Mitochondrial disorders are a heterogeneous group of rare but potentially serious diseases. Although the pathophysiologic changes associated with the mitochondrial abnormalities that define these illnesses are fairly well described in some cases, they remain poorly understood in many others.1 Their low incidence complicates efforts to study these diseases and to provide evidence-based standards for the perioperative management of those who suffer from them.2 Accordingly, case reports and retrospective investigation have proven to be an important source of information regarding their care, even for those most familiar with treating them.3
Here we present the case of a 27-year-old female patient with mitochondrial myopathy secondary to complex III electron transport chain enzyme deficiency and a history suggestive of malignant hyperthermia (MH) susceptibility who received a combination of fentanyl, ketamine, and methohexital for induction, as well as methohexital, sufentanil, and dexmedetomidine for the maintenance of general anesthesia during 2 consecutive surgeries. These surgeries included laparoscopic resection of an adenocarcinoma of the sigmoid colon and left video-assisted thoracic surgery (VATS) lower lobe wedge resection of a metastatic pulmonary lesion.
A 27-year-old, 164-cm, 54-kg woman with mitochondrial myopathy, suspected MH susceptibility, and a recent diagnosis of adenocarcinoma of the sigmoid colon presented for laparoscopy-assisted sigmoid resection. Review of her medical history revealed that early symptoms of her mitochondrial disorder included severe exercise-induced rhabdomyolysis, and that subsequent workup resulted in a diagnosis of a complex III electron transport chain enzyme deficiency. She had multiple episodes of functional limitation (including difficulty with ambulation) because of cramping and fatigue throughout her early adulthood. Between episodes, she remained relatively asymptomatic and was ultimately able to complete nursing school and work as a nurse in the intensive care unit. She suffered from no obvious neurologic deficits, and a cardiac workup with electrocardiogram and transthoracic echocardiography was unremarkable. Despite an absence of a clear personal or family history of MH, MH susceptibility was listed in her medical record. No other significant comorbidities were noted in her history.
The case was booked as the first case of the day, and medications administered preoperatively included acetaminophen 1000 mg, gabapentin 300 mg, and midazolam 4 mg. Intraoperatively, general anesthesia was induced with ketamine 20 mg and methohexital 70 mg. Cisatracurium 14 mg and fentanyl 100 µg were used to facilitate intubation and to blunt sympathetic response to laryngoscopy, respectively. General anesthesia was maintained with a dexmedetomidine infusion at 0.5 µg/kg/h, a methohexital infusion at 45 to 60 µg/kg/min, and a sufentanil infusion at 0.3 µg/kg/h that was started shortly after induction and continued until about 30 minutes before procedure completion. A BIS monitor (Medtronic/Covidien, Minneapolis, MN) was used to monitor the anesthetic depth. Additional analgesics provided intraoperatively included hydromorphone 1 mg and ketorolac 30 mg. An infusion of D5NS was provided throughout the case.
The room temperature was kept at 24°C and upper and lower-body Bair Huggers (3M, Diegem, Belgium) were placed to ensure normothermia was maintained. Dexamethasone 4 mg, metoclopramide 10 mg, and zofran 8 mg were provided as prophylactic antiemetics. The patient remained hemodynamically stable throughout, woke without signs of respiratory insufficiency, was extubated in the operating room, did not suffer from postoperative nausea and vomiting (PONV), denied intraoperative awareness, reported adequate postoperative pain control, remained metabolically stable, and was discharged without an issue on postoperative day 2.
The patient returned 11 months later for bronchoscopy followed by VATS left lower lobe wedge resection for a metastatic lung lesion. A similar anesthetic strategy was used for this case with fentanyl 100 µg, ketamine 20 mg, and methohexital 150 mg given during induction. For the maintenance of her general anesthesia, a total of 455 mg of methohexital supplemented with infusions of dexmedetomidine at 0.5 to 0.7 µg/kg/h and sufentanil at 0.3 µg/kg/h was administered. Again, the patient remained stable perioperatively, showed no signs of disease-related complications, and was discharged after an uneventful postoperative course. The CARE checklist 2016 was used when compiling a case report based on these anesthetics.4
Patients with mitochondrial disorders provide a unique challenge for the anesthesia provider because (1) these disorders are rare and thus may be encountered infrequently by individual practitioners, (2) the clinical presentation of this heterogeneous group is highly variable,2 and (3) there is a relative absence of high-quality evidence to help guide the perioperative management of this group of patients. Furthermore, the disruption of cellular energy production associated with mitochondrial dysfunction leaves high-energy demand organs and tissues (ie, brain, heart, and skeletal muscles) vulnerable during the perioperative period.5 Generally speaking, this places those with mitochondrial dysfunction at a particularly high risk for neurologic dysfunction, respiratory failure, cardiac depression, conduction defects, dysphagia, and overall metabolic decompensation. Therefore, a thorough preoperative assessment of pre-existing disease-related disability, avoidance of factors that increase tissue energy consumption, and prevention of elements that place additional burden on mitochondria are important components of their perioperative management.6
Preoperative history of our patient failed to reveal signs of respiratory weakness or neurologic disability, and preoperative electrocardiogram and transthoracic echocardiography were negative for signs of serious disease-related cardiac dysfunction. Measures taken to decrease the metabolic burden on her mitochondria included scheduling her as the first case of the day and providing her with glucose containing fluids so that glucose was available as a mitochondria-independent energy source for her tissues.5 Lactate-containing fluids were avoided to minimize the need to process this substrate. Normothermia was maintained to avoid shivering, and a multimodal analgesic strategy was used to blunt intraoperative and postoperative sympathetic response to intubation and surgical intervention. An aggressive approach to PONV prevention was adopted to obviate energy expenditure associated with vomiting and minimize time to reinitiation of per os intake.
This patient’s care was further complicated by her report of MH susceptibility. Historically, all patients with neuromuscular disorders, including mitochondrial myopathies, were considered to be at risk of developing this potentially life-threatening reaction on exposure to volatile anesthetics and/or succinylcholine.3 More recent evidence suggests that, outside of specific diseases such as King syndrome and central core disease, this group is no more susceptible to this complication than the general population.3,6 Although our patient did not suffer from a disease with a proven association with MH susceptibility, the diagnosis was listed in her chart. In the absence of access to the results of any testing that she may have undergone, the use of succinylcholine and volatile anesthetics was avoided.
Consideration of alternative hypnotic agents revealed that nearly every anesthetic drug that has been studied depresses mitochondrial function to some degree.5 Among the available therapeutics, propofol’s negative effect is perhaps one of the most profound. It has been shown to depress mitochondrial function via multiple pathways, ultimately inhibiting electron transport chain function and fatty acid transport into the organelle via at least 4 different mechanisms.5 Although propofol has been used successfully and safely as an induction and maintenance agent for some short procedures,5 its use as the primary hypnotic for this patient’s surgeries was avoided given the potentially prolonged duration of our cases.
Alternative agents considered included ketamine, midazolam, and barbiturates. Although these medications may be relatively safe in this patient population when used in a limited fashion, they have all been associated with inhibition of complex I of the electron transport chain.5,7 In addition, adverse side effects associated with high doses such as a prolonged recovery time made them less than ideal as stand-alone agents for our patient. Given its reliable hypnotic effect and titratability, we ultimately elected to use methohexital as the primary anesthetic agent for both induction and maintenance, but reduced the total dose required via supplementing its use with other anesthetic drugs. We chose to supplement it with ketamine during induction in an effort to counterbalance the negative effects of methohexital on the cardiovascular systems with ketamine’s sympathomimetic hemodynamic effects. During the maintenance phase, we chose to supplement its use with the hypnotic agent dexmedetomidine. We elected not to use nitrous oxide in our patient in an effort to minimize the risk of PONV and to maximize her oxygenation during the VATS surgery.
Dexmedetomidine is a selective α2-adrenergic agonist whose beneficial effects include sympatholysis, sedation, hypnosis, anxiolysis, amnesia, analgesia, and shivering prevention. Notably, it has also been shown to have beneficial effects on the mitochondrial membrane in ischemic rats.3 Although the theoretical advantage that these effects provide for patients with mitochondrial disorders is clear, low diseases incidence has complicated efforts to systematically study its use in these patients. In fact, to our knowledge, no one has ever completed a controlled trial to evaluate the use of dexmedetomidine or any other hypnotic agent in mitochondrial myopathy patients.2 Although a few case reports demonstrating the use of dexmedetomidine in a patient with mitochondrial myopathy have been published, its use has not been reported previously for cases of this duration, for a series of anesthetics in the same patient, or in a patient with the specific diagnosis of complex III enzyme deficiency. Therefore, it is important to recognize that much work still needs to be done to determine exactly how dexmedetomidine affects mitochondrial function in vivo in this heterogeneous population. Our case series represents an important early contribution to a growing body of evidence suggesting that it may be a useful agent to consider when managing these challenging cases.
Name: Elliott L. Woodward, MB, BCh, BAO.
Contribution: This author helped prepare the manuscript.
Name: Zhiling Xiong, MD, PhD.
Contribution: This author helped prepare the manuscript.
This manuscript was handled by: Raymond C. Roy, MD.
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