Author: Matías A. Loewy
The anesthesiology community is concerned by severe and unexpected episodes of sensitivity to volatile general anesthetics (particularly sevoflurane) in patients of Venezuelan maternal lineage — especially boys — with at least 36 cases identified since 2021 in the US, Spain, and several Latin American countries. Researchers strongly suspect a mitochondrial variation or mutation, which until now was considered of “uncertain” clinical significance, is involved in most cases, according to a study soon to be published led by Eduardo Ruiz-Pesini, PhD, of the Department of Biochemistry, Molecular and Cellular Biology at the University of Zaragoza, Zaragoza, Spain.
Concern intensified in late January when the American Society of Anesthesiologists (ASA) and the Society for Pediatric Anesthesia (SPA) jointly issued an alert about serious neurologic complications, including stroke and death, in healthy adult and pediatric patients of Venezuelan ancestry after routine general anesthesia. The statement suggests that any patient with direct Venezuelan maternal ancestry should be considered at risk.
The Venezuelan Society of Anesthesiology posted a notice on social media on February 4 attempting to reassure the public and the medical community: “We are very likely facing an extremely rare condition” while acknowledging the epidemiologic challenge of determining the magnitude of a genetic founder effect that has turned a routine practice into a life-threatening risk for a specific subgroup.
Unexpected Postoperative Neuropathy
According to the Venezuelan society’s reconstruction, the first cases were reported in July 2025 by the Chilean Society of Anesthesiology. In a letter to other Chilean medical societies, they said they had been informed of five clinical cases of previously healthy Venezuelan children who, after surgical procedures without evident complications, did not awaken in the recovery phase or awoke with severe neurologic impairment. All had received “anesthetic techniques widely validated and used in the pediatric population.” The following week an additional adult case was identified.
“They were routine anesthetics given to previously healthy patients — elective cases and short urgent procedures, ranging from brief to prolonged operations — performed on ASA physical status 1 individuals, in whom you would never expect a complication,” Valeria Epulef, president of the Chilean Society of Anesthesiology, said in an interview with Willaim Jorland Sierraalta, MD, Anesthesiology, Northwestern Medical Group, Chicago.
The surgical procedures included a dermoepidermal graft, flexor tendon repair, video-assisted thoracoscopic surgery, adenoidectomy and tonsillectomy, full dental restoration, and two inguinal hernia repairs, according to a detailed case description by members of the University of Chile, Santiago, Chile, and Chile’s Ministry of Health published in the journal Anesthesiology.
The median age of the seven affected patients in Chile was 5 years (range, 1-36 years); five were male. All received sevoflurane and fentanyl, and six (86%) received propofol. Most showed symptoms on emergence from anesthesia. Four progressed to severe clinical courses with intracranial hypertension secondary to cerebral edema, resulting in death within 1-22 days. Three patients developed serious neurologic, cognitive, and motor sequelae. Neuroimaging findings often involved bilateral lesions in the basal ganglia with additional involvement of the cerebellum, substantia nigra, and other deep gray matter structures, suggesting a hypoxic-ischemic encephalopathy.
In searching for similar reports, Epulef and Chilean colleagues learned that Spain had also recorded similar events: previously healthy Venezuelan patients who suffered brain injury after receiving sevoflurane anesthesia, in whom another common factor was identified — a point variant or mutation in the mitochondrial gene for nicotinamide adenine dinucleotide dehydrogenase 4 that affects complex I of the mitochondrial respiratory chain.
The variant, identified as m.11232T>C in the MT-ND4 gene, is classified as of “uncertain” clinical significance under American College of Medical Genetics and Genomics and Association for Molecular Pathology interpretation guidelines. But it appears to wake up and show its worst effects in the presence of certain anesthetics.
“It is a genetically based mitochondrial dysfunction that produces no signs or symptoms except in reported cases after exposure to volatile anesthetics, especially sevoflurane — not because sevoflurane is uniquely triggering but because it is the most widely used anesthetic [since its introduction in the 1990s, more than 1 billion patients have received anesthesia with this drug globally],” Diana Finkel, director of the anesthesiology specialist training program at the University of Buenos Aires, Buenos Aires, Argentina, told Medscape Spain.
In September 2025, the Spanish Society of Anesthesiology and Resuscitation issued an alert about cases in Spain and estimated preliminarily that the population frequency of this mutation that increases susceptibility to severe complications from anesthetics “would be fewer than 1 in 414 children” while acknowledging that figure could be imprecise given the lack of broader controls.
Unexpected Postoperative Tragedies
In November 2025, biochemist Ruiz-Pesini, who is also affiliated with the Aragón Health Research Institute (IIS Aragón) in Zaragoza and the Spanish Network of Biomedical Research on Rare Diseases (CIBERER) in Madrid, Spain, presented details of eight additional clinical cases: Venezuela (5), Spain (1), the US (1), and Germany (1) at the 25th Venezuelan Congress of Anesthesiology in Caracas, Venezuela. The presentation was rebroadcast and discussed in an online seminar by the Venezuelan Society of Anesthesiology in January. Ruiz-Pesini declined to comment further to Medscape Spain while awaiting publication.
The episodes described, occurring between 2005 and 2025, resulted in severe neurologic injury after exposure to anesthetics, with sevoflurane the common factor in all cases. Affected patients were boys younger than 16 years and of Venezuelan origin, although the cohort is small, and it is unclear whether age or sex are meaningful risk factors. Procedures were routine — tonsillectomy, fracture fixation, knee arthroplasty, varicocele repair, umbilical hernia repair, and cochlear implant surgery. “The outcome, because it was so unexpected, has been especially painful for the families and very traumatic for the anesthesiologists who performed the procedures. I was told they repeatedly reviewed their intraoperative practices and could find no error,” Ruiz-Pesini recalled in her presentation.
The patients also shared another characteristic: the genetic variant at position 11,232 of mitochondrial DNA (a thymine instead of a cytosine) “associated with a phenotype of basal ganglia degeneration,” Ruiz-Pesini said. In vitro studies showed that cells with that genetic alteration exposed to sevoflurane at concentrations comparable to those in anesthetized patients experienced “drastic reductions in mitochondrial activity or oxygen consumption,” leading to immediate energetic collapse. The effect was far less pronounced when cells were exposed to propofol.
Outside the Venezuelan lineage, this variant is virtually unknown worldwide. The probability of finding it by chance in the eight patients studied was 1 in 1800 trillion, Ruiz-Pesini calculated. Five of the eight were from Carabobo or had mothers or maternal grandmothers from that state, and Ruiz-Pesini estimated the haplotype containing the variant is 15 times more frequently in that state than in the rest of the country.
Rumors and Reaction
Initial dissemination of the cases from Chile, the US, and Spain prompted suspicions in Venezuela about a “Venezuelan gene” and fears of discrimination. “There is nothing concrete yet. The important thing is not to stigmatize Venezuelans,” said Daniel Sánchez, former president of the Venezuelan Society of Anesthesiology. “I would tell countries where cases occurred to review their anesthesia protocols, the type of drug they are using, and whether it’s sterile because people want to label Venezuelan children, and when those who are abroad arrive at a hospital, people will be scared,” said Huníades Urbina-Medina, president of the National Academy of Medicine of Venezuela, in an interview with journalist María Alesia Sosa.
But experts say this is not about blame or stigma. “No one is blaming Venezuelans for the problem these patients are experiencing. In fact, I understand Venezuela has been an independent state since 1830. The variant likely predates that — it probably arose in a woman who lived in the region that corresponds today to Carabobo and, due to local reproduction, its frequency increased,” Ruiz-Pesini said.
Yaremi Hernández Castillo, internist from Venezuela who lives in Germany and is the mother of one of the affected patients — the first identified — recounted that her son, now 34, suffered severe neurologic problems twice, in 2005 and 2007, both after sevoflurane anesthesia for fracture surgery in Germany. Years later, when a 15-year-old cousin in the US experienced a similar event, concern mounted. “I searched at different medical centers, and no one listened,” she told journalist Shirley Varnagy. She eventually connected with Ruiz-Pesini and his team in Zaragoza, which led to the discovery of the mutation. Preventing new cases became her life’s mission.
“So far this variant has only been identified in patients of Venezuelan origin. That does not exclude its presence in other populations, but it has been found in Venezuela. This has nothing to do with segregation, xenophobia, or politics — it’s a reality that exists and has existed more in Venezuelan patients. Just as, for example, Huntington’s disease has a higher prevalence in the state of Zulia in Venezuela than in many other countries, a region anywhere could have a higher prevalence of a genetic condition, and this time it happened in Venezuela,” Hernández Castillo said.
What Should Be Done?
Because this is a recent finding with few publications and its true magnitude is unknown, “the exposure-event association is not quantified,” Finkel noted, and there is not yet an established clinical protocol to prevent these severe complications during routine procedures.
Sequencing to search for the mitochondrial variant in patients with maternal Venezuelan ancestry before surgery is a natural option, but it faces economic barriers and huge logistical challenges in Venezuela and countries with large migrant populations — and it is not feasible for emergency surgeries. “You can do it; it’s expensive, but if you test many people, the cost comes down,” Hernández Castillo said. In addition, family records of a maternal ancestor from Venezuela or Carabobo may be lost over generations.
In July 2025, the Chilean Ministry of Health issued a circular on clinical management of possible perioperative neurologic events, focusing on patients with Venezuelan maternal ancestry. It emphasized improving preanesthetic evaluations, concentrating on early recognition of possible mitochondrial dysfunction, for example, prior delayed emergence after anesthesia or anesthesia histories in the mother, siblings, or maternal grandmothers. The document also proposed “carefully balancing the need for general anesthesia for a particular procedure,” prioritizing agents considered safe in cases of mitochondrial dysfunction, and — if suspicion is “well founded” — considering avoiding halogenated agents such as sevoflurane and using propofol or regional or neuroaxial techniques when possible.
The Spanish Society of Anesthesiology and Resuscitation’s advisory likewise proposed provisional preventive measures, including genetic evaluation and investigation in Venezuelan children with a suggestive family history before elective procedures and avoiding volatile anesthetics in urgent surgeries.
In its January alert, the ASA and SPA did not recommend a blanket approach for all patients with Venezuelan ancestry by maternal line but emphasized that those who carry the mutation should avoid inhaled anesthesia; therefore, “regional anesthesia should be considered, and additional monitoring to observe any rapid changes in brain activity” is advisable.
In Venezuela, where the entire patient population could have an increased risk, the challenge is greater. The Venezuelan Society of Anesthesiology recommended a “directed medical history” as a preoperative screening tool. Useful questions include: Did any maternal relative take a long time to wake up, become very weak, or go to intensive care “as a precaution” after surgery? Did any maternal cousin or uncle have an unexplained death in childhood after minor procedures? Does the mother or any siblings have chronic fatigue, ptosis (drooping eyelids), severe migraines, or exercise intolerance that could suggest an underlying mitochondrial disorder?
The society also noted two laboratory methods to identify the mutation: (1) restriction fragment length polymorphism polymerase chain reaction — effective and economical for individual diagnosis from saliva samples but not suitable for hundreds of samples at once; and (2) sequencing — which enables high-throughput testing but requires better-equipped laboratories.
Measuring indirect, nonspecific markers of mitochondrial dysfunction such as serum lactate is less reliable because many affected patients “only decompensate under anesthetic stress.”
The society stressed that if clinicians proceed with general anesthesia in a patient suspected of carrying the mutation because of urgency or lack of testing, they should use a depth-of-anesthesia monitor to detect any abrupt drop in bispectral index during a gentle induction with low doses of sevoflurane.
Another option is to avoid exposure to inhaled anesthetics altogether, an approach that may be appropriate for patients with higher risk. During the Venezuelan Society of Anesthesiology’s online seminar, Luis Ignacio Rodríguez, Venezuelan pediatric anesthesiologist practicing in the US, said that when the preoperative or family history suggests risk, “it would be better in those cases to proceed directly to total intravenous anesthesia.”