September 25, 2002
NIH suspended ARDS Lung experiment in Aug / AHRP filed complaint re: ARDS in July
On July 29, 2002 The Alliance for Human Research Protection (AHRP) filed a complaint with the federal Office of Human Research Protections (OHRP), expressing ethical and methodological concerns about an acute respiratory distress study (ARDS) conducted at 12 research centers. The study compared two volumes of oxygen ventilated into 861 acutely ill patients, most of who were incapacitated and could not give informed consent.
We now learn from Newhouse News service (below) that in August an NIH panel suspended another ARDS study for safety reasons. Furthermore, the ARDS ventilation study is being severely criticized by senior NIH researchers in a forthcoming article in the Amer Journal of Respiratory and Critical Care Medicine.
Newhouse News reports: “according to the NIH scientists who are criticizing the trial, its methodology was flawed. The experimental low tidal volume was compared with a higher tidal volume that didn’t truly represent standard treatment, the critics concluded.
Patients placed in the ARDS network’s “traditional” ventilation group did not represent a valid control group, the critics said, because the breaths they received were of higher volume than most doctors normally used. The low breaths appeared safer for the 432 patients who got the experimental therapy, critics said, but the conclusion was faulty because the experimental treatment was being compared against a dubious standard. In addition, they said, those patients and the other 429 patients included in the “traditional” group may have been put at risk because they received larger- or smaller-than-customary breaths that could have resulted in dangerous lung pressures. Methods used in the suspended fluid study were similarly flawed, the NIH critics said..”
The AHRP has been on record raising concerns about the systemic failure of the current institutional review board system to adequately protect patients—i.e., human subjects– from harmful experiments. The system fails to ensure that rigorous review precedes approval of the research. Since the entire process is left to the discretion of colleagues who are almost all employees of the same institution, an inherent conflict of interest puts human subjects at increased risk.
The original letter of complaint by AHRP is on our website as is OHRP’s Aug. 28 response, and our Sept 4 response:
Safety Warnings Halt National Study on Lung Sickness
By BRUCE TAYLOR SEEMAN
c.2002 Newhouse News Service
BETHESDA, Md. — The National Institutes of Health has stopped an experiment by a prominent team of research scientists after critics said the group’s method of studying a lethal lung sickness was flawed and could have harmed patients.
Federal officials suspended the national clinical trial after a pair of senior NIH scientists wrote a paper assailing the team’s scientific approach, particularly in a milestone 1996-99 study that established a new standard for treating patients on ventilators — machines that help critically ill patients breathe.
“Overall, this study design may have resulted in substantial numbers of control patients receiving inferior treatment,” the critics wrote in a paper that will be published soon in the American Journal of Respiratory and Critical Care Medicine.
It is unusual for such research to be challenged so bluntly, particularly when the criticism is aimed at veteran scientists whose work includes a landmark clinical trial that resulted in a new and widely accepted therapeutic technique.
Dr. Gordon R. Bernard, a Vanderbilt University professor of medicine and a leader of the research team, said he was optimistic that the suspended experiment would be allowed to resume soon, most likely without modifications. Patients enrolled in the tests were treated appropriately, he said.
The issue is being weighed by an NIH panel that includes a representative from the agency’s Office for Human Research Protection, which investigates patient safety concerns. A closed-door meeting was held Aug. 30, but NIH officials have not said whether the suspended trial will continue.
The scientists being criticized are specialists who investigate acute respiratory distress syndrome, or ARDS, a severe inflammatory condition that requires hospitalization and kills about one in three of the 150,000 Americans it afflicts each year.
Many ARDS patients need hydration, and the trial now on hold was comparing conservative versus liberal fluid therapies. Conducted by doctors in hospital intensive care units associated with 20 medical institutions, the study had enrolled nearly half of 1,000 study subjects when it was stopped in late July.
The team conducting the research is known as ARDSNet. Funded by NIH grants, it is a consortium of pulmonary and critical care physicians and other specialists who have investigated new treatments for ARDS since 1994.
The critics at NIH said work by the ARDSNet group violated one of clinical experimentation’s basic tenets — inclusion of a valid “control group,” or a set of patients who receive current, customary care.
Control groups are important because they provide a starting point against which to contrast an experimental therapy. Without a valid control, researchers can’t reliably compare an experimental therapy against current medical practice.
Control groups are also valuable tools to protect patients enrolled in studies. If a study lacks a control, it is difficult for scientists to contrast subjects’ injury or death rates against what may occur normally.
Bernard said his team voluntarily shut down the fluid study July 25. After re-examining its work, the ARDSNet group concluded the studies were conducted properly, he said.
The fate of the suspended study rests with the National Heart, Lung and Blood Institute, the division of NIH that funds ARDSNet research. Dr. James P. Kiley, director of the division of lung diseases at the NHLBI, said the current study is on “clinical hold.”
“Whenever we get concerns about patient safety, we stop, we pause, we take a look,” Kiley said. It was premature to judge whether patients had been hurt in ARDSNet trials, Kiley said.
Bernard said his team remains confident that its techniques are solid, including those used in the earlier ventilator study.
“We’re very confident in the study that we conducted, and we are practicing medicine based on those results,” Bernard said.
The group’s 1996-99 ventilator study, published in the May 4, 2000, New England Journal of Medicine, established a new benchmark for treating ARDS patients. It provided doctors with a guideline when deciding what size breaths should be given to patients on mechanical ventilators. Operation of ventilators is considered a key to ARDS survival.
“This is the first large clinical trial to demonstrate a more effective treatment for ARDS patients,” Dr. Claude Lenfant, director of the NHLBI, said at the time. “The findings will improve the care of these patients and save thousands of lives each year.”
The NIH scientists who challenged the work were led by Drs. Peter Q. Eichacker and Charles Natanson, senior researchers in the NIH Department of Critical Care Medicine. They were writing on behalf of a five-member group. Both men declined to be quoted, citing the sensitive nature of the controversy.
Their paper has been posted for subscribers on the Web site of the American Journal of Respiratory and Critical Care Medicine (http://ajrccm.atsjournals.org). Dr. Martin J. Tobin, editor of the journal, said the NIH paper addresses a fundamental question.
“Ultimately, you say, `How do we improve lives?”‘ said Tobin, chief of pulmonary and critical care medicine at Loyola University Chicago. “And if that is the bottom line, it’s important to include an arm that includes usual care. And I don’t believe that point has been articulated as clearly before.”
The schism between scientists represents a frustrating chapter for ARDS specialists, patients and families eager for definitive progress against a baffling medical problem.
About one in three patients develops ARDS as a result of sepsis, a bodywide infection. But ARDS often occurs within 24-48 hours of a lung injury or onset of a lung disease.
ARDS drowns patients’ lungs in fluid and stunts oxygen delivery. Blood and fluid leak into the spaces between the lung’s tiny air sacs, impairing function. Patients become short of breath, and doctors may hear crackling or wheezing sounds in the lungs.
With decreased oxygen delivery to body tissue, the skin may become blue. The heart, brain or other organs may malfunction. Serious complications, such as kidney failure, may occur immediately or weeks later.
Oxygen is often delivered though a mask to address breathing difficulties. If that doesn’t work, doctors use ventilators to deliver oxygen and air through a tube in the nose or mouth, or through the trachea. Pressure forces the mixture into the lungs. Many ARDS patients also need fluid therapy.
Clinical researchers regard ARDS as a complex research specialty. Patient recruitment for studies is difficult because victims are very sick, often can’t speak and may decline quickly. Because the condition affects so many body systems, treatment is complicated.
The ARDSNet team has initiated six studies since 1994. Three were abandoned due to disappointing results. One, testing steroids as a therapy for extremely ill ARDS patients, is ongoing. The other two are the fluid study, now on hold, and the ventilator study that ended in 1999 and was hailed as a landmark.
The ventilator study took aim at a vexing question: What volume of the oxygen and air blend should ARDS patients receive in each breath? Too much can overinflate the lung’s air sacs; too little can cause the sacs to collapse.
The ventilator study was completed early, after 861 patients rather than 1,000, because results were so promising. It concluded that small breaths, measured in “low tidal volume,” resulted in a lower death rate — 31 percent versus 40 percent for large breaths.
The American Academy of Family Physicians called the finding an “encouraging breakthrough” and incorporated the standard into treatment recommendations.
But according to the NIH scientists who are criticizing the trial, its methodology was flawed. The experimental low tidal volume was compared with a higher tidal volume that didn’t truly represent standard treatment, the critics concluded.
Patients placed in the ARDS network’s “traditional” ventilation group did not represent a valid control group, the critics said, because the breaths they received were of higher volume than most doctors normally used.
The low breaths appeared safer for the 432 patients who got the experimental therapy, critics said, but the conclusion was faulty because the experimental treatment was being compared against a dubious standard.
In addition, they said, those patients and the other 429 patients included in the “traditional” group may have been put at risk because they received larger- or smaller-than-customary breaths that could have resulted in dangerous lung pressures.
Methods used in the suspended fluid study were similarly flawed, the NIH critics said.
The suspended experiment, intended to test “conservative” and “liberal” fluid management, “does not contain an arm which represents routine care, the group against which researchers ultimately want to make comparisons,” Eichacker and Natanson wrote.
Bernard said critics of the ventilator study are concluding too much by comparing the ARDSNet research to other studies on the same subject. Their technique, called a “metaanalysis,” is prone to statistical missteps, Bernard said.
“We think there are no grounds for drawing any conclusions from their metaanalysis,” said Bernard, who called the critics’ statistical conclusions “pure speculation.”
Bernard said it is a mistake to fault his group for not having a valid control group. With an illness as complex as ARDS, and with large variables in treatment from patient to patient, it is “almost naive” to think a standard practice can be definitively established, Bernard said.
The ARDSNet team successfully established a standard representing traditional care at the time of the ventilator study, and conclusions based on that measure were valid, Bernard said. He said suggestions that patients may have been harmed are unfounded.
“I’m confident that the procedures we used were sufficiently close, at that time, to standard practice.”
Dr. John J. Marini, an internationally known researcher of ventilator-induced lung injuries, said the critics’ analysis may suffer from flaws of its own, chiefly its statistical methods.
But the paper makes a persuasive argument, Marini said, that ARDSNet research did not establish that patients receiving the smallest ventilator breaths are necessarily better off than those receiving moderate breaths.
“I can’t disagree with that,” Marini, a University of Minnesota professor of medicine, said of the criticism. “We can’t say we know for sure.”
The suspended ARDSNet research was conducted at clinical centers associated with these institutions: Massachusetts General Hospital in Boston; the University of California San Francisco; the Cleveland Clinic; the University of Colorado; Duke University; the University of Maryland/Johns Hopkins University; the University of Michigan; the University of Pennsylvania; the University of Utah; Vanderbilt University; the University of Washington; Baylor College of Medicine in Houston; Baystate Medical Center, Springfield, Mass.; Louisiana State Health Sciences Center; St. Paul’s Hospital in Vancouver, British Columbia; the University of Chicago; the University of Texas Health Sciences Center, San Antonio; the University of Virginia; the University of Pittsburgh; Wake Forest University.
(Bruce Taylor Seeman can be contacted at firstname.lastname@example.org)
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