On January 27, 2026, a joint communication from the American Society of Anesthesiologists and the Society for Pediatric Anesthesia alerted its members.
Recent communications from South American anesthesia societies describe healthy adult and pediatric patients of Venezuelan ancestry who have had unexpected catastrophic outcomes, including severe neurologic damage with basal ganglia infarcts and death, after routine anesthetic exposures. Since word of these cases has spread, additional cases in Europe and the United States have been identified.
Most of what is known about the clinical cases has been shared only through personal communication or non-peer-reviewed publications. Although complete anesthetic and medical records are protected health information and, therefore, not accessible in most cases, the Society for Pediatric Anesthesia (SPA) and the American Society of Anesthesiologists (ASA) believe the severity of these cases warrants developing and sharing expert opinion despite incomplete and emerging clinical and scientific information.
Detailed family histories were taken in a subset of affected patients. These patients were all of Venezuelan heritage, and several had family members who had adverse outcomes after an otherwise uneventful anesthetic. Almost all the affected patients are reported to have received sevoflurane, although the duration and concentrations are unknown. A few of the patients reportedly received propofol infusions without incident. Critically, we do not know the granular details of each anesthetic. Thus, it is impossible to know all the drugs administered to each patient, their doses, concentrations, and/or durations. There is also limited information on the use of depth-of-anesthesia monitoring in these cohorts.
Genetic testing performed on a subset of these patients identified multiple mitochondrial mutations. The best described, at this time, is a point mutation of the NADH dehydrogenase 4 (ND4) gene (mtND4m.11232T>C), a subunit of complex I of the mitochondrial electron transport chain. Complex I is a known target of volatile anesthetics and is also known to be inhibited by propofol. Prior work has shown that impaired complex I activity correlates with hypersensitivity to volatile anesthetics in animals and humans. There is currently no available point-of-care screening test for the ND4 mutation.
ND4 is a protein subunit of complex I that is maternally inherited through mitochondrial DNA. In this population, patients expressing the mutant gene do not appear to exhibit significant signs of mitochondrial dysfunction until anesthetic exposure. Inhibition of complex I by volatile anesthetics can decrease ATP production, thereby suppressing central nervous system activity. Propofol may also inhibit mitochondrial function at multiple sites, including complex I. However, the relative risks between sevoflurane and propofol in these patients are unknown at this time.
These recommendations are provided in a situation where much more is unknown than known. As a consequence, these recommendations are broad and somewhat imprecise. Anesthesiologists must use their own knowledge and judgment on how to approach this issue with their patients. ASA and SPA will update these recommendations as more information becomes available.
The recommendation was to screen for risk:
At this time, we recommend anesthesiologists consider asking their patients about potential maternal Venezuelan heritage. However, a negative family history of anesthetic complications does not rule out the risk caused by this type of genetic mutation. All mitochondrial DNA is inherited directly from the mother. Therefore, any patient with direct maternal Venezuelan lineage should be considered at risk.
Genetic Testing
- Mitochondrial DNA sequencing of patients and/or their maternal relatives is available to confirm the presence of the mutation. Additionally, it is important to alert testing laboratories of the specific mutation of interest (mtND4 m.11232T>C). Historically, laboratories have interpreted this mutation as a normal variant. The genetic laboratory should be asked to report whether this mutation is present or absent.
- Anesthesiologists should consider consulting their local genetics experts to identify laboratories that can perform genetic testing in patients at risk and to assist in the management of any patients or families found to have the mutation of concern (mtND4 m.11232T>C).
- Informed consent should be obtained from the patient or authorized caregiver for any genetic testing.
Clinical Management:
- The optimal and safest anesthetic for patients with this ND4 mutation has not been established.
- Given the majority of affected patients are reported to have received sevoflurane, consider avoiding the use of all volatile anesthetics until more information is available.
- Regional anesthesia should be considered for appropriate patients and procedures.
- Based on verbal reports, patients who have had complications from sevoflurane-based anesthetics have had uneventful propofol anesthetics. It is not yet known whether prolonged use of propofol infusions is safe in the population.
- Midazolam, dexmedetomidine, ketamine, and short/ultra short-acting opioids have not been implicated.
- Anesthetic depth monitoring with processed EEG to avoid burst suppression may be advisable. Some patients with complex I gene mutations show a rapid change (decrease) in EEG activity with exposure to volatile anesthetics. It is unknown, at this time, if this rapid change is seen in patients of Venezuelan ancestry with the mutation.
- Patients at risk should be monitored after general anesthesia for return to their neurocognitive baseline. Consider extended postoperative observation and monitoring of acid-base status if complications are suspected.
How should surgeons be thinking about this?
- This mainly needs to be addressed by your anesthesiologists.
- The anesthesiologist should be aware of the issue with maternal Venezuelan descent. I see no problem with a surgeon asking the patient if they have maternal Venezuelan descent to screen, but the anesthesiologist needs to be captain of this ship, as some anesthetic agents seem to be better tolerated relative to others in this cohort. The choice of anesthetic matters in such patients.
- For those patients with maternal Venezuelan descent, recommendation is for anesthesiologist to send the pt for genetic testing or to see a genetic counselor to discuss testing.
- Sevoflurane seems to be a problematic agent in patients with the mutation. The article suggests propofol is likely safe. Midazolam, dexmedetomidine, ketamine, and short/ultra-short-acting opioids have not been implicated.
- There are still many unknowns.
This uncertainty may create a lot of worry for some patients and surgeons. I expect more information over time to clarify what a reasonably prudent surgeon (and anesthesiologist) should advise and do over time.
There are situations where state law and good practice dictates ordering specific tests prior to performing a specific procedure.
Texas Administrative Code requires serum pseudocholinesterase testing prior to Electroconvulsive Therapy (ECT) if there is no documentation of the previous successful use of muscle relaxants or no record of prior testing. ECT for treatment-resistant depression causes seizure activity. Muscle relaxants (paralytic agents) are used to pre-treat to prevent a patient from fracturing a limb from a violent seizure. If an anesthesiologist uses succinylcholine as the paralytic agent of choice, and the patient has pseudocholinesterase deficiency, that patient will not rapidly metabolize the agent. Pseudocholinesterase is a liver-produced enzyme that rapidly metabolizes the muscle relaxant succinylcholine (usually within 10 minutes). Patients with pseudocholinesterase deficiency (genetic or acquired) cannot break down this drug efficiently, leading to prolonged neuromuscular blockade (paralysis) and apnea, requiring extended mechanical ventilation.
And, finally, prior to scheduled surgery, individuals at risk for malignant hyperthermia (MH) are often tested via muscle biopsy or genetic analysis.
In Vitro Contracture Test (CHCT/IVCT): This is the most accurate diagnostic test (approx. 78% overall accuracy) for MH susceptibility. It involves a surgical biopsy of muscle tissue (usually from the thigh) that is immediately tested in a specialized lab.
Genetic Testing: A less invasive blood test that identifies specific gene mutations (mainly RYR1) linked to MH susceptibility. It is particularly useful for identifying at-risk relatives if a mutation is already known in the family, but it has lower sensitivity compared to CHCT.
Testing is recommended for individuals with a suspected clinical history of MH (severe muscle rigidity, high fever during anesthesia) or first-degree relatives of a known MH-susceptible patient.
As full genome tests head down to the $100 range, the threshold for ordering such tests will go down. What will go up? The need to better understand when these tests are indicated, how to interpret them, and how to act on the results.
What do you think?
Any substance that decreases ATP levels or production is dangerous. It may be possible to do active research on tissue cultures in the laboratory to determine which anesthesia medications decreases/inhibits ATP production. This can be performed without risk to human populations.
This kind of research, and other approaches should not be undertaken in a vacuum of effort. The Venezuelan government should take a prominent position in this research.
Of course there are medical/legal implications for failure to take appropriate measures for anesthesia for patients with this ancestry. But vastly more efforts need to be taken.
This research door is hardly even open yet.
Michael M. Rosenblatt, DPM
1) Such testing is typically only available at a university hospital.
2) Such testing is not available and would take days or weeks in a rural hospital setting.
3) The best screen is a good history!!! That will avoid the need for a lot of genetic testing, except in adoption cases where parental background is unknown.
4) Re the Texas statute for pseudocholinesterase testing before ECT, I avoided the issue of problems of succinylcholine delayed breakdown, by using a different short acting muscle relaxant, that did not depend upon that mechanism of drug metabolism.
5) ECT should be done in a fully monitored setting (ie the OR). The way it was done over 40 years ago when I was in training, was on the psych ward, with a manual blood pressure cuff, no pulse oximeter, no ETCO2 monitor, and a crash cart EKG, with an ambu bag. After the monitoring standards came into effect, in 1987, we had to have full monitoring that could not be reproduced on the psych ward. We scheduled ECTs at the end of the OR schedule, and did them with full formal monitoring.
6) Processed EEG monitoring was something I introduced to my rural hospital in the 1990s. I later had a nurse manager rip it out of my OR saying that because it was not being used in a famous university hospital, we could not use it in our local hospital. Funny that 30 years later this type of advanced monitoring has come back into vogue.
7)In this specific case it would be foolhardy to implicate all inhalation anesthetics when only sevoflurane has been implicated. This particular anesthetic is primarily used for pediatric inductions. It would be useful to know the duration of exposure, and the procedure types. There is also the option of doing an induction with sevoflurane, and then switching to sevoflurane. Starting IVs for an IV induction for a short procedure, in small pediatric cases, is quite traumatic, especially in an outpatient setting. One could do an induction with sevoflurance or isoflurane, but few anesthesiologists have been trained to do that, due to the breath holds that occur due to the pungency of the anesthetic. But they can be done, if one is properly trained and prepared to do so, and if those agents are not implicated in anesthetic deaths.