The European Society of Intensive Care Medicine (ESICM) is conducting its international conference this week. This conference has traditionally been a hotbed for breaking results from clinical trials. In this post, I would like to briefly highlight four clinical trials whose results were presented during the President’s Session of Clinical Trials in Intensive Care yesterday. Specifically, this post will briefly summarize the HYPRESS trial (Hydrocortisone for Prevention of Septic Shock), the DESIRE trial (Dexmedetomidine for ventilated septic patients in ICU), NAVA versus Pressure Support Ventilation, and the MACMAN trial (McGrath VL versus Macintosh DL for orotracheal intubation in intensive care patients).
The HYPRESS trial was published in JAMA simultaneous with its presentation at ESICM (Keh D, et al. JAMA. 2016;Published online October 3). This double-blind, placebo controlled trial randomized 380 patients within 48 hours of developing severe sepsis to either a continuous infusion of 200mg hydrocortisone per day for 5 days followed by a taper or placebo. The primary endpoint was the development of septic shock within 14 days. Secondary endpoints included ICU and 180 day mortality, secondary infections, weaning failure, weakness, and hyperglycemia. Hydrocortisone did not significantly reduce the incidence of septic shock (21.2% vs. 22.9%; P=0.70), ICU, hospital, 28 day or 180 day mortality, or ICU or hospital lengths of stay. It also did not decrease the incidence of mechanical ventilation, renal replacement therapy, or SOFA score through day 14. Overall, this study does not support the use of hydrocortisone in patients with severe sepsis to improve outcomes. Interestingly, with previous meta-analysis suggesting that steroids may improve outcomes in patients with pneumonia, 45% of patients in this study had pneumonia, although significantly lower percentage in the hydrocortisone arm (37.6 vs 53.4%). Because of this, I think trying to extrapolate the results of hydrocortisone in this subgroup of this study is likely to not be that informative for the use of steroids in patients with severe pneumonia.
The DESIRE trial (or Dexmedetomidine for ventilated septic patients) was another randomized trial presented at ESICM (DESIRE Trial), although it is not yet published. 200 ventilated patients with sepsis who were expected to require at least another 24 hours of ventilation were randomized to open label dexmedetomidine added to standard sedation or standard sedation alone. Patients with underlying liver disease, drug abuse, or pregnancy were excluded. The dose of dexmedetomidine was relatively low (0.1 – 0.7 mcg/kg/h) and it may have been too low as evidenced by the fact that both arms received the same amount of fentanyl analgesia and midazolam sedation. Dexmedetomidine did not significantly reduce the primary endpoint of 28 day mortality (22 vs. 30%) or ventilator-free days to day 28. Mortality in the control arm was lower than expected leaving the study a bit underpowered to detect a significant difference in mortality. Regardless, these data do not support the addition of dexmedetomidine to standard sedation to improve the outcomes of mechanically ventilated patients with sepsis.
Neurally Adjusted Ventilator Assist (NAVA) is a newer mode of ventilation designed to improve ventilator synchrony. NAVA utilizes a special NG tube which senses the electrical activity of the diaphragm to both trigger a breath and determine how big of a breath to deliver to the patient. Numerous studies have shown that this decreases the delay between when the patient starts a breath and when the ventilator delivers a breath. This randomized controlled trial in French ICUs randomized mechanically ventilated patients recovering from acute respiratory failure to NAVA compared to Pressure Support Ventilation (PSV) for up to 14 days (Demoule A, et al. Intensive Care Med. 2016; epub ahead of press). Patients were considered recovering from acute respiratory failure when they were on 50% FiO2 and 8 cm H2O of PEEP or less, not on high dose vasopressors, able to tolerate 30 minutes of PSV with pressure of less than 30 cm H2O, and only requiring light sedation. Patients were maintained on a NAVA or PSV level that targeted tidal volumes of 6-8 ml/kg body weight. The primary endpoint was a clinically irrelevant outcome, namely the probability of remaining in either NAVA or PSV for the 48 hours without returning to assisted mode of ventilation. Clinical outcomes, such as ventilator-free days and mortality were secondary outcomes, along with ventilator asynchrony. Reasons for return to assist mode of ventilation were standardized and included respiratory distress, worsening hypoxia or hypercapnea, need for sedation for procedures, hypotension or arrhythmias. NAVA did not increase the time not needing assisted ventilation compared to PSV, although it did improve asynchrony. Similarly, it did not increase ventilator free days or reduce mortality. Overall, while numerous studies have now demonstrated improved patient ventilator synchrony with NAVA, none have demonstrated improvement in ventilator weaning or clinical outcomes. As such, NAVA is a novel mode of ventilation struggling to find its niche in clinical practice.
Lastly, the MACMAN trial was presented. MACMAN is a randomized trial comparing the McGrath videolaryngoscope to Macintosh direct laryngoscopy for orotracheal intubation in critically ill patients. I detail the results of this study, along with other studies comparing video with direct laryngoscopy in a previous blog post (Better to See and Fail Then Never See At All). In brief, the McGrath videolaryngoscope resulted in better glottic views than direct laryngoscopy, but not improved first pass success rates. Other clinical outcomes, including time to successful intubation, lowest oxygen saturation, duration of ventilation, ICU length of stay, and mortality were also similar between groups. This is consistent with other studies which have demonstrated improved glottic views with VL, but not better first attempt intubation rates. Overall, guidelines which strongly recommend the use of VL for intubating critically ill patients, especially for inexperienced operators, should be re-examined. Data from the robust trials suggests that VL may improve your view, but does not improve your chance at successfully intubating on the first attempt.
That’s a quick summary of Monday’s clinical trial results presented at ESICM. Stay tuned for a brief summary of the clinical trial results presented on Tuesday in the very near future.