Katrina R. Viviano,     Madison, Wisconsin

Elizabeth J. Thomovsky,     West Lafayette, Indiana

Adverse Drug Events

An ADE is broadly defined in human medicine as “any noxious, unintended, and undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis, or therapy… [This excludes] therapeutic failures, intentional or accidental poisoning or drug abuse, and adverse effects due to errors in administration or compliance” (Bowman, Carlstedt, and Black, 1994). These ADEs can be dose-dependent (predictable) or dose-independent (unpredictable) and are relatively common in human ICUs, reported at approximately 29.7 per 100 ICU admissions (WHO, 2000). There are no data available about the incidence of ADEs in veterinary ICU patients.

Drug administration is a key part in the treatment and management of ICU patients. The clinician can minimize ADEs and maximize medication efficacy by considering both the pharmacologic properties of the drugs being administered and patient characteristics that can modify drug effects. Factors that contribute to ADEs can be divided into two categories: drug-related factors and patient-related factors. Drug-related factors refer to the basic physical and chemical incompatibilities that exist when certain drugs are combined. These most commonly occur when drugs are given in succession through an intravenous catheter or fluid delivery line and can be anticipated (Table 6-1). A less appreciated drug-related factor that can contribute to ADEs is the formulation. For example, long-acting drug formulations such as methylprednisolone acetate, triamcinolone acetonide, and cefovecin can persist in the body for weeks, eliminating the option of drug withdrawal if side effects develop. In addition, long-acting glucocorticoids do not allow a controlled dose taper and long-acting antibiotics increase the risk of developing antimicrobial resistance.

More difficult to predict are those patient-related factors that predispose to ADEs. ICU patient populations at increased risk for ADEs include those that are dehydrated or have decreased total body water, receiving multiple concurrent medications (polypharmacy), or that have altered organ function (Table 6-2). In addition, the very young and elderly patient populations are at increased risk for ADEs. A number of examples can be cited and are the main focus of this chapter.

Most drugs are metabolized by the liver and excreted by the kidneys, and therefore dysfunction of these organs may limit excretory capacity of drugs. Similarly, whenever there is decreased drug delivery (e.g., with decreased perfusion, severe dehydration, or massive vasodilation), the kidneys and liver cannot effectively remove drugs from the body. Drugs also must be distributed from the blood to various organs to exert their effects. Disorders such as severe dehydration, vasodilation, and cardiac disease may alter blood flow, affecting drug distribution. The distribution of lipophilic drugs to tissues also is altered in older patients owing to a greater proportion of body fat when compared with younger animals. Finally, protein binding affects drug distribution such that liver failure, systemic inflammation, or protein loss can alter drug distribution throughout the body.

Liver Disease

Alterations in drug clearance, drug extraction, and drug biotransformation and metabolism are major concerns in cases of liver disease. Clearance depends largely on hepatic blood flow and protein binding. Key drug (phase I and phase II) metabolizing enzymes housed in the liver are essential to convert lipophilic drugs to more soluble metabolites needed for excretion in the urine or the bile. To reduce the risk of toxicity, drugs metabolized exclusively by the liver should have dosages reduced when hepatic failure is evident. For example, dose reductions should be considered for metronidazole, chloramphenicol (dog), phenobarbital, and benzodiazepines in the setting of liver failure, accepting that there are no specific algorithms available in veterinary patients to estimate the degree of dose reduction. For most other drugs, unless fulminant liver failure is present it is difficult to accurately predict the need for dosage adjustments associated with liver disease. Drugs whose liver metabolism is limited by hepatic blood flow (i.e., lidocaine, propranolol, midazolam, and opioids) may have increased plasma drug concentration in patients with altered hepatic blood flow associated with impaired cardiovascular function or hypotension. Additionally, the use of these drugs in patients with chronic liver disease or with portosystemic shunting may increase the risk of side effects or systemic toxicity.

The major phase I metabolic machinery of the liver is the cytochrome P450 (CYP 450) enzyme system. Drugs can either inhibit or induce CYP 450 enzymes and result in clinically significant drug-drug interactions if coadministered. Additionally, cholestasis can sometimes decrease the activity of CYP 450 enzymes in the liver. Table 6-3 summarizes some of these potentially significant drug interactions based on CYP 450 enzyme inhibition or induction.