Anesthesia & the Autistic Child by Sym C. Rankin, RN, CRNA

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BIOMEDICAL
ANESTHESIA
By Sym C. Rankin, RN, CRNA
Sym C. Rankin, RN, CRNA, is a graduate of the University of Southwestern Louisiana and the Charity Hospital School of Nurse Anesthesia (New Orleans). As a practicing anesthetist for over 25 years, she has witnessed an alarming increase in chronic and autoimmune diseases. Those observations became less academic and more personal after her son was diagnosed with autism. Her
The Autistic Child
son’s journey of recovery led to Sym’s realization that mainstream medicine is far more interested in merely treating symptoms than in asking the difficult questions of why those symptoms exist. She recently joined the practice at True Health Medical Center in Naperville, Illinois, and hopes that she can help other families on the same journey.
T
his article represents my educated observations as an experienced nurse anesthetist who also happens to be the mother of a child on the road to recovery from an autism spectrum disorder (ASD). I am also a practitioner taking care of autistic children, so I look at these issues from a different perspective than my anesthesia peers. The following observations suggest a need to take heed of certain issues that might have an impact on the delivery of anesthesia in individual cases and also suggests a need for rigorous study of the potential problems autistic individuals may have when undergoing anesthesia. As a practicing anesthetist for over 25 years, I have been in a position to observe trends in the patients I help treat. In recent years, I have seen an increase in children in the operating room for various procedures. A disproportionate number of those children have diagnosed developmental delays and behavioral problems in addition to their medical problems. There are no available statistics to quantify the numbers, but my anecdotal observations tell me that children need anesthesia in numbers that would have shocked us a decade or more ago.
The trends I have seen should come as no surprise because autism spectrum disorders have reached epidemic numbers, and autistic children tend to have health problems. I am seeing an increase in the number of these children needing radiological procedures such as an MRI or a CT scan as well as increasing numbers of autistic children for various ENT and dental procedures. I am not the only one who has observed these trends. Recently, my profession has begun to address the special considerations of autistic children and children with behavioral problems. They are called “difficult pediatric patients.”1 This is a new term in my profession; we didn’t need such a phrase 25 years ago when I started my career. A recent educational review article2 discussed anesthetic considerations for cerebral palsy patients, based primarily on their physical problems (e.g., risk for aspiration, difficulties positioning the patient, and interactions with anti-spastic and anti-epileptic medications). Autistic children, on the other hand, were primarily looked at from a behavioral standpoint (e.g., minimizing waiting time, providing quiet areas for pre- and post-operative
care, and involving parents). The typical anesthesia provider is aware of the behavioral problems in our children and will do anything to make the anesthetic experience as smooth as possible. Most anesthesia providers will have a preoperative telephone interview to discuss our children’s needs. They will minimize waiting times, provide quiet areas, and be very open to parental involvement. But that provider may not realize that he or she needs to look at the metabolic problems in autistic children and consider how those problems may affect anesthetic choice. Anesthesia providers generally are aware of the prevalence of diagnosed ADHD and the various drugs those children may be on. They understand that autistic children may also be on stimulant or antipsychotic drugs; therefore, they must regard specific, necessary anesthetic considerations. For example, when some of these drugs are combined with certain anesthetic drugs, an increase in central nervous system depression may result. Thus, the anesthesia provider knows to avoid or minimize use of the problematic agent. But the anesthesia provider who sees that as the only concern is missing something very important.
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Many parents tell me their child was different or regressed after an anesthetic. To those of us who have taken a hard look at the biochemical problems underlying our children’s autistic manifestations, those anecdotal reports should come as no surprise. An anesthetic may represent yet another toxic insult our children get exposed to. Therefore, we must help anesthesia providers understand the physical and biomedical problems our children have so that the providers may minimize the insults. Not surprisingly, part of the problem is the same mindset we see in the mainstream medical community at large. Mainstream physicians generally react to the physical problems of ASD children in the way their training taught them. Clinicians use pharmaceutical drugs to manage behaviors, without looking at what might be causing those behaviors. Because most anesthesia providers are very much part of the mainstream, they see only “autistic” behaviors, and they try to compensate for those behaviors by sedating the child. Such a provider does not understand the metabolic problems underlying those behaviors. So, they will default to protocols that may include drugs that might cause problems. It’s hard to blame the anesthesia community for its blindness, considering the lack of any professional guidance and resources. The Autism Research Institute (ARI) has two articles devoted to concerns with anesthesia on its Web site. The first 3 provides both a good general overview of anesthesia for parents and some general advice to anesthesia providers. Although the advice is accurate to a point, it fails to warn of specific problems autistic children may encounter with anesthetic drugs. The second ARI article addresses anesthesia for dental procedures 4 . The author states, “There are no data that any anesthetic drugs cause or worsen autism, nor are there any published data on
preferred drugs for anesthetizing autistic children.” Although it was true (at least when the article was written) that there were no studies directly examining the impact of anesthesia on children with ASD, there is published data that cautions about using particular agents with patients who have certain metabolic problems. Many of those metabolic problems are the same physical problems that, depending on one’s point of view, are underlying many autistic manifestations (or at least would be labeled comorbidities). Recently published research supports the potential for problems5. 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 exposure, 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 very 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, may result in “learning disabilities.” Although use of halothane and nitrous oxide is not as common as it used to be, it is not a terribly great leap to hypothesize that use of similar chemicals and toxins may play a role in triggering or exacerbating manifestations of ASD. All that being said, anesthesia is unavoidable for children who need to undergo surgical procedures. The goal in such cases is to minimize the risk. To do that, the anesthesia provider must be made aware of the unique problems your child has. In general, these are the things your anesthesiologist does not know:  Your child has a medical disease — not some mysterious mental disease that is solely genetic in origin.  Your child may have gastrointestinal dysfunction, immune system dysregulation, inflammation, mitochondrial dysfunction, heavy metal poisoning, oxidative stress, and chronic inflammation.  Most importantly, your child probably has impaired detoxification systems and may not be able to metabolize drugs efficiently. In basic terms, anesthesia consists of three distinct elements controlled by pharmaceutical agents:  Amnesia (i.e., the patient is asleep and remembers nothing);  Analgesia (i.e., the patient feels no pain); and  Muscle relaxation (i.e., the patient doesn’t move).
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An anesthetic may represent yet another toxic insult our children get exposed to. Therefore, we must help anesthesia providers understand the physical and biomedical problems our children have so that the providers may minimize the insults.
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BIOMEDICAL
There is no single agent to handle all three elements, so a combination of drugs must be used. The anesthesia provider titrates the drugs to effect a proper balance, taking into account the unique condition of the patient. (Indeed, because anesthesiologists and nurse anesthetists are used to taking unique biochemical factors into account for each patient, you may find it easier to discuss your child’s condition with them than you have with other mainstream physicians.) Anesthesia is generally administered through two methods: intravenous and mask induction of gas. For adult patients, an IV is started, and usually a sedative and/or narcotic is given as a premedication. Then an induction agent is given to put the patient to sleep. Propofol is often used as the induction agent. Then the airway is secured and an anesthetic gas is used to keep the patient asleep. Often a narcotic is added for pain relief. Sometimes using an intravenous catheter is possible for children, but more often that access is not easily obtained and an inhalation induction is used instead. A high flow rate is used for the gas, which is delivered through a mask on the child. After a few breaths, the child is asleep, IV access is able to be obtained, the airway is secured, and gas is used to maintain the anesthetic. When you meet with your anesthesiologist or nurse anesthetist, be prepared to discuss the methods of anesthesia delivery and the exact drugs he or she intends to use. Do not be afraid to ask questions about the nature of specific drugs and how they work in the body. Many of the drugs used in anesthesia should be considered relatively safe. For example, Versed® (a benzodiazepine used for sedation, amnesia, and anti-anxiety) and fentanyl (a potent narcotic) are relatively short-acting and are not heavily metabolized. Other drugs may present opportunities to make choices. Propofol, a short-acting agent, is administered intravenously and is used for induction and also for maintenance of a general anesthetic (i.e., keeping the patient asleep). It may be problematic for patients with an allergy to soy or eggs; it contains soybean oil and egg phospholipid. Concerns have
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Special attention must be paid to the use of nitrous oxide.
sedation in dental procedures. In addition, it is used on occasion as a carrier gas with sevoflurane in mask inductions. That is, nitrous oxide is utilized for a second-gas effect to increase the concentration of another inhaled anesthetic agent, thereby allowing the patient to get to sleep faster. In the last decade, various concerns have been raised about the use of nitrous oxide: inactivation of methionine synthase, increase of post-operative nausea, relatively poor amnesic properties, and even contribution to greenhouse gasses. Because of these concerns, nitrous oxide use in the operating room has dramatically declined in recent years and will likely approach zero in the coming years. That being said, nitrous oxide is still being used (especially in the dental setting) and may present specific problems for autistic children with common underlying conditions. Nitrous oxide depletes the B12/folate system. It deactivates methionine synthase, which is an enzyme that catalyzes the conversion of homocysteine and methyltetrahydrofolate to methionine and tetrahydrofolate. Such a deactivation in a patient with a defect in the MTHFR (methylenetetrahydrofolate reductase) gene, which is associated with diminished enzyme activity, could result in increased homocysteine levels, increased oxidative stress, and activated NMDA glutamate receptors. All of these could contribute to inflammation; additionally, nitrous oxide also may cause hematologic problems, neuropathy, and neurotoxic effects7. For years, the anesthetic community was told that nitrous oxide was the perfect anesthetic. Now we know better. A study published in 2003 discussed the effects of two subsequent nitrous oxide exposures, MTHFR mutation, and the fatal neurological outcome due to a methionine deficiency.8 In 2007, Dr. Victor Baum presented a paper at a pediatric anesthesiology meeting that made us all rethink using nitrous oxide as an anesthetic.9
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also been raised regarding a potential for propofol to exacerbate mitochondrial disease. Unfortunately, however, all general anesthetics have a tendency to inhibit mitochondrial function. Moreover, the documented difficulties noted with propofol stem from long-term use in the ICU setting, exceeding the exposure most patients would encounter6 . Under most circumstances, propofol can be safely used. But if there is a concern about its use, your provider may determine that inhalation induction may be appropriate using sevoflurane. Only two-to-five percent of sevoflurane is metabolized in the body, making it an excellent choice for many patients. (An older inhalant, halothane, is rarely used now because of its tendency to be heavily metabolized.) Sometimes the provider may want to use ketamine. It is a dissociative anesthetic; in essence, it is a hallucinogenic. It is usually used for sedation, especially for short procedures like changing dressings on burns. In children – especially so-called difficult pediatric patients – it may be used to make it easier to start an IV. Ketamine’s advantage is that it doesn’t depress respirations like other anesthetics might. It’s also easy to use; it can be given orally, intramuscularly, or intravenously. Typical side effects, however, include open eyes, nystagmus, increased salivation, and emergence delirium. Ketamine alters the patient’s sensory perception, which raises questions about its use for our children due to the sensory issues many autistic children have. Special attention must be paid to the use of nitrous oxide. It is one of the oldest anesthetics used today and is still used for
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Methylation is important for detoxification, myelin sheath formation, neurotransmitters and DNA synthesis. How can we help the anesthetic provider understand that this is one of the underlying problems that we see in autism? How can we help our anesthetic provider understand that some of our children have genetic mutations such as CBS (cystathionine beta synthase) and MTHFR, which will affect how they detoxify drugs? How can we help the providers understand that our children have increased oxidative stress and decreased methylation? How can we help them understand that most of our children have gut problems that interfere with the absorption of many vitamin co-factors needed for methlylation and detoxification? How do we help them realize that many developmentally delayed children have some type of mitochondrial dysfunction that may affect the provider’s choice of an anesthetic? How can we help them understand that many anesthetic drugs affect autonomic nervous system function and can have untoward effects in the autistic population? How can we help them realize that their choices in the operating room may have detrimental effects on our child when they return home? Unfortunately, most anesthesia providers have not seen any of the published research discussing biomedical problems in the autistic population. As with other medical disciplines, parents of autistic children have difficulty with the mainstream mindset when we try to explain our children’s problems to anesthesia providers. We can help educate our anesthetic providers about our children’s metabolic problems by referring them to studies, many of which are listed on the Autism Research Institute’s Web site10. The best starting point is Dr. Martha Herbert’s well-reasoned 2005 article titled
“Autism: A brain disorder or a disorder that affects the brain?” that clearly lays out the need to embrace a new paradigm in understanding autism11. In addition, the 2004 article by Dr. S. Jill James and her colleagues, “Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism,” clearly explains the methylation problems in autistic individuals that can lead to increased oxidative stress12 . These pathways were considered in other neurological diseases but never linked to autism before Dr. James’ work. This article also discusses the use of B12, folinic acid, and betaine to increase methylation and reverse the effects of oxidative stress. This is critical information for anesthesia providers. A recent article from 2008 by Dr. Richard Deth, et al. addresses the environmental and genetic factors that can lead to autism13. The article describes a “redox/methylation hypothesis of autism,” in which oxidative stress, initiated by environmental factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks. This article underscores the need to minimize oxidative stress that can result from anesthesia. The anesthetics that are commonly used may contribute to the toxic load, deplete B12, and affect methylation. Dr. Jon Poling’s paper published in 2006 on developmental regression and mitochondrial dysfunction in autism also helps to explain the overall impact anesthetic choice may have14 . The mitochondria represent the energy portion of our cells, and mitochondria are necessary for the Kreb’s cycle, fatty acid oxidation, metabolism of amino acids, and oxidative phosphorylation. The increased risk of certain anesthetics for patients with mitochondrial problems has been
widely reported in anesthesia journals, and Dr. Poling’s conclusions should be easily understood. Armed with better information, the anesthesia provider should be able to understand the metabolic problems our children have; in many respects, they are the same problems we see in the increasing population of chronically ill adults. What can you do as parents and professionals to help your anesthesia provider recognize your child’s unique problems? When your child is scheduled to undergo a procedure, consider discussing the following issues during the preoperative conference:  Ask not to use nitrous oxide. Most of our kids have a documented B12 deficiency.  Discuss specific medical and metabolic problems concerning your child. Tell your provider of any genetic, methylation, detoxification, and mitochondrial issues.  Consider placement of an IV without sedation. Many of our children undergo multiple blood draws and intravenous treatments. If your child can tolerate an IV placement, let your anesthesiologist know that because the provider usually will not expect children to tolerate this procedure.  Inform the anesthesia provider of all medications, supplements, and IgE allergies.  Make sure the provider understands that your child has difficulty detoxifying drugs.  Ask the provider to keep the anesthetic as simple as possible.  Discuss any other drugs that might be given in conjunction with the anesthetics (e.g., acetaminophen, steroids, and antiemetics). The most important thing to discuss with the providers is detoxification pathways. Let them know that your child may have a
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The most important thing to discuss with the providers is detoxification pathways. Let them know that your child may have a problem with glutathione production and have defects in the methlylation pathways. A child’s liver is not able to detox as much as an adult. The need is to “keep it simple.”
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BIOMEDICAL
their emotional state – just like anyone else, and it should be explained to them what is going to happen. The receptive language and intelligence of most autistic children is much higher than the general public thinks. Unfortunately, surgery is often necessary, and that involves an anesthetic to prevent the sympathetic system activation that a pain response elicits. It can be done safely by an informed anesthesia provider. As with any toxic exposure, we can limit the harm and increase detoxification pathways to encourage elimination. During administration of an anesthetic, the patient is given drugs that must be metabolized by the liver, using various enzymes systems to convert fat-soluble toxins into water soluble substances that can be excreted in the urine or the bile. At home, you can help that process, using the same liver detoxification protocols you may already be using.         Activated charcoal DMG, TMG, methyl B12, methylfolate Epsom salt baths Silymarin (milk thistle) Bentonite clay Antioxidants – vitamins A, C, E Magnesium Glutathione
References Schure, AY. Difficult pediatric patients: Anesthetic considerations for children with behavioral problems.” Current Reviews for Nurse Anesthetists, Vol. 31 (21) (Feb. 2009).
1 2 3
Ibid.
Kirz, L. Surgical anesthesia and autism. http://www.autism.com/families/life/kirz. htm.
4 Novak, RJ. Dental anesthesia for the autistic child. http://www.autism.com/ families/life/dental.htm. 5 Wilder, RT, Flick, RP, Sprung, J, et al. Early exposure to anesthesia and learning disabilities in a population-based cohort. Anesthesiology, April 2005; 110(4): 796-804. 6 Morgan, P. When Propofol is problematic. Presentation at 12th annual joint winter meeting of the Society of Pediatric Anesthesia and American Academy of Pediatrics. http://www.pedsanesthesia. org/meetings/2007winter/pdfs/MorganFriday1130-1150am.pdf. 7 See Selzer, RR, Rosenblatt, DS, Laxova, R, Hogan, K. Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. New England Journal of Medicine, July 2003; 349: 45–50. Kalikiri, PC, Sachan Gajraj Singh Sachan, R. Nitrous oxide induced elevation of plasma homocysteine and methylmalonic acid levels and their clinical implications. The Internet Journal of Anesthesiology, 2004; Vol. 8 (2). Baum, VC. When nitrous oxide is no laughing matter: Nitrous oxide and pediatric anesthesia. Paediatric Anaesthesia, Sept. 2007; 17(9):824-30. 8 9
problem with glutathione production and have defects in the methlylation pathways. A child’s liver is not able to detox as much as an adult. The need is to “keep it simple.” Instead of giving three different drugs at the same time for nausea, why not simply replace fluids to prevent dehydration, which is the major cause of post-operative nausea. A mother once asked advice about an upcoming procedure because of problems with a prior dental anesthetic. The child was given Versed®, ketamine, Decadron®, nitrous oxide and sevoflurane. The mother complained her son was “out of it” for two days after the procedure. We discussed the questions she should ask her anesthesia provider for the next procedure; as a result, the anesthetic was conducted with just Versed® and sevoflurane. The mother used homeopathics at home for the pain and swelling. Her child suffered no ill effects from the anesthetic. Anesthesia can be done successfully in a very simple way. When a neurotypical child goes to the dentist, does he or she get all of the drugs that many providers seem to feel are necessary for our ASD children? That is the problem with the way children on the spectrum are treated. Too many anesthesia providers are more concerned with behavioral issues than they are with the underlying physical condition. Instead of heavily sedating autistic children, the providers should consider using fewer drugs, adjusting the dosages to achieve the desired effect. ASD children, in essence, should be approached in the same manner that an anesthesia provider approaches hepatic- and renal-impaired patients. In addition to this higher degree of respect for their medical condition, our children should be treated with respect for
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Most anesthesiologists and nurse anesthetists want to make the anesthetic experience go as smoothly as possible. After all, it is their job to make the patient feel good. 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, and it is likewise the mission of all parents.
Selzer, et al, supra. Baum, VC, supra. http://www.autism.com/
10 11
Herbert MR. Autism: A brain disorder or a disorder that affects the brain? Clinical Neuropsychiatry, 2005; 2(6):354-79.
12 James SJ, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr, Dec. 2004; 80(6):1611-7.
SELECTED COMMON ANESTHESIA DRUG NAMES
GENERIC fentanyl halothane ketamine midazolam sevoflurane BRAND Sublimaze® Fluothane® Ketalar® Versed® Ultane®
Deth, R, Muratore, C, Benzecry J, PowerCharnitsky, VA, Waly, M. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. Neurotoxicology, Jan. 2008;29(1):190-201.
13 14
Poling, JS, Frye, RE, Shoffner, J, Zimmerman, AW. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol, Feb. 2006; 21(2):170-2.
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