Editorial Opinion
The Neonatologist’s Role in Pediatric Anesthesia Neurotoxicity Robert Williams, MD; Robert Pfister, MD; Ian Black, MD “But I don’t want to go among mad people,” Alice remarked. “Oh, you can’t help that,” said the Cat: “we’re all mad here. I’m mad. You’re mad.” “How do you know I’m mad?” said Alice. “You must be,” said the Cat, “or you wouldn’t have come here.” Lewis Carroll, Alice’s Adventures in Wonderland
Each year, millions of children worldwide undergo anesthesia to facilitate surgical, diagnostic, and therapeutic procedures. According to all currently available clinical measurements, modern neonatal anesthesia appears to be Related article page 746 extremely safe. 1 However, during the past decade disturbing evidence has begun to accumulate concerning the neurotoxicity of commonly used anesthetic agents and sedatives. A fundamental assumption of anesthetic practice has always been that the effects of sedatives and anesthetic agents resolve when these drugs are metabolized and excreted from the body. This core assumption has recently been challenged by compelling evidence2-5 in animals that administration of these drugs may permanently change the architecture and function of the central nervous system. In this context, we welcome the publication by Morriss et al6 in this issue of the journal. However, as is true with every human neurotoxicity study to date, their work raises as many questions as it answers. Pediatricians and neonatologists have a vital role to play as we attempt to unravel the mysteries of an extraordinarily murky field of research where, as Alice found, things continue to grow curiouser and curiouser. A growing body of evidence2-5 links the administration of all commonly used anesthetic and sedative agents (notably including propofol and midazolam) with long-term central nervous system damage and dysfunction when administered to young animals during periods of rapid brain growth. Histologic evidence of increased neuroapoptosis and dendritic cell damage has been convincingly demonstrated across a wide variety of species ranging from nematodes to subhuman primates. Deficits in learning, memory, and even maternal behavior appear to correlate with these central nervous system changes. Translation of this animal evidence for neurotoxicity has proven problematic, and the clinical relevance for humans remains unknown. Several human studies7,8 have shown an association with either single or multiple exposures to anesthesia and surgery with postoperative cognitive deficits including impaired academic achievement testing, poor performance on the Bayley Scales of Infant Development tests, increased likelihood of learning disabilities, and developmental deficiencies in specific central nervous system domains. Other studies9 have found no relationship between exposure to a single gen-
eral anesthetic and postoperative cognitive deficits. Recent editorials10-12 highlight the difficulties in interpretation of these studies. In the present study, Morriss et al6 used retrospective cohort logistic regression analysis to assess the association of surgical intervention with the combined outcome of death or adverse neurodevelopmental outcome among very low-birth-weight infants. Their findings suggest that surgical interventions of increasing complexity are associated with a statistically significant increased risk of death or adverse neurodevelopmental outcome at 18 to 22 months’ corrected age. The authors further speculate that the role of general anesthesia is responsible for these differences. In addition to involving the neonatal community in this debate, a significant strength of this study is the very large database used (nearly 3000 infants exposed to surgery). However, the nature of the database did not permit closer analysis of the types of anesthetics. Regional anesthetic techniques, such as spinal anesthesia, are not thought to be associated with neurotoxicity. The authors attempt to use this assumption to compare outcomes based on the type of anesthesia that may have been administered: regional anesthesia for minor procedures vs general anesthesia for major procedures. However, the type of anesthesia was not available in their database. In addition, the use of regional anesthesia in infants is a distinctly minority practice and it is uncertain how many infants received general anesthesia or regional anesthesia. Consequently, without further specific information regarding the types of anesthesia administered, the conclusions of Morriss et al6 must remain speculative. Ultimately, this study falls victim to the same limitation that affects all currently available human neurotoxicity research: the inability to separate the need for surgery and the potential effects of the perioperative experience from the potential neurotoxic effects of general anesthesia. It is very concerning that human studies have demonstrated subtle deficits in learning and behavior—exactly what the animal work would predict. However, the perioperative experience is an extraordinarily complex milieu. Many factors must be accounted for, including potential genotypic differences, indication for surgery, perioperative inflammation and stress responses, hypothermia, hyperoxemia, hypoxemia, and exposure to drugs other than anesthetics, such as corticosteroids and antibiotics. Ideally, a randomized clinical trial would examine the outcomes of infants exposed to surgery and general anesthesia with an alternative to general anesthesia not thought to be neurotoxic. This is the strategy behind the Multisite Randomized Controlled Trial Comparing Regional and General Anesthesia for Effects on Neurodevelopmental Outcome and Apnea in Infants (GAS) study,13 a comparison of neurodevelopmental outcomes in infants undergoing inguinal hernia repair under either
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Copyright 2014 American Medical Association. All rights reserved.
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Opinion Editorial
general or spinal anesthesia. Although enrollment in the GAS study has been completed, final results of the primary outcome (the Wechsler Preschool and Primary Scale of Intelligence) will not be assessed until the enrolled infants reach age 5 years. Future trials should be adequately powered to detect subtle differences and should include behavioral outcomes. Neonatal intensive care unit follow-up registries and neurodevelopmental outcome databases could routinely capture indication for surgeries, comorbidities and confounders, and exposure to potentially neurotoxic agents, including details of duration and exposure to anesthetic agents as well as other sedatives used in the neonatal intensive care unit. Because many centers and physicians have a tradition or preference for providing anesthesia (regional vs general) for these types of procedures, this question would be suitable for cluster randomized trial methods, using the medical center as the unit of randomization rather than the patient. Disadvantages of this include greater complexity in design and analysis, and a requirement for more participants to obtain the same statistical power. While we wait for definitive information there is much we can do. At the present time, there is no definitive evidence that exposure to general anesthesia causes neurotoxicity and neither surgery nor anesthesia should be withheld from children if needed. In the absence of definitive evidence, we encourage broad multidisciplinary discussion of the gap in knowledge as well as the potential risks, benefits, and other options. Historically, the pediatrician notes a surgical indication and consults a surgeon who then arranges for anesthesia. No single entity currently takes ownership for the decision to provide anesthesia vs other options. Heightened awareness could allow pediatricians and surgeons to begin this dialogue with families. In some cases there are mitigating options. Any potential risk is plausibly associated with younger ages, and current recommendations are that, if possible, procedures should be deferred until the child is older. If delaying a diagnostic or surgical procedure is not possible, techniques that do not
ARTICLE INFORMATION Author Affiliations: Department of Anesthesia, Vermont Children’s Hospital, University of Vermont, Burlington; Department of Pediatrics, Vermont Children’s Hospital, University of Vermont, Burlington. Corresponding Author: Robert Williams, MD, Departments of Anesthesia and Pediatrics, Vermont Children’s Hospital, University of Vermont, 111 Colchester Ave, Burlington, VT 05401 ([email protected]). Published Online: June 16, 2014. doi:10.1001/jamapediatrics.2014.469. Conflict of Interest Disclosures: None reported. REFERENCES 1. Flick RP, Sprung J, Harrison TE, et al. Perioperative cardiac arrests in children between 702
involve exposure to potentially neurotoxic agents should be considered. For example, the use of novel swaddling devices (eg, Med-Vac vacuum immobilization bag; CFI Medical Solutions Inc) for infants undergoing magnetic resonance imaging has been demonstrated14 to be a reliable method of avoiding exposure to general anesthesia and should be considered. When feasible, pain should be assessed using objective validated tools and managed with nonpharmacologic measures. A variety of nonpharmacologic pain prevention and relief techniques have been demonstrated15 to reduce pain in neonates. These include use of oral sucrose/glucose, breastfeeding, nonnutritive sucking, direct skin-to-skin contact, facilitated tuck (holding the arms and legs in a flexed position), swaddling, and developmental care, which includes limiting environmental stimuli, lateral positioning, and the use of supportive bedding. Clearly, these techniques will not be sufficient for most operative or painful procedures. Although there is no current evidence to indicate the superiority of any specific anesthetic technique, the use of regional anesthesia (typically, infant spinal anesthesia) should be considered. Several surgical procedures, including inguinal hernia repair, gastroschisis repair, circumcision, and pyloromyotomy, can be performed using spinal anesthesia.16,17 Infant spinal anesthesia has an established record of safety and can be used for surgical procedures in the abdomen and lower extremities. An initial study by our group provides reassurance as to the long-term cognitive outcome of infants who underwent surgery under spinal anesthesia.18 The use of spinal anesthesia is limited, but appears to be increasing.17,19 The GAS13 study involved 28 centers in 7 countries and demonstrated that disparate surgical and anesthesia teams can effectively provide spinal anesthesia to infants. Neonatologists and pediatricians should be aware of this option for suitable procedures. Although the animal evidence for anesthetic neurotoxicity is compelling, at present the risk in humans remains theoretical. Neonatologists, pediatricians, surgeons, and anesthesiologists should be aware of the potential neurotoxicity of sedatives and anesthetic agents in young children, as well as the limitations of the available evidence.
1988 and 2005 at a tertiary referral center: a study of 92,881 patients. Anesthesiology. 2007;106(2): 226-237. 2. Takaenoki Y, Satoh Y, Araki Y, et al. Neonatal exposure to sevoflurane in mice causes deficits in maternal behavior later in adulthood. Anesthesiology. 2014;120(2):403-415. 3. 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. 4. Brambrink AM, Back SA, Riddle A, et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72 (4):525-535. 5. 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. 6. Morriss FH Jr, Saha S, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Surgery and neurodevelopmental outcome of very low-birth-weight infants [published online June 16, 2014]. JAMA Pediatr. doi: 10.1001/jamapediatrics.2014.307. 7. Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5): e1053-e1061. doi:10.1542/peds.2011-0351. 8. 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. doi:10.1542/peds .2011-3822.
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Editorial Opinion
9. Hansen TG, Flick R; Danish Registry Study Group; Mayo Clinic Pediatric Anesthesia and Learning Disabilities Study Group. Anesthetic effects on the developing brain: insights from epidemiology. Anesthesiology. 2009;110(1):1-3. 10. Williams RK. The pediatrician and anesthesia neurotoxicity. Pediatrics. 2011;128(5):e1268-e1270. doi:10.1542/peds.2011-2489. 11. Flick RP, Warner DOA. A users’ guide to interpreting observational studies of pediatric anesthetic neurotoxicity: the lessons of Sir Bradford Hill. Anesthesiology. 2012;117(3):459-462. 12. Williams RK, Adams DC, Black IH. While we wait. Anesth Analg. 2011;112(5):1239-1241. 13. McCann ME, Bellinger D, Arnup S, et al. The GAS study: perioperative outcomes in an RCT comparing spinal and general anesthesia for infant hernia
pyloromyotomy procedure. Paediatr Anaesth. 2003;13(1):32-37.
repair. Paper presented at: American Society of Anesthesiologists Annual Meeting; October 15, 2013; San Francisco, CA.
17. Williams RK, Adams DC, Aladjem EV, et al. The safety and efficacy of spinal anesthesia for surgery in infants: the Vermont Infant Spinal Registry. Anesth Analg. 2006;102(1):67-71.
14. Mathur AM, Neil JJ, McKinstry RC, Inder TE. Transport, monitoring, and successful brain MR imaging in unsedated neonates. Pediatr Radiol. 2008;38(3):260-264. 15. Batton DG, Barrington KJ, Wallman C; American Academy of Pediatrics Committee on Fetus and Newborn; American Academy of Pediatrics Section on Surgery; Canadian Paediatric Society Fetus and Newborn Committee. Prevention and management of pain in the neonate: an update. Pediatrics. 2006;118(5):2231-2241.
18. Williams RK, Black I, Howard D, et al. Cognitive outcome after spinal anesthesia and surgery during infancy. Anesth Analg. In press. 19. Rukewe A, Alonge T, Fatiregun A. Spinal anesthesia in children: no longer an anathema! Paediatr Anaesth. 2010;20(11):1036-1039.
16. Somri M, Gaitini LA, Vaida SJ, et al. The effectiveness and safety of spinal anaesthesia in the
Increasing Safe Teenaged Driving Time to Integrate the Growing Evidence Base Corinne Peek-Asa, PhD; Daniel V. McGehee, PhD; Beth E. Ebel, MD
Road traffic crashes, among the top 10 leading causes of death worldwide, are increasingly recognized as a public health priority.1 Regardless of a country’s licensing policies, novice drivers are at increased risk for crashes.2-4 In the United Related article page 764 States, which allows driving at a relatively young age (14-16 years), motor vehicle crashes are the leading cause of death for teenagers. With increasing awareness of the high motor vehicle crash rates among newly licensed teenaged drivers have come interventions to prevent crashes and reduce their health burden. Legislative approaches have been a major component of these interventions. For example, graduated driver’s licensure (GDL) policies limit risky driving situations (eg, teenaged passengers, mobile phone use, late night driving) and gradually allow more responsibility as new drivers gain driving experience. A strong body of research has demonstrated that GDL policies have been effective in reducing crashes in novice drivers,5,6 and a New Jersey license decal program that improved enforcement of GDL laws was also associated with lower crash incidence in new drivers.7 Although evaluations of other policies focused on young drivers such as zerotolerance alcohol policies are less frequent, they also generally show that policy approaches are effective.8 The presence of primary enforcement of seat belt laws, which reduce crash risk for all drivers, has been important in reducing serious injury and death when a crash has occurred and encourage seat belt use among older drivers who provide the role model for youth. Despite these policies, crash rates for teenaged drivers remain unacceptably high, and effective prevention programs are needed. An evidence base for teenaged driving interventions is emerging. Existing approaches have several goals: increase and/or improve supervised driving practice, which is primar-
ily done with parents; provide information to teenagers and parents about driving behavior and performance, thus allowing parents to be more informed about their teenager’s driving behavior; increase the role of parents in monitoring independent teenaged driving, usually through a contract that creates agreement in rules and expectations and provides increasing opportunities for independent driving; and increase and improve parent communication. Existing approaches also use a range of delivery methods, from passive information provided to teenagers and parents to in-vehicle video feedback devices.9-11 Research on innovative new methods for intervention delivery are needed, such as options for financial incentives through insurance programs, approaches for early identification and targeting of high-risk drivers, and programs that introduce a safe driving culture in early childhood. One challenge for this emerging field is to identify the “sweet spots” that balance the intervention’s reach to the optimal population with program cost, timing, and acceptability. For example, in-vehicle video devices show strong effects in reducing driving errors, but they are not easily scalable to a broad audience due to a perception of cost and initial concerns over invasion of privacy. However, they effectively provide objective information to parents and teenagers to identify “coachable” moments, with the goal of improving driving by learning from near-miss opportunities. At the other end of the spectrum, interventions that provide information to teenagers and parents through a variety of multimedia delivery methods are less expensive and have been less effective in the absence of driving laws. Aiming to fill the gap in evidence-based parent-focused interventions, Mirman and colleagues12 evaluated the Teen Driving Plan (TDP) in this issue of JAMA Pediatrics. The TDP aims to increase the quantity and diversity of parent-supervised driv-
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Copyright 2014 American Medical Association. All rights reserved.
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The Neonatologist’s Role in Pediatric Anesthesia Neurotoxicity Robert Williams, MD; Robert Pfister, MD; Ian Black, MD “But I don’t want to go among mad people,” Alice remarked. “Oh, you can’t help that,” said the Cat: “we’re all mad here. I’m mad. You’re mad.” “How do you know I’m mad?” said Alice. “You must be,” said the Cat, “or you wouldn’t have come here.” Lewis Carroll, Alice’s Adventures in Wonderland
Each year, millions of children worldwide undergo anesthesia to facilitate surgical, diagnostic, and therapeutic procedures. According to all currently available clinical measurements, modern neonatal anesthesia appears to be Related article page 746 extremely safe. 1 However, during the past decade disturbing evidence has begun to accumulate concerning the neurotoxicity of commonly used anesthetic agents and sedatives. A fundamental assumption of anesthetic practice has always been that the effects of sedatives and anesthetic agents resolve when these drugs are metabolized and excreted from the body. This core assumption has recently been challenged by compelling evidence2-5 in animals that administration of these drugs may permanently change the architecture and function of the central nervous system. In this context, we welcome the publication by Morriss et al6 in this issue of the journal. However, as is true with every human neurotoxicity study to date, their work raises as many questions as it answers. Pediatricians and neonatologists have a vital role to play as we attempt to unravel the mysteries of an extraordinarily murky field of research where, as Alice found, things continue to grow curiouser and curiouser. A growing body of evidence2-5 links the administration of all commonly used anesthetic and sedative agents (notably including propofol and midazolam) with long-term central nervous system damage and dysfunction when administered to young animals during periods of rapid brain growth. Histologic evidence of increased neuroapoptosis and dendritic cell damage has been convincingly demonstrated across a wide variety of species ranging from nematodes to subhuman primates. Deficits in learning, memory, and even maternal behavior appear to correlate with these central nervous system changes. Translation of this animal evidence for neurotoxicity has proven problematic, and the clinical relevance for humans remains unknown. Several human studies7,8 have shown an association with either single or multiple exposures to anesthesia and surgery with postoperative cognitive deficits including impaired academic achievement testing, poor performance on the Bayley Scales of Infant Development tests, increased likelihood of learning disabilities, and developmental deficiencies in specific central nervous system domains. Other studies9 have found no relationship between exposure to a single gen-
eral anesthetic and postoperative cognitive deficits. Recent editorials10-12 highlight the difficulties in interpretation of these studies. In the present study, Morriss et al6 used retrospective cohort logistic regression analysis to assess the association of surgical intervention with the combined outcome of death or adverse neurodevelopmental outcome among very low-birth-weight infants. Their findings suggest that surgical interventions of increasing complexity are associated with a statistically significant increased risk of death or adverse neurodevelopmental outcome at 18 to 22 months’ corrected age. The authors further speculate that the role of general anesthesia is responsible for these differences. In addition to involving the neonatal community in this debate, a significant strength of this study is the very large database used (nearly 3000 infants exposed to surgery). However, the nature of the database did not permit closer analysis of the types of anesthetics. Regional anesthetic techniques, such as spinal anesthesia, are not thought to be associated with neurotoxicity. The authors attempt to use this assumption to compare outcomes based on the type of anesthesia that may have been administered: regional anesthesia for minor procedures vs general anesthesia for major procedures. However, the type of anesthesia was not available in their database. In addition, the use of regional anesthesia in infants is a distinctly minority practice and it is uncertain how many infants received general anesthesia or regional anesthesia. Consequently, without further specific information regarding the types of anesthesia administered, the conclusions of Morriss et al6 must remain speculative. Ultimately, this study falls victim to the same limitation that affects all currently available human neurotoxicity research: the inability to separate the need for surgery and the potential effects of the perioperative experience from the potential neurotoxic effects of general anesthesia. It is very concerning that human studies have demonstrated subtle deficits in learning and behavior—exactly what the animal work would predict. However, the perioperative experience is an extraordinarily complex milieu. Many factors must be accounted for, including potential genotypic differences, indication for surgery, perioperative inflammation and stress responses, hypothermia, hyperoxemia, hypoxemia, and exposure to drugs other than anesthetics, such as corticosteroids and antibiotics. Ideally, a randomized clinical trial would examine the outcomes of infants exposed to surgery and general anesthesia with an alternative to general anesthesia not thought to be neurotoxic. This is the strategy behind the Multisite Randomized Controlled Trial Comparing Regional and General Anesthesia for Effects on Neurodevelopmental Outcome and Apnea in Infants (GAS) study,13 a comparison of neurodevelopmental outcomes in infants undergoing inguinal hernia repair under either
jamapediatrics.com
JAMA Pediatrics August 2014 Volume 168, Number 8
Copyright 2014 American Medical Association. All rights reserved.
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701
Opinion Editorial
general or spinal anesthesia. Although enrollment in the GAS study has been completed, final results of the primary outcome (the Wechsler Preschool and Primary Scale of Intelligence) will not be assessed until the enrolled infants reach age 5 years. Future trials should be adequately powered to detect subtle differences and should include behavioral outcomes. Neonatal intensive care unit follow-up registries and neurodevelopmental outcome databases could routinely capture indication for surgeries, comorbidities and confounders, and exposure to potentially neurotoxic agents, including details of duration and exposure to anesthetic agents as well as other sedatives used in the neonatal intensive care unit. Because many centers and physicians have a tradition or preference for providing anesthesia (regional vs general) for these types of procedures, this question would be suitable for cluster randomized trial methods, using the medical center as the unit of randomization rather than the patient. Disadvantages of this include greater complexity in design and analysis, and a requirement for more participants to obtain the same statistical power. While we wait for definitive information there is much we can do. At the present time, there is no definitive evidence that exposure to general anesthesia causes neurotoxicity and neither surgery nor anesthesia should be withheld from children if needed. In the absence of definitive evidence, we encourage broad multidisciplinary discussion of the gap in knowledge as well as the potential risks, benefits, and other options. Historically, the pediatrician notes a surgical indication and consults a surgeon who then arranges for anesthesia. No single entity currently takes ownership for the decision to provide anesthesia vs other options. Heightened awareness could allow pediatricians and surgeons to begin this dialogue with families. In some cases there are mitigating options. Any potential risk is plausibly associated with younger ages, and current recommendations are that, if possible, procedures should be deferred until the child is older. If delaying a diagnostic or surgical procedure is not possible, techniques that do not
ARTICLE INFORMATION Author Affiliations: Department of Anesthesia, Vermont Children’s Hospital, University of Vermont, Burlington; Department of Pediatrics, Vermont Children’s Hospital, University of Vermont, Burlington. Corresponding Author: Robert Williams, MD, Departments of Anesthesia and Pediatrics, Vermont Children’s Hospital, University of Vermont, 111 Colchester Ave, Burlington, VT 05401 ([email protected]). Published Online: June 16, 2014. doi:10.1001/jamapediatrics.2014.469. Conflict of Interest Disclosures: None reported. REFERENCES 1. Flick RP, Sprung J, Harrison TE, et al. Perioperative cardiac arrests in children between 702
involve exposure to potentially neurotoxic agents should be considered. For example, the use of novel swaddling devices (eg, Med-Vac vacuum immobilization bag; CFI Medical Solutions Inc) for infants undergoing magnetic resonance imaging has been demonstrated14 to be a reliable method of avoiding exposure to general anesthesia and should be considered. When feasible, pain should be assessed using objective validated tools and managed with nonpharmacologic measures. A variety of nonpharmacologic pain prevention and relief techniques have been demonstrated15 to reduce pain in neonates. These include use of oral sucrose/glucose, breastfeeding, nonnutritive sucking, direct skin-to-skin contact, facilitated tuck (holding the arms and legs in a flexed position), swaddling, and developmental care, which includes limiting environmental stimuli, lateral positioning, and the use of supportive bedding. Clearly, these techniques will not be sufficient for most operative or painful procedures. Although there is no current evidence to indicate the superiority of any specific anesthetic technique, the use of regional anesthesia (typically, infant spinal anesthesia) should be considered. Several surgical procedures, including inguinal hernia repair, gastroschisis repair, circumcision, and pyloromyotomy, can be performed using spinal anesthesia.16,17 Infant spinal anesthesia has an established record of safety and can be used for surgical procedures in the abdomen and lower extremities. An initial study by our group provides reassurance as to the long-term cognitive outcome of infants who underwent surgery under spinal anesthesia.18 The use of spinal anesthesia is limited, but appears to be increasing.17,19 The GAS13 study involved 28 centers in 7 countries and demonstrated that disparate surgical and anesthesia teams can effectively provide spinal anesthesia to infants. Neonatologists and pediatricians should be aware of this option for suitable procedures. Although the animal evidence for anesthetic neurotoxicity is compelling, at present the risk in humans remains theoretical. Neonatologists, pediatricians, surgeons, and anesthesiologists should be aware of the potential neurotoxicity of sedatives and anesthetic agents in young children, as well as the limitations of the available evidence.
1988 and 2005 at a tertiary referral center: a study of 92,881 patients. Anesthesiology. 2007;106(2): 226-237. 2. Takaenoki Y, Satoh Y, Araki Y, et al. Neonatal exposure to sevoflurane in mice causes deficits in maternal behavior later in adulthood. Anesthesiology. 2014;120(2):403-415. 3. 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. 4. Brambrink AM, Back SA, Riddle A, et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72 (4):525-535. 5. 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. 6. Morriss FH Jr, Saha S, Bell EF, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Surgery and neurodevelopmental outcome of very low-birth-weight infants [published online June 16, 2014]. JAMA Pediatr. doi: 10.1001/jamapediatrics.2014.307. 7. Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5): e1053-e1061. doi:10.1542/peds.2011-0351. 8. 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. doi:10.1542/peds .2011-3822.
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Copyright 2014 American Medical Association. All rights reserved.
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Editorial Opinion
9. Hansen TG, Flick R; Danish Registry Study Group; Mayo Clinic Pediatric Anesthesia and Learning Disabilities Study Group. Anesthetic effects on the developing brain: insights from epidemiology. Anesthesiology. 2009;110(1):1-3. 10. Williams RK. The pediatrician and anesthesia neurotoxicity. Pediatrics. 2011;128(5):e1268-e1270. doi:10.1542/peds.2011-2489. 11. Flick RP, Warner DOA. A users’ guide to interpreting observational studies of pediatric anesthetic neurotoxicity: the lessons of Sir Bradford Hill. Anesthesiology. 2012;117(3):459-462. 12. Williams RK, Adams DC, Black IH. While we wait. Anesth Analg. 2011;112(5):1239-1241. 13. McCann ME, Bellinger D, Arnup S, et al. The GAS study: perioperative outcomes in an RCT comparing spinal and general anesthesia for infant hernia
pyloromyotomy procedure. Paediatr Anaesth. 2003;13(1):32-37.
repair. Paper presented at: American Society of Anesthesiologists Annual Meeting; October 15, 2013; San Francisco, CA.
17. Williams RK, Adams DC, Aladjem EV, et al. The safety and efficacy of spinal anesthesia for surgery in infants: the Vermont Infant Spinal Registry. Anesth Analg. 2006;102(1):67-71.
14. Mathur AM, Neil JJ, McKinstry RC, Inder TE. Transport, monitoring, and successful brain MR imaging in unsedated neonates. Pediatr Radiol. 2008;38(3):260-264. 15. Batton DG, Barrington KJ, Wallman C; American Academy of Pediatrics Committee on Fetus and Newborn; American Academy of Pediatrics Section on Surgery; Canadian Paediatric Society Fetus and Newborn Committee. Prevention and management of pain in the neonate: an update. Pediatrics. 2006;118(5):2231-2241.
18. Williams RK, Black I, Howard D, et al. Cognitive outcome after spinal anesthesia and surgery during infancy. Anesth Analg. In press. 19. Rukewe A, Alonge T, Fatiregun A. Spinal anesthesia in children: no longer an anathema! Paediatr Anaesth. 2010;20(11):1036-1039.
16. Somri M, Gaitini LA, Vaida SJ, et al. The effectiveness and safety of spinal anaesthesia in the
Increasing Safe Teenaged Driving Time to Integrate the Growing Evidence Base Corinne Peek-Asa, PhD; Daniel V. McGehee, PhD; Beth E. Ebel, MD
Road traffic crashes, among the top 10 leading causes of death worldwide, are increasingly recognized as a public health priority.1 Regardless of a country’s licensing policies, novice drivers are at increased risk for crashes.2-4 In the United Related article page 764 States, which allows driving at a relatively young age (14-16 years), motor vehicle crashes are the leading cause of death for teenagers. With increasing awareness of the high motor vehicle crash rates among newly licensed teenaged drivers have come interventions to prevent crashes and reduce their health burden. Legislative approaches have been a major component of these interventions. For example, graduated driver’s licensure (GDL) policies limit risky driving situations (eg, teenaged passengers, mobile phone use, late night driving) and gradually allow more responsibility as new drivers gain driving experience. A strong body of research has demonstrated that GDL policies have been effective in reducing crashes in novice drivers,5,6 and a New Jersey license decal program that improved enforcement of GDL laws was also associated with lower crash incidence in new drivers.7 Although evaluations of other policies focused on young drivers such as zerotolerance alcohol policies are less frequent, they also generally show that policy approaches are effective.8 The presence of primary enforcement of seat belt laws, which reduce crash risk for all drivers, has been important in reducing serious injury and death when a crash has occurred and encourage seat belt use among older drivers who provide the role model for youth. Despite these policies, crash rates for teenaged drivers remain unacceptably high, and effective prevention programs are needed. An evidence base for teenaged driving interventions is emerging. Existing approaches have several goals: increase and/or improve supervised driving practice, which is primar-
ily done with parents; provide information to teenagers and parents about driving behavior and performance, thus allowing parents to be more informed about their teenager’s driving behavior; increase the role of parents in monitoring independent teenaged driving, usually through a contract that creates agreement in rules and expectations and provides increasing opportunities for independent driving; and increase and improve parent communication. Existing approaches also use a range of delivery methods, from passive information provided to teenagers and parents to in-vehicle video feedback devices.9-11 Research on innovative new methods for intervention delivery are needed, such as options for financial incentives through insurance programs, approaches for early identification and targeting of high-risk drivers, and programs that introduce a safe driving culture in early childhood. One challenge for this emerging field is to identify the “sweet spots” that balance the intervention’s reach to the optimal population with program cost, timing, and acceptability. For example, in-vehicle video devices show strong effects in reducing driving errors, but they are not easily scalable to a broad audience due to a perception of cost and initial concerns over invasion of privacy. However, they effectively provide objective information to parents and teenagers to identify “coachable” moments, with the goal of improving driving by learning from near-miss opportunities. At the other end of the spectrum, interventions that provide information to teenagers and parents through a variety of multimedia delivery methods are less expensive and have been less effective in the absence of driving laws. Aiming to fill the gap in evidence-based parent-focused interventions, Mirman and colleagues12 evaluated the Teen Driving Plan (TDP) in this issue of JAMA Pediatrics. The TDP aims to increase the quantity and diversity of parent-supervised driv-
jamapediatrics.com
JAMA Pediatrics August 2014 Volume 168, Number 8
Copyright 2014 American Medical Association. All rights reserved.
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703
