A 24 year old previously healthy woman has died as a result of participating in a research project as an experimental subject.
Her death raises serious questions about the safety and ethics of human experimentation. The woman, Ellen Roche, worked as a laboratory technician at the Johns Hopkins Bayview Medical Center's Asthma and Allergy Center in Baltimore, Maryland.
She volunteered as a research subject in a baseline physiological test, which induced asthmatic reactions in people without asthma to determine how bronchiolar reflexes differ between the two populations. Specifically, the study was designed to test a controversial theory of asthma, which holds that people with asthma and those without both react similarly to inhaled irritants—experiencing bronchiolar vasoconstriction—but that people without asthma are able to overcome this reaction through deep inspiration.
The researchers sought to elucidate the neural mechanisms underlying these reactions. The study was directed by Dr Alkis Togias, an associate professor and clinical immunologist at the Johns Hopkins Medical Institutions.
It was funded by a grant from the National Institutes of Health in Bethesda, Maryland, and was a follow up to previous work in which Togias had shown that people without asthma can resist the bronchoconstrictive effects of inhaled methacholine via deep breathing but that asthmatics could not. Additionally, he showed that if the people without asthma were instructed not to take deep breaths before inhaling the substance, they too developed symptoms of asthma.
Methacholine is an acetylcholine agonist that induces bronchoconstriction. It is commonly used in experiments of lung function and is considered to be generally safe as its effects are transient and reversible with bronchodilators. People with asthma have an exaggerated response to the substance and wheeze at a lower dose than do people without asthma.
Ms Roche was the third participant recruited for the follow up study, and she died in the second phase of the experiment. Like all study participants, she signed an informed consent form that warned of possible side effects of wheezing, chest tightness, and transient dyspnoea. The possibility of a fatal outcome was not entertained in the consent form.
In the first phase of the experiment, involving four to five visits, participants were asked to inhale methacholine with and without taking deep breaths before inhalation. In the second phase, starting with the sixth visit, some of the participants, including Ms Roche, were administered hexamethonium before inhaling methacholine and breathing deeply.
Hexamethonium is a ganglion blocker active in both the sympathetic and parasympathetic nervous systems. It would be expected to derail the protective mechanism of lung relaxation induced by deep breathing. Hexamethonium was used as an antihypertensive agent in the 1940s and '50s but was withdrawn by the Food and Drug Administration in the early '70s because superior antihypertensive drugs had emerged.
Additionally, a handful of cases of adverse pulmonary reactions to hexamethonium were reported in medical journals in the 1950s. These reactions included the development of bronchiolitis obliterans organising pneumonia (BOOP) and the acute respiratory distress syndrome (ARDS).
Ms Roche reportedly became ill—complaining of shortness of breath, dry cough, wheezing, and myalgias—within a day of entering the experiment. She reported these symptoms 36 hours later, but continued through to the sixth visit. She subsequently developed a fever, flu-like symptoms, and changes on chest radiography and was admitted to the hospital for treatment and observation.
Laboratory tests showed a 35% reduction in lung function. Her course rapidly declined, with the development of the acute respiratory distress syndrome and renal failure. She died within a month of entering the experiment. The study was suspended.
Her death was reported to University's Institutional Review Board and to the Office of Human Research Protections, the division of the US Department of Health and Human Services responsible for enforcing the ethical treatment of research subjects and investigating deaths and adverse reactions in federally funded studies.
After the death of Ms Roche, Dr Solbert Permutt, a pulmonologist at Johns Hopkins University and one of the investigators, issued an advisory letter to fellow researchers warning them to avoid hexamethonium in human experiments. Doctors at his university were also considering whether an infectious agent, perhaps from a contaminated spirometer, was responsible. A postmortem examination was performed, but the results are not yet available to the public and media. The Office of Human Research Protections will not disclose its findings or recommendations until the conclusion of the investigation.
Ms Roche's death is particularly disturbing because she was a healthy volunteer who had absolutely nothing to gain, other than a nominal fee of $365 (£260), by participating in the experiment. Moreover, the experiment was a baseline test, not a therapeutic trial.
As such, her death is considered even more distressing than that of Jesse Gelsinger, an 18 year old man with a hepatic enzyme defect. Mr Gelsinger volunteered for a gene therapy experiment at the University of Pennsylvania, with fatal results (BMJ 2000;320:602).