Identifying "Triggers"

Several tools and tips are available to help healthcare professionals establish that an ADE has occurred. "Triggers" are surrogate markers suggesting that some unfavorable outcome has occurred with a drug therapy. One of the simplest ways to identify triggers is to review a patient's medication profile and search for any drugs that were recently or abruptly discontinued. Although there are many reasons why a drug might have been discontinued, at least one possibility is that the patient experienced an ADR.

Clinicians also can review a patient's medication profile and look for any new allergies that have been added to the patient's history. For example, if someone is listed as "NKDA" (no known drug allergies) upon hospital admission, but then a new drug allergy is added to the patient's chart during the hospitalization, that would suggest that an adverse event may have occurred, such as an allergic reaction to a prescribed drug.

Similarly, a review of the patient's medication profile may reveal new orders for medications that are antidotes or alternative therapies, which also may suggest that an ADR has occurred. Consider, for example, a patient who is listed as NKDA and who receives the drug piperacillin during a hospital stay. A review of the patient's record reveals that at some point, the piperacillin was discontinued and the drug aztreonam was initiated. The "trigger" here is the switch from one antibiotic to another. Aztreonam is a beta-lactam antibiotic of the monobactam class, and it is used almost exclusively in patients with a beta-lactam antibiotic allergy. In aztreonam, the primary allergenic determinant -- the intact beta-lactam ring -- is "split" by a carbohydrate chain, disallowing for cross-reactivity in patients who are allergenic to that particular intact ring structure.

Table 3 lists some known drug "triggers" that, when added to a patient's orders during a hospitalization, suggest that an ADR has occurred.

Table 3. Drug "Triggers"

Healthcare workers often are hesitant to report potential ADRs if they are not absolutely certain that the drug was the cause of the adverse outcome. Although probability is sometimes difficult to determine, it is important to realize that a 100% certainty is more the exception than the rule. Thus, a degree of uncertainty should not deter the reporting of any event with some type of temporal relationship to a specific drug therapy.

Still, clinical judgment alone may not be sufficient for a clinician to decide whether a drug was the likely cause of a certain adverse event, and in fact, reliance on clinical judgment alone has shown poor correlation with the correct identification of ADRs. Fortunately, there are tools available to augment the clinician's judgment call.

One of the most widely used and validated tools to assess the likelihood that a specific drug is the cause of an ADR is the Naranjo algorithm^[23] (Table 4). This algorithm uses a series of 10 questions, with numerical values assigned to each answer, to determine an overall score for drug-related probability.

Table 4. Naranjo Algorithm*

*Adapted from Naranjo CA, Busto U, Sellars EM, et al. Clin Pharmacol Ther. 1981;30:239-245.

The total score is calculated by adding the scores for each of the 10 questions, and these final scores indicate the likelihood that the event in question was an ADE:

Definite ≥ 9
Probable 5-8
Possible 1-4
Doubtful <>

Along with a probability assessment, an ADE report should provide a meaningful description of the event and its outcome, as well as any contributing or competing factors, and, of course, the patient's medication history. Contributing and competing factors may be present when concurrent disease states or conditions make a patient more susceptible to an ADR. The next case illustrates this concept:

Mr. B is a 68-year-old man with a history of colon cancer. He also has a past medical history that is significant for heart failure and atrial fibrillation. His regular medications include dofetilide 250 mg every 12 hours for atrial fibrillation, furosemide 40 mg once daily, and warfarin 5 mg daily. He also recently received treatment for his colon cancer with 5-fluorouracil (5-FU). A week after this last treatment, he developed significant diarrhea. He continued to take all of his other medications as prescribed. He presents to the emergency department after experiencing new palpitations, and he also exhibits unusual bruises on his extremities. On admission, he is noted to have an INR (international normalized ratio) of 7.5 and a potassium level of 2.5 mEq/L. An EKG reveals a QTc interval of 686 msec with ventricular polymorphism.

After reviewing and analyzing this case, we can conclude that all of Mr. B's conditions are drug-induced. What are the factors involved, and how do they exacerbate each other?

1. Diarrhea is an adverse effect of 5-FU.
2. Diarrhea can lead to hypokalemia and other electrolyte imbalances.
3. Furosemide can lead to hypokalemia, and in the setting of concomitant diarrhea, this effect is augmented.
4. Hypokalemia is a predisposing factor to increase QTc prolongation in the setting of a patient's use of antiarrhythmic agents such as dofetilide.
5. 5-FU also has an interaction with warfarin, increasing INR levels.