Sultan Qaboos University Med J, May 2014, Vol. 14, Iss. 2, pp. e236-240, Epub. 7TH Apr 14 Submitted 26TH Jul 13 Revisions Req. 24TH Sep, 21ST Nov & 31ST Dec 13; Revisions Recd. 22ND Oct & 3RD Dec 13 & 9TH Jan 14 Accepted 16TH Jan 14 Phaeochromocytoma is a neuro-endrocrine tumour (NET) which presents multidimensional challenges during surgical resection in spite of our improved understanding of its physiological and clinical behaviour. The most common manifestations of this clinical condition include hypertension, headaches, palpitations, diaphoresis (episodic sweating) and feelings of doom. The incidence of phaeochromocytoma in the general population is 1–8/1,000,000.1 The triad of headaches, diaphoresis and palpitations is found in 20–40% of patients while 13% remain asymptomatic with high levels of catecholamines due to the downregulation of receptors.1 Five types of genes are known to be important in hereditary phaeochromocytomas and paragangliomas; these are found in 25% of patients with phaeochromocytoma [Table 1]. Genes encoding succinate dehydrogenase subunits D (SDHD) and B (SDHB) are found to be implicated in familial non- syndromic phaeochromocytomas.1,2 Departments of 1Anaesthesia & Intensive Care and 3Medicine, Sultan Qaboos University Hospital; 2Department of Medicine, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman *Corresponding Author e-mail: sanathkumarbs@yahoo.com معاجلة ناجحة لورم القوامت باستخدام دواء البيتالول عن طريق الفم قبل العملية واستخدام كربيتات املغنيسيوم بالتسريب أثناء العملية اجلراحية تقرير أربعة حاالت �صاناث كومار٬ روهيت ديت٬ نيكول�س ودهاو�س٬ اأميمه ال�صافعي٬ كارن نولني abstract: Phaeochromocytoma is a rare neuroendocrine catecholamine-secreting tumour. This type of tumour poses multidimensional anaesthetic challenges as it has an unpredictable clinical course during surgical resection. The alpha-blocking agent phenoxybenzamine remained the mainstay in preoperative preparation before the introduction of beta-blocking agents. We report four cases operated between 2009–2012 at Sultan Qaboos University Hospital, Muscat, Oman. The cases were prepared with oral labetalol, as the alpha-blocking drug phenoxybenzamine was not immediately available. Responses to simulated stress were tested in the theatre before surgery. Anaesthesia was induced under invasive arterial pressure monitoring and magnesium sulphate infusion. Rare intraoperative surges in blood pressure during tumour manipulation were treated with sodium nitroprusside infusions and phentolamine boluses. All of the patients had an uneventful postoperative recovery. Preoperative treatment with labetalol has rarely been reported and can be considered as a potential therapeutic option with optimal patient monitoring if phenoxybenzamine is unavailable. Keywords: Pheochromocytoma; Labetalol; Phenoxybenzamine; Phentolamine; Magnesium Sulfate; Intraoperative Care; Case Report; Oman. امللخ�ص: ورم القوامت يف الغدة الكظرية حالة نادرة ت�صبب ارتفاع هرمون الأدرنالني. هذا النوع من الورم يفر�س حتديات متعددةعند عملية التخدير لأنه يوؤدي اإىل ارتفاع حاد يف �صغط الدم و م�صاعفات �رشيرية ل ميكن التنبوؤ بها اأثناءال�صتئ�صال اجلراحي. تبقى عقارات حا�رشات الألفا: فينوك�صي بنزامني العماد الول يف ال�صيطرة على ارتفاع �صغط الدم و التح�صري ملا قبل اجلراحة قبل ظهور عقارات حا�رشات البيتا. يف هذا التقرير ن�صتعر�س اأربع حالت اأجريت لهم عمليات جراحية بني 2012-2009 يف م�صت�صفى جامعة ال�صلطان قابو�س ، م�صقط، �صلطنة عمان. مت التح�صري لهذه احلالت باإعطاء لبيتالول عن طريق الفم لأن عقار فينوك�صي بنزامني مل يكن متوفرا يف الوقت املنا�صب. مت اختبار ال�صتجابه للإجهاد امل�صتحث يف غرفة العمليات قبل اجلراحة. مت التخدير حتت مراقبة ال�صغط ال�رشياين داخل ال�رشايني مع ت�رشيب كربيتات املغني�صيوم. ارتفاعات �صغط الدم نادرة اأثناء عمليه ا�صتئ�صال الورم وقد مت علجها بت�رشيب مادة �صوديوم نيرتوبرو�صيد وعقار فنتول امني. وقد تعافى جميع املر�صى املذكورين بدون م�صاعفات بعد العمليات التي اأجريت لهم. نادرا مامت الإبلغ عن ا�صتخدام علج لبيتالول قبل اجلراحة وميكن اعتباره خيارا علجيا حمتمل يف ظل عدم توافر عقار فينوك�صي بنزامني حتت املراقبة الطبية الأمثل للمري�س. مفتاح الكلمات: ورم القوامت؛ لبيتالول؛ فينوك�صي بنزامني؛ فينتولمني؛ كربيتات املغني�صيوم؛ رعاية جراحة داخلية؛ تقارير حالت؛ عمان. Successful Management of Phaeochromocytoma using Preoperative Oral Labetalol and Intraoperative Magnesium Sulphate Report of four cases *Sanath Kumar B. S.,1 Rohit Date,1 Nicholas Woodhouse,2 Omayma El-Shafie,3 Karin Nollain1 CASE REPORT Sanath Kumar B. S., Rohit Date, Nicholas Woodhouse, Omayma El-Shafie and Karin Nollain Case Report | e237 Different drugs and anaesthetic techniques are used for the perioperative management of patients with phaeochromocytoma.3–5 Although α-adrenoceptor antagonists are the mainstay of perioperative blood pressure control, the use of various combinations of α- and β-adrenoceptor antagonists has been reported.3–5 Pretreatment with oral labetalol, as used in these cases, has rarely been reported, whereas intravenous labetalol and magnesium sulphate have been used for the rapid preparation of a patient with a phaeochromocytoma.6 The following four cases highlight the possibility of using oral labetalol for preoperative management. The findings indicate that labetalol may be used in the preoperative management of phaeochromocytoma as a therapeutic option, especially if phenoxybenzamine is not available. Two of the four cases of phaeochromocytoma were siblings. One of the siblings presented with severe episodic hypertension (Case 1) and the other with postural hypotension after standing for 30 minutes (Case 2). However, when the latter was subjected to simulated stressful conditions in the anaesthesia induction room, he developed severe tachycardia and hypertension. The other two patients had long-established histories of serious classical phaeochromocytoma symptoms (Cases 3 and 4). None of the cases had comorbidities. All underwent open adrenalectomies and were operated on between 2009–2012 at Sultan Qaboos University Hospital, Muscat, Oman. Case 1 A 13-year-old girl presented with a three-year history of headaches, sweating, palpitations and severe hypertension. On initial admission to a peripheral hospital, her blood pressure was 180/120 mmHg. The diagnosis of phaeochromocytoma was made based on a computed tomography (CT) scan of the abdomen, which showed bilateral adrenal masses. Her plasma catecholamine and chromogranin A (CGA) levels were high [Table 2]. The initial echocardiogram (ECHO) showed a systolic dysfunction with global hypokinaesia and an ejection fraction (EF) of 46%. Since phenoxybenzamine is not available in Oman, she was treated with oral labetalol up to 400 mg twice a day (BD). After six weeks, the blood pressure was under control, the ECHO was normal and the EF was 64%. The haematocrit was 31 g/dL, indicating an expansion of the extracellular volume. Before being scheduled for a bilateral adrenalectomy, she was taken to the induction room to undergo a simulated stress test while her blood pressure and heart rate were monitored. Her haemodynamics remained within normal limits at this time as well as during subsequent postural changes. The night before the surgery, the patient received lorazepam, a fluid preloaded with Ringer’s lactate solution, and midazolam as premedication. Before inducing anaesthesia, a bolus of magnesium sulphate (50 mg/Kg) was given followed by a maintenance dose of 15 mg/Kg/hour. Under invasive arterial pressure monitoring, the induction was done with fentanyl, propofol, cisatracurium and lidocaine (1.5 mg/Kg) prior to intubation. During the manipulation of the tumour, hypertensive derangements with short spikes up to 200 mmHg systolic were controlled with an infusion of sodium nitroprusside (SNP) and boluses of phentolamine, a potent α-adrenoceptor antagonist. Under an adequate volume replacement and hydrocortisone supplementation, the patient remained haemodynamically stable after tumour Table 1: Genetic correlations in phaeochromocytomas Genetic basis of phaeochromocytomas Familial Bilateral Malignant Multiple SDHD RET SDHB SDHD SDHB VHL VHL SDHB VHL SDHD VHL RET Frequency of susceptibility genes in patients with phaeochromocytoma or paraganglioma in percent RET VHL NF1 SDH Others 5 9 2 SDHD: 5 SDHC: 1 SDHB: 5 SDHAF2: <1 SDHA: <1 TMEM127: 2 MAX: <1 RET = roto-oncogene; VHL = von Hippel-Lindau disease tumour suppressor gene; NF1 = neurofibromatosistype 1 tumour suppressor gene; SDH = succinate dehydrogenase complex with subunit genes SDHB, SDHC and SDHD; MAX = MYC-associated factor X gene. Table 2: Plasma levels of circulating catecholamine and chromogranin in the four patients Case NADR in pmol/L Adrenaline in pmol/L Dopamine in pmol/L CGA in µg/L 1 23,670 140 266 700 2 32,048 <54 3,012 300 3 38,400 1,104 - - 4 3,294 240 64 1,233 Normal ranges 650–2,433 <273 <475 27–94 NADR = noradrenaline; CGA = plasma catecholamine and chromogranin A. Successful Management of Phaeochromocytoma using Preoperative Oral Labetalol and Intraoperative Magnesium Sulphate Report of four cases e238 | SQU Medical Journal, May 2014, Volume 14, Issue 2 removal without any vasoactive drugs. Case 2 A 16-year-old boy, the brother of the first case, was diagnosed with phaeochromocytoma by CT scan after elevated CGA levels were found during family screening. He had a single right adrenal tumour but was asymptomatic apart from attacks of fainting during long periods of standing. His blood pressure and heart rate were normal despite high plasma noradrenaline levels [Table 1]. The routine investigations, including electrocardiography (ECG) and ECHO, were normal. The patient’s response to simulated stressful conditions was cross-checked in the anaesthesia induction room; he developed severe tachycardia with 170 beats per minute and his blood pressure rose to 190/130 mmHg; this was associated with dizziness when in an upright position [Figure 1]. As a result, the patient was treated preoperatively with labetalol (100 mg BD) for two weeks. After that time, he was exposed to simulated stress again without developing tachycardia or hypertension [Figure 2]. The preoperative preparations and induction of anaesthesia were performed similarly to the first case. During the manipulation of the tumour, the blood pressure spikes were controlled with infusions of SNP and boluses of phentolamine. After the removal of the tumour, the patient required a low dose of phenylephrine infusion for a short period. Case 3 A 37-year-old woman presented with a three-year history of severe paroxysmal headaches, palpitations and hypertension. A CT scan of the abdomen showed a right adrenal tumour with elevated plasma catecholamine and CGA levels [Table 2]. The patient had been on labetalol (400 mg BD) during the previous month and her symptoms had mostly subsided with only short episodes of palpitations. The ECG and ECHO were normal. During the stress simulation, the haemodynamics parameters remained within normal limits with minimal postural changes and so the patient was admitted for an open right adrenalectomy. The preoperative preparations of hydration, anaesthesia induction and intraoperative management were similar to those of the previous two cases. The patient had more frequent hypertensive derangements during the tumour dissection, which were controlled by phentolamine boluses. She did not require any vasopressor support after the removal of the tumour. Case 4 A 50-year-old woman presented with a more than three-year history of headaches, palpitations and sweating, and had a palpable painful mass in her upper left abdomen. The CT scan revealed an extensive infarction of a huge left adrenal tumour and only slightly increased plasma levels of noradrenaline [Table 2]. Although she was normotensive, a small dose of labetalol (25 mg BD) was given for 15 days prior to surgery and her symptoms subsided to only short episodes of palpitations. The ECG and ECHO were normal. During the stress simulation, her haemodynamics remained within normal limits with no postural changes. The patient was admitted for an open left adrenalectomy. The preoperative preparations and anaesthetic management were similar to those of the previous three cases. However, her blood pressure did not fluctuate much during the tumour dissection except for a mild hypertensive episode (170/90 mmHg) which was managed with a Figure 1: Marked postural fluctuations in heart rate, systolic blood pressure and diastolic blood pressure in Case 2 before starting treatment with labetalol. SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate. Figure 2: After two weeks on labetalol, the haemodynamic variables of Case 2 showed minimal postural fluctuations. SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate. Sanath Kumar B. S., Rohit Date, Nicholas Woodhouse, Omayma El-Shafie and Karin Nollain Case Report | e239 phentolamine bolus. She did not require vasopressor support after the removal of the tumour. All four cases had uneventful postoperative periods and were extubated in the Intensive Care Unit after a few hours of observation. Discussion The problems surrounding the pre- and perioperative management of phaeochromocytoma have been well described in the literature.3,4 The main objective in the preoperative management of these patients is to control the blood pressure, heart rate and arrhythmias, and to allow restoration of blood volume.3,5 There is no consensus on the best pharmacological agent or optimal duration of therapy for the preparation of these patients for surgery. Traditionally, phenoxybenzamine, a non-selective α-adrenergic antagonist, has been the mainstay of perioperative treatment.4,6–9 The greatest advantage of using phenoxybenzamine is its long duration of action. This is due to its non-competitive irreversible blockade which helps to avert the effects of surges of catecholamine release, particularly during the surgical manipulation of the tumour.4,10,11 After the removal of the tumour, the side-effects, such as postural hypotension and somnolence, may continue into the postoperative period; additionally, patients may require vasopressor support.4,12 However, phenoxybenzamine blocks α-2-adrenoreceptors, which may facilitate the noradrenaline release, resulting in undesirable chronotropic and inotropic effects.12 In some cases, these have been controlled with adjuvant β-adrenoreceptor antagonists.4,13 The other disadvantages of using phenoxybenzamine are its other side-effects—headaches and stuffy nose—which have been reported to reduce patient compliance with the medication regime.3,4 A variety of pharmacological agents, like prazocin, doxazocin and calcium channel blockers, have also been used in the preparation of patients with phaeochromocytoma.3,4,6 In the current case series, since phenoxybenzamine was not available, labetalol was used which is known to combine a selective competitive α-1- and non-selective competitive β-adrenoreceptor antagonist with the ratio of α:β antagonism being 1:3 after oral and 1:7 after intravenous administration.14 Cases have been reported where intravenous labetalol along with magnesium sulphate was used for the rapid preparation of patients with phaeochromocytoma without untoward effects.7 However, there is also a report in the literature of one incident of cardiovascular collapse where intravenous labetalol was used in an emergency to control blood pressure in a patient with an undiagnosed phaeochromocytoma.15 Two additional reports of oral labetalol used for preoperative preparation have been recorded. One case displayed a hypertensive response while in the other report three patients were successfully prepared without untoward incidents.16–18 The administration of labetalol lowers systemic blood pressure by decreasing systemic vascular resistance due to the α-1-blockade where reflex tachycardia is attenuated by a simultaneous β-blockade.7 Continued oral labetalol medication on the day of surgery has one advantage—the peak action of the drug occurs four hours after administration, acts during the operation on the active site and then wears off at the right time. This contributes to the patient’s circulatory stability after the removal of the tumour. Two of the four patients in the current series, who responded normally to the simulated stress and were classically hypertensive, responded well to 100–400 mg of labetalol BD. One of the normotensive patients, Case 2, had high noradrenaline levels. When exposed to simulated stress, he responded adversely with marked tachycardia and hypertension. However, two weeks after starting labetalol, a repeated stress test showed great improvement in the patient. Given the history of this case, the authors support the recommendation to prepare normotensive phaeochromocytomas with an α-adrenergic blockade.3,19,20 Case 4, who had an enormous infarcted adrenal mass with only slightly elevated noradrenaline levels, responded normally to a stress test after a small dose (25 mg) of labetalol BD. Pacak explains the wide range of clinical presen- tations among patients with phaeochromocytoma as a “desensitisation” of the receptors. Therefore, some patients will need significant amounts of adrenoreceptor blockers while others may not—despite high-circulating catecholamine concentrations.16 From the first use of magnesium sulphate in the anaesthetic management of phaeochromocytoma, there have been multiple case series which have confirmed its use during surgery. It has also been used in three patients with phaeochromocytoma, all of whom presented with severe cardiovascular instability.21–23 In the current cases series, magnesium sulphate was used in all cases as it inhibits the release of catecholamine from the adrenal medulla and adrenergic nerve endings; it has direct vasodilatory effects and anti-arrhythmic properties.21 Since the patients in this series were on oral labetalol and the Successful Management of Phaeochromocytoma using Preoperative Oral Labetalol and Intraoperative Magnesium Sulphate Report of four cases e240 | SQU Medical Journal, May 2014, Volume 14, Issue 2 severity of blood pressure derangements during surgery could not be anticipated, the potent alpha- blocker, phentolamine, was kept available and used during the tumour dissection. In addition, magnesium sulphate infusions were used in all of the patients— from the induction of anaesthesia until the final removal of the tumour. This may have contributed to the patients’ successful outcomes. In the postoperative period, especially after the removal of the tumour, there were no significant hypotensive episodes which required inotropic support. All patients were haemodynamically stable and extubated after a few hours of observation. Conclusion The traditional view of a preoperative stabilisation phase with phenoxybenzamine has stood the test of time. Although the use of labetalol is controversial as the first choice of treatment in the preparation of these types of patients, this pilot report of four cases has shown that oral labetalol, in combination with magnesium sulfate used intraoperatively, may be a potential therapeutic option in patients with phaeochromocytoma if phenoxybenzamine is not available. Despite the fact that these patients were exposed to simulated stress, the authors do not recommend this as a routine practice; the Roizen criteria should still be met if applicable. 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