Anaesthesia for resection of phaeochromocytoma in a patient with myasthenia gravis : A case report

Introduction Myasthenia gravis is a disease affecting the nicotinic acetylcholine receptor of the post-synaptic membrane of the neuromuscular junction, causing muscle fatigue and weakness. Phaeochromocytoma is a neuroendocrine tumour of the medulla of the adrenal glands or extra-adrenal chromaffin tissue that secretes excessive amounts of catecholamines. We report a rare case of myasthenia gravis and phaeochromocytoma, two anaesthetically challenging conditions co-existing in the same patient, and discuss the anaesthetic considerations and management during the surgical resection of phaeochromocytoma. Case report A 74-year-old lady with ocular myasthenia gravis and ventricular septal defect was diagnosed with phaeochromocytoma during a surveillance computed tomography scan postthymectomy and radiotherapy. She was optimised preoperatively by various multidisciplinary teams prior to the resection of phaeochromocytoma. Our anaesthetic technique included thoracic epidural analgesia, general anaesthesia with the use of Bonfils endoscope for intubation and total intravenous anaesthesia for maintenance, cautious dosing of muscle relaxants and the use of pharmacological agents during tumour manipulation. Conclusion Perioperative management of phaeochromocytoma remains an anaesthetic challenge. We have described a safe and effective strategy for anaesthesia in this unusual patient with concomitant myasthenia gravis. Introduction Myasthenia gravis (MG) is a neuromuscular disorder with antibodies against the post-synaptic nicotinic acetylcholine receptor at the neuromuscular junction, decreasing the ability of the neuromuscular endplate to transmit nerve signal, causing muscle weakness. The myasthenic patient poses several challenges to anaesthetists, including the development of myasthenic crisis caused by surgical stress and the postsurgical risk of respiratory failure. Phaeochromocytoma (PCC) is a rare tumour arising from chromaffin calls in the adrenal medulla or in other paraganglia of the sympathetic nervous system. Once the diagnosis has been confirmed by elevated urinary catecholamines, medical therapy is commenced to inhibit the end-organ actions of the catecholamines, pending surgical excision by endocrine surgeons as the curative procedure. Magnetic resonance imaging and computerised tomography (CT) both provide accurate localisation of the majority of PCCs. We report a case of MG and PCC, two anaesthetically challenging conditions co-existing in the same patient, and discuss the anaesthetic considerations and management during the surgical resection of PCC. Searching Medline data from 1966 to July 2012 revealed no previous case reports of anaesthetic management of these two diseases in the same patient. Case report A 74-year-old lady, 172 cm, 48 kg, presented with a background history of hypertension, diabetes mellitus, hyperlipidemia, small perimembranous ventricular septal defect and ocular MG. Her MG has been stable on pyridostigmine 120 mg tds. She underwent total thymectomy for stage II thymoma 2 years ago, followed by postoperative radiotherapy. Surveillance CT thorax done 6 months post-thymectomy showed an incidental finding of a soft tissue mass 2.8 × 2.4 cm in the gastrohepatic region, which was found to be enlarging in the repeat CT abdomen pelvis performed 3 months later. She was referred to surgery and endocrinology. Twenty-four-hour urine collection revealed elevated levels of epinephrine, metanephrine and normetanephrine, and the diagnosis of PCC was made. In preparation for open resection of PCC, she was started on alpha blockade with phenoxybenzamine 10 mg bd, and the dosage was increased progressively. Subsequently, beta blockade was added. Neurology review confirmed ocular MG with no generalised MG symptoms or signs. Cardiology review deemed the patient at low cardiac risk for operation. She was admitted to the ward 3 days before the operation for intravenous hydration. Preoperatively, she was on losartan 50 mg om, atenolol 50 mg bd, phenoxybenzamine 40 mg bd. BP at home trended below 140/60 mmHg. However, BP on admission was high at 180/70. Amlodipine 5mg om was added, although the hypertension was partly attributed to anxiety. Subsequently in the ward, there was a small postural drop of BP * Corresponding author Email: sam_kent_loh@hotmail.com Department of Anaesthesiology, Singapore General Hospital, Singapore


Introduction
Myasthenia gravis (MG) is a neuromuscular disorder with antibodies against the post-synaptic nicotinic acetylcholine receptor at the neuromuscular junction, decreasing the ability of the neuromuscular endplate to transmit nerve signal, causing muscle weakness.The myasthenic patient poses several challenges to anaesthetists, including the development of myasthenic crisis caused by surgical stress and the postsurgical risk of respiratory failure.
Phaeochromocytoma (PCC) is a rare tumour arising from chromaffin calls in the adrenal medulla or in other paraganglia of the sympathetic nervous system.Once the diagnosis has been confirmed by elevated urinary catecholamines, medical therapy is commenced to inhibit the end-organ actions of the catecholamines, pending surgical excision by endocrine surgeons as the curative procedure.Magnetic resonance imaging and computerised tomography (CT) both provide accurate localisation of the majority of PCCs.
We report a case of MG and PCC, two anaesthetically challenging conditions co-existing in the same patient, and discuss the anaesthetic considerations and management during the surgical resection of PCC.Searching Medline data from 1966 to July 2012 revealed no previous case reports of anaesthetic management of these two diseases in the same patient.

Case report
A 74-year-old lady, 172 cm, 48 kg, presented with a background history of hypertension, diabetes mellitus, hyperlipidemia, small perimembranous ventricular septal defect and ocular MG.Her MG has been stable on pyridostigmine 120 mg tds.She underwent total thymectomy for stage II thymoma 2 years ago, followed by postoperative radiotherapy.Surveillance CT thorax done 6 months post-thymectomy showed an incidental finding of a soft tissue mass 2.8 × 2.4 cm in the gastrohepatic region, which was found to be enlarging in the repeat CT abdomen pelvis performed 3 months later.She was referred to surgery and endocrinology.Twenty-four-hour urine collection revealed elevated levels of epinephrine, metanephrine and normetanephrine, and the diagnosis of PCC was made.In preparation for open resection of PCC, she was started on alpha blockade with phenoxybenzamine 10 mg bd, and the dosage was increased progressively.Subsequently, beta blockade was added.Neurology review confirmed ocular MG with no generalised MG symptoms or signs.Cardiology review deemed the patient at low cardiac risk for operation.
She was admitted to the ward 3 days before the operation for intravenous hydration.Preoperatively, she was on losartan 50 mg om, atenolol 50 mg bd, phenoxybenzamine 40 mg bd.BP at home trended below 140/60 mmHg.However, BP on admission was high at 180/70.Amlodipine 5mg om was added, although the hypertension was partly attributed to anxiety.Subsequently in the ward, there was a small postural drop of BP

Discussion
Thorough preoperative evaluation, continuing the daily pyridostigmine, careful monitoring during surgery, sufficient respiration prior to extubation and sufficient respiration and analgesia post-surgery minimise the risk of postoperative mechanical ventilation for MG patients 2 .In addition, this MG patient with PCC should ideally be managed by an experienced team of endocrinologists, endocrine surgeons and anaesthetists 3 .Our patient was optimised preoperatively by various multidisciplinary teams prior to the resection of PCC.
Preoperative pharmacological control of the adverse effects of circulating catecholamines is essential to control arterial pressure, heart rate and arrhythmias and to allow blood volume to be restored to normal 3 .Phenoxybenzamine has been the mainstay of preoperative control of blood pressure in patients with PCC 4 .It produces non-competitive blockade as a result of covalent binding to the receptor 5 , preventing the effects of surges of catecholamine release during the preoperative period 4,6 .In this patient, phenoxybenzamine was started in small doses and increased gradually until she complained of the side effects of postural hypotension and a stuffy nose 3 .Subsequent introduction of beta-adrenoceptor antagonist (atenolol) is aimed at limiting tachycardia with or without cardiac arrhythmias caused by the secreting tumour and at blocking excessive cardiac sympathetic drive secondary to suppression of the presynaptic alpha-2-regulating mechanism by phenyoxybenzamine 3 .
Prolonged exposure of the circulation to high-circulating noradrenaline concentrations results in constriction of both arteriolar and venous segments with a marked decrease in circulating blood volume.Induction of anaesthesia may cause widespread venodilation, leading to profound arterial hypotension 3 .She was therefore admitted a few days prior to the operation for intravenous nitroprusside 0.04 µg/kg/min were used briefly for about 7 min.Upon resection of PCC, BP was 85/38 mmHg.A total of IV ephedrine 12 mg, IV phenylephrine 700 mcg and IV noradrenaline at 0.03 µg/kg/min were administered to maintain the blood pressure (target MAP 65 mmHg).Operative finding was that of a 4 × 3cm paraganglioma medial to the left adrenal gland.During the 4-h operation, the patient received a total of 3 l of Ringer's lactate, 500 ml of hydroxyethyl starch (Voluven) and 1 unit (293 ml) of blood.The estimated blood loss was about 300 ml, the lowest haematocrit being 24%.TOF tested with a peripheral nerve stimulator was 4 with no fade 3 h after the muscle relaxant was given at induction with no top-up dose subsequently.Although she was breathing spontaneously, she appeared to be weak clinically (her hand grip strength was diminished); hence we decided to keep the patient intubated till she was served her usual dose of pyridostigmine.
She returned to the ICU postoperatively where pyridostigmine was resumed immediately.She was then extubated the following day.Chest physiotherapy and incentive spirometry were instituted.Her postoperative BP was 110-130/60-70mmHg.All antihypertensives were hence discontinued.Epidural ropivacaine 0.2% with 2mcg/ml fentanyl at 8 ml/h infusion achieved sensory block between the levels T4-12, and the epidural catheter was removed on postoperative day (POD) 2. The postoperative course was complicated by complete consolidation-collapse of her right lung lower lobe and partial collapse of right lung middle lobe, requiring re-intubation on POD 3, IV antibiotics, mucolytics and intensive chest physiotherapy.She was extubated 3 days later and discharged from hospital stable on POD 14. BP control at home was 120-130 mmHg systolic.Twenty-four-hour urine collection repeated in the outpatient setting was normalised.
[130/80 mmHg (sitting) → 120/70 mmHg (standing)].ECG showed no premature ventricular complex or ST or T wave changes.Based on the following criteria published by Roizen demonstrating adequate alphablockade 1 , these criteria were met.She was sent to the ICU the day before the operation for insertion of intra-arterial and central venous lines and optimisation of hydration.Central venous pressure (CVP) was aimed at 10-12 mmHg.On the day of the operation, pre-induction CVP was 10 mmHg.Half an hour before induction, a thoracic epidural was inserted at T9/10 interspace.Test dose of 5 ml 1.5% lignocaine with 1:200K adrenaline achieved a sensory block of T8-T10.Her starting preoperative BP was 172/77 mmHg and HR 68.IV phentolamine 3 mg in total was administered in titrated boluses.Anaesthesia was induced with propofol and remifentanil.Due to her multiple crowns, Bonfils intubation endoscope was used.Rocuronium was administered in 10-mg aliquots under train of four (TOF) monitoring.Eventually, 40 mg of rocuronium was given to facilitate tracheal intubation.Anaesthesia was maintained with TCI propofol ranging between 1.6 µg/ml and 4µg/ml, titrated to BIS readings.Analgesia was provided with IV remifentanil ranging between 0.5 µg/kg/min and 3.4 µg/ kg/min, epidural bupivacaine 0.25% boluses, followed by epidural ropivacaine 0.2% with 2 µg/ml fentanyl infusion at 4 ml/h, increasing to 9 ml/h towards the end of the operation.
During tumour manipulation, IV GTN 40 µg/min and IV sodium of the contralateral adrenal gland was suppressed and the patient's relevant adrenoceptors were down-regulated 3 .
Patients pretreated with phenoxybenzamine may be unresponsive to large doses of alpha1-adrenoceptor agonists such as phenylephrine or noradrenaline due to the persistent alpha-adrenoceptor blockade 3 .After the resection of PCC, we managed to treat the hypotension with a combination of ephedrine, phenylephrine and noradrenaline and adequate fluid replacement.
Optimal pain management is important because stress caused by pain may develop into a myasthenic crisis 2 .The use of epidural analgesia offers the advantage of better postoperative pain control and respiratory function 7 .With minimal opioid use, their harmful effect on the respiratory and gastrointestinal function can be avoided.The quicker the gut function is normalised, the faster the patient can resume her usual oral medication of cholinesterase inhibitors 2 .Unfortunately, the patient's postoperative course was complicated by lung consolidation-collapse.This happened despite strategies to optimise her respiratory status, which included adequate epidural analgesia, aggressive chest physiotherapy, incentive spirometry and early resumption of pyridostigmine.Perhaps, the thoracic epidural could have been left in for a longer period postoperatively, as pain might have prevented her full participation in chest physiotherapy.

Conclusion
Perioperative management of PCC remains an anaesthetic challenge.We have described a safe and effective strategy for anaesthesia in this unusual patient with concomitant MG.

Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images.A copy of the written consent is available for review by the editor-in-chief of this journal.
hydration.She was admitted to ICU a day prior to the resection.Intra-arterial and central venous lines were inserted, so as to guide blood pressure and fluid management.She was generously given 5.6 l of fluids over 24 h to increase her CVP to >8 mmHg.
For this patient, we have elected to use the combination of total intravenous anaesthesia (propofol and remifentanil) and segmental mid-thoracic epidural analgesia for surgery.This prevents the patient from coughing on the tracheal tube intraoperatively and provides satisfactory conditions for surgical incision and exposure of the tumour 3 .Manipulation of the PCC during open surgery, however gently performed, causes a brisk haemodynamic pressor response.In our case, a combined regional and general anaesthetic technique with the use of selective adrenergic antagonists helps suppress haemodynamic surges in response to tumour manipulation 3 .
MG patients present an increased sensitivity to neuromuscular depolarising blocking agents (NMBAs) because of reduced number of receptors.Once the epidural block is effective, it can minimise the need for further doses of intravenous opioid or NMBA during open abdominal surgery [3,[7][8][9] .It is essential to use neuromuscular monitoring during surgery and ensure full recovery (TOF >90%) prior to terminating the anaesthetics 2 .Our technique of anaesthesia during induction involved a single dose of muscle relaxant guided by neuromuscular monitoring (TOF).At the end of the resection, even though TOF was 4 with no fade, the patient appeared weak clinically.We felt that it would be more prudent to keep the patient intubated and transferred to the ICU to be served her usual dose of pyridostigmine.
The main postoperative complication is persistent arterial hypotension that may be refractory to intravascular volume replacement and adrenoceptor agonists.While the excised tumour was active, the catecholamine output