Management of pheochromocytoma during pregnancy DAVID LEAK, MB, MRCP, FRCP[C], FRCP (EDIN), FACC; J.J. CARROLL, MD, FRCS[C]; D.C. ROBINSON, MD, FRCS[C]; E.J. ASHWORTH, MB, FRCP[C]
To reduce the high maternal and fetal mortality in pheochromocytoma of pregnancy, therapy is advocated with phenoxybenzamine and propranolol to obtain adequate a- and f1-adrenergic receptor blockade. In early pregnancy control of symptoms may be difficult, but the patient may be carried to term with such medical therapy. Delivery should be by cesarean section before the onset of labour, with, if possible, simultaneous removal of the tumour. Additional preoperative preparation with phenoxybenzamine and propranolol and careful intraoperative management are essential. During her third pregnancy a 29-year-old woman was found to have a pheochromocytoma of the left adrenal gland. After the medical therapy and preparation described, the infant was delivered by cesarean section and the mother's left adrenal gland excised. Eight-year follow-up, including during a fourth pregnancy, showed no recurrence of tumour in the mother and only mild hypertension. The infant developed normally. Dans le but de reduire le fort taux de mortalite maternelle et foetale relie au pheochromocytome durant Ia grossesse, on preconise un traitement associant phenoxybenzamine et propranolol afin dobtenir un bloquage ad6quat des r6cepteurs a- et 13-adr6nergiques. Au debut de Ia grossesse le contr6le des sympt6mes peut .tre difficile a realiser, mais Ia patlente peut 6tre menee a terme grAce a un tel traitement. L'accouchement par cesarienne devrait Atre pratique avant le debut du travail, avec, si possible, l'ablation simultanee de Ia tumeur. Une preparation preop6ratoire a Ia phenoxybenzamine et au propranolol et un traitement prudent durant l'operation sont essentiels. Durant sa troisieme grossesse on a decouvert chez une femme de 29 ans un pheochromocytome de Ia surrenale gauche. Apres le traitement et Ia pr6paration precites, le bebe a ete accouche par c6sarienne et on a proc.de chez Ia mere a l'excision de Ia surrenale gauche. Une periode de postobservation de 8 ans, comprenant From the departments of medicine, surgery, obstetrics and gynecology, and anesthesia, Henderson General Hospital and McMaster University, Hamilton Reprint requests to: Dr. D. Leak, Chariton Centre, 25 Charlton Ave. E, Ste. 701, Hamilton, Ont. L8N 1Y2
une quatrieme grossesse, n.a montr6 aucune recidive de Ia tumeur et n'a r6v6le qu'une legere hypertension. L.enfant s'est developpe normalement.
ing; the large decrease was thought to reflect a moderately increased value at the first office visit and the expected decrease during the 2nd trimester of pregnancy. During her first pregnancy, 5 years beAlthough pheochromocytoma is rela- fore referral, she had mild toxemia. The tively rare it has considerable notoriety 4145-g fetus died intrapartum after a probecause of its various modes of pre- tracted labour because of cephalopelvic disproportion in a breech presentation. sentation and high mortality if undiag- Autopsy of the fetus showed cerebral hemnosed. Surgical removal of pheochro- orrhage. mocytoma remains the ideal treatment, During the second pregnancy, a year but long-term medical control of symp- later, blood pressure readings were normal toms is now readily achieved by the (110 to 130/60 to 80 mm Hg) until a- and fi-adrenergic blocking drugs and the 38th week, when a pressure of 140/85 is often the treatment of choice in mm Hg was recorded. Urinalysis gave norcases of recurrent or malignant pheo- mal results. Possible early toxemia was chromocytoma. With adequate pre- diagnosed and treatment with chlorothiazide and reserpine was commenced. The operative control of the cardiovascular following week her pressure was 130/60 response to fluctuating concentrations mm Hg. Elective cesarean section was of circulating catecholamines and re- performed under general anesthesia, the expansion of the blood volume the drugs including cyclopropane. A 443 1-g surgical mortality has decreased from baby was delivered in good condition. about 25%' to a range of less than Towards the end of the procedure the mother's condition deteriorated rapidly; 5%2 to 15%.' Pheochromocytoma in pregnancy has she became hypotensive and cyanosed, and been associated with a maternal mor- signs of pulmonary edema developed. The pulse was regular at 150 beats/mm and tality of 48% and a fetal mortality of the blood pressure was 78/60 mm Hg. 47% .. Thus, it is important to know (a) This situation was controlled by intrawhether long-term medical manage- venous administration of digoxin, aminoment, throughout the pregnancy if nec- phylline ethylenediamine, and metaraminessary, is safe for both mother and ol. The patient's condition improved fetus and (b) how safe surgical re- rapidly over the next 4 hours and within moval of the tumour is, for both mother 14 days she was discharged. The only and fetus with proper preoperative objective abnormality detected after respreparation with a- and p-blocking olution of the pulmonary edema was minor flattening of the T waves in the drugs. In this paper we present an il- ECG slight cardiac enlargement. Her lustrative case and review these ques- blood and pressure was 130/90 mm Hg imtions. mediately after discharge and she was able to undertake the normal domestic chores Case report and care of a young baby without any problem. Clinical history and findings The patient's third pregnancy proceeded A 29-year-old woman was referred to normally until the 28th week, when her us at the 12th week of her third pregnancy blood pressure increased to 145/95 mm because of previous hypertension. A year Hg and treatment with hydrochlorothibefore, when her blood pressure had been azide was begun. The pressure decreased 185 to 190/105 to 110 mm Hg while she to 120 to 130/80 to 85 mm Hg until was taking reserpine, 0.25 mg bid, a diag- the 38th week, when she began to comnosis of essential hypertension had been plain of severe headaches and excessive made: the heart was not enlarged; the sweating for the first time. She had profundi, electrocardiogram (ECG), intra- nounced hypertension lying down and a venous pyelogram and urinalysis results striking decrease in pressure when she were normal; and the serum creatinine stood; values of 210/140 mm Hg lying and blood urea nitrogen (BUN) values and 140/90 mm Hg standing were rewere normal, at 0.8 and 17.4 mg/dl, re- corded. She was therefore admitted to spectively. hospital immediately with a diagnosis of Current treatment was guanethidine, 10 suspected pheochromocytoma. mg/d, and hydrochlorothiazide, 50 mg bid. At rest in hospital her pulse was regular She was obese (weight, 93.52 kg) and her at 110 beats/mm and the supine blood blood pressure was 180/110 mg Hg lying pressure was 160/110 mm Hg. The fetus and 140/80 mm Hg standing. The fundi showed a vertex presentation and was fully were normal. Effort tolerance was good developed. The following values were and she had no cardiac symptoms. Both noted: fasting blood glucose, 112 mg/dl; drugs were withdrawn and the blood pres- BUN, 10 mg/dl; serum creatinine, 0.7 sure settled to values of approximately mg/dl; and fasting serum triglycerides, 135/80 mm Hg sitting and 140/80 stand- 554 mg/dl. Serum electrolyte values were CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116 371
normal. Urinary vanillylmandelic acid (VMA) estimations were made immediately; values for the first two 24-hour urine samples were 14.5 and 20.8 mg/d, respectively (normal, 0.7 to 6.8 mg/d). The chest radiograph was normal. While these investigations were being done the patient was treated with hydrochiorothiazide, 50 mg/d. Her blood pressure averaged 150/90 mm Hg lying and 120/90 mm Hg standing during the 1st week in hospital. Management of delivery On the basis of the clinical picture and high urinary VMA excretion a diagnosis of pheochromocytoma was accepted. It was decided to do an elective cesarean section, after preparation of the patient for 3 days with phenoxybenzamine and propranolol therapy, with exploration and excision of the pheochromocytoma if this proved feasible. The protocol of Ross and associates5 called for phenoxybenzamine therapy, 1 mg/kg given intravenously in 250 ml of 5% dextrose in water over 1 hour. In view of the pregnancy and the then uncertain effects of this drug on the fetus the initial dose of phenoxybenzamine was 40 mg, which is less than half the recommended dose, given over 1 hour (patient's weight, 98.2 kg). In the first 15 minutes of the infusion her blood pressure decreased from 160/110 to 110/90 mm Hg (Fig. 1). The infusion was slowed so as to maintain the pressure at 110/70 mm Hg and it lasted 6½ hours. During the initial reduction in pressure the maternal heart rate increased from 100 to 130 beats/mm but settled to 100 to 110 beats/mm when the infusion was slowed. The fetal heart rate showed an episode of tachycardia, probably in response to maternal hypotension; later, during the slow infusion, it was stable and remained at 130 to 140 beats/mm during this part of the procedure. The following day a smaller dose of phenoxybenzamine (20 mg) was given intravenously over 2 hours. The resting blood pressure was 140/90 mm Hg and during treatment the pressure decreased to 110/80 mm Hg. Immediately after this infusion half the recommended dose of
z
propranolol (20 mg) by mouth slowed the thought to be free of tumour. No abnormaternal heart rate from 120 to approxi- mality was detected in the right adrenal mately 100 to 110 beats/mm. Two hours gland and there was no elevation of blood later a further 40 mg of propranolol pressure during palpation. With palpation slowed the maternal heart rate to between of the left adrenal gland the systolic pres95 and 100 beats/mm without affecting sure increased to 250 mm Hg but was rathe fetal heart rate, which averaged be- pidly controlled by intravenous administratween 136 and 140 beats/mm throughout. tion of phentolamine. The incision was The day before operation a further 40 then extended to the xyphoid process and mg of phenoxybenzamine was given in- left adrenalectomy was performed. During travenously over 6 hours. The blood pres- the whole procedure only six intermittent sure was controlled at about 120/80 mm doses of phentolamine were required. After Hg. After this infusion 40 mg of propran- removal of the tumour the decreasing olol was given; 2 hours later a second blood pressure was controlled by intradose was given. venous infusion of 1500 ml of blood (the The morning of the operation 10 mg estimated blood loss), followed by intraof propranolol was given because the venous saline and Ringer's lactate. mother's pulse rate was over 100 beats/ The patient left the operating room in mm (Fig. 2). When she went to the good condition but after she was moved to operating room her blood pressure was the intensive care unit, approximately 14 120/70 mm Hg. Her heart rate was 104 m away, her blood pressure decreased, and the fetal heart rate, 132 beats/mm. requiring a noradrenalin infusion for stab(All measurements were made with the ilization. Serial postoperative VMA remother supine.) Anesthesia was induced cordings showed a return to normal values with sodium thiopental and maintained (Table I). The patient recovered uneventwith nitrous oxide and oxygen; relaxation fully and was discharged 3 weeks after was obtained with succinylcholine and admission. At 4 months her blood pressure curare. The systolic blood pressure in- was 130/70 mm Hg lying and 120/85 mm creased during induction to 170 mm Hg Hg standing. The urinary excretion of but arrhythmia did not occur. During the VMA was 4 mg and 3.2 mg/d on 2 sucoperation continuous electrocardiographic, cessive days. The chest radiograph showed central venous pressure and arterial pres- normal heart size and the EGG was sure recordings were made. Elevations of normal. blood pressure were controlled by intermittent 5-mg doses of phentolamine given Pathologic findings intravenously. The left adrenal gland consisted of a A subumbilical midline incision was thin cortex stretched over a central tumour made. During manipulation of the uterus mass 5.0 cm in diameter. The tumour was the systolic blood pressure increased to 200 composed of sheets and cords of large mm Hg but was easily controlled with cells with pale-staining cytoplasm and subphentolamine. A 5400-g girl with an stantial variation in both size and shape Apgar score of 9 was delivered in good of the nuclei. Sections stained with potascondition and the uterus was resutured. sium dichromate showed many cells with The abdomen was then carefully and sys- dark yellow-brown pigment, suggesting a tematically explored for tumour. The tumour of chromaffin tissue (pheochromobladder, ovaries, cul-de-sac, iliac and ob- cytoma). turator nodes, organs of Zuckerkandl (para-aortic bodies), para-aortic nodes, pan- Follow-up creas, kidneys, spleen and liver were The patient's fourth pregnancy was un0 -I
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To reduce the high maternal and fetal mortality in pheochromocytoma of pregnancy, therapy is advocated with phenoxybenzamine and propranolol to obtain adequate a- and f1-adrenergic receptor blockade. In early pregnancy control of symptoms may be difficult, but the patient may be carried to term with such medical therapy. Delivery should be by cesarean section before the onset of labour, with, if possible, simultaneous removal of the tumour. Additional preoperative preparation with phenoxybenzamine and propranolol and careful intraoperative management are essential. During her third pregnancy a 29-year-old woman was found to have a pheochromocytoma of the left adrenal gland. After the medical therapy and preparation described, the infant was delivered by cesarean section and the mother's left adrenal gland excised. Eight-year follow-up, including during a fourth pregnancy, showed no recurrence of tumour in the mother and only mild hypertension. The infant developed normally. Dans le but de reduire le fort taux de mortalite maternelle et foetale relie au pheochromocytome durant Ia grossesse, on preconise un traitement associant phenoxybenzamine et propranolol afin dobtenir un bloquage ad6quat des r6cepteurs a- et 13-adr6nergiques. Au debut de Ia grossesse le contr6le des sympt6mes peut .tre difficile a realiser, mais Ia patlente peut 6tre menee a terme grAce a un tel traitement. L'accouchement par cesarienne devrait Atre pratique avant le debut du travail, avec, si possible, l'ablation simultanee de Ia tumeur. Une preparation preop6ratoire a Ia phenoxybenzamine et au propranolol et un traitement prudent durant l'operation sont essentiels. Durant sa troisieme grossesse on a decouvert chez une femme de 29 ans un pheochromocytome de Ia surrenale gauche. Apres le traitement et Ia pr6paration precites, le bebe a ete accouche par c6sarienne et on a proc.de chez Ia mere a l'excision de Ia surrenale gauche. Une periode de postobservation de 8 ans, comprenant From the departments of medicine, surgery, obstetrics and gynecology, and anesthesia, Henderson General Hospital and McMaster University, Hamilton Reprint requests to: Dr. D. Leak, Chariton Centre, 25 Charlton Ave. E, Ste. 701, Hamilton, Ont. L8N 1Y2
une quatrieme grossesse, n.a montr6 aucune recidive de Ia tumeur et n'a r6v6le qu'une legere hypertension. L.enfant s'est developpe normalement.
ing; the large decrease was thought to reflect a moderately increased value at the first office visit and the expected decrease during the 2nd trimester of pregnancy. During her first pregnancy, 5 years beAlthough pheochromocytoma is rela- fore referral, she had mild toxemia. The tively rare it has considerable notoriety 4145-g fetus died intrapartum after a probecause of its various modes of pre- tracted labour because of cephalopelvic disproportion in a breech presentation. sentation and high mortality if undiag- Autopsy of the fetus showed cerebral hemnosed. Surgical removal of pheochro- orrhage. mocytoma remains the ideal treatment, During the second pregnancy, a year but long-term medical control of symp- later, blood pressure readings were normal toms is now readily achieved by the (110 to 130/60 to 80 mm Hg) until a- and fi-adrenergic blocking drugs and the 38th week, when a pressure of 140/85 is often the treatment of choice in mm Hg was recorded. Urinalysis gave norcases of recurrent or malignant pheo- mal results. Possible early toxemia was chromocytoma. With adequate pre- diagnosed and treatment with chlorothiazide and reserpine was commenced. The operative control of the cardiovascular following week her pressure was 130/60 response to fluctuating concentrations mm Hg. Elective cesarean section was of circulating catecholamines and re- performed under general anesthesia, the expansion of the blood volume the drugs including cyclopropane. A 443 1-g surgical mortality has decreased from baby was delivered in good condition. about 25%' to a range of less than Towards the end of the procedure the mother's condition deteriorated rapidly; 5%2 to 15%.' Pheochromocytoma in pregnancy has she became hypotensive and cyanosed, and been associated with a maternal mor- signs of pulmonary edema developed. The pulse was regular at 150 beats/mm and tality of 48% and a fetal mortality of the blood pressure was 78/60 mm Hg. 47% .. Thus, it is important to know (a) This situation was controlled by intrawhether long-term medical manage- venous administration of digoxin, aminoment, throughout the pregnancy if nec- phylline ethylenediamine, and metaraminessary, is safe for both mother and ol. The patient's condition improved fetus and (b) how safe surgical re- rapidly over the next 4 hours and within moval of the tumour is, for both mother 14 days she was discharged. The only and fetus with proper preoperative objective abnormality detected after respreparation with a- and p-blocking olution of the pulmonary edema was minor flattening of the T waves in the drugs. In this paper we present an il- ECG slight cardiac enlargement. Her lustrative case and review these ques- blood and pressure was 130/90 mm Hg imtions. mediately after discharge and she was able to undertake the normal domestic chores Case report and care of a young baby without any problem. Clinical history and findings The patient's third pregnancy proceeded A 29-year-old woman was referred to normally until the 28th week, when her us at the 12th week of her third pregnancy blood pressure increased to 145/95 mm because of previous hypertension. A year Hg and treatment with hydrochlorothibefore, when her blood pressure had been azide was begun. The pressure decreased 185 to 190/105 to 110 mm Hg while she to 120 to 130/80 to 85 mm Hg until was taking reserpine, 0.25 mg bid, a diag- the 38th week, when she began to comnosis of essential hypertension had been plain of severe headaches and excessive made: the heart was not enlarged; the sweating for the first time. She had profundi, electrocardiogram (ECG), intra- nounced hypertension lying down and a venous pyelogram and urinalysis results striking decrease in pressure when she were normal; and the serum creatinine stood; values of 210/140 mm Hg lying and blood urea nitrogen (BUN) values and 140/90 mm Hg standing were rewere normal, at 0.8 and 17.4 mg/dl, re- corded. She was therefore admitted to spectively. hospital immediately with a diagnosis of Current treatment was guanethidine, 10 suspected pheochromocytoma. mg/d, and hydrochlorothiazide, 50 mg bid. At rest in hospital her pulse was regular She was obese (weight, 93.52 kg) and her at 110 beats/mm and the supine blood blood pressure was 180/110 mg Hg lying pressure was 160/110 mm Hg. The fetus and 140/80 mm Hg standing. The fundi showed a vertex presentation and was fully were normal. Effort tolerance was good developed. The following values were and she had no cardiac symptoms. Both noted: fasting blood glucose, 112 mg/dl; drugs were withdrawn and the blood pres- BUN, 10 mg/dl; serum creatinine, 0.7 sure settled to values of approximately mg/dl; and fasting serum triglycerides, 135/80 mm Hg sitting and 140/80 stand- 554 mg/dl. Serum electrolyte values were CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116 371
normal. Urinary vanillylmandelic acid (VMA) estimations were made immediately; values for the first two 24-hour urine samples were 14.5 and 20.8 mg/d, respectively (normal, 0.7 to 6.8 mg/d). The chest radiograph was normal. While these investigations were being done the patient was treated with hydrochiorothiazide, 50 mg/d. Her blood pressure averaged 150/90 mm Hg lying and 120/90 mm Hg standing during the 1st week in hospital. Management of delivery On the basis of the clinical picture and high urinary VMA excretion a diagnosis of pheochromocytoma was accepted. It was decided to do an elective cesarean section, after preparation of the patient for 3 days with phenoxybenzamine and propranolol therapy, with exploration and excision of the pheochromocytoma if this proved feasible. The protocol of Ross and associates5 called for phenoxybenzamine therapy, 1 mg/kg given intravenously in 250 ml of 5% dextrose in water over 1 hour. In view of the pregnancy and the then uncertain effects of this drug on the fetus the initial dose of phenoxybenzamine was 40 mg, which is less than half the recommended dose, given over 1 hour (patient's weight, 98.2 kg). In the first 15 minutes of the infusion her blood pressure decreased from 160/110 to 110/90 mm Hg (Fig. 1). The infusion was slowed so as to maintain the pressure at 110/70 mm Hg and it lasted 6½ hours. During the initial reduction in pressure the maternal heart rate increased from 100 to 130 beats/mm but settled to 100 to 110 beats/mm when the infusion was slowed. The fetal heart rate showed an episode of tachycardia, probably in response to maternal hypotension; later, during the slow infusion, it was stable and remained at 130 to 140 beats/mm during this part of the procedure. The following day a smaller dose of phenoxybenzamine (20 mg) was given intravenously over 2 hours. The resting blood pressure was 140/90 mm Hg and during treatment the pressure decreased to 110/80 mm Hg. Immediately after this infusion half the recommended dose of
z
propranolol (20 mg) by mouth slowed the thought to be free of tumour. No abnormaternal heart rate from 120 to approxi- mality was detected in the right adrenal mately 100 to 110 beats/mm. Two hours gland and there was no elevation of blood later a further 40 mg of propranolol pressure during palpation. With palpation slowed the maternal heart rate to between of the left adrenal gland the systolic pres95 and 100 beats/mm without affecting sure increased to 250 mm Hg but was rathe fetal heart rate, which averaged be- pidly controlled by intravenous administratween 136 and 140 beats/mm throughout. tion of phentolamine. The incision was The day before operation a further 40 then extended to the xyphoid process and mg of phenoxybenzamine was given in- left adrenalectomy was performed. During travenously over 6 hours. The blood pres- the whole procedure only six intermittent sure was controlled at about 120/80 mm doses of phentolamine were required. After Hg. After this infusion 40 mg of propran- removal of the tumour the decreasing olol was given; 2 hours later a second blood pressure was controlled by intradose was given. venous infusion of 1500 ml of blood (the The morning of the operation 10 mg estimated blood loss), followed by intraof propranolol was given because the venous saline and Ringer's lactate. mother's pulse rate was over 100 beats/ The patient left the operating room in mm (Fig. 2). When she went to the good condition but after she was moved to operating room her blood pressure was the intensive care unit, approximately 14 120/70 mm Hg. Her heart rate was 104 m away, her blood pressure decreased, and the fetal heart rate, 132 beats/mm. requiring a noradrenalin infusion for stab(All measurements were made with the ilization. Serial postoperative VMA remother supine.) Anesthesia was induced cordings showed a return to normal values with sodium thiopental and maintained (Table I). The patient recovered uneventwith nitrous oxide and oxygen; relaxation fully and was discharged 3 weeks after was obtained with succinylcholine and admission. At 4 months her blood pressure curare. The systolic blood pressure in- was 130/70 mm Hg lying and 120/85 mm creased during induction to 170 mm Hg Hg standing. The urinary excretion of but arrhythmia did not occur. During the VMA was 4 mg and 3.2 mg/d on 2 sucoperation continuous electrocardiographic, cessive days. The chest radiograph showed central venous pressure and arterial pres- normal heart size and the EGG was sure recordings were made. Elevations of normal. blood pressure were controlled by intermittent 5-mg doses of phentolamine given Pathologic findings intravenously. The left adrenal gland consisted of a A subumbilical midline incision was thin cortex stretched over a central tumour made. During manipulation of the uterus mass 5.0 cm in diameter. The tumour was the systolic blood pressure increased to 200 composed of sheets and cords of large mm Hg but was easily controlled with cells with pale-staining cytoplasm and subphentolamine. A 5400-g girl with an stantial variation in both size and shape Apgar score of 9 was delivered in good of the nuclei. Sections stained with potascondition and the uterus was resutured. sium dichromate showed many cells with The abdomen was then carefully and sys- dark yellow-brown pigment, suggesting a tematically explored for tumour. The tumour of chromaffin tissue (pheochromobladder, ovaries, cul-de-sac, iliac and ob- cytoma). turator nodes, organs of Zuckerkandl (para-aortic bodies), para-aortic nodes, pan- Follow-up creas, kidneys, spleen and liver were The patient's fourth pregnancy was un0 -I
o 00 z
00 Zo.
