ANAESTHESIA FOR THE CARCINOID SYNDROME: A REPORT OF NINE CASES*

RAYMOND MILLER, ARVIND U. PATEL, RICHARD R.P. WARNER, AND IRVING H. PARNES

IT tS WELL RECOGNIZED that patients with the planned. Pantopon and atropine were used for carcinoid syndrome are difficult to manage during premedication. Anaesthesia was induced with anaesthesia. I': Although the syndrome is rare, lnnovar and thiopentone. Tracheal intubation the number of such patients undergoing anaes- was facilitated with succinylcholine and thereaf- thesia is increasing because long-term medical ter anaesthesia and muscle relaxation were main- therapy is prolonging survival and surgical inter- rained with nitrous oxide and oxygen, fentanyl vention either for resection of the primary tu- and pancuronium. Anaesthesia was initially un- mor, excision of hepatic metastases, or hepatic eventful but greatly increased peristalsis of the dearterialization is becoming more common. 3 small bowel was observed. When the stomach The total reported anaesthetic experience with was mobilized the blood pressure rose from the carcinoid syndrome is modest. Mason and 17.29/I 0.64 k Pa ( 130/80 m m Hg) to 23.94113.3 k Pa Steane (1976) in a comprehensive review of the (180/100 m m blg) and the pulse rate from 80 to 160 relevance of this syndrome to the anaesthetist beats per minute. Intense bronchospasm also de- found a total of only 40 anaesthetics described in veloped and it became difficult to ventilate the nine papers. I They found that the incidence of patient. Blood gas analysis revealed a respiratory complications, including hypotension, bron- alkalosis and a metabolic acidosis. Halothane chospasm or hypertension was high, occurring in was added to the inspired mixture and hydro- 27 of the reported cases. During the past two cortisone was administered intravenously with- years nine patients with the carcinoid syndrome out effect. No specific antiserotonin or anti- were anaesthetized in our own institution, seven bradykinin agents were available in the operat- of whom were managed by the authors. The ing room. Bronchospasm, hypertension and hazards of anaesthesia in an unprepared and un- tachycardia persisted until a wide gastric resec- recognized patient are illustrated by one case, but tion of the tumor area had been performed, when the low incidence of significant complications in the patient's condition dramatically improved. the remaining eight patients differs from the pub- No further problems were encountered. Hepatic lished experience of others and prompted the fol- metastases were not found. Post-operatively lowing brief case reports. Pre-operative labora- 5HIAA levels were within normal limits. tory data of interest are summarized in Table I. Patient 2 Patient I A 44-year-old very apprehensive female with a A 35-year-old male was investigated for history of severe facial flushing, facial swelling, anaemia and weight loss. 4 There was no history urinary frequency and galactorrhoea was found of cutaneous flushing, wheezing, abdominal pain, to have increased bowel sounds, rapid transit of a or diarrhoea. Radiological studies indicated a barium meal through the small intestine and ele- polypoid gastric lesion which, following endo- vated urinary 5HIAA and serum 5 hydroxytryp- scopic biopsy was found to be a carcinoid tumor. tophan levels. An exploratory laparotomy was Serum serotonin and urinary 5-Hydroxyin- scheduled. Premedication consisted of pantopon doleacetic acid (5HIAA) levels were within the and scopolamine, lnnovar and thiopentone were normal range. Resection of the gastric tumor was used for induction and succinylcholine given to facilitate intubation. Anaesthesia and relaxation *This study was supported in part by the Carcinoid were maintained with nitrous oxide oxygen, fen- Tumor and Serotonin Research Foundation, Inc. Raymond Miller, M.D., Associate Clinical Professor tanyl and pancuronium. During induction of of Anesthesiology; Arvind U. Patel, M.D., Resident in anaesthesia severe facial flushing occurred. Anesthesiology; Richard R.P. Warner, M.B., As- Thereafter flushing occurred after each incre- sociate Clinical Professor of Medicine; Irving H. ment of fentanyl or pancuronium was adminis- Parnes, M.D., Senior Clinical Instructor in Surgery. Mount Sinai Medical Center of the City University of tered throughout the procedure, the duration of New York, Fifth Avenue and 100th Street, New York, which was two and three-quarter hours. There New York, 10029. were no cardiovascular or respiratory complica- 240 Canad. Anaesth. Soc. J., vol. 25, no. 3, May 1978 TABLE I PRE-OPERATIVE LABORATORY DA'rA." NINE PATIENTS WITH CARCINOID SYNDROME

Serum lag/m Urine rag/25 hours Urine IJg/24 hours Plasma l~g/ml Serotonin 5 Hydroxytryptophan Tryptophan 5 HIAA Indoleacetic acid Tryptamine Histamine Patient (Normal 0.08--0.31) (normal < 0.02) (normal 9.5-16.0) (normal 2-8) (Normal 3-8) (Normal 25-125) (normal 25-65)

0.11 10.0 5.5 0.17 0.05 13.0 5.9 89 41 0.38 0.09 9.0 15.0 0.77 5.2 211.0 5.1 416 37 1.15 3.6 17.8 4.9 165 0.54 4.1 20.4 512 169 43 0.45 6.9 128 4.9 510 40 0,18 9,7 52.5 5.1 286 61 2.0 1.9 435 16.5 318 242 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL lions. No primary tumor was found but liver tions of serum serotonin and urinary 5HIAA biopsy revealed anaplastic adenocarcinoma. excretion, unresponsive to medical therapy de- spite receiving a variety of therapeutic agents, 5 Patient 3 Pre-operadvely they were maintained on A 76-year-old female with clinical features in- steroids and cyproheptadine. Neomycin orally cluding abdominal pain, flushing, and hypermotil- and fructose 10 per cent intravenously were ad- ity of small bowel, suggesting carcinoid syn- ministered for three days pre-operalively. drome, was investigated. Serum serotonin, five Aprotonin (Trasylol) 200,000 units was given hydroxytryptophan and urinary 5HIAA levels intravenously immediately before induction of were elevated and exploratory laparotomy was anaesthesia or during induction. planned. Premedication consisted of secobar- Aprotonin, methotrimeprazine, angiotensin bitone and atropine. A thiopentone, pancuro- amide, methoxamine, and hydrocortisone were nium, nitrous oxide oxygen sequence was used to held ready in the operating rooms. provide anaesthesia and relaxation. Following In addition to routine monitoring aids, the induction, a mean blood pressure of 14.63 kPa mean arterial pressure was recorded through a (110 mm Hg) was maintained, but on one occa- catheter placed in a radial artery and arterial sion as the bowel was manipulated, the pressure blood was withdrawn at intervals for blood gas rose to 26.6 kPa (200 mm Hg). Methotrimep- analysis. razine 2.5 mg was administered intravenously The same anaesthetic technique was used for" and the blood pressure returned to its former all five patients. Premedication consisted of sec- level after two or three minutes. Except for this obarbitone and atropine. Thiopentone, pan- brief hypertensive episode anaesthesia was un- curonium, nitrous oxide and oxygen were the eventful. No tumor was found in the abdomen. only agents used. All patients were ventilated Subsequently, a thyroid tumor was discovered. mechanically and a moderate respiratory al- The nodule was "cold" on scan. The patient kalosis was maintained. Reversal of neuromuscu- refused further surgery, was treated with lar blockade was achieved with atropine and chemotherapy and both her symptoms and the prostigmine. thyroid nodule subsided. Patient 5 Patient 4 A 52-year-old female with severe flushing, A 65-year-old female with proven carcinoid diarrhoea, and a history of a small bowel resec- syndrome and a history of small bowel resection tion for a carcinoid tumor of Meckels diver- was admitted because of severe diarrhoea, flush- ticulum with elevated serotonin and 5HIAA ing and weight loss, as a candidate for hepatic levels underwent three hours of anaesthesia for" dearlerialization. Serum serotonin and urinary hepatic artery ligation. Facial flushing was noted 5H IAA levels were elevated. on several occasions. The mean blood pressure She was maintained on steroids, Iomotil and rose on two occasions from 12 to 16 kPa (90 to 120 methysergide, but medical therapy was ineffec- mm Hg) but these hypertensive episodes were tive. She developed intestinal obstruction and successfully treated with 2.5 mg of methotri- signs of peritonitis which necessitated an emer- meprazine intravenously and were of brief dura- gency laparotomy with extensive lysis of adhe- tion. Postoperatively the patient was awake after sions. Numerous liver metastases were noted. five minutes but appeared drowsy for several Premedication consisted of secobarbitone and hours. atropine. Anaesthesia consisted of a thiopen- Patient 6 tone, pancuronium, nitrous oxide and oxygen se- A 66-year-old male with a history of small quence. During the three-and-a-half-hour opera- bowel carcinoid, flushing, diarrhoea, and weight tion no problems relating to the carcinoid syn- loss, underwent three hours of anaesthesia for drome occurred. The blood pressure remained hepatic artery ligation. Two modest hypertensive consistently in the range 10.64/7.98 kPa (80/60 episodes occurred when mean blood pressure mm Hg) despite adequate fluid replacement but rose from 14.63 to 21.28 kPa (110 to 160 mm Hg) this problem was clearly related to septicaemia and these were treated with methotrimeprazine. and hypovolaemia. No other problems were encountered. Five patients were anaesthetized for hepatic artery tigation. These patients were proven cases Patient 7 of the carcinoid syndrome with persistent eleva- A 54-year-old female with severe symptoms of MILLER, el al.: ANAESTHESIA FOR CARCINO[D SYNDROME 243 the carcinoid syndrome, increased serotonin and times associated with the carcinoid syndrome 5HIAA levels and decreasing response to chem- were not assayed. The combination of hyperten- otherapy for biopsy-proven carcinoid tumor un- sion and bronchospasm is unusual since bron- derwent two hours of anaesthesia for hepatic ar- chospasm is usually associated with hypotension tery ligation. 6 Fifteen minutes after intubation and thought to be due to bradykinin release, t'2 bronchospasm developed. Hydrocortisone 200 Hypertension and tachycardia are thought to be mg and aprotonin 20,000 units were given with due to an outpouring of serotonin. J,2 Foregut car- some improvement. Aprotonin 100,000 units and cinoid tumors are of neuro-ectodermal origin and hydrocortisone 100 mg were given intravenously in addition to serotonin may secrete a variety of during the next hour, during which broncho- hormonal agents including histamine, adrena- spasm gradually diminished. At the end of the line, adrenocorticotrophic hormone, melanocyte operation the chest was clear. In the recovery stimulating hormone, insulin, glucagon, gastrin room she was drowsy for one hour post- and secretin. Gastric carcinoid tumors in particu- operatively. lar are sometimes associated with increased his- tamine secretion. Patient 8 Foregut carcinoids may also secrete 5-hy- A 51-year-old female with a history of lung droxytryptophan, a serotonin precursor, and his- resection for bronchial carcinoid and persistent tamine; such tumors are known to be associated flushing, diarrhoea and weight loss, underwent with severe atypical carcinoid syndrome. Furth- four hours of anaesthesia for hepatic artery liga- ermore, prostaglandins are frequently produced tion. On three occasions the mean blood pressure by carcinoid tumors and may be responsible for rose from 13.3 to 21.28 kPa (100 to 160 mm Hg) flushing and bronchospasm. 8 but was easily restored with methotrimeprazine In patient 2 the clinical features suggesting car- 2.5 mg intravenously. cinoid syndrome and the modest elevation of uri- nary 5HIAA levels in the presence of metastatic Patient 9 adenocarcinoma may indicate aberrant hormone A 65-year-old male was admitted with surgi- production from a non-carcinoid tumor, also re- cally proven carcinoid of small bowel, extensive sulting in an aTtypical carcinoid syndrome. hepatic metastases, carcinoid heart disease with Hypotension was not a problem in this group of congestive failure and organic mental syndrome patients. suffering from severe flushing, diarrhoea and Delayed awakening occurred in two patients weakness unresponsive to chemotherapy. Sero- without leading to any untoward sequelae. In tonin and urinary 5HIAA levels were elevated. most cases drug administration was limited to He received diazepam and Innovar for sedation secobarbitone, atropine, thiopentone, pancuro- while undergoing angiography with local anaes- nium, and nitrous oxide. The technique used was thesia. No problems occurred, This patient had essentially that described by Mason and Steane an abnormal response to cyproheptadine, sleep- who, however, also used fentanyl. 9 We chose to ing for 12 hours after a single dose and this drug ,exclude fentanyl because this agent may occa- was subsequently withheld. There were no com- sionally cause ventilatory difficulties due to mus- plications during two and a half hours of general cle rigidity, ~0 anaesthesia for hepatic artery ligation. Most agents used during anaesthesia may be associated with histamine or" serotonin release DISCUSSION and, therefore, it would seem prudent to limit the number of drugs used. The use of morphine for Excluding one patient, the complications oc- premedication in two patients and succinyl- curring during anaesthesia were minor in nature. choline for intubation in three patients was inap- Hypertensive episodes occurred in four addi- propriate. Morphine may provoke serotonin or tional patients and bronchospasm in one, but the histamine release, t~ The increase in intra- degree of bronchospasm and vasomotor instabil- abdominal pressure occurring after succinyl- ity was only life-threatening in the patient with a choline ~2 may precipitate a carcinoid crisis. gastric carcinoid tumor (Patient 1). This patient Steroids, aprotonin and methotrimeprazine was atypical as there were no pre-operative have been considered helpful in the anaesthetic symptoms of the carcinoid syndrome, nor were management of patients with the carcinoid syn- abnormal levels of serotonin or its metabolites drome. detected. Other vasoactive substances some- Steroids are sometimes very effective in con- 244 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL trolling severe prolonged flushing and probably RF,SUMF- act by blocking kinin release. Though useful prophylactically they are probably ineffective Les auteurs rapportent leur exp6rience once kinins have been liberated. ~ anesth6sique de neuf cas de malades pr6sentant Aprotonin inhibits tumor kallikrein in vitro but un syndrome carcinoide. A I'exception d'un cas its intravenous administration has not been effec- or) est survenu un bronchospasme important avec tive in controlling spontaneous or provoked flush- hypertension, ils n'ont observ6 que des complica- ing. t4 tions mineures. Les st6roi'des, l'aprotonine et la Aprotonin is not universally available. It may, m6thoxymeprazine sont des agents qui peuvent however, be helpful as an antikinin agent when contribuer/~ la bonne marche de ces interven- bronchospasm occurs. 2 In those cases undergo- tions. Comme m~thode d'anesth~sie, I'emploi de ing hepatic artery ligation, informed consent was thiopenthal, de protoxyde d'azote et de pan- obtained for the use ofaprotonin, but whether the curonium s'est avGr6 une technique satisfaisante. administration was beneficial is unclear. Cer- tainly no ill effects were associated with aproto- REFERENCES nin administration. The recommended vasopres- I. MASON, R.A. & STEANE, P.A. Carcinoid syn- sots, ~5 angiotensin and methoxamine, were not drome: its relevance to the anaesthetist. Anaes- used; but from the experience of others it is t hesia 31 : 228-242 (1976). clearly necessary to have one of these agents 2. DERY,T. Theoretical and clinical considerations in available. anesthesia for secreting carcinoid tumors. Can Anaesth. Soc. J. 18:245-263 (1971). Methotrimeprazine is a potent antiserotonin 3. MALAFOSSE,M. Carcinoid tumors: surgical prob- agent and was very effective in controlling hyper- lems. Clinics in Gastroenterology 3:711-719 tension. 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