Terlipressin for Treating Intraoperative Hypotension: Can it Unmask Myocardial Ischemia?

Terlipressin is a prodrug rapidly metabolized to lysine-vasopressin by endopeptidases. It is indicated for the treatment of gastrointestinal bleeding in patients with rupture of esophageal varices (1,2). This drug has been suggested as the ideal drug for patients with long-term angiotensin-converting enzyme inhibitor (ACEI) treatment when hypotension occurs during induction of anesthesia (3). Although the potential for vasopressin to cause coronary spasm is known, coronary events or myocardial ischemia have not been described during the administration of terlipressin. We report a case of myocardial ischemia occurring simultaneously with an episode of severe hypertension after terlipressin administration to treat an episode of refractory hypotension during general anesthesia. Case Report A 61-yr-old male (110 kg) was scheduled for asymptomatic (63 mm-diameter) infrarenal abdominal aortic aneurysm repair using an endoprosthesis. The patient had a history of chronic hypertension and was a current smoker. The patient experienced unstable angina 7 yr before for which a left ventricular anterior descending artery percutaneous transluminal coronary angioplasty had been performed. Subsequently, the patient had no residual angina while taking β-adrenergic (acebutolol) and calcium-channel (amlodipine) blockers and aspirin. Three months before surgery, echocardiography revealed moderate left ventricular hypertrophy and ejection fraction of 67% without wall motion abnormalities. A stress test performed under β-adrenergic blockade achieved up to 94% of theoretical maximal rate and was interpreted as negative. The patient was premedicated orally with 5 mg midazolam, 5 mg amlodipine, and 100 mg acebutolol. The resting heart rate and blood pressure were respectively 60 bpm and 140/75 mm Hg. After intravolume expansion with 10 mL · kg−1 lactated Ringer’s solution, anesthesia was induced by using 3 μg · mL−1 propofol target-controlled infusion associated with 0.3 μg · kg−1 sufentanil and 0.5 mg · kg−1 atracurium to facilitate orotracheal intubation. ST segment deviations were continuously analyzed in leads II, V4, and V5. After induction of general anesthesia, invasive arterial pressure decreased from 110/50 mm Hg to 80/40 mm Hg and heart rate remained stable. Hypotension was treated by decreasing propofol target-controlled infusion (1.5 μg · mL−1), 6 mg ephedrine, and infusion of 500 mL colloids. Forty-five minutes later, while waiting for the surgeon, systolic arterial pressure was still below 85 mm Hg with heart rate of 55 bpm despite repeated administration of ephedrine up to a cumulative dose of 36 mg. No change in ST segment analysis had been observed at that time. Then 1 mg terlipressin (Glypressine, Ferring, Malmöe, Sweden) was injected. After the bolus administration, arterial pressure immediately increased to 230/116 mm Hg and heart rate decreased to 44 bpm and was associated with a 5-mm ST segment increase in V4-V5 (Fig. 1). The hypertension and ST segment increase were corrected within 4 min with IV 7.5 mg nitroglycerine. Electrocardiogram revealed a sinus rhythm and a 3-mm ST segment increase in anterior leads. A coronary arteriography identified an occlusion of the proximal left ventricular anterior descending artery. Reperfusion was successfully performed by percutaneous transluminal coronary angioplasty, stenting and antiplatelet drug (abciximab), within 60 min after the initial event (Fig. 2). After tracheal extubation on day 1, echocardiography showed moderate septal hypokinesia with 65% left ventricular ejection fraction. The electrocardiogram was normalized (Fig. 3) and cardiac troponin I concentrations remained below 0.5 ng · mL−1 (normal value < 1.5 ng · mL−1). The patient was discharged on day 5, receiving acebutolol, aspirin, and clopidogrel. Two months later, the patient underwent abdominal aortic aneurysm surgery without adverse cardiac outcome.Figure 1: Intraoperative electrocardiogram recording in lead V5 after the 1 mg IV bolus of terlipressin. Arterial blood pressure and heart rate were respectively 230/116 mm Hg and 44 bpm, and associated with a 5 mm ST segment increase in V5.Figure 2: Coronary arteriography, performed within 60 min after the terlipressin administration, identified an occlusion of proximal left anterior descending artery (arrow) (A). Revascularization was successfully performed by percutaneous transluminal coronary angioplasty and stenting (arrows) with use of IV antiplatelet drug (B).Figure 3: Postoperative 12-lead electrocardiogram (ECG) revealed a sinus rhythm and a 3 mm ST segment increase in anterior leads (A). After percutaneous transluminal coronary angioplasty, ECG was completely corrected (B) and similar to the preoperative 12-lead ECG (sinus rhythm and chronic inverted T wave in anterior leads).Discussion We report the first observation of intraoperative hypertension-associated myocardial ischemia after terlipressin bolus in a patient with coronary artery disease. Appropriate hemodynamic management with early revascularization of a coronary artery occlusion avoided the occurrence of myocardial infarction. This case report describes the worsening of a left ventricular anterior descending artery stenosis. A coronary artery spasm or an acute increase of left ventricular afterload, both likely induced by terlipressin, may be hypothesized. The acute increase of systemic vascular resistances may increase left ventricular wall stress and myocardial oxygen consumption and then induce the rupture of a coronary endothelial atheromatous plaque. In addition, vasopressin has some thrombotic effects by releasing factor von Willebrand and activating tissue plasminogen activator inhibitor. However, these effects have been only reported with vasopressin and a synthetic analog, desmopressin, and not after terlipressin administration in healthy volunteers or in cirrhotic patients (4,5). Lysine-vasopressin, like arginine-vasopressin, the human endogenous form of vasopressin, activates specific vascular receptors V1, inducing artery vasoconstriction. However, whether the same effect may be observed on coronary arteries is still a subject of controversy; vasopressin induces moderate coronary vasodilation (6,7) or vasoconstriction (8) depending on endothelial nitric oxide. In addition, the systemic and coronary effects of vasopressin may be associated with hypertension and coronary spasm as observed in this case report. Terlipressin, when administered in anesthetized patients chronically treated with ACEI, was consistently successful in treatment of hypotension refractory to ephedrine (3). Mean arterial pressure and systemic vascular resistances evaluated from left ventricular wall stress on transesophageal echocardiography increased by 24% and 47% respectively, without influence on myocardial performances. In the study by Eyraud et al. (3) no patient experienced myocardial ischemia or adverse cardiac outcome although 40% of the study patients had known ischemic heart disease. Long term treatment with ACEI significantly affects the decreased vasoconstrictive effects of sympathetic agonists during general anesthesia (9). In these patients with the renin-angiotensin and sympathetic systems blunted by general anesthesia and specific inhibitors (10,11), an agonist of the third hormonal vasopressor system, vasopressin, is predictably suited to treat a hypotensive episode during general anesthesia. Terlipressin has been proposed as an appropriate drug to treat hypotensive episodes refractory to ephedrine in anesthetized patients chronically treated with ACEI. However, we suggest that terlipressin should be use cautiously in patients with coronary artery disease especially if they are not chronically treated with renin-angiotensin system inhibitors.