Trial by Fire: Critics Demand That a Huge

Trial by Fire: Critics Demand That an enormous Sepsis Study Be Stopped

A large government trial comparing treatments for a life-threatening condition called sepsis is putting participants in danger of organ failure and even death, critics charge, and should be immediately shut down.

A detailed analysis of the trial design prepared by senior investigators at the National Institutes of Health Clinical Center in Bethesda, Md., concluded that the study “places seriously ill patients in danger without the likelihood of gaining information which will provide benefits either to the themes or to future patients.”

In a letter to the federal department for Human Research Protection, representatives of Public Citizen’s Health Research Group compared the study, called Clovers, to “an experiment that would be conducted on laboratory animals.”

“The human subjects of the Clovers trial, as designed and currently conducted, are unwitting guinea pigs in a physiology experiment,” Dr. Michael Carome and Dr. Sidney M. Wolfe wrote in their letter.

Begun in March, Clovers is funded by the N.I.H. — despite the criticism of its own investigators — and aims to enroll 2,320 patients at 44 hospitals around the country.

In interviews, the scientists leading the study defended its design, saying that participants are receiving all the care that sepsis patients normally would receive.

“The guideline is patient safety, which takes priority over all else,” said Dr. Nathan I. Shapiro, a professor of emergency medicine at Harvard Medical School and cochairman of the protocol committee for the study.

Sepsis develops when the body mounts an overwhelming attack against an infection, causing inflammation throughout the body. It is first treated with antibiotics.

If sepsis progresses, the body may experience a catastrophic cascade of changes, including blood clots and leaky blood vessels that impede blood flow to organs.

At least one million Americans are diagnosed with sepsis every year, and the death rate is high: up to 30 percent succumb to the illness.

But while most adults know they need to seek care immediately for an attack or stroke, only about half know that sepsis requires urgent medical attention, consistent with a survey by Sepsis Alliance, a nonprofit organization.

Signs of sepsis include an abnormally high or low temperature, an underlying infection (which may not be apparent without a blood test), signs of confusion or sleepiness, and feelings of utmost illness, pain or discomfort that make people feel they're close to dying.

Clovers are meant to check a replacement strategy for treating septic shock, a dangerous drop by blood pressure that chokes blood flow to organs, affects the heart and can result in death.

The goal of the trial is to determine whether it is better to limit fluids and start vasopressors — drugs that constrict blood vessels — quickly, or to use more intravenous fluids and postpone giving the drugs to patients.

At issue is whether or not patients participating in Clovers are being given treatment that deviates from usual care — such a lot in order that lives could also be endangered by the research.

Participants are only enrolled for twenty-four hours, but the primary hours of treatment are critical for survival.

When patients experience septic shock, current guidelines involve raising vital sign by administering fluids within the primary three hours of care, then administering vasopressors within the primary six hours if patients don't answer fluids.

Vasopressors can be administered early on, during or after the infusion of fluids; a new treatment guideline for hospitals says the drugs should be started within the primary hour if patients aren’t responding to intravenous fluids.

Many physicians are critical of rigid guidelines like this one because they don’t allow for individualizing treatment and appear to discount the doctor’s clinical judgment.

Both fluids in large amounts and vasopressors can cause serious complications, but when a patient’s condition continues to deteriorate, doctors use both interventions, adjusting them depending on the severity of illness.

They generally start with fluids, which in small amounts are considered less toxic than vasopressors.

But participants in Clovers are randomly assigned to a “liberal fluids” group who receive large infusions of fluids in a very short time but limits the use of vasopressors, or to a “restrictive fluids” group during which fluids are minimized and drug treatment began earlier.

Scientists leading the study note that treatment isn't hard and fast, and demand that each one  participants are becoming medical aid that “falls within the range of usual care.”

Still, they recently altered one among the treatment protocols after physicians within the study complained that its protocols were inconsistent with their practices.

The recent protocol modification slowed the rapid infusion of fluids within the first group, the “liberal fluids" arm of the trial. But the change could delay administration of vasopressors in that group even when vital sign remains dangerously low.

Critics say the change didn't allay their concerns: Patients in both treatment arms potentially could go without lifesaving therapy and aren't being properly informed of the risks.

“Both vasopressors and fluids are lifesaving and inadequate or excessive amounts of either one can cause death,” Dr. Carome said.

If neither treatment arm approximates usual care, as critics contend, the investigators maybe unable to draw meaningful conclusions — they won’t skills the 2 experimental treatments stack up against the usual care.

It will also be difficult for safety monitors to know if participants are dying at abnormally high rates.