Looking at anesthetic neurotoxicity in pediatric sedation

In 2016 and 2017, the US Food and Drug Administration (FDA) issued a warning and subsequent labeling change for anesthetic drugs with concerns that repeated or lengthy use of sedation and general anesthesia in children aged younger than 3 years may impact brain development.¹ Although not calling for delay of medically necessary procedures, the FDA did state that healthcare providers should consider delaying elective procedures when medically appropriate.

Prior to the late 1980s, the concept of neonatal pain during procedures was not acknowledged and thought to be a behavioral reflex rather than a conscious experience of pain. However, multiple studies subsequently demonstrated neonates did respond to painful stimuli and that these stimuli could be managed. Further failure to manage pain can lead to both short- and long-term complications.² These warnings need to be considered within that context.

This article will review both animal and human studies so that pediatricians can have informed discussion with parents and caregivers whose children may be faced with procedures requiring sedation or general anesthesia.

What’s the concern?

Multiple animal studies have demonstrated significant long-term and possible permanent damage to the developing brain in the areas of behavior, learning, and memory following administration of anesthetic agents. Pathophysiologic mechanisms for the neurodevelopmental effects include increased apoptosis of neurons, glia, and oligodendrocytes; impaired neurogenesis; synaptic and axonal dysgenesis; perturbed neurotrophic signaling; mitochondrial dysfunction; and neuroinflammation.³

Specific agents in rodent models

TRIPLE COCKTAIL OF ANESTHESIA

A 2003 study administering midazolam, isoflurane, and nitrous oxide (a triple cocktail commonly used in pediatric anesthesia) to 7-day old rat pups demonstrated apoptotic neurodegeneration and deficits in hippocampal synaptic function following 6 hours of anesthesia. The baby rats demonstrated immediate, persistent, and ongoing deficits in learning, working memory, and reference memory as evidenced by performance in several different maze activities.⁴ In animal studies, there appears to be a direct correlation with time under anesthesia and abnormalities seen in the brain.⁵

LAUGHING GAS/NITROUS OXIDE/XENON

Several studies have demonstrated that xenon, nitrous oxide, or midazolam administered alone were not associated with neurodegeneration. Administered with other agents, xenon or nitrous oxide may also attenuate the impact of other anesthetics. A 2007 study showed nitrous oxide or xenon alone did not cause cell death and that xenon reduced isoflurane-induced cell death.⁶ Other rodent studies have demonstrated similar results with xenon and nitrous oxide attenuating neurodegeneration and hypoxia making it worse.^6,7

Jevtovic-Todorovic’s 2003 study examined both single exposures as well as continuous infusion of anesthetic agents and found that rat pups suffered no immediate or long-term neurodegeneration with administration of nitrous oxide or midazolam alone, but combination with isoflurane was associated with increased cell death and neurodegeneration.⁴ Other studies have found conflicting results with only administration of midazolam but that the administration of melatonin prior to anesthesia has an attenuating effect on neurodegeneration.^8,9

Specific agents in nonhuman primates

KETAMINE

Given that outcomes in rats may not truly represent outcomes in humans, studies have also been performed in primates. A 2012 study administered intravenous ketamine for 5 hours to rhesus neonates (day 6 of life) or to pregnant rhesus females at 120 days’ gestation (full-term is 165 days). Pregnant rhesus females were delivered via cesarean delivery 3 hours following infusion. Both fetal and neonatal brains exposed to ketamine experienced significantly more brain apoptosis compared with controls. Fetal exposure led to 2.2 times more neurodegeneration compared with neonatal exposure.10 Other rhesus monkey studies with ketamine also have demonstrated neurodegeneration and poor long-term outcomes.^11,12

PROPOFOL

Because common anesthetics such as ketamine and isoflurane demonstrated neurodegeneration, other investigators examined other anesthetic agents in nonhuman primates. Propofol anesthesia was delivered to fetal rhesus macaques at gestational age 120 days, or rhesus neonates using the same protocol as described above. Compared with isoflurane, propofol infusion for 5 hours led to less neurodegeneration in both fetal rhesus macaques and rhesus neonates. Unlike ketamine exposure, neurodegeneration was similar in both fetal and neonatal rhesus monkeys.¹³

Takeaways for pediatricians

Although it’s clear that administration of anesthetics leads to neurodegeneration in rats and primates, children receive lower doses (in terms of mg/kg) and are generally exposed for much shorter durations of time, and the animals were not undergoing a painful surgical procedure. Similarly, these experimental studies did not monitor the animals as closely as a child undergoing surgery would be monitored.

There is also the question of whether adverse developmental outcomes in rats are similar, meaningful, and equivalent to poor developmental outcomes in children. However, better-controlled studies in progressively larger animals (sheep, pigs, monkeys) did not account for all the developmental issues seen post-anesthesia.¹⁴ As a result, the pediatrician needs to acknowledge preclinical data indicating the possibility that anesthesia may be neurotoxic and potentially damaging to pediatric development.¹³

Human data

A variety of studies have attempted to examine neurotoxicity in children following anesthesia.

RAINE STUDY

The Western Australian Pregnancy Cohort (Raine) study was originally designed to examine the effects of prenatal ultrasound on 2608 infants born between 1989 and 1992.¹⁵ Detailed demographics and medical history were collected prenatally and included assessments at ages 1, 2, 3, 5, 8, 10, 13, and 16 years. In this group, 321 children were exposed to anesthesia before age 3 years and 2287 children were unexposed.

NEUROPSYCHOLOGIC AND FUNCTIONAL TESTING at the 10-year follow-up visit was the primary outcome for this study and utilized validated and reliable tests:¹⁵

·      Cognition: Symbol Digit Modality Test (SDMT); Raven’s Colored Progressive Matrices (CPM)

·      Language: Clinical Evaluation of Language Fundamentals (CELF); Peabody Picture Vocabulary Test (PPVT)

·      Gross/Fine Motor Function: McCarron Assessment of Neuromuscular Development (MAND)

·      Behavioral problems: Child Behavior Checklist (CBCL)

Anesthesia was associated with significantly worse scores in tests of receptive, expressive, total language  cognition, and abstract reasoning measured by CPM. Differences were not seen between exposed and unexposed children in behavior and motor function domains. After adjusting for confounders, anesthesia before age 3 years was associated with increased risk of disability in receptive language (CELF), expressive language (CELF), total language (CELF) and abstract reasoning (CPM).

MASK STUDY

The Mayo Anesthesia Safety in Kids (MASK) study¹⁶ examined whether (unexposed, singly exposed, and multiply exposed children born in Olmsted County, Minnesota, from 1994 to 2007) children requiring general anesthesia before age 3 years suffered adverse neurodevelopment outcomes. In the cohort, 997 children underwent neuropsychologic testing (full-scale intelligence quotient [IQ] standard score of the Wechsler Abbreviated Scale of Intelligence) at ages 8 to 12 years or 15 to 20 years. Results demonstrated the IQ did not vary significantly across groups. However, processing speed and fine motor abilities did vary significantly in the multiply exposed compared with singly exposed children. Parents of multiply exposed children also reported more problems with behavior and reading. It is important to note that all the differences seen were secondary outcomes and should be interpreted with caution.

Interestingly, one of the tests administered to rhesus monkeys, the Operant Test Battery (OTB), can be and was also administered to children in the MASK study. The OTB examines aspects of learning, motivation, impulse control, and short-term memory. Children exposed to general anesthesia did not experience similar deficits on OTB tasks that were previously observed in nonhuman primates.¹⁷

PANDA STUDY

The Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study¹⁸ looked at 105 sibling pairs born within 3 years of each other with one of the children undergoing inguinal hernia repair under general anesthesia before age 3 years and the other not having any anesthesia exposure before age 3 years. The goal was to determine if a single anesthesia exposure before age 3 years in otherwise healthy children was associated with impaired neurocognitive development and abnormal behavior between ages 8 to 15 years. Children prospectively underwent a neurocognitive and behavior battery that included measures of IQ; expressive and receptive language; verbal reasoning; memory; attention; executive function; motor skills; academic skills; adaptive skills; and parental rating.

Clinical data from the surgical procedure and anesthesia were retrospectively abstracted from hospital records. Mean duration of anesthesia was 84 minutes with a range of 20 to 240 minutes. Mean age of IQ testing was 10.6 for children receiving anesthesia and 10.9 for those not. The IQ scores were not statistically or clinically different between the 2 groups (difference, 0.2 IQ points).¹⁸ Similarly, there were no significant differences in the secondary outcomes of mean scores of memory, attention, visuospatial function, executive function, language, motor and processing speed, or behavior.

It is important to note that this study utilized similar comprehensive neuropsychologic assessments and did not find similar secondary outcomes as the MASK study did.¹⁶ Thus, among healthy children undergoing a single anesthesia expo- sure before age 3 years, significant neurodevelopment differences were not seen.

GAS TRIAL

The General Anesthesia Study (GAS) trial¹⁹ is the only completed randomized controlled trial (RCT) of anesthesia-induced neurotoxicity.¹⁴ This international open-label trial randomized 772 children aged younger than 5 years undergoing inguinal herniorrhaphy to either an awake-regional anesthesia group or to a sevoflurane-based general anesthesia group in a 1:1 fashion. The primary outcome measure was full-scale IQ (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III), and assessors were blinded to treatment arm. Secondary outcomes at age 2 years included cognitive scores on the Bayley Scales of Infant and Toddler Development and various measures of language, memory, attention, executive function, motor skills, academic skills, adaptive skills, and parental ratings at age 5 years.¹⁴ Median duration of anesthesia was 54 minutes with an average of less than 34 minutes. Mean FSIQ were equivalent for the awake-regional anesthesia group and the sevoflurane-based general anesthesia group. Likewise, differences in secondary outcomes were not clinically significant.

Certain groups experience higher risk

Certain medical, socioeconomic, or psychosocial comorbidities may confer higher risk and may not be easily studied. Children with congenital heart disease will often experience significantly more exposure to anesthesia than described in the MASK, PANDA, and GAS studies. It is not feasible to perform a GAS-like RCT in these groups. As a result, less rigorous observational and nonrandomized designs will be implemented and the results are subject to bias and residual confounding. However, several such studies of cardiac patients have shown inverse associations in children’s IQ scores at age 4 to 5 years.²⁰ Importantly some of the studies in congenital heart patients have not shown adverse outcomes for several years identifying the importance of long-term follow-up.²¹

Conclusions

Whereas animal and retrospective studies demonstrating possible neurotoxic and developmental impacts following anesthesia should concern the pediatrician, data from the MASK, PANDA, and GAS studies provide strong evidence that a one-hour or less single exposure to general anesthesia is not associated with an increased risk of neurodevelopmental deficit in later childhood.¹⁴ Given that more than half of all pediatric procedures in children aged younger than 3 years last less than one hour should also be reassuring.¹³

However, there are many practical questions that remain unanswered: Is it better to have all planned procedures for an individual patient coordinated under one anesthetic procedure/exposure or should the procedures for a given individual be separated as several short anesthetic exposures? There is no good answer to this question as it has not been addressed in animal or human studies. Similarly, recommendations for particular mixtures of anesthetic agents are not possible based on the current state of knowledge.

The pediatrician needs to be aware of ongoing research and development so that he or she can be aware and recommend adjuvants in development that might prevent anesthesia-associated neurotoxicity; report findings to the FDA that may be related to anesthetic exposure; and have appropriate discussions with patients’ parents and caregivers regarding anesthesia.

References:

1. US Food and Drug Administration. FDA Drug Safety Communication: FDA approves label changes for use of general anesthetic and sedation drugs in young children. Available at: https://www.fda.gov/drugs/drug-safety-andavailability/fda-drug-safety-communication-fda-approves-label-changes-use-general-anesthetic-and-sedation-drugs. Updated April 27, 2017. Accessed September 4, 2019.

2. Hall RW, Anand KJ. Pain management in newborns. Clin Perinatol. 2014;41(4):895-924.

3. Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci. 2016;17(11):705-717.

4. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876-882.

5. Wise-Faberowski L, Zhang H, Ing R, Pearlstein RD, Warner DS. Isoflurane-induced neuronal degeneration: an evaluation in organotypic hippocampal slice cultures. Anesth Analg. 2005;101(3):651-657, table of contents.

6. Ma D, Williamson P, Januszewski A, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology. 2007;106(4):746-753.

7. Shu Y, Patel SM, Pac-Soo C, et al. Xenon pretreatment attenuates anesthetic-induced apoptosis in the developing brain in comparison with nitrous oxide and hypoxia. Anesthesiology, 2010;113(2):360-368.

8. Yon JH, Carter LB, Reiter RJ, Jevtovic-Todorovic V. Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis. 2006;21(3):522-530.

9. Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol. 2005;146(2):189-197.

10. Brambrink AM, Evers AS, Avidan MS, et al. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology. 2012; 116(2):372-384.

11. Paule MG, Li M, Allen RR, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33(2):220-230.

12. Slikker W Jr, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci. 2007;98(1):145-158.

13. Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink A. Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth. 2013; 110 suppl 1:i29-i38.

14. Bellinger DC, Calderon J. Neurotoxicity of general anesthetics in children: evidence and uncertainties. Curr Opin Pediatr. 2019;31(2):267-273.

15. Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130)3):e476-e485.

16. Warner DO, Zaccariello MJ, Katusic SK, et al. Neuropsychological and behavioral outcomes after exposure of young children to procedures requiring general anesthesia: the Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology. 2018;129(1):89-105.

17. Warner DO, Chelonis JJ, Paule MG, et al. Performance on the Operant Test Battery in young children exposed to procedures requiring general anaesthesia: the MASK study. Br J Anaesth. 2019;122(4):470-479.

18. Sun LS, Li G, Miller TL, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA. 2016;315(21):2312-2320.

19. McCann ME, de Graaff JC, Dorris L, et al; GAS Consortium. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019;393(10172):664-677.

20. Diaz LK, Gaynor JW, Koh SJ, et al. Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. 2016;152(2):482-489.

21. Guerra GG, Robertson CM, Alton GY, et al: Western Canadian Complex Pediatric Therapies Follow-up Group. Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth. 2011;21(9): 932-941.