Mitochondrial myopathy is characterized by pathologic mitochondrial dysfunction in oxidative phosphorylation. Mitochondria are cell organelles whose primary function is to produce energy as adenosine triphosphate (ATP) from glucose in a process called oxidative phosphorylation. The electron transport chain, a series of transmembrane protein complexes located on the inner mitochondrial membrane, uses glucose byproducts from glycolysis and the Krebs cycle in a cascade of reactions culminating in the production of ATP catalyzed by ATP synthase.
Patients with mitochondrial myopathy who undergo general anesthesia (GA) reportedly have susceptibility to malignant hyperthermia,1,2 resistance to or prolonged effects from muscle relaxants,3 and may develop fatal hyperkalemia4,5 if given depolarizing neuromuscular-blocking drugs. We report the anesthetic management of a 59-year-old woman with mitochondrial myopathy who underwent elective laparoscopic cholecystectomy and hemorrhoidectomy, and we review the available literature discussing GA in adults with this relatively rare clinical entity.
Consent for publication of this case report was obtained from the patient.
A 59-year-old woman (height 150 cm, weight 45.3 kg, and body mass index 20.1 kg/m2) with mitochondrial myopathy was scheduled for laparoscopic cholecystectomy and conventional hemorrhoidectomy at our institution. She had no other significant comorbidities. She was not diagnosed with mitochondrial myopathy until the age of 47 years, but she had been experiencing long-standing proximal limb weakness, poor exercise tolerance, and bulbar dysfunction before her diagnosis. Her brother and sister also had this diagnosis but had more severe muscular weakness than the patient. She had never had a surgical procedure or received GA or regional anesthesia, and she had never before been hospitalized for decompensated episodes of mitochondrial myopathy. She was taking no medications apart from coenzyme Q10. Family history regarding GA was unremarkable: only her mother had ever received GA, and the associated surgical procedure was uneventful.
Physical examination revealed nasal speech and decreased motor power of 4/5 in all 4 limbs proximally. There was no atrophy or hypotonia of the limbs. Assessment of the airway was unremarkable except for a slightly receding chin and prominent upper incisors. The results of her laboratory tests, electrocardiogram, 2-dimensional transthoracic echocardiogram, treadmill stress test, and lung function tests were within normal limits. Cardiovascular and respiratory function tests had been ordered by her neurologist to assess her baseline cardiac and respiratory functions.
Preoperative management involved increasing her regular dose of coenzyme Q10 from 100 to 200 mg daily to reduce the likelihood of side effects resulting from surgical stress.6 At the start of the procedure, an 18-G IV cannula was inserted into the dorsum of the left hand, and standard monitors were placed. The preinduction vital signs were arterial blood pressure 160/83 mm Hg, heart rate 87 bpm, 100% oxyhemoglobin saturation while breathing room air; normal sinus rhythm was noted on lead II of the 3-lead electrocardiogram.
Although the patient was awake and spontaneously breathing, we topically anesthetized the airway with 4 sprays of cophenylcaine to the nasal cavities, 4 sprays of 10% lidocaine into the hypopharynx via a size 6 nasal airway, and a total of 4 mL of 2% lidocaine administered with an atomizer and deposited equally with the aid of a tongue depressor into the hypopharynx and oropharynx. The patient was administered oxygen for 2 minutes, resulting in an end-tidal oxygen concentration of 87%.
Deep sedation was induced with IV infusion of 2.5 ng/xsmL remifentanil (Minto model effect-site concentration), a 20-mg bolus of 1% propofol, and 50 μg fentanyl. A lubricated size 6 nasal airway was then inserted into the right nostril. After loss of consciousness was confirmed, tracheal intubation was achieved on the first attempt with a video laryngoscope (Glidescope, Verathon Medical Inc., Bothell, WA) and a size 7 endotracheal tube (Smiths Portex endotracheal tube, Smiths Medical International Ltd., Hythe, Kent, UK). There was no unwanted movement or gagging from the patient throughout the intubation process. The time from application of topical local anesthetic application to the nasopharynx and oropharynx until the endotracheal tube had been secured was approximately 5 minutes.
A balanced anesthesia technique was chosen. Hypnosis was maintained with desflurane (maximum 6.4%) and an oxygen/air mixture of 50/50, and analgesia was maintained with remifentanil infusion (Minto model effect-site concentration 1 to 1.5 ng/mL). A nasal temperature probe was inserted, and temperature was maintained >36°C. Invasive positive pressure ventilation was maintained throughout the operations with time-cycled, volume-controlled ventilation at a tidal volume of 400 mL, a respiratory rate of 12 to 16 breaths per minute, and a pulmonary end-expiratory pressure of 5 mm Hg. Two episodes of hypotension (lowest mean arterial blood pressure 55 mm Hg and systolic pressure 78 mm Hg) were successfully managed with a bolus of ephedrine (5 mg) each time.
The laparoscopic cholecystectomy was performed, followed by the hemorrhoidectomy, with a change in position from supine to lithotomy. Anesthesia lasted 120 minutes, and the trachea was extubated uneventfully in the operating room with an ongoing infusion of remifentanil (1 ng/mL). A total of 700 mL of dextrose-saline crystalloid solution was administered. There were no incidents of unwanted movement, no difficulty with ventilation, no difficulty achieving and maintaining pneumoperitoneum, and no surgical technical difficulty resulting from the omission of neuromuscular blockade. Planned postoperative analgesia included a single IV bolus of 2 mg morphine as well as an infiltration of 9 mL of 0.5% bupivacaine to the abdominal incisions and another 8 mL to the anal incision.
After observation in the recovery room for 1 hour, with no episodes of oxyhemoglobin desaturation, the patient was admitted to the high-dependency ward for further postoperative monitoring. She was discharged from the hospital on the first postoperative day with good pain control with oral analgesics and no complications of surgery or anesthesia.
We reviewed the literature regarding adult patients, defined as patients aged 21 years or older, diagnosed with any form of mitochondrial myopathy who received GA for any surgical procedure. We searched PubMed/Medline and Embase databases. All available publications regardless of year of publication were examined.
We identified 27 case reports and 1 case series from 1993 to 2013 describing several different techniques of anesthesia for adults with mitochondrial myopathy. Articles that were not written in English or did not have an English-language abstract (6 case reports) were excluded. We also excluded articles describing local anesthesia or monitored anesthetic care (1 case report) or regional or central-neuraxial anesthesia (5 case reports) because these anesthetic techniques were not considered for this particular patient. Thus, our analysis included 15 case reports and 1 case series. The following data were reviewed: emergency or elective surgery, type of anesthesia used, drugs used, and intraoperative and postoperative adverse events and complications (Table 1).
Twenty-four patients and 34 GAs were described. Total intravenous anesthesia was used in 18 cases, inhaled anesthesia in 14, combined inhaled GA and epidural anesthesia in 1, and the specific type of GA was not specified in 1 case. Tracheal intubation was chosen for airway management in all but 4 cases: 3 in which a laryngeal mask airway was used and 1 in which the patient’s trachea was already intubated before surgery. Of all the cases in which intubation was performed after induction, neuromuscular-blocking drug administration was omitted in only 2. Awake or modified awake intubation techniques were not used in any case.
Regarding intraoperative events, 2 patients had respiratory depression postulated to be secondary to opioid administration (fentanyl and remifentanil), 2 patients had prolonged neuromuscular blockade, 2 patients had sinus bradycardia that responded to atropine administration, and 1 patient had cardiac arrest.
In the postoperative period, hyponatremia was noted in 3 patients, but we considered all 3 cases to be unrelated to the anesthetic technique and more likely to be due to the underlying medical condition of the patient. One patient who underwent cardiac transplantation developed postoperative acute kidney injury, which necessitated hemodialysis support, and adrenal insufficiency. One mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) patient who underwent open gastrectomy developed metabolic complications: intraoperative hypothermia and postoperative lactic metabolic acidosis and hypovolemic shock that necessitated tracheal reintubation and admission to the intensive care unit. A Kearns-Sayre patient who underwent exploratory laparotomy and appendectomy had cardiac arrhythmias and type 2 respiratory failure postoperatively, also necessitating tracheal reintubation and admission to the intensive care unit. A patient with Luft disease had a postoperative episode of metabolic decompensation that caused tachycardia, hyperthermia, and dyspnea.
Our literature review was limited by the exclusion of non-English language articles and gray literature, which refers to written material that is not published commercially, including but not limited to manuscripts under consideration for publication and preliminary drafts and articles in nonindexed journals.
Mitochondrial myopathies may be caused by defects of mitochondrial DNA or nuclear DNA. The mitochondrial DNA defects are transmitted by maternal inheritance. Nuclear DNA defects may be transmitted in an autosomal recessive or an autosomal dominant manner. The incidence of mitochondrial myopathy is estimated at 4 to 7 per 100,0007a although under-reporting may have made this estimate artificially low. Numerous possible mutations in genes coding for either the electron transport chain proteins or auxiliary proteins involved in oxidative phosphorylation result in a wide spectrum of clinical presentations. Progressive skeletal muscle weakness and exercise intolerance are cardinal features; weakness of facial and bulbar muscles is also common. Effects on other organ systems, such as neurological, cardiac, gastrointestinal, or metabolic, may manifest as seizures, learning difficulties, deafness, visual impairment, stroke-like episodes, cardiomyopathy, cardiac conduction defects, gastrointestinal disturbances, diabetes, lactic acidosis, and pancreatic insufficiency. The prognosis is variable, ranging from functional impairment to death.
Diagnosing mitochondrial disease is complex because of its clinical and genetic variability. Diagnosis relies on family history, muscle biopsy to test intermyofibrillar accumulation of mitochondria, biochemical investigations such as testing for increased serum lactate levels, and exercise testing to show decreased maximal oxygen consumption. Several diagnostic criteria and scoring systems have also been proposed, such as those reported by Walker et al.,8 Bernier et al.,9 and Morava et al.10 Direct testing of mitochondrial genes may be useful, especially when there is a recognizable clinical syndrome, such as Kearns-Sayre syndrome or MELAS.
No clinical trials have been conducted in adult patients with mitochondrial myopathy to study the effects of anesthetic drugs and techniques and the incidence of related intraoperative and postoperative complications. The available data consist of level 4 evidence in the forms of published case reports, retrospective reviews of anesthetic charts of patients, and expert opinion.
Anesthetic concerns in patients with mitochondrial myopathy include the risk of postoperative respiratory compromise, exaggerated sensitivity to neuromuscular-blocking drugs and opioids, acute metabolic decompensation causing lactic acidosis and electrolyte abnormalities, acute encephalopathy, neuromuscular weakness, and cardiac dysfunction or arrhythmia.11 The association between mitochondrial myopathy and malignant hyperthermia remains unproven; thus, the Malignant Hyperthermia Association of the United States recommends that volatile anesthetics not be routinely avoided and that succinylcholine be used with caution.b
We acknowledge that it is unusual for the patient to be scheduled for 2 procedures at the same time. She was originally scheduled for a cholecystectomy and then attended our preoperative assessment clinic and was counseled regarding standard GA risks and specific risks pertaining to mitochondrial myopathy. She subsequently decided to undergo 2 operations in the same session to avoid both a second GA and the use of a regional technique for the hemorrhoidectomy.
Our concerns regarding this particular patient were the possibility of neuromuscular weakness and respiratory depression (due to GA,11 neuromuscular-blocking drugs,3,12 and/or opioids),13 aspiration risk related to her bulbar dysfunction (necessitating rapidly securing the airway), and the possibility of lactic acidosis after acute metabolic decompensation. To avoid triggering metabolic decompensation, the procedure was listed as the first case of the day to shorten the patient’s fasting time, crystalloid solutions containing lactate were avoided, and normothermia was maintained.
To minimize aspiration risk and mitigate its potential complications, we ensured an adequate fasting period for our patient. We believed that awake tracheal intubation was not inferior to rapid sequence intubation with cricoid pressure and decided to prioritize avoidance of neuromuscular-blocking drugs in our technique.3,12 Use of a modified awake intubation technique, with adequate topical anesthesia of the upper airway and deep sedation, enabled us to rapidly and safely intubate the trachea without the use of muscle relaxants. Neuromuscular-blocking drugs were omitted in 3 other reported cases, including cochlear implantation in a child,14 renal transplantation in an adult,15 and excision of a maxillary cyst in an adult.13 However, a modified awake intubation technique was not used in any of these cases.
In our case, despite the omission of neuromuscular blockade, there were no difficulties with surgical access or providing optimal surgical conditions. We speculate that the patient may have already had a baseline loss of muscle tone that was not clinically apparent. Additionally, a level of anesthesia sufficient to prevent movement probably also facilitated surgery without the need for neuromuscular-blocking drugs. We were also able to use a continuous, mandatory invasive positive pressure ventilation mode without difficulty.
In conclusion, mitochondrial myopathies encompass a broad spectrum of diseases with vastly variable clinical presentations. Most of the case reports identified in our literature review focused on patients with MELAS or Kearns-Sayre syndrome, which constitute only a small subset of patients with mitochondrial myopathy. The condition is probably underdiagnosed, and it is possible that undiagnosed symptomatic patients have undergone surgery uneventfully. We speculate that survival into adulthood implies a less debilitating or complicated course of disease, possibly resulting in a better safety profile for anesthesia and surgery.
Because mitochondrial myopathy is uncommonly diagnosed, clinicians are not confident or well prepared for the perioperative management of these patients, particularly in the emergency setting. In addition, it is not feasible to conduct clinical trials in enough affected patients to establish guidelines for anesthetic management, due to the rarity of this disease. Therefore, case reports are likely to remain the main source of information for anesthesiologists.
a Genge A, Massie R. Mitochondrial myopathies: clinical features and diagnosis. Up-to-date Web site. Available at: http://www.uptodate.com/contents/mitochondrial-myopathies-clinical-features-and-diagnosis. Accessed October 29, 2013.
b Does Mitochondrial Myopathy (MM) Increase an Individual’s Susceptibility to Malignant Hyperthermia (MH)? Available at: http://www.mhaus.org/healthcare-professionals/mhaus-recommendations/mitochondrial-myopathy. Accessed October 29, 2013.
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