Good To Know: April 24, 2025
Don't get negative about these negative trials, now
Email cut off? Click the title to view the whole post online or in the Substack app. -Ed.
ARDS, Mechanical Ventilation
Inhaled volatile anesthetics vs propofol for sedation in vented patients (SESAR Trial)
All sedatives have side effects; other than limiting sedation to the minimal necessary dose during mechanical ventilation, the optimal approach (if one exists) has always been unclear.
Inhaled volatile anesthetics seem to produce anti-inflammatory and lung-protective effects, in small studies testing them as sedative agents in mechanically ventilated patients.
There has also been a signal of clinical benefit. In a systematic review of nine randomized trials published in 2012 through 2022, volatile sedation administered in the ICU through a specialized conserving device reduced times to awakening and extubation, total duration of mechanical ventilation, and ICU length of stay.
In the SESAR trial at 37 ICUs in France (Jabaudon et al JAMA 2025), 687 vented patients with ARDS (by Berlin criteria) were randomized to the volatile anesthetic sevoflurane or I.V. propofol as their primary sedation agent. After seven, 28 and 90 days of follow-up:
More patients in the sevoflurane group had died (a 9% absolute increase in mortality, number needed to harm of 11 with sevoflurane).
There was no difference in median total duration of sedation (7 days) or ventilator-free days between groups.
Sevoflurane patients had more days in the ICU and greater rates of acute kidney injury.
The mechanism of potential harm was unclear, but sevoflurane has been associated with cardiovascular depression, nephrotoxicity, and the production of toxic by-products in certain absorption systems.
The anesthetic delivery and recycling device used in the trial is named “Anaconda,” after the world’s largest predatory constricting snake that slowly suffocates its victims.
The device fits into standard ventilator circuits, but because it leaks, it requires active “scavenging” of gas to prevent the anesthetization of ICU staff and bedside family members.
Isoflurane, an alternative to sevoflurane, is currently being tested as a sedation agent in mechanically ventilated ICU patients in two randomized trials (NCT05312385 and NCT05327296).
SEPSIS
Thymosin-alpha 1: the latest wonder drug for sepsis? (TESTS trial)
As in, I wonder why so many single-center trials were so strongly positive?
Thymosin-alpha 1 (Tα1) is a naturally occurring peptide involved in immune modulation that has been investigated as a potential adjunctive treatment for sepsis due to its immune-modulating properties. Tα1 enhances T-cell function and the production of IL-2 and IFN-γ, among other properties.
As early as 2004, Tα1 showed promise in saving lives in sepsis. Multiple randomized trials were performed, with at least 19 published since 2004.
All 19 were in China.
In one of the largest (ETASS), a multicenter trial at six Chinese centers (Wu et al Critical Care 2013), Tα1 produced an amazing 9% absolute risk reduction (a number needed to treat of only 11 to save a life), albeit with a p = 0.06.
A systematic review and meta-analysis of the 10 trials from China reporting mortality confirmed that Tα1’s benefits were even greater than realized: a 40% relative risk reduction in mortality (this would represent an average absolute reduction from 35% to 21%, or from 50% to 30%, e.g.)
TESTS, a double-blind, placebo-controlled multicenter trial at 22 centers was then performed, also in China, and published in BMJ in 2025 (Wu et al).
It was negative, with near-identical mortality between groups (23.4% thymosin vs 24.1% placebo).
Acute kidney injury according to fluid strategy in septic shock: Meta-analysis
A systematic review and meta-analysis of nine randomized trials (n=3,718) testing liberal vs. conservative fluid management strategies for patients with septic shock concluded that a restrictive strategy produced less severe acute kidney injury.
Three studies were done in the USA, two in Denmark, one in Australia and New Zealand, one in Switzerland, and one in both the USA and UK.
The pooled risk ratio for severe AKI with a restrictive strategy was 0.87 (a 13% relative risk reduction). Shorter durations of mechanical ventilation were also observed with a restrictive fluids strategy, but heterogeneity between studies was high.
Surgery and Post-Op Care
Prevention of Post-Op Pulmonary Complications (PRIME-AIR trial)
Post-operative pulmonary complications like pneumonia and recurrent respiratory failure are common, sometimes deadly, and difficult to prevent.
In the PRIME-AIR trial (Fernandez-Bustamante et al Lancet Respiratory Medicine 2025), 794 patients at multiple U.S. academic centers undergoing prolonged open abdominal surgery and considered to be at intermediate to high risk for postoperative pulmonary complications were randomized to usual care or a bundle of interventions including:
preoperative education,
intraoperative protective ventilation with individualized positive end-expiratory pressure (PEEP) to maximise respiratory system compliance,
individualized intraoperative neuromuscular blockade administration and reversal based on patient weight and train-of-four monitoring,
postoperative supervised incentive spirometry, and
encouragement to get out of bed and walk as soon as able.
Patients with BMI≥35 were excluded, although one would presume these would be the patients at highest risk for complications. The NIH funded the trial.
Despite good adherence with bundle elements, there were no differences observed in the frequency or severity of pulmonary complications (hypoxemia, respiratory symptoms, atelectasis, bronchospasm, respiratory infections, hypercapnia, pneumonia, pleural effusion, pneumothorax, or ventilator dependence), mortality, or other outcomes.
Fernandez-Bustamante et al Lancet Respiratory Medicine 2025
Hematology and Hemorrhages
According to a large international observational study, a large proportion of fresh frozen plasma (FFP) transfusions lack a good indication and may be avoidable.
The data was messy, but as many as 20-25% of plasma transfusions were performed prophylactically for patients who were not bleeding, not about to undergo invasive procedures, and had INRs <3.0.
Glucose Control
The best evidence from randomized trials suggests tight glucose control does not improve outcomes in the ICU.
U.S. healthcare payment policy nevertheless incentivizes glucose control, based on the findings of confounded observational studies.
Continuous glucose monitoring in the hospital thus represents a potentially lucrative new market for manufacturers and the associated industries that strive to help U.S. hospitals meet Medicare targets for avoiding hyperglycemia in hospitalized patients.
So far, the results haven’t been impressive for CGM.
A new randomized trial (Franck et al Chest 2025) was also negative, although it was too small to move the (fingerstick) needle.
At a VA hospital in Gainesville, Florida, among 85 ICU patients randomized to continuous glucose monitoring vs. usual care, both groups spent about 61% of the time in the goal glucose range of 70 to 180 mg/dL.
