MITOXIC- Why Anesthesia may not be good for any of us, especially Mitochondrial disease Patients

After hearing a friend tell me the story this week of her daughter’s pre-op surgery experience at a major Children’s Hospital (ranking among the top 10 in the country), I knew that this post had been in my draft folder waaay too long and it was time to publish it, in hopes that it will make a positive difference in another child’s life.

My friend’s story:

” There was an interesting moment when I was speaking with the anesthesiologist who was probably 60+ years old. I asked specifically what drugs they would use. He said that they’d start off with nitrous oxide. I told him that she couldn’t have nitrous because of an MTHFR genetic snp, And he looked at me like I had two heads. So did the 20 something anesthesia resident but she started googling it on her phone as we were talking. They left the room and came back and said there was another drug that they could use. Then there were several residents med students who were pretty surprised that I knew about this genetic susceptibility & curious to know more.”

I am convinced my friend saved her daughter’s life with her knowledge and her willingness to advocate for her daughter in that moment. In our journey, I have come across so many parents who have had children who react adversely to anesthesia, interestingly enough many of them NOW have a diagnosis of mito, autism, developmental delays, seizure disorders and neurological complications.

Anesthesia is necessary. This post is not anti-anesthesia. But I believe, like with so many other exposures in our environment, that there are reasons to be cautious with this group of powerful chemical agent.

A while ago, this article came across my news feed:

“Researchers from Cincinnati Children’s Hospital Medical Center report June 5 the Annals of Neurology that testing in laboratory mice shows anesthesia’s neurotoxic effects depend on the age of brain neurons – not the age of the animal undergoing anesthesia, as once thought.” (emphasis added)

And even though this article is over a year old, I found it interesting to read the comments from mothers of children who had undergone anesthesia many times, some as many as 20-30 times in their short 5-10 year lifespans. They commented saying that no one had ever warned them of the dangers of anesthesia or that it could have any negative impact on their child’s health. My jaw was on the floor. Why? Because ever since enteringthe mitochondrial community, there are 3 commonalities that I have seen in a strikingly LARGE percentage of mito patients: Adverse, idiopathic, unexplained, “weird” , unheard of reactions  to: 1) medications (including supplements), 2) vaccines, and 3) ANESTHESIA.

When I dig into the literature, I quickly find that I am not the only person to have made this observation, and I am very grateful for the individuals who have dedicated their careers to studying the impact of anesthesia on humans, especially those with mitochondrial disease. Below is a recap of some of my research and literature searches on how anesthesia impacts different groups of individuals including those with mitochondrial disease, those with autism, young children and all of us.

Children and Anesthesia

Anesthesia Research: Impact On Children And The Developing Brain

All of the anesthesia gases that are used (sevoflurane, isoflurane, desflurane, nitrous oxide), and common IV medicines like propofol and midazolam all cause injury in the neonatal animal models of the developing brain. Opioid medications such as morphine or fentanyl, and the newer sedative agent dexmedetomidine, have not been shown to cause this injury thus far, although more research is needed.

Use of anesthetic agents in neonates and young children.

 Animal studies suggest that neurodegeneration, with possible cognitive sequelae, is a potential long-term risk of anesthetics in neonatal and young pediatric patients. The existing nonclinical data implicate not only NMDA-receptor antagonists, but also drugs that potentiate gamma-aminobutyric acid signal transduction, as potentially neurotoxic to the developing brain. The potential for the combination of drugs that have activity at both receptor systems or that can induce more or less neurotoxicity is not clear; however, recent nonclinical data suggest that some combinations may be more neurotoxic than the individual components.

Mechanistic Insights into Neurotoxicity Induced by Anesthetics in the Developing Brain

Compelling evidence has shown that exposure to anesthetics used in the clinic can cause neurodegeneration in the mammalian developing brain, but the basis of this is not clear. Neurotoxicity induced by exposure to anesthestics in early life involves neuroapoptosis and impairment of neurodevelopmental processes such as neurogenesis, synaptogenesis and immature glial development. These effects may subsequently contribute to behavior abnormalities in later life.

Autism and Anesthesia

Thinking Out Loud- Anesthesia and Autism

I am the only co-founder of TMR whose child’s autism was triggered by anesthesia.    My son’s story mimics the all too familiar vaccine-injury stories which seem to be multiplying in droves.  The only difference?  His regression occurred after an elective surgery I will regret the rest of my life.

After learning about the chemical components of anesthesia and how they affect glutathione, methylation, and metabolic pathways, I feel strongly that our ASD community needs education and awareness on the topic.  Why?  Because many of our children will need surgery in their lifetimes.   Many of them will have to be put under for dental procedures.  Is there a way to navigate a necessary chemical exposure so as to minimize side-effects and potential regressions?  Watch as I discuss anesthesia and our ASD children with my hero, Sym Rankin.

Risk of Anesthesia Regression in Children with Autism Spectrum Disorder and Mitochondrial Dysfunction

Children with autism spectrum disorder (ASD) have a range of medical problems involving many organ systems. A subset of children with ASD hasve abnormal mitochondrial energy production and function that contributes to their physical, cognitive, and behavioral impairments. The presence of mitochondrial dysfunction increases the risk for potential damage to the brain, which is dependent on oxidative metabolism. This risk is more pronounced during procedures that require anesthesia. Because ASD children often undergo medical procedures (like endoscopies, adenoidectomies, tonsillectomies, and ear tube placement) requiring anesthesia, regression with anesthesia is of particular concern for the subset of children with ASD and mitochondrial dysfunction.

Anesthesia and Autistic Individuals

Recently published research supports the potential for problems.3 A retrospective study based on medical and school records from over 5,000 children born between 1976 and 1982 in Olmstead County, Minnesota, found that one exposure to anesthesia was not harmful. More than one, however, doubled the risk that a child would be identified as having a learning disability before the age of 19. That risk increased with a longer duration of the anesthetic. The exposures were between birth and four years of age: a very critical time of brain development.

The anesthetics primarily used in the procedures under review in the Olmsted County study were halothane and nitrous oxide. Halothane is a highly fat-soluble drug that is difficult for the liver to metabolize. Nitrous oxide can deactivate methionine synthase, which is a B12-dependent enzyme important in the methylation cycle. What we can learn from that study is that administering a fat-soluble toxin, followed by inhibition of DNA methylation, might result in “learning disabilities.” Although use of halothane and nitrous oxide is not as common as it used to be, it is not a great leap to hypothesize that use of similar chemicals and toxins might play a role in triggering or exacerbating manifestations of ASD.

As an anesthetic provider, I consider it part of my mission to help educate my colleagues and to help them understand that our children are sick – not just autistic. That is also my mission as a parent, as it is the mission of all parents.

Toxic Agents- Recap of Society for Pediatric Anesthesia Lecture

Dr. Maynes began his lecture by suggesting that anesthesiologists need to take a holistic look at how our interventions impact our patients’ physiology and metabolism. Focusing on the mitochondria as a mediator of cellular physiology, he reviewed its critical role in many cellular pathways including the cellular stress response, aging and neurodegenerative diseases, and the generation of reactive oxygen species as a non-pathologic signaling pathway.

He next noted that there are many different points in the electron transport chain where multiple anesthetic agents influence mitochondrial activity, while these drugs can impact mitochondrial integrity as well. For example, studies have shown that exposure to one MAC hour of isoflurane alters mitochondrial morphology, exposure to ketamine decreases mitochondrial biomass, isoflurane, propofol, ketamine, and midazolam can alter mitochondrial membrane polarization, and sevoflurane can affect mitochondrial fusion and induce protein misfolding.

In addition, various anesthetics can induce changes in mitochondrial DNA, and these changes in the mitochondrial genome can impact cell function as well. While opioids, in general, have less effect on mitochondrial function, Dr. Maynes pointed out that morphine is a specific inhibitor of isocitrate dehydrogenase (IDH-1), an enzyme involved in the conversion of isocitrate to alpha-ketoglutarate in the citric acid cycle. Importantly, mutations in IDH-1 affect DNA methylation, providing a potential link between the morphine we routinely administer and changes in DNA methylation, a finding not uncommon in various cancers.

Moving on, he reported that autism is the most prevalent secondary diagnosis in children undergoing an anesthetic at Sick Kids, while evidence of “atypical” mitochondrial deficiency is present in approximately 40% of children with autism, suggesting that this population of children may be particularly sensitive to our anesthetic agents.

MTHFR and Anesthesia

When Nitrous Oxide is No Laughing Matter

Nitrous oxide inhibits the activity of methionine synthetase, which converts homocysteine to methionine, raising homocysteine levels. It has been suggested that N2O be avoided in these patients. There has been a report of a fatal outcome in a patient with type III disease due to compound heterozygosity including a novel MTHFR mutation (1755 G→A), which was inherited in concert with two common MTHFR polymorphisms, both of which are associated with diminished enzyme activity.(11) This previously undiagnosed child had exposure to N2O twice within four days. Twenty-five days after the first exposure seizures and apnea developed, with hypotonia and areflexia.

Death was from a respiratory arrest on postoperative day 46. Presumably the N2O induced inhibition of methionine synthetase (see below) in addition to the genetic defect in tetrahydrofolate reductase and led to death secondary to methionine deficiency.

Adverse Effect of Nitrous Oxide in a Child with 5,10-Methylenetetrahydrofolate Reductase Deficiency

“patients with a diagnosis of severe MTHFR deficiency should not receive nitrous oxide as anesthesia. In the case of emergency procedures, patients whose clinical presentation fits that of severe MTHFR deficiency, even if the disorder has not been diagnosed, should also not receive nitrous oxide. In the case of elective procedures, patients whose clinical presentation fits that of severe MTHFR deficiency should be evaluated, and the diagnosis should be ruled out before anesthesia with nitrous oxide is contemplated.”

General anesthesia and methylenetetrahydrofolate reductase deficiency.

Methylenetetrahydrofolate reductase (MTHFR) deficiency is an autosomal recessive disorder with a spectrum of manifestations including neurological symptoms, premature arteriosclerosis, and venous and arterial thrombosis. Most patients are heterozygous for multiple MTHFR substitutions; small minorities are homozygous for mutations at this locus. Among these mutations, the C677T polymorphism is the most deleterious. Nitrous oxide use in anesthesia leads to significant increases in plasma homocysteine. We present a patient undergoing urgent surgery with a preoperative diagnosis of homozygous MTHFR deficiency.

Anesthesia and Your Genetics- Blog Talk Radio Show: Dr. Jess Armine

Nurse anesthetist, Sym Cusimano Rankin, RN, CRNA witnessed an alarming increase in chronic and autoimmune diseases; and as a mother, she has seen her son’s journey of recovery from autism. Autistic children often undergo medical and dental procedures requiring anesthesia. All anesthetic agents have relative risks and benefits. Special caution is warranted with agents that effect methylation and mitochondrial function

Mitochondrial Disease and Anesthesia

Anesthesia and Mitochondrial Cytopathies

An increased awareness is needed whenever a person with a mitochondrial cytopathy is contemplating or undergoing a surgical procedure. By virtue of the illness itself, there are greater risks involved with every medical intervention. The safest anesthetic is not known and the choice of anesthetic must be individualized to the patient’s particular needs. Although anesthetic agents may play a contributing factor in causing an adverse event associated with surgery, the illness, the stress of that illness, the surgical procedure and concurrent infections may play a larger role in causing neurologic deterioration.

Mitochondrial disorders and general anaesthesia: a case series and review

Meticulous individual assessment is important due to the diverse nature of mitochondrial disease and, as with any surgical case, careful attention to fluid management is essential. Preoperative fasting in this patient group may be particularly hazardous as they have a tendency to develop lactic acidosis which will be exacerbated by periods of metabolic stress such as that seen during surgical procedures and perioperative fasting. We recommend the routine, perioperative use of lactate free i.v. fluids in all patients with mitochondrial disease undergoing GA (such as 5% dextrose–0.9% saline). I.V. fluids should be commenced during the preoperative fasting period to allow maintenance of normoglycaemia, as excessive glycolytic oxidation of glucose in this patient group may increase plasma lactate levels.

As may be expected, those patients with more severe clinical disease seem to be at greater risk after GA and further work should be directed towards Leigh’s disease in particular, especially those with documented variable respiratory drive.

Mitoaction’s Webinar on Anesthesia

Anesthesia poses specific risks for children and adults with mitochondrial disease. Join  us this month with Dr. Andre Mattman from Vancouver General Hospital to learn more about risks, precautions and recommendations for anesthesia use in mitochondrial disease patients.

Anesthetic Considerations in Mitochondrial Disease- UMD

All clinical manifestations of MD, including seizures, arrhythmias, cardiac dysfunction, myopathy, and endocrinopathies, can be worsened by trauma, illness, or surgical stress. Although the prevalence of MD is high (Skladal et al 2003), the heterogeneity of disease phenotypes makes clinical trials difficult. No controlled trials of different anesthetic agents or techniques have been conducted in patients with MD. Adverse effects on mitochondrial function of many agents used in anesthesia have been documented in vitro, but there are few reports of adverse events in vivo. Even agents like propofol, for which adverse effects have been reported both in vitro and in vivo, have been used successfully in isolated cases. Thus, the theoretical effects of any agent need to be considered in the general context of any one patient’s medical history. It is important to realize that the absence of published reports of adverse effects with any given agent does not mean that the agent is safe to use but may simply reflect a publication bias.

Nitrous Oxide and Monkeys & Methionine: Pathogenesis of subacute combined degeneration: a result of methyl group deficiency.

Four pairs of monkeys were maintained in an atmosphere of nitrous oxide under conditions which had previously been shown to produce subacute combined degeneration (SCD) of the spinal cord. The diet of one of each pair was supplemented with methionine. In every case the monkey with the unsupplemented diet became ataxic at around 10 weeks and the disorder progressed over a period of 2-3 weeks until the animal was moribund. During this period there was no detectable clinical change in the monkeys receiving methionine supplementation. Microscopical examination of the spinal cord and peripheral nerves of the unsupplemented monkeys showed the classical changes of SCD. The histological changes correlated with the clinical observations. Sections form the methionine-supplemented monkeys showed no change or only slight changes. These results suggest that, in these animals, inability to resynthesise methionine from homocysteine leads to SCD. It seems probable that the primary lesion producing SCD in human beings with pernicious anaemia is also inability to maintain methionine biosynthesis.

I will end with another story from a mom. As parents we MUST become our child’s best advocate. NO ONE knows them better than we do, as their parents.

“My son went in to Children’s Hospital today for his tongue tie surgery. And wouldn’t you know it, he gets a surgeon from Europe who takes me aside to discuss him not being vaccinated. He says: “since he’s 2, and you chose not to vaccinate him, his immune system is very strong and he will be able to process the anesthesia so don’t worry mom, you did good.” There are doctors out there who know the truth and support us “whacko” parents. And he was right. My son flew through like a champ and within minutes of waking up, could walk completely steadily and had zero side effects of the anesthesia.”

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