The purpose of this article is to highlight the medical issues surrounding anesthesia and autism so parents are better informed prior to their child having a procedure that requires it.
In addition, parents need to be aware that some children have regressed into autism after undergoing anesthesia or sedation.
Procedures such as endoscopies, colonoscopies and ear tube placement are all common medical procedures that require anesthesia or sedation.
It is important to know the associated risks before anesthesia and or sedation is selected and before the procedure takes place.
This is important because there is very little knowledge in the general medical community about the link between mitochondrial disease, autism and anesthesia/sedation risks.
Some children have an undiagnosed mitochondrial disorder which impairs energy production and makes anesthesia selection, procedures and precautions even more critical.
With anesthesia there are always some associated risks and even being cautious, there is no guarantee that the procedure will not have complications.
Becoming better informed and advocating for the careful selection of anesthesia and sedation in you child with your chosen anesthesiologist will reduce the likelihood of problems for your child.
Potential Anesthesia Complications
What complications are sometimes seen in children following anesthesia and sedation?
For many children, anesthesia and sedation present no complications.
However, for some children, anesthesia comes with significant adverse reactions such as:
- Complete regression into autism
- Great difficulty coming out of the anesthesia
- Exceeding a normal time frame for “recovery”
- Developmental regressions: The loss of developmental skills such as:
- Expressive and receptive language
- Gross motor skills
- Fine motor skills
- Cognitive skills
- Overall neurological deterioration (skill loss may be permanent in some children)
- Excessive fatigue and reduced energy levels following anesthesia or sedation (for days, weeks, or ongoing)
- Exacerbation or revelation of mitochondrial dysfunction
- Death, in the most extreme cases
For some children, the effects of anesthesia are catastrophic because they may lose years of language and developmental gains after anesthesia and sedation in a massive developmental regression.
Risk Factors for Anesthesia Complications
A few of the risk factors for adverse reactions from anesthesia are:
- A history of seizures
- Autism or other neurodevelopmental disorder such as ADD/ADHD, learning disabilities or Sensory Processing Disorder
- Preoperative respiratory problems
- Poor clinical condition of the patient prior to the procedure
- Undiagnosed or diagnosed mitochondrial dysfunction (disorder of energy production) such as mitochondrial oxidative phosphorylation (OXPHOS)
- MTHFR genetic defect
Testing Checklist Before Anesthesia Administration
The following testing should be considered by your physician prior to giving anesthesia to a child:
- Check for MTHFR mutations/deficiency
- Check homocysteine level
- Check serum B12 status
- Check methylmalonic acid assays (especially if the child is suspected to be B12 deficient)
- Check fasting glucose levels to make sure there are not problems with glucose metabolism
- Check a child’s lactate levels (on a morning fast, without a tourniquet, in a free-flowing venipuncture)
Dr. Richard Kelly, a well known geneticist from the Kennedy Krieger Institute, who is also knowledgeable about autism, has stated that the following labs should be completed prior to anesthesia (in children with known mitochondrial disease) to reduce the risk of complication during and after anesthesia and sedation.
“Prior to the anesthesia, the patient should have a complete physical examination and laboratory testing pertinent to known and potential medical problems.
Baseline laboratory testing at the time of admission or in the previous week for outpatient procedures should include:
- Comprehensive metabolic profile
- CBC with differential
- Creatine kinase
There is increasing evidence that a large number of children with autism have underlying mitochondrial myopathies, also known as respiratory chain disorders or disorders of energy production.
Leading experts in the field of mitochondrial medicine – Bruce Cohen MD, John Soffner MD, and Glenn DeBoer MD – made the following recommendations for patients with mitochondrial disease:
- Strict attention should be made to respiratory function before, during and after surgery, especially in patients with abnormal preoperative respiratory signs and symptoms. Vigorous respiratory physiotherapy should be standard postoperative care in patients with pulmonary difficulties. Early use of ventilation, maintaining normal oxygenation, Co2 elimination and vigorous respiratory physiotherapy should be standard preoperative care in any patient with pulmonary difficulties.
- There should be a heightened level of suspicion for infection such as pneumonia, which should be promptly treated.
- Lactated Ringer’s solution (also known as Ringer’s lactate) should be avoided as an intravenous fluid during the procedure, as it contains lactic acid (and these children generally have elevated blood lactate levels).
- Normal blood glucose, body temperature, and acid-based balance should be maintained during surgery. Low blood glucose should be avoided. However, a high blood glucose may indicate an acute disturbance in pyruvate metabolism or oxidative phosphorylation. In this situation, lactic acid levels may be elevated.
- Avoid depolarizing muscle relaxants (such as succinylcholine) although these have been safely used in many patients with mitochondrial diseases.
- Anesthesia with combinations of barbiturates, narcotics, benzodiazepines, and nitrous oxide also pose a theoretical risk for patients with disorders of OXPHOS.This risk should be considered only as a potential risk unless a patient has experienced a bad reaction to any of the medications.The apparent paradox between the two methods of general anesthesia must be addressed with each patient, and the anesthesiologist must determine what is the safest route.
- Animal studies indicate that propofol, an intravenous anesthetic, impairs mitochondrial function to a greater degree than other anesthetics. However, this drug has been used safely as an anesthetic in many patients with mitochondrial cytopathies. There have been observations that prolonged continuous use (days) at high dosages to treat frequent seizures cause as syndrome similar to mitochondrial failure, and therefore prolonged use in a patient with mitochondrial cytopathies may not be safe.
- Delay elective surgery if there is any evidence of infection. Potent inhalational anesthetic agents appear to be safe in the majority of patients with mitochondrial disease. In patients at risk for MH (malignant hypothermia), such as those patients with myopathies that are often associated with their mitochondrial disease, the risks and alternative methods of anesthesia must be considered by the physician. Certainly if there has been a previous adverse reaction in the patient or family member, these agents should be avoided.”
Nitrous Oxide and MTHFR
Many children have an undiagnosed MTHFR defect, making nitrous oxide a poor choice.
“On the strength of the current findings, we believe that 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.”
Homocysteine and Methylmalonic Acid
“Blood homocysteine assays by High Performance Liquid Chromatography (HPLC) should be considered before using nitrous oxide as anesthesia in patients with a personal or family history of cardiovascular disease, but in whom the well-established risk factors for cardiovascular disease such as smoking, high blood cholesterol, high blood pressure, diabetes, physical inactivity and obesity do not exist.
If these patients show elevated homocysteine levels, further work up for the etiology of elevated homocysteine levels should be done before using nitrous oxide as anesthesia.
In patients with B vitamin complex (B6, B12 and folate) deficiency as the cause of elevated homocysteine levels, a one-week course of oral B vitamins can prevent the postoperative increase in homocysteine from nitrous oxide.”
Pramood C. Kalikiri, MD and Reena Sachan Garjraj Singh Sachan MD continued on to report:
“Patients with suspected B12 deficiency (megaloblastic anemia and neurological dysfunction) should undergo serum B12 and methylmalonic acid assays before using nitrous oxide as anesthesia to prevent postoperative morbidity and mortality due to myocardial ischemia and neurological deterioration resulting from elevated plasma homocysteine and methylmalonic acid levels respectively.
If B12 deficiency is diagnosed, the patient should receive a one-week course of B vitamins before using nitrous oxide to prevent postoperative complications such as myocardial ischemia and neurological dysfunction.”
What to Discuss with Your Child’s Anesthesiologist
In a presentation at the Autism One Conference in May 2009, Sonja Hintz, RN, BSN and Sym Rankin CRNA, APRN from True Health Medical Center in Naperville, Illinois (where they worked with Anju Usman MD) discussed the risk of anesthesia in children with autism and proposed the following:
Prior to the procedure, discuss the following with the anesthesiologist:
- Ask not to use nitrous oxide. Many children with autism have a vitamin B12 deficiency, and nitrous oxide depletes levels of B12.
- Consider placement of an IV without sedation (midazolam (Versed) or other)
- Inform the anesthesiologist of all medications and supplements your child is taking at the time of the procedure
- Make the anesthesiologist aware of IgE allergies
- Make the anesthesiologist aware that your child has difficulty detoxing
- Discuss any other drugs that might also be given during the procedure
How should a parent best advocate for their child prior to a procedure requiring anesthesia and sedation?
- Know what type of anesthesia and sedation your child is getting prior to the procedure
- Get some lab work done in advance on your child (see above list)
- Communicate your concerns to the doctor and anesthesiologist clearly and in writing prior to the procedure.
- Share this page with your doctor and anesthesiologist prior to the procedure.
- Make sure your child’s doctors fully understand the complex issues surrounding children with autism, undiagnosed mitochondrial disease and anesthesia and sedation selection in this patient population.
Precautions to Consider Before Anesthesia
As discussed above, it is imperative that you know your child’s MTHFR status beforehand, as it can affect the response to anesthesia or sedation. To this end:
- Work with a naturopath or functional-medicine doctor to determine if any methylated B vitamins such as vitamins B6, B12 and/or folate should be given one week prior to the procedure.
- Make sure your child is well hydrated (with water) prior to the procedure
- Minimize the length of the fast required before the procedure
- Request that your child be the first procedure of the day
See Dr. Kelly’s article for further information on fasting prior to the procedure and discuss this with your child’s physician and anesthesiologist.
Considerations After Anesthesia
Work with a naturopath or functional-medicine doctor to detoxify your child from the anesthesia, which may take months or longer to clear from your child’s body.
Discuss the following potential detoxifiers:
- Activated charcoal
- DMG, TMG, methyl B12, methylfolate
- Epsom salt baths
- Silymarin (milk thistle)
- Bentonite clay
- Antioxidants such as vitamins A, C and E
- Reduced glutathione
Effects of Anesthetic Agents on Mitochondrial Function
Many types of anesthesia have often been found to have a negative effect on people with mitochondrial dysfunction, which is why it is important to determine if your child may have it before undergoing anesthesia or sedation.
This is likely caused by inhibition of metabolism by anesthetics.
- Barbiturates: Inhibit Complex I activity at high levels
- Benzodiazepines: Inhibit adenosine nucleotide translocase
- Propofol and/or lipid carrier: Inhibits mitochondrial function
- Halothane: Increased risk for heart rhythm disturbances
- Nitrous oxide (N2O): Neurotoxic, possibly by increasing nitric oxide production, which inhibits cis-acotinase and iron-containing electron transport enzymes; affecting energy production
- Non-depolarizing agents: Increased sensitivity to the paralytic effects and prolonged responses reported
- Local anesthetics: Bupivacaine uncouples oxidation and phosphorylation
Some of the precautions taken in mitochondrial patients should also be considered in children with autism when anesthesia is selected because some children with autism share problems with energy production just like children with diagnosed mitochondrial myopathies.
Both groups may have elevated blood lactate, glucose metabolism issues, trunk muscle weakness, and respiratory problems.
Mitochondrial Oxidative Phosphorylation (OXPHOS)
A lot of recent research has emerged suggesting that many children with autism may actually have an underlying mitochondrial myopathy known as mitochondrial oxidative phosphorylation (OXPHOS).
In a population-based survey of school age children with autism, 7% of those who were fully tested met criteria for definite mitochondrial respiratory chain disorders and were also clinically indistinguishable from other children with autism.
In 2008, at the American Academy of Neurology’s 60th Annual Meeting, the following data was presented.
“A retrospective analysis of 41 children with autism who were being evaluated for suspected mitochondrial disease showed that 32 (78%) had defects in skeletal muscle oxidative phosphorylation (OXPHOS) enzyme function and 29 of 39 (74%) harbored abnormalities in the OXPHOS proteins.”
This emerging research suggests that mitochondrial disorders are extremely prevalent among children with autism which makes them “at risk” for anesthesia complications, like other children who have confirmed of clinically diagnosed mitochondrial disease.
What this indicates is that many children with autism actually have underlying disorders of mitochondrial oxidative phosphorylation, due to mitochondrial disease, but remain essentially “undiagnosed”.
Children that have a diagnosis of a definitive mitochondrial myopathy are aware of the risks involved in procedures requiring anesthesia and the following precautions are taken with these children when using anesthesia and sedation.
Complex I Subunit Ilambda Impairment
To what extent a child has a reduction in Complex I enzyme function (within sub-unit Ilambda) appears to translate to a patient’s surgery and anesthesia response.
What this research group has discovered is that a typical functional dose of anesthesia may be too high a dose if sub-Complex I Ilambda isn’t working correctly in a patient and they further hypothesis that this may be what is responsible for hypersensitivity to anesthesia in some patients resulting in subsequent poor anesthesia response.
This is important research as it will help provide more information about the inner workings of mitochondria and what is actually happening when a child has an adverse reaction to anesthesia and sedation.
Why do some children with autism experience terrible and irreversible adverse reactions to anesthesia while others do not?
Could it be that some children with autism actually have reduced mitochondrial function within sub unit Ilambda within Complex I?
Malignant Hyprethermia (MH) Precautions
Acknowledge the potential for problems in patients with muscle disease, those with a past history or a family history of malignant hypothermia.
Avoid depolarizing drugs such as succinylcholine; and use non-depolarizing agents such as pancuronium instead.
Avoid the potent inhalational agents such as halothane and enthrone. Use agents such as nitrous oxide, barbiturates, benzodiazepines, andnarcotics.
Preparations for MH
Have adequate amounts of Dantrolene available and use it as soon as the first signs of MH occur.
“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 neurological deterioration.”
Still Looking for Answers?
Visit the Epidemic Answers Provider Directory to find a practitioner near you.
Baum, V.C. When Nitrous Oxide is no laughing matter: Nitrous oxide and pediatric anesthesia. Pediatric Anesthesia. 2007(17)9:824-830.
Breuer, M.E., et al. The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases. Neurobiology of Disease. Mar 2012(51).
Carreras, M.A., et al. Mitochondrial Function and Nitric Oxide Utilization. Biological Research. 2000(33)2.
Cassels, C. Mitochondrial Dysfunction May Play a Role in Autistic Spectrum Disorders Etiology. Medscape Medical News. 15 Apr 2008.
Cohen, B.H., et al. Anesthesia and Mitochondrial Cytopathies. United Mitochondrial Disease Foundation. 1998.
Davi, A. Has Your Child with Autistic Symptoms Been Properly Screened for a Subset of Mitochondrial Disease Known as OXPHOS?…Probably Not. The Autism File. 2010(36).
Falk, M.J., et al. Subcomplex Ilambda specifically controls integrated mitochondrial functions in Caenorhabditis elegans. PLoS One. 2009 Aug 12;4(8).
Gordon, T.R., et al. Anesthetic Management of a Child With Unspecified Mitochondrial Disease in an Outpatient Dental Setting. 31 Dec 2016, 64(1):33-38.
Hintz, S., et al. How to Get Your Mainstream Physician To See Beyond Autism. Autism One Conference. 2009.
Jeffrey, S., et al. Video Highlights From the American Academy of Neurology 60th Annual Meeting. American Academy of Neurology (AAN) 60th Annual Meeting. April 12-19, 2008.
Kalikiri, P.C., et al (2004) Nitrous Oxide Induced Elevations of Plasma Homocysteine and Methylmalonic Acid Levels and Their Implications. The Internet Journal of Anesthesiology. 2004(8)2.
Kayser, E.B., et al. Mitochondrial Complex I Function Affects Halothane Sensitivity in Caenorhabditis Elegans. Anesthesiology. Aug 2004. 101:365-372.
Kelly, R. Information for Anesthesiologists and Surgeons for Operative and Preoperative Care of Patients with Mitochondrial Disease. Kennedy Krieger Institute. 2009.
Li, Y., et al. Association between MTHFR C677T/A1298C and susceptibility to autism spectrum disorders: a meta-analysis. BMC Pediatrics. 2020(20)449.
Morgan, P.G. When Propofol is Problematic. Society of Pediatric Anesthesia.
Morgan, P.G., et al. Mitochondrial Defects and Anesthetic Sensitivity. Anesthesiology. 2002 May; 96(5)1268-1270.
Niezgoda, J., et al. Anesthetic Considerations in Patients with Mitochondrial Defects. Paediatr Anaesth. 2013 Sep; 23(9): 785–793.
Oliveira G, et al. Mitochondrial Dysfunction in Autism Spectrum Disorders: A Population-Based Study. Developmental Medicine and Child Neurology. 2005 Mar. 47(3)185-189.
Rankin, S.C. Anesthesia & ASD. The Autism File. 2009.
Selzer, R.R., et al. Adverse Effects of Nitrous Oxide in a Child with 5, 10-Methylenetetrahydrofolate Reductase Deficiency. New England Journal of Medicine. 03 Jul 2003. 349:45-50.
Weissman, J.R., et al. Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis. PLoS ONE. 2008 Nov 26. 3(11):e3815.