1 Department of Anaesthesia, 2 Department of Surgery and 3 Division of Operative Critical Care, University of Basel/Kantonsspital, CH-4031 Basel, Switzerland and 4 Department of Anaesthesia, Kantonsspital Aarau, CH-5001 Aarau, Switzerland
* Corresponding author. Bloomsbury Institute of Intensive Care Medicine, University College London, Mortimer Street, London W1T 3AA, UK. E-mail: Stotzm{at}hotmail.com
Accepted for publication August 6, 2004.
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Abstract |
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Keywords: complications, neuroleptic malignant syndrome ; complications, Parkinson's disease ; neuromuscular relaxant, sodium dantrolene ; pharmacology, inhibitors, levodopabenserazide ; tolcapone
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Introduction |
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Case report |
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On the day of the operation (day 0) the patient received his regular morning medication of levodopabenserazide and tolcapone and, for sedation, lorazepam. Thiopental was used to induce anaesthesia and pancuronium was used to facilitate endotracheal intubation. Anaesthesia was maintained with isoflurane and fentanyl. The operation, CABG using four vein grafts, and the anaesthetic course were uneventful. After the operation the patient was transferred to our intensive care unit with a low-dose norepinephrine infusion rate of 2 to 6 µg min1, which stabilized his mean arterial pressure between 70 and 80 mm Hg. His trachea was extubated 14 h after the operation. The thoracic drainage was 900 ml during the first 18 h after the operation, resulting in a haemoglobin concentration of 9.1 g dl1.
The next morning (day 1), the patient received his regular oral medication (levodopabenserazide and tolcapone) in combination with acetaminophen, aspirin and heparin sodium. About 2 h later he became pale and sweaty, and was in distress. The mean arterial pressure fell to 55 mm Hg without tachycardia and there was no obvious bleeding. Fluid resuscitation with 500 ml of hetastarch 6% and 800 ml of lactated Ringer's solution produced no improvement. Neither increasing the norepinephrine infusion to 10 µg min1 nor repeated doses of phenylephrine was effective in elevating the mean arterial pressure. An epinephrine infusion was then initiated, at a rate of 8 µg min1, and the mean arterial pressure began to improve (70 mm Hg). The haemoglobin (9.812.1 g dl1) and electrolyte concentrations (sodium 137139 mmol l1 and potassium 3.94.7 mmol l1) remained within the normal ranges, but an increasing metabolic acidosis developed despite improvement of the patient's blood pressure (for values and time course see Table 1).
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General anaesthesia was induced with etomidate, and intubation of the trachea was facilitated with succinylcholine. During this procedure, the systolic arterial blood pressure fell to a minimum value of 40 mm Hg, but was restored with repeated doses of epinephrine (1 mg in total), additional fluid administration and a short period of external chest compression. Because of the patient's haemodynamic instability, anaesthesia was maintained with midazolam and fentanyl. During laparotomy, no intestinal perforation or ischaemia was found. Four tumours, each measuring 1 cm in diameter, were found on the small intestine and resected; subsequent histological examination revealed a multifocal low-grade malignant carcinoid tumour. Otherwise the anaesthetic course was uneventful, arterial pressure was maintained with continuous infusion of norepinephrine and epinephrine, and no increase in was noted during the intervention.
During surgery, repeated blood gas samples showed a worsening metabolic acidosis. Because of the patient's record of receiving tolcapone and his progressive muscle rigidity, NMS was suspected and sodium dantrolene was administered in a dose of 2.5 mg kg1. The acidosis resolved almost completely within 15 min and the patient's cardiovascular status stabilized. After the operation, mechanical ventilation was continued and the patient was transferred back to the intensive care unit. The muscular rigidity had resolved and did not return. The remaining acidosis resolved with a single adminstration of 100 ml of sodium bicarbonate 8.4%. The attending neurologist continued levodopabenserazide therapy but withheld tolcapone after this episode.
Subsequently, the patient suffered from multiple organ dysfunction syndrome with pulmonary, hepatic, pancreatic and renal impairment. Blood cultures that were taken before the abdominal operation showed no growth of microorganisms. The creatine kinase concentration reached a maximum of 1350 U l1 (normal 50200 U l1) and the liver enzyme concentrations peaked on day 3. A needle muscle biopsy from the left lateral vastus muscle on day 4 showed no histological necrosis and appeared normal under enzyme-histochemical examination. The 5-hydroxyindoleacetic acid concentration, as a marker of the extent of the carcinoid tumour, was within the normal range. After an initial improvement of his condition, the patient died unexpectedly of acute heart failure on day 12.
The postmortem findings revealed an acute myocardial infarction. No metastases of the carcinoid tumour were detected. Brain autopsy showed numerous Lewy bodies in the neocortical region.
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Discussion |
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Risk factors for developing NMS are organic brain disease, mental retardation and catatonia.7 The sympathoadrenal hyperactivity in patients seems to play a major role,7 reflecting an imbalance in the levels of monoamine metabolites in the cerebrospinal fluid.8 Patients with dementia of the Lewy body type, as found in the postmortem autopsy of our patient, are even more sensitive to neuroleptic medication and NMS.9 It is not known whether patients with dementia of the Lewy body type are also more susceptible to NMS after discontinuation of antiParkinsonian medication, but it can be postulated in our case.
The diagnostic characteristics for NMS consist of major criteria (fever, rigidity and elevated creatine phosphokinase) and minor criteria (tachycardia, abnormal arterial blood pressure, tachypnoea, altered consciousness, diaphoresis and leucocytosis). The diagnosis of NMS can be difficult, as these symptoms may be missing.1013 In our patient, the absence of fever was misleading at the beginning of the clinical course when hypotension, increasing muscular rigidity and abdominal pain were the predominant symptoms. The clinical findings of increasing pain and acidosis, together with subdiaphragmatic air collection, led us to suspect a ruptured viscus. Subdiaphragmatic air collection may be caused by peritoneal perforation and is sometimes seen after introducing the thoracic drainage in CABG. After the exclusion of abdominal perforation, the patient's medical history, which showed discontinuation of antiParkinsonian medication, led to the diagnosis. Muscular rigidity is responsible for rhabdomyolysis and the elevation in creatine kinase concentration during NMS. We did not detect myonecrosis in the biopsy performed, but histological changes in NMS are not specific and constant.14 15
The specific time for development of NMS varies, and may range from hours1 to months.7 In our patient, the first symptoms developed 26 h after the last administration of levodopabenserazide and tolcapone. We suggest two reasons for the early and fulminant course of the NMS in our patient. First, tolcapone is highly protein bound (>99%) and the expanded volume of distribution during cardiopulmonary bypass could have led to a rapid fall in plasma concentration. Secondly, since gastric emptying is delayed after CABG, delayed intestinal absorption of the antiParkinsonian medication after the operation on day 1 may have resulted in low plasma levels.16 This may explain why the onset of symptoms started after the regular administration of levodopabenserazide and tolcapone on day 1.
The clinical course of NMS is unpredictable. It can range from altered consciousness and elevated body-core temperature to myocardial infarction,17 cardiac failure18 and even multiple organ dysfunction. Our patient presented with vasodilation and shock of unknown origin, similar to septic shock, which was unresponsive to fluid resuscitation or to peripheral vasoconstrictors. After the exclusion of excessive blood loss with no apparent sign of bleeding and a negative chest radiograph, the muscular rigidity of the abdominal wall mimicked peritonitis which could have been an explanation for the worsening condition of the patient and led us to suspect a ruptured viscus. Finally, review of the patient's medication led to diagnosis after the intraoperative exclusion of an abdominal problem.
The treatment of NMS depends on early recognition. General treatment, including hydration, nutrition and reduction of fever, is essential; and secondary complications (e.g. hypoxia, acidosis and renal failure) must be treated aggressively. Withdrawal of the neuroleptic agent, if administered previously, is crucial. Dopamine agonists such as bromocriptine and amantadine hydrochloride have been used successfully to treat NMS. The use of glutamate receptor antagonists has also been advocated.19 Sodium dantrolene, a non-specific direct-acting muscle relaxant used to treat malignant hyperthermia, can also be effective in NMS; its ability to elicit muscle relaxation seems to decrease body temperature and diminish oxygen consumption. In our patient, metabolic acidosis significantly decreased after the use of sodium dantrolene and resolved with the subsequent single dose of sodium bicarbonate.
NMS occurring perioperatively may prove difficult to distinguish from malignant hyperthermia as the clinical course may be very similar (Table 2). In our case, the delay in onset of symptoms after the discontinuation of potent inhalational anaesthetics precludes malignant hyperthermia. Further differential diagnoses of NMS include neuroleptic-induced heatstroke, acute lethal catatonia, monoamine oxidase inhibitor drug interaction, central anticholinergic crisis and akinetic crisis in the advanced stages of Parkinson's disease. The akinetic crisis is characterized by severe rigidity, progressive immobilization with concomitant hyperthermia, vegetative dystonia and tachycardia. Therefore the severe form of an akinetic crisis is not easy to distinguish from NMS;19 20 although these two entities do not differ with regard to symptoms, their therapies and clinical courses do. Akinetic crisis can develop in patients at an advanced stage of Parkinson's disease after reduction or cessation of dopaminergic therapy.21 We postulate that the clinical course of our patient provides good evidence for NMS.
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Conclusion |
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References |
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