Anesthesia-Induced Neuronal Apoptosis During ... - Semantic Scholar

Anesthesia-Induced Neuronal Apoptosis During Synaptogenesis: A Review of the Literature Grace Kline Loftis, CRNA, MSN Shawn Collins, CRNA, PhD, DNP Mason McDowell, CRNA, MSNA Anesthesia is generally accepted as safe in most adult populations; however, in pediatric patients questions exist regarding the potential for long-term detrimental effects. Various anesthetic agents are associated with neuronal degeneration when administered to neonatal animals. The mechanism of damage is thought to be via accelerated apoptosis, a normally beneficial process in the maintenance of homeostasis. This review of the literature examines the current evidence in neonatal rodents, nonhuman primates, and humans experiencing anesthesia-induced neuronal apoptosis. Included are studies published between the years 2000 and 2010. Much of the early research subjects were rodents, with more recent studies examining

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he concept of “do no harm” permeates healthcare doctrine worldwide, and in no field is this more crucial than in pediatric anesthesia. Pediatric patients are a particularly vulnerable population, and with close to 3 million children in the United States undergoing anesthesia annually, according to the 2004 National Hospital Discharge Survey.1 Therefore, the prudent anesthesia provider should be aware of potential implications of the agents administered. In recent years multiple studies have illustrated a link between various anesthetic agents and neuronal damage in neonatal animals. This research has brought to the forefront the notion of safety when administering anesthetics to pediatric patients. The question remains, however, whether these studies are applicable to humans. This review discusses the significance and timeliness of the question of anesthetic-induced neuronal apoptosis in humans. In recent years, numerous studies have been conducted with the aim of clarifying the issue. The findings of the research as a whole demonstrate 3 key points: (1) N-methyl-d-aspartate (NMDA) antagonists and GABAergic agents consistently produce dose-dependent neuronal apoptosis in rodents, (2) these agents may produce apoptosis in nonhuman primates, and (3) limited human studies with anesthetics have produced variable results. Agents most frequently analyzed include ketamine, isoflurane, and propofol, all of which bear clinical relevance to human pediatric anesthesia practice. The apop-

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nonhuman primates. Retrospective research of human populations is included as well, some of which is currently underway. Clear evidence exists that neuronal apoptosis occurs when anesthetics are administered to neonatal rodents and primates, and behavioral and cognitive testing from some authors indicate longterm effects persist well into an animal’s adulthood. Preliminary human trials reveal a link between anesthesia and subsequent developmental delays. This review of the literature clarifies the need for further research in humans. Keywords: Anesthesia, apoptosis, neonate, neuroapoptosis, neurodegeneration.

totic effects of these agents appear to be dose-dependent, with multiple studies finding increased levels of neuronal apoptosis with increased drug dosage or exposure duration. The dose-dependent nature of anesthetic-induced neuronal apoptosis is confirmed by 2 human-based retrospective studies.2,3 Dosing of anesthetic agents in much of the animal research is quite high, approaching toxicologic levels in many cases if applied to human subjects. Researchers have determined, however, that the effective dose in small animals for most agents is significantly higher than in humans.4-7 In addition to dose-dependency, anesthetic-induced neuronal apoptosis appears to increase dramatically when combinations of drugs are administered.1,8 In their landmark study, Jevtovic´-Todorovic´ et al8 saw profound, widespread apoptosis in rodents exposed to a clinically relevant combination of midazolam, isoflurane, and nitrous oxide. These researchers, as well as Fredriksson et al,9 found significant neurobehavioral and cognitive delays in rodents receiving a combination treatment when compared to controls. Current pediatric anesthesia practice frequently involves the utilization of a variety of sedative and anesthetic agents. Many of these act as agonists at the γ-aminobutyric acid (GABA) receptor’s alpha subunit, or as NMDA antagonists. Most anesthetic agents affect one or both of these receptor sites, including barbiturates, benzodiazepines, propofol, ketamine, nitrous oxide, and

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Stratmann et al, 200918

Jevtovic´-Todorovic´ et al, 20038

Fredriksson et al, 20049

P5-7 mice

Cattano et al, 20084

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Propofol doses of 50 mg/kg and greater associated with significant neuronal apoptosis compared to control group Minimum propofol dose, which induced neuronal apoptosis was approximately one fourth the determined ED50 in infant mice

Immunohistochemistry assessed 6 h postexposure/activated caspase-3 staining

Male P7 rats n = 141

Male P60 rats n = 40

Behavioral studies: n = unknown

Long-term potentiation: n = 48

Histopathology studies: n = 16

4 h exposure duration

1 MAC

Isoflurane

Midazolam 9 mg/kg IP + isoflurane 0.75 volume % + nitrous oxide 75 volume % × 6 h (triple cocktail) Control group received room air for 6 h or DMSO solution IP for midazolam control

Fear conditioning and spatial reference testing

Behavioral studies performed on rats exposed to “triple cocktail” and control group at multiple ages

LTP: evoked responses of hippocampal slices


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At 5 mo postexposure, exposed rats demonstrated significantly decreased demonstration of conditioned fear.

Fear conditioning similar between exposed and control groups at 4 mo postexposure

Exposed rats had decreased performance in both spatial reference memory and fear conditioning training.

Behavioral studies: Triple-anesthetic cocktail produced long-term spatial learning and memory impairments.

LTP: Triple cocktail produced significant suppression of LTP compared to other groups.

Triple-cocktail exposure resulted in “robust” apoptosis in all subjects, with more widespread damage than with midazolam + isoflurane.

Midazolam + isoflurane produced significant apoptosis compared with the same concentration of isoflurane alone.

Animals treated with isoflurane alone showed dose-dependent neurodegeneration.

Histopathology: N2O alone and midazolam alone did not produce a significant increase in apoptotic neurons when compared to control animals.

Ketamine 50 mg/kg SC + Diazepam 5 mg/kg SC Vehicle (0.9% NS) N2O, isoflurane, or midazolam alone Histopathology studies: Silver staining, and in combination in varying doses and activated caspase-3 staining, electron microscopy durations

activity and spatial learning performance

Diazepam 5 mg/kg SC

P7 rats

Fluoro-Jade B staining 24 h after exposure Apoptosis most pronounced in ketamine + diazepam group Behavioral tests for spontaneous motor

Ketamine 50 mg/kg SC

Decreased habituation and impaired spatial learning in ketamine alone and ketamine + diazepam groups

ED50 of propofol in infant mice determined to be 200 mg/kg

Propofol ED50 determined by animal’s response to painful stimuli

Results and conclusions

n = 16-24

Experiment 2: Propofol 25-300 mg/kg IP injection Control group saline injection

Experiment 1: Determination of minimum propofol dose required to induce anesthesia

Drug(s) and length of exposure Method

P10 mice

Experiment 2: n = unknown

Experiment 1: n = 36

Sample type and size

Authors (y)

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Abbreviations: IP, intraperitoneal; ED50, median effective dose; SC, subcutaneous; NS, normal saline; LTP, long-term potentiation; DMSO, dimethyl sulfoxide; MAC, minimum alveolar concentration, DNA, deoxyribonucleic acid. Note: DMSO is a frequently used solvent in experimental protocols.

Table 1. Summary of Selected Experimental Studies Utilizing Rodents in Assessment of Anesthesia-Induced Neuronal Apoptosis

Blank control (no treatment) Positive control 2.5 g/kg ethanol SC injection × 2

Control groups: 30% O2 Room air

Electron microscopy

Number of activated caspase-3 positive cells in sevoflurane group was significantly increased when compared to control group, but was less than ethanol group. Proportion of single-strand DNA-positive cells significantly higher in sevoflurane group when compared to control group but less than ethanol group. Immunohistochemistry: Cleaved caspase-3 detection singlestrand DNA labeling to detect singlestrand DNA seen during apoptosis n = 54

Sevoflurane group: 1.7% sevoflurane + 30% O2 for 2 h P7 mouse pups Zhang et al (2008)17

Behavioral analysis: Alterations in patterns of locomotion, rearing, and total activity found in animals exposed to ketamine. These persisted into adulthood and were dose-dependent.

Behavioral analysis: age 55 d and 155 d to assess locomotion, rearing, and total activity in a novel environment

Ketamine 25 mg/kg SC

Vehicle (0.9% NS) SC Behavioral analysis n = 160

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Protein analysis: some proteins significantly increased in ketamine-exposed animals in the hippocampus, but not the cortex. Could impair normal dendritic and axonal growth in the developing brain. Ketamine 10 mg/kg SC

Protein analysis n = 130

Protein analysis: for alterations in protein levels associated with neuronal survival, growth, and synaptogenesis Ketamine 5 mg/kg SC P10 male mice Viberg et al, 200816


inhaled anesthetics. Both NMDA antagonists and GABAA mimetic agents have been extensively studied in animal models. The majority of research utilized a rodent model, involving mouse or rat pups. These studies have unequivocally shown neuronal degeneration following administration of anesthetic agents.8-10 Early research by Olney et al11 illustrated the potential for detrimental effects of GABA-mimetic and NMDA antagonist activity of ethanol in infant rats. Because of concerns regarding generalizability to a human population, researchers have recently begun utilizing infant primates as a more appropriate model.7,12 Concerns regarding the safety of anesthetic agents in infants and children prompted the US Food and Drug Administration (FDA) to launch a research program entitled SmartTots (Strategies for Mitigating Anesthesia Related Neurotoxicity in Tots), along with various nongovernmental agencies (see http://iars.org/smarttots). The project aims to investigate the long-term effects of anesthesia in infants and children. Facilities worldwide have been recruited to gather data regarding the neurodevelopmental outcomes in pediatric anesthesia patients, with results available in 2 to 5 years. This group of studies will provide a more comprehensive picture of the applicability of the animal research to a human population.

Methods A systematic search strategy was utilized to identify articles pertinent to the literature review. Multiple literature searches were performed via the following search engines: Academic Premier, CINAHL, and MEDLINE through the Western Carolina University library. Search keywords included neonatal, anesthesia, neuroapoptosis, development, brain, neuronal, apoptosis, and degeneration. The review was primarily limited to original research published between the years 2000 and 2010, although some fundamental knowledge articles were included from years prior to 2000. Reference lists from pertinent articles were reviewed for citations of additional articles deemed relevant. Current clinical trials and research studies were examined via the FDA website. The SmartTots program was reviewed, and selected research abstracts presented by the initiative are included in this review.

Results A total of 71 articles were selected from the literature for inclusion in this literature review. However, with careful analysis 15 of the most pertinent studies were selected for this manuscript. Twenty studies involved rodent models, 6 of which are presented here (Table 1), and 2 involved nonhuman primates, both of which are included in this manuscript (Table 2). Seven articles involved human subjects, 5 of which are included here (Table 3).

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Abbreviation: IM, intramuscular.

Control group: No sedation

n = 18

Table 2. Summary of Selected Experimental Studies Utilizing Nonhuman Primates in Assessment of Anesthesia-Induced Neuronal Apoptosis

Ketamine infusion for 9 or 24 h produced increased caspase-3 positive cells compared with controls, most prominently in layers II and III of the frontal cortex. Silver staining

Fluoro-Jade C staining

No neurotoxic effects evident in animals receiving ketamine infusion for 3 h

Ketamine group: Initial 20 mg/kg IM injection, followed by infusion 20-50 mg/kg/h to achieve a light plane of anesthesia for 3, 9, or 24 h P5-6 rhesus monkeys Zou et al, 20097

Control group n=5

Isoflurane group n=5

Control group: 5 h exposure to room air

Activated caspase-3 staining

Sparse and randomly distributed apoptosis in control brains; however, in the experimental group apoptotic neurons were abundant and concentrated in specific layers.

Median density of apoptotic cells in the experimental group was 32.5 cells/mm3, while the median density in control group was 2.5 cells/mm3 (difference significant at P = .008). Activated caspase-3 staining Isoflurane group: 5 h exposure at 0.71.5% end-tidal P6 r hesus monkeys Brambrink et al, 201012

Drug(s) and length of exposure Method

• Studies Using Rodent Models. The overwhelming majority of data suggesting that anesthetic exposure is neurotoxic to the developing brain are derived from research on rats and mice (see Table 1). While all studies examined for this review involved determination of apoptosis at a cellular level, researchers involved with some studies also evaluated neurobehavioral effects of anesthetic exposure in the weeks and months following exposure. The rodent’s spatial learning and memory, as well as motor activity, were a part of these assessments. Neurobehavioral effects were frequently assessed by the animal’s performance in various maze tests with novel environments and by evaluating the animal’s social interactions. Some of the most compelling findings came from a 2003 study by Jevtovic´ -Todorovic´ et al.8 These researchers exposed 7-day-old rats to a combination of midazolam, isoflurane, and nitrous oxide for a total of 6 hours. The researchers found significantly increased apoptosis when rats were treated with midazolam plus isoflurane

Sample type and size

Results

Authors (y)

All mammals undergo a specific period of synaptogenesis, or brain growth spurt, early in life, during which millions of neurons are formed and synaptic connections are made. During this time, brain growth is accelerated because of expansion of the dendrites from newly differentiated neurons, which form new synaptic connections.8 New neurons are formed, and many astroglia and oligodendroglia are created.9 The timeframe for the brain growth spurt period varies among species. In rodents, synaptogenesis begins just before birth, peaks at around 4 days postbirth, and continues for approximately 2 to 3 weeks. The human brain growth spurt commences in the third trimester of pregnancy, peaks at approximately 5 months of age, and lasts until 2 to 3 years of age.8,9,13 Apoptosis, also known as programmed cell death or cellular suicide, is a natural and essential process in development and survival. The number of brain cells produced during synaptogenesis exceeds that which is required, and through the process of apoptosis extraneous neurons are eliminated. In addition, damaged or defective cells are removed via apoptosis throughout the life span. A variety of factors may initiate apoptosis, including various cytokines, hormones, drugs, and hypoxia.14 Apoptosis is initiated by activated caspase-3, which attacks both the DNA of the cell as well as the cell’s cytoskeleton, producing DNA fragmentation and modulated plasma membrane components.14,15 Characteristic features of the apoptotic cell are condensation of the cytoplasm, blebbing of the plasma membrane, and apoptotic bodies containing intact cell organelles and fragments of the cell nucleus.14 These hallmark morphological changes associated with apoptosis are due to the effects of the caspase-3 protein.

Results and conclusions

Background



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n = 5,357 children, 593 of whom Determine whether an association received one or more general exists between exposure to anesthesia anesthetics prior to age 4 years prior to 4 years of age and the development of any learning disability

In children with 2 or more exposures, risk of learning disability was significantly increased (35.1% incidence).

No increase in risk for development of a learning disability in children with a single anesthetic exposure (20.4% incidence).

Increased duration of anesthetic exposure produced significantly poorer academic achievement.

Concluded that very poor academic performance was more likely in children who underwent general anesthesia prior to 1 year of age than among the normative population.

Table 3. Summary of Selected Descriptive Studies Examining Long-Term Anesthesia Effects in Humans

Wilder et al, 20092

n = 131 of these children had documented achievement test scores

11% of exposed children scored below the 5th percentile. Normative state scores: 5% scoring below the 5th percentile.

n = 231 children who received general anesthesia prior to age 1 year

Thomas et al, 20103 Analyze the achievement test scores of children who received general anesthesia during infancy.

Evaluate association between Children exposed to anesthesia under age 3 years were more than twice as anesthesia exposure under age 3 likely to develop behavioral and developmental disorders. (34.1 cases per 100 n = 668 exposed to anesthesia children vs 15.7 cases per 100 children). one or more times under 3 years years and risk of developmental and behavioral disorders in a large cohort of of age twins.

Authors assert a statistically significant association between hernia repair before age 3 and risk of behavioral or developmental disorders.

Cox proportional hazard model to control for age, sex, race, and confounding diagnoses at birth

Incidence rate for the nonexposed group: 5.4 cases per 1,000 person-years.

Incidence of behavioral and developmental disorders for exposed group: 19.6 cases per 1,000 person-years.

n = 11,648 children

history of hernia repair in the first 3 years of life

n = 383 children who underwent Assess the association between hernia inguinal hernia repair prior to repair surgery before age 3 with the age 3 development of developmental and/or behavioral disorders. n = 5,050 children with no

Sample type characteristics Study purpose Results and conclusions

Dimaggio et al, 201020

DiMaggio et al, 200919

Authors (y)

vs control animals. The neurodegeneration was found to be even more considerable when nitrous oxide was added to the midazolam/isoflurane combination (“triple cocktail”). This study utilized multiple methods of quantitatively and qualitatively evaluating neuronal apoptosis. The triple cocktail produced long-term impairments in spatial learning and memory, as well as deficiencies in acquisition and retention of information.8 Fredriksson et al9 also examined the effects of a combination of anesthetic agents, namely ketamine and diazepam. Rodents were assigned to 1 of 3 experimental groups (ketamine only, diazepam only, or ketamine plus diazepam) or 1 control group (normal saline injection). Researchers involved with this study found that not only was there significant apoptosis immediately following treatment, but also behavioral alterations persisted at 55 days postexposure. These effects were most pronounced among those rodents exposed to ketamine alone or to ketamine plus diazepam.9 Viberg et al16 evaluated mice at 2 and 4 months of age that had received ketamine, 5, 10, or 25 mg/kg at postnatal day 10. Testing consisted of spontaneous behavior observation, reflecting the animal’s ability to habituate to a novel environment, and the integration of sensory input into motor output. Testing at 4 months of age revealed significant dose-dependent deficiencies in all test variables.16 These results led this group of researchers to conclude that the apoptosis seen with ketamine administration in the neonatal mouse produced subsequent alterations in spontaneous behavior, learning, and memory. These deficits appeared to persist into adulthood, and were clearly dose-dependent and related to impedance of proteins vital to neurological development. Zhang et al17 demonstrated an increased density in apoptotic cells following 2 hours of exposure to 1.7% sevoflurane in postnatal day 7 mice pups. These findings were confirmed utilizing both cleaved caspase-3 staining and single-stranded DNA labeling techniques. The researchers noted that the experimental concentration of 1.7% corresponds roughly to 0.75 minimum alveolar concentration (MAC) of sevoflurane, suggesting that even subclinical concentrations may be neurotoxic to the immature brain.17 In a 2009 study by Stratmann et al,18 7-day-old rat pups were exposed to 1 MAC of isoflurane for durations of 1, 2 or 4 hours. These rodents subsequently underwent testing at 8 weeks of age to evaluate fear conditioning and learning ability. Long-term neurocognitive deficits were observed only in those rat pups that had been exposed to 4 hours of isoflurane in infancy, as opposed to those exposed for 1 or 2 hours. This group displayed deficits in spatial reference memory and working memory.18 While studies looking at the effects of propofol use on the neonatal brain are limited, there are several recentlypublished studies specifically focused on this drug.

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Cattano et al4 determined the minimal dose required for induction of anesthesia in the neonatal mouse to be 200 mg/kg. They then treated groups of neonatal mice with intraperitoneal injections of propofol at doses from 25 to 300 mg/kg. The researchers saw significant histological apoptotic changes following treatment with propofol doses of 50 mg/kg and greater.4 These findings suggest that subclinical doses of propofol are capable of inducing neuronal cell death; the minimal apoptosis-inducing dose of 50 mg/kg is just 25% of the dose required for induction of anesthesia.

Studies Using Nonhuman Primate Models There are limited studies using nonhuman primates to study the neurological effects of anesthesia exposure in infancy (see Table 2). Zou et al7 found that the neurotoxic effects of ketamine occur in both a dose and duration-dependent manner. These researchers found that exposure of 5- and 6-day-old rhesus monkeys to ketamine for durations of 9 and 24 hours produced significant increases in frontal cortex neuronal apoptosis compared to controls. However, an exposure time of 3 hours was not associated with significant histopathological differences between experimental and control groups. The selection of a 9-hour exposure was meant to reflect an exposure of extremely long duration, and the 24-hour exposure served as a positive control for ketamine-induced damage. The 3-hour duration was based on what the authors felt was a typical anesthetic exposure for the pediatric patient. The researchers suggest that ketamineassociated neurodegeneration is duration-dependent with exposure times of 3 hours or less appearing benign in neonatal monkeys.7 Brambrink et al12 exposed 6-day-old rhesus macaques to isoflurane at concentrations maintained between 0.7 and 1.5% end tidal for 5 hours. Immunohistochemical evaluation of the primate brains revealed a statistically significant increase in apoptotic cell density in those exposed to isoflurane, amounting to a 13-fold increase compared to controls. In the control group animals, apoptotic cells were sparse and randomly distributed. Conversely, the experimental group animals exhibited more abundant apoptosis that was concentrated in specific layers and regions of the brain tissue.12

Studies Using Human Samples It is unclear to what extent research data on rodents and nonhuman primates can be extended toward understanding the effects of anesthesia in humans. The nature of this research innately limits the ability to feasibly and ethically conduct experimental research with human samples. For this reason, the current research continues to rely on rodent populations as well as the more recent use of nonhuman primate species. Whether or not findings in rodents or monkeys can reasonably be used to draw


conclusions in humans is debatable. For the medical community to determine whether anesthetic-induced neurodegeneration is a legitimate risk to infants and children entering the clinical setting, there must be evidence supporting the phenomenon in humans. One strategy for studying the neurological effects of neonatal anesthesia in humans involves the use of retrospective cohorts. These studies seek to evaluate the presence of a significant relationship between early encounters with anesthesia and the subsequent development of neurocognitive or behavioral difficulties (see Table 3). Dimaggio et al19 looked for a relationship between early anesthetic exposure and the presence of behavioral and learning disorders using a retrospective cohort of 383 children. The researchers obtained their sample from children who had undergone inguinal hernia repair prior to age 3. After controlling for age, race, sex, and the presence of any complicating birth-related diagnosis, the researchers found that inguinal hernia repair before the age of 3 approximately doubled the risk of subsequent diagnosis with a behavioral or learning disorder, a statistically significant finding.19 Wilder et al2 performed a similar study involving the retrospective analysis of a birth cohort of 5,357 children. Medical records were reviewed to identify children who had undergone procedures necessitating general anesthesia before the age of 4. School records were reviewed to identify children diagnosed with learning disabilities in reading, writing, or math. Statistical analysis revealed that exposure to 2 or more general anesthetics before the age of 4 was associated with a 35.1% incidence of learning disability diagnosis. Children with no history of anesthetic exposure had only a 20% incidence of such a diagnosis.2 These were statistically significant findings; however, the authors acknowledge the limitation of multiple potential unidentified confounders. An additional study performed by DiMaggio et al20 was a large twin study that enrolled 5,824 twin pairs. From this sample, 668 children had undergone anesthesia one or more times before age 3. In children with a history of anesthesia exposure, the incidence of developmental and/or behavioral disorders was more than double that of children with no history of exposure.20 Academic performance is arguably one of the best indicators of neurocognitive development in children. Thomas et al3 evaluated the achievement test scores of 131 children ages 7 to 17 who had received general anesthesia during infancy (ie, exposed children). These scores were compared to statewide normative data. While the state normative scores below the fifth percentile accounted for just 5% of the population, 11% of exposed children fell below the fifth percentile. This information led these researchers to conclude that poor academic performance was more likely in children who underwent a general anesthetic prior to age 1. In addition, those children with


increased duration of anesthetic exposure exhibited significantly poorer academic achievement, potentially reflecting the dose-dependent nature of anesthetic-induced neuronal injury.3 The research of Kalkman et al21 examined the association between age at the time of first anesthetic exposure and the subsequent development of behavioral disturbances.21 They found behavioral disturbances were more common among the children in their sample who underwent anesthesia prior to age 2 years. Their data, however, failed to reach statistical significance, and the researchers cite the need for a larger sample size and further studies on the topic.

Conclusion There is overwhelming evidence that exposure to various anesthetic agents causes neuronal apoptosis in neonatal animals; however, the applicability of this research to human populations is unknown. New data are rapidly becoming evident as researchers worldwide tackle this important topic. To see how this research applies to anesthetic practice, the anesthesia provider must understand basic concepts central to neuronal apoptosis and anesthetic toxicity. The implications of the research on anesthesia induced neuronal apoptosis can be viewed as twofold: research implications and practice implications. The research implications are clear and are emphasized by the majority of authors proficient in the subject. Conclusive studies must meet many stringent requirements, and one challenge to the assessment of anesthesia-induced neuronal apoptosis is the selection of outcome measures. It is difficult to determine which measures best assess the effects of anesthesia upon neurocognitive or behavioral development. Four primary categories of clinical outcomes are generally thought to be central to the assessment of consequences of neuronal apoptosis in humans: cognitive functions (eg, IQ, academic performance), biomarkers (eg, serum and/or imaging studies), morbidity (eg, diagnoses of mental retardation, learning disability, etc), and mortality.22 Conversely, the practice implications are vague and frequently speculative at this point. Multiple studies report combinations of anesthetic agents appear to produce more robust and widespread neuronal apoptosis than do single drugs.8-9 These findings lead some researchers to suggest a “less is more” technique, limiting the anesthetic to just 1 or 2 agents.9 Because of the dose-dependent nature of neuronal apoptosis in neonatal rodent models, other researchers propose limiting the duration of anesthetic exposure in neonates.23-24 According to the FDA’s SmartTots Initiative, there is “no scientific basis for delaying essential surgery” (SAFEKIDS FAQ). However, the substantial evidence in animals clarifies the need for further investigation based

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on human models. Large-scale studies in humans, both retrospective and prospective, are needed to definitively confirm or refute the link between anesthesia exposure in neonates and long-term problems. Several authors have described a number of methods of reducing the risk of neuronal injury from anesthetic exposure in young children. These include dexmedetomidine, lithium, melatonin, and others.15,25,26 Further research is needed in this area to determine the neuroprotective efficacy of such interventions. It is the duty of the responsible anesthesia provider to be well apprised of the current data to protect the vulnerable pediatric population. Research employing human models is underway worldwide to better understand the long-term implications of neonatal exposure to anesthesia. Although such studies face a multitude of challenges, they are crucial in establishing a proper margin of safety for neonatal patients. REFERENCES 1. Sun LS, Li G, Dimaggio C, et al. Anesthesia and neurodevelopment in children: time for an answer? Anesthesiology. 2008;109(5): 757-61. doi:10.1097/ALN.0b013e31818a37fd. 2. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796-804. doi:10.1097/01.anes.0000344728.34332.5d. 3. Thomas JJ, Choi JY, Bayman EO, et al. Does anesthesia exposure in infancy affect academic performance in childhood? [Abstract ISS-A4]. Paper presented at the IARS and SAFEKIDS International Science Symposium: Anesthetic-Induced Neonatal Neuronal Injury, Honolulu, HI, March 20, 2010. http://www.iars.org/documents/ISS%20 Handout%20and%20Cover%20Final.pdf. Accessed April 17, 2012. 4. Cattano D, Young C, Straiko MM, Olney JW. Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg. 2008;106(6):1712-1714. doi:10.1213/ane.0b013e318172ba0a. 5. Kungys G, Kim J, Jinks SL, Atherley RJ, Antognini JF. Propofol produces immobility via action in the ventral horn of the spinal cord by a GABAergic mechanism. Anesth Analg. 2009;108(5):1531-1537. 6. Waterman AE, Livingston A. Effects of age and sex on ketamine anaesthesia in the rat. Br J Anaesth. 1978;50:885-889. 7. Zou X, Patterson TA, Divine RL, et al. Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain. Int J Dev Neurosci. 2009;27(7):727-731. doi:10.1016/j.ijdevneu.2009.06.010. 8. 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. 9. Fredriksson A, Archer T, Alm H, Gordh T, Eriksson P. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav Brain Res. 2004; 153(2):367-376. doi: 10.1016/j.bbr.2003.12.026. 10. Loepke AW, Istaphanous GK, McAuliffe JJ 3rd, et al. The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg. 2009;108(1):90-104. doi: 10.1213/ane.0b013e31818cdb29. 11. Olney JW, Ishimaru MJ, Bittigau P, Ikonomidou C. Ethanol-induced apoptotic neurodegeneration in the developing brain. Apoptosis. 2000;5(6):515-521. doi:10.1023/A:1009685428847.

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AUTHORS Grace Kline Loftis, CRNA, MSN, is a staff nurse anesthetist with Asheville Anesthesia Associates in Asheville, North Carolina. She was a student at Western Carolina University, Cullowhee, North Carolina, at the time this paper was written. Shawn Collins, CRNA, PhD, DNP, is program director of the Nurse Anesthesia Program at Western Carolina University School of Nursing, Candler, North Carolina. Email: [email protected]. Mason McDowell, CRNA, MSNA, is the assistant program director of the Nurse Anesthesia Program at Western Carolina University School of Nursing.
