Asthma is a pulmonary condition in which bronchoconstriction, edema, and mucus secretion impede airflow.  Its clinical manifestation could range from minor wheezing to a life-threatening condition.  A wide array of factors could bring about bronchoconstriction in anyone, however, scientists believe that non-asthmatics have the ability to relax the bronchial smooth muscles and thus regain normal airway flow while this corrective reflex is somehow blocked in asthmatics.  In order to test this hypothesis Dr. Togias and his team plan to induce bronchoconstriction among healthy non-asthmatic volunteers using a first drug.  They would then give some of the subjects a second drug, hexamethonium, which would block the corrective bronchodilatory reflex which would, in effect, sustain the bronchoconstriction – and mimic asthma.  I assume that the control group would not be given hexamethonium to allow their airways to dilate and restore normal airway flow.  During the investigation one of the volunteers who was given hexamethonium subsequently went into respiratory failure and died.  I believe there were major flaws in the protocol itself that led to this unfortunate end.       

The design of the experiment is such that the investigators would induce bronchoconstriction and then block the corrective bronchodilatory reflex by giving hexamethonium which is a nicotinic ganglionic blocker.  In other words the end result they were trying to achieve in the experimental cohort was the asthmatic state – that of bronchoconstriction.  While this design would answer the question posed by the investigators, I believe it would have been much better, and a whole lot safer, if they had done the converse of the experiment.  They could have asked for asthmatic volunteers and induced bronchoconstriction in the first place. Then they could have used a nicotinic ganglionic agonist – as the second drug - on the experimental cohort while giving a commonly used bronchodilator to the control group.  If their hypothesis were true, then the subjects in both cohorts would show evidence of bronchodilation – which is a much safer end condition than its opposite.  It is a lot easier to manage experimental subjects when the desired end result is a positive one rather than a pathologic condition.  Furthermore, this way the scientists could claim that the investigation is not merely experimental in nature but likewise has a possible therapeutic component to it. 

Another aspect of the study design that could be questioned is whether it had clear cut guidelines as to how adverse reactions would be monitored and evaluated and what procedure would be taken to address such an occurrence.  The first subject developed a week-long cough but nothing seemed to have been done to definitely determine whether this was a direct result of hexamethonium intake or some other extraneous factor.  Whenever undertaking a study it would be better to consider any adverse reaction a consequence of the experimental treatment until proven otherwise.  This would allow for a much closer monitoring of subjects which could minimize serious consequences by identifying them early on.   

A third flaw centers on the second drug used – hexamethonium.  This drug, which as mentioned above is a nicotinic ganglionic antagonist or blocker, used to be counted among the antihypertensive medications until 1972 when the Food and Drug Administration (FDA) withdrew its approval citing its ineffectiveness.  Furthermore, there seems to have been a number of studies that have shown serious toxicity tied to hexamethonium which caused pulmonary pathology.[1]  Were the investigators even aware of these studies?  As the primary investigator, Dr. Togias was responsible for doing the review of all relevant background research.  Some might say that the toxicity studies were very old and therefore did not show up during the search which only came up with the more recent studies.  This, I believe, makes it even more paramount on the part of Dr. Togias to consult the FDA regarding the drug he was planning to use.  These two facts – the toxicity of hexamethonium and its lack of FDA approval – are quite significant and should have been known by the investigating team.  The IRB that approved the study should also shoulder some responsibility since its job was to evaluate the protocol and ensure the safety of the subjects involved in the study.  

As a result of all this, the information shared with the volunteers with regards the drug hexamethonium was inaccurate and therefore the informed consent forms that they signed were invalid.  This is a huge mistake on the part of the investigators which, consequently, makes them responsible for whatever happens to the study subjects.