ESICM ICU Clinical Trials (Part 2)

Yesterday, I blogged about the first group of clinical trials with results presented at European Society of Intensive Care Medicine International Conference (ESICM Update #1).  This blog will try to summarize some of the trials presented in the session on Tuesday, October 4.  The four studies from this session that I will briefly discuss include: Long-term outcomes of the TRISS randomized trial, the GRAVITY-VAP trial (lateral trendelenberg vs semirecumbent position to prevent VAP), the CLASSIC trial (restricting resuscitation fluid in patients with septic shock), and the OPERA trial (post-operative high flow nasal cannula vs conventional oxygen in patients after major abdominal surgery).

Let’s start with long term outcomes from the TRISS trial.  The TRISS trial was a randomized trial of lower (7 g/dL) versus higher (9 g/dL) hemoglobin transfusion threshold in patients with septic shock.  That study showed no difference in mortality for the two different hemoglobin transfusion thresholds.  However, patients did leave the hospital with different hemoglobin levels.  So it is not unreasonable to think that their course might have been different since anemia is a big contributor to quality of life.  In this long-terms outcome study, the authors followed patients to assess mortality at both 1 year and longest follow-up time and also quality of life scores at 1 year (Rygard SL, et al. Intensive Care Med. 2016; Epub ahead of print September 30, 2016).  All of these outcomes were defined a priori during the initial study.  Of the 1005 patients enrolled in the study, 1 year follow-up was available for an impressive 997 (99%) and quality of life assessments for 629 of the 777 Danish (81%) patients.  Similar to the shorter term outcomes, lower and higher transfusion thresholds during septic shock had similar 1 year mortality rates (53.5% vs. 54.6% for RR 0.97 for lower transfusion threshold) and longest follow-up mortality rates (mean follow up 21 months; 56.7% vs. 61.6%; HR 0.88).  There was also no difference in overall quality of life scores, nor in the mental or physical domains of the quality of life scores at 1 year.  My impression of these results is two-fold:  I am not overly surprised that different transfusion thresholds did not alter longer term outcomes (although admittedly, they needed to assess these outcomes since it did result in different hemoglobin levels at discharge).  Secondly, this study once again demonstrates the severe morbidity and mortality associated with septic shock. Over half of patients were deceased one year after their septic shock episode.

The GRAVITY-VAP trial is an interesting trial of positioning of mechanically ventilated patients to prevent ventilator associated pneumonia (GRAVITY-VAP).  Although this trial is not yet published, I will try to summarize the results as presented at the conference.  The trial randomized mechanically ventilated patients to either care in the lateral trendelenberg position (LTP) or the standard semi-recumbent position (SRP).  It turns out that the LTP was about -5 degrees of tilt compared to an average of 34 degrees in the SRP.  The primary outcome was microbiologically confirmed (via bronchoscopy) VAP.  The trial was stopped early for low rates of VAP in the control arm – however, despite this, the LTP resulted in significantly less microbiologically confirmed VAP than the SRP (4% vs. 0.8%; P<0.05).  However, this did not translate into any difference in clinical outcomes, including length of ventilation, ventilator-free days, ICU length of stay, or ICU mortality.  And ICU mortality actually had a trend toward being lower in the SRP.  My thoughts on this mirror my thoughts on many VAP prevention trials – we seem to find interventions that decrease VAP, but do not alter hard, patient-centered clinical outcomes such as duration of mechanical ventilation, ICU or hospital length of stay, or mortality.  I am not sure of the clinical utility of these interventions.  And this trial has a few confounders, including twice as many patients in the LTP arm were ventilated through endotracheal tubes with subglottic suctioning as compared to the SRP arm.  While ventilating patients in the lateral trendelenberg position is intriguing, it does not appear to improve the outcomes of our critically ill patients.

The CLASSIC trial is a trial of two different resuscitation strategies for patients in septic shock after initial resuscitation (i.e. once they were admitted to the ICU)(Hjortrup PB, et al. Intensive Care Med. Epub ahead of print September 30, 2016).  In order to be eligible, patients needed to be on norepinephrine for septic shock, have completed 30 ml/kg of fluid resuscitation, and be within 12 hours of shock onset.  Patients with renal failure or refractory hypoxemia were excluded.  151 patients from both Danish and Finnish ICUs were randomized.  Both arms of this study utilized protocol driven resuscitation – the restricted arm allowed small boluses of crystalloid (250-500cc) for severe hypoperfusion (defined by any of lactate > 4, MAP< 50 mmHg, mottling beyond the kneecap, or oliguria in the first 2 hours).  In the control group, IV crystalloid boluses could be given as long as hemodynamic variables were thought to improve.  The co-primary endpoints were amount of resuscitation fluids given in the first 5 days and during the entire ICU stay.  Clinical outcomes, including renal failure, 90 day mortality, and ventilator free days were included as exploratory outcomes.  Over the first 5 days, the mean difference in iv resuscitation fluids was only 1.2L between groups, and the difference over the entire ICU stay was only 1.4L, albeit both were statistically significant.  Average difference in cumulative fluid balance over the first 5 days was 1148 mL and only 475 mL for the entire ICU stay (not statistically significantly different for either time period).  However, worsening of acute kidney injury was significantly lower in the restricted group (37% of patients compared to 54% in the standard group; OR 0.46; P=0.03).  While not statistically significant, 90-day mortality also was numerically lower (33% vs. 41%) in the restricted group.  Overall, this is an interesting study.  I firmly believe that over-resuscitating our patients is detrimental to them – and I think we over resuscitate most of our patients.  So my “prior” belief in this area makes me want to believe that restricting fluid, even in patients with septic shock, will improve outcomes.  However, despite a fairly strict protocol restricting fluid, the overall difference in resuscitation fluids and cumulative fluid balance was small between the groups.  And I find it a bit hard to believe that this small difference had a big effect on clinical outcomes.  This trial will be replicated on a larger scale, and I greatly look forward to seeing the results of that trial.

And last but not least, the OPERA trial.  The OPERA trial randomized 220 abdominal surgery patients with moderate to high risk of developing pulmonary complications to either high flow nasal cannula (HFNC) or conventional oxygen therapy post-operatively (Futier E, et al. Trials. 2013;14:341).  Patients with obesity (defined as BMI>35) or known OSA were excluded. The HFNC was administered as 50-60L/min of flow, and oxygen was titrated in both groups to maintain saturations > 95%.  The HFNC was applied overnight after surgery until the morning of post-operative day 1.  The primary endpoint was hypoxemia (defined as P/F<300) at 1 hour post-operatively with secondary endpoints being hypoxemia the morning of post-op day 1 and pulmonary complications.  In this study, HFNC failed to demonstrate benefit over conventional oxygen.  There was no difference in hypoxemia at one hour (21% vs. 24%) or the next morning (27 vs. 30%).  There also was no difference in pulmonary complications post-operatively between the groups.  Given these results, routine use of HFNC in moderate to high risk patients post abdominal surgery cannot be recommended.

That’s a summary of some of the ICU clinical trials presented at ESICM on Tuesday, October 4.  I hope you enjoyed the reading and learned a little in the process.  I will try to post summaries of the trial results presented in the Hot Topics session soon.


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