Mitochondrial cytopathies

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
(long chain fatty acids transport in the mitochondrial membrane)

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
         hyper - and hypothermia

-         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
              -         central block: OK if no demyelination
                -         difficult if scoliosis
                -         peripheral block: OK unless axonal neuropathy is present



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)


preoperative
period

-        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


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, OConnor 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