But study used non-standard PEEP ventilation strategy

A ventilation strategy with lower positive end-expiratory pressure (PEEP) held its own against a higher-PEEP strategy in patients without acute respiratory distress syndrome (ARDS) according to researchers in the Netherlands, although Canadian experts pointed out that neither strategy was in line with standard care.

In the non-inferiority trial performed at eight ICUs, “patients randomized to the lower PEEP strategy had a median of 18 ventilator-free days while patients randomized to the higher PEEP strategy had a median of 17 ventilator-free days at day 28 (mean ratio 1.04, 1-sided 95% CI 0.95 to infinity, P=0.007 for non-inferiority),” reported Marcus J. Schultz, MD, PhD, of the Amsterdam University Medical Centers and co-authors in RELAx Collaborative Group.

The lower boundary of the 95% CI was within the non-inferiority margin of −10%, they stated in JAMA.

The authors also reported no meaningful differences in the following between the two PEEP groups for secondary endpoints:

  • Severe hypoxemia: 20.6% vs 17.6% (risk ratio 1.17, 95% CI 0.90 to 1.51, P=0.99).
  • Need for rescue strategy: 19.7% vs 14.6% (RR 1.35, 95% CI to 1.02 to 1.79, adjusted P=0.54).

The study authors noted that the fraction of inspired oxygen (FiO2) also differed significantly between the two groups over the first five days of ventilation (day 1: mean ~0.4 for lower PEEP group versus ~0.35 for higher PEEP group; day 5: mean ~0.45 for lower PEEP group versus ~0.35 for higher PEEP group.

In an editorial accompanying the study, Arthur S. Slutsky, MD, of St. Michael’s Hospital in Toronto, and co-authors pointed out that rates of severe hypoxemia, and the need for rescue therapy “were numerically higher (but not statistically significantly different in adjusted analysis) in the lower PEEP group, suggesting the possibility that lower PEEP may have been inferior for some patients.”

They also brought up the issue of standard of care. “The investigators chose 8 cm H2O, rather than 5 cm H2O, as their control strategy based on evidence that ’usual care’ PEEP has drifted higher over time,” they wrote. “However, based on other large observational studies, it appears that clinicians largely use PEEP levels less than 8 cm H2O for this patient population.”

While the results may well apply to the “average patient without ARDS… given the concern about possible increased rates of hypoxemia and need for rescue strategies in the lower PEEP group, an intermediate option of 5 to 8 cm H2O that is consistent with the current PEEP management for many non-ARDS patients is likely reasonable and may be safer than a very low PEEP strategy,” Slutsky and co-authors advised.

The study was conducted pre-pandemic, so how the findings might apply to pandemic patients is unknown, but other researchers have advocated for lower and higher PEEP levels in Covid-19 patients.

The current trial was done from Oct. 2017 to Dec. 2019, and randomized participants to invasive ventilation using either lower PEEP (between 0 and 5 cm H2O, n=476 patients), or higher PEEP (8 cm H2O, n=493). Mean patient age in the lower PEEP cohort was 65.5 (34.5% women) while mean age of the patients in the higher PEEP cohort was 66 (36.9% women).

The primary outcome was the number of ventilator-free days at day 28. Patients who died or received invasive ventilation for more than 28 days were considered to have 0 ventilator-free days. Secondary outcomes included ICU and hospital lengths of stay (LOS), as well as 28-day mortality.

The authors reported that mortality at 28 days was not statistically significantly different between the two groups — 38.4% in the lower PEEP group versus 42.0% in the higher PEEP group (hazard ratio 0.89, 95% CI 0.73 to 1.09, P=0.99). “There were no statistically significant differences in other secondary outcomes,” they added, such as ICU LOS (mean 8.1 versus 7.2 days, respectively) and hospital LOS (mean 19.9 days versus 19).

However, the authors acknowledged that the point estimate for the percentage requiring rescue strategies was greater in the lower PEEP group so the study may have been underpowered to detect a statistically significant difference.

Other study included the fact that blinding was not possible because of the nature of the intervention; some patients were missed because of screening failures; and randomization within 1 hour after start of ventilation was not always possible.

“Future trials of PEEP should be designed using strategies that individualize PEEP according to a specific patient’s physiology rather than focusing simply on dose,’ Slutsky’s group advised.

  1. A strategy with lower PEEP was non-inferior to a strategy using higher PEEP in patients in the ICU without acute respiratory distress syndrome (ARDS).

  2. Patients randomized to the lower PEEP strategy had a median of 18 ventilator-free days while patients randomized to the higher PEEP strategy had a median of 17 ventilator-free days at day 28.

Shalmali Pal, Contributing Writer, BreakingMED™

The study was funded by the Netherlands Organization for Health Research and Development (ZonMW) and the Amsterdam University Medical Centers, Location AMC.

Schultz reported relationships with Hamilton. Co-authors reported relationships with, and/or support from, ZOLL, Dräger Medical, GE Healthcare, and Ambu.

Slutsky reported relationships with Krypton, Baxter, and Novalung/Xenios. A co-author reported relationships with Timpel Research and Getinge.

Cat ID: 152

Topic ID: 89,152,501,728,791,730,192,152,195,925