- Email: [email protected]
Anesthesia for glucagonoma resection
Anesthesia Resection
for Glucagonoma
Nikola A. Boskovski, MD, PhD,* James W. Chapin, MD,? Gerald L. Becker, MD,? James A. Edney, MD,+ William C. Sanders, DO,5 Lawrence A. Wolpert, DOS Departments Center,
of’ Anesthesiology
Omaha,
Anesthetic experience with three cases of the resection of glucagonoma, a rare tumor of alpha cells of pancreatic islets, is presented. Marked increases of bloodglucagon and glucose levels, with the potential for clinically significant metabolic and myocardial dysfunction, did not occur during anesthesia and surgery. Associated tumors of other endocrine cell types also were absent in the three study patients. Strategies ,for anticipating and managing other perioperative problems associated with glucagonoma also are d&cussed. Keywords: Carbohydrate metabolism; adenoma; glucagon; glucagonoma; glucose; neoplasms; islet cell tumor. *Corresponding Anesthesiology
Author and Assistant Professor,
tAssociate Professor,
Department
$Assistant Professor, Department IResident, Department
Department
of
of Anesthesiology of Surgery
of Anesthesiology
Address reprint requests to Dr. Boskovski at the Department of Anesthesiology, University of Nebraska Medical Center, 600 S. 42nd Street, Omaha, NE 68198-4455, USA. Received for publication December 12, 1989; revised manuscript accepted for publication May 15, 1990. 0 1991 Butterworth-Heinemann
48
J. Clin. Anesth.,
vol. 3, January/February
lYY1
and
Surgery,
University
of Nebraska
Medical
NE.
Introduction Only recently defined as a clinical entity,’ glucagonoma is a tumor of pancreatic islet alpha cells that grows slowly and metastasizes locally.2.3 These rare tumors (only 60 reported cases) characteristically synthesize and secrete increased amounts of glucagon, which serve as a definitive diagnostic marker and contribute to a characteristic clinical syndrome: glucose intolerance, migratory dermatitis, diarrhea, weight loss, mucosal inflammation, psychological disturbances, and thromboembolic disorders.g The treatment of choice for glucagonoma is surgical resection.4 A ppropriate anesthetic management must recognize that plasma levels of glucagon are usually increased even under basal conditions and may increase considerably more during intraoperative manipulation of tumor-containing tissue. Glucagon has several different actions that could produce clinically significant problems at excessive circulating levels of hormone.g Glucagon activates both glycogenolysis and gluconeogenesis in the liver and also suppresses insulin release, all of which act to increase blood glucose. Myocardial contractility also is increased through direct action of glucagon on the heart. Glucagon also stimulates release of adrenal hormones, which could contribute to both metabolic and cardiovascular abnormalities. Only a single case report of glucagonoma has appeared in the anesthesiology literature.” This report
Annthesia [or glucugonovna wwtion:
describes three additional cases during which there were no problems specific to glucagon or the syndrome and emphasizes some general strategies for anesthetic management of glucagonoma.
Case Report I A 39-year-old white female presented with a P-year history of fatigue, leg edema, amenorrhea, migratory rash, glossitis, stomatitis, and a weight loss of 7 kg over the previous 2 months. Biopsy examination of the maculopapular rash, which had been refractory to steroids, was consistent with the early stages of necrolytic migratory erythema typically associated with glucagonoma. Preoperative blood glucagon levels were 540 to 1,520 pg/ml (normal range is 20 to 100 pg/ml in the fasting adult) (Table 1). Computed tomography (CT) examination of the abdomen was negative, but arteriography showed numerous small hypervascular areas in the liver and a 0.5 to 1 .O cm blush in the region of the pancreatic tail compatible with an islet cell tumor. Other laboratory findings included a hemoglobin of 9.1 g/d1 with normal indices. WBC, BUN, electrolytes, liver function tests, and blood coagulation tests all were normal. There was no history of previous illnesses or allergies. Medication included topical zinc sulfate for treatment of skin lesions. The review of systems was
Table
1.
Perioperative
Concentrations
unremarkable, as was the physical examination, except for a maculopapular rash, with scaling and ulceration most prominent on the lower extremities. Premeditation consisted of droperidol 1.25 mg and morphine sulfate 2 mg administered intravenously (IV). Following induction with thiopental sodium 540 mg, intubation was facilitated with curare 3 mg and succinylcholine 100 mg. Anesthesia was maintained with enflurane 0.5% to 1.5% and muscle relaxation with pancuronium. Electrocardiogram (EKG), blood pressure (BP), esophageal temperature, precordial heart sounds, central venous pressure (CVP), urine output, inspired oxygen concentration, and ventilatory exchange were monitored. BP and heart rate (HR) were stable throughout the anesthetic course. Blood glucose (Dextrostix) ranged from 140 to 180 mg/dl after a value of 500 mg/dl early in the anesthetic course following a liter of 5% dextrose in lactated Ringer’s solution (D5LR). Glucagon levels were 99 pg/ ml and 177 pg/ml after tumor removal. A mass was palpated in the distal pancreas, and no intra-abdominal metastases were found. A distal pancreatectomy, splenectomy, cholecystectomy, and liver biopsy were performed. Muscle relaxation was reversed with glycopyrrolate 0.4 mg and neostigmine 5 mg. Recovery room and postoperative courses were uneventful, and the patient was discharged on the seventh postoperative day. In the recovery room and on postoperative day 1, glucagon levels were 73
of Plasma
Glucagon
and Blood
Glucagon* (pgW Case 1 Preoperative Intraoperative-post-tumor 60 min 75 min Recovery room Postoperative (day 1) Case 2 Preoperative Intraoperative-post-tumor 30 min 60 min Recovery room Postoperative (day 4) Case 3 Preoperative Intraoperative-post-tumor 30 min 60 min *Normal
glucagon
Boskovski et al.
Glucose Glucose (m&W
540 to 1,520
109
99 177 73 94
181 122 107
471
89
293 254 24 20
146 293 115 104
529
101
256 320
252 246
removal
removal
removal
levels are 20 to 100 pgiml
in the fasting
adult.
J. Clin.
Anesth.,
vol. 3, January/February
1991
49
Case Reports
pg/ml and 94 pg/ml, respectively (Table 1). Pathologic inspection of the tumor specimen confirmed glucagonoma.
gonoma. The latter was first diagnosed in 1975, at which time a subtotal pancreatectomy and splenectomy were done. The patient later underwent a partial lung ., resection for a metastasis. A previous subtotal parathyroidectomy also had been done prior to 1975. At the time of this admission, a CT scan showed liver metastases and a renal cyst. In addition, the patient had a migratory rash, unstable serum glucose (11 to 13 mgi (50 to 400 mg/dl), and hypercalcemia dl). He had experienced a 6 kg weight loss over 2 months. The serum electrolytes were unremarkable, and the serum parathyroid hormone value was below normal (less than 10 pg/ml). The serum glucagon level was 529 pg/ml (normal range is 200 to 100 pg/ml (Table 1). Tests for a catecholamine-secreting tumor were negative. Prior to the operative procedure, hyperglycemia was treated with nonprotamine Hagedorn (NPH) insulin and regular insulin on a sliding scale. The hypercalcemia was treated with mithramycin, resulting in a serum calcium level of 10.1 mg/dl on the day of surgery. Premeditation for surgery consisted of lorazepam 2 mg orally at bedtime the night before surgery and 2 mg orally at 6 A.M. on the day of surgery. Induction consisted of thiopental sodium 200 mg and vecuronium 7 mg. During the 8-hour surgery, anesthesia was maintained with isoflurane, N,O, and 0,. Muscle relaxation was maintained with pancuronium and vecuronium. Monitors consisted of a radial arterial line, right internal jugular CVP line, pulse oximeter, endtidal carbon dioxide (CO,) monitor, esophageal stethoscope, and temperature probe. The serum glucose level was 10 1 mg/dl preoperatively and decreased to 73 mg/dl early in the case. To avert the possibility of intraoperative hypoglycemia, IV fluids were supplemented with D5LR until glucose increased to 284 mgi dl. D5LR was then discontinued, and the glucose level ranged between 200 and 300 mgidl for the remainder of the procedure. No insulin was given either preoperatively or intraoperatively. Vital signs were stable during most of the case, although episodes of acute blood loss were associated with transient decreases in BP, which resolved with further administration of blood products and volume replacement. Fourteen units of packed red blood cells, 2 units of fresh frozen plasma, IO units of cryoprecipitate, and epsilon aminocaproic acid were given, with coagulation therapy guided principally by thromboelastography and sonoclot analysis. Although the patient had a history of hypercalcemia, calcium chloride was required to counteract the effects of dilution and titrated blood products and to a
Case Report 2 A 44-year-old white female had experienced a variety of symptoms referable to dryness and irritation of oropharyngeal, conjunctival, and vaginal mucosae for approximately 2 years, then developed an erythematous, pruritic rash around the ankles. She also reported frequent diarrhea and a 30-pound weight loss over that same period of time. Although abdominal ultrasound and CT failed to localize a tumor, the diagnosis of glucagonoma was confirmed by the finding of increased glucagon levels upon selective sampling of pancreatic venous blood during angiography. Past medical history included several food allergies, recurrent urinary tract infections over the previous 2 years, and mitral valve prolapse. Tubal ligation had been performed 10 years earlier under general anesthesia without complication. Physical examination demonstrated a 56 kg, 157 cm white female with diffusely dry skin and multiple hyperkeratotic, erythematous lesions on the face. Fasting blood glucose was 89 mgldl, plasma zinc was decreased, serum iron was low, and plasma glucagon was significantly increased at 47 1 pg/ml (normal range is 20 to 100 pg/ml) (Table 1). Premeditation of IV midazolam 2 mg and morphine IO mg was given. Anesthesia was induced with thiopental sodium 250 mg, and vecuronium was given to facilitate endotracheal intubation and intraoperative muscle relaxation. Anesthesia was maintained with nitrous oxide (N,O) and oxygen (0,) 1: 1 and isoflurane 0.5% to 1.5%, supplemented with a total of 250 kg fentanyl. The plasma glucagon levels were 293 and 254 pg/ml at 30 and 60 minutes, respectively, after tumor removal; they were 24 and 20 pg/ml in the recovery room and on postoperative day 4 (Table 1). The tumor was located in the tail of the pancreas; no metastases or adenopathy were noted. Distal pancreatectomy, splenectomy, and liver biopsy were performed. Neuromuscular blockade was reversed with neostigmine and atropine. The entire postoperative course was uneventful, and the patient was discharged on the seventh postoperative day. Pathologic examination of the pancreas demonstrated glucagonoma.
Case Report 3 A 5l-year-old male was scheduled to undergo an exploratory laparotomy and debulking of a gluca50
J. Clin. Anesth.,
vol. 3, January/February
1991
Anesthesia /or glucugonoma
keep the serum ionized calcium levels in the normal range. A left adrenalectomy and a right hepatic lobectomy were performed. Pathologic examination demonstrated metastatic glucagonoma. Mechanical ventilation was required for 4 days postoperatively. The remainder of the postoperative course was uneventful except for a low-grade fever for which no cause was found. Discharged on the twenty-third postoperative day, the patient was readmitted with a recurrent and intensified fever 2 weeks later. A subhepatic abscess was diagnosed and drained. A drainage tube was placed, and the patient was discharged 1 week later.
Discussion Under basal conditions, metabolic regulation in most cases of glucagonoma is minimally disturbed. Fasting blood sugars are usually normal, and an overtly diabetic state with the potential for ketoacidosis is rare.3 However, appropriate anesthetic management of glucagonoma must anticipate how such patients will respond during anesthesia and surgery, which in and of themselves can produce alterations in metabolic and cardiovascular function that may interact with those attributable to the underlying endocrine disorder. Blood glucose levels normally tend to increase during anesthesia and surgery, especially with intra-abdominal procedures. 7 Afferent neurogenic stimuli increase sympathetic outflow and release catecholamines. Kossman et aLa reported that an increase in blood glucose seen during abdominal aortic surgery under neuroleptic anesthesia could be blocked by high The catecholamines, by mechaepidural anesthesia. nisms distinct from those of glucagon, also stimulate hepatic glycogenolysis and gluconeogenesis.Y Catecholamines also may increase blood glucose through decreases in peripheral glucose use, either directly or indirectly, by inhibiting insulin release from the pancreas.“’ Halogenated volatile anesthetics also may affect the same variables. Although halothane suppresses catecholamine release, it nonetheless is associated with insulin resistance, glucose intolerance, and increased hepatic glycogenolysis.“,12 Kossman et al8 determined that blood levels of cortisol, glucagon, and insulin remained constant under general or regional anesthesia. However, most studies have reported increases in circulating concentrations of catabolic hormones in response to surgical trauma. Okubo13 reported that plasma glucagon increased to 1.3 to 1.5 times normal during N,O/halothane anes-
rrrrcfion:
Boskovski rt al.
thesia and remained increased during recovery. In addition, blood glucose increased to 1.6 to 1.7 times normal during anesthesia and remained increased through the first postoperative day. Russell et a1.l4 reported increased levels of plasma glucagon in a wide variety of surgical procedures. The specific factors responsible for the typical amount of glucagon released during surgery (twofold to threefold increases) are not known.15 Despite the combined potential for intraoperative stress and increased glucagon availability to increase blood glucose, that situation did not develop in any of the three cases of glucagonoma presented in this paper or in the one case previously described.6 In case 1 of this report, glucose increased to 500 mg/dl immediately following “routine” preoperative infusion of 1 liter of D5LR. Clearly, administration of glucose in any form to a patient with glucagonoma should not be performed as a routine procedure and should be guided by monitoring of blood glucose levels. Intraoperative increases of glucose levels in the present patients were modest and clinically inconsequential; no insulin was administered. In addition, there was no abnormality of myocardial function or cardiovascular regulation attributable to the coexistence of stress and endocrine disorder. A rigid formula for anesthetic management during glucagonoma resection is clearly not appropriate. In the four cases referred to above, perioperative glucagon levels were only moderately increased (~2,000 pg/ml; normal range is 20 to 100 pg/ml), whereas in other reported cases, glucagon levels have exceeded 10,000 pg/m1.16 In the latter instances, a frankly diabetic state with or without ketoacidosis may have already existed or may have developed intraoperatively. Also, myocardial hypertrophy has been reported with chronically increased glucagon levels.‘” Other potential problems may arise as a result of the fact that a sizable fraction of glucagonomas occur in association with other endocrinopathies, including Zollinger-Ellison syndrome, insulinoma, and multiple endocrine adenomatosis (Types I and II). Pheochromocytoma is an MEA-II tumor reportedly associated with glucagonoma.17 Yano et aLIs reported a case of glucagon-secreting islet cell carcinoma that also produced insulin and somatostatin and decreased blood glucose to 40 mg/dl during fasting. A diagnostic workup of glucagonoma must ascertain the coexistence of other such endocrine disorders so that appropriate anesthetic management can be devised. Periodic intraoperative blood glucose monitoring is a cornerstone of any such plan, along with careful attention to cardiovascular function, especially if glucagonoma is associated with an insulin- or cateJ. Clin. Anesth.,
vol. 3, January/February
1991
51
cholamine-secreting tumor. Concomitants of glucagonoma per se, such as thromboembolic disorders or tluid/electrolyte imbalances resulting from weight loss and/or diarrhea, also may complicate intraoperative management and should be managed by standard therapy. In summary, the authors have added three cases to the one previously reported on the anesthetic experience with resection of glucagonoma. No anesthetic difficulties resulted from the increased glucagon levels, the glucose levels were easily managed, and no cardiac problems were related to glucagon. None of the three study patients had the extremely high glucagon levels that are occasionally seen with this tumor and have the potential to create problems. Associated endocrine tumors, such as pheochromocytoma, that have anesthetic implications also did not occur in these three patients.
References 1. McCavran MH, Unger RH, Recant L, et al: A glucagonsecreting alpha-cell carcinoma of‘the pancreas. N Engl J Med 1966;274:1408-12. 2. Friesen SK: Tumors of the endocrine pancreas. N Engl J Med 1982;306:580-90. 3. Montenegro-Roads F, Samann S: Clucagonoma tumors and syndrome. Curr Probl Cancer 198 1;6: l-54.
4. Prinz RA, Badrinath K, Banerji M, et al: Operative and chemotherapeutic management of‘ malignant glucagon-producing tumors. Surge? 1981;90:713-9. 5. Shafrir E, Bergman M, Felig P: The endocrine pancreas: diabetes mellitus. In Felig P, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and Metabolism. 2d ed. New York: McGraw-Hill, 1987; 1083-5. 6. Nicoll VMS, Catling JS: Anesthetic management of glucagonoma. Anaesthesia 1985;40: 152-7.
52
J. Clin. Anesth.,
vol. 3, January/February
1991
7. Clarke RSJ: ‘l‘he hyperglycemic
response to different types of surgery and anesthesia. Br J Anuesth 1970;42:45-
52. 8. Kossman B, Volk E, Spilker ED, et al: Influence of thoracic epidural analgesic on glucose, cortisol, insulin, and glucagon responses to surgery. Reg Anaesth 1982;7:107-9. 9. Biebuyck JF: Anesthesia and hepatic metabolism. Anethesiology 1973;39: 188-98. 10. Cooper CM, Paterson JL, Mashiter K, Hall GM: Betaadrenergic blockade and the metabolic response to surgery. BrJ Anaesth 1980;52:1231-7. 11. Merin KG, Samuelson PN, Schalch DS: Major inhalation anesthetics and carbohydrate metabolism. ,4nrslh Analg 1971;50:625-32. 12. Biebuyck JF, Lund 1’: Effects of halothane and other anaesthetic agents on the concentrarions of rat liver metabolites in viva. &fol Phal-macol 1974; 103474-83. 13. Okubo I‘: Effect of anesthesia and surgery on carbohydrate metabolism and endocrine function including glucagon in man. Masui 1979;28: 1062-Y. 14. Russell RCG, Walker CJ, Bloom SK: Hyperglucagonemia in the surgical patient. Br Mrd J 1975; 1: 10-3. 15. ‘I‘rayner (1, Hall GM: Endocrine and metabolic changes during surgery: anaesthetic implications. H1-./ Ann&h 1981;53:153-60. 16. Takemiya M, Miyayama H, Takeya M: A postmortem study of malignant glucagonoma with heart muscle hypertiophy, including chemical, histochemical, immunohistological and ultrastructural observations. Hum Pathol 1981:12:988-99. 17. Yao H, Fukiyama K, Kawano Y, et al: Recurrent pheochromocytoma associated with glucagonoma. A case report. Endocrine/ Jpn 1983;30: 163-6. 18. Yano ‘I‘. Yamamoto N, Kuimori K, et al: Glucagonsecreting pancreatic islet cell carcinoma, containing insulin and somatostatin, with hypoglycemic attack. Am,] Cast~oenterol 1982;77:387-91.
for Glucagonoma
Nikola A. Boskovski, MD, PhD,* James W. Chapin, MD,? Gerald L. Becker, MD,? James A. Edney, MD,+ William C. Sanders, DO,5 Lawrence A. Wolpert, DOS Departments Center,
of’ Anesthesiology
Omaha,
Anesthetic experience with three cases of the resection of glucagonoma, a rare tumor of alpha cells of pancreatic islets, is presented. Marked increases of bloodglucagon and glucose levels, with the potential for clinically significant metabolic and myocardial dysfunction, did not occur during anesthesia and surgery. Associated tumors of other endocrine cell types also were absent in the three study patients. Strategies ,for anticipating and managing other perioperative problems associated with glucagonoma also are d&cussed. Keywords: Carbohydrate metabolism; adenoma; glucagon; glucagonoma; glucose; neoplasms; islet cell tumor. *Corresponding Anesthesiology
Author and Assistant Professor,
tAssociate Professor,
Department
$Assistant Professor, Department IResident, Department
Department
of
of Anesthesiology of Surgery
of Anesthesiology
Address reprint requests to Dr. Boskovski at the Department of Anesthesiology, University of Nebraska Medical Center, 600 S. 42nd Street, Omaha, NE 68198-4455, USA. Received for publication December 12, 1989; revised manuscript accepted for publication May 15, 1990. 0 1991 Butterworth-Heinemann
48
J. Clin. Anesth.,
vol. 3, January/February
lYY1
and
Surgery,
University
of Nebraska
Medical
NE.
Introduction Only recently defined as a clinical entity,’ glucagonoma is a tumor of pancreatic islet alpha cells that grows slowly and metastasizes locally.2.3 These rare tumors (only 60 reported cases) characteristically synthesize and secrete increased amounts of glucagon, which serve as a definitive diagnostic marker and contribute to a characteristic clinical syndrome: glucose intolerance, migratory dermatitis, diarrhea, weight loss, mucosal inflammation, psychological disturbances, and thromboembolic disorders.g The treatment of choice for glucagonoma is surgical resection.4 A ppropriate anesthetic management must recognize that plasma levels of glucagon are usually increased even under basal conditions and may increase considerably more during intraoperative manipulation of tumor-containing tissue. Glucagon has several different actions that could produce clinically significant problems at excessive circulating levels of hormone.g Glucagon activates both glycogenolysis and gluconeogenesis in the liver and also suppresses insulin release, all of which act to increase blood glucose. Myocardial contractility also is increased through direct action of glucagon on the heart. Glucagon also stimulates release of adrenal hormones, which could contribute to both metabolic and cardiovascular abnormalities. Only a single case report of glucagonoma has appeared in the anesthesiology literature.” This report
Annthesia [or glucugonovna wwtion:
describes three additional cases during which there were no problems specific to glucagon or the syndrome and emphasizes some general strategies for anesthetic management of glucagonoma.
Case Report I A 39-year-old white female presented with a P-year history of fatigue, leg edema, amenorrhea, migratory rash, glossitis, stomatitis, and a weight loss of 7 kg over the previous 2 months. Biopsy examination of the maculopapular rash, which had been refractory to steroids, was consistent with the early stages of necrolytic migratory erythema typically associated with glucagonoma. Preoperative blood glucagon levels were 540 to 1,520 pg/ml (normal range is 20 to 100 pg/ml in the fasting adult) (Table 1). Computed tomography (CT) examination of the abdomen was negative, but arteriography showed numerous small hypervascular areas in the liver and a 0.5 to 1 .O cm blush in the region of the pancreatic tail compatible with an islet cell tumor. Other laboratory findings included a hemoglobin of 9.1 g/d1 with normal indices. WBC, BUN, electrolytes, liver function tests, and blood coagulation tests all were normal. There was no history of previous illnesses or allergies. Medication included topical zinc sulfate for treatment of skin lesions. The review of systems was
Table
1.
Perioperative
Concentrations
unremarkable, as was the physical examination, except for a maculopapular rash, with scaling and ulceration most prominent on the lower extremities. Premeditation consisted of droperidol 1.25 mg and morphine sulfate 2 mg administered intravenously (IV). Following induction with thiopental sodium 540 mg, intubation was facilitated with curare 3 mg and succinylcholine 100 mg. Anesthesia was maintained with enflurane 0.5% to 1.5% and muscle relaxation with pancuronium. Electrocardiogram (EKG), blood pressure (BP), esophageal temperature, precordial heart sounds, central venous pressure (CVP), urine output, inspired oxygen concentration, and ventilatory exchange were monitored. BP and heart rate (HR) were stable throughout the anesthetic course. Blood glucose (Dextrostix) ranged from 140 to 180 mg/dl after a value of 500 mg/dl early in the anesthetic course following a liter of 5% dextrose in lactated Ringer’s solution (D5LR). Glucagon levels were 99 pg/ ml and 177 pg/ml after tumor removal. A mass was palpated in the distal pancreas, and no intra-abdominal metastases were found. A distal pancreatectomy, splenectomy, cholecystectomy, and liver biopsy were performed. Muscle relaxation was reversed with glycopyrrolate 0.4 mg and neostigmine 5 mg. Recovery room and postoperative courses were uneventful, and the patient was discharged on the seventh postoperative day. In the recovery room and on postoperative day 1, glucagon levels were 73
of Plasma
Glucagon
and Blood
Glucagon* (pgW Case 1 Preoperative Intraoperative-post-tumor 60 min 75 min Recovery room Postoperative (day 1) Case 2 Preoperative Intraoperative-post-tumor 30 min 60 min Recovery room Postoperative (day 4) Case 3 Preoperative Intraoperative-post-tumor 30 min 60 min *Normal
glucagon
Boskovski et al.
Glucose Glucose (m&W
540 to 1,520
109
99 177 73 94
181 122 107
471
89
293 254 24 20
146 293 115 104
529
101
256 320
252 246
removal
removal
removal
levels are 20 to 100 pgiml
in the fasting
adult.
J. Clin.
Anesth.,
vol. 3, January/February
1991
49
Case Reports
pg/ml and 94 pg/ml, respectively (Table 1). Pathologic inspection of the tumor specimen confirmed glucagonoma.
gonoma. The latter was first diagnosed in 1975, at which time a subtotal pancreatectomy and splenectomy were done. The patient later underwent a partial lung ., resection for a metastasis. A previous subtotal parathyroidectomy also had been done prior to 1975. At the time of this admission, a CT scan showed liver metastases and a renal cyst. In addition, the patient had a migratory rash, unstable serum glucose (11 to 13 mgi (50 to 400 mg/dl), and hypercalcemia dl). He had experienced a 6 kg weight loss over 2 months. The serum electrolytes were unremarkable, and the serum parathyroid hormone value was below normal (less than 10 pg/ml). The serum glucagon level was 529 pg/ml (normal range is 200 to 100 pg/ml (Table 1). Tests for a catecholamine-secreting tumor were negative. Prior to the operative procedure, hyperglycemia was treated with nonprotamine Hagedorn (NPH) insulin and regular insulin on a sliding scale. The hypercalcemia was treated with mithramycin, resulting in a serum calcium level of 10.1 mg/dl on the day of surgery. Premeditation for surgery consisted of lorazepam 2 mg orally at bedtime the night before surgery and 2 mg orally at 6 A.M. on the day of surgery. Induction consisted of thiopental sodium 200 mg and vecuronium 7 mg. During the 8-hour surgery, anesthesia was maintained with isoflurane, N,O, and 0,. Muscle relaxation was maintained with pancuronium and vecuronium. Monitors consisted of a radial arterial line, right internal jugular CVP line, pulse oximeter, endtidal carbon dioxide (CO,) monitor, esophageal stethoscope, and temperature probe. The serum glucose level was 10 1 mg/dl preoperatively and decreased to 73 mg/dl early in the case. To avert the possibility of intraoperative hypoglycemia, IV fluids were supplemented with D5LR until glucose increased to 284 mgi dl. D5LR was then discontinued, and the glucose level ranged between 200 and 300 mgidl for the remainder of the procedure. No insulin was given either preoperatively or intraoperatively. Vital signs were stable during most of the case, although episodes of acute blood loss were associated with transient decreases in BP, which resolved with further administration of blood products and volume replacement. Fourteen units of packed red blood cells, 2 units of fresh frozen plasma, IO units of cryoprecipitate, and epsilon aminocaproic acid were given, with coagulation therapy guided principally by thromboelastography and sonoclot analysis. Although the patient had a history of hypercalcemia, calcium chloride was required to counteract the effects of dilution and titrated blood products and to a
Case Report 2 A 44-year-old white female had experienced a variety of symptoms referable to dryness and irritation of oropharyngeal, conjunctival, and vaginal mucosae for approximately 2 years, then developed an erythematous, pruritic rash around the ankles. She also reported frequent diarrhea and a 30-pound weight loss over that same period of time. Although abdominal ultrasound and CT failed to localize a tumor, the diagnosis of glucagonoma was confirmed by the finding of increased glucagon levels upon selective sampling of pancreatic venous blood during angiography. Past medical history included several food allergies, recurrent urinary tract infections over the previous 2 years, and mitral valve prolapse. Tubal ligation had been performed 10 years earlier under general anesthesia without complication. Physical examination demonstrated a 56 kg, 157 cm white female with diffusely dry skin and multiple hyperkeratotic, erythematous lesions on the face. Fasting blood glucose was 89 mgldl, plasma zinc was decreased, serum iron was low, and plasma glucagon was significantly increased at 47 1 pg/ml (normal range is 20 to 100 pg/ml) (Table 1). Premeditation of IV midazolam 2 mg and morphine IO mg was given. Anesthesia was induced with thiopental sodium 250 mg, and vecuronium was given to facilitate endotracheal intubation and intraoperative muscle relaxation. Anesthesia was maintained with nitrous oxide (N,O) and oxygen (0,) 1: 1 and isoflurane 0.5% to 1.5%, supplemented with a total of 250 kg fentanyl. The plasma glucagon levels were 293 and 254 pg/ml at 30 and 60 minutes, respectively, after tumor removal; they were 24 and 20 pg/ml in the recovery room and on postoperative day 4 (Table 1). The tumor was located in the tail of the pancreas; no metastases or adenopathy were noted. Distal pancreatectomy, splenectomy, and liver biopsy were performed. Neuromuscular blockade was reversed with neostigmine and atropine. The entire postoperative course was uneventful, and the patient was discharged on the seventh postoperative day. Pathologic examination of the pancreas demonstrated glucagonoma.
Case Report 3 A 5l-year-old male was scheduled to undergo an exploratory laparotomy and debulking of a gluca50
J. Clin. Anesth.,
vol. 3, January/February
1991
Anesthesia /or glucugonoma
keep the serum ionized calcium levels in the normal range. A left adrenalectomy and a right hepatic lobectomy were performed. Pathologic examination demonstrated metastatic glucagonoma. Mechanical ventilation was required for 4 days postoperatively. The remainder of the postoperative course was uneventful except for a low-grade fever for which no cause was found. Discharged on the twenty-third postoperative day, the patient was readmitted with a recurrent and intensified fever 2 weeks later. A subhepatic abscess was diagnosed and drained. A drainage tube was placed, and the patient was discharged 1 week later.
Discussion Under basal conditions, metabolic regulation in most cases of glucagonoma is minimally disturbed. Fasting blood sugars are usually normal, and an overtly diabetic state with the potential for ketoacidosis is rare.3 However, appropriate anesthetic management of glucagonoma must anticipate how such patients will respond during anesthesia and surgery, which in and of themselves can produce alterations in metabolic and cardiovascular function that may interact with those attributable to the underlying endocrine disorder. Blood glucose levels normally tend to increase during anesthesia and surgery, especially with intra-abdominal procedures. 7 Afferent neurogenic stimuli increase sympathetic outflow and release catecholamines. Kossman et aLa reported that an increase in blood glucose seen during abdominal aortic surgery under neuroleptic anesthesia could be blocked by high The catecholamines, by mechaepidural anesthesia. nisms distinct from those of glucagon, also stimulate hepatic glycogenolysis and gluconeogenesis.Y Catecholamines also may increase blood glucose through decreases in peripheral glucose use, either directly or indirectly, by inhibiting insulin release from the pancreas.“’ Halogenated volatile anesthetics also may affect the same variables. Although halothane suppresses catecholamine release, it nonetheless is associated with insulin resistance, glucose intolerance, and increased hepatic glycogenolysis.“,12 Kossman et al8 determined that blood levels of cortisol, glucagon, and insulin remained constant under general or regional anesthesia. However, most studies have reported increases in circulating concentrations of catabolic hormones in response to surgical trauma. Okubo13 reported that plasma glucagon increased to 1.3 to 1.5 times normal during N,O/halothane anes-
rrrrcfion:
Boskovski rt al.
thesia and remained increased during recovery. In addition, blood glucose increased to 1.6 to 1.7 times normal during anesthesia and remained increased through the first postoperative day. Russell et a1.l4 reported increased levels of plasma glucagon in a wide variety of surgical procedures. The specific factors responsible for the typical amount of glucagon released during surgery (twofold to threefold increases) are not known.15 Despite the combined potential for intraoperative stress and increased glucagon availability to increase blood glucose, that situation did not develop in any of the three cases of glucagonoma presented in this paper or in the one case previously described.6 In case 1 of this report, glucose increased to 500 mg/dl immediately following “routine” preoperative infusion of 1 liter of D5LR. Clearly, administration of glucose in any form to a patient with glucagonoma should not be performed as a routine procedure and should be guided by monitoring of blood glucose levels. Intraoperative increases of glucose levels in the present patients were modest and clinically inconsequential; no insulin was administered. In addition, there was no abnormality of myocardial function or cardiovascular regulation attributable to the coexistence of stress and endocrine disorder. A rigid formula for anesthetic management during glucagonoma resection is clearly not appropriate. In the four cases referred to above, perioperative glucagon levels were only moderately increased (~2,000 pg/ml; normal range is 20 to 100 pg/ml), whereas in other reported cases, glucagon levels have exceeded 10,000 pg/m1.16 In the latter instances, a frankly diabetic state with or without ketoacidosis may have already existed or may have developed intraoperatively. Also, myocardial hypertrophy has been reported with chronically increased glucagon levels.‘” Other potential problems may arise as a result of the fact that a sizable fraction of glucagonomas occur in association with other endocrinopathies, including Zollinger-Ellison syndrome, insulinoma, and multiple endocrine adenomatosis (Types I and II). Pheochromocytoma is an MEA-II tumor reportedly associated with glucagonoma.17 Yano et aLIs reported a case of glucagon-secreting islet cell carcinoma that also produced insulin and somatostatin and decreased blood glucose to 40 mg/dl during fasting. A diagnostic workup of glucagonoma must ascertain the coexistence of other such endocrine disorders so that appropriate anesthetic management can be devised. Periodic intraoperative blood glucose monitoring is a cornerstone of any such plan, along with careful attention to cardiovascular function, especially if glucagonoma is associated with an insulin- or cateJ. Clin. Anesth.,
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cholamine-secreting tumor. Concomitants of glucagonoma per se, such as thromboembolic disorders or tluid/electrolyte imbalances resulting from weight loss and/or diarrhea, also may complicate intraoperative management and should be managed by standard therapy. In summary, the authors have added three cases to the one previously reported on the anesthetic experience with resection of glucagonoma. No anesthetic difficulties resulted from the increased glucagon levels, the glucose levels were easily managed, and no cardiac problems were related to glucagon. None of the three study patients had the extremely high glucagon levels that are occasionally seen with this tumor and have the potential to create problems. Associated endocrine tumors, such as pheochromocytoma, that have anesthetic implications also did not occur in these three patients.
References 1. McCavran MH, Unger RH, Recant L, et al: A glucagonsecreting alpha-cell carcinoma of‘the pancreas. N Engl J Med 1966;274:1408-12. 2. Friesen SK: Tumors of the endocrine pancreas. N Engl J Med 1982;306:580-90. 3. Montenegro-Roads F, Samann S: Clucagonoma tumors and syndrome. Curr Probl Cancer 198 1;6: l-54.
4. Prinz RA, Badrinath K, Banerji M, et al: Operative and chemotherapeutic management of‘ malignant glucagon-producing tumors. Surge? 1981;90:713-9. 5. Shafrir E, Bergman M, Felig P: The endocrine pancreas: diabetes mellitus. In Felig P, Baxter JD, Broadus AE, Frohman LA, eds. Endocrinology and Metabolism. 2d ed. New York: McGraw-Hill, 1987; 1083-5. 6. Nicoll VMS, Catling JS: Anesthetic management of glucagonoma. Anaesthesia 1985;40: 152-7.
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7. Clarke RSJ: ‘l‘he hyperglycemic
response to different types of surgery and anesthesia. Br J Anuesth 1970;42:45-
52. 8. Kossman B, Volk E, Spilker ED, et al: Influence of thoracic epidural analgesic on glucose, cortisol, insulin, and glucagon responses to surgery. Reg Anaesth 1982;7:107-9. 9. Biebuyck JF: Anesthesia and hepatic metabolism. Anethesiology 1973;39: 188-98. 10. Cooper CM, Paterson JL, Mashiter K, Hall GM: Betaadrenergic blockade and the metabolic response to surgery. BrJ Anaesth 1980;52:1231-7. 11. Merin KG, Samuelson PN, Schalch DS: Major inhalation anesthetics and carbohydrate metabolism. ,4nrslh Analg 1971;50:625-32. 12. Biebuyck JF, Lund 1’: Effects of halothane and other anaesthetic agents on the concentrarions of rat liver metabolites in viva. &fol Phal-macol 1974; 103474-83. 13. Okubo I‘: Effect of anesthesia and surgery on carbohydrate metabolism and endocrine function including glucagon in man. Masui 1979;28: 1062-Y. 14. Russell RCG, Walker CJ, Bloom SK: Hyperglucagonemia in the surgical patient. Br Mrd J 1975; 1: 10-3. 15. ‘I‘rayner (1, Hall GM: Endocrine and metabolic changes during surgery: anaesthetic implications. H1-./ Ann&h 1981;53:153-60. 16. Takemiya M, Miyayama H, Takeya M: A postmortem study of malignant glucagonoma with heart muscle hypertiophy, including chemical, histochemical, immunohistological and ultrastructural observations. Hum Pathol 1981:12:988-99. 17. Yao H, Fukiyama K, Kawano Y, et al: Recurrent pheochromocytoma associated with glucagonoma. A case report. Endocrine/ Jpn 1983;30: 163-6. 18. Yano ‘I‘. Yamamoto N, Kuimori K, et al: Glucagonsecreting pancreatic islet cell carcinoma, containing insulin and somatostatin, with hypoglycemic attack. Am,] Cast~oenterol 1982;77:387-91.