Octreotide, a long-acting synthetic cyclic octapeptide, is a somatostatin analog used for treatment of carcinoid syndrome symptoms. Octreotide may be a life-saving treatment in the case of an acute carcinoid crisis but at the same time may have effects on cardiac conduction. We present a patient who received a bolus of octreotide during resection of metastatic carcinoid tumor and developed symptomatic bradycardia, Mobitz type II, and third degree atrioventricular block. Despite the well-known fact that somatostatin has physiologic importance in the neurohumoral control of cardiac impulse formation and conduction (1–5), its synthetic analog octreotide has never been associated with severe cardiac conduction defects, such as that seen in our patient. Moreover, a recent textbook of anesthesiology suggested that IV administration of large doses of octreotide is safe (6).
A 67-yr-old man, weighing 95 kg, underwent abdominal laparotomy for liver resection of metastatic carcinoid tumor. Relevant medical history consisted of long-standing hypertension, which was treated with felodipine 10 mg twice daily and enalapril 20 mg twice daily. His preoperative symptoms consisted of facial flushing, palpitations, and diarrhea consistent with carcinoid syndrome. These symptoms were preoperatively treated with octreotide 100 μg sc twice daily. He denied any allergies and had no anesthesia history.
Preoperative electrocardiogram (ECG) showed normal sinus rhythm of 78 bpm and was entirely normal. His preoperative transthoracic echocardiogram showed moderate diastolic dysfunction but was otherwise normal. All preoperative laboratory values were within normal limits. After all of the standard ASA anesthesia monitors were applied, a radial 20-gauge arterial catheter was inserted. Before the induction, his arterial blood pressure was 140/75 mm Hg, and his heart rate was 90 bpm. General anesthesia was induced with IV fentanyl 250 μg, propofol 150 mg, and succinylcholine 120 mg to facilitate endotracheal intubation. Anesthesia was maintained with isoflurane and muscle paralysis with cisatracurium 8 mg. Approximately 10 min after the induction of anesthesia and immediately after surgical incision, we gave a prophylactic bolus dose of octreotide 100 μg IV. Up until that time, the patient’s intraoperative course had been uneventful, with his arterial blood pressure at 135/78 mm Hg, and his heart rate at 85 bpm. Immediately after the octreotide was given, the heart rate acutely decreased to 35 bpm, and arterial blood pressure decreased to 85/40 mm Hg. There was no increase in arterial blood pressure preceding the bradycardia. Ephedrine 20 mg IV was given, as well as a fluid bolus of 500 mL of lactated Ringer’s solution, resulting in a heart rate increase to 82 bpm and arterial blood pressure increase to 155/90 mm Hg. During this event, we at first did not associate the administration of octreotide with the hemodynamic changes. After a 30-min period of intraoperative hemodynamic stability and while manipulating the liver, the patient’s face became flushed without changes in hemodynamics. We administered an additional bolus of 100 μg of octreotide IV. Immediately after the injection, the heart rate decreased to 45 bpm, followed by a 3-s asystolic pause, then by a 1-min period of atrioventricular dissociation consistent with third degree atrioventricular block. This episode was followed by an approximately 20-s episode of second-degree (Mobitz type II) atrioventricular block. Arterial blood pressure at that time was 75/34 mm Hg. We immediately placed external cardiac pacing pads. Simultaneously, we administered ephedrine 20 mg and glycopyrrolate 0.2 mg IV, resulting in the heart rate and arterial blood pressure increasing to 100 bpm and 155/86 mm Hg, respectively. The patient remained hemodynamically stable throughout the remainder of surgery. No additional octreotide was administered. At the end of the surgery, the patient’s trachea was extubated, and he was transferred to the recovery room. His postoperative 12-lead ECG, cardiac enzymes, electrolytes, and arterial blood gas values were all within normal limits.
The rest of this patient’s hospitalization was uneventful. Because the patient had no cardiac history and the rhythm disturbances occurred with a close temporal association to the administration of the bolus doses of octreotide, the cardiologist determined that there was no need for further electrophysiologic evaluation of this patient’s cardiac conduction system.
This is the first case in the anesthesia literature illustrating severe hemodynamic sequelae after administering octreotide in an anesthetized patient undergoing carcinoid tumor surgery. In this patient, an IV bolus of octreotide resulted in hemodynamically significant bradycardia, Mobitz type II atrioventricular block, and complete heart block. Mild bradycardia has been described after octreotide administration in other clinical settings, although infrequently (7–9). The manufacturer’s product information suggests the possibility of bradycardia and dysrhythmias (9%) in acromegalic patients receiving octreotide, but these ECG changes are not uncommon in acromegalic patients, irrespective of octreotide treatment (9). Herrington et al. (7) described a patient who was receiving octreotide subcutaneously and who developed bradycardia (38 bpm) without heart block. In several other reports, octreotide administration did not consistently demonstrate a reduction of heart rate (10–12). In a small series of patients with acromegaly receiving octreotide subcutaneously, the mean heart rate decreased, and the mean systemic vascular resistance increased, both statistically significantly (13). However, in some of these studies (13,14), it is impossible to distinguish between indirect long-term beneficial effects of octreotide on heart function (improved congestive heart failure, which would result in decrease in heart rate) from its direct pharmacologic effects (4,5). Therefore, it is more meaningful to assess the effects of octreotide or somatostatin on heart rate in acute clinical situations (5,15,16). A significant bradycardia was recorded with octreotide (15), and termination of supraventricular tachyarrhythmias has been accomplished with somatostatin (3,5,16). In both reports, the drugs were administered IV. We believe that our patient experienced severe bradycardia primarily because of the rapidly administered large dose of octreotide IV. In another report, the modest reduction of heart rate was found when a smaller diluted bolus dose was given (25 μg in 10 mL of normal saline) (15). Indeed, it seems that bradycardia occurs less often in patients who are receiving octreotide subcutaneously (12,17), compared with those who are receiving it IV (10,11,15). Furthermore, slower IV infusions of octreotide, 100 μg/h during two hours (11) or 50 μg/h (10), have less negative chronotropic effects than faster IV infusion rates (250 μg/10 min) (5).
The mechanisms by which octreotide can cause bradycardia are numerous, and it is still not known if these effects are mediated indirectly through its effects on systemic circulation (18) or directly through ionic mechanisms at the level of heart (4). Octreotide increases systemic vascular resistance, and bradycardia may be a baroreceptor-induced reflexive response to increase in the systemic blood pressure (15,18). This mechanism, based on reflexive bradycardia, may be assumed only in patients who developed hypertension before bradycardia after octreotide was administered. This did not occur in our patient who simultaneously developed bradycardia and hypotension. Furthermore, the bradycardia in our patient was associated with atrioventricular block, suggesting that the pathogenesis was more likely via a direct action of octreotide on the heart. There is another possibility of an indirect mechanism of octreotide-induced bradycardia. Octreotide suppresses the secretion of vasoactive intestinal peptide (VIP) (19), which can increase the heart rate even more so than norepinephrine (20). Therefore, by blocking VIP, octreotide may cause bradycardia.
The most plausible explanation for bradycardia after octreotide is through its direct effects on the heart. Control of the cardiovascular system is provided not only by a regulatory influence of the classical neurotransmitters acetylcholine and norepinephrine, but also via some regulatory peptides, such as somatostatin. Somatostatin-like immunoreactivity was found in the heart of several mammals (4,21), including humans (4). It was detected in the human atrial and ventricular myocardium, conductive system of the heart, and cardiac postganglionic parasympathetic neurons (4). Somatostatin coexists with acetylcholine in presynaptic vagal endings and may be released by high-frequency stimulation of the vagus nerve (2). The main cardiac effects of somatostatin are heart rate deceleration, decrease of myocardial contractility, and slowing of the propagation velocity along the cardiac conduction system (21). IV infusions of somatostatin slow the sinus rate and depress atrioventricular conduction (4). Somatostatin also plays a role in cardiac rhythmogenesis. It modifies the electrophysiological properties of cardiac pacemakers, modulates the cardiac chronotropic action of the autonomic nervous system, and prevents supraventricular tachyarrhythmias. The cardiovascular effects of somatostatin may result from its modulatory action on presynaptic release of acetylcholine, norepinephrine, and other humoral substances. However, some effects of somatostatin result from its neurotransmitter action, which is provided by the interaction with specific somatostatin receptors. Somatostatin receptors belong to the family of G-protein coupled receptors, and activation of these receptors results in inhibition of adenylyl cyclase (resulting in a decrease in intracellular cyclic adenosine monophosphate concentration), which decreases conductance of voltage sensitive calcium channels (via an inhibition of inward calcium current) and activation of potassium membrane conductance (22,23). Because of its ability to slow the heart rate by prolonging atrioventricular conduction time and refractoriness (3,5), somatostatin has been successfully used to treat supraventricular tachycardia (5,16); these effects were comparable to the effects of verapamil (3). We believe that octreotide has caused bradycardia and atrioventricular conduction abnormality primarily by acting directly on the cardiac conduction system.
Octreotide may be a life-saving treatment in the case of an acute carcinoid crisis, but when given as an IV bolus and in larger doses (≥100 μg), it may cause significant effects on the arterial blood pressure, heart rate, and cardiac conduction system. Perioperative physicians especially need to be aware of these potential effects because they may be more likely to occur during surgery because of the larger doses and boluses that are used to treat acute symptoms secondary to tumor manipulation. As suggested by the evidence in the literature, it may be advisable to dilute octreotide and infuse it slowly with continuous monitoring of the ECG. In a case of carcinoid crisis, when octreotide is given as a bolus, the anesthesiologist should be prepared to treat significant bradycardia and cardiac conduction delays.
1. Osadchii OE, Pokrovskii VM. Somatostatin as a regulator of cardiovascular system functions. Usp Fiziol Nauk 1998; 29: 24–41.
2. Preston E, Courtice GP. Cardiac vagal effects in the toad are attenuated by repetitive vagal stimulation. Neuropeptides 1993; 25: 193–8.
3. Webb SC, Krikler DM, Hendry WG, et al. Electrophysiological actions of somatostatin on the atrioventricular junction in sinus rhythm and reentry tachycardia. Br Heart J 1986; 56: 236–41.
4. Day SM, Gu J, Polak JM, Bloom SR. Somatostatin in the human heart and comparison with guinea pig and rat heart. Br Heart J 1985; 53: 153–7.
5. Ghirlanda G, Santarelli P, Uccioli L, et al. Electrophysiologic effects of somatostatin in man. Peptides 1986; 7: 265–6.
6. Kinney MAO, Warner ME. Anesthesia for patients with carcinoid tumors. In: Faust RJ, ed. Anesthesiology review. 3rd ed. New York: Churchill Livingstone, 2002: 506–7.
7. Herrington AM, George KW, Moulds CC. Octreotide-induced bradycardia. Pharmacotherapy 1998; 18: 413–6.
8. Wilinsky MP, Berndt EM. Octreotide acetate (Sandostatin) induced bradycardia: a case report. Hosp Pharm 1997; 32: 1225–61.
9. Physician’s Desk Reference. Montvale, NJ: Medical Economics Company, Inc, 2001.
10. Eriksson LS, Brundin T, Soderlund C, Wahren J. Haemodynamic effects of a long-acting somatostatin analogue in patients with liver cirrhosis. Scand J Gastroenterol 1987; 22: 919–25.
11. Erbas T, Usman A, Erbas B, et al. Short-term effects of somatostatin analogue (SMS 201–995) on left ventricular function in healthy persons: a scintigraphic study. J Endocrinol Invest 1993; 16: 857–61.
12. Sabat M, Guarner C, Soriano G, et al. Effect of subcutaneous administration of octreotide on endogenous vasoactive systems and renal function in cirrhotic patients with ascites. Dig Dis Sci 1998; 43: 2184–9.
13. Chanson P, Timsit J, Masquet C, et al. Cardiovascular effects of the somatostatin analog octreotide in acromegaly. Ann Intern Med 1990; 113: 921–5.
14. Thuesen L, Christensen SE, Weeke J, et al. The cardiovascular effects of octreotide treatment in acromegaly: an echocardiographic study. Clin Endocrinol (Oxf) 1989; 30: 619–25.
15. McCormick PA, Chin J, Greenslade L, et al. Cardiovascular effects of octreotide in patients with hepatic cirrhosis. Hepatology 1995; 21: 1255–60.
16. Greco AV, Ghirlanda G, Barone C, et al. Somatostatin in paroxysmal supraventricular and junctional tachycardia. BMJ (Clin Res Ed) 1984; 288: 28.
17. Zironi G, Rossi C, Siringo S, et al. Short- and long-term hemodynamic response to octreotide in portal hypertensive patients: a double-blind, controlled study. Liver 1996; 16: 225–34.
18. Gaudin C, Moreau R, Champigneulle B, et al. Short-term cardiovascular effects of somatostatin in patients with cirrhosis. Liver 1995; 15: 236–41.
19. Katz MD, Erstad BL. Octreotide, a new somatostatin analogue. Clin Pharm 1989; 8: 255–73.
20. Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res 2001; 49: 27–37.
21. Wiley JW, Uccioli L, Owyang C, Yamada T. Somatostatin stimulates acetylcholine release in the canine heart. Am J Physiol 1989; 257: H483–7.
22. Reisine T, Bell GI. Molecular biology of somatostatin receptors. Endocr Rev 1995; 16: 427–42.
23. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996; 334: 246–54.