Implications of Mitochondrial Dysfunction for the Anesthetic and Perioperative Management: A Case Report of Spinal Fusion, Genetic Confusion, and a Patient’s Perspective Linda S. Aglio, MD, MS,* Brian T. Lockhart, MD,* Jeantine E. Lunshof, PhD,†‡ and Christoph S. Nabzdyk, MD* We describe a patient’s personal struggle with a symptom complex consisting of profound muscle weakness requiring pyridostigmine, and metabolic abnormalities suggestive of mitochondrial disease. This included a profound sensitivity to opioids, which in the past caused severe respiratory depression during a prior hospital admission. Interestingly, the patient herself is a professor of ethics in genomic sciences, and she and her medical team thus far have not been able to formally diagnose her with mitochondrial disease. The patient now presented for a multilevel lumbar spine fusion and her hospital course and perspective on her medical odyssey are described here. (A&A Case Reports. 2017;XXX:00–00.) M itochondrial diseases affect some of the most fundamental cellular energy processes and represent a diverse group of disorders that are infrequently managed by anesthesiologists. A minimum prevalence of 1 in 5000 has been described. Disorders involving the respiratory chain are the most commonly inherited neurologic ailments caused by mutations in the mitochondrial or nuclear DNA.1 Mitochondrial disorders may affect many organ systems. Important decisions the anesthesiologists face with patients having mitochondrial disease include which chronic medications to take the morning of surgery. Given the patient’s inability to fast due to oxidative phosphorylation abnormalities and secondary impairment of β-oxidation of fat, another concern is the duration of preoperative fasting and clear liquid “nothing per os.” Routine anesthetic adjuvants should preferably be avoided or be administered with their “usual” doses reduced. Exaggerated sensitivity to opioids and neuromuscular blocking agents as well as drug toxicities pose additional challenges for perioperative analgesia and safety, respectively. In light of these complexities, comprehensive monitoring, including invasive monitoring for improved hemodynamic and metabolic patient surveillance should be considered early.2 Written consent for publishing this article was obtained from the patient who also co-authored this article. From the *Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; †Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; and ‡Department of Genetics, Harvard Medical School, Boston, Massachusetts. Accepted for publication September 8, 2017. Funding: None. The authors declare no conflicts of interest. Address correspondence to Linda S. Aglio, MD, MS, 75 Francis St, Boston, MA 02115. Address e-mail to email@example.com. Copyright © 2017 International Anesthesia Research Society DOI: 10.1213/XAA.0000000000000641 CASE Mitochondrial myopathy was suspected in this patient on the basis of clinical symptoms and certain histologic evaluations. However, genetic testing has not confirmed mitochondrial disease. The patient is a 60-year-old woman (height, 171 cm; weight, 64.8 kg; and body mass index, 22.2 kg/m2) who was scheduled to undergo an extensive L3 to S1 spinal fusion for kyphoscoliosis. This procedure is associated with severe postoperative pain and thus high opioid requirements, a potential for significant blood loss, and overall metabolic stress for the body. Before this surgery, the patient’s symptoms included a long history of exercise intolerance, migraine-associated vomiting, dysautonomia, gastrointestinal dysmotility and gastroesophageal reflux, fatigue, and myopathy. Concern for some existing degree of mitochondrial dysfunction was raised by the results of a muscle biopsy showing dispersed, atrophic fibers. Immunohistologic evaluation also revealed decreased expression of some mitochondrial enzymes such as succinic dehydrogenase stain and cytochrome c oxidase hinting at a possible mitochondrial disease.3 However, mitochondrial DNA testing revealed only benign polymorphisms and, based on nuclear whole-genome sequencing, no formal genetic diagnosis of mitochondrial disease could be made. In addition, the patient had previously undergone level 3 cardiopulmonary exercise testing, an invasive method used to assess the performance of the heart and lungs at rest and during exercise. The cardiopulmonary exercise testing revealed normal lung function and maximum cardiac output during the test, but decreased maximum oxygen consumption suggestive of an oxidative myopathy.4 Other comorbidities included hypothyroidism, Raynaud disease, a history of recurrent sepsis, and a history of breast cancer. Her medications, taken the day of surgery, included pyridostigmine 60 mg three times a day, levothyroxine, sumatriptan, domperidone, N-acetylcysteine, and omeprazole. Regular medications that were omitted day of surgery included α-lipoic acid, vitamins C, D, and E, ubiquinol, polyethylene glycol, and indomethacin. The patient’s surgical history included a bilateral mastectomy in 2008 in the Netherlands. The general anesthetic XXX 2017 • Volume XXX • Number XXXcases-anesthesia-analgesia.org 1 Copyright © 2017 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. regimen included 2.8%–3.8% desflurane, 500 mg/h propofol infusion intravenously (IV), 25 µg sufentanil IV, 75 mg diclofenac IV, and a 50 mg/h ketamine infusion IV. Postoperatively, pain was treated with 3 piritramide boluses (a synthetic opioid marketed in Europe) 3.0, 2.5, 3.0 mg, at 15-minute intervals. It is 0.75 as potent as morphine. Within 24 hours, the patient experienced significant respiratory depression. The ketamine infusion was immediately stopped. Reintubation was not required. The patient reported sensitivity to several different opioids including episodes of life-threatening respiratory depression in response to otherwise standard doses of codeine, tramadol, and a fentanyl patch. Preoperatively, a 20 gauge IV cannula was inserted in the left forearm and a maintenance infusion of 5% dextrose normal saline was administered overnight. Preinduction vital signs were: arterial blood pressure 130/90 mm Hg, heart rate 80 bpm, respiratory rate 20 bpm, temperature 36.3°C orally, 100% oxyhemoglobin saturation while breathing room air, normal sinus rhythm on lead II of a 5-lead electrocardiogram. The patient was able to do a good head lift. Mild sedation was induced with midazolam 4 mg IV titrated over 45 minutes while maintaining a 95% oxyhemoglobin saturation while breathing spontaneously with 4 L/min oxygen administered via nasal cannula. We utilized the operating room setting to safely titrate fentanyl to effect to help us understand the patient’s sensitivity to fentanyl, because she was likely to receive fentanyl for postsurgical pain control. The patient was then given fentanyl 5–10 µg every 5–10 minutes with continuous monitoring of respiratory status. She eventually reported feeling lightheaded. The patient tolerated a total of 75 µg fentanyl before the onset of deep sedation which raised concerns for developing respiratory depression. Anesthesia was induced IV with lidocaine 100 mg of 2% lidocaine, etomidate 0.3 mg/kg, and an additional 25 µg of fentanyl. To blunt the stress response evoked by intubation and to allow intubation without the use of a neuromuscular blocking agent, a 100-μg bolus of remifentanil was given shortly before laryngoscopy, and intubation with a 7.0 cuffed, styled Portex endotracheal tube was facilitated with a C-Mac (D-Blade) video laryngoscope. There was no movement or gagging throughout the intubation. A femoral arterial catheter was placed. Radial access was not used due to the patient’s history of Raynaud disease. Three intraoperative arterial blood gases were obtained. The pH ranged from 7.37 to 7.40, Paco2 36–38 mm Hg, and Pao2s were stable in the high 200s mmHg. Chemistries drawn were only significant for mild hypokalemia (3.3 mEq/L), while intraoperative magnesium and lactate remained normal (1.8 mg/dL and 0.7 mM/L, respectively). A left triple lumen central venous catheter was placed via the subclavian approach. Anesthesia was maintained with a total IV anesthetic that consisted of 200 µg/kg/min propofol infusion, 0.125–0.15 µg/kg/min remifentanil infusion, and 8 µg/kg/min ketamine infusion. Ketamine has been shown to increase bispectral index (BIS) values in a dose-dependent fashion. Despite the intraoperative use of ketamine infusion, the BIS values remained below our target value of 60 at the aforementioned doses of propofol and remifentanil throughout the case. A body temperature greater than 36°C was maintained. 2 cases-anesthesia-analgesia.org Positive pressure ventilation was used throughout the procedure with time-cycled, volume-controlled ventilation at a tidal volume of 450 mL, a respiratory rate of 9–13 breaths per minute, and a positive end-respiratory pressure of 3 mm Hg. Electromyography monitoring was performed throughout the case. The procedure length was 540 minutes. A total of 500 mL of 5% albumin and 1850 mL of dextrose 0.45% normal saline were given, and the estimated blood loss was 800 mL. On wake up, the patient’s pain appeared to be well controlled; however, the patient displayed an irregular and slow respiratory rate of 6 breaths per minute. All infusions were discontinued before extubation. The patient was able to participate in a neurologic assessment; however, she remained intubated and was subsequently transferred to the intensive care unit pending improvement of her respiratory status. Approximately 2 hours postoperatively, the patient’s respiratory status had normalized. The patient was awake, responsive, and able communicate that she was in pain. A 10 µg IV fentanyl bolus was administered without any respiratory compromise. This was 12 hours after the administration of the initial dose of fentanyl. The patient was then successfully extubated and an additional 10 µg of IV fentanyl was administered for persisting moderate pain. No additional opioids were administered for the rest of the hospital stay and the patient’s pain remained adequately addressed. DISCUSSION In researching the literature for mitochondrial disorders (PubMed/Medline and Embase) regarding patients 21 and older, who received general anesthesia, we found 16 case reports and 1 case series. Non-English articles were excluded. Twenty-five patients and 35 general anesthetics were described. Of all the cases in which intubation was performed after induction, neuromuscular blocking drug administration was omitted in only 2. A modified awake intubation technique was used in 1 case, and in the other, a bolus of morphine was used.5,6 In all cases, a pure total IV anesthetic infusion technique was used with neuromuscular blocking drugs. Despite significant progress, clinical studies that assess the effects of anesthetics, the stress of surgery, and the associated metabolic derangements are lacking. Therapy is mostly symptomatic, and management of the genetic basics of these disorders remains limited. Therefore, decisions must be made based on case reports, the physician’s previous experience, and theoretical risks based on basic physiology and pharmacology.7–10 There is no literature specific to the average opioid requirement after an L3 to S1 fusion in patients without mitochondrial dysfunction; however, there is 1 study that found the average patient after open laminectomy required at least 40 and up to 100 mg of IV morphine. Another study compared giving intraoperative sufentanil and methadone before the end of spine surgery, during which patients received 175 ± 56 µg IV sufentanil or 14.9 ± 3.34 mg methadone. Even 48 hours after surgery, these 2 groups of patients required on average 63 and 25 mg of IV morphine equivalents, respectively. Our patient received the intraoperative morphine equivalent of approximately 10 mg morphine, 20 µg sufentanil, or 2 mg methadone. The patient’s postoperative opioid requirement A & A CASE REPORTS Copyright © 2017 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. of 20 µg of fentanyl is equivalent to approximately 2 mg morphine, which is profoundly less than the requirements that have been reported. This also implies that patients with minimal opioid tolerance will inevitably be overdosed when standard doses of routine opioid medications are administered. This patient’s history reflects this notion. Overall concerns for this patient were the possibility of neuromuscular weakness and respiratory depression as reported in cases where neuromuscular blocking drugs of anesthetic agents were used11; metabolic derangements that might result from prolonged fasting and aggravated with the use of lactate-containing crystalloids; and adequate venous access and arterial blood pressure monitoring due to the Raynaud disease. We elected to omit the use of neuromuscular blockade agents given our desire not to confound our patient’s baseline state with any medications that could be avoided. In addition, pyridostigmine itself can decrease the efficacy of both nondepolarizing agents and succinylcholine. It may be prudent to avoid neuromuscular blockade agents in patients with myopathies to avoid a variable if postoperative weakness is exhibited; particularly given the relative ease with which a patient with favorable body habitus can be intubated with video laryngoscopy even in the absence of neuromuscular blockade. Furthermore, with our patient taking pyridostigmine, we did not want to introduce a similar medication into her regimen with neuromuscular blockade reversal at the end of the case. Mitochondrial dysfunction patients are reported to have a higher susceptibility to propofol-related infusion syndrome.12–14 This is a potentially fatal condition that debilitates mitochondrial fatty acid metabolism, blocks β-adrenoreceptors and cardiac calcium channels, and disturbs the electron transport chain. In the absence of a definitive diagnosis of mitochondrial disease and the fact that the patient had previously tolerated a propofol anesthetic, the decision was made to use propofol again. The majority of relevant literature does not suggest an increased risk of malignant hyperthermia in patients with mitochondrial disease. However, we decided to avoid volatile anesthetics given the patient’s lack of definitive mitochondrial disorder diagnosis and profound musculature-related symptoms. Because the nature of mitochondrial disease is diverse, an individualized plan should be carefully considered for each patient with a diagnosis of mitochondrial dysfunction or myopathy. For example, at our same institution, a patient with a mitochondrial myopathy had an anesthetic maintained with methohexital and demedetomidine to avoid propofol.15 However, we had the luxury of knowing that our patient had tolerated propofol used for anesthetic maintenance in the past. Fortunately, our patient had no issues with fasting overnight and tolerated crystalloid maintenance without any significant metabolic derangements. Her CO2 remained normal throughout with standard ventilator settings. This patient’s documented sensitivity to standard doses of opioids provided an additional challenge. Our anesthetic management used a total IV anesthetic infusion technique, not previously described in such patients. Interestingly, our patient is clinically stable on a regimen of 60 mg pyridostigmine 3 times a day. She tested negative for myasthenia gravis. However, the improvement with pyridostigmine suggests that a variant congenital myasthenic syndrome should be considered. While much research in congenital myasthenic syndromes has been done, many patients remain genetically undiagnosed. Our patient did not have a diagnosis of myasthenic syndrome. Our patient contributed the following comments: Listening to a patient’s narrative is time well spent, in particular since patients with mitochondrial disorders may appear clinically completely normal when at rest, in the absence of triggers during a “quiet” phase of the disorder. Yet, the knowledge about their individual disorder, symptoms, risks, and past derailments is known only to them. Routine procedures like preoperative fasting, administration of “standard” medications or normal physical stress, as trivial as long standing, sitting, or waiting without the opportunity to rest, can cause an acute and severe deterioration—extremely upsetting for patients and their caregivers. Misinterpretations and misdiagnosis in terms of pathologic anxiety or worse can lead to escalation of distress and adverse outcomes. Lack of knowledge about mitochondrial dysfunction on the part of the health care professional, or disbelief of or reluctance to listen to the patient’s history in their own words, not only undermines trust but also may lead to a critical condition in the patient that could have been easily avoided. I experienced great personal relief that the many hours of anesthesia ended well. The clinical heterogeneity of mitochondrial disorders present unique challenges for an anesthesiologist, particularly when a definitive diagnosis has not yet been elucidated and symptoms are broad and varied. Thorough review of medical and surgical history is paramount, and in this case led to an anesthetic that avoided muscle relaxation, electrolyte abnormalities, and myopathy exacerbation, and provided comfort with minimal and well-titrated opioid management. E DISCLOSURES Name: Linda S. Aglio, MD, MS. Contribution: This author helped design the study, and write and edit the manuscript. Name: Brian T. Lockhart, MD. Contribution: This author helped collect the data, contribute to the discussion, and edit the manuscript. Name: Jeantine E. Lunshof, PhD. Contribution: This author helped contribute to the discussion. Name: Christoph S. Nabzdyk, MD. Contribution: This author helped collect the data, contribute to the discussion, and edit the manuscript. This manuscript was handled by: Raymond C. Roy, MD. REFERENCES 1.Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF. The epidemiology of mitochondrial disorders--past, present and future. Biochim Biophys Acta. 2004;1659:115–120. 2.Fricker RM, Raffelsberger T, Rauch-Shorny S, et al. Positive malignant hyperthermia susceptibility in vitro test in a patient with mitochondrial myopathy and myoadenylate deaminase deficiency. Anesthesiology. 2002;97:1635–1637. 3. Milone M, Wong LJ. Diagnosis of mitochondrial myopathies. Mol Genet Metab. 2013;110:35–41. 4.Jeppesen TD, Schwartz M, Olsen DB, Vissing J. 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