Death of a healthy research subject after an inhalation study — old lessons to be re-learned

Abstract

Considering the number of healthy subjects involved annually in phase I clinical drug trials and physiological experiments it is perhaps surprising (and gratifying) how seldom serious adverse events and deaths are encountered. In 1998 this Journal reported on the death of a volunteer subject at the University of Rochester, USA, following a bronchoscopic procedure [1]. Recently another case, this time at the prestigious Johns Hopkins University, USA, has been widely reported. Details of this case have emerged slowly over a period of weeks since the actual event occurred in June 2001. The chronology of the tragedy seems to be as follows: in April, Ellen Roche (a previously healthy 24-year-old laboratory technician) volunteered to participate in a study intended to elucidate physiological mechanisms involved in asthma. As part of the study protocol all subjects inhaled methacholine (a standard procedure to produce bronchoconstriction, the response being exaggerated in asthmatics); some of the subjects also inhaled hexamethonium bromide, a ganglion-blocking agent once used for the treatment of hypertension [2]. The underlying hypothesis under test was that in normal subjects deep inspiration stimulates intrapulmonary stretch receptors, triggering a reflex leading to bronchial smooth muscle relaxation, and that this putative mechanism should be blocked by hexamethonium [3]. Different sources give slightly different dates for the course of events leading to the subject’s death, but in essence it appears that she inhaled about 1 g of hexamethonium on a single occasion, and within 24 h complained of dry cough, dyspnoea, and ’flu-like symptoms. An X-ray showed signs of ‘early pneumonitis’ and she was admitted to hospital. Her condition deteriorated, she was transferred to an intensive care unit, and died on 2 June from progressive hypotension and multi-organ failure. The autopsy is reported to have shown extensive, but non-specific lung damage [4]. An internal investigation at Johns Hopkins found only minor flaws in the study design; but shortly afterwards investigators from the US Office for Human Research Protections (OHRP) of the Department of Health and Human Services (DHHS) conducted an urgent site visit, found 31 infractions of proper research procedure, and suspended all government-funded clinical studies at the university. Johns Hopkins protested vigorously, and over the ensuing few days the DHHS and the university agreed a compromise whereby clinical studies could resume where investigators could verify that this was in the best interests of the study subjects [5]. Among specific criticisms of the study in which Ellen Roche died, the OHRP determined that both the Johns Hopkins Institutional Review Board (IRB) and principal investigator (Dr Algis Togias) had failed to obtain published literature about the known association between hexamethonium and lung toxicity, and had administered hexamethonium bromide that was labelled ‘for laboratory use only’. They also noted that the consent form signed by Ms Roche had given no indication that the use of inhaled hexamethonium was experimental, and not approved by the US Food and Drug Administration (FDA) [6]. Subsequently it has emerged that Dr Togias relied in part on a study performed in 1978 at the University of California in San Francisco (UCSF) in arguing the safety of inhaled hexamethonium. However, UCSF researchers reviewing this study have noted that two out of five study subjects experienced adverse events necessitating their withdrawal from the study; one of these presented to the emergency department 4 days after inhaling hexamethonium with dyspnoea and chest tightness, which was diagnosed as ‘compatible with viral pneumonia’ [7]. It has also been reported in the US news media that ‘sodium compounds’ were added to the hexamethonium without notifying the IRB – if correct, a clear deviation from the protocol. What lessons can be learned from this tragic occurrence? First, inhaling any medication is not without risk. Bronchospasm can occur, even in normal subjects; this may be a paradoxical reaction to the drug itself, but is often due to non-drug components (e.g. propellants, preservatives) or to extremes of pH or osmolality of an inhaled solution [8]. Unless scrupulously cleaned and maintained, nebulizers may harbour and transmit infection [9]. Hypersensitivity pneumonitis is a potential risk, possibly more likely to occur with inhaled proteins. Oral hexamethonium itself is well recognized to be associated with a syndrome of intra-alveolar fibrinous oedema, giving rise to cough and dyspnoea, which if therapy is continued may progress to intra-alveolar and interstitial lung fibrosis [10–12]. This is one reason why this agent fell into disuse as an antihypertensive;