪ Lack of blinding of clinicians and patients/families (however difficult in such a trial)
 ▪ Slow recruitment of 249 patients over 6 years, leading to potential trial fatigue and/or change of practice.
 ▪ Expertise of ECMO centers not clearly defined ▪ Importance of VV ECMO configuration is uncertain (i.e. femoral-jugular versus femoral-femoral approach)
▪ Majority of ARDS patients in this trial were male and had pneumonia and septic shock. Extrapolation to other ARDS patient groups is uncertain
 ▪ The trial does not distinguish between the use of VV ECMO and VA ECMO. In particular, 7 cross over control patients underwent VA ECMO for cardiac arrest

Will EOLIA change my practise of ECMO in ARDS : There is no right or wrong answer !!! but, we should continue to use ECMO for clinical benefit in selected group of patients with the help of experts and dedicated ECMO centre as a rescue therapy in severe ARDS patients. The result of the trial produce equipoise among the clinicians due to crossover of patients. However until now there is very less data on this intervention in ARDS patients and it might be difficult to conduct another new large RCT in near future to rule out this uncertainty. Also with the diversity in practices of ECMO all over the world and with evolving technology of ECMO there is substantial consensus around use of early ECMO in ARDS.
Dr Ketan kargirwar

Good Reviews.
Please post your mail ID if you need the PDF
Stolmeijer. A Systematic Review of the Effects of Hyperoxia in Acutely Ill Patients: Should We Aim for Less? Biomed Res Int 2018;2018:7841295 

Gårdlund. Six subphenotypes in septic shock: Latent class analysis of the PROWESS Shock study. J Crit Care 2018;epublished June 8th 
Ergan. How should we monitor patients with acute respiratory failure treated with noninvasive ventilation? European Respiratory Review 2018;27:170101

New Article Review

This week an interesting Phase 3 RCT evaluating the effect of Bicarbonate on outcomes among critically ill patients was published

Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial
Samir Jaber et al ; www.thelancet.com Published online June 14, 2018 http://dx.doi.org/10.1016/S0140-6736(18)31080-8

Sodium Bicarbonate infusions have been used quite extensively in ICUs for acidotic patients with varied thresholds and targets of pH.
There are both proponents as well as opponents to this approach.
The BICAR-ICU study evaluated the effect of 125-250 ml of 4.2% NaHCO3 on the 28 day mortality amongst a varied cohort of critically ill patients. Total volume was capped at 1000ml. A total of 389 patients were randomized to control and intervention groups. The pH threshold was <7.20 and the target was 7.30. Nearly half the patients had septic shock. Blood gases were done 1-4 hrs after the completion of the infusion. Primary endpoint was 28 day mortality. Patients with AKI (AKIN st 2-3 ) were identified as a subgroup apriori. The investigators found no difference in the entire cohort, between the two groups in relation to the primary outcome. However, a positive effect was noted in the subgroup of patients with AKI. The patients who received NaHCO3 needed lesser no of RRT sessions and came off RRT quicker. But there was no difference either in ICU or hospital length of stay.

My opinion: The use of bicarbonate in this study happened at a pH higher than what is generally considered as a "dangerous" pH. The volume of drug used also was higher than normally used. There may be some role in AKIN 2-3 AKI but the solution used was hyperosmolar. We need to identify patients who benefit from this intevention

Sorry to miss the Saturday commitment for good publications.
The latest issue of Nephrology Dialysis and Transplantation published a meta analysis of intensity of RRT.

Renal replacement therapy intensity for acute kidney injury and recovery to dialysis independence: a systematic review and individual patient data meta-analysis

Ying Wang,  Martin Gallagher ,  Qiang Li , Serigne Lo,  Alan Cass,  Simon Finfer,  John Myburgh Catherine Bouman,  Robert Faulhaber-Walter,  John A Kellum ...

The common problem faced in intensive care is timing and intensity of renal replacement therapy. It is a popular concept that higher intensity of RRT leads to better outcomes and higher rates of dialysis independence. However, there is no consensus on whether higher intensity should be the norm.

          Kellum et al carried out a meta analysis of eight high quality studies measuring high intensity RRT against 28 day mortality as primary end point. RRT independence was the secondary outcome of interest. Analysis of data from more than three thousand patients revealed no mortality benefit with intensive regimens of RRT. The analysis also revealed that patients who received intensive prescriptions of RRT remained dependent on dialysis at 28 days. 

           The reviewers concluded that Intensive RRT prescription confers no survival benefit among patients with severe AKI. On the other hand intensive RRT might prolong the liberation from RRT.

My opinion: We need to be careful while prescribing RRT in severe AKI. Prescribing intensive RRT based on clinical severity might not yield the desired results

Couple of good reviews to be read

1. The issue of fluid management in ARDS is increasingly being spoken about.
Tagami et al have reviewed this topic well in the current issue of Current opinion in Critical Care. An excellent diagnostic framework has been posted.
2. A two series guideline has been published on Takatsubo Cardiomyopathy in the European Heart Journal

Journal Review

This week we begin our journey of information sharing.

We generally believe that a meta analysis is the ultimate guide or benchmark for evidence based practice.
Koster et al published an interesting review titled
Systematic overview and critical appraisal of meta-analyses of interventions in intensive care medicine 
This was published in Acta Anaesthesiologica Scandinavica
The authors raised a pertinent question regarding the critical appraisal method of the RCTs included in several often quoted meta analyses pertaining to the field of Intensive Care Medicine.
Out of a total of 467 meta analyses identified, only 1 in 9 satisfied basic scientific criteria for analysis. Out of these 56 or so meta analyses only 4 (four)  0.9% showed a low risk of bias. The rest of the analyses had a bias component which makes their interpretation complicated.

My opinion: It is good to rely on a meta analysis to guide some decisions in practice. However, we should be able to understand the scientific strength of the RCTs included so that we don't get caught in the "Garbage in Garbage out" phenomenon.

GCC tomorrow

Why you should be involved?

A wide array of clinically relevant topics are being discussed by handpicked faculty in an interactive and thought provoking format. 

Gujarat Critical Care meeting starts tomorrow at Ahmedabad.
The entire meeting can be viewed on line at http//estv.in/gcc2018/

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 This forum has been created for facilitating exchange of information regarding meetings, studies, difficult scenarios and training programs pertaining to Intensive Care. Please share your experiences and concerns regarding any aspect of intensive care. Please do not reveal patient identity