What to do with case reports: is folly that succeeds folly nonetheless?

Clinical toxicology is a rapidly evolving discipline. Each new pharmaceutical agent, illicit drug, industrial chemical, and household product carries the potential for human toxicity. In addition, combinations of these agents offer limitless possibilities for adverse events, all of which need to be interpreted and shared. Case reports provide the perfect forum for the initial discussion of these observations. Yet, applying the data gained from case reports to daily practice is often difficult. The evidence-based approach assigns very little power to case reports because of their limited ability to confirm associations, rare ability to assign causation, and complete inability to calculate incidence or prevalence. As such, changing practice based on case reports is inherently dangerous. For example, shortly after the introduction of tricyclic antidepressants (TCAs), their cardiovascular and neurological toxicities were rapidly appreciated. Case reports in the early to mid-1970s suggested that administration of physostigmine was beneficial (1–4). Animal models were contradictory, showing minimal benefit (5) or clear exacerbation of toxicity (6). Despite this, noted toxicologists of the time recommended physostigmine and countless patients were treated. Although it is unclear how many benefited from this practice, it is probably safe to say that it was without harm for the majority. Despite the fact that no controlled study of physostigmine in humans with TCA was ever published, the practice of routine administration of physostigmine to patients with TCA toxicity continued. Several years later, two cases of asystole temporally related to physostigmine administration raised concern about this practice (7). After subsequent reevaluation of the data, risks, benefits, and alternatives therapies (such as sodium bicarbonate) physostigmine was abandoned as an antidote for patients with TCA toxicity, but this process took years. By today’s standards, the initial case reports would have been deemed insufficient by many clinicians to begin the routine administration of physostigmine without sound animal data or a human trial. Conversely, had there been reasonable data to support the use of physostigmine in this setting, the cases presented by Pentel and Peterson would have been judged inadequate to alter practice, as a causal relationship between physostigmine use and asystole was challenged by several prominent clinicians of the time. In the current issue of J. Toxicol.—Clin. Toxicol. Van Deusen et al. present an interesting case report of an 89-year-old woman with a wide-complex bradycardia and altered mental status (8). In addition to being treated with a transvenous pacemaker, she was given dextrose, insulin, calcium chloride, and furosemide when her potassium was found to be 9.9 mmol/L. Subsequently, her serum digoxin level was reported as 8.4 ng/mL. Digoxin-specific Fab were administered, she underwent hemodialysis for hyperkalemia, and ultimately did well. The authors review the limited human case reports and the somewhat conflicting animal data that gave rise to the dogma that calcium salts are contraindicated in cardioactive steroid toxicity. They also question the frequently offered suggestion that transvenous pacemakers are contraindicated in the setting of cardioactive steroid toxicity, a caveat drawn from a a single study (9). Although they correctly call for a more thorough evaluation of the problem, it is unlikely that any ethics committee would approve a randomized human trial. So, how are we to interpret their presentation and analysis of the literature? Life has taught us that there