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Anesthetic management of an obstetric patient with MELAS syndrome: case report and literature review
International Journal of Obstetric Anesthesia (2009) 17, 370–373 0959-289X/$ - see front matter c 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijoa.2007.11.011
CASE REPORT
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Anesthetic management of an obstetric patient with MELAS syndrome: case report and literature review M. Maurtua, A. Torres, V. Ibarra, G. DeBoer, J. Dolak Department of General Anesthesiology and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, OH, USA ABSTRACT Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) is a mitochondrial disorder associated with neurologic, cardiac, neuromuscular, hepatic, metabolic and gastrointestinal dysfunction and potential anesthetic and obstetric complications. The case of a parturient with MELAS syndrome requiring labor analgesia is presented. A Medline literature search limited to the English language was undertaken to review cases of MELAS syndrome. Based on our experience and literature review, parturients with MELAS syndrome appear to benefit from neuraxial analgesia and anesthesia, which blunt excessive oxygen consumption and acidosis. c 2008 Elsevier Ltd. All rights reserved.
Keywords: MELAS syndrome; Mitochondrial cytopathy; Pregnancy; Labor analgesia and anesthesia
Introduction MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is a mitochondrial disorder that may cause cognitive, neuromuscular, metabolic, cardiac, hepatic and gastrointestinal dysfunction. Anesthesiologists should be knowledgeable about the presentation and management of this disorder and the anesthetic management of a parturient with MELAS syndrome requiring labor analgesia.
Case report A 31-year-old G1P0 at 38 weeks of gestation with MELAS syndrome presented to the obstetric anesthesia service for evaluation before the onset of labor. Her medical history included migraine headaches, chronic constipation, asthma and paroxysmal supraventricular tachycardia (for which she had undergone radiofrequency ablation). MELAS syndrome was diagnosed by a geneticist after similar mitochondrial disorders had been found in a maternal aunt and two cousins. Her blood and urine samples revealed the T3271C MELAS Accepted November 2007 Correspondence to: M. Maurtua MD, Staff Anesthesiologist, Department of General Anesthesiology, E-31, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: +216 445 1151; fax: +216 444 2294. E-mail address: [email protected]
mutation. The patient was afebrile with a blood pressure of 117/70 mmHg, pulse 80 beats/min and respiratory rate 16 breaths/min. Her physical examination was unremarkable. All laboratory values were within normal range, except for a mildly elevated serum lactic acid level of 2.4 mmol/L (normal range 0.5-2.2 mmol/L). The patient requested an epidural catheter for labor analgesia, which was placed uneventfully at the lumbar 3-4 interspace in the sitting position using an 18-gauge Tuohy needle. Following a negative test dose, a 10-mL bolus of 0.125% bupivacaine with fentanyl 5 lg/mL and epinephrine 1.65 lg/mL was administered, resulting in a T10 sensory level. Labor analgesia was maintained with an infusion of 0.0625% bupivacaine with fentanyl 1.25 lg/mL and epinephrine 1.25lg/mL at 12 mL/h. During labor, the patient was normothermic and hemodynamically stable. A female newborn was delivered with Apgar scores of 9 at 1 min and 9 at 5 min. The patient’s post-partum lactate level was elevated to 3.9 mmol/L, but the patient and her infant did well and were discharged home on post-partum day two.
Discussion MELAS syndrome is a mitochondrial disorder characterized by encephalopathy that may present at a young age with dementia, seizures or stroke-like episodes. Recurrent headaches and vomiting can also be present. The most consistent laboratory feature is lactic acidosis.
M. Maurtua et al. Cerebral imaging with computed tomography and magnetic resonance imaging often reveals evidence of cortical infarction or atrophy.1,2 The areas of infarction, which are not typically localized to a particular vascular territory,1,3 have been postulated to result from metabolic insufficiency of the cerebral tissues rather than an embolic or hemorrhagic cause.2 Cardiac and skeletal muscle may also be involved in MELAS syndrome. Cardiac involvement includes conduction abnormalities such as Wolff-Parkinson-White syndrome, conduction blocks and hypertrophic cardiomyopathy.4 Our patient had a history of supraventricular tachycardia. Pathologic examination of skeletal muscle using a modified Gomori trichrome stain often reveals ragged red fibers that represent proliferating mitochondrial elements; these elements are associated with biochemical abnormalities of the respiratory chain.1 In this respect MELAS is similar to other mitochondrial disorders such as Kearns-Sayre syndrome and myoclonic epilepsy. The most common mitochondrial DNA point mutation associated with MELAS is an A-to-G transition at nucleotide 3243 of transfer DNA (MELAS 3243). However, our patient had the more rare T-to-C transition at nucleotide 3271 (MELAS 3271).2 Another mutation in subunit four of complex I is described in the literature. There is significant phenotypic variability in MELAS. While some patients suffer from multiple strokes, seizures and limb weakness, others, such as our patient, are less severely affected. This phenotypic variability is probably due to a feature of mitochondrial inheritance termed ‘‘heteroplasmy’’. Within each individual cell there are multiple mitochondria, each containing multiple genomes. During cell division, these mitochondria are distributed randomly among daughter cells, with various cells or tissues receiving a mixture of normal and mutant genomes (heteroplasmy). If a threshold level of mutant mitochondria is reached within a particular tissue, organ dysfunction and clinical disorders may occur. Anesthetic management of patients with MELAS syndrome has rarely been reported. The Japanese literature discusses two 11-year-old girls who successfully underwent general anesthesia with fentanyl, midazolam and nitrous oxide.5 Triggering agents for malignant hyperthermia (MH) such as volatile anesthetics and succinylcholine were specifically avoided in these cases, and arterial blood gases were frequently monitored. Thompson and Wahr described the case of a 20-year-old man with MELAS in whom general anesthesia was maintained with propofol and cisatracurium infusions.6 Again, MH triggering agents were avoided and the patient did well. Spinal anesthesia using 15 mg of isobaric bupivacaine for a 33-year-old male undergoing an appendectomy was reported by Hsiao et al.7 No residual neuromuscular abnormalities were noted at a three-week follow-up. Maslow and Lisbon also described giving spinal anes-
371 thesia using hyperbaric tetracaine to a 40-year-old male with MELAS syndrome and a bimalleolar ankle fracture; the patient had no complications.8 Of interest, this patient had previously undergone general anesthesia including succinylcholine and volatile anesthesia without complications.8 Although women with MELAS syndrome undergoing labor and delivery have been described, none of these reports mentioned labor analgesia. Kokawa et al. described a 31-year-old female with a history of seizures who developed significant muscle weakness of the extremities at 27 weeks of gestation.9 Investigation revealed severe metabolic acidosis (pH 7.286 and lactate 4.4 mmol/L). As in our patient, a mitochondrial DNA mutation at the 3271 position was found. She was treated with 7% bicarbonate and intravenous hydration with improvement. At 38 weeks of gestation she delivered a male infant without complications. Kovilam et a1. described a 28-year-old gravid female in whom MELAS syndrome had been diagnosed before the current pregnancy.10 She had seizures, myopathy, cardiac arrhythmias, neuropathy and migraine-like events. She was induced at 36 weeks of gestation for ‘‘worsening symptoms’’ and delivered a 2100-g infant uneventfully. Anesthetic management of patients with MELAS syndrome should include a careful examination of the neurologic, cardiac, muscular, and metabolic systems. Due to the variability in phenotypic expression of this disorder, the degree of dysfunction should be assessed. Neurological examination should ascertain cognitive dysfunction, muscular weakness, and neuropathy. Regional anesthesia may not be optimal for patients with significant cognitive impairment, respiratory muscle weakness or liver dysfunction sufficient to affect coagulation status. Cardiac involvement warrants further preoperative evaluation including possible cardiology consultation and a baseline electrocardiogram. In normal patients, oxygen consumption increases 20% during pregnancy and may increase by a further 63% during labor.11,12 Regional analgesia, however, may reduce this increase in oxygen consumption by 25% during the second stage of labor.11 While this effect of regional analgesia might seem beneficial to patients with MELAS syndrome, their disease severity and exercise tolerance vary. Patients experiencing dyspnea with minor exertion and decompensated lactic acidosis should be considered for elective cesarean section, since labor, even with epidural analgesia, may worsen the lactic acidosis.11,12 Rosaeg et al. documented the successful use of epidural anesthesia for cesarean section in a patient with mitochondrial myopathy, in whom intraoperative and postoperative serum lactate concentration decreased.12 Although the association between MH and MELAS syndrome remains controversial, MH has been described in a single pediatric patient with MELAS syndrome after the use of succinylcholine.13 Hence a number of reports
372 recommend the avoidance of triggering agents in this group of patients.6,9,14 At our institution, however, volatile anesthetic agents are regularly used in patients with mitochondrial cytopathy, without a single case of MH. Nevertheless, succinylcholine should probably be avoided in patients with underlying myopathy because of the risk of hyperkalemia after its administration. Patients with mitochondrial myopathy may also be more sensitive to non-depolarizing neuromuscular blockade,15,16 so neuromuscular blockade should be closely monitored and shorter-acting non-depolarizing muscle relaxants should be considered. Several common intravenous induction agents may produce mitochondrial dysfunction. Propofol impairs the mitochondrial electron transport chain by inducing a rise in malonyl carnitine, which subsequently inhibits carnitine palmytil transferase I, a protein involved in the mitochondrial transport of long-chain fatty acids.17 Propofol also inhibits complex II of the respiratory chain resulting in an increase of C5-acylcarnitine.17,18 These mitochondrial effects of propofol are believed to be responsible for the ‘‘propofol infusion syndrome’’ described in pediatric intensive care unit patients receiving prolonged propofol infusions. Propofol infusion syndrome presents with similar clinicopathological characteristics as mitochondrial cytopathies, including lactic acidosis, myocardial dysfunction and renal failure. Propofol should therefore be avoided in patients with MELAS syndrome especially if prolonged infusions are required for sedation or anesthetic maintenance.17,18 Other intravenous anesthetics such as midazolam, thiopental, ketamine and even fentanyl, have been found to decrease mitochondrial ATP synthesis in in vitro models. However, in our institution, both ketamine infusions and fentanyl have been used in patients with MELAS syndrome without known sequelae.19–23 Since patients with MELAS syndrome may present with gastrointestinal involvement (gastroesophageal reflux, nausea and vomiting), it is important to take precautions against aspiration, including rapid-sequence induction if general anesthesia is required.2 It is sensible to avoid lactate administration, for example in Ringer’s lactate infusion, due to the increased lactate production in these patients. Additionally, the patient should be kept normothermic to avoid the increased oxygen consumption associated with shivering. In addition to standard monitors, during general anesthesia an arterial line should be considered to allow monitoring of the metabolic status. In conclusion, MELAS syndrome is a mitochondrial encephalomyopathy in which metabolic demands and subsequent acidosis must be avoided. Regional analgesia and anesthesia may be beneficial in reducing metabolic demands associated with the stress and pain of labor and delivery. If general anesthesia is required, pro-
MELAS syndrome in obstetrics, anesthetic management pofol infusions should be avoided to prevent further decreasing mitochondrial adenosine triphosphate production.
References 1. Koo B, Becker L E, Chuang S et al. Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): Clinical, radiological, pathological, and genetic observations. Ann Neurol 1993; 34: 25–32. 2. Hirano M, Pavlakis S G. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): current concepts. J Child Neurol 1994; 9: 4–13. 3. Di Trapani G, Gregori B, Servidei S, Ricci E, Sabatelli M, Tonali P. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Clin Neuropathol 1997; 16: 195–200. 4. Okajima Y, Tanabe Y, Takayanagi M, Aotuska H. A follow up study of myocardial involvement in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Heart 1998; 80: 292–5. 5. Itaya K, Takahata O, Mamiya K et al. Anesthetic management of two patients with mitochondrial encphalopathy, lactic acidosis and stroke-like episodes. Masui 1995; 44: 710–2. 6. Thompson V A, Wahr J A. Anesthetic considerations in patients presenting with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Anesth Analg 1997; 85: 1404–6. 7. Hsiao P N, Cheng Y J, Tseng H C, Chuang Y H, Kao P F, Tsai S K. Spinal anesthesia in MELAS syndrome: a case with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Acta Anaesthesiologica Sin 2000; 38: 107–10. 8. Maslow A, Lisbon A. Anesthetic considerations in patients with mitochondrial dysfunction. Anesth Analg 1993; 76: 884–6. 9. Kokawa N, Ishii Y, Yamoto M, Nakano R. Pregnancy and delivery complicated by mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Obstet Gynecol 1998; 91: 865. 10. Kovilam O P, Cahill W, Siddiqi T A. Pregnancy with mitochondrial encephalopathy, lactic acidosis, and strokelike episodes syndrome. Obstet Gynecol 1999; 93(5 Pt 2): 853. 11. Hagerdal M, Morgan C W, Sumner A E, Gutsche B B. Minute ventilation and oxygen consumption during labor with epidural analgesia. Anesthesiology 1983; 59: 425–7. 12. Rosaeg O P, Morrison S, MacLeod J P. Anaesthetic management of labour and delivery in the parturient with mitochondrial myopathy. Can J Anaesth 1996; 43: 403–7. 13. Otani Y, Teruhisa M, Takateru I, Matsuda I, Tamari H. A case of malignant hyperthermia with mitochondrial dysfunction. Brain Dev 1985; 7: 249. 14. Bolton P, Peutrell J, Zuberi S, Robinison P. Anaesthesia for an adolescent with mitochondrial encephalomyopathy-lactic acidosis-stroke-like episodes syndrome. Paediatr Anaesth 2003; 13: 453–6. 15. Finsterer J, Stratil U, Bittner R, Sporn P. Increased sensitivity to rocuronium and atracurium in mitochondrial myopathy. Can J Anaesth 1998; 45: 781–4. 16. Naguib M, el Dawlatly A A, Ashour M, al-Bunyan M. Sensitivity to mivacurium in a patient with mitochondrial myopathy. Anesthesiology 1996; 84: 1506–9. 17. Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003; 29: 1417–25.
M. Maurtua et al. 18. Wolf A, Weir P, Segar P, Stone J, Shield J. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet 2001; 357: 606–7. 19. Colleoni M, Costa B, Gori E, Santagostino A. Biochemical characterization of the effects of the benzodiazepine, midazolam, on mitochondrial electron transfer. Pharmacol Toxicol 1996; 78: 69–76. 20. Chance B, Williams G R, Hollunger G. Inhibition of electron and energy transfer in mitochondria. I. Effects of amytal. Thiopental, rotenone, progesterone, and methylene glycol. J Biol Chem 1963; 238: 418–31.
373 21. Anderson C M, Norquist B A, Vesce S et al. Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death. J Neurosci 2002; 22: 9203–9. 22. Markham A, Cameron I, White J. The effect of ketamine hydrochloride, a non-barbiturate parenteral anesthetic on oxidative phosphorylation in rat liver mitochondria. Biochem Pharmacol 1981; 30: 2165–8. 23. Zamparelli M, Eaton S, Quant P A, McEwan A, Spitz L, Pierro A. Analgesic doses of fentanyl impair oxidative metabolism of neonatal hepatocytes. J Pediatr Surg 1999; 34: 260–3.
CASE REPORT
www.obstetanesthesia.com
Anesthetic management of an obstetric patient with MELAS syndrome: case report and literature review M. Maurtua, A. Torres, V. Ibarra, G. DeBoer, J. Dolak Department of General Anesthesiology and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, OH, USA ABSTRACT Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) is a mitochondrial disorder associated with neurologic, cardiac, neuromuscular, hepatic, metabolic and gastrointestinal dysfunction and potential anesthetic and obstetric complications. The case of a parturient with MELAS syndrome requiring labor analgesia is presented. A Medline literature search limited to the English language was undertaken to review cases of MELAS syndrome. Based on our experience and literature review, parturients with MELAS syndrome appear to benefit from neuraxial analgesia and anesthesia, which blunt excessive oxygen consumption and acidosis. c 2008 Elsevier Ltd. All rights reserved.
Keywords: MELAS syndrome; Mitochondrial cytopathy; Pregnancy; Labor analgesia and anesthesia
Introduction MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is a mitochondrial disorder that may cause cognitive, neuromuscular, metabolic, cardiac, hepatic and gastrointestinal dysfunction. Anesthesiologists should be knowledgeable about the presentation and management of this disorder and the anesthetic management of a parturient with MELAS syndrome requiring labor analgesia.
Case report A 31-year-old G1P0 at 38 weeks of gestation with MELAS syndrome presented to the obstetric anesthesia service for evaluation before the onset of labor. Her medical history included migraine headaches, chronic constipation, asthma and paroxysmal supraventricular tachycardia (for which she had undergone radiofrequency ablation). MELAS syndrome was diagnosed by a geneticist after similar mitochondrial disorders had been found in a maternal aunt and two cousins. Her blood and urine samples revealed the T3271C MELAS Accepted November 2007 Correspondence to: M. Maurtua MD, Staff Anesthesiologist, Department of General Anesthesiology, E-31, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: +216 445 1151; fax: +216 444 2294. E-mail address: [email protected]
mutation. The patient was afebrile with a blood pressure of 117/70 mmHg, pulse 80 beats/min and respiratory rate 16 breaths/min. Her physical examination was unremarkable. All laboratory values were within normal range, except for a mildly elevated serum lactic acid level of 2.4 mmol/L (normal range 0.5-2.2 mmol/L). The patient requested an epidural catheter for labor analgesia, which was placed uneventfully at the lumbar 3-4 interspace in the sitting position using an 18-gauge Tuohy needle. Following a negative test dose, a 10-mL bolus of 0.125% bupivacaine with fentanyl 5 lg/mL and epinephrine 1.65 lg/mL was administered, resulting in a T10 sensory level. Labor analgesia was maintained with an infusion of 0.0625% bupivacaine with fentanyl 1.25 lg/mL and epinephrine 1.25lg/mL at 12 mL/h. During labor, the patient was normothermic and hemodynamically stable. A female newborn was delivered with Apgar scores of 9 at 1 min and 9 at 5 min. The patient’s post-partum lactate level was elevated to 3.9 mmol/L, but the patient and her infant did well and were discharged home on post-partum day two.
Discussion MELAS syndrome is a mitochondrial disorder characterized by encephalopathy that may present at a young age with dementia, seizures or stroke-like episodes. Recurrent headaches and vomiting can also be present. The most consistent laboratory feature is lactic acidosis.
M. Maurtua et al. Cerebral imaging with computed tomography and magnetic resonance imaging often reveals evidence of cortical infarction or atrophy.1,2 The areas of infarction, which are not typically localized to a particular vascular territory,1,3 have been postulated to result from metabolic insufficiency of the cerebral tissues rather than an embolic or hemorrhagic cause.2 Cardiac and skeletal muscle may also be involved in MELAS syndrome. Cardiac involvement includes conduction abnormalities such as Wolff-Parkinson-White syndrome, conduction blocks and hypertrophic cardiomyopathy.4 Our patient had a history of supraventricular tachycardia. Pathologic examination of skeletal muscle using a modified Gomori trichrome stain often reveals ragged red fibers that represent proliferating mitochondrial elements; these elements are associated with biochemical abnormalities of the respiratory chain.1 In this respect MELAS is similar to other mitochondrial disorders such as Kearns-Sayre syndrome and myoclonic epilepsy. The most common mitochondrial DNA point mutation associated with MELAS is an A-to-G transition at nucleotide 3243 of transfer DNA (MELAS 3243). However, our patient had the more rare T-to-C transition at nucleotide 3271 (MELAS 3271).2 Another mutation in subunit four of complex I is described in the literature. There is significant phenotypic variability in MELAS. While some patients suffer from multiple strokes, seizures and limb weakness, others, such as our patient, are less severely affected. This phenotypic variability is probably due to a feature of mitochondrial inheritance termed ‘‘heteroplasmy’’. Within each individual cell there are multiple mitochondria, each containing multiple genomes. During cell division, these mitochondria are distributed randomly among daughter cells, with various cells or tissues receiving a mixture of normal and mutant genomes (heteroplasmy). If a threshold level of mutant mitochondria is reached within a particular tissue, organ dysfunction and clinical disorders may occur. Anesthetic management of patients with MELAS syndrome has rarely been reported. The Japanese literature discusses two 11-year-old girls who successfully underwent general anesthesia with fentanyl, midazolam and nitrous oxide.5 Triggering agents for malignant hyperthermia (MH) such as volatile anesthetics and succinylcholine were specifically avoided in these cases, and arterial blood gases were frequently monitored. Thompson and Wahr described the case of a 20-year-old man with MELAS in whom general anesthesia was maintained with propofol and cisatracurium infusions.6 Again, MH triggering agents were avoided and the patient did well. Spinal anesthesia using 15 mg of isobaric bupivacaine for a 33-year-old male undergoing an appendectomy was reported by Hsiao et al.7 No residual neuromuscular abnormalities were noted at a three-week follow-up. Maslow and Lisbon also described giving spinal anes-
371 thesia using hyperbaric tetracaine to a 40-year-old male with MELAS syndrome and a bimalleolar ankle fracture; the patient had no complications.8 Of interest, this patient had previously undergone general anesthesia including succinylcholine and volatile anesthesia without complications.8 Although women with MELAS syndrome undergoing labor and delivery have been described, none of these reports mentioned labor analgesia. Kokawa et al. described a 31-year-old female with a history of seizures who developed significant muscle weakness of the extremities at 27 weeks of gestation.9 Investigation revealed severe metabolic acidosis (pH 7.286 and lactate 4.4 mmol/L). As in our patient, a mitochondrial DNA mutation at the 3271 position was found. She was treated with 7% bicarbonate and intravenous hydration with improvement. At 38 weeks of gestation she delivered a male infant without complications. Kovilam et a1. described a 28-year-old gravid female in whom MELAS syndrome had been diagnosed before the current pregnancy.10 She had seizures, myopathy, cardiac arrhythmias, neuropathy and migraine-like events. She was induced at 36 weeks of gestation for ‘‘worsening symptoms’’ and delivered a 2100-g infant uneventfully. Anesthetic management of patients with MELAS syndrome should include a careful examination of the neurologic, cardiac, muscular, and metabolic systems. Due to the variability in phenotypic expression of this disorder, the degree of dysfunction should be assessed. Neurological examination should ascertain cognitive dysfunction, muscular weakness, and neuropathy. Regional anesthesia may not be optimal for patients with significant cognitive impairment, respiratory muscle weakness or liver dysfunction sufficient to affect coagulation status. Cardiac involvement warrants further preoperative evaluation including possible cardiology consultation and a baseline electrocardiogram. In normal patients, oxygen consumption increases 20% during pregnancy and may increase by a further 63% during labor.11,12 Regional analgesia, however, may reduce this increase in oxygen consumption by 25% during the second stage of labor.11 While this effect of regional analgesia might seem beneficial to patients with MELAS syndrome, their disease severity and exercise tolerance vary. Patients experiencing dyspnea with minor exertion and decompensated lactic acidosis should be considered for elective cesarean section, since labor, even with epidural analgesia, may worsen the lactic acidosis.11,12 Rosaeg et al. documented the successful use of epidural anesthesia for cesarean section in a patient with mitochondrial myopathy, in whom intraoperative and postoperative serum lactate concentration decreased.12 Although the association between MH and MELAS syndrome remains controversial, MH has been described in a single pediatric patient with MELAS syndrome after the use of succinylcholine.13 Hence a number of reports
372 recommend the avoidance of triggering agents in this group of patients.6,9,14 At our institution, however, volatile anesthetic agents are regularly used in patients with mitochondrial cytopathy, without a single case of MH. Nevertheless, succinylcholine should probably be avoided in patients with underlying myopathy because of the risk of hyperkalemia after its administration. Patients with mitochondrial myopathy may also be more sensitive to non-depolarizing neuromuscular blockade,15,16 so neuromuscular blockade should be closely monitored and shorter-acting non-depolarizing muscle relaxants should be considered. Several common intravenous induction agents may produce mitochondrial dysfunction. Propofol impairs the mitochondrial electron transport chain by inducing a rise in malonyl carnitine, which subsequently inhibits carnitine palmytil transferase I, a protein involved in the mitochondrial transport of long-chain fatty acids.17 Propofol also inhibits complex II of the respiratory chain resulting in an increase of C5-acylcarnitine.17,18 These mitochondrial effects of propofol are believed to be responsible for the ‘‘propofol infusion syndrome’’ described in pediatric intensive care unit patients receiving prolonged propofol infusions. Propofol infusion syndrome presents with similar clinicopathological characteristics as mitochondrial cytopathies, including lactic acidosis, myocardial dysfunction and renal failure. Propofol should therefore be avoided in patients with MELAS syndrome especially if prolonged infusions are required for sedation or anesthetic maintenance.17,18 Other intravenous anesthetics such as midazolam, thiopental, ketamine and even fentanyl, have been found to decrease mitochondrial ATP synthesis in in vitro models. However, in our institution, both ketamine infusions and fentanyl have been used in patients with MELAS syndrome without known sequelae.19–23 Since patients with MELAS syndrome may present with gastrointestinal involvement (gastroesophageal reflux, nausea and vomiting), it is important to take precautions against aspiration, including rapid-sequence induction if general anesthesia is required.2 It is sensible to avoid lactate administration, for example in Ringer’s lactate infusion, due to the increased lactate production in these patients. Additionally, the patient should be kept normothermic to avoid the increased oxygen consumption associated with shivering. In addition to standard monitors, during general anesthesia an arterial line should be considered to allow monitoring of the metabolic status. In conclusion, MELAS syndrome is a mitochondrial encephalomyopathy in which metabolic demands and subsequent acidosis must be avoided. Regional analgesia and anesthesia may be beneficial in reducing metabolic demands associated with the stress and pain of labor and delivery. If general anesthesia is required, pro-
MELAS syndrome in obstetrics, anesthetic management pofol infusions should be avoided to prevent further decreasing mitochondrial adenosine triphosphate production.
References 1. Koo B, Becker L E, Chuang S et al. Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): Clinical, radiological, pathological, and genetic observations. Ann Neurol 1993; 34: 25–32. 2. Hirano M, Pavlakis S G. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): current concepts. J Child Neurol 1994; 9: 4–13. 3. Di Trapani G, Gregori B, Servidei S, Ricci E, Sabatelli M, Tonali P. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Clin Neuropathol 1997; 16: 195–200. 4. Okajima Y, Tanabe Y, Takayanagi M, Aotuska H. A follow up study of myocardial involvement in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Heart 1998; 80: 292–5. 5. Itaya K, Takahata O, Mamiya K et al. Anesthetic management of two patients with mitochondrial encphalopathy, lactic acidosis and stroke-like episodes. Masui 1995; 44: 710–2. 6. Thompson V A, Wahr J A. Anesthetic considerations in patients presenting with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Anesth Analg 1997; 85: 1404–6. 7. Hsiao P N, Cheng Y J, Tseng H C, Chuang Y H, Kao P F, Tsai S K. Spinal anesthesia in MELAS syndrome: a case with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Acta Anaesthesiologica Sin 2000; 38: 107–10. 8. Maslow A, Lisbon A. Anesthetic considerations in patients with mitochondrial dysfunction. Anesth Analg 1993; 76: 884–6. 9. Kokawa N, Ishii Y, Yamoto M, Nakano R. Pregnancy and delivery complicated by mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Obstet Gynecol 1998; 91: 865. 10. Kovilam O P, Cahill W, Siddiqi T A. Pregnancy with mitochondrial encephalopathy, lactic acidosis, and strokelike episodes syndrome. Obstet Gynecol 1999; 93(5 Pt 2): 853. 11. Hagerdal M, Morgan C W, Sumner A E, Gutsche B B. Minute ventilation and oxygen consumption during labor with epidural analgesia. Anesthesiology 1983; 59: 425–7. 12. Rosaeg O P, Morrison S, MacLeod J P. Anaesthetic management of labour and delivery in the parturient with mitochondrial myopathy. Can J Anaesth 1996; 43: 403–7. 13. Otani Y, Teruhisa M, Takateru I, Matsuda I, Tamari H. A case of malignant hyperthermia with mitochondrial dysfunction. Brain Dev 1985; 7: 249. 14. Bolton P, Peutrell J, Zuberi S, Robinison P. Anaesthesia for an adolescent with mitochondrial encephalomyopathy-lactic acidosis-stroke-like episodes syndrome. Paediatr Anaesth 2003; 13: 453–6. 15. Finsterer J, Stratil U, Bittner R, Sporn P. Increased sensitivity to rocuronium and atracurium in mitochondrial myopathy. Can J Anaesth 1998; 45: 781–4. 16. Naguib M, el Dawlatly A A, Ashour M, al-Bunyan M. Sensitivity to mivacurium in a patient with mitochondrial myopathy. Anesthesiology 1996; 84: 1506–9. 17. Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003; 29: 1417–25.
M. Maurtua et al. 18. Wolf A, Weir P, Segar P, Stone J, Shield J. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet 2001; 357: 606–7. 19. Colleoni M, Costa B, Gori E, Santagostino A. Biochemical characterization of the effects of the benzodiazepine, midazolam, on mitochondrial electron transfer. Pharmacol Toxicol 1996; 78: 69–76. 20. Chance B, Williams G R, Hollunger G. Inhibition of electron and energy transfer in mitochondria. I. Effects of amytal. Thiopental, rotenone, progesterone, and methylene glycol. J Biol Chem 1963; 238: 418–31.
373 21. Anderson C M, Norquist B A, Vesce S et al. Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death. J Neurosci 2002; 22: 9203–9. 22. Markham A, Cameron I, White J. The effect of ketamine hydrochloride, a non-barbiturate parenteral anesthetic on oxidative phosphorylation in rat liver mitochondria. Biochem Pharmacol 1981; 30: 2165–8. 23. Zamparelli M, Eaton S, Quant P A, McEwan A, Spitz L, Pierro A. Analgesic doses of fentanyl impair oxidative metabolism of neonatal hepatocytes. J Pediatr Surg 1999; 34: 260–3.