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 (see those terms)


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. One study on the mouse showed a deleterious effect.

bupivacaine

inhibition of acylcarnitine translocase (lesser effect with lidocaine and ropivacaine)


Patients suffering from an abnormality of the complex I of the respiratory chain seem more sensitive to the effects of sevoflurane: it is therefore wise to monitor the depth of anesthesia with spectral monitoring of the EEG.

However, all anesthetic agents have been used without serious consequences in these patients: it seems that maintaining metabolic homeostasis during perioperative period is a major element of safety.



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 (venous blood should be ideally sampled without   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 (except in case of recent degradation or metabolic crisis)  as well as inhalatory (sevoflurane) with monitoring of the EEG in order to avoid an excessive depth

-         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, prefer acetates) 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); prefer solution with acetates (as Plasmalyte&®)

-        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. 

-        Hsieh VC, Niezgoda J, Sedensky MM, Hoppel CL, Morgan PG.
Anesthetic hypersensitivity in a case-controlled  series of patients with mitochondrial disease. 
Anesth Analg 2021, 133 : 924-32

-        van den Bersselaar L.R., Heytens L., Silva H.C.A., Reimann J., Tasca G., Díaz-Cambronero O., Løkken N., Hellblom A., Hopkins P.M., Rueffe H., Bastian B., Vilchez J.J., Gillies R., Johannsen S., Veyckemans F., Muenster T., Klein A., Littman R., Jungbluth H., Riazi S., Voermans N.C., Snoeck M.J.M. 
The European Neuromuscular Centre consensus statement on anaesthesia in patients with neuromuscular disorders.
Eur J Neurol 2022; doi.org/10.1111/ene.15526

-        De Vries MC, Brown DA, Allen ME, Bindoff L,Gorman GS, Karaa A, Keshavan N, Lamperti C, McFarland R, Ng YS, O'Callaghan M, Pitceathly RDS, Rahman S, Russell FGM, Varhaug KN, Schirris TJJ, Mancuso M.
Safety of drug use in patients with a primary mitochondrial disease: An international Delphi-based consensus.
J Inherit Metab Dis 2020;43:800-18

-        Spencer KA, Mulholland M, Snell J, Howe M, James K, Hanaford RA, Morgan PG, Sedensky M, Johnson SC.
Volatile anaesthetic toxicity in the genetic mitochondrial disease Leigh syndrome.  
Br J Anaesth 2023 ; 131 : 832-46


Updated: November 2023