Joint Statement on Anaesthesia-Related Mitochondrial Pharmacogenetic Risk in Individuals with Venezuelan Maternal Ancestry

European Society of Anaesthesiology and Intensive Care (ESAIC)
European Society of Paediatric Anaesthesia (ESPA)
European Reference Network (ERN) EURO-NMD Mitochondrial Working Group
European Mitochondrial (E-MIT) Society

Background

Recent communications from major anaesthesiology societies have highlighted emerging reports of severe neurological complications, including basal ganglia infarction and death, following routine general anaesthesia in previously healthy individuals with Venezuelan maternal ancestry. Most reported cases involved exposure to sevoflurane, although details regarding duration and concentrations of exposure remain limited.

Since word of these cases has spread, additional cases in Europe and the United States have been identified. Concurrently, on February 18th an Anaesthesiology publication summarizing a Report from the Chilean Ministry of Health has outlined a possible mitochondrial pharmacogenetic susceptibility to severe neurologic events after general anaesthesia (doi: 10.1097/ALN.0000000000005935). Experimental and mechanistic data published in Anesthesiology (doi.org/10.1097/ALN.0000000000006029) suggest that sevoflurane, at concentrations observed during clinical procedures, can inhibit mitochondrial respiratory complex I, resulting in a significant reduction in cellular oxygen consumption and energy production.

Genetic testing was performed in ten of the fourteen initially reported cases, and all carried the mtDNA m.11232T>C homoplasmic variant of mitochondrial DNA, affecting the NADH dehydrogenase 4 (MT-ND4) gene, a component of complex I of the electron transport chain.

Although the precise pathogenic mechanisms remain under investigation, the convergence of clinical observations and emerging molecular evidence has raised concern regarding a potential ancestry-related mitochondrial susceptibility to certain anaesthetic agents.

Position Statement

The European Society of Anaesthesiology and Intensive Care, the European Society of Paediatric Anaesthesia, the ERN EURO-NMD Mitochondrial Working Group, and the E-MIT Society jointly acknowledge the following:

Nature of the Reported Risk

Reported anaesthesia-related neurological complications appear to be associated with mitochondrial genetic susceptibility, particularly the homoplasmic mtDNA variant m.11232T>C in the MT-ND4 gene. This variant has been reported almost exclusively in individuals with Venezuelan maternal ancestry. In affected individuals, clinical manifestations of mitochondrial dysfunction are absent prior to anaesthetic exposure. Current evidence remains limited, and further research is needed to clarify the magnitude of risk, the mechanisms involved, and the role of different anaesthetic agents.

Identification of Individuals Potentially at Risk

During pre-anaesthetic evaluation, clinicians may consider asking patients about maternal Venezuelan ancestry, as mitochondrial DNA is inherited exclusively through the maternal lineage.

Patients with direct maternal lineage from Venezuela may be considered potentially at risk until further evidence clarifies the clinical relevance of this genetic variant.

A detailed history should also include questions regarding:

• Previous unexplained severe neurological events following anaesthesia
• Family history of unexpected complications following anaesthesia
• Unexplained postoperative neurological deterioration in otherwise healthy individuals

Both children and adults may potentially be affected.

Genetic Testing

Mitochondrial DNA sequencing can identify the MT-ND4 m.11232T>C variant.

Important considerations include:

• Some genetic laboratories may have historically classified this variant as a benign polymorphism.
• Consultation with clinical geneticists or mitochondrial disease specialists is advisable when testing is possible or considered.
• The availability and implementation of genetic screening may vary between countries and centres.

At present, routine population-wide genetic screening cannot be universally recommended. However, testing may be considered in individuals with Venezuelan maternal ancestry undergoing planned surgical procedures when testing is accessible and feasible.

Considerations for Anaesthetic Management

In patients considered potentially at risk, and in the absence of definitive genetic results, anaesthetic management should be carefully considered.

Possible risk-mitigation strategies may include:

• Avoidance of Volatile Anaesthetic Agents. Because most reported cases involved exposure to sevoflurane, clinicians may consider avoiding volatile anaesthetic agents until further evidence becomes available.
• Total Intravenous Anaesthesia (TIVA)as anaesthesia of choice. Propofol may be used cautiously, at low doses and for the shortest possible duration. One strategy could be to combine propofol with other adjuvants that decrease its consumption, such as dexmedetomidine. No experience has been reported so far with remimazolam in this context.
• Whenever appropriate for the surgical procedure, regional anaesthesia techniques may be considered.

Monitoring

Enhanced intraoperative monitoring may include:

• Processed EEG monitoring (pEEG) to assess depth of anaesthesia
• Near-infrared spectroscopy (NIRS) to monitor cerebral oxygenation
• Measurement of blood lactates level, as in other mitochondrial diseases, although no data are available so far on their usefulness in this pathology

Conclusion

This statement reflects the current understanding and expert consensus regarding a potential anaesthesia-related mitochondrial pharmacogenetic susceptibility in individuals with Venezuelan maternal ancestry. Given the limited evidence currently available, this document does not constitute a formal clinical guideline. Rather, it aims to increase awareness among anaesthesiologists and encourage cautious perioperative management while additional evidence is gathered. The participating societies will continue to monitor emerging data and will update recommendations as further evidence becomes available.