Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

CHAPTER 14 – Mitochondrial Diseases

Richard J. Levy, MD,
Stanley Muravchick, MD, PhD

  

 

Background

  

 

Effect of Anesthetics on Mitochondrial Function

  

 

Inhalational and Local Anesthetics

  

 

Barbiturates and Propofol

  

 

Other Effects

  

 

Inherited Disorders with Childhood Onset

  

 

Inherited Disorders with Adult-Onset and Acquired Mitochondrial Dysfunction

  

 

Inherited Disorders

  

 

Acquired Mitochondrial Disorders—Acute Onset

  

 

Acquired Mitochondrial Disorders—Gradual Onset

  

 

Apoptosis and Death

  

 

Preoperative Evaluation

  

 

Anesthetic Management

  

 

Conclusion

The terms mitochondrial myopathy or inherited mitochondrial encephalomyopathy originally encompassed a grouping of pediatric neurologic syndromes produced by maternally inherited mitochondrial genetic defects. However, it is now clear that respiratory chain deficiencies undermine metabolic energy production, produce excessive levels of “free radical” reactive oxygen species (ROS), and may generate almost any symptom, in any organ system, at any stage of life. Therefore, the scope of human disease attributable to the inherited, acutely acquired, or insidious onset of impaired mitochondrial function may be far more broad than previously believed.

In addition to the energy production essential for life, the hundreds of mitochondria found in every cell also provide a wide variety of metabolic and cell regulatory functions. For example, hepatic mitochondria provide detoxification of ammonia. In neurons, they are essential for neurotransmitter synthesis. Therefore, mitochondrial dysfunction is emerging as a pivotal factor in the etiology of sepsis, neurodegenerative disorders, diabetes, arteriosclerotic disease, and even normal human aging. [1] [2] In this chapter we provide an overview of current concepts of the perioperative assessment and anesthetic management of pediatric and adult patients with uncommon mitochondrial-based syndromes. In addition, we discuss more familiar disease states that are now thought to be manifestations of organ system dysfunction attributable to disruption or depression of aerobic metabolism or other aspects of mitochondrial function.

BACKGROUND

Mitochondria produce adenosine triphosphate (ATP) by oxidative phosphorylation via an electron transport chain composed of five enzyme complexes located on the inner mitochondrial membrane ( Fig. 14-1 ). Reduction of molecular oxygen is coupled to phosphorylation of adenosine diphosphate (ADP), resulting in ATP synthesis.[3] The reduced cofactors nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), generated by the Krebs cycle and by fatty acid oxidation, donate electrons to complex I (NADH dehydrogenase) and complex II (succinate dehydrogenase). Electrons are then transferred to coenzyme Q and subsequently to complex III. From complex III, reduced cytochrome c donates its electrons to complex IV (cytochrome c oxidase), resulting in the reduction of molecular oxygen to water. Complexes I, III, and IV actively pump hydrogen ions across the inner membrane of the mitochondrion into the intermembrane space, creating an electrochemical gradient. Influx of protons back into the mitochondrial matrix through complex V results in ATP synthesis.[4] This process of oxidative phosphorylation is the major intracellular source of the free radicals (O2-, H2O2, and OH-) that are generated as byproducts of the interaction between excess electrons and oxygen.

 
 

FIGURE 14-1  The electron transport chain needed for oxidative phosphorylation is located on complexes I to V on the inner mitochondrial membrane. The Krebs cycle and fatty acid oxidation yield NADH and FADH2, which initiate electron transfer to the respiratory chain. Coenzyme Q (Q) and cytochrome c (C) transport electrons to complex III and complex IV, respectively. Complex V uses the hydrogen ion gradient (H+) created by hydrogen pumps within complexes I, III, and IV to phosphorylate adenosine diphosphate (ADP) to synthesize adenosine triphosphate (ATP).

 

 

The enzymes, membranes, and other molecular components of these five major enzyme/protein complexes needed for mitochondrial oxidative phosphorylation are encoded in a complementary manner by the circular genome found within the mitochondrion itself, as well as by the much larger nuclear genome of the host cell. The mitochondrial genome encodes for 13 essential subunits of the electron transport chain, two types of ribosomal ribonucleic acid (rRNA), and 22 forms of transfer RNA (tRNA). Each mitochondrion contains multiple copies of mitochondrial deoxyribonucleic acid (mtDNA). Nuclear DNA (nDNA) encodes an additional 900 proteins that are needed for normal mitochondrial function.

The complementary relationship between two genomes within each cell and the putative evolution of the mitochondrion from a free-living organism into an organelle within the cell have been known and discussed by cell biologists only within the past three or four decades. The implications of this biologic curiosity with regard to our understanding of embryology, evolution, aging, and even the mechanism of death itself may be profound. The mitochondrion, through a central role in the modulation of bioenergetics and cellular apoptosis (see later), may also serve as both a “biosensor” for oxidative stress and as the final determinant of cellular viability.

The most severe inherited mitochondrial disease syndromes become clinically apparent during infancy, but a few were eventually described in which symptoms did not appear until early adulthood. The original descriptions of the mitochondrial diseases of childhood assumed that there was maternal transmission of mitochondria and of both normal (“wild type”) and mutant mtDNA. Because mutant mtDNA coexists with wild-type mtDNA, variability in the severity of all these inherited conditions is thought to reflect heteroplasmy, the random differences in the proportion of mutant mtDNA distributed throughout the target tissues during embryogenesis. For the mitochondrial disorders of adult onset, variability in disease severity and an exceptionally wide range of phenotypic symptom patterns are thought to reflect both heteroplasmy and the markedly different and progressively changing metabolic demands of different target tissues during adulthood. Hundreds of mtDNA mutations have already been identified in detail and classified as mitochondrial myopathies, encephalomyopathies, or cytopathies. [5] [6]

A recent report of a patient with mutated mtDNA of paternal origin, however, suggests that some paternal mtDNA also survives in the zygote and therefore may also contribute to the mtDNA pool.[7] The important role of defects in nDNA in disorders characterized by declining mitochondrial bioenergetics has also been clarified, reflecting the fact that the interaction of nuclear and mitochondrial genomes has become better understood.[8] It is now clear that there are subunits of the electron transport chain not encoded by mtDNA that arise from nDNA. Diseases caused by nuclear genes that do not encode subunits but affect mtDNA stability are an especially interesting group of mitochondrial disorders. In these syndromes, a primary nuclear gene defect causes secondary mtDNA information loss or deletion, which leads to subsequent tissue dysfunction in the form of disrupted oxidative phosphorylation. Therefore, there are some genetically determined defects in oxidative phosphorylation that follow classic mendelian patterns of dominant-recessive genetic transmission, rather than the maternal patterns usually associated with mtDNA defects.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

EFFECT OF ANESTHETICS ON MITOCHONDRIAL FUNCTION

The effects of anesthetics on mitochondrial function were first investigated in the 1930s. Although the mechanisms of action are still not all established, it is now clear that virtually all volatile, local, and intravenous anesthetics have significant depressant effects on mitochondrial energy production. These effects are believed to occur primarily at the level of the electron transport chain on the inner membrane of mitochondria. Early studies reported inhibition of the oxidation of glucose, lactate, and pyruvate by narcotics; and more recent work explores the mechanism of reduced oxygen consumption in the brain after treatment with barbiturates.[9] A common final pathway of depressed bioenergetic activity, possibly through a variety of intracellular or mitochondrial mechanisms, may, at least in part, also explain the primary anesthetic effects of these drugs.[10] There is, however, need for caution with regard to the interpretation of the available data on this subject because much of the work examining anesthetic-induced mitochondrial dysfunction has been done in vitro, in isolated mitochondria, not in functioning cells. Furthermore, the anesthetic concentrations used to inhibit mitochondrial function experimentally have been up to 10-fold higher than concentrations used clinically, although it appears that anesthetics inhibit mitochondria in a dose-dependent fashion. These are major limitations in this field of investigation and should be taken into consideration when reviewing the subject.

Inhalational and Local Anesthetics

Nitrous oxide and the potent inhalational agents have significant effects on mitochondrial respiration. [11] [12] [13] [14] In cardiac mitochondria, halothane, isoflurane, and sevoflurane have all been shown to inhibit complex I of the electron transport chain.[12] At concentrations equal to 2 MAC (minimal alveolar concentration), complex I activity is reduced by 20% following exposure to halothane and isoflurane, and by 10% following exposure to sevoflurane. Oxidative phosphorylation in liver mitochondria is also measurably disrupted after exposure to halothane. Concentrations of 0.5% to 2% halothane lead to reversible inhibition of complex I (NADH: ubiquinone oxidoreductase) in the electron transport chain. Halothane-induced mitochondrial inhibition in the liver is further exacerbated by the addition of nitrous oxide.[13] Local anesthetics have also been shown to disrupt oxidative phosphorylation [14] [15] and significantly degrade bioenergetic capacity in mitochondrial isolates.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Barbiturates and Propofol

Barbiturate effects have been well studied in the brain, heart, and liver. Like the inhalational agents, barbiturates inhibit complex I of the electron transport chain. This inhibition, however, occurs at serum levels that far exceed those required to produce the anesthetic effect. Propofol disrupts electron transport in the respiratory chain.[16] Decreased oxygen consumption and inhibited electron flow have been demonstrated in cardiac mitochondria exposed to propofol.[17] Similarly, work with mitochondria from the liver has demonstrated that propofol inhibits complex I of the electron transport chain.[18] Table 14-1 is a summary of the effect of various anesthetic agents on mitochondrial function.

TABLE 14-1   -- Effect of Anesthetics on Mitochondrial Function

  

 

Volatile agents inhibit complex I.

  

 

Barbiturates inhibit complex I.

  

 

Propofol inhibits complex I and slows electron transport of respiratory chain.

  

 

Local anesthetics disrupt oxidative phosphorylation by unknown mechanisms.

 

 

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

Other Effects

Exposure to the volatile anesthetics has also been shown to alter the ability of the mitochondrion to respond to rising levels of ROS, a “preconditioning” effect that may protect the cell if it is subsequently exposed to periods of hypoxia or ischemia. Although the mechanism of “anesthetic preconditioning” remains speculative, anesthetic agents appear to disrupt mitochondrial bioenergetics sufficiently that they produce the low levels of oxidative stress that induce short-term genetic expression of heat shock protein (HSP) or other protective substances. HSP can also be induced by brief, sublethal episodes of ischemia or hypoxia, suggesting that the prophylactic administration of HSP or similar interventions may have potential therapeutic value for cardiac protection and neuroprotection during major surgery, during which tissue perfusion or oxygenation is disrupted.[19]

Therefore, anesthetics may not only depress bioenergetic activity but may also affect other functions of the mitochondrion, such as the role of this organelle as a “biosensor” for oxidative stress or perhaps the role of the mitochondrion as an effector organelle for cellular apoptosis. Accumulation of ROS increases outer membrane permeability of the mitochondrion and leads to the ingress of potassium and ionized calcium and to the release of cytochrome c and other “pro-apoptotic” soluble proteins. Leakage of cytochrome c from mitochondria not only rapidly degrades the bioenergetic capacity of the cell by removing a key component of the respiratory chain but also appears to trigger the release of caspases, which are cysteine-containing protease enzymes. They, in turn, activate other enzymes that digest nDNA, the final step in “cell suicide,” or apoptosis.

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INHERITED DISORDERS WITH CHILDHOOD ONSET

Mitochondrial diseases with childhood onset often present in the newborn period. The clinical features may be quite variable because a single organ system or multiple organ systems may be affected. The organ systems most often involved are the central (CNS) and peripheral nervous systems, liver, heart, kidneys, muscle, gastrointestinal tract, skin, and a number of endocrine glands. Nonspecific signs include lethargy, irritability, hyperactivity, and poor feeding. The presentation can be very abrupt and dramatic, with acute onset of hypothermia or hyperthermia, cyanosis, seizures, emesis, diarrhea, or jaundice. Some of the more insidious signs and symptoms of mitochondrial disease in the newborn are listed in Table 14-2 .

TABLE 14-2   -- Differential Diagnosis of Signs and Symptoms of Mitochondrial Disorders in the Newborn Period

  

 

Unexplained sepsis or recurrent severe infection

  

 

Organic acidemias such as maple syrup urine disease and methylmalonic aciduria

  

 

Urea cycle defects such as ornithine transcarbamylase deficiency

  

 

Carbohydrate disorders such as galactosemia or hereditary fructose intolerance

  

 

Aminoacidopathies such as homocystinuria, tyrosinemia, and nonketotic hyperglycemia

  

 

Endocrinopathies such as congenital adrenal hyperplasia and congenital diabetes

 

 

MtDNA depletion syndrome (MDS) is a severe disease of childhood characterized by liver failure and neurologic abnormalities, in which tissue-specific loss of mtDNA is seen. MDS is thought to be caused by a putative nuclear gene that controls mtDNA replication or stability.[20] Similarly, children with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) may have multiple mtDNA deletions and/or mtDNA depletion that results from an nDNA mutation.[21] Although nonspecific gastrointestinal and hepatic symptoms are commonly found in most mitochondrial disorders, they are among the cardinal manifestations of primary mitochondrial diseases such as MDS and MNGIE.

CNS manifestations of mitochondrial disorders include encephalopathy, a cardinal feature of Leigh's syndrome. Seizures and ataxia also occur with myoclonic epilepsy with ragged-red fibers (MERRF). Dementia and stroke-like symptoms are a major feature of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). When the peripheral nervous system is involved there may be axonal sensory neuropathies. Cardiac involvement with pediatric mitochondrial disease may produce hypertrophic cardiomyopathy, seen with MELAS, or dilated cardiomyopathy, heart block, and pre-excitation syndrome, features of Leber's hereditary optic neuropathy (LHON). Impaired renal bioenergetics produce tubular acidosis; muscle abnormalities present largely as myopathies. Hepatic failure, dysphagia, pseudo-obstruction, and constipation all suggest gastrointestinal impairment. Vision and hearing are often impaired by ophthalmoplegia, ptosis, cataracts, optic atrophy, pigmentary retinopathy, and sensorineural deafness. Endocrine organ involvement manifests as diabetes mellitus, hypoparathyroidism, hypothyroidism, and gonadal failure. Typical symptoms and signs of the most well-known mtDNA-related syndromes are listed in Table 14-3 .


TABLE 14-3   -- Symptoms and Signs of Mitochondrial Disorder

Disease

Mutation

Inheritance

Symptoms and Signs

Kearns-Sayre syndrome

Large-scale mtDNA deletion

Sporadic

Ataxia, peripheral neuropathy, muscle weakness, ophthalmoplegia, ptosis, pigmentary retinopathy, sideroblastic anemia, diabetes mellitus, short stature, hypoparathyroidism, cardiomyopathy, conduction defects, sensorineural hearing loss, Fanconi syndrome, lactic acidosis, ragged-red fibers on muscle biopsy

Progressive external ophthalmoplegia

Large-scale mtDNA deletion

Sporadic

Muscle weakness, ophthalmoplegia, ptosis, lactic acidosis, ragged-red fibers on muscle biopsy

Pearson's syndrome

Large-scale mtDNA deletion

Sporadic

Ophthalmoplegia, sideroblastic anemia, pancreatic dysfunction, Fanconi syndrome, lactic acidosis, ragged-red fibers on muscle biopsy

Myoclonic epilepsy with ragged-red fibers (MERRF)

mtDNA point mutation, tRNA abnormality

Maternal

Seizures, ataxia, myoclonus, psychomotor regression, peripheral neuropathy, muscle weakness, short stature, sensorineural hearing loss, lactic acidosis, ragged-red fibers on muscle biopsy

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)

mtDNA point mutation, tRNA abnormality

Maternal

Seizures, ataxia, myoclonus, psychomotor regression, abnormality hemiparesis, cortical blindness, migraine, dystonia, peripheral neuropathy, muscle weakness, diabetes mellitus, short stature, cardiomyopathy, conduction defects, intestinal pseudo-obstruction, sensorineural hearing loss, Fanconi syndrome, lactic acidosis, ragged-red fibers on muscle biopsy

Aminoglycoside-induced deafness

tRNA abnormality

 

Cardiomyopathy, sensorineural hearing loss

Neuropathy, ataxia, and retinitis pigmentosa (NARP)

mtDNA point mutations, mRNA abnormality

Maternal

Ataxia, peripheral neuropathy, muscle weakness, pigmentary retinopathy, optic atrophy, sensorineural hearing loss

Maternally inherited Leigh's syndrome

mtDNA point mutation, mRNA abnormality

Maternal

Seizures, ataxia, psychomotor regression, dystonia, muscle weakness, abnormality pigmentary retinopathy, optic atrophy, cardiomyopathy, lactic acidosis

Leber's hereditary optic neuropathy

Multiple mtDNA point mutations, mRNA abnormality

Maternal

Dystonia, optic atrophy, conduction defects

 

 

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INHERITED DISORDERS WITH ADULT-ONSET AND ACQUIRED MITOCHONDRIAL DYSFUNCTION

Inherited Disorders

Inherited neurologic/metabolic syndromes produced by genetic defects that disrupt mitochondrial energy production are typically seen during infancy, or they may first be apparent only many years later. They can appear during the early-to-middle adult years in the form of declining organ system reserve in tissues such as brain and retina that require maintenance of relatively high rates of metabolic activity for normal functioning. Symptoms include progressive motor weakness and lethargy, decreased color or night vision, and ataxia. Like those of most syndromes of infancy, adult mitochondrial syndromes such as NARP are caused by maternally transmitted mutations of mtDNA. The acronym NARP reflects the fundamental clinical stigmata of that disorder, that is, sensory neuropathy, ataxia, and retinitis pigmentosa. In NARP, a point mutation at base pair position 8993 of mtDNA produces defects in ATPase. Consequently, reduced enzymatic activity and lower rates of ATP production are found in mitochondrial isolates of lymphoblastoid cell lines obtained from NARP patients, and there are increased brain levels of phosphocreatine and inorganic phosphate in NARP patients compared with age- and sex-matched control subjects, suggesting generalized impairment of the efficiency of oxidative metabolic pathways.[22] The specific genetic defects that produce NARP and several other mitochondrial disorders have been identified ( Fig. 14-2 ).

 
 

FIGURE 14-2  Inherited mitochondrial syndromes and disorders can reflect single-point, multiple-point, or large-scale errors in mitochondrial DNA (mtDNA).

 

 

Some of the pathognomonic features of adult-onset mitochondrial disorders may also occur long after the syndrome itself is established by secondary characteristics. For example, stroke-like episodes may not appear until decades after initial clinical onset of MELAS.[23] A progressive decrease in cardiac, muscle, and nervous system functional reserve probably begins long before the appearance of overt signs or symptoms but can usually be confirmed by careful and detailed review of the patient's history and ability to accomplish the normal activities of daily life.

Even when the focus of mitochondrial disease was limited to the inherited disorders of childhood, it was suspected that mtDNA missense mutations could play an etiologic role in a wide range of neurodegenerative disorders.[24] Among the adult neurodegenerative diseases, a mitochondrial focus has now been clearly established for Parkinson's disease,[25] Alzheimer's dementia, and amyotrophic lateral sclerosis.[26] More recently, the spinal cord atrophy of multiple sclerosis has been attributed to inflammation that may be controlled by a mitochondrion-driven, genetically determined mechanism similar to that of other neurodegenerative disorders.[27] However, there are other important processes implicated in neurodegenerative disorders, several of which involve degradation of proteins or compromise of the mechanisms by which damaged proteins are cleared from within neurons. Oxidative modification of proteins, perhaps by increased levels of ROS, causes them to become dysfunctional and makes them targets for selective destruction by the proteolytic machinery of the proteasomal system. This system is distributed in the cytosol, nucleus, and endoplasmic reticulum of the neuron and contains a multicatalytic protease complex and various regulatory and control elements.[28]

Several adult-onset clinical syndromes associated with multiple mtDNA deletions have been characterized, the most frequently described being autosomal dominant progressive external ophthalmoplegia (adPEO). Alper's syndrome, Pearson's marrow-pancreas syndrome,[29] and Navajo neuropathy are all proven or suspected primary mitochondrial hepatopathies, although there are even less well-described secondary mitochondrial hepatopathies in which mitochondrial dysfunction is due to alcohol abuse, drugs, or other hepatotoxins. Mitochondrial defects are now also associated with predispositions to two types of inherited neoplasia syndromes.[30] There is growing evidence that mitochondrial dysfunction plays a pivotal, if not necessarily etiologic, role in renal disease, adult-onset diabetes, and perhaps a wide variety of cardiomyopathies. The most frequent renal symptom is proximal tubular dysfunction, usually as de Toni-Debré-Fanconi syndrome, and, less often, renal tubular acidosis, Bartter's syndrome, chronic tubulointerstitial nephritis, or nephrotic syndrome.[31]

Examination of mitochondrial respiration in the skeletal muscle of patients with occlusive peripheral arterial disease suggests that mitochondrial respiratory activity is abnormal. Impaired bioenergetics may be a pathophysiologic component of this group of disorders.[32] Similarly, an increase in oxidative stress is now believed to contribute to the pathology of vascular disease in stroke, hypertension, and diabetes.[33] A 40% reduction in oxidative phosphorylation as assessed in vivo by magnetic resonance spectroscopy suggests that age-associated decline in mitochondrial function contributes to the reduced insulin-stimulated muscle glucose metabolism that characterizes insulin resistance in the elderly.[34] This insulin resistance appears to reflect an inherited defect of fatty acid metabolism.[35]

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Acquired Mitochondrial Disorders—Acute Onset

Cardiac mitochondria are obviously essential to myocardial energy production and ionic homeostasis, but they also control myocardial cell viability. Most drugs used to treat myocardial ischemia may exert their cardioprotective effects via their actions on cardiac mitochondrial function.[36] Accumulating evidence also suggests that ROS play an important role in the development and progression of heart failure, regardless of the etiology.[37] Under pathophysiologic conditions, ROS have the potential to cause cellular damage and dysfunction. Recent experimental studies have suggested a possible causal role for increased ROS in the development of contractile dysfunction after myocardial infarction.[38] Whether the effects of increasing myocardial ROS are beneficial or harmful will depend on site, source, and amount of ROS produced and on the overall metabolic status of the myocyte. In addition to direct effects on cellular, enzymatic, and protein function, ROS have been implicated in the development of agonist-induced cardiac hypertrophy, cardiomyocyte apoptosis, and the subsequent remodeling of the failing myocardium. These alterations in phenotype are driven by metabolically sensitive gene expression, and in this way ROS may act as potent intracellular second messengers.

Another example of an acquired mitochondrial disorder of acute onset is overwhelming infection. Sepsis, the systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS) are the leading causes of morbidity and mortality in critically ill surgical patients. Despite improvements in monitoring and therapy, as well as advances in our understanding of the pathophysiology of sepsis, mortality rates remain between 40% and 60%.[39] Pulmonary impairment manifests early as acute lung injury and acute respiratory distress syndrome (ARDS). Acute-onset cardiovascular, hepatic, and renal dysfunction are common, and most organs develop multiple abnormalities in their metabolic pathways and enzyme systems. Some studies have demonstrated decreased ATP levels during prolonged sepsis, suggesting that impaired bioenergetics may play a role in diffuse cellular and organ dysfunction under these circumstances.[40] However, other investigators have demonstrated normal ATP levels in various tissues during sepsis, although this does not necessarily imply normal mitochondrial bioenergetics because cells and organ systems are capable of reducing their energy requirements during sepsis. Therefore, review of the sepsis literature with regard to bioenergetics can be confusing.

A potentially unifying concept regarding the role of mitochondria in sepsis is that of “cytopathic hypoxia,” the inability of cells to use molecular oxygen to produce ATP.[41] In effect, pathologically impaired bioenergetic capacity would be masked by decreased ATP demand due to downregulation. Cytopathic hypoxia may reflect altered enzyme function because of inhibition of any or all of the five complexes of the electron transport chain. It may also be caused by abnormalities in genetic transcription or translation or by changes in electron chain enzyme kinetics. Messenger RNA (mRNA) synthesis could be disrupted by abnormalities of either nuclear or mitochondrial transcription, since the subunits of the five respiratory chain enzymes arise from both nDNA and mtDNA. Errors in translation, the process of protein synthesis from mRNA, could also result in decreased electron chain function. Finally, the kinetic activity of each enzyme is dependent on pH and temperature. Therefore, sepsis-related abnormalities in pH, temperature, or the presence of inhibitors or conformational changes in enzyme structure could disrupt oxidative metabolism and explain the appearance of cytopathic hypoxia during sepsis.[42]

There are, in fact, clinical data to support the concept of cytopathic hypoxia in sepsis. Cytochrome oxidase subunit I mRNA and protein levels are decreased in the heart and in macrophages in both sepsis and sepsis-related disorders.[43] In addition, decreased cardiac cytochrome oxidase subunit IV and complex II protein levels have been demonstrated, as well as impaired function of each of the enzymes of the electron transport chain.[44] Myocardial cytochrome oxidase is reversibly inhibited early in sepsis but appears to become irreversibly inhibited during the later phase of sepsis.[45] Possible causes of mitochondrial enzyme inhibition during sepsis include nitric oxide (NO), peroxynitrite, ROS, and carbon monoxide. NO is produced by the enzyme nitric oxide synthase and is a reversible inhibitor of complex IV.[46] Peroxynitrite, a reactive nitrogen species, is formed when NO reacts with ROS and it inhibits complex I, II, and V and irreversibly inhibits cytochrome oxidase.[47] ROS cause lipid peroxidation, damaging membranes and mtDNA and irreversibly inhibiting complex IV.[48] Carbon monoxide, produced when heme is broken down by heme oxygenase, is an irreversible inhibitor of cytochrome oxidase. In fact, all of these potential inhibitors are produced in various tissues during sepsis and may contribute to sepsis-associated mitochondrial dysfunction.

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Acquired Mitochondrial Disorders—Gradual Onset

Within the past two decades, loss of mitochondrial bioenergetic capacity has become a highly plausible and intriguing explanation for the ubiquitous and insidious deterioration of organ system functional reserve that characterizes normal human aging.[1] Because it is a universal phenomenon, the declining bioenergetics that characterize the middle to late adult years should be viewed as a physiologic process rather than an age-related disease. Oxidative stress, in general terms, describes the progressive accumulation of ROS within or around mitochondria and implies disruption of the equilibrium among the mediators of oxidative metabolism and mitochondrial integrity. Mitochondrial DNA is thought to be exposed to progressively increasing levels of ROS throughout adulthood, and it becomes increasingly vulnerable to oxidative damage and mutation during these years of exposure, as scavenging and repair mechanisms become less effective.[49] At higher “oxidative stress” levels, free radicals such as superoxide are also believed capable of damaging or destroying membranes and other cellular and organelle microarchitecture directly. This may lead to a decline in bioenergetic capacity, as well as impaired synthesis of protective enzymes such as superoxide dismutase that scavenge ROS from the cytosol. In effect, cellular aging may be a “vicious cycle” of progressive bioenergetic failure in the mitochondria and rising levels of ROS ( Fig. 14-3 ).

 
 

FIGURE 14-3  Schematic representation of the mitochondrial “cycle of aging” and the link between bioenergetics and the increased risk of perioperative morbidity and mortality in a geriatric population.

 

 

Currently, therefore, biogerontologists have focused on the role of long-term oxidative stress[50] as a cause of the increasing damage to mitochondrial DNA and intracellular protein[51] that is believed to explain the decline in functional reserve that characterizes aging mammalian tissues.[52] There is a growing body of experimental and observational data to support the concept that aging is, in effect, a complex expression of chronic oxygen toxicity. More than two dozen mutations of mtDNA have been observed in the somatic tissues of aged human individuals. Although these mutations are present at relatively low levels, they accumulate exponentially with increasing age in skeletal muscle, cardiac muscle, and other human tissues as normal mtDNA declines.[53] Accelerated aging syndromes such as Down, Werner's, and the Hutchinson-Gilford syndromes are characterized not only by shortened life span but also by symptoms and disorders associated with increased oxidative stress.[54]

Because ROS are ephemeral and present in minute quantities, they have yet to be measured within organelles directly. Therefore, it may be premature to state that they are the primary etiologic factor in processes of aging. Nevertheless, if years of vigorous aerobic metabolism and ROS production inevitably lead to progressive failure of a genetically predetermined capacity of human cells to scavenge free radicals and to clear the random damage to mtDNA caused by ROS, this concept is extremely attractive because it is compatible with both stochastic (random “wear and tear”) and nonstochastic (“programmed”) theories of aging.

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Apoptosis and Death

Apoptosis, programmed cell death, and the related concept of mitochondrial self-destruction (“mitoptosis”) may be the physiologic links between the progressive decline in organ system functional reserve inevitably associated with mammalian aging and the equally inevitable onset of death. As currently envisioned, rising levels of oxidative stress eventually outstrip intrinsic mechanisms for scavenging ROS and for repairing ROS-induced damage to organelles, proteins, and nucleotides. As the stress levels rise, the mitochondrion undergoes an increase in outer membrane permeability that leads to release of “pro-apoptotic” substances. At low intracellular concentrations, NO appears to inhibit or suppress apoptosis. At higher levels, however, ROS and NO may actually function as “death messengers” in the presence of elevated intracellular or intramitochondrial calcium.

Many pro-apoptotic molecules act to increase mitochondrial membrane permeability and release the soluble proteins from the mitochondrial intermembrane space that can precipitate rapid cell destruction. Leakage of cytochrome c from mitochondria, for example, not only rapidly degrades the bioenergetic capacity of the cell by removing a key component of the respiratory chain but also appears to trigger the release of caspases, which are cysteine-containing proteases. Caspases, in turn, activate nucleases, enzymes that digest nDNA, the final step of “cell suicide.” Therefore, despite their fundamental and life-long value as the energy sources within each cell, once the process of apoptosis has been activated, mitochondria are rapidly converted into what have been called “killer organelles.”[55]

There may be other pathways for apoptosis that do not require caspase activation, primarily via apoptosis-inducing factor (AIF), a flavoprotein normally sequestered in the intermembrane region of the mitochondrion. AIF normally stabilizes mitochondrial membrane permeability, but once released into the cytosol, it can damage both nuclear and mitochondrial DNA. In addition, there is evidence that, under conditions of extreme oxidative stress, ROS can directly trigger an apoptotic response independent of both the cytochrome-caspase mechanism and the pathway utilized by AIF. Cytokines such as HSP help to protect cellular integrity during sepsis[56] and can be induced by ischemic or hypoxic preconditioning. HSP appears to interfere specifically with the AIF-mediated apoptotic pathway and may have great therapeutic potential for cardiac protection and neuroprotection.[57]

As the complexity of mitochondrial function and apoptosis unfolds, it has become clear that understanding this process may be essential, not only to understand aging and death, but also to understand mechanisms of both inherited and acquired disease. Carcinogenesis may reflect an unbalancing of the dynamic equilibrium between pro-apoptotic and anti-apoptotic forces. Propagation of viruses probably requires suppression of apoptosis, and it is unlikely that cellular development and tissue specialization during embryogenesis could occur without short-term suppression of apoptosis. Because caspases are involved in most apoptotic processes, understanding the source and mechanism of endogenous and exogenous caspase inhibitors may also be key to learning about, and eventually altering, these events.

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PREOPERATIVE EVALUATION

Owing to the heteroplasmy of mitochondria in tissues, as discussed earlier, patients with mitochondrial disorders may present with a wide variety of symptoms, many of them extremely vague or subtle, even if a defined mtDNA mutation is involved. Mitochondrial cytopathy should be included in the differential diagnosis whenever clinical signs and symptoms include persistent muscle pain associated with weakness or fatigue,[58] or if there is diffuse multisystem involvement that does not clearly fit an established pattern of conventional disease.[59] Subclinical hepatic and renal involvement is common, but the diagnosis of a mitochondrial-based respiratory chain deficiency is rarely entertained even when renal symptoms are present, unless they are associated with evidence of skeletal muscle weakness or encephalopathy.

If a mitochondrial myopathy is suspected, diagnostic investigations should include screening for increased lactate/pyruvate and ketone body molar ratios and measurement of serum and cerebrospinal fluid lactate. With a very high index of suspicion, skeletal muscle biopsy may confirm the presence of characteristic “ragged-red fibers,” which reflect accumulations of defective mitochondria, excess glycogen granules, and cytochrome c oxidase-deficient cells. The biopsy can also provide material for genetic analysis and subsequent genetic counseling. Because mitochondrial cytopathies involve enzymatic defects in ATP production that lead to organ dysfunction, common sequelae are lactic acidosis and abnormalities in glucose metabolism. For pediatric patients, initial investigation to confirm the diagnosis involves blood and urine testing, although normal lactate and glucose do not necessarily rule out the presence of mitochondrial disease. Table 14-4 lists the most common laboratory tests used to detect mitochondrial disorders.[60] As in adults, confirmatory diagnostic studies include skin or muscle biopsies for microscopic evaluation and mtDNA analysis.

TABLE 14-4   -- Initial Laboratory Investigation for Suspected Mitochondrial Disorders

  

 

Glucose

  

 

Electrolytes with anion gap

  

 

Complete blood cell count

  

 

Blood urea nitrogen

  

 

Lactate, pyruvate, and lactate/pyruvate ratio

  

 

Ammonia

  

 

Creatinine kinase

  

 

Biotinidase level

  

 

Blood and urine amino acids

  

 

Blood and urine organic acids

  

 

Acyl carnitines

  

 

Skin and muscle biopsies

 

 

To define the extent to which declining mitochondrial energy production has produced clinical compromise in patients with adult-onset mitochondrial disease, extensive preoperative assessment of organ system functional reserve is more useful rather than traditional preoperative tests used to screen for the presence of specific disease entities. Unique concerns regarding comorbidity include decreased anesthetic requirement and susceptibility to prolonged drug-induced nervous system depression because of impaired neuronal bioenergetics, even when overt encephalopathy has not yet developed, as well as intrinsic skeletal muscle hypotonia and cardiomyopathy with increased risk of sudden death from conduction abnormalities. Skeletal muscle weakness may produce a general decrease in aerobic work capacity that may compromise postoperative ventilation following upper abdominal or thoracic surgery,[61] and subclinical erosion of hepatorenal reserve may further predispose these patients to prolonged drug effects and delayed recovery from anesthesia, muscle relaxants, and opioids.

Many of these clinical concerns may be exacerbated by acute or sustained stress ( Table 14-5 ). Many neurologists recommend a diet and nutritional supplements rich in antioxidants, as well as treatment with vitamins and various cofactors such as coenzyme Q ( Table 14-6 ), although there are little data supporting this approach as a mandatory preoperative regimen. Therefore, optimization of the patient's physical status and treatment of the stigmata of acquired or adult-onset mitochondrial diseases remains supportive. Preoperative therapy should focus on serious overt clinical manifestations such as cardiac dysrhythmias,[62] muscle weakness, and postural imbalance and endocrinopathy.


TABLE 14-5   -- Questions to Ask Primary Physician, Neurologist, or Metabolic Specialist

  

 

Any existing comorbidities involving:

  

 

Central nervous system?

  

 

Heart?

  

 

Lungs?

  

 

Skeletal muscle?

  

 

Hepatorenal systems?

  

 

Any abnormalities with glucose regulation?

  

 

Any recent illnesses, infection, or sustained stress?

  

 

Any previous adverse drug reactions and allergies?

  

 

Any prior anesthetic exposure or complications? Obtain anesthesia records.

 

 


TABLE 14-6   -- Possible Concurrent Therapy for Patients with Mitochondrial Disorders

  

 

Coenzyme Q,

  

 

L-Carnitine

  

 

Riboflavin (vitamin B2)

  

 

Acetyl-L-carnitine

  

 

Thiamine (vitamin B1)

  

 

Nicotinamide (vitamin B3)

  

 

Vitamin E

  

 

Vitamin C

  

 

Lipoic acid

  

 

Selenium

  

 

Beta-carotene

  

 

Biotin

  

 

Folic acid

  

 

Calcium, magnesium, phosphorous

  

 

Vitamin K

  

 

Succinate

  

 

Creatine

  

 

Citrates

  

 

Prednisone

 

 

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

ANESTHETIC MANAGEMENT

Surgical patients with mitochondrial disease should be considered at significant increased risk of adverse outcome compared with the general population. Perioperative adverse events in these patients include stroke, deterioration of neurologic status, coma, seizures, respiratory failure, arrhythmias, and death. Therefore, informing the patients and their families of these risks is an important part of the preoperative evaluation. Although patients with inherited mitochondrial encephalomyopathies have been exposed to many different general anesthetic regimens without apparent adverse consequences, [63] [64] it still remains unclear whether there is a “safe” or “best” anesthetic for these patients. There is continuing controversy regarding whether the anesthetic plan should, or should not, include neuromuscular blockade, especially in children ( Table 14-7 ).

TABLE 14-7   -- Intraoperative Management

  

 

Consider intensive care unit for postoperative ventilation or monitoring.

  

 

Use glucose-containing intravenous fluid.

  

 

Maintain normal temperature and pH.

  

 

Avoid natural airway or prolonged spontaneous ventilation during anesthesia.

  

 

Consider adding arterial cannula for arterial blood gases, glucose, and lactate to routine monitors.

  

 

Have dantrolene or malignant hyperthermia cart available.

  

 

Consider total intravenous anesthetic with avoidance of malignant hyperthermia “triggers.”

 

 

Susceptibility to malignant hyperthermia (MH) or myasthenia-like sensitivity to neuromuscular blockade are issues typically considered for patients with more familiar muscular dystrophies and neurogenic myopathies, but these concerns are probably not crucial for most forms of inherited mitochondrial encephalopathy and myopathy. [65] [66] Nevertheless, there is one report suggesting increased sensitivity to nondepolarizing blockade[67] and many discussions of anesthesia for mitochondrial disease that nevertheless recommend MH precautions.[68] Only the very rare mitochondrial myopathies with “multicore” or “minicore” histology may actually be associated with MH.[69] Avoidance of depolarizing muscle relaxants may further reduce the possibility of MH, but the residual effects of nondepolarizing agents in patients with compromised hepatorenal function may exacerbate intrinsic muscle weakness. Therefore, anesthetic techniques requiring spontaneous intraoperative ventilation that offer an opportunity for airway obstruction intraoperatively should probably be avoided. Muscle weakness may also increase the risk of ventilatory failure postoperatively. Endotracheal intubation with positive-pressure ventilation will prevent intraoperative ventilatory failure, but the anesthesiologist must decide if the patient should be extubated immediately after surgery or remain intubated and receive prolonged recovery in an intensive care unit. “Late-onset mitochondrial myopathy” may be age-related and yet still reflect primary mitochondrial dysfunction owing to the clonal expansion of different mtDNA deletions in individual fiber segments. Although the origin of these mtDNA mutations is not clear, the phenotype seems to represent an exaggerated form of what is observed in the normal aging process.[70]

Patients with mitochondrial cytopathy are usually instructed not to fast for long durations and to eat small frequent meals, a regimen that can be problematic in the setting of perioperative NPO guidelines. To avoid metabolic crisis in children, an intravenous infusion of glucose should be initiated during the period of preoperative fasting. Choice of intravenous fluids may also be important intraoperatively, with most anesthesiologists choosing to avoid Ringer's solution because of the lactate load. Monitoring and controlling normal blood glucose, body temperature, and acid-base values is crucial intraoperatively and postoperatively, and as with any anesthetic, an electrocardiogram should be monitored along with blood pressure, pulse-oximetry, temperature, and exhaled gas concentrations. In addition, arterial catheterization should be considered to facilitate frequent sampling for blood glucose, arterial blood gases, and serum lactate levels.

There are few reports that describe the anesthetic treatment of adult-onset or acquired mitochondrial encephalomyopathy,[71] and only one, for example, dealing with NARP syndrome.[72] Clinical reports suggest that patients with other mitochondrial disorders “do well” with regional anesthetics, despite the fact that these agents, like those used for general anesthesia, depress mitochondrial bioenergetics. In addition, there is reason to suspect that some of the effects of anesthetics on mitochondria may be beneficial in the event of tissue hypoxia or ischemia. It is now clear that the phenomenon of anesthetic preconditioning, in which prior exposure to volatile anesthetics reduces tissue injury after an ischemic or hypoxic episode, is mediated through their effects on the mitochondria, either directly or via several possible signaling pathways.[73]

The nervous system may play a particularly prominent role in our understanding of the consequences of altered mitochondrial function, whether inherited or acquired. Consciousness is the most complex manifestation of nervous system function. Because cortical neurons and deeper nervous system tissues with high rates of neurotransmitter synthesis have very high rates of oxygen utilization, depression of mitochondrial bioenergetics or organelle injury due to oxidative stress usually compromises nervous system function before other tissues appear to be affected. Therefore, resistance to loss of consciousness, one possible definition of anesthetic requirement, could provide the clinician with a metric for assessing remaining nervous system functional reserve. Recent preliminary data, in fact, suggest that extreme sensitivity to anesthetics may reflect greatly reduced reserve and a high risk of susceptibility to neurodegenerative disorders, postoperative cognitive decline, and even long-term mortality in elderly patients.[74] Increasing age and deeper levels of anesthesia are also independently but significantly predictive of increased mortality within 1 year of surgery.[75]

Basic genetic manipulation in subprimates confirms a direct link between mitochondrial genetics and anesthetic requirement.[76] Children with inherited mitochondrial disorders have been shown to have significantly increased sensitivity to volatile anesthetics.[77] In addition, a general relationship between declining anesthetic requirement and increasing age has been unequivocally established for adults in the general population ( Fig. 14-4 ).

 
 

FIGURE 14-4  The progressive decline in relative anesthetic requirement (MAC or ED50) that occurs during adulthood is a consistent characteristic reported for a wide variety of inhaled and injectable anesthetic agents. This phenomenon, shown here as a graphic representation of data from nonsedated human subjects, probably reflects a generalized process within the central nervous system that may involve declining mitochondrial bioenergetics.

 

 

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

CONCLUSION

Mitochondrial dysfunction may be fundamental to a very broad spectrum of human disease, both inherited and acquired, and perhaps even to aging and death itself. Full understanding of the status of mitochondrial bioenergetics may eventually play a life-critical role in caring for patients with mitochondrial disorders, in anticipating the responses of children and adults to anesthetics, and in avoiding perioperative ischemic or hypoxic injuries. At the present time, however, the basic principles of anesthetic management of children and adults with genetically transmitted mitochondrial disorders include awareness of the decreased bioenergetic capacity of major organ systems and special attention to the clinical implications of generalized weakness and myopathy, cardiac arrhythmias and dysfunction, sensorineural compromise, and impaired hepatorenal function.

Copyright © 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Copyright © 2005 Saunders, An Imprint of Elsevier

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