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Mitochondrial myopathies and anaesthesia

Shipton, E. A.; Prosser, D. O.

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European Journal of Anaesthesiology: March 2004 - Volume 21 - Issue 3 - p 173-178


The cellular machinery for energy metabolism comprises the Kreb's cycle, fatty acid oxidation and oxidative phosphorylation all of which are found within the mitochondria [1]. Human mitochondrial deoxyribonucleic acid (DNA) is a double-stranded circular molecule that encodes 37 gene products (13 proteins, 2 ribonucleic acids and 22 transfer ribonucleic acids) over 16 569 base pairs [2]. Part of the polypeptide subunits involved in oxidative phosphorylation are encoded by mitochondrial DNA [3]. Each human cell contains multiple mitochondria. Each mitochondrion may contain 10 or more mitochondrial DNA molecules [2]. Usually all copies of the mitochondrial DNA are identical, and this is referred to as homoplasmy [2]. The mitochondria produce the energy requirements of muscle cells through the reduction and oxidation reactions of the electron transfer chain and oxidative phosphorylation, giving rise to adenosine triphosphate (ATP) production [4]. There are a comparable and growing number of mutations within the mitochondrial DNA [2]. In mitochondrial disorders, there are more than a hundred described conditions reflecting the fact that nearly all organ systems use oxidative metabolism [2]. Each disease spectrum may correspond to several sets of mutations, each set affecting a mitochondrial transfer RNA or a respiratory chain protein subunit [2]. Mitochondrial myopathies are therefore genetically and phenotypically a heterogeneous group of disorders caused by structural or functional abnormalities in mitochondria leading to involvement of nervous system and muscles (mitochondrial encephalomyopathies) and other organ systems [5]. They have an estimated incidence of 1 in 4000 and a broad spectrum of clinical presentations [6]. The age of symptom onset may vary from birth to late adulthood with most cases presenting by the age of 20 [5,6]. As such, they may constitute one of the largest diagnostic categories of neurogenetic disorders among adults.

Abnormalities of electron transport and oxidative phosphorylation are the most common causes of mitochondrial myopathies [5]. The oxidative phosphorylation pathway consists of five protein complexes. Complex I and II independently transfer electrons to coenzyme Q and then sequentially to complexes III-V [1]. In isolated mitochondria, complex I is capable of using several carbon sources as fuel, among them pyruvate (when coupled to malate) and glutamate [1]. Complex II is restricted to the use of succinate as an energy source. The remaining complexes can act independently with specific electron donors [1]. Mitochondrial DNA encodes portions of respiratory chain enzymes [7]. Mutations result in defects in translation of respiratory chain enzymes that reduce the capacity of oxidative phosphorylation [7]. Neurons and muscle cells with a high metabolic turnover are excessively affected [7]. Cardiac involvement may lead to cardiac myopathies and conduction defects [6]. Kidney (glomerulopathies) and liver cells are less affected.

To study the effects of anaesthetic agents on oxidative phosphorylation, a nematode, Caenorhabditis elegans has been used [1]. Defective complex I functioning decreased the effective concentration of volatile anaesthetics by 20% of that of the wild type [1]. Defects in complex II functioning did not affect anaesthetic sensitivity in this animal model [1]. With both complex I and II defects, the nematodes moved normally but were short-lived and were very sensitive to hyperoxia [1]. A new animal model for mitochondrial myopathy has been developed by disrupting the gene for mitochondrial transcription factor in the skeletal muscle of the mouse [8].

Three groups of underlying mitochondrial abnormalities are recognized [5,6]. Firstly, there are the respiratory chain deficiencies (complexes I-IV). Secondly, there are mitochondrial DNA mutations involved in the pathogenesis of the mitochondrial encephalomyopathies (e.g. the mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE) and myoclonic epilepsy with ragged red fibres (MERRF) syndromes - see later). Thirdly, there are mitochondrial deletions (Kearns-Sayre syndrome) with multisystemic involvement. More recently, Schapira has devised a classification scheme for mitochondrial disorders based primarily on whether or not the affected gene product is directly involved in oxidative phosphorylation (class I) and whether it is transcribed by mitochondrial RNA or nuclear RNA (class II) [9]. The understanding of a genetic disorder state proceeds through three stages from recognition of the disorder or syndrome, to discovery and mapping of the related mutation(s), and finally, to elucidation of the biochemical/biophysical mechanism leading to the disease phenotype [2]. Identifying the specific biochemical and genetic abnormalities is possible in many patients with mitochondrial encephalomyopathies.

The diagnosis is established by evidence of multineuraxial contribution together with raised serum lactic acid and positive muscle biopsy for mitochondrial abnormalities confirmed by genetic analysis for mitochondrial DNA or nuclear gene mutations [5]. Although a polymerase chain reaction test performed on DNA from blood samples can detect deletions in mitochondrial DNA, the best means of achieving definitive diagnosis is via analysis of a muscle biopsy, with quantification of the level of deletion using Southern blot analysis [7]. Mitochondrial DNA is maternally inherited, as during the formation of the zygote, all mitochondria come from the ovum [6]. Two characteristics of mitochondrial DNA, namely heteroplasmy and threshold level allow for variable phenotypical expression, resulting in family members with identical DNA mutations presenting different clinical phenotypes [10]. The insidious onset and pleiotropic phenotype of these disorders often makes diagnosis difficult [11]. Therefore the peculiar genetic characteristics of mitochondrial DNA (maternal inheritance, heteroplasmy and mitotic segregation) impart distinctive properties to these disorders.

In the mitochondrial myopathies, the characteristic pathologic findings in skeletal muscle are as follows [5]: (a) on trichrome stain, the ragged red fibres have a peripheral rim of red material caused by the subsarcolemmal aggregation of mitochondria; (b) dense peripheral staining for the activity of succinic dehydrogenase occurs, which is a mitochondrial enzyme involved in the tricarboxylic acid cycle and can be seen in ragged red fibres; (c) there is a presence of many fibres negative for the activity of cytochrome oxidase, which is complex IV of the respiratory chain enzymes; (d) combined succinic dehydrogenase/cytochrome oxidase staining demonstrates ragged red fibres to be cytochrome oxidase negative and (e) electron microscopy shows both an increase in mitochondria and the presence of morphologically abnormal mitochondria (inclusions, giant mitochondria).

Currently, no specific therapy exists for any of these conditions [6]. There are only anecdotal reports of symptomatic success with a number of vitamins and co-factors (thiamine, riboflavin, vitamins C and K, carnitine) and glucocorticoids [4,5]. Coenzyme Q10 has proved beneficial in some studies [5,12]. The use of phenytoin and barbiturates in controlling epilepsy in these patients has been questioned [13]. High carbohydrate diets have been recommended to compensate for impaired gluconeogenesis and to reduce lipolysis [5].

Chronic progressive external opthalmoplegia presents with ptosis, opthalmoplegia and limb myopathy. MERRF syndrome is characterized by mitochondrial myopathy, seizures, myoclonus, intellectual deterioration, ataxia and deafness [5]. It is maternally inherited with onset in late childhood. Serum and cerebrospinal fluid lactate are increased. Most often, point mutations are found on the lysine transfer RNA gene of mitochondrial DNA (nucleotides 8344 and 8356) [5]. MELAS syndrome is a classical mitochondrial encephalomyopathy with multisystem involvement and variable clinical presentations [7]. Normal early development most often occurs followed in childhood by the onset of myopathy (with exercise intolerance), encephalopathy, lactic acidosis, stroke-like episodes (hemiparesis, hemianopia, cortical blindness), and seizures and dementia [5]. Other features include episodic vomiting and deafness [5]. About 80% of the MELAS syndrome is caused by A-to-G substitution of the leucine transfer RNA gene of mitochondrial DNA identified at nucleotide 3243 [7].

The Kearns-Sayre syndrome is a sporadic, non-inherited disorder with onset before the age of 20 yr. It presents with progressive external opthalmoplegia, cardiac conduction block and pigmentary retinal degeneration [5]. Other features include dysphagia and skeletal muscle weakness, deafness, ataxia, dementia, episodic coma and endocrine abnormalities (e.g. short stature, hypogonadism) [5]. Cerebrospinal fluid lactate, pyruvate and protein (>100 mg dL−1) levels are elevated [5]. There are variable numbers of ragged red fibres on muscle biopsy [5]. Wild and mutant populations of mitochondrial DNA are present in the same cell, the mutations of the latter consisting of single mitochondrial DNA deletions.

MNGIE is characterized by ptosis, progressive opthalmoplegia, gastrointestinal dysmotility, thin body habitus, peripheral neuropathy, myopathy, leukoencephalopathy and lactic acidosis [2]. Multiple mitochondrial DNA deletions or depletions (or both) are present [2]. Neuropathy, ataxia and retinitis pigmentosa (NARP) is a syndrome featuring proximal muscle weakness, sensory neuropathy, seizures, dementia and retinal pigmentary degeneration [11]. The underlying defect involves a mitochondrial ATP synthase gene coding subunit 6 of complex V. Mutations at nucleotide 8993 are also responsible for the presentation of the more severe, fatal Leigh syndrome phenotype [11]. Leigh syndrome (sub-acute necrotizing encephalopathy) is frequently associated with cytochrome oxidase deficiency, though no disease-related mutations of the mitochondrial DNA-encoded cytochrome oxidase subunits have been reported [2]. Leber's hereditary optic neuropathy is a syndrome showing painless bilateral, sub-acute visual loss with dyschromatopsia. The primary mitochondrial DNA mutations are at nucleotide positions 11778 (NADH dehydrogenase-4 gene), 14459 (NADH dehydrogenase-6 gene) and 3460 (NADH dehydrogenase-1 gene) [2].

Mitochondrial myopathies present with proximal muscle weakness with raised lactic acid and positive muscle biopsy for mitochondrial cytopathy [10]. Fatigue and poor stamina are prominent clinical features. Movement disorders (dystonia, myoclonus, chorea, athetosis and tremors) have been described as due to mitochondrial abnormalities [10].

Patients may present for anaesthesia as part of the investigative process [10]. Muscle biopsies that require general anaesthesia are performed in young children to determine the specific aspect of mitochondrial function affected [1]. Mitochondria are a potential site of action of general and local anaesthetics [14]. As the central nervous system has a high demand for energy, patients with mitochondrial myopathies may be sensitive to anaesthesia [1]. There is no single anaesthetic technique that is indicated [15]. There are case reports of the successful use of general as well as regional anaesthesia, despite local anaesthetics disrupting oxidative phosphorylation in mitochondrial isolates [6,11]. Differing techniques and anaesthetic agents have been used with success [1,4,6,7,10-12,15-17]. Yet there have been reports of serious complications occurring during and after anaesthetic administration [1]. Total intravenous (i.v.) anaesthesia (propofol, alfentanil) has been used to avoid any drugs that could precipitate malignant hyperthermia [6]. It is also a useful technique to use in young children to avoid masseter rigidity (that may mimic malignant hyperthermia) with volatile (halothane) induction [12].

The use of regional anaesthesia eliminates the risk of prolonged muscle relaxation, central nervous system depression and the possibility of malignant hyperthermia as well as providing good postoperative analgesia [7]. In mitochondria, local anaesthetics uncouple oxidative phosphorylation and inhibit enzymatic complexes [14]. The uncoupling effect of local anaesthetics corresponds to the dissipation of the transmembrane proton gradient [14]. This leads to a reduced efficiency of ATP synthesis [14]. The depressant effects of bupivacaine on mitochondrial function are reinforced in the hypoxic left ventricle [14]. Although no neurological sequelae have been reported following spinal or epidural anaesthesia, it should be avoided in the presence of neurological abnormalities of the peripheral nerves or of the spinal cord [7]. Full blood counts are performed to eliminate any macrocytic anaemia, neutropaenia and thrombocytopaenia in these patients [10]. With any hepatic dysfunction, assessment of coagulation function should precede any central neuraxial block [10]. Caudal anaesthesia can be a useful adjunct to general anaesthesia in children [12].

Volatile anaesthetics affect the brain and the heart. Both these organs are highly dependent on oxidative phosphorylation [1]. At higher than clinical doses, volatile anaesthetic agents reduce oxidative phosphorylation in cell-free studies in isolated mitochondria [1]. The volatile anaesthetics inhibit gas-1 gene and decrease the function of complex I, enhancing the inhibitory effects of volatile anaesthetics in the patients with mitochondrial disorders [15]. Complex I has been found to be the most sensitive step in oxidative phosphorylation to inhibition by volatile anaesthetics, requiring very low doses of sevoflurane to reach a bispectral index value of 60 [1]. Halothane and sevoflurane inhibit norepinephrine-induced glucose uptake in neonatal cardiomyocytes. With the use of volatile anaesthetic agents, lactic acidosis can result [15].

Preoperative work-up of patients should include an erythrocyte sedimentation rate, full blood count, electrolytes (including calcium and magnesium), serum glucose, glycosylated haemoglobin (HbA1C), lactate, pyruvate, serum creatinine kinase, liver and renal profiles, thyroid function tests, arterial blood gas and urine analysis [6]. In the planning of perioperative care, multidisciplinary consultations may be required as patients are usually treated by a variety of medical specialists. Other specialist investigations may include electromyography, nerve conduction studies and audiograms, magnetic resonance imaging, magnetic resonance spectroscopy and positron emission tomography [5,7,12,15].

A preoperative assessment of functional organ system reserve is required [11]. The peripheral musculature may show fatigue, and the respiratory and swallowing functions may be impaired [13]. The degree of neurological and musculoskeletal compromise should be determined preoperatively [13]. Measurement of the venous partial pressure of oxygen during aerobic forearm exercise provides an easily performed screening test that detects impaired oxygen use and the severity of oxidative impairment in patients with mitochondrial myopathy and exercise intolerance [18]. Respiratory function is frequently compromised before surgery and patients are at a higher risk of postoperative respiratory complications [6]. A history of chest infections and apnoea should be sought [10]. Pulmonary flow volume loops, a chest X-ray and blood gases are indicated preoperatively in these patients. Respiratory depressants should be avoided with premedication as respiratory responses to hypoxaemia and hypercapnia are impaired [10]. Patients with progressive bulbar muscle involvement are especially predisposed to aspiration and care must be taken to reduce gastric volume and acid secretion, and to keep the gastric pH above 2.5 with the use of adequate (but not prolonged) fasting, nasogastric and percutaneous gastrostomy tubes, histamine-2 receptor antagonists, proton pump inhibitors and non-particulate antacids [6].

A 12-lead electrocardiograph should be performed preoperatively to eliminate cardiomyopathies (dilated and hypertrophic), pre-excitation syndromes (Wolf-Parkinson-White), conduction defects (heart blocks) and hypertension all of which may require further work-up using echocardiography [6,10,16]. There is increased risk of sudden death from conduction abnormalities [11]. Atrioventricular conduction blocks occur in patients with Kearns-Sayer syndrome [10].

Exercise intolerance and limb weakness are indicative of muscle wasting arousing concerns for suxamethonium-induced hyperkalaemia and sensitivity to neuromuscular blocking agents [16]. Malignant hyperthermia has been reported in a single case after induction with the use of suxamethonium [19]. The association with malignant hyperthermia remains unproven [6]. It is thought sensible to avoid the use of known triggering agents until definitive data becomes available [4].

Liver function and hepatic mitochondrial redox potentials can be measured by arterial and venous ketone body ratios, calculated by the ratio of acetoacetate to 3-hydroxybutyrate [15]. If the liver and kidney are affected, this might lead to altered pharmacokinetics and pharmacodynamics of any drugs used [6,10]. This implies careful drug dose titration [6,10]. Indeed, all body systems may be affected.

Metabolic dysfunction due to liver involvement may result in altered glucose, lactate and protein metabolism [6]. Glucose management can be challenging requiring frequent assessment [17]. In the newborn, glucose represents the sole energy supply to the heart [15]. In children, preoperative hypoglycaemia should be avoided by the i.v. infusion of glucose-containing fluids or glucose-containing solutions up to 3 h preinduction [17]. The prevalence of diabetes is higher in patients with mitochondrial myopathies [7,11,16].

Patients often have elevated serum lactate levels [5,7]. Although a raised lactic acid concentration is not considered to be a specific test, it points to the diagnosis especially when significantly elevated [5]. Lactic acidosis is usually worsened by stress [7]. In mitochondrial myopathies, high lactate production may contribute to the decreased muscle function observed by inhibiting the production of interleukin-6 [20]. Any increases in metabolic stress that may provoke or worsen lactic acidosis should be avoided [10]. Adequate oxygenation and minimization of oxygen demands, stable cardiovascular functions, maintenance of normal serum glucose levels, and acid-base and electrolyte balance help to minimize acidosis [10,16].

Communication may be a problem in these patients due to sensory deprivation [10,12]. The presence of a parent or guardian during induction is beneficial. Excessive preoperative fasting should be avoided and good hydration maintained [21]. Monitoring should be matched to the clinical state and the surgery performed. A basic minimum would be continuous electrocardiograph and pulse rate, non-invasive blood pressure, pulse oximetry, capnography and temperature monitoring [4,10,12,15,17]. Temperature monitoring with a nasopharyngeal probe is essential to maintain normothermia [16]. All i.v. fluids and epidural local anaesthetic solutions should be warmed to body temperature [4]. It is advisable to avoid Ringer's lactate to prevent an exacerbation of lactic acidosis [15]. Maintaining normothermia (core and surface), normoglycaemia and avoiding metabolic stress are important in the perioperative management of these patients [15]. In cardiac bypass, normothermia during the bypass avoids mitochondrial stress from hypothermia [15].

Aerobic metabolism is already dysfunctional [10], and any increases in basic metabolic rate (such as perioperative shivering) should be prevented [7]. Any increases in oxygen consumption should be minimized by maintaining normal body temperature and adequate surgical anaesthesia (either general or regional) should be provided [7]. A cardiovascularly stable anaesthetic is recommended [16]. Any anaesthetic agents that depress cardiovascular function should be avoided. During spontaneous breathing, all opioids and sedative-hypnotics should be carefully titrated due to the decreased ventilatory response to hypoxia and hypercarbia [16].

Effective perioperative analgesia will avoid increases in metabolism, provide comfort and allow early ambulation [7]. In spontaneously breathing patients, the cautious use of opioids is advised as opioids may further impair regulation of breathing and lead to a respiratory acidosis (in addition to any underlying metabolic acidosis) [10]. A multimodal analgesic approach should be used involving the use of opioid administration (via i.v. infusion or patient-controlled analgesia), non-steroidal anti-inflammatory drugs and the use of local anaesthesia at wound sites, peripheral nerves, regional plexuses and neuraxially [10].

In labour and delivery in women with mitochondrial myopathies, the management should be individualized according to the severity of the disease and by multidisciplinary consensus [4]. Epidural analgesia reduces stress and work associated with labour and reduces oxygen demand during labour [4]. Patients with documented increased lactate concentrations at rest and exercise are best managed with elective Caesarean sections as soon as fetal lung maturity has been confirmed under regional anaesthesia to prevent life-threatening lactic acidosis during labour [4].

Unusual sensitivity to i.v. induction agents (thiopentone, etomidate) can occur in these patients [10,16]. The effects of propofol and midazolam on the mitochondrial respiratory chain activity have been studied in vitro[17]. Both drugs inhibit coupling between mitochondrial respiration and oxidative phosphorylation in vitro[17]. It is thought that propofol modifies mitochondrial enzyme conformations [17]. Propofol and midazolam decrease complex I respiratory chain in a dose-dependent manner [17]. Complex IV respiratory chain activity is unaffected by midazolam [17]. The clinical outcome of these in vitro studies remains unclear [17].

Given the potential for increased sensitivity to nondepolarizing muscle relaxants in these patients, long-acting agents should be avoided [17]. Intermediate acting relaxants such as vecuronium and rocuronium have been used at reduced dosages [6,17]. Neuromuscular blockade should be monitored with a nerve stimulator (train-of-four or double burst stimulation) [6]. This will guide further relaxant administration. Reversal of non-depolarizing muscle relaxants with neostigmine and glycopyrrolate can then be undertaken once the four twitches have returned [6].

After major surgery, vigilant monitoring of respiratory function should be maintained in the intensive care unit [15]. With low hepatic mitochondrial activity, phagocytosis by Kupffer cells and the reticuloendothelial system activity decline. This may result in an increase in the incidence of postoperative infections [15].

While uncommon, mitochondrial myopathies present specific difficulties with regards to anaesthesia. There have been few recommendations in the anaesthetic literature as to their appropriate management [8,10]. In the post genome era, however, new genomic or proteonomic tools are emerging to aid in the diagnosis and potentially the therapy of mitochondrial myopathies [2]. Increased understanding of the pathophysiology involved will lead to better anaesthetic management of these conditions.


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ANAESTHESIA, general, regional; MITOCHONDRIAL MYOPATHIES, MELAS syndrome, Kearns-Sayre syndrome, MERRF syndrome, Leigh disease

© 2004 European Society of Anaesthesiology