History

Between 1915 and 1925, one family experienced three anesthetic-induced MH deaths with rigidity and hyperthermia and was puzzled for decades regarding the cause of these deaths. MHS was eventually confirmed in three descendants by in vitro muscle biopsy tests. In 1929, Ombrédanne described anesthesia-induced postoperative hyperthermia and pallor in children accompanied by significant mortality but did not detect any familial relationships. Critical worldwide attention to MH began in 1960 when Denborough and associates reported a 21-year-old Australian with an open leg fracture who was more anxious about anesthesia than about surgery because 10 of his relatives died during or after anesthesia. Denborough and colleagues initially anesthetized him with the then-new agent halothane, halted it when signs of MH appeared, successfully treated the symptoms, aborted the syndrome, and subsequently used spinal anesthesia. Further evaluations by George Locher in Wausau, Wisconsin, and Beverly Britt in Toronto, Canada, led to the discovery that MH risk was indeed familial. It was also found that the cause of the syndrome was the result of skeletal muscle involvement rather than central loss of temperature control by the recognition of increased muscle metabolism or muscle rigidity early in the syndrome, low-threshold contracture responses, and elevated creatine kinase (CK) values.

Interestingly, a similar syndrome was discovered in swine inbred with breeding patterns designed to produce a rapid growth rate and superior muscle development (e.g. , Landrace, Piétrain, Duroc, and Poland China). Porcine stress syndrome , which is associated with increased metabolism, acidosis, rigidity, fever, and death from rapid deterioration of muscle and results in pale, soft, exudative pork, can be triggered by any stress, such as separation, shipping conditions, weaning, fighting, coitus, or preparation for slaughter, and had become a significant problem for meat production. In 1966, Hall and coworkers reported that a syndrome that appeared to be identical to MH could be induced in stress-susceptible swine by the administration of halothane and succinylcholine. The cause of this syndrome in pigs was discovered to be a single missense mutation in RyR1 , and all susceptible swine have the same Arg615Cys mutation in the SR calcium release channel RyR1.

In 1975, Harrison described the efficacy of dantrolene in preventing and treating porcine MH, which was rapidly confirmed in humans by a multihospital evaluation of dantrolene used to treat anesthetic-induced MH episodes. Today, dantrolene still remains the primary pharmacologic approach for successful MH therapy.

Physiology and Pathophysiology of Excitation-Contraction Coupling and Malignant Hyperthermia

MH is a syndrome caused by dysregulation of excitation-contraction (EC) coupling in skeletal muscle. Normal muscle contraction is initiated by nerve impulses arriving at the neuromuscular junction (i.e. , the motor end plate) that trigger the release of acetylcholine from the nerve terminal. Acetylcholine activates nicotinic cholinergic receptors (nAChR), nonselective cation channels located at the postsynaptic neuromuscular junction, that are essential for local depolarization of the surface muscle membrane (sarcolemma) and initiating action potentials that propagate rapidly along the sarcolemma of muscle cells. Invaginations of the sarcolemma (termed transverse or T tubules) act as conduits to rapidly and uniformly direct-action potentials deep within the myofibrils where they transduce a conformational change in the “voltage sensor” protein Ca _V 1.1. A central T-tubule is flanked on both sides by a terminal cisternae element from the SR that contains the Ca ²⁺ release channels (RyR1). Conformational changes in Ca _V 1.1 residing within the T-tubule are mechanically transmitted to RyR1 residing in the junctional face of the SR. More specifically, physical coupling of four Ca _V 1.1 (dihydropyridine receptor) units to every second RyR1 channel form linear arrays at specialized junctions ( triadic junctions ) that are essential for linking electrical signals at the T tubules with the release of Ca ²⁺ stored within the SR. Release of SR Ca ²⁺ causes the free, cytoplasmic (sarcoplasmic) Ca ²⁺ concentration to increase from 10 ^–7 M to about 10 ^–5 M. This released Ca ²⁺ binds to contractile proteins (troponin C and tropomyosin) in the thin filament to expose myosin’s actin binding sites which allow shortening and force development by the muscle fibers (i.e. , muscle contraction). The entire process is termed excitation-contraction coupling (EC coupling) Intracellular Ca ²⁺ pumps (i.e. , sarcoplasmic/endoplasmic reticulum Ca ²⁺ -adenosine triphosphatase [ATPase], or SERCA) rapidly sequester Ca ²⁺ back into the SR lumen, and muscle relaxation begins when the Ca ²⁺ concentration falls below 10 ^–6 M and ends when the resting sarcoplasmic Ca ²⁺ concentration is restored to 10 ^–7 M. Because both contraction and relaxation are energy-related processes that consume adenosine triphosphate (ATP), knowing the molecular events contributing to EC coupling and the subsequent relaxation phase is essential to understanding the cause of MH ( Fig. 35.1 ). Clinical and laboratory data from humans, swine, and mice with knock-in mutations indicate that the fulminant MH syndrome is associated with a persistent increase in the concentration of sarcoplasmic Ca ²⁺ . The increased activity of pumps and exchangers trying to correct the increase in sarcoplasmic Ca ²⁺ associated with triggered MH increases the need for ATP, which in turn produces heat. Thus the common etiological feature of the disorder is hyperthermia. The rigidity that is frequently seen during a fulminant MH episode is the result of the inability of the Ca ²⁺ pumps and transporters to reduce the unbound sarcoplasmic Ca ²⁺ below the contractile threshold (10 ^–6 M). Dantrolene is an effective therapeutic for treatment of fulminant MH because it reduces the concentration of sarcoplasmic Ca ²⁺ to below contractile threshold. However, the pathway by which dantrolene lowers sarcoplasmic Ca ²⁺ is complex and still not fully understood. Dantrolene’s ability to suppress Ca ²⁺ release from SR appears to depend on elevated sarcoplasmic Mg ²⁺ concentration ; however the drug also attenuates depolarized-triggered Ca ²⁺ entry mediated by Ca _V 1.1, which is exacerbated in MHS muscle cells and MH normal muscle cells exposed to ryanodine. Thus whether dantrolene directly inhibits RyR1 or requires additional intermediates within the triad junctions remains to be clarified.

Key ion channels involved in neuromuscular transmission and excitation-contraction coupling. Nerve impulses arriving at the nerve terminal activate voltage-gated Ca ²⁺ channels (1). The resulting increase in cytoplasmic Ca ²⁺ concentration is essential for the exocytosis of acetylcholine. Binding of acetylcholine to postsynaptic nicotinic cholinergic receptors (nAChR) activates an integral nonselective cation channel that depolarizes the sarcolemma (2). Depolarizing the sarcolemma to threshold activates voltage-gated Na ⁺ channels (3), which initiates action potential impulses that propagate deep into the muscle through the transverse tubule system. Within the transverse tubule system, L-type voltage-gated Ca ²⁺ channels sense membrane depolarization and undergo a conformational change (4). A physical link between these voltage sensors and the ryanodine receptor (RyR1) sarcoplasmic reticulum Ca ²⁺ channel is the means by which the electrical signal is transferred from the T tubule to Ca ²⁺ release from the sarcoplasmic reticulum (5).

Modified from Alberts B, Bray D, Lewis J, et al. Molecular Biology of the Cell . 3rd ed. New York: Garland Press; 1994.

Ryanodine Receptors

Ryanodine receptors (RyRs) within the muscle are synonymous with the junctional foot protein/SR calcium release channel, and are so named because they specifically bind the toxic plant alkaloid ryanodine, which can activate or inhibit the channel depending on its concentration. In all mammals there are three RyR isoforms. In humans, they are encoded by three genes located on chromosomes 19q13.1, 1q42.1-q43, and 15q14-q15, for the “skeletal” (RyR1), “cardiac” (RyR2), and “brain” (RyR3) isoforms, respectively. Each functional RyR is a homotetramer consisting of four identical subunits (∼5000 amino acids each), and an accessory protein, calstabin 1 (FK506 12-kd binding protein [FKBP12]). . The total mass of the tetramer exceeds 2 mega-Daltons. Thus it is one of the largest known proteins and the largest known channel in mammalian species. Evidence of direct coupling of Ca _V 1.1 and RyR1 has been demonstrated both by expressing chimeric Ca _V 1.1/Ca _V 1.2 cDNA in dysgenic myotubes that lack constitutive expression of Ca _V 1.1 and chimeric RyR1/RyR2/3 cDNA in dyspedic myotubes that lack constitutive expression of RyR1, 2, and 3. Such studies have provided compelling evidence that the cytoplasmic region between repeats II and III (i.e. , cytosolic II-III loop) of Ca _V 1.1 contains a stretch of 46 amino acids (L720 to Q765) and multiple regions of RyR1 that are essential for engaging bidirectional signaling between Ca _V 1.1 and RyR1.

In the last two decades, our understanding of EC coupling has increased significantly by identifying protein-protein interactions that regulate both the release and sequestration of Ca ²⁺ within skeletal muscle. The elemental unit of function has been named the Ca ²⁺ release unit (CRU), and it is localized within junctional regions of T-tubule and SR membranes. The CRU is a macromolecular assembly of interacting proteins that participate in regulating EC coupling. RyR1 is a high-conductance channel that regulates release of SR Ca ²⁺ and is the central component of the CRU. The functional RyR1 tetramer anchored within the SR membrane physically spans the junctional space to interact with tetrads composed of four voltage-activated Ca _V 1.1 subunits within the T-tubule membrane. This physical interaction engages a form of bidirectional signaling that tightly regulates the function of both proteins. Moreover, interaction of Ca _V 1.1 and RyR1 does not occur in isolation, but are further subject to regulation by a number of proteins localized within the triad junction, including Homer 1, which physically binds and functionally couples target proteins, calstabin 1, triadin, junctin, Mg29, junctophilin 1 and 2, calsequestrin, calmodulin, STAC 3, the catalytic and regulatory subunits of protein kinase A, and protein phosphatase 1. . It is likely that this list is not complete and that there are other critical components which make up this tightly regulated macromolecular complex. More importantly, there is increasing experimental evidence that mutations found in RyR1 ( _MH RyR) or Ca _V 1.1 ( _MH Ca _V 1.1) can alter protein-protein interactions in the CRU, as well as alter the functional fidelity of bidirectional signals.

In the presence of certain chemical substances, MH mutations in RyR1 or DHPR cause severe dysregulation of RyR1 channel function. This can be seen in vitro as a heightened sensitivity to volatile anesthetics, 4-chloro- m -cresol, caffeine, ryanodine, and potassium depolarization. Chemically induced dysfunction of the RyR1 complex appears to be the principal cause of triggering uncontrolled skeletal muscle metabolic acidosis (aerobic and glycolytic), rigidity, and hyperkalemia, but the mechanisms governing the syndrome are unclear. Also unclear is the relationship among exertional heat illness, exertional rhabdomyolysis, and MHS, an area that requires more investigation and, if possible, controlled clinical studies.

Two essential cations greatly shape the kinetics and magnitude of Ca ²⁺ release in response to depolarizing triggers: Ca ²⁺ itself and Mg ²⁺ . The normal RyR1 complex responds to Ca ²⁺ in a biphasic manner. First, Ca ²⁺ activates the channel in a graded manner between 100 nM and 100 μM, whereas higher concentrations inhibit channel activity. This biphasic action is thought to occur via binding of Ca ²⁺ to two classes of regulatory sites on RyR1, a high-affinity stimulatory site and a low-affinity inhibitory site. Mg ²⁺ -induced inhibition is the second important physiologic regulator of RyR1 activity in skeletal muscle. Mg ²⁺ inhibits RyR1 in a cooperative manner (n _H ≈ 2; 50% inhibitory concentration [IC ₅₀ ] ≈ 650 μM). It is likely that Mg ²⁺ acts by competing with Ca ²⁺ at its activator sites and by binding to yet unidentified low-affinity inhibitory sites. It is possible that MH mutations introduce allosteric instability into the RyR1 complex which leads to a reduction of inhibition rather than directly altering the binding properties of Ca ²⁺ or Mg ²⁺ , or both, at the activator or inhibitor sites. Therefore hypersensitivity to pharmacologic agents is likely to be closely tied to altered responses to physiologic ligands. However, whether MHS channels are primarily hyposensitive to inhibition by Mg ²⁺ or Ca ²⁺ (or both), are hypersensitive to activation by Ca ²⁺ , or exhibit altered sensitivities in both directions to both ions seems to be highly dependent on the location of the MH mutation. Studies have also pursued the “leaky channel” hypothesis by examining SR preparations from homozygous R615C MHS pigs and heterozygous R163C and C512S mice. They observed a significantly lower Ca ²⁺ loading capacity (38%, 23%, and 22% lower than matched wild type mice, respectively) primarily mediated by the presence of leaky channels that remain active even with 100 nM extravesicular Ca ²⁺ . Recent studies indicated that expression of Ca _V 1.1 represses the basal activity of the ryanodine-insensitive RyR1 leaky state. It is important that MHS mutations appear to not only alter bidirectional signaling during EC coupling and inherent regulation of RyR1 channel functions, but also weaken negative regulation conferred by Ca _V 1.1 on RyR1 Ca ²⁺ leak under nontriggering conditions. These findings at the molecular and cellular level using knock-in MHS mice confirm earlier measurements made in porcine and human MHS muscles, myotubes, and myoball preparations and in dyspedic myotubes expressing _MH RyR1 cDNAs, all of which have been shown to have chronically elevated resting cytoplasmic [Ca ²⁺ ] _i .

Results from both functional and structural evidence suggests that long-range interdomain interactions between regions of RyR1 are involved in channel regulation by stabilizing protein conformations critical for normal channel transitions. A three-dimensional reconstruction of RyR1 by Samso and coworkers shows that the RyR1 architecture is designed to support long-range allosteric pathways such as coupling with Ca _V 1.1 and binding to ligands such as calmodulin and FKBP12. This structural model for gating has been recently confirmed at molecular scale resolution by several laboratories.

Voltage-Gated Calcium Channels: role of Ca _v 1.1

Although the majority of mutations that confer MHS reside in the RyR1 gene, three mutations in the CACNA1S gene encoding for the Ca _V 1.1 subunit of skeletal muscle have been linked to human MHS. The Arg1086His mutation in the intracellular loop connecting homologous repeats III and IV of Ca _V 1.1 represented the first MH-causing mutation so far identified in a protein other than RyR1. Physiological characterization of the R1086H mutation further demonstrated that sensitivity of RyR1 activity was significantly enhanced by membrane depolarization or by pharmacologic activators of RyR1 (e.g. , caffeine). In addition, Pirone and associates have identified an MHS-causing Thr1354Ser mutation in the S5-S6 extracellular pore-loop region of the homologous repeat IV of Ca _V 1.1 Expression of the T1354S mutation also accelerated L-type Ca ²⁺ current kinetics and also contributed to an increase in RyR1-mediated Ca ²⁺ release. The Arg174Trp Ca _V 1.1 MH mutation occurs at the innermost basic residue of the IS4 voltage-sensing helix, a residue conserved among all Ca _V channels. Unlike the other Ca _V 1.1 MHS mutations, homozygous expression of R174W completely ablates the L-type current, but despite this, has no influence on normal EC coupling. In murine studies, muscle fibers from Het R174W animals verify the increased sensitivity of Ca ²⁺ release to caffeine and halothane compared with myotubes expressing wild type Ca _V 1.1, but whether this mutation is sufficient to confer anesthetic- or heat-triggered fulminant MH remains to be tested.

Factors Other than Ryanodine Receptor Abnormalities

Other cellular processes can affect MH episodes. It has been demonstrated that concurrent administration of nondepolarizing neuromuscular blocking drugs at the same time as triggering agents can delay or prevent the onset of clinical MH syndrome. Pretreatment of MHS pigs with sufficient nondepolarizing neuromuscular blocking agent, which is used to completely abolish muscle twitch elicited by electrical stimulation of the nerve, prevented halothane from triggering the clinical syndrome for 90 minutes, the longest time point tested. However, in the continued presence of halothane, when function of the neuromuscular junction was restored by administration of the cholinesterase inhibitor neostigmine, clinical MH was triggered immediately. This suggested a close relationship between functional neuromuscular junctions or depolarization of the sarcolemma (or both) and the clinical syndrome.

In myotubes, sarcolemmal excitation-coupled Ca ²⁺ entry (ECCE) is sensitive to the conformation of the RyR1 and is enhanced by several mutations in RyR1, including MH mutations. ECCE appears to be an inherent property of Ca _V 1.1 during long or repetitive depolarization of myotubes, possibly mediated by shifting Ca _V 1.1 to the mode 2 gating conformation. Nevertheless, enhanced ECCE in MHS muscle may contribute to an increased sensitivity to depolarization and appears to be one target for dantrolene’s abrogation of responses to both electrical and potassium chloride depolarization. Although CACNA1S expression undergoes developmental switching to a splice variant that downregulates Ca ²⁺ current density of Ca _V 1.1 channels in adult fibers, mutations that maintain Ca ²⁺ current density more similar to those measured with embryonic myotubes has recently been shown to promote muscle pathology.

In addition to ECCE, classic store-operated capacitive Ca ²⁺ entry pathways similar to the store-operated Ca ²⁺ entry (SOCE) seen in nonexcitable cells have been shown to be present in skeletal muscle and appear to be more active in MHS muscles both at rest as a response to chronic store depletion and during an MH crisis. These SOCE channels have also been suggested to be a target for dantrolene, but this has not been validated by other studies. Together, these data suggest that _MH RyRs or _MH Ca _V 1.1 assume a conformation that enhances Ca ²⁺ entry via ECCE or SOCE (or both). This enhanced entry, when combined with decreased sensitivity of _MH RyRs to Ca ²⁺ and Mg ²⁺ inhibition, could provide cellular conditions that heighten sensitivity to triggering agents and perpetuate the fulminant clinical MH syndrome.

Dantrolene

Dantrolene is the only medication that has been shown to be effective in reversing the symptoms of MH. Preadministration of dantrolene will also prevent the development of fulminant MH in homozygous pigs or MH mice when exposed to a triggering stimulus. Dantrolene sodium is a hydantoin derivative (1-[5-(4-nitrophenyl)-2-furanyl]methylene]imino]-2,4-imidazolidinedione) that does not block neuromuscular transmission, but causes muscle weakness by direct muscular action. The properties of dantrolene have been closely correlated with its ability to reduce efflux of Ca ²⁺ from the SR in vitro. Dantrolene (20 μM) counteracts the effect of reduced Mg ²⁺ inhibition in MH-affected muscle. Dantrolene (20 μM) can inhibit the enhanced sensitivity to caffeine seen in MH muscles, and both dantrolene and its more water-soluble analog azumolene (150 μM) have been shown to reduce depolarization-induced release of Ca ²⁺ , both in muscle and in triadic vesicles. The idea that dantrolene suppresses SR Ca ²⁺ release as a result of direct interactions with RyR1 is somewhat controversial. Paul-Pletzer and associates demonstrated that [ ³ H]azidodantrolene specifically labels the amino terminus of RyR1 defined by the 1400-amino acid residue N-terminal calpain digestion fragment of RyR1. More detailed analysis further localized the [ ³ H]azidodantrolene binding site to a single domain containing the core sequence corresponding to amino acid residues 590 through 609 of RyR1. However, to date, we lack evidence of a direct action of dantrolene on single RyR1 channels studied in lipid bilayers, even though they are reconstituted with calstabin 1, ATP, and activating concentrations of Ca ²⁺ , which suggests that dantrolene’s main action is to alter key protein-protein interactions. The recent discovery that inhibition of SR Ca ²⁺ release by dantrolene requires Mg ²⁺ may help resolve the controversy of the conflicting observations on dantrolene inhibition of RyR1 channel activity in Mg ²⁺ -free bilayer experiments.

Distribution of RyR1 Mutations

The missense mutations associated with MHS, CCD, or, in some cases, both, are dispersed throughout the coding region of the RyR1 gene, and all allow transcription of a protein that is putatively functional. Until recently, it was thought that most RyR1 mutations were clustered in three “hot spots:” between amino acid residues 35 and 614 (MH/CCD region 1), between amino acid residues 2163 and 2458 (MH/CCD region 2) in the sarcoplasmic foot region of the protein, and between amino acids 4643 and 4898 in the carboxyl-terminal transmembrane loop or pore region (MHS/CCD region 3) ( Fig. 35.2 ). It appears that the supposition that there were “hot spots” was simply due to bias in sample analysis inasmuch as the missense mutations associated with MH or CCD (or both) are scattered over 54 of the 107 exons of RyR1 . Approximately 41% of reported MH mutations are found in multiple families. CCD mutations are predominantly found in the C-terminal region of the gene (exons 85-103), and only 10 mutations (17%) have been described in more than one family: R4861H ( n = 14), V4849I ( n = 9), I4898T ( n = 7), L4824P ( n = 4), A4940T ( n = 4), G4638D ( n = 3), R4893W ( n = 3), R4861C ( n = 2), R4893Q ( n = 2), and G4899E ( n = 2).

Schematic representation of the triad junction of skeletal muscle shows the junctional foot protein (ryanodine [RyR1] receptor) and its associated proteins. In skeletal muscle, the α _1S -subunit of the dihydropyridine receptor (DHPR) participates in excitation-contraction coupling. These physical links transmit essential signals across the narrow gap of the triadic junction that activate the RyR1 and release Ca ²⁺ from the sarcoplasmic reticulum.

Modified from Pessah IN, Lynch C III, Gronert GA: Complex pharmacology of malignant hyperthermia. Anesthesiology 1996;84:1275.

The true ethnic distribution of MH and CCD is difficult to ascertain. MH and CCD have been reported in Western populations predominantly, but this is likely the result of the manner and frequency in which cases are reported. It does appear that some mutations are clustered in a given region of the world, but the distribution and frequency appear to be somewhat population specific. In the United Kingdom, 69 RyR1 mutations have been discovered, 25 of which are found only in a single family. G2434R is found in approximately 40% of the 434 mutation-positive MH families investigated in the United Kingdom, with the next most common mutations being T2206M (10%) and G341R (8%). In Switzerland, V2168M and I2336H are the predominant mutations, and in Germany, R163C (MH and CCD), R614C (MH), T2206M (MH), G2434R (MH), and R2454H (MH) have each been detected in five or more independent cases. G341R and R614C are common in France, and R614C has also been found in several MH families from Italy and Canada. G341R has been found frequently in Belgium. The mutation common to Europe and North America is G2434R, which occurs in 4% to 7% of European and 5.5% of North American families. Single-family mutations are the most common mutations reported in Japanese, Chinese, Taiwanese, Australian, and New Zealand MH families with the exception of the R163C mutation reported in a large population in rural New South Wales in Australia and the T4826I mutation which is found in numerous families in the Maori population of New Zealand. However, despite these two exceptions, it is likely that the reason for unique family mutations in Asia and Australasia may reflect the small number of cases investigated there. Because genetic screening in European and North American studies has predominantly targeted only regions 1 and 2 of the original hot spots in the gene, the absence of RyR1 mutations in some of the screened population could be explained by RyR1 mutations located outside these two regions or by involvement of other genes.

Inheritance and Penetrance of Malignant Hyperthermia

Inheritance of human MH can no longer be considered to be solely autosomal dominant with variable penetrance because more than one MH-linked mutation has been identified in some probands and families. Six non-consanguineous families harbor at least two RyR1 mutations that have both been linked to MHS, and in two of those families, one is an RyR1 mutation and the second is a Ca _V 1.1 mutation. Although MHS homozygotes are common in affected pigs, they are rare in humans and only found in 50% of currently available transgenic mouse populations. The known MHS homozygous humans also appear clinically normal, but exhibit stronger responses to in vitro contracture test (IVCT) and caffeine/halothane contracture tests (CHCTs) than heterozygous individuals do. Homozygosity of two MH mutations in “hot spot” 1 leads to perinatal lethality in mice. Double heterozygous individuals do not appear to show any additive effect of the second mutation on IVCT.

In Vitro Contracture Test and Caffeine Halothane Contracture Test

The gold standard for diagnosis of MH is the halothane and caffeine muscle contracture test, also known as the IVCT or the CHCT. There are two protocols developed by the European Malignant Hyperthermia Group (EMHG) and the North American Malignant Hyperthermia Group (NAMHG), respectively. The two protocols are similar, but not identical. For the purpose of differentiation, we designate IVCT to the EMHG protocol and CHCT to the NAMHG protocol.

For IVCT, the muscle biopsy will be performed on the quadriceps (either vastus medialis or vastus lateralis) and consists of three parts: a static caffeine test, a static halothane test, and a dynamic halothane test. For the static caffeine test, a stepwise increased concentration (0.5, 1, 1.5, 2, 3, 4, and 32 mmol/L) is applied. The lowest concentration of caffeine which produces a sustained increase of at least 0.2 g in baseline tension is reported as the caffeine threshold. Then, the halothane threshold is obtained using the same method by exposing the muscle to halothane concentrations of 0.5%, 1%, 2%, and 3% v/v. The dynamic halothane test is performed with the muscle stretched at a constant rate of 4 mm/min to achieve a force of approximately 3 g and held at the new length for 1 min for a 3 min exposure to halothane. For each cycle, halothane concentration will be increased from 0.5%, 1%, 2%, to 3% v/v: volume (solute) per volume (solvent). The concentration of halothane which produces a sustained increase of at least 0.2 g in the muscle tension compared to the pre-halothane control is defined as the dynamic halothane threshold. The IVCT protocol classifies the patients into three groups: MH Susceptible (MHS _HC ) group with a caffeine threshold at the caffeine concentration of 2 mmol or less and a halothane threshold of 2% v/v halothane or less; MH Normal (MHN) group with a caffeine threshold at the caffeine concentration of 3 mmol or more without a halothane response at 2% v/v; MHS _H and MHS _C groups which describe individuals that used to be classified as MHE (equivocal) who are only responsive to either halothane or caffeine alone. The MHE descriptor was dropped because use of the ‘equivocal’ label outside of its laboratory context has the potential to confuse patients and clinicians unfamiliar with its derivation.

For CHCT, a muscle biopsy can be taken from the following sites in the order of preference: (1) the vastus group, (2) the rectus abdominis, and (3) other muscle groups under special circumstances. Required tests include exposure of muscle to 3% v/v halothane alone and to incremental caffeine concentrations (0.5, 1, 2, 4 mmol, and 8.0 mmol if the response at 4 mmol is <1 g, and 32 mmol) alone. Optional tests include exposure of muscle to a combination of both 1% halothane and incremental caffeine concentrations, and to 2% v/v halothane alone. According to CHCT protocol, an individual is MHS when either of the halothane or the caffeine test is positive, and MHN when both tests are negative.

The sensitivity of IVCT was reported to be 99.0% (95% confidence interval [CI] 94.8%-100%) if the MHE group is considered susceptible and the specificity of IVCT was 93.6% (95% CI 89.2%-96.5%), while the sensitivity and specificity of CHCT was 97% (95% CI 84%-100%) and 78% (95% CI 69%-85%), respectively. Recently, fluoroquinolones and statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, were found to induce significant contractures in MHS muscle bundles, but not in MHN. Ondansetron and 3,4-methylenedioxymethamphetamine (MDMA) may also dose-dependently induce contracture or increase the sensitivity of the contractile apparatus to calcium in both MHS and MHN fibers. Modifications to the IVCT protocol by adding ryanodine or 4-chloro- m -cresol, a RyR-specific agonist, has been reported, but has not been included in the standard protocol. Furthermore, Metterlein and associates studied the possibility of replacing halothane with newer volatile agents in IVCT. At increasing concentration, except for sevoflurane, all newer volatile agents, including enflurane, isoflurane, and desflurane, induced significantly greater contractures in MHS muscle compared to MHN bundles. However, within the MHS muscle bundles, halothane produced significantly higher contractures, and was considered the strongest discriminator for MH using the IVCT protocol. A direct application of high sevoflurane concentration of 8%, instead of the stepwise application, has been shown to induce significantly stronger contractures in MHS subjects. Nevertheless, from the retrospective analysis of the Japanese MH database, there was no evidence between the severity of MH triggered by sevoflurane and isoflurane, or other agents, suggesting sevoflurane is a weak or weaker MH triggering agent.

Discordance Between Genetic and in Vitro Contracture Test/Caffeine/Halothane Contracture Tests Malignant Hyperthermia Testing

Discordance has confounded linkage analysis worldwide. Examples include MHN patients carrying an RyR1 mutation associated with MH and MHS patients who do not carry the familial RyR1 mutation. Several explanations are possible, the most likely being that IVCT/CHCT is not clinically precise and that the thresholds for IVCT or CHCT are inexact. This would lead to errors in determining whether a patient was MHN or MHS. A second possibility is variable penetrance with possible allelic silencing, and a third is that individuals with discordance have mutations in other unknown genes or modifier genes that affect the function of RyR1 and its phenotypic penetrance. The discrepancy between the incidence estimates of MH events and the prevalence estimates also points to possible epigenetic factors at work. Carpenter and associates have suggested that the severity of MHS may be related to the RyR1 variant and mutation found within the highly conserved regions of RyR1 gene. The rarity of large kindreds with MH makes linkage analysis and understanding variability in clinical manifestations difficult. Robinson and associates demonstrated by the transmission disequilibrium test that loci on chromosomes 5 and 7 and, to a lesser extent, loci on chromosomes 1 and 7 influence susceptibility to MH.

Guidelines for Genetic Screening

In 2000, the European MH group (EMHG) formulated guidelines for RyR1 mutation screening with linkage data to other loci for some MH families, but all MH investigators emphasized the vital role of IVCT in the diagnosis of MH. These guidelines for screening have reduced the number of relatives requiring contracture testing without increasing the risk of misdiagnosis. In 2015, the EMHG published a revision of the guidelines for the investigation of MHS. This updated guideline provided a detailed patient referral criteria and clinical interpretation of IVCT results ( https://www.emhg.org/testing-for-mh-1 ).

Only a small number of MHS families have been investigated extensively in North America by phenotyping, linkage analysis, and screening of specific genes. Collaborative protocols over the past several years between MH biopsy centers and molecular biologists have screened 209 unrelated MHS subjects for mutations in the RyR1 gene (see Distribution of RyR1 Mutations).

Larach and coworkers reported a 34.8% morbidity rate in 181 MH cases reported to the NAMHR between January 1987 and December 2006. They also reported that the occurrence was more frequent in young males (75%) (median age of 22.0) and 75% of these patients had undergone at least one general anesthetic with no observed signs of MHS. This underscores the complication of determining the prevalence of MHS in the absence of an inexpensive MH diagnostic test.

Anesthetic Triggering

Anesthetic drugs that trigger MH include ether, halothane, enflurane, isoflurane, desflurane, sevoflurane, and depolarizing muscle relaxants, the only currently used of which is succinylcholine. Desflurane and sevoflurane appear to be less potent triggers than halothane and produce a more gradual onset of MH. The onset may be explosive if succinylcholine is used. MHS swine were traditionally screened by induction with a volatile anesthetic, which led to pronounced hind limb rigidity within 5 minutes, frequently sooner. Prior exercise even an hour before induction of anesthesia increased the severity and hastened the onset of rigidity in swine. Similarly, in the new knock-in mouse models, the onset of limb rigidity after commencing exposure to volatile anesthetics is very rapid. There are also several modifying factors that are more likely to be present in humans than in pigs or mice and can alter (or even prevent) the onset of clinical MH. Mild hypothermia and preadministration of barbiturates, tranquilizers, propofol, or nondepolarizing neuromuscular blockers delay or prevent the onset of MH in MHS humans, thus making them respond less predictably than swine or MH knock-in mice. There have been many instances in which fulminant MH has been reported in patients who have previously tolerated potent triggers without difficulty. The reason behind why this occurs is unknown, but it is likely to be related to prior or concurrent administration of drugs that prevent or delay onset of the syndrome, as described earlier, or unknown environmental influences that help provoke the positive incident. Thus onset of the syndrome in humans is extremely variable both in initial symptoms and in the time of onset of the syndrome. Its onset is so variable that making the diagnosis in the setting of a clinical anesthetic can be quite difficult. Although not perfect, the clinical grading scale developed by Larach and colleagues is a useful way for clinicians to retrospectively determine whether a patient who responded abnormally to anesthesia is in any way likely to actually have had a clinical MH episode. However, MH is most easily diagnosed prospectively by vigilance, recognizing its signs and symptoms, and knowing how to treat the syndrome.

The two classic clinical manifestations of fulminant MH syndrome may start in one of the following two scenarios.

• 1.
  

  Rigidity after induction with thiopental and succinylcholine, but successful intubation, followed rapidly by the symptoms listed after scenario 2.

  
  
• 2.
  

  Normal response to induction of anesthesia and uneventful anesthetic course until onset of the following symptoms:

  
  
• ▪
  

  Unexplained sinus tachycardia or ventricular arrhythmias, or both

  
  
• ▪
  

  Tachypnea if spontaneous ventilation is present

  
  
• ▪
  

  Unexplained decrease in O ₂ saturation (because of a decrease in venous O ₂ saturation)

  
  
• ▪
  

  Increased end-tidal PCO ₂ with adequate ventilation (and in most cases unchanged ventilation)

  
  
• ▪
  

  Unexpected metabolic and respiratory acidosis

  
  
• ▪
  

  Central venous desaturation

  
  
• ▪
  

  Increase in body temperature above 38.8°C with no obvious cause

The usually muted onset of MH (scenario 2) is in most cases detected quickly by the development of tachycardia, increased levels of expired CO ₂ , and muscle rigidity. It can be delayed for several reasons and may not be overt until the patient is in the recovery room. Once initiated, the course of MH can be rapid. When clinical signs such as increased expired CO ₂ , muscle rigidity, tachycardia, and fever suggest MH, more than one abnormal sign must be observed before making the diagnosis because according to a metaanalysis of many reported cases, a single adverse sign does not usually indicate MH. The mechanism by which anesthetics and depolarizing muscle relaxants trigger MH is unsolved, but it cannot be ignored that they are etiologic agents and that early diagnosis is critical for successful treatment.

Nonanesthetic Malignant Hyperthermia

MH can be triggered by stress such as exercise and overheating, known as “awake” MH. Numerous anecdotal reports of MH-like episodes in humans after stressful situations were reported. Measurement of plasma catecholamine levels during exercise showed no differences between MHS and normal individuals. Therefore it is unlikely that these responses were provoked by sympathetic overdrive or catecholamine surge.

Wappler and associates reported RyR1 mutations in three of twelve unrelated patients with exercise-induced rhabdomyolysis (ER); and 10 of those same 12 patients produced abnormal contracture response with IVCT. One had an equivocal response. In susceptible swine, environmental stress such as exercise, heat, anoxia, apprehension, and excitement triggers fulminant MH (see History). These responses are related to muscle movement or to increased temperature. Increased ambient temperature triggers fulminant MH in four strains of heterozygous MH mice and in two homozygous strains. Epidemiologic studies have shown that exercise-induced symptoms, including rhabdomyolysis, may occur more frequently in MHS patients ; and an Arg401Cys RyR1 mutation was present in three cases of exercise-induced rhabdomyolysis. Other reports are largely anecdotal and relate heat stroke, sudden and unexpected death, unusual stress and fatigue, or myalgias to possible “awake” MH episodes. Stresses associated with these episodes include exercise and environmental exposure to volatile nonanesthetic vapors. In the United States, MHAUS provided recommendations of adverse effects of heat and exercise in relation to MHS.

Masseter Spasm (“Thiopental-Succinylcholine or Halothane-Succinylcholine Rigidity”)

A masseter spasm or trismus is defined as jaw muscle rigidity in association with limb muscle flaccidity after the administration of succinylcholine. The masseter and lateral pterygoid muscles contain slow tonic fibers that can respond to depolarizing neuromuscular blockers with a contracture. This is manifested clinically on exposure to succinylcholine as an increase in jaw muscle tone, and was well defined by van der Spek and associates. There is a spectrum of responses, for example, a tight jaw that becomes a rigid jaw and then a very rigid jaw ( Fig. 35.3 ). This jaw rigidity may occur even after pretreatment with a “defasciculating” dose of a nondepolarizing relaxant. If there is rigidity of other muscles in addition to trismus, the association with MH is absolute; anesthesia should be halted as soon as possible and treatment of MH begun.

Succinylcholine usually increases jaw muscle tone slightly. In some patients this increase is moderate, and in very few, the effect is extreme (i.e., “jaws of steel”). As many as 50% of this latter group may be susceptible to malignant hyperthermia (MH) . Somewhere in the area of the declining curve is the boundary for the MH population.

However, in more than 80% of patients with trismus but no rigidity of other muscles, it is a variant found in normal patients. If trismus occurs, proper monitoring should include end-expired CO ₂ , examination for pigmenturia, and arterial or venous blood sampling for CK, acid-base status, and electrolyte levels, particularly potassium. Although scientifically unproven, it is thought that the initial tightness of the jaw and its duration may predict the gravity of the response. MHAUS recommends following CK and urine myoglobin for 36 hours with 6-hour intervals. Patients with masseter spasm should be observed closely for at least 12 hours.

Core Myopathies

CCD is a rare hereditary disease. It was first reported in 1956 by Magee and Shy. A recent population study in northern England revealed a prevalence of 1:250,000. In 1971, Engel and colleagues reported a related congenital myopathy, multicore disease. Subsequently, various designations of the terms were reported for the variations of the disease, including minicore myopathy and multiminicore myopathy. MmD is now the most official term for these variations sponsored by the European Neuromuscular Centre.

As mentioned, most CCD cases are due to dominant missense mutations in the RyR1 gene. Clinically, CCD patients present with muscle weakness of variable degree and histologically with central cores in the skeleton muscle type I fibers. MmD is considered a recessively inherited myopathy with severe axial weakness, while respirator, bulbar, and extraocular muscles are commonly affected. MmD has a heterogenous genetic association with a recessive mutation in the SEPN1 gene on chromosome 1p36 and in the RyR1 gene. Both type 1 and type 2 fibers may be affected.

Serum CK levels in CCD patients are often normal but may be elevated up to 6 to 14 times in rare cases. Muscle ultrasound often demonstrates increased echogenicity in the quadriceps muscle with relative sparing of the rectus muscle. This characteristic pattern of selective involvement can also be seen on the muscle MRI and has been reported in the patients with typical CCD, which seems to be distinctive to conditions linked to RyR1 locus.

The relationship between CCD and MHS is complex. A positive IVCT test has been confirmed in many patients with CCD, whereas MHS has been excluded in some. In consideration of the strong link and potential risk, it is advisable to consider all patients with CCD at risk for MH unless the patient has a negative IVCT. Although MHS has not been reported in SEPN1 -related myopathies, it is prudent to apply a nontriggering approach to MmD patients, given the potential risk in RyR1 -related MmD. Clinical MH reactions have been reported in MmD patients.

King-Denborough Syndrome

To address the KDS, we first introduce Noonan syndrome, an autosomal dominant condition involving the face, cardiovascular, hematological, and skeletal systems. Named after Dr. Jacquline Anne Noonan, a pediatric cardiologist, typical Noonan syndrome features delayed puberty, down-slanting or wide-set eyes, hearing loss, low-set or abnormal shaped ears, mild mental retardation (in about 25% of the cases), ptosis, short statue, small penis and undescended testicles in males, pectus excavatum, and a webbed and short neck. The incidence is 1:1000-1:2500 live births. Fifty percent of the patients have protein-tyrosine phosphatase, nonreceptor-type II ( PTPN2 ) mutations. Other genes involved are SOS1, KRAS, RAF1, BRAF, MEK1, and NRAS , and they encode proteins that are part of the Ras (a GTPase)-mitogen activated protein kinase (RAS-MAPK) signaling pathway. Noonan syndrome was recently defined as part of the neuro-cardio-facial-cutaneous syndrome family. An earlier study with a series of 27 patients demonstrated one case of mildly elevated CK despite multiple uneventful cases of general anesthesia with halothane and succinylcholine. Although there is weak evidence for MHS for patients with Noonan syndrome, its resemblances to KDS should raise the concern for the confirmation of the diagnosis. Prevalence of bleeding disorders in Noonan syndrome was reported to be from 20% to 89%, ranging from thrombocytopenia to platelet dysfunction to von Willebrand disease to factor deficiencies. Routine screening including, but not limited to, bleeding history, platelet count, coagulation panel, and factor XI level, was recommended. Hematological consultation becomes appropriate if any of these tests are abnormal. The high palatal arch, dental malocclusion, and the webbed neck of Noonan syndrome make tracheal intubation potentially risky. Nevertheless, odontoid hypoplasia and atlanto-axial instability may result in cervical cord compression. Preoperative cervical spine evaluation is advisable. Right ventricular function needs to be monitored closely because 30% to 50% of the patients with Noonan syndrome have pulmonary stenosis. Regional anesthesia in Noonan patients may be technically challenging due to the prevalence of scoliosis. The spread of local anesthetic can be unpredictable.

KDS features the dysmorphic facial and skeletal abnormalities similar to Noonan syndrome and congenital myopathy with proximal muscle weakness. Sporadic cases have been reported in the literature. The inheritance pattern of the disease is not clear. Elevated baseline CK appears in approximately one half of the KDS patients. A heterozygous A97G point mutation in exon 2 of the RyR1 , causing a substitution of lysine for glutamine at amino acid residue 33 (Lys33Glu), was reported. This substitution creates a major polarity change, from positive to negative, in a known hot spot for an MH causative mutation. Dowling and associates recently identified RyR1 mutation in three out of the four patients with KDS, which supports the hypothesis of its genetic heterogeneity. Given the strong evidence for MHS in KDS patients, MH triggering agents should be avoided for anesthesia on KDS patients.

Treatment

Acute management for MH can be summarized as follows:

• 1.
  

  Discontinue all triggering anesthetics, maintain intravenous agents, such as sedatives, opioids, and nondepolarizing muscular blockers as needed, and hyperventilate with 100% oxygen with a fresh flow to at least 10 L/min. With increased aerobic metabolism, normal ventilation must increase. However, CO ₂ production is also increased because of neutralization of fixed acid by bicarbonate; hyperventilation removes this additional CO ₂ .

  
  
• 2.
  

  Administer dantrolene rapidly (2.5 mg/kg intravenously [IV] to a total dose of 10 mg/kg IV) every 5 to 10 minutes until the initial symptoms subside.

  
  
• 3.
  

  Administer bicarbonate (1-4 mEq/kg IV) to correct the metabolic acidosis with frequent monitoring of blood gases and pH.

  
  
• 4.
  

  Control fever by administering iced fluids, cooling the body surface, cooling body cavities with sterile iced fluids, and if necessary, using a heat exchanger with a pump oxygenator. Cooling should be halted at 38°C to prevent inadvertent hypothermia.

  
  
• 5.
  

  Monitor and treat arrhythmia. Advanced cardiac life support protocol may be applied.

  
  
• 6.
  

  Monitor and maintain urinary output to greater than 1 to 2 mL/kg/h and establish diuresis if urine output is inadequate. Administer bicarbonate to alkalinize urine to protect the kidney from myoglobinuria-induced renal failure.

  
  
• 7.
  

  Further therapy is guided by blood gases, electrolytes, CK, temperature, muscle tone, and urinary output. Hyperkalemia should be treated with bicarbonate, glucose, and insulin, typically 10 units of regular insulin and 50 mL of 50% dextrose for adult patients. The most effective way to lower serum potassium is reversal of MH by effective doses (ED) of dantrolene. In severe cases, calcium chloride or calcium gluconate may be used.

  
  
• 8.
  

  Recent data demonstrated that magnesium level could be a prerequisite for dantrolene efficacy in managing MH crisis.

  
  
• 9.
  

  Analyze coagulation studies (e.g. , international normalized ratio [INR], platelet count, prothrombin time, fibrinogen, fibrin split, or degradation products).

  
  
• 10.
  

  Once the initial reaction is controlled, continued monitoring in the intensive care unit for 24 to 48 hours is usually recommended.

Adequate personnel support is critical to the successful management of such a crisis. Discontinuation of the trigger may be adequate therapy for acute MH if the onset is slow or if exposure was brief. Changing the breathing circuit and CO ₂ absorbent can be time-consuming. However, application of activated charcoal filters may rapidly reduce the volatile anesthetic concentration to an acceptable level in less than2 minutes, if they are readily available.

Dantrolene used to be packaged in 20-mg bottles with sodium hydroxide for a pH of 9.5 (otherwise it will not dissolve) and with 3 g of mannitol (converts the hypotonic solution to isotonic). The initial dose should be 2.5 mg/kg dantrolene reconstituted in sterile water and administered intravenously. Dantrolene must be reconstituted in sterile water rather than salt solutions or it will precipitate. It has been shown that prewarming of sterile water may expedite the solubilization of dantrolene compared to water in ambient temperature. In 2009, a newer, rapid soluble lyophilized powder form of dantrolene became available for intravenous use. It reconstitutes in less than a minute which is much faster than the older version. The higher dosing capacity, 250 mg per vial, of the newer version of dantrolene also reduces the storage space with a similar recommended shelf life as the older versions.

In awake, healthy volunteers, the maximum twitch depression occurs at a dantrolene dose of 2.4 mg/kg. Therefore it is not surprising that at therapeutic concentrations, dantrolene may prolong the need for intubation and assisted ventilation. Brandom and associates reviewed the complications associated with the administration of dantrolene from 1987 to 2006 using the dataset in the NAMHR via the AMRA reports and found that the most frequent complications of dantrolene were muscle weakness (21.7%), phlebitis (9%), gastrointestinal upset (4.1%), respiratory failure (3.8%), hyperkalemia (3.3%), and excessive secretions (8.2%). Given its high pH, it is advisable to administer dantrolene through a large bore IV line. It has been demonstrated that dantrolene interferes with EC coupling of murine intestinal smooth muscle cells, rat gastric fundus, and colon, which in part explains its gastrointestinal side effect. Caution should be used when ondansetron is to be used in this setting. As a serotonin antagonist, ondansetron may increase serotonin at the 5-HT _2A receptor in the presynaptic space. In MHS individuals, agonism of 5-HT _2A receptor may produce a deranged response, precipitating MH.

The clinical course will determine further therapy and studies. Dantrolene should probably be repeated at least every 10 to 15 hours, since it has a half-life of at least 10 hours in children and adults. The total dose of dantrolene that can be used is up to 30 mg/kg in some cases. Recrudescence of MH can approach 50%, usually within 6.5 hours. When indicated, calcium and cardiac glycosides may be used safely. They can be lifesaving during persistent hyperkalemia. Slow voltage-gated calcium channel blockers do not increase porcine survival. Instead, a recent study by Migita demonstrated that calcium channel blockers, including dihydropyridine (i.e. , nifedipine), phenylalkylamine (i.e. , verapamil), and benzothiazepine (i.e. , diltiazem), led to increased [Ca ²⁺ ] _i in human skeletal muscle cells. Interestingly, the potency of such calcium release is correlated with the number of binding sites on DHPR (i.e., nifedipine > verapamil > diltiazem). Clinical doses of dantrolene were only able to attenuate 20% of the nifedipine-induced [Ca ²⁺ ] _i surge. Current recommendations of MHAUS discourage the use of calcium channel blockers in the presence of dantrolene because they can worsen the hyperkalemia resulting in cardiac arrest. Although administration of magnesium sulfate could not prevent the development of MH and did not influence the clinical course in succinylcholine-induced MH, recent data suggested that dantrolene might require magnesium to arrest the course of MH triggered by halothane. Permanent neurologic sequelae, such as coma or paralysis, may occur in advanced cases, probably because of inadequate cerebral oxygenation and perfusion for the increased metabolism and because of the fever, acidosis, hypo-osmolality with fluid shifts, and potassium release.

For MH cases diagnosed in the ambulatory surgical centers, guidelines have been recently proposed for the transferring of care to receiving hospital facilities. Although it is preferable that immediate treatment and stabilization of the patient be achieved onsite, several factors need to be considered before implementation of a transfer plan, which include capabilities of the available professionals at the initial treatment and receiving facilities, clinical best interests of patients, and capabilities of the transfer team. The validity of stocking dantrolene in ambulatory surgery centers was confirmed with a cost-effectiveness analysis.

Evaluation of Susceptibility

Evaluation of susceptibility includes a history and physical examination to detect any subclinical abnormality. A genealogy with specific information about anesthetic exposure and agents can estimate the likelihood of exposure to triggering agents. Blood CK values, when determined in a resting, fasting state without recent trauma, reflect muscle membrane stability. When the CK level is elevated in a close relative of a person with known MHS, the relative may be considered to have MHS without contracture testing. If the CK level is normal on several occasions, there is no predictive value, and contracture studies are necessary. The patient must travel to the test center for a surgical biopsy to ensure viability and accurate results. Muscle biopsy contracture studies, performed at about 30 centers around the world, involve exposure of the muscle biopsy sample to halothane, caffeine, and, in the North American test, to halothane plus caffeine. Sensitivity to 4-chloro- m -cresol or ryanodine have also been used by some centers. It is also important to note that contracture responses are sometimes positive in patients with myopathies that bear no direct relationship to MH and therefore may not indicate susceptibility. Dantrolene must be avoided before biopsy because it masks the response to contracture-producing drugs. After a patient is diagnosed as being MHS, DNA testing for mutations should follow. When a mutation is detected, other relatives with that mutation should be considered to be MHS without the need for an invasive contracture test, and they need not travel to a testing center (see Genetics).

MHS patients and all patients who are not biopsy tested, but who present with a clinical picture that suggests a high probability for MHS, should be given advice. Precautions are necessary in regard to general anesthesia, and triggers include all potent volatile agents and succinylcholine. Awake episodes are uncommon, and if not experienced before diagnosis, they are an unlikely problem. The true predictive value (i.e. , percentage of positive results that are true positives) or efficiency (i.e. , percentage of all results that are true, whether positive or negative) of contracture testing in determining susceptibility in the general population cannot be estimated because of the selection process that has been used to date for testing (i.e. , limited to those with anesthesia reactions who do not have any other muscle disease pathology). False-positive results from cautious interpretation or decreased specificity are masked because the patient will never be exposed to triggering agents. A promising innovative in vivo human application involves physiologically based microdialysis infusion of caffeine or halothane into muscle of MHS patients to trigger exaggerated localized changes in acid-base balance. White blood cells express RyR1-MHS and provide a substrate for a less invasive analysis for susceptibility but have the limitation that not all causative mutations are expressed in the white blood cells. Nuclear magnetic resonance has promise, but to date it has been difficult to standardize a stress, such as forearm ischemia, that can differentiate susceptibles from normals.

For anesthesia assessment of the non-MHS pregnant patient carrying a potential MHS fetus, the parturient should be treated as MHS until the fetus is delivered. For emergencies in such patients, the use of succinylcholine, although little of the drug crosses the placenta, is controversial.

Anesthetic Considerations

It has been speculated that general anesthesia and surgery may increase the risk for aggravation of MS. Presently, there is no general consensus on this matter, and patients should therefore be informed of the potential for aggravated symptoms in the postoperative period. In general, preoperative chronic immunosuppressive medication should be continued during the perioperative period. Patients with MS are sensitive to physical (pain, fever, infection) and emotional stress, which makes it more likely that symptoms will be intensified in the perioperative period. Increased body temperature is often cited as an offending mechanism, possibly by causing a complete block of conduction in demyelinated nerves. Body temperature should therefore be closely monitored and controlled during the perioperative period. Great care must be exercised to minimize changes in fluid homeostasis, and central hemodynamics (preload, afterload) and to maintain respiration. Although intravenous induction agents and volatile anesthetics have been used safely, it is wise to avoid administering depolarizing neuromuscular blocking drugs to MS patients. MS-induced denervation, or misuse myopathy, may lead to a risk for succinylcholine-induced hyperkalemia, which can result in fatal cardiac arrhythmias. Nondepolarizing neuromuscular blockers are safe to use but should be dosed cautiously as both prolonged responses (increased sensitivity in patients with preexisting muscle weakness) and resistance to these NMBAs have been reported. The use of rocuronium with sugammadex to ensure full reversal has been suggested as a safe alternative. It is speculated that the demyelination associated with MS renders the spinal cord susceptible to the neurotoxic effects of the local anesthetics. Epidural application of low concentrations of local anesthetics has, nevertheless, been successfully used in MS patients. Spinal anesthesia, on the other hand, has been implicated in postoperative exacerbations of symptoms in MS. As the blood–brain barrier may also be damaged by demyelination, spinal anesthesia is usually not recommended for these patients. A recent metaanalysis of 37 reports found that the MS symptoms were worsened in 10 of 231 patients, but despite the association no clear cause-effect relationship could be identified. Notably, postpartum worsening of MS symptoms is noted in 20% of females. The need for postoperative care is dependent on the preoperative symptoms, type of surgery, and status of the patient at the end of the surgical procedure. In this context, MS patients with severe weakness and respiratory distress, including pharyngeal dysfunction, may need extended postoperative care, such as noninvasive respiratory support and intense physiotherapy, to avoid further impairment of their pulmonary function ( Box 35.3 ).

Anesthetic Considerations

Bulbar involvement in combination with respiratory muscle weakness leads to a risk for aspiration and pulmonary complications. Notably, these patients may have increased sensitivity to the respiratory depressant effects of sedatives and hypnotics. There are reports of sympathetic hyperreactivity and autonomic failure. Sympathetic hyperreactivity and autonomic dysfunction, often manifested as orthostatic hypotension and resting tachycardia but also significant hypotension or even pulseless electrical activity upon anesthesia induction, have been reported, and should be considered during the perioperative management of these patients. Succinylcholine should be avoided because of the risk for hyperkalemia as a result of denervation and immobilization. Nondepolarizing NMBA may cause prolonged and pronounced neuromuscular blockade and hence should be used with great caution. General anesthesia may be associated with exaggerated ventilatory depression. Regional anesthesia is also often avoided for fear of exacerbating disease symptoms. Both general and epidural anesthesia have, however, been successfully administered to these patients without reported complications ( Box 35.4 ).

Anesthetic Considerations

Cranial nerve paralysis and autonomic dysfunction predispose these patients to an increased risk for aspiration. Aspiration precautions, including decompression of the stomach, should therefore be considered before the induction of anesthesia. Absence of compensatory cardiovascular responses may be associated with exaggerated hypotension at anesthesia induction or in response to hypovolemia. Conversely, laryngoscopy or noxious stimuli can be associated with an exaggerated increase in blood pressure. The hemodynamic instability is typically short-lived and self-limited, but small doses of short-acting and titratable vasoactive medications may be required. Careful hemodynamic monitoring is essential and continuous monitoring of the blood pressure with an arterial catheter is often considered. These patients may also exhibit abnormal responses to NMBA; succinylcholine should not be used because of the risk of hyperkalemia. Nondepolarizing muscle relaxants are not contraindicated but should be avoided as a result of the increased sensitivity and risk for prolonged muscle weakness in the postoperative period. The risk for autonomic dysfunction, respiratory failure, and aspiration may require assisted or mechanical ventilation, even in the postoperative period. If these agents are used, the neuromuscular transmission should be closely monitored with a nerve stimulator as both resistance and sensitivity to these agents have been reported. Great care should be taken to maintain circulatory stability, including adequate cardiac preload and afterload. Careful hemodynamic monitoring is therefore essential in these patients.

Regional anesthesia is employed by some practitioners but its use remains controversial as it has been reported to cause worsening of neurological symptoms. General anesthesia can be used; however, the combination of general anesthesia and epidural anesthesia is more controversial ( Box 35.5 ).

Critical Illness Polyneuropathy and Critical Illness Myopathy

Despite earlier reports of a rapid development of weakness, muscle atrophy, and polyneuropathy in critically ill patients, it was not until the 1987 report by Bolton and associates that the characteristic widespread axonal degeneration of motor and sensory fibers and the extensive denervation atrophy of limb and respiratory muscle associated with this polyneuropathy were clearly identified. Although the true incidence of critical illness polyneuropathy (CIP) is difficult to determine, critical illness neuropathy and myopathy are believed to affect up to 50% of all patients remaining in the intensive care unit for more than 2 weeks. It is typically manifested as profound symmetric limb weakness, with reduced or absent tendon reflexes and diaphragmatic and intercostal weakness. It affects the lower extremities to a greater extent than upper extremities, and distal muscle groups more severely than the proximal. The autonomic function is not affected and the extraocular eye movements remain intact. In CIP, there is no evidence of neuromuscular junction disorder and the electromyography and nerve conduction study findings are consistent with axonal motor and sensory polyneuropathy, with amplitude reduction of motor and sensory action potentials, and slowed conduction velocities. Serum CK levels are usually normal. Conversely, a sensory nerve action potential is often normal in critical illness myopathy but compound muscle action potentials are diminished and electromyography is consistent with myopathy. Serum CK levels may be elevated. No specific treatments are currently available, and management is supportive with aggressive and early rehabilitation. Use of sedation, paralytics, and corticosteroids should be limited, and aggressive control of hyperglycemia has been suggested to reduce the incidence of CIP by 44%.

Anesthetic Considerations

Anesthetic considerations in CIP patients are similar to those with other acquired neuropathies (see above), and include protection of nerve compression sites, particularly the ulnar and peroneal nerves. Prolonged immobility in critically ill patients is associated with a relative increase in immature acetylcholine receptors that can lead to an insensitivity to nondepolarizing NMBA. Conversely, the sensitivity to depolarizing neuromuscular blockers is increased, with a risk for increased potassium efflux after succinylcholine administration ( Box 35.6 ).

Anesthetic Considerations

The anesthesia experience in patients with CMT disease is limited because of the small number of cases. Major considerations include the use of hypnotic agents, muscle relaxants, volatile agents, and neuraxial techniques. CMT type 1 patients have been reported to have significantly increased sensitivity to thiopental at induction that correlates with the severity of both motor and sensory defects. However, total intravenous anesthesia (TIVA) has been performed successfully in a number of cases without any reported problems.

Because of the reduced number of acetylcholine receptors, sensitivity to nondepolarizing muscle relaxants is elevated and the response to succinylcholine is also reduced. Although succinylcholine has been used without adverse effect, the risk of an exaggerated hyperkalemic response may be sufficient to preclude it from being used in patients with suspected muscular denervation. Prolonged neuromuscular blockade with vecuronium has been reported. As a result of the large variety of disabilities in this patient group, careful baseline assessment of neuromuscular status should be conducted before the use of nondepolarizing neuromuscular relaxants. Normal response to atracurium and mivacurium has been demonstrated. Both TIVA and volatile anesthetics have been used safely in CMT patients in a series of cases. Neuraxial techniques for obstetric procedures have been reported to generally be successful in CMT patients. However, the use of regional anesthesia can be controversial given that the possible complications may exacerbate the neurologic symptoms. Similar medicolegal concerns may apply to the surgical and anesthesia positioning of CMT patients because of the sensory deficits and limb deformities.

Diagnosis and Differential Diagnosis

Chronic elevation of the serum CPK level is a general indication of muscle disease. Three serum tests showing elevated CPK levels obtained one month apart is diagnostic of muscular dystrophy. CPK represents leakage of enzyme from muscle cells and does not correlate with severity of the disease. CPK could reach 50 to 300 times the normal value in early stages of the disease. The level tends to decrease with the loss of muscle mass. Elevation of the MB fraction of CK precludes its use as a marker for cardiac injury. EMG can be supportive of the diagnosis; however, it can be very difficult to perform on children. Muscle biopsy, followed by immunostaining or Western blot analysis for dystrophin, is recommended for diagnostic testing. Multiple polymerase chain reactions are also useful in detecting more than 98% of the existing deletions. The result is usually available within 24 hours, which may render muscle biopsy, the old “gold standard,” obsolete.

Anesthetic Considerations

Patients with DMD and BMD may require anesthesia for muscle biopsy, correction of scoliosis, release of contractures, and exploratory laparotomy for ileus, as well as for dental and obstetric procedures. As the natural course of the disease progresses, the risk of surgery increases concomitant with the increased comorbid conditions associated with the later phase of the disease. However, perioperative complications are not proportional to the severity of the disease. They occur even in mildly affected patients. Consequently, patients should undergo careful preoperative consultation and evaluation.

Fifty to seventy percent of patients with muscular dystrophy demonstrate some cardiac abnormality, although it is clinically significant in only ten percent. Preoperative cardiology assessment with an ECG and echocardiography is essential. Continuous cardiac Holter monitoring is necessary if an arrhythmia is captured on the ECG or if the patient describes symptoms that can be related to cardiac arrhythmias. An echocardiography will demonstrate mitral valve prolapse in 10% to 25% of patients. It may also show posterobasilar hypokinesis in a thin-walled ventricle and a slow relaxation phase with normal contraction characterizing the cardiomyopathy seen in DMD. However, echocardiography may not always reflect the ability of the diseased myocardium to respond to perioperative stress. A stress echocardiography using angiotensin to detect latent heart failure and identify inducible contraction abnormalities has been advocated.

An estimated 30% of deaths in individuals with DMD are due to respiratory causes. Therefore careful preoperative pulmonary assessment is important. Webster demonstrated that the manual muscle strength test has a strong statistical correlation with all of the timed functional tests. Peak expiratory flow was not only easy to perform, but also correlated statistically with all timed functional tests. The correlation was not significant for VC or forced expiratory volume in 1 second (FEV ₁ ).

Intraoperatively, in terms of airway management, patients with DMD and BMD may have decreased laryngeal reflexes and prolonged gastric emptying time, which increases the risk for aspiration. Decreased ability to cough up the accumulation of oral secretions predisposes muscular dystrophy patients to postoperative respiratory tract infections. Masseter spasm is also a possible complication during induction of anesthesia in these patients. Preparedness for a difficult airway is necessary, especially in patients with potential airway problems.

Postoperatively, DMD patients are at an increased risk for respiratory compromise. Retrospective reviews have indicated that the incidence of prolonged postoperative ventilation (>36 hours) was greatest in DMD patients who had a preoperative FVC of less than 40% of the predicted value. Preoperative pulmonary function studies are valuable in determining the postoperative course. Patients with a VC of greater than 30% of the predicted value can usually be extubated immediately after surgery. Sleep apnea may also compound the condition and contribute to the development of pulmonary hypertension. Continuous positive airway pressure and bilevel positive airway pressure have been demonstrated to be effective in the management of postoperative respiratory depression. Delayed pulmonary insufficiency may occur up to 36 hours postoperatively despite the apparent recovery of skeletal muscle strength.

Reports have suggested a relationship between DMD/BMD and MH, but this association is not based on good rational grounds. Whereas the risk for an MH mutation in DMD/BMD patients is similar to that of the general population, the incidence of MH-like anesthetic events has been reported to be 0.002 with DMD and 0.00036 with BMD. Unexplained cardiac arrest and acute heart failure have been reported in DMD/BMD patients. Succinylcholine is contraindicated in these patients because of the potential for rhabdomyolysis and hyperkalemia as a result of their unstable sarcolemmal membranes. Succinylcholine-induced hyperkalemia during acute rhabdomyolysis is more likely to result in cardiac arrest and unsuccessful resuscitation than is the potassium efflux resulting from upregulation of acetylcholine receptors in burn patients. Although the use of nondepolarizing muscle relaxants is usually accompanied by an increase in both maximal effect and duration of action, proper and rapid reversal with sugammadex may put some of these concerns to rest. Current off-label experience in infants and children has been favorable. Narcotics can be used, but small incremental dosing and short-acting medications are recommended given the respiratory depression associated with these medications, as well as the reports of inadvertent reactions to volatile anesthetics,

Recently, TIVA has become more popular. However, consideration needs to be given to the myocardial status of the patient when propofol or barbiturates are used because they may lead to profound hypotension and reduced organ perfusion. Regional anesthesia may be a good alternative to general anesthesia because it avoids the risk of triggering agents and respiratory depression and enables the use of local anesthetics for postoperative analgesia. It may also facilitate chest physiotherapy.

Recent breakthroughs in gene therapy are shining new lights into the management of these relatively common disorders. We have not seen reports on anesthesia management for DMD/BMD patients who had received gene therapy.

Anesthetic Considerations

General considerations for MD are similar to those for other muscular dystrophies. Mathieu and coworkers conducted a retrospective study on the anesthetic and surgical complications of MD. The majority of complications were found to be pulmonary related and significantly more frequent in patients undergoing upper abdominal operations and those with severe disability, as assessed by the presence of proximal limb weakness. The pulmonary complications of MD are the result of hypotonia, chronic aspiration, and central and peripheral hypoventilation. Smooth muscle atrophy, which leads to poor gastric motility, when coupled with a diminished cough reflex, promotes aspiration.

Succinylcholine will produce contractions lasting for several minutes, thus making intubation and ventilation a challenge. These contractions are not antagonized by nondepolarizing muscle relaxants. Other agents, including methohexital, etomidate, propofol, and even neostigmine, may also induce myotonic reactions. Short-acting nondepolarizing muscle relaxants or avoidance of relaxation is therefore advised. Case reports have demonstrated normal responses to sugammadex when rocuronium was used as the neuromuscular blockade.

Triggering factors, such as hypothermia, shivering, and mechanical or electrical stimulation, may cause a myotonic reaction. The reaction can be treated with phenytoin (4-6 mg/kg/day) or quinine (0.3-1.5 g/day). Furthermore, MD patients can be very sensitive to anesthetic agents, with hypersomnolence and CO ₂ retention sometimes being observed. Careful titration with relatively short-acting anesthetic agents may be beneficial. Close cardiac monitoring is required for MD patients. Pacing equipment should be readily available because a third of first-degree atrioventricular blocks may not respond to atropine. All patients should be treated as though they have both cardiomyopathy and conduction defects.

Anesthetic Considerations

As with many muscle diseases, there have been reports that MC patients are predisposed to MH, but as is the case for almost all of them, there are no data to support this hypothesis. However, depolarizing muscle relaxants can lead to severe masseter spasms in MC patients. Generalized spasms involving the respiratory and skeletal muscles have been reported. The findings resemble those of MH, so dantrolene is sometimes administered. Because dantrolene is an inhibitor of calcium release from the SR, it can usually abolish the myotonia effectively. Some believe that local anesthetics and class Ib antiarrhythmic drugs such as lidocaine should be used for myotonic reactions rather than dantrolene. Because shivering in the operating room can trigger the myotonic reaction, MC patients should be kept normothermic during surgery.

Anesthetic Considerations

Reports of anesthesia for patients with MTM are sparse. Nontriggering general anesthesia has been used because of the unfounded concern of possible susceptibility to MH. Agents such as propofol, fentanyl, remifentanil, and nitrous oxide have been used successfully without adverse effects. The possibility of a prolonged effect of nondepolarizing muscle relaxants has been suggested with mechanomyography. However, in reality, intubation of such patients may not require any muscle relaxant because of their hypotonic state. Costi and van der Walt suspected that the defect in MTM is distal to the neuromuscular junction, whereas Dorchies and coworkers suggested that muscles in MTM might be intrinsically normal, with myotubularin-deficient motor neurons involved in development of the disease.

Anesthesia Considerations

Anesthesia case reports for GSD I patients are rare. Patients with GSD I diseases should be given intravenous glucose-containing fluid preoperatively when they have fasted. Lactate-containing solutions should be avoided because these patients are not able to convert the lactic acid to glycogen. Patients need to be monitored frequently to avoid hypoglycemia.

Anesthetic Considerations

Anesthesia reports in AMD patients are rare. Isolated intraoperative cardiac arrest during halothane anesthesia in infantile AMD has been documented. Despite the problem noted with halothane, enflurane and sevoflurane have been used without complications. Theoretically, total intravenous general anesthesia with propofol may cause a reduction in afterload leading to an increased risk for myocardial ischemia. This may become significant when the patient is tachycardic.

Subendocardial ischemia may occur in patients with a thickened ventricular wall and results in higher left ventricular end-diastolic pressure at lower ventricular volume. Close cardiac monitoring is therefore necessary. A central venous or pulmonary artery catheter is not essential in patients who are normovolemic without preexisting heart failure. Adequate filling pressure and normal to high systemic vascular resistance (SVR) are required to ensure effective coronary perfusion. Ketamine has been used successfully in a number of cases because of its ability to maintain SVR and contractility. Respiratory failure and muscle weakness are the other concerns for anesthesiologists. A spectrum of uses of muscle relaxants from none to atracurium to rocuronium have been attempted. Low-dose rocuronium, 0.5 mg/kg, with close monitoring of neuromuscular function and adequate use of reversal agents, has been sufficient to prevent prolonged postoperative weakness. Depolarizing agents should be avoided because of the potential risk of hyperkalemia and rhabdomyolysis.

Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes

MELAS is the most common mitochondrial encephalomyopathy. Onset is most commonly before age 20. Seizures are common and stroke-like episodes (“stroke-like” because they do not conform to vascular distributions) may produce hemiparesis, hemianopia, and cortical blindness. Any patient with a stroke below the age of 40 should be worked up for MELAS. Associated findings include diabetes mellitus, hearing loss, pituitary and thyroid hypofunction, and lack of secondary sexual characteristics. In its full expression, MELAS leads to dementia, a bedridden state, and death. There is no specific treatment.

Myoclonic Epilepsy with Ragged Red Fibers

MERRF is a multisystem disorder characterized by myoclonus, generalized epilepsy, ataxia, and ragged red fibers on muscle biopsy. Other clinical features may include hearing loss, peripheral neuropathy, optic atrophy, dementia, short stature, and exercise intolerance. Cardiomyopathy is occasionally present. Laboratory features include an increased lactate at rest and exercise, and a myopathic picture on EMG and electroencephalogram showing generalized spike and wave discharges with background slowing. Only supportive treatment is available.

Anesthetic Considerations

The anesthesiologist may be involved in the care of patients with mitochondrial disease in multiple situations—often in the setting of obtaining a muscle biopsy in a child with an undiagnosed myopathy. These patients may also present for surgery for procedures related to the disease (such as implantation of a permanent pacemaker in a patient with KSS ), for incidental medical problems, as well as in the labor and delivery suite for labor analgesia. The diversity of clinical presentations encountered in the mitochondrial myopathies discourages a “one size fits all” approach to anesthesia. Rather, each patient should be thoroughly evaluated and the anesthetic plan tailored to the patient’s specific needs.

Preoperative Evaluation

Given the heterogeneous types of mitochondrial disease, patients with mitochondrial disease will need a comprehensive preoperative evaluation with a particular focus on neurologic, cardiac, respiratory, musculoskeletal, endocrinopathic, and metabolic compromise. An ECG and echocardiogram should be considered in patients with signs and symptoms of cardiomyopathy or conduction defects (or both). Although normal lactate and glucose levels cannot rule out mitochondrial diseases, laboratory studies consisting of glucose, electrolytes with anion gap, complete blood count, blood urea nitrogen, lactate, pyruvate, ammonia, CK, biotinidase, acyl carnitines, and blood and urine amino and organic acids could be used as initial investigation for suspected mitochondrial disorders. Further workup should include an erythrocyte sedimentation rate, glycosylated hemoglobin (HbA _1C ), liver and renal profiles, thyroid function tests, arterial blood gas, and urinalysis. Multidisciplinary consultation with special laboratory and imaging studies may be required.

Induction and Maintenance of Anesthesia

Anesthesia has a significant impact on mitochondrial function. Both barbiturates and propofol inhibit complex I of the electron transport chain. Local anesthetics have been demonstrated to disrupt oxidative phosphorylation and decrease the bioenergetic capacity of mitochondria. Sensitivity to intravenous barbiturates and etomidate has been reported. Fortunately, notwithstanding the potential pitfalls mentioned above, almost every anesthetic technique has been safely used in patients with mitochondrial disease. Midazolam, thiopental, propofol, remifentanil, and ketamine have all been used safely. Notably, propofol and midazolam are known to inhibit the mitochondrial respiratory chain in a dose-dependent manner. Indeed, mitochondrial dysfunction has been postulated as a mechanism for the propofol infusion syndrome. It is safe to use propofol as an anesthetic induction agent, but the use of a propofol infusion for long periods should probably be avoided.

Premedication should avoid respiratory depression caused by impaired respiratory responses to hypoxemia. Volatile agents such as halothane, isoflurane, and sevoflurane have been shown to inhibit complex I. This direct inhibition of mitochondrial electron transport system enzymes and altered mitochondrial bioenergetics in the heart were thought to be the mechanism of cardiac preconditioning by volatile anesthetics. Inhaled sevoflurane has been widely used for induction because of its low pungency. In some cases, halothane and isoflurane have also been used. Isoflurane has been recommended as the agent of choice in patients with Kearns-Sayre syndrome because rhythm disturbances have been reported with halothane in such patients. In addition, artificial pacing capability is recommended when dealing with this specific subset of patients. With use of the bispectral index, higher sensitivity to volatile agents has been suggested in children with mitochondrial diseases, especially with dysfunction of complex I. However, its methodology has been criticized. A decreased minimum alveolar concentration of halothane in patients with mental retardation has also been reported.

Despite no real evidence and the fact that volatile anesthetics are frequently the anesthetic of choice when muscle relaxants are considered, several papers have expressed concern that these myopathies are associated with increased sensitivity to MH. This conclusion is not supported by any data. Increased sensitivity to nondepolarizing muscle relaxants has been documented for mivacurium, atracurium, and rocuronium. In contrast, normal responses to depolarizing and nondepolarizing neuromuscular blockers such as pancuronium, vecuronium, and atracurium are also reported. Although muscle relaxants are not absolutely contraindicated based on current literature and research, it is necessary for anesthesia practitioners to cautiously administer depolarizing or nondepolarizing neuromuscular blockers to those patients with mitochondrial diseases and to use neuromuscular monitoring. Presently, there is no evidence to support an association between MH and mitochondrial disease. However, it may be prudent to avoid succinylcholine in patients with extensive myopathy to minimize the risk of hyperkalemia, although the safe use of succinylcholine has been documented in at least one patient with KSS.

Nonsteroidal antiinflammatory drugs and regional techniques consisting of local, spinal, and epidural administration have been reported. However, it is suggested that regional anesthesia be performed when neurologic abnormalities of the spinal cord and peripheral nerves have definitely been ruled out. Importantly, coagulation function should be assessed because of the possibility of hepatic dysfunction.

Opioids should be used with caution because of the increased risk for respiratory depression and their potential to induce respiratory acidosis in addition to the underlying metabolic acidosis. Because patients with mitochondrial diseases have dysfunctional aerobic metabolism, any increase in the basic metabolic rate should be prevented. Shivering, hypoxia, fasting, and hypotension in such patients may exacerbate the lactic acidosis and should therefore be avoided. Finally, the increased postoperative infection rate in patients with mitochondrial diseases may be due to low hepatic mitochondrial activity, phagocytosis by Kupffer cells, and decreased activity of the reticuloendothelial system.

Perhaps more important than the specific choice of anesthetic agents are the implications of patients’ co-morbidities and metabolic status. Normothermia should be maintained during surgeries, and intravenous fluids should be warmed to body temperature. Lactated Ringer (LR) should probably be avoided given the risk of preexisting lactic acidosis (although there is no evidence that LR has worsened acidosis when it has been used ). There have been multiple reports of hyponatremia (and occasional hyperkalemia) in these patients. Adrenal insufficiency should be considered in such a picture, particularly when accompanied by hypotension. Finally, these patients are at increased risk of cardiac conduction abnormalities and cardiomyopathy that should be taken into consideration while formulating an anesthetic plan ( Box 35.7 ).

Box 35.7

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