Clarifying Adverse Drug Events: A Clinician's Guide to Terminology, Documentation, and Reporting

Since the early 1990s, adverse drug events have received significant attention from researchers in quality and patient safety (1). Nationally recognized quality experts have identified adverse drug events as a top safety priority (2) because these events are the most common type of iatrogenic injury (3). Studies have indicated that adverse drug events occur almost daily in medium-sized hospitals and outpatient panels (4-6). However, despite the high morbidity and mortality, physicians often do not recognize or appropriately treat instances of drug-related harm (7, 8). We believe that inadequate recognition and treatment of drug-related harm are, in part, a result of what has been called a Tower of Babel of terminology (1). Terms originally developed in the narrow context of drug effects in a clinical and regulatory setting are now being applied in the broader context of quality improvement in health care delivery systems (9). As might be expected, the expanding role of these terms has been coupled with their use in contradictory ways, even within the same discipline (4, 7, 10-14). In this paper, we use the case of an actual patient as a framework to explain the recognition, treatment, documentation, and reporting of drug-related harm. Adverse Events versus Adverse Drug Reactions Mr. J. was a 70-year-old man with nephrotic syndrome (thought to be related to a congenital single kidney), pneumoconiosis, and a history of gout and myocardial infarction. He presented to the hospital with increasing bilateral leg edema and pain, for which he had been taking over-the-counter ibuprofen, 400 mg three times a day for 3 days and once a day for the preceding 3 weeks. His other outpatient medications were simvastatin, 40 mg at bedtime; aspirin, 81 mg once daily; and metoprolol, 50 mg twice daily. In the emergency department, his serum creatinine level was 680 mol/L (7.7 mg/dL), much higher than the baseline of 290 mol/L (3.3 mg/dL) 11 months earlier. He was admitted to the hospital. The patient experienced an adverse event while using ibuprofen. Is this event a side effect, an adverse drug reaction, a medication error, or an exacerbation of his underlying renal and cardiac disease? Terms that initially arose from the field of pharmacovigilance, such as adverse event and adverse drug reaction, can help physicians relate the edema and renal failure to ibuprofen. Pharmacovigilance is the study of drug-related injuries for the purpose of making warning or withdrawal recommendations for pharmaceutical products. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, of which the U.S. Food and Drug Administration (FDA) and the World Health Organization are members, defines an adverse event as any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment (15). The term adverse event is not particularly helpful to physicians, but it provides context for the more clinically useful term adverse drug reaction. The International Conference on Harmonisation defines an adverse drug reaction as a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function (15). Therefore, an adverse drug reaction is an adverse event with a causal link to a drug. Table 1 (16-20) summarizes these key terms. Table 1. Summary of Definitions Relevant to Drug-Related Harm Assessing Causal Associations After admission to the hospital, a battery of serologic tests, a microscopic urine examination, and abdominal ultrasonography did not yield specific information about the origin of Mr. J.'s exacerbated renal failure. Assessing causal connections between agents and disease is fundamental to the practice of medicine and to the understanding of adverse drug reactions (21, 22). In this case, the treatment and prognosis for Mr. J.'s renal failure largely depend on whether it was exacerbated by ibuprofen or was due to the progression of his underlying disease. The discipline of pharmacovigilance has yielded tools (16, 23-25) to assess the likelihood of a causal connection between a drug and an adverse event on a case-by-case basis. These tools address the following criteria: time relationships between the drug use and the adverse event, pathophysiology of the adverse event, competing causes for the adverse event, response to dechallenge (for example, discontinuation of therapy with the drug or dose reduction), and response to rechallenge (for example, drug readministration). Table 2 organizes these criteria to gauge the causal link between a drug and an adverse event in terms of 4 discrete levels of certainty (certain, probable/likely, possible, and unlikely). Table 2. Grades of Certainty That an Event Is Linked to a Drug The causality criteria listed in Table 2 can be applied to the case of Mr. J. The timing and classic pathophysiologic association of ibuprofen with the edema and worsening renal failure may first seem to result in a certain causal association. However, other explanations for the event, such as advancing intrinsic renal failure or cardiac disease, are present, and information on the effect of drug withdrawal is not available at this point in the hospitalization. These conditions result in a possible causality rating, which accurately captures the uncertainty in the causal analysis. The strength of a causal association may be revised as more information becomes available. The day after admission, Mr. J. developed painful, swollen joints. After sodium urate crystals were found in the synovial fluid, polyarticular gout was diagnosed and prednisone therapy was started. Despite administration of a 1-L normal saline challenge and subsequent high-dose furosemide, the patient remained oliguric with an elevated creatinine level. Before dialysis could begin, he became hypertensive; the metoprolol dose was increased to 100 mg twice a day. Within 2 hours of the increased metoprolol dose, the patient developed respiratory distress and was transferred to the medical intensive care unit, where he was intubated and pulmonary edema was diagnosed. Admitted because of 2 adverse eventsedema and renal failureMr. J. developed 4 subsequent adverse events: a gout flair, hypertension, pulmonary edema, and respiratory distress. A consideration of pathophysiologic pathways and causal associations can also help the physician identify adverse drug reactions in complex clinical scenarios. The basic unit of an adverse event is the sequence of pathophysiologically related events originating from one pharmacologic effect of the drug. In Mr. J.'s case, the presumed pharmacologic effect was the inhibited production of prostaglandin in the afferent glomerular arteriole, which led to decreased plasma filtration. The consequent events of uric acid retention, sodium retention, and fluid retention all resulted from ibuprofen's inhibition of prostaglandin production. In general, a drug may be considered a contributory cause of an adverse event if, had the drug not been administered, 1) the event would not have happened at all, 2) the event would have occurred later than it actually did, or 3) the event would have been less severe. Ibuprofen may have contributed to the edema and may have exacerbated renal failure. The fluid bolus increased the fluid overload and may have caused hypertension. The subsequent increase in metoprolol probably contributed to cardiac decompensation and pulmonary edema. In contrast, the gout flair is a renal failuremediated secondary or indirect effect (17) of ibuprofen and does not merit consideration as a separate adverse drug reaction. Medication Error After spending 2 days in the medical intensive care unit and having several liters of fluid removed by dialysis, Mr. J. was extubated and prepared for transfer to the medical ward. Just before transfer, he became tachycardic and diaphoretic; an electrocardiogram showed new precordial T-wave inversions. After consultation with the cardiologist, the intern prescribed 12.5 g of tirofiban. The pharmacy prepared and the nurse administered 12.5 mga thousand-fold overdose. The patient developed a 3-cm hematoma on the back of his hand at a previous venipuncture site and oozing from his dialysis catheter site. He underwent urgent, prolonged dialysis and multiple blood laboratory checks. Misreading physician orders and preparing a dangerous dose of a drug is a classic medication error. Medication error is commonly defined as any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Such events may be related to professional practice, health care products, procedures and systems, including prescribing; order communications; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use. (19) Most medication errors do not harm patients. Some authors estimate that less than 1% of medication errors result in harm (26). Some types of errors may present minimal potential for harm, such as a missed dose of simvastatin. Other types of errors pose substantial risk to the patient but are intercepted before reaching the patient; these have been called near misses, close calls, or potential adverse drug events (27). For example, the nurse who was about to administer the tirofiban to Mr. J. might have noticed that the dose was inappropriate and could have returned the drug to the pharmacy. Adverse Drug Event versus Adverse Drug Reaction Several days after Mr. J. was transferred back to the medical ward, his gout recurred. It was discovered that the intern did not include the prednisone prescription when she wrote orders for the patient'