乌鸦传媒

SAN DIEGO -- Acetaminophen (Tylenol) for severe sepsis patients improved renal function but gave mixed signals in terms of changes in the expected oxidative injury mechanism, researchers found in a pilot trial.

Creatinine levels were lower in patients given the fever reducer for 3 days after admission to the ICU with severe sepsis, , of Vanderbilt University in Nashville, Tenn., and colleagues found in the ACROSS trial.

That was true both at the end of the 3 days (P=0.039) and beyond to day 4 (P=0.004), and to discharge or death (P=0.02), they reported here at the American Thoracic Society meeting.

"Even small changes in creatinine in patients with sepsis are associated with increased length of stay and mortality, and acetaminophen may be an intervention to improve these poor outcomes," Janz told attendees while calling for further study.

But the trial missed its primary outcome of a reduction in oxidative injury as measured by F₂-isoprostanes on day three.

Acetaminophen acts to reduce oxidized hemoglobin components (cell-free hemoglobin, a potent oxidant) that have been linked to poor outcomes in adults with sepsis in observational research, Janz explained.

The trial did show that the F2-isoprostanes were lower in acetaminophen-treated patients on day two (P=0.047).

The signal that the drug was having some benefit is worth following up with a further trial, said , of Germany's University of Kiel, a moderator at the session.

"These are people at the bottom end of prognosis, and this is why we all agree with all the caveats we have, to do a trial like this from an intensivist's point of view is very applaudable," he told 乌鸦传媒.

The other moderator, , of Columbia University in New York City, agreed, called the findings "potentially very important."

The ACROSS (Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis) trial included 40 patients admitted to the ICU within 24 hours with severe sepsis and detectable cell-free hemoglobin. They were randomized to acetaminophen (1 g by mouth every 6 hours) or placebo at a single center.

Patients with acute or chronic liver disease or elevated liver enzymes were excluded.

When looking only at the 36 patients who never required renal replacement therapy, the impact on creatinine levels was significant at day three (P=0.048) and every point thereafter.

Survival to hospital discharge numerically favored acetaminophen at over 90% compared with about 60% in the placebo group, but the trial wasn't powered for mortality and didn't show a significant impact (P=0.196).

That finding was at least reassuring that the treatment wasn't harming sepsis patients, Janz noted at the late-breaking clinical trial session.

The major adverse event of concern was hepatic injury with acetaminophen, but there was no significant difference between groups in elevated liver enzymes (9.5% versus 4.3% with placebo, P=0.599).

"It seems surprisingly safe even though these people are really sick," Rabe told 乌鸦传媒, noting that the short-term administration likely accounted for the lack of risk in that regard.

But this is about the top dose, Barr noted.

A phase 3 trial is planned, Janz told 乌鸦传媒. Further biomarkers of kidney function, such as urinary neutrophil gelatinase-associated lipocalin (NGAL) as a marker of early injury, would be valuable, he noted.

Comment