Image showing bacteria next to blood cells in a blood vessel to illustrate what happens prior to sepsis setting in
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A clinical trial sponsored by the National Institutes of Health (NIH) has shown that acetaminophen reduces the risk of sepsis patients experiencing organ damage or developing acute respiratory distress syndrome.

The study results, published in JAMA, showed that while patients in the trial did not show improved mortality rates regardless of the severity of their sepsis, the acetaminophen treatments did show the greatest benefit for patients at highest risk of organ damage. The findings showed that these patients needed less assisted ventilation and had a slight—though not statistically significant—decrease in mortality.

Finding effective ways to treat sepsis, is a big challenge for health centers. It is the most common form of death for people without a heart condition admitted to the emergency department and is the tenth leading cause of death among people overall. It is characterized by the human immune system running amok and it begins attacking the body’s vital organs. During sepsis, a person’s red blood cells become injured and die at very high rates, releasing what is called “cell-free hemoglobin” into the bloodstream. It’s the body’s inability to remove the excess hemoglobin that leads to organ damage.

Earlier research by study first author Lorraine Ware, MD, a professor of medicine and pulmonary and critical care at Vanderbilt University had shown that acetaminophen can block the harmful effects on the lungs of cell-free hemoglobin. Other, more limited, research has also shown that acetaminophen might work better in people with more severe sepsis. In these cases the patients have higher levels of cell-free hemoglobin and are at higher risk of developing acute respiratory distress syndrome and higher risk of death.

One thing that could help doctors fight sepsis is developing a diagnostic that can identify high levels of cell-free hemoglobin as a biomarker for sepsis. This could help the care team determine quickly which patients could benefit from acetaminophen treatment.

“One problem in critical care is the patients get sick so fast, that we do not normally have time to figure out which biomarkers help predict which therapy could give the best outcome,” said senior author Michael Matthay, MD, professor of medicine and anesthesia at the University of California, San Francisco. “We hope that these findings will underscore the potential therapeutic value of using a biomarker to help successfully find a treatment that will work when patients need it the most.”

For this clinical trial, the researchers enrolled 447 adults with sepsis and respiratory and circulatory organ dysfunction spanning 40 academic medical centers from October 2021 to April 2023. Patients were randomized with one group receiving acetaminophen intravenously every six hours for five days. The control group received placebo on the same regimen. Patients were followed for 28 days post treatment. The team also conducted an analysis of only those patients with levels of cell-free hemoglobin above a predefined threshold. Of special interest to the researchers was how many patients stayed alive with no organ support such as ventilation or treatments for kidney failure.

The data showed that the treatment was safe for all patients, but there was no difference in liver injury, low blood pressure, or other adverse events compared with the placebo group. When examining secondary outcomes, the team found significantly lower rates of organ injury and acute respiratory distress syndrome in the acetaminophen group.

In the subset of patients with higher cell-free hemoglobin levels, the researchers found:

  • 8% of patients in the acetaminophen group needed assisted ventilation compared to 23% of patients in the placebo group; and
  • After 28 days, 12% of patients in the acetaminophen group had died, compared to 21% in the placebo group.

“While the anticipated effects of acetaminophen therapy were not realized for all sepsis patients, this study shows that it still holds promise for the most critically ill” said James Kiley, PhD, director of the division of lung diseases at the National Heart, Lung, and Blood Institute, part of NIH. “Though, more research is needed to uncover the mechanisms and validate these results.”

With the results for critically ill patients in this current study trending in the right direction, Ware and Matthay are now planning a larger clinical trial, one that will likely enroll only those patients with higher cell-free hemoglobin levels.

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