REVIEW ARTICLE Mitochondrial disorders and general anaesthesia: a case series and review

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1 British Journal of Anaesthesia 100 (4): (2008) doi: /bja/aen014 Advance Access publication February 19, 2008 REVIEW ARTICLE Mitochondrial disorders and general anaesthesia: a case series and review E. J. Footitt 1, M. D. Sinha 1, J. A. J. Raiman 1, A. Dhawan 3, S. Moganasundram 2 and M. P. Champion 1 * 1 Department of Paediatric Metabolic Medicine and 2 Department of Anaesthesia, Evelina Children s Hospital, Guy s and St Thomas NHS Foundation Trust, Lambeth Palace Road, London SE1 7EH, UK. 3 Department of Paediatric Hepatology, King s College Hospital, Denmark Hill, London SE5 9RS, UK *Corresponding author. michael.champion@gstt.nhs.uk Patients with mitochondrial disease are at risk of metabolic decompensation and often require general anaesthesia (GA) as part of their diagnostic work up and subsequent management. However, the evidence base for the use of GA is limited and inconclusive. We have documented the practice and outcome in the use of GA in paediatric patients with mitochondrial disease using a retrospective case review study of 38 mitochondrial patients who had undergone 58 anaesthetics within the regional metabolic service for the period A variety of anaesthetic agents were used and the pattern of use reflects that seen in standard paediatric practice. There were no episodes of malignant hyperthermia and no documented intraoperative events attributable to the GA. Three postoperative adverse events were noted; one episode of hypovolaemia, one episode of acute on chronic renal failure, and one episode of metabolic decompensation 12 h post-muscle biopsy. Despite theoretical concern about this group of patients, adverse events after GA are rare and in most cases unrelated to the anaesthesia. Further prospective studies of GA in mitochondrial disease are required to create evidence-based clinical guidelines for safe practice. Br J Anaesth 2008; 100: Keywords: anaesthesia, general; complications; metabolism, ATP; metabolism, lactate; surgery, paediatric Mitochondria are double-membrane bound, intracellular organelles present in all cells except erythrocytes. Their primary function is the generation of adenosine triphosphate (ATP) via aerobic respiration. However, mitochondria also host several other metabolic pathways, including the tricarboxylic acid (TCA) cycle, urea cycle, b-fatty acid oxidation, and lipid and cholesterol synthesis. The term mitochondrial disorder refers to the group of conditions caused by impairment of the respiratory chain which is involved in the generation of ATP by oxidative phosphorylation. 17 Mitochondrial disorders represent a biochemically and clinically diverse group of conditions that can affect any part of the body, with organs with a high energy requirement such as brain, muscle, liver, heart, and kidney being particularly vulnerable. Historically, mitochondrial disorders were considered to be only a neuromuscular disease; however, due to the ubiquitous nature of oxidative phosphorylation, a defect of the respiratory chain should be considered in a variety of clinical presentations and at any age. Alongside specific clinical syndromes, mitochondrial disease should also be suspected where there is an unexplained constellation of signs with a progressive course involving seemingly unrelated organs or tissues. 14 The genetic basis of mitochondrial disease is an advancing field of research and its complexities have a major impact upon clinical disease and management. The mitochondrion is unique among human organelles as each contains several copies of a small, circular, double-stranded mitochondrial DNA molecule (mtdna). The vast majority of mitochondrial proteins, however, including most of the proteins involved in electron transport, are encoded by nuclear genes. 46 Defects in nuclear DNA may be inherited in an autosomal recessive, dominant, or X-linked pattern. mtdna point mutations are maternally inherited and show huge phenotypic heterogeneity. 17 There are thousands of mtdna molecules per cell and millions per individual and any mtdna mutation may # The Board of Management and Trustees of the British Journal of Anaesthesia All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Mitochondrial disorders and general anaesthesia affect all (homoplasmy) or only part (heteroplasmy) of the total mitochondria in each cell. The notion that the percentage of mutant mtdna load contributes to disease expression is a fundamental concept in mitochondrial disease. The phenotypic presentation of any particular mutation is therefore dependent on a number of factors: the severity of the DNA mutation, the proportion of mitochondria affected, and the susceptibility of various tissues to impaired mitochondrial energy metabolism. 417 Diagnostic confirmation is not straightforward in mitochondrial disease and a high index of clinical suspicion is essential. A multi-system search for disease is warranted to identify further organ systems affected that were not clinically apparent at presentation. Initial screening tests for the presence of a mitochondrial disorder include the determination of lactate pre- and post-prandially. 14 A persistent hyperlactaemia with elevated lactate/pyruvate ratios is highly suggestive of a respiratory chain disorder and should prompt further investigation. Not all patients with respiratory chain disorders will demonstrate these abnormalities, however, and radiological imaging may provide further supportive (although not diagnostic) information alongside the clinical picture. In particular, brain MRI may show characteristic abnormalities with lytic lesions in the basal ganglia and thalamus, sometimes extending into the midbrain. Thus, clinical features alone are rarely pathognomonic in mitochondrial disease and although laboratory and radiological investigations provide important clues, muscle biopsy remains an essential part of the diagnostic process. Muscle is almost always involved to some extent in inborn errors of mitochondrial metabolism and histochemical, electron microscopic, and biochemical studies (including estimation of respiratory chain enzyme function) on skeletal muscle allow definitive diagnosis in the majority of cases. 4 Open muscle biopsy under general anaesthesia (GA) is preferred to ensure suitability of biopsy material for respiratory chain enzyme analysis. GA is therefore a common requirement for these patients, both for diagnosis and for ongoing disease management such as gastrostomy or central line insertion. As with many disorders of intermediary metabolism, children with mitochondrial disorders are at risk of metabolic decompensation. This may occur with intercurrent illness or reduced oral intake/fasting and rapidly result in a lactic acidosis leading to metabolic encephalopathy. At present, treatment remains limited and does not alter the disease course. It is largely supportive and children with multiple, often complex neuro-developmental problems should be cared for in multi-professional teams. Management involves supplementation with co-factors, nutritional support, and medical treatment of complications such as metabolic decompensation and seizures. Advice on the avoidance of certain drugs which are known to interfere with normal mitochondrial function such as valproate and barbituarates is also essential. Although it poses a challenge to clinicians, genetic counselling also forms an important aspect of care for the family of a child with mitochondrial disease Mitochondria are a potential site of action for general anaesthetic agents 20 and it is feasible that children with mitochondrial disease will respond abnormally to anaesthetic drugs. There are various concerns with regard to GA in this patient group, with a generally held belief that patients with mitochondrial disease are at increased risk during anaesthesia. These concerns in part relate to the general stress response to surgery which may be particularly detrimental in this patient group, but also to the use of the anaesthetic agents themselves. However, the evidence base in the literature for this belief is limited (Table 1) It consists predominantly of case reports and short patient series and it is most notable for the variety of anaesthetic approaches and variable patient response. It provides little useful evidence base or guidance for clinicians and anaesthetists involved in the care of these complex patients. Our aim was to document current practice and the incidence of adverse events occurring during GA in a series of children with mitochondrial disease, to assist the development of evidence-based guidelines. Methods We undertook a retrospective case review study of mitochondrial patients who had undergone GA for surgical procedures within the regional metabolic service for the period The indication for GA was based on clinical need. Eligible patients were identified from the paediatric metabolic database. Inclusion criteria: children of any age with mitochondrial disorder diagnosed as per the modified Walker diagnostic criteria for respiratory chain disorders in children. 1 These criteria comprise major and minor features in various clinical, histology, enzymology, functional, and molecular parameters to produce a definite, probable, or possible diagnosis of respiratory chain disorder (Table 2). Exclusion criteria: patients who appeared on paediatric metabolic database who did not meet modified Walker criteria. We undertook a review of anaesthetic records: drug and fluid prescription charts were available from patient records. For each anaesthetic episode, we documented agents (anaesthetic), duration, and recorded stability of physiological parameters (heart rate, arterial pressure, and pulse oximetry). Any observation of intraoperative adverse event was documented from charts as recorded by the anaesthetist. Adverse events were classified as (i) mechanical/airway related or (ii) metabolic decompensation for the duration of the inpatient admission. A procedure performed within the immediate 24 h after the decision to 437

3 Footitt et al. Table 1 Summary of published literature in mitochondrial disease and GA. RCE, respiratory chain enzyme; MERRF, myoclonic epilepsy with ragged red fibres; MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Author (year) Number of cases Anaesthetic agent(s) Diagnosis Adverse event/outcome Driessen and colleagues (2007) Various Various RCE deficiencies Nil Vilela and colleagues (2005) 24 1 Propofol, fentanyl, sevoflurane, MERRF Nil midazolam Singh and colleagues (2004) 21 1 Propofol, alfentanil MELAS Nil Henike and Schaffranietz (2004) 11 1 Propofol, alfentanil, cis-atracurium Mitochondrial Respiratory complications encephalomyopathy Cooper and Fox (2003) 5 1 Propofol, desflurane, fentanyl, vecuronium Leigh s disease Aspiration pneumonia, progressive brain stem necrosis. Death day 62 postprocedure Morgan and colleagues (2002) Sevoflurane, fentanyl Various RCE deficiencies Nil Sharma and colleagues (2001) 18 1 Propofol, fentanyl, rocuronium, Complex I and IV deficiency Nil morphine Thiel and colleagues (2001) 22 1 Propofol, fentanyl MELAS Hyperlactaemia no clinical consequence Wallace and colleagues (1998) 25 1 Halothane, atracurium, morphine Complex III and IV deficiency Nil Finsterer and colleagues (1998) 9 1 Propofol, fentanyl, midazolam Mitochondrial myopathy Increased sensitivity to rocuronium, atracurium Casta and colleagues (1997) 3 1 Midazolam, thiopentone, fentanyl, isoflurane, pancuronium Thompson and Wahr (1997) 23 1 Midazolam, propofol, cis-atracurium, fentanyl, neostigmine undertake it was classified as an acute. All other procedures were classified as elective. We did not review pre- and postoperative biochemistry or blood gas analysis as they were not routinely performed in all patients. We do report these in patients where any adverse event was recorded. Results Forty-two cases with suspected mitochondrial disease that had undergone GA between 1989 and 2005 were identified. Four cases were excluded as they did not strictly fulfil the Walker diagnostic criteria. Thirty-eight patients underwent 69 episodes of GA, for which anaesthetic records were available in the notes of 58. Data presented are for the 58 episodes in 38 patients. Fifty episodes were elective and eight acute. The median age was 4 yr (range ) with 27 male and 11 female patients. There were 50 elective procedures. These included 27 muscle biopsies with or without lumbar puncture, eight MRI of the brain, five otolaryngological procedures, five central line insertions, four gastrostomy insertions, and one liver transplant. There were eight acute procedures Complex I, III, and IV deficiency MELAS neuromuscular block Focal neurological signs, white matter degeneration on MRI Death 5 weeks post-surgery Nil Shenkman and colleagues (1997) 19 1 Ketamine, midazolam, propofol Leigh s syndrome Nil Naguib and colleagues (1996) 15 1 Propofol, mivacurium Mitochondrial myopathy Extreme sensitivity to mivacurium prolonged recovery Maslow and Lisbon (1993) 12 Triggering agent Nil Grattan-Smith and colleagues 16 Various agents including (1990) 10 Papaveretum (morphine and codeine) Leigh s syndrome Postop respiratory failure in three patients who received Papaveretum Burns and Shelley (1989) 2 Triggering agent Mitochondrial dysfunction Nil Ohatani and colleagues (1985) 16 1 Suxamethonium Mitochondrial dysfunction Malignant hyperthermia which included five central line insertions, one bronchoscopy, one laparotomy and one muscle biopsy. The median duration of procedure was 1 h (range ). Inhalation and i.v. agents were used to induce and maintain anaesthesia with a variety of neuromuscular blocking agents, analgesics, and other drugs (Table 3). In our series, a variety of i.v. fluids were used in 34/58 (59%) cases; in 26/34 (76%) fluid therapy began before operation. Ten per cent dextrose was used in 9/34 (26%), 0.45% saline and 5% dextrose in 6/34 (18%), Hartman s in 6/34 (18%), 0.9% saline in 4/34 (11%), 0.18% saline and 4% dextrose in 2/34 (6%), and 5% dextrose in 1/34 (3%), blood products in 1/34 (3%) case. The type of fluid was unspecified in 5/34 (15%) cases. There were no significant documented intraoperative adverse events attributable to the anaesthesia. There was one difficult intubation recorded and one desaturation related to secretions which responded to airway suctioning. There were no episodes of malignant hyperthermia or rhabdomyolysis. Three significant adverse clinical events occurred after operation (Table 4). Two were related to inadequate fluid replacement and one was a metabolic decompensation. 438

4 Mitochondrial disorders and general anaesthesia Table 2 Modified Walker diagnostic criteria for respiratory chain disorders in children. Definite diagnosis: two major OR one major plus two minor. Probable diagnosis: one major plus one minor OR at least three minor. Possible diagnosis: single major OR two minor (one of which must be clinical) Major Clinical Clinically complete RC encephalomyopathy OR mitochondrial cytopathy defined as fulfilling all three of the following conditions: unexplained combination of multisystemic symptoms to include at least three systems; progressive clinical course with episodes of exacerbation or a family history that is indicative of a mtdna mutation; and exclusion of other metabolic and non-metabolic disorders Histology.2% red ragged fibres in skeletal muscle Enzymology.2% COX-negative fibres,30% activity of any RC complex in a cell line,30% activity of the same RC complex activity in 2 tissues Functional Fibroblast ATP synthesis rates.3 SD below mean Molecular Identification of a nuclear or mtdna mutation of undisputed pathogenicity Minor Clinical Symptoms compatible with a RC defect Histology Any ragged red fibres.2% subsarcolemmal mitochondrial accumulations Widespread EM abnormalities in any tissue Enzymology 30 40% activity of ay RC complex in a cell line 30 40% activity of the same RC complex in 2 tissues Functional Fibroblast ATP synthesis rates 2 3 SD below mean Fibroblasts unable to grow on media with glucose replaced by galactose Molecular Identification of a nuclear or mtdna mutation of probable pathogenicity Metabolic One or more metabolic indicators of impaired RC function Discussion This is a large paediatric case series and represents the broad age range and clinical spectrum of multi-system involvement seen in mitochondrial disease. The variety of surgical procedures is typical of that encountered in this patient group and our series includes both elective and emergency procedures of variable duration. Anaesthetic technique was at the discretion of the anaesthetist involved and on an individual patient basis. A variety of anaesthetic agents were used and the pattern of agent use reflects that seen in standard paediatric anaesthetic practice. This review demonstrates that, despite theoretical concern about this cohort of patients, metabolic decompensation after GA is rare (one case in 58 episodes). As with any retrospective case notes review, medical records were incomplete or not available in some cases. In five cases, the GA was performed at peripheral hospital sites and these notes were not reviewed. In this series, suxamethonium was used in two cases without any adverse sequelae. In keeping with usual practice, however, non-depolarizing neuromuscular relaxants Table 3 Anaesthetic agents and other pharmacological agents in 58 procedures Induction Sevoflurane 21 Isoflurane 1 Propofol 28 Thiopentone 5 Midazolam and fentanyl 3 Maintenance Sevoflurane 21 Isoflurane 30 Sevoflurane and isoflurane 3 Propofol 4 Neuromuscular relaxants Atracurium 26 Pancuronium 1 Rocuronium 1 Suxamethonium 2 Opiates Fentanyl 24 Alfentanil 3 Morphine 2 Codeine 1 Remifentanil 1 Other Midazolam 4 Neostigmine 7 were used more frequently and no abnormal or exaggerated response was noted. Three adverse clinical events are described in this series, all of which occurred after the immediate postoperative period when the child had left the anaesthetic recovery area. The first was a 2-yr-old girl who developed hypovolaemia and required volume resuscitation after a procedure for multiple diagnostic biopsies and therapeutic aspiration of abdominal ascites. Inadequate volume replacement during surgery, in combination with the use of propofol (vasodilator effect) for induction of anaesthesia, probably contributed to the acute hypotension and hypovolaemia in this case and was unrelated to the underlying mitochondrial disease. The second case was an 8-yr-old girl who developed acute on chronic renal failure in 3 4 days after surgery for gastrostomy insertion and muscle biopsy. Gastrostomy feeding was slow to be established. Plasma lactate levels remained stable in the postoperative period and her clinical presentation was not typical of that seen in a metabolic decompensation. We therefore believe that the renal deterioration was unlikely to be related to the use of GA in mitochondrial disease. This patient has subsequently undergone another episode of GA for insertion of central line that was well tolerated and uneventful. The third case was a 1-month-old male infant who presented with seizures and neurological regression. Initial investigations demonstrated elevated plasma lactate and brain MRI changes consistent with Leigh s disease and muscle biopsy was performed at 6 weeks of age to further clarify the diagnosis. The procedure itself was 439

5 Footitt et al. Table 4 Adverse events documented in the study group Case 1 Case 2 Case 3 Procedure Diagnostic biopsies and ascitic tap Gastrostomy and muscle biopsy Muscle biopsy Duration (min) Clinical details Complex IV deficiency. Developmental delay, Complex I deficiency. Chronic renal Leigh disease seizures, nephrotic syndrome, hepatic dysfunction failure, faltering growth, lactic acidosis I.V. fluid 10% dextrose Hartman s 10% dextrose Induction agent Propofol Propofol Propofol Maintenance agent Sevoflurane Isoflurane Sevoflurane Opiate Fentanyl Fentanyl Fentanyl Benzodiazepine Midazolam Neuromuscular Atracurium Atracurium relaxant Complication Hypovolaemia Renal impairment Respiratory failure and metabolic acidosis uncomplicated and he returned to the ward after an apparently uneventful GA. Within 24 h, there was an acute deterioration with respiratory failure and metabolic acidosis with increasing plasma lactate levels. He was stabilized on the paediatric ICU, but unfortunately never recovered from this episode and died 3 days later when intensive care was withdrawn. It is difficult to clarify the impact of the surgical procedure and GA in this particular case, although there is a clear temporal relationship between the episode of GA for muscle biopsy and his metabolic decompensation. This child had severe, progressive neurometabolic disease and his clinical condition had deteriorated significantly, even in the short time since initial presentation. A previous report 10 described three patients with Leigh s disease who developed respiratory failure after GA. A variety of anaesthetic agents were used in each case, although it was noted that the same opiate-based, pre-medication (Papaveretum) was used in all three children. It is difficult, however, to draw any conclusions from this small sample. The authors highlighted pre-existing respiratory abnormalities as the only discriminating factor when comparing these three patients with others with Leigh s disease who underwent GA without a problem. In our case, no respiratory abnormality was documented before operation, although his clinical deterioration followed a similar pattern. It has been suggested that a combination of postoperative raised inflammatory mediators (inhibitors of the mitochondrial electron transport chain) in patients with an oxidative phosphorylation defect might lead to a critical degree of mitochondrial failure, particularly in the central nervous system. This may cause clinical deterioration unrelated to the nature of the anaesthetic agents used. 3 Further work in this area may help to clarify the effect of the surgical stress response in mitochondrial patients. This review of anaesthetic episodes demonstrates that routine management of mitochondrial patients undergoing GA did not differ to that seen in the normal paediatric population and our results suggest that there is no case for avoiding any particular anaesthetic agent in these patients. This is in agreement with recently published data 7 which reviewed anaesthetic morbidity after GA for muscle biopsy alone in children with mitochondrial defects. It would seem pertinent, however, to avoid the prolonged use of propofol for maintenance of anaesthesia and to use neuromuscular relaxants judiciously. Meticulous individual assessment is important due to the diverse nature of mitochondrial disease and, as with any surgical case, careful attention to fluid management is essential. Preoperative fasting in this patient group may be particularly hazardous as they have a tendency to develop lactic acidosis which will be exacerbated by periods of metabolic stress such as that seen during surgical procedures and perioperative fasting. We recommend the routine, perioperative use of lactate free i.v. fluids in all patients with mitochondrial disease undergoing GA (such as 5% dextrose 0.9% saline). I.V. fluids should be commenced during the preoperative fasting period to allow maintenance of normoglycaemia, as excessive glycolytic oxidation of glucose in this patient group may increase plasma lactate levels. As may be expected, those patients with more severe clinical disease seem to be at greater risk after GA and further work should be directed towards Leigh s disease in particular, especially those with documented variable respiratory drive. Further prospective studies will enable a thorough analysis of perioperative patient management and the use of GA in mitochondrial disease, with the aim to create evidence-based clinical guidelines. References 1 Bernier FP, Boneh A, Dennett X, et al. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002; 59: Burns AM, Shelley MP. Anaesthesia for patients with mitochondrial myopathy. Anaesthesia 1989; 14: Casta A, Quackenbush EJ, Houck C, et al. Perioperative white matter degeneration and death in a patient with a defect in mitochondrial oxidative phosphorylation. Anesthesiology 1997; 87:

6 Mitochondrial disorders and general anaesthesia 4 Clarke JTR. A Clinical Guide to Inherited Metabolic Diseases, 3rd Edn. Cambridge: Cambridge University Press; 14 7, Cooper MA, Fox R. Anesthesia for corrective spinal surgery in a patient with Leigh s disease. Anesth Analg 2003; 97: DiMauro S, Schon E. Mitochondrial respiratory-chain diseases. New Engl J Med 2007; 348: Driessen J, Willems S, Dercksen S, Giele J, Van der Staak F, Smeitink J. Anaesthesia-related morbidity and mortality after surgery for muscle biopsy in children with mitochondrial defects. Pediatr Anesth 2007; 17: Filosto M, Mancuso M. Mitochondrial diseases a nosological update. Acta Neurol Scand 2007; 115: Finsterer J, Sratil U, Bittner R, et al. Increased sensitivity to rocuronium and atracurium in mitochondrial myopathy. Can J Anaesth 1998; 45: Grattan-Smith PJ, Shield LK, Collins KJ. Acute respiratory failure precipitated by general anesthesia in Leigh s syndrome. J Child Neurol 1990; 5: Heinke W, Schaffranietz L. Anaesthesia for combined pancreatic and renal transplantation in a patient with mitochondrial encephalopathy a case report. Anaesthesiol Reanim 2004; 29: Maslow A, Lisbon A. Anesthetic considerations in patients with mitochondrial dysfunction. Anesth Analg 1993; 76: Morgan PG, Hoppel CL, Sedensky MM. Mitochondrial defects and anaesthetic sensitivity. Anaesthesiology 2002; 96: Munnich A. Defects of the respiratory chain. In: Fernandes J, Saudubray J-M, van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases, 4th Edn. Springer, 2006; Naguib M, El Dawlatly AA, Ashour M, et al. Sensitivity to mivacurium in a patient with mitochondrial myopathy. Anesthesiology 1996; 84: Ohtani Y, Miike T, Ishitshu T, et al. A case of malignant hyperthermia with mitochondrial dysfunction. Brain Dev 1985; 7: Schapira AHV. Mitochondrial disease. Lancet 2006; 368: Sharma AD, Erb T, Schulman SR, et al. Anaesthetic considerations for a child with combined Prader Willi syndrome and mitochondrial myopathy. Paediatr Anaesth 2001; 11: Shenkman Z, Krichevski I, Elpeleg O, Joseph A, Kadari A. Can J Anaesth 1997; 44: Shipton EA, Prosser DO. Mitochondrial myopathies and anaesthesia. Eur J Anaesthesiol 2004; 21: Singh B, Low PS, Yeo JF. MELAS: a case report. Ann Acad Med 2004; 33: Thiel A, Ritzka M, Saur G. Anesthesia in mitochondrial encephalomyopathies. Anaesthesiol Intensivmed Notfallmed Schmerzther 2001; 36: Thompson VA, Wahr JA. Anaesthetic considerations in patients presenting with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. Anesth Analg 1997; 85: Vilela H, Garcia-Fernandez J, Parodi E, et al. Anaesthetic management of a patient with MERRF syndrome. Pediatr Anesth 2005; 15: Wallace JJ, Perndt H, Skinner F, et al. Anaesthesia and mitochondrial disease. Pediatr Anaesth 1998; 8: