TORONTO, June 16 -- A process that removes toxins from the blood of
patients with sepsis appears to have significantly reduced mortality in a small
randomized controlled trial, Italian researchers said.
The benefit was sufficiently striking that the so-called EUPHAS trial -- for
Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis -- was stopped early,
Claudio Ronco, M.D., of St. Bortolo Hospital in Vicenza, Italy, and colleagues
reported in the June 17 issue of the Journal of the American Medical
Association.
Larger studies are needed to "confirm these encouraging findings," the
researchers said.
But in an accompanying editorial, the decision to stop the trial early was
sharply criticized as being based on "a secondary analysis of an underpowered
study."
The decision leaves a "promising" therapy in limbo, argued John Kellum, M.D., of
the University of Pittsburgh School of Medicine, and Shigehiko Uchino, M.D., of
Jikei University School of Medicine in Tokyo.
The theory behind polymyxin B hemoperfusion is that the endotoxins generated by
gram-negative bacteria play a significant role in the pathogenesis of sepsis.
Polymyxin B -- an antibiotic with high affinity for endotoxin -- is bound to
polystyrene fibers in a device that allows the patient's blood to pass through,
removing endotoxins.
The procedure is widely used in Japan, but lacks supporting data from clinical
trials. To help fill the gap, Dr. Ronco and colleagues organized a randomized
clinical trial in which 30 patients got conventional treatment for sepsis and 34
got conventional therapy as well as two sessions of polymyxin B hemoperfusion.
Patients were eligible if they had severe sepsis or septic shock owing to
intra-abdominal cavity infection that required emergency abdominal surgery.
The primary endpoints were change in mean arterial pressure and need for
vasopressor drugs. Secondary outcomes included the fraction of inspired oxygen
ratio, change in organ dysfunction measured using Sequential Organ Failure
Assessment (SOFA) scores, and 28-day mortality.
Initially, the researchers had planned to enroll 60 patients in each group, with
an interim analysis after 30 patients had been enrolled and followed until
discharge.
But the interim analysis showed significant benefits for the hemoperfusion arm
and the trial was stopped.
The president of the ethics committee "declared it unethical to deprive a
potentially beneficial therapy to a group of patients that carry high
mortality," the researchers said.
Specifically, the analysis showed:
* At 72 hours, mean arterial pressure increased from 76 to 84 millimeters of
mercury in the perfusion group (significant at P=0.001) but did not change in
the control group.
* At the same time, vasopressor requirements decreased significantly (at
P<0.001) in the polymyxin B group but did not change in the control group.
* The fraction of inspired oxygen ratio increased slightly in the polymyxin B
group (marginally significant at P=0.049) but not in the conventional therapy
group.
* SOFA scores improved significantly (at P<0.001) in the polymyxin B group (from
minus 3.3 to minus 0.1) but not in the conventional therapy group.
* And 28-day mortality was 32% (or 11 of the 34 patients) in the polymyxin B
group and 53% (or 16 of 30 patients) in the control group.
The adjusted hazard ratio for death was 0.36, with a 95% confidence interval
from 0.16 to 0.80, which was significant at P=0.01.
The researchers cautioned that the study was not blinded, owing to the nature of
the intervention, and added that the early halt meant the number of patients
involved is "modest."
But the study leaves the issue of the efficacy of the method hanging, according
to Drs. Kellum and Uchino.
In essence, they said in their editorial, "an oversight body has, on the basis
of a secondary analysis of an underpowered study, changed the standard of care
for a series of hospitals participating in the study."
They noted that the statistical mortality benefit could have been "abolished"
had a single patient had a different outcome.
The study doesn't provide a definitive answer as to whether the method saves
lives, Drs. Kellum and Uchino said, and the position that further study would be
unethical should be rescinded.
"Indeed, willful ignorance of the true effect of polymyxin B hemoperfusion,
whatever it is, is unethical," they said. "To keep this promising therapy in the
shadows of opinion and insufficient evidence would be to withhold potentially
beneficial treatment from patients deprived of it, should it be effective, or to
put patients at risk, should it be harmful."
Primary source: Journal of the American Medical Association
Source reference:
Cruz DN, et al "Early Use of Polymyxin B Hemoperfusion in Abdominal Septic
Shock: The EUPHAS Randomized Controlled Trial" JAMA 2009; 301(23): 2445-52.
