Is it safe to administer dobutamine 40 ug/kg/min in obese patients during cardiac stress testing?

Fråga: Is it safe to administer dobutamine 40 ug/kg/min in obese patients during cardiac stress testing?

Sammanfattning: Theoretically, dobutamine doses based on total body weight may over-estimate the requirements in obese patients, since the additional body fat is not paralleled by a proportionally increased drug clearance. However, two studies using dobutamine 40 ug/kg/min in obese patients raised no safety concerns. Furthermore, the close monitoring of patients undergoing dobutamine stress test would hopefully detect over-dosing before it results in any grave consequences.

Svar: Dobutamine is a synthetic catecholamine given during cardiac stress test to elicit signs of myocardial ischemia and impaired ventricular performance. Dose-response studies with 5, 10, 20, 30 and 40 ug/kg/min have showed increased heart rate and cardiac output at each dose and overdosing may result in hypertension, peripheral vasoconstriction, myocardial ischemia and arrhythmias. The mean plasma half-life is only 2 minutes, attributable to rapid redistribution and metabolism. The mean volume of distribution is 0.2 L/kg, suggestive of a distribution to the extracellular fluid compartment. However, the pharmacokinetics of dobutamine are highly variable, and individual dose adjustment is often necessary (1).

Two studies have addressed the safety of the dobutamine stress transesophageal echocardiography in obese patients (2,3). In both studies dobutamine doses were escalated to 40 ug/kg/min. The first study included 23 obese patients (body weight 118-215 kg) with suspected coronary artery disease (2). During the stress test, four patients reported chest pain and regional wall motion abnormalities was noted in nine. Ten patients developed significant hypotension at the highest dose, but quick resolution was seen after the infusions were stopped. The mean peak heart rate was 133 beats per minute, and none of the patients developed any cardiac arrhytmias. No atropine was used to further increase heart rate in this study, due to safety concerns.

The second study was based on retrospective data from 90 patients with body mass index (BMI) >27.5 and 86 patients with BMI <27.5 undergoing dobutamine stress test for various reasons (3). Minor complications occurred in one third of the patients, regardless of weight group. However, transient hypertension was more common in obese patients compared to nonobese (20 vs 6 percent), while transient hypotension was more common in the nonobese (22 vs 9 percent). Major complications (major hypo- or hypertension or ventricular arrhythmia) occurred in three obese and four nonobese patients. Mean peak systolic blood pressure was 12 mmHg higher in the obese patients compared to the nonobese, but this difference was evident already at baseline. Peak heart rates were similar in the two groups.

The influence of obesity on the pharmacokinetics of drugs vary markedly between different substances, but the volume of distribution of water-soluble drugs such as dobutamine (4) is usually more closely correlated to the lean body mass than to the total body weight (5). However, the short half-life of dobutamine means that steady-state would be achieved within ten minutes and in this situation it is not the volume of distribution but the clearance of the drug that determines the concentration reached on a specific dose. The relationship between body weight and drug clearance is usually complex and depends on the elimination routes involved. Dobutamine is extensively metabolised by catechol-O-methyltransferase (COMT) in the liver (6). However, COMT is widely distributed throughout the body and is also present in plasma (6), where it could probably contribute to the rapid elimination of dobutamine. One would not expect a linear relationship between body weight and the metabolic capacity of the liver or plasma. Hence, dobutamine doses based on total body weight probably over-estimate the requirements in obese individuals.