The Anesthetic Management of a patient with Mitochondrial Myopathy A Case Study By Krista Douglass USC Program of Nurse Anesthesia Mitochondrial Myopathy Mitochondrial principal source of cellular energy metabolism. Necessary for Krebs cycle, fatty acid oxidation, oxidative phosphorylation Affects tissues requiring most energy- muscle and nerve Mitochondrial defects- maternal Manifestations can be mild to severe Related to ratio of mutated genes to normal genes Pathology Heterogeneous group of diseases Effect mitochondrial energy metabolism Result in decreased aerobic ATP production, impairment of energy- requiring functions Affects tissues and organs w/ highest energy demand, i.e. skeletal, cardiac, CNS Pathology Hundreds of histologic manifestations, RNA/ DNA mutations Mutations along mitochondrial respiratory chain, myoadenylate deaminase deficincy, base pair substitutions (C-T, T-C), mtDNA point mutations, thymidine kinase 2 gene/ deoxyguanosine kinase gene mutations These mutations result in mitochondrial respiratory chain dysfunctions Mitochondrial Myopathy Diagnosis is by muscle biopsy Hallmark- Ragged Red Fibers seen with Gomori trichrome stain Fibers also contain excess glycogen and increased lipid droplets, cytochrome c oxidase deficiency Presence of elevated lactic acid levels in blood and CSF can be helpful but not all patients have this Thompson, Viginia A. MD; Wahr, Joyce A. MD. (1997). Anesthetic considerations I patients presenting with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (melas) syndrome. Anesthesia & Analgesia. 85(6); pp1404-1406. Common Manifestations Leigh’s Synd- seizures, hypotonia, fatigue, nystagmus, poor reflexes, swallowing difficulties, respiratory fatigue, poor motor function, ataxia. MELAS (mitochondrial encephalopathy lactic acidosis and stroke-like episodes)- short stature, seizures, stroke-like episodes w/ neurological deficits, HA, cognitive regression and disease progression. http://www.specialchild.com. Mitochondrial Myopathy. November 11, 2003. http://www.thedoctorsdoctor.com. Mitochondrial Myopathy. April 5, 2004. Common Manifestations Kearns-Sayre Syndrome- progressive external ophthalmoplegia, pigmentary retinopathy, heart block and high CSF protein concentration MERRF (myoclonus epilepsy w/ ragged red fibers)- myoclonus, epilepsy, progressive ataxia, muscle weakness/ degeneration, deafness and dementia. Hallmark- ragged red fiber. http://www.specialchild.com. Mitochondrial Myopathy. November 11, 2003. http://www.thedoctorsdoctor.com. Mitochondrial Myopathy. April 5, 2004. Case Study 8 year old girl Admitted for chronic constipation & cyclic vomiting Scheduled for laparoscopic appendacostomy A stoma is made from the appendix Patient is able to irrigate the GI tract daily Prevention of constipation At birth, Apgar scores at 1 and 5 mins were 8/9 Case Study At 3 months of age- patient had a GI procedure (mother could not recall procedure, not on chart) At 6 months of age- Dx with a mild form of Mitochondrial Myopathy Recent past medical history- episodes of cyclic vomiting Chronic constipation Exercise intolerance Heat exhaustion Symptoms of disease limited to GI tract (chronic constipation and vomiting) Anesthetic Management Premed- 2mg Midazolam PO IV induction, Propofol 100mg ETT 5.5 placed without NDMR Air:O2 1:1 Maintenance TIVA, propofol infusion between 100-200 mcg/kg/min, Remifentanil 0.150 mcg/kg/min TPN continued from ward Normal Saline used for intravenous fluid requirements Anesthesia cont Nitrous Oxide was used for first 45 mins then discontinued No muscle relaxant used No other inhalational gases used Temp within normal limits throughout Blood sugar checked after 1 hr= 112 Procedure performed successfully Pt. emerged from anesthesia without complications Goals of Anesthesia for this patient Provide a continuous level of deep anesthesia without MH triggering agents No inhalational gases; no muscle relaxants Optimal functioning for mitochondria by keeping pt warm, continued TPN, NS instead of LR Avoid lactic acidosis Anesthetic Considerations for Mitochondrial Myopathy patients Mitochondrial dysfunction affects function of nervous and muscular system Volatile anesthetics affect same systems- these patients have abnormal sensitivity General anesthetics shown to depress oxidative phosphorylation in isolated mitochondria Morgan et al. (2002) Mitochondrial defects and anesthetic sensitivity. Anesthesiology. 96(5):1268-1272. Anesthetic Considerations Myopathy patients reported to be sensitive to thiopental Susceptible to develop AV blocks, BBB to 3rd degree block Decreased ventilatory responds to hypoxia and hypercapnia Naguib et al (1996). Sensitivity to mivacurium in a patient with mitochondrial myopathy. Anesthesiology. 84(6):1506- 1509. Anesthetic Considerations Conflicting reports of response to neuromuscular blocking drugs Naguib et al (2002)- myopathy patient with extreme sensitivity to mivacurium Robertson et al (1984)- extreme sensitivity to d-tubocurarine with lack of reversal by neostigmine Anesthetic Considerations Lessel et al (1969)- sensitivity to succinylcholine in woman with ocular myopathy D’Ambra et al (1979)- “suggested mitochondrial myopathy did not involve NM junction”; pt showed normal repose to pancuronium and succinylcholine. Naguib et al. (1996). Sensitivity to mivacurium in a patient with mitochondrial myopathy. Anesthesiology. 84(6):pp1506-1509. Anesthetic Considerations Spinal anesthesia report to be safe Although local anesthetics disrupt oxidative phosphorylation – these patients reported to do well Increased MH susceptibility related to mitochondrial involvement in pathogenesis of MH Mitochondrial Ca+ efflux- perpetuation of MH Fricker et al. (2002). Positive malignant hyperthermia susceptiblity in vitro test in a patient with mitochondrialmyopahty and myoadenylate deaminase deficiency. Anesthesiology. 97(6):1635-1637. Summary Preoperative assessment of functional organ system reserve rather than disease presence Reduced anesthetic requirement Susceptibility to prolonged NS depression Enhanced sensitivity to NM blockade Increased risk of MH Increased risk of sudden death from conduction abnormalities Ciccotelli, et al (1997). An adult with inherited mitochondrial encephalomyopathy: report of a case. Anesthesiology. 87(5):1240-1242. References Ciccotelli, Kristine Kloss MD, RPh; Prak, Eline Luning AB; Muravchick, S. MD, PhD. (1997) An adult with inherited mitochondrial encephalmyopathy; report of a case. Anesthesiology, 87(5);1240-1242. Frickler, Ruth MD; Rafffelsberger, Thomas MD; Rauch-Shorny, Sigrid MD; Finsterer, Josef MD; Muller-Reible, Clemens PhD; Gilly, Hermann PhD; Bittner, Reginald MD. (2002). Positive malignant hyperthermia susceptiblity in vitro test in a patient with mitochondrial myopathy and ayoadenylate deaminase deficiency. Anesthesiology, 97(6); 1635-1637. References Garcia-Velasco, A.; Gomez-Escalonilla, C.; Guerra- Vales, J.M.; Cabella, A.; Campos, Y.; Arenas, J. (203). Intestinal pseudo-obstruction and urinary retention: cardinal features of a mitochonrial DNA related disease. Journal of Internal Medicine. 253(3); 381-385. Mancuso, Michangelo MD; Filosto, Massimiliano MD; Bonilla, Eduardo MD; Hirano, Michio MD; Shanske, Sara PhD; Vu, Tuan H. MD; DiMauro, Salvatore MD. (2003). Mitochondrial myopathy of childhood associated with mitochondrial dna depletion and homozygous mutation in the tk2 gene. Archives Neurology. 60(7); 1007-1009. References Morgan, Phil G. MD; Hoppel, Charles L. MD; Sedensky, Margaret M. MD. (2002). Mitochondrial defects and anesthestic sensitivity. Anesthesiology. 96(5); pp. 1268- 1270. Naguib, Mohamed MB.; el Dawlatly, Abdel Azim MB MD; Ashour, Mahmoud MB; Al-Bunyan, Muneera MB. (1996). Sensitivity to mivacurium in a patient with mitochondrial myopathy. Anesthesiology. 84(6); pp. 1506-1509. Thompson, Viginia A. MD; Wahr, Joyce A. MD. (1997). Anesthetic considerations I patients presenting with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (melas) syndrome. Anesthesia & Analgesia. 85(6); pp1404-1406. References Savarese JJ, Ali HH, Basta SJ, Embree PB, Scott RPF, Sunder N, Weakly JN, Wastila WB, El-Sayad HA. (1998) The clinical neuromuscular pharmacology of mivacurium chloride; a short-acting nondepolarizing ester neuromuscular blocking drug. Anesthesiology. 68:723-32. http://www.specialchild.com. Mitochondrial Myopathy. November 11, 2003. http://www.mitomap.org. The Report of the Committee on the Human Mitochondrial Genome. April 3, 2004. http://www.thedoctorsdoctor.com. Mitochondrial Myopathy. April 5, 2004.