Mitochondrial cytopathies
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Mitochondria are the place where many metabolic reactions that are essential for the proper functioning of cells and tissues occur. These are primarily: the respiratory chain (ATP synthesis), Krebs cycle (pyruvate-dehydrogenase, pyruvate kinase), ß-oxidation of fatty acids (SCAD, MCAD, LCAD, VLCAD), the urea cycle (elimination of NH4).
While in fact any metabolic abnormality of one of these metabolic pathways is strictly speaking a cytopathy or mitochondrial disease, this term is generally synonymous with a pathology of the respiratory chain, for example Kearns-Sayres syndrome, Leigh disease, MELAS, MERFF, MNGIE, NARP syndromes.
Anesthetic implications:
Anesthetic considerations summarized in the table below relate essentially to the pathologies of the respiratory chain but are applicable to all mitochondrial diseases. The presence of a mitochondrial cytopathy does not expose to an increased risk of malignant hyperthermia by comparison with the normal population. However, it is always possible that a patient presents with both pathologies (see personal and familial medical history) (Nelson et al. 2017).
All anaesthetic agents interfere with mitochondrial function in vitro (see table):
Agent |
in vitro mitochondrial effect |
barbiturates |
complex I inhibition |
etomidate |
complex I inhibition and weak effect on complex III |
propofol |
complexes I, II III inhibition acylcarnitine transferase type 1 inhibition
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benzodiazepines |
complexes I, II, III inhibition |
kétamine |
complex I inhibition ? increased metabolism ? |
dexmedetomidine |
none reported |
fentanyl, remifentanil |
minimal |
morphine |
mild complex I inhibition |
halogenated volatile agents |
complexe I, coenzyme Q inhibition and mild effect on complex V |
bupivacaine |
inhibition of acylcarnitine translocase (lesser effect with lidocaine and ropivacaine) |
However, all of these agents have been used without serious consequences in these patients: it seems that the maintaining of metabolic homeostasis in perioperative period is a major element of security.
Preoperative |
- neurological assessment: epilepsy? spasticity? muscular atrophy? - cardiological assessment: ECG (conduction), echography (cardiomyopathy) - metabolic assessment: SGOT, SGPT, renal function, endocrine disorders ? - check the baseline blood lactate level (blood should be ideally sampled without using a tourniquet) - swallowing disorders ? GERD? Apnea? - treatment: anti-epileptic drug (s), carnitine supplements, ketogenic diet ? - avoid elective surgery in case of fever (risk of neurological deterioration?) |
Anesthesia |
- short fasting period or provide a glucose-containing infusion as soon as the fasting is started (except in case of ketogenic diet) - usual dose of carnitine and antiepileptic drug on the morning of anesthesia/surgery - IV (single-dose propofol is OK) or inhalation (sevoflurane) induction - avoid using a continuous infusion of propofol: increased risk of PRIS?moreover, propofol on respiratory chain (factors II and IV) and on the intramitochondrial transport of long-chain fatty acids - infusion of maintenance: glucose 5% + electrolytes (avoid lactates) except in case of cetogenic diet - monitor: blood glucose and lactate - avoid hyper - and hypoventilation
- avoid succinylcholine in case of muscle involvement - avoid the prolonged use of tourniquet - monitoring of the curarization - morphine: risk of decreased response to hypoxia or the hypercarbia. Remifentanil ? - decreased reliability of the analysis of the EEG for measuring the depth of anesthesia? - no increased risk of malignant hyperthermia even if a few instances of positive contracture tests to caffeine and halothane have been reported - regional anesthesia
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PACU |
- risk of decreased response to hypoxia or hypercarbia - monitor: blood glucose and lactate - sometimes important postoperative hyperthermia (24-48 h) |
Anesthetic aspects of the management of a patient with anomaly of the respiratory chain (mitochondrial cytopathy)
- take advice from the neuropediatrician: efficacy of the diet, which treatment in case of seizure, side effects (urinary lithiases ?) - evaluation: RBC, WC, platelets, electrolytes, urea, creatinine, Ca, Mg, albumin and prealbumin (nutrition). SGOT and SGPT levels are often moderately elevated - avoid prolonged fasting: clear unsweetened fluids allowed - avoid sweetened fluids in the premedication - avoid IV administration of carbohydrates containing IV fluids - check glycemia at induction: ideally 50-80 mg/dL |
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anesthesia |
- propofol: OK for induction but avoid TIVA: source of glycerol, risk of PRIS and pancreatitis - fluids: 0.9 % NaCl (risk of worsening metabolic acidosis) or Ringer lactate (but lactate promotes gluconeogenesis) - avoid corticosteroids: dexamethasone? - avoid carbohydrate-containing medications (glucose, mannitol, glycerol) if possible - the transfusion of labile blood products is a hidden intake of carbohydrates - in case of hypoglycemia, correct with low doses of glucose (0.25g/kg) - monitor glycemia, pH, electrolytes, NaHCO3 |
postoperative |
- resume the ketogenic diet as soon as possible - check ketone bodies (urine): between 40 and 160 mg/dL or at least 2 ++ |
Ketogenic diet: perianesthetic recommendations
References:
- Vanlander AV, Jorens PG, Smet J, De Paepe B et al.
Inborn oxidative phosphorylation defect as risk factor for propofol infusion syndrome.
Acta Anaesthesiol Scand 2012; 56:520-5
- Dewhirst E, Rehman S, Tobias JD.
Perioperative care of an infant with pyruvate deshydrogenase deficiency.
South Afr J Anaesth Analg 2012; 18 :115-8
- Niezgoda J, Morgan PG.
Anesthetic considerations in patients with mitochondrial defects.
Pediatr Anesth 2013; 23: 785-93.
- Mtaweh H, Bayir H, Kochanek PM, Bell MJ.
Effect of a single dose of propofol and lack of dextrose administration in a child with mitochondrial disease: a case report.
J Child Neurol 2014; 29: NP 40-6.
- Finsterer J, Michalek-Sauberer A, Höfteberger R.
Malignant hyperthermia susceptibility in a patient with meitochondrial disorder.
Metab Brain Dis 2009 ; 24 : 501-6
- Nouette-Gaulain K, Robin F, Semjen F, Obre E, Bellance N, Biais M, Rossignol R.
Cytopathies mitochondriales et anesthésie.
Anesth Réanim 2016 ; 2 : 300-8.
- Nelson JH, Kaplan RF.
Anesthetic management of 2 pediatric patients with concurrent diagnoses of mitochondrial disease and malignant hyperthermia susceptibility : a case report.
A&A Case Reports 2017 (in press).
- Smith A, Dunne E, Mannion M, O’Connor C, Knerr I et al.
A review of anaesthetic outcomes in patients with genetically confirmed mitochondrial disorders.
Eur J Pediatr 2017; 176: 83-8.
- Kloesel B, Holzman RS.
Anesthetic management of patients with inborn errors of metabolism.
Anesth Analg 2017; 125: 822-236
- Savard M, Dupré N, Turgeon AF, Desbiens R, Langevin S, Brunet D.
Propofol-related infusion syndrome heralding a mitochondrial disease : case report.
Neurology 2013 ; 81 : 770-1.
- Hsieh VC, Krane J, Morgan PG.
Mitochondrial diseases and anesthesia.
J Inborn Metab & Screening 2017; 5 : 1-5.
- Conover ZR, Talai A, Klockau KS, Ing RJ, Chaterjee D.
Perioperative management of children on ketogenic dietary therapies.
Anesth Analg 2020 ; 131 :1872-82.
Updated: November 2020