Special Articles  |   August 2004
Anesthetic Agents and the Immature Brain: Are These Toxic or Therapeutic?
Author Affiliations & Notes
  • Kanwaljeet J.S. Anand, M.B.B.S., D. Phil.
  • Sulpicio G. Soriano, M.D.
  • * Morris and Hettie Oakley Endowed Chair for Critical Care Medicine, Professor of Pediatrics, Anesthesiology, Pharmacology, Anatomy & Neurobiology, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, Arkansas; † Associate Professor of Anaesthesia, Harvard Medical School, Senior Associate in Anesthesia, Children’s Hospital, Boston, Massachusetts.
Article Information
Special Articles
Special Articles   |   August 2004
Anesthetic Agents and the Immature Brain: Are These Toxic or Therapeutic?
Anesthesiology 8 2004, Vol.101, 527-530. doi:
Anesthesiology 8 2004, Vol.101, 527-530. doi:
ABOUT 1.5 million fetuses or newborns are exposed to anesthetic agents each year.1 After their initial report in Science  2 suggesting that anesthetic drugs such as nitrous oxide, ketamine or other N  -methyl-d-aspartate receptor antagonists lead to enhanced apoptosis in immature neurons, Olney et al.  have reported that newborn rats exposed to commonly used anesthetic agents (isoflurane, midazolam, and nitrous oxide) also develop neurodegenerative changes in multiple areas of the brain, associated with long-term deficits in learning and memory.3 The same investigators have reported similar neurodegenerative changes in rat pups exposed to other anesthetic agents, anticonvulsant drugs, or ethanol2,4–7 and voiced their “concern that agents used in pediatric and obstetrical medicine for purposes of sedation, anesthesia, and seizure management may cause apoptotic neuronal death in the developing human brain.”5 This has led to public outcry over the long-term effects of anesthesia or sedation given to pregnant women or to newborn infants requiring surgical operations after birth.8–13 Calls for avoiding these agents in newborns raises the specter of surgical procedures being performed with minimal or no anesthesia, as was routine practice 20 years ago.14 
Accumulating data on the development of the pain-responsive15–19 and stress-responsive20–22 systems in the developing brain, together with increases in stress responses, morbidity, and mortality in lightly anesthetized neonates,23–25 have led to the routine use of anesthesia and postoperative analgesia even for critically ill newborns.26,27 Are the findings of Olney et al.  significant enough to withhold anesthesia from neonates undergoing surgical operations or other invasive procedures? This issue needs to be addressed urgently, especially as no clinician would like to withhold anesthetics during a surgical procedure nor would any wish to expose their neonatal patients to potentially neurotoxic drugs.
Anesthetic Agents and Neurodegenerative Mechanisms
Brain development in preterm and term neonates is characterized by naturally occurring neuronal death by apoptotic mechanisms.28–30 The cellular expression of regulator protein Bcl-2 and effector enzyme caspase-3 appear to mediate the increased vulnerability to neuronal apoptosis in the immature brain,31,32 which affects more than 50 percent of cortical neurons after 28 weeks of human gestation.28 An increased vulnerability to apoptosis is not limited to neurons but extends to immature oligodendroglia and astrocytes as well, particularly following free radical injury.33,34 Immature neurons are also susceptible to excitotoxic damage because of an increased magnitude of ligand-gated calcium currents mediated via  excitatory N  -methyl-d-aspartate receptors,35–37 ultimately leading to neuronal excitotoxic damage.38,39 
Accentuated neurodegenerative mechanisms in the immature brain thus increase neuronal susceptibility to various metabolic events (hypoglycemia, hypoxia, infection, ischemia, seizures) or exposure to anesthetic agents.40 Anesthetic and anticonvulsant drugs that block N  -methyl-d-aspartate receptors (e.g.  , ketamine) or activate γ-amino butyric acid-type A receptors (e.g.  , midazolam) consistently increase neuronal apoptosis in the neonatal brain,2–7 suggesting that the physiologic simulation of N  -methyl-d-aspartate receptors is necessary for neuronal synaptogenesis, differentiation, and survival during development. Lack of N  -methyl-d-aspartate receptor activation by glutamate decreases synaptogenesis and cell-to-cell interactions.41,42 Anesthetic agents directly suppress neuronal activation and also reduce extracellular concentrations of excitatory neurotransmitters,43 thereby reducing the developmental inputs to immature neurons.
In evaluating the clinical relevance of these findings, we must consider the major differences in complexity and adaptability between human and rodent brains and also the developmental differences between neonatal rats and humans.44,45 Additional methodological issues to be considered before extrapolating these results to neonatal anesthesia in humans include (a) a prolonged duration of exposure to anesthetic agents; (b) the nutritional and metabolic needs of neonates receiving general anesthesia; (c) the routine use of continuous respiratory, hemodynamic, and other forms of monitoring and support during anesthesia; (d) dose-related effects of certain anesthetic agents; and (e) divergent effects of anesthetic drugs given in the presence or absence of surgical pain or stress. Each of these issues is discussed below.
Duration of Exposure to Anesthetic Drugs
Neurodegenerative changes in the developing brain occurred following prolonged exposure to anesthesia in neonatal rats,2,6 confirming earlier findings from exposure to halothane or N  -methyl-d-aspartate receptor blockade.46,47 From a developmental perspective, this duration of exposure would be equivalent to producing general anesthesia for several weeks in the human neonate,44 which occurs rarely, if ever, in the clinical setting. Repeated ketamine injections increase neuronal cell death in multiple areas of the neonatal rat brain and lead to a significant decrease in weight gain.48 Rat pups receiving ketamine for 6–9 h exhibited poor feeding behavior and increased neurodegeneration, whereas single doses of ketamine did not affect weight gain or neuronal cell death. These studies suggest that prolonged exposure to anesthetic drugs may be an essential factor in this phenomenon.48 Although recent data presented at the annual meeting of the American Association for the Advancement of Science on February 14, 200449 suggest that brief exposure to alcohol or anesthetic drugs may also trigger two- to fourfold increases in neuronal apoptosis,50 it remains unclear whether these neurons would have died at later developmental stages and whether these transient increases in neuronal apoptosis have any long-term consequences.
Effects of Malnutrition on the Immature Brain
Rodent pups do not suckle during or after general anesthesia. Decreased weight gain following prolonged ketamine anesthesia points to the role of nutrition in early brain development.48 Clinical and experimental research have linked malnutrition to decreased brain growth and learning disabilities,51–53 although Olney et al.  do not report the nutritional support given or weight gain data from their experiments.2–7 The identification of milk in the gastric contents of neonatal rat pups does not imply adequate nutrition because both general anesthesia and breast milk significantly delay gastric emptying in neonates.54 Human neonates routinely receive nutritional support and metabolic monitoring in the perioperative period, thus minimizing the risks for hypoglycemia and impaired nutrition.
Anesthesia and Cerebral Oxygen Delivery
Anesthetic drugs suppress brain activity but also depress circulation and respiration in a dose-dependent manner, leading to decreased cerebral perfusion and hypoxia. Administration of anesthetic drugs to human neonates is accompanied by continuous monitoring of blood pressure, heart rate, and oxygen saturations, with multiple therapies aimed to optimize these parameters. Hypoxia and ischemia during prolonged anesthesia could easily trigger widespread neurodegeneration in the immature brain,55–57 given the lack of similar monitoring or support in newborn rat pups.2–7 
Dose-Related Effects of Anesthetic Agents
Anesthetic drugs also have dose-dependent cellular effects. For example, ketamine acts as an antiinflammatory agent at subanesthetic concentrations (0.1–0.5 μg/ml),58,59 whereas higher concentrations (50–200 μg/ml) produce a nonspecific cytostatic effect.60 High doses of ketamine may also promote seizures,61 a property shared by other anesthetic agents.62 The ketamine doses used by Ikonomidou et al.  2 (140 mg/kg) would be expected to produce cytostatic or epileptogenic effects in neonatal rats, which may significantly contribute to the neuronal apoptosis63,64 reported in these studies.
Anesthesia With and Without Painful Stimulation
Prolonged anesthesia produces a loss of developmentally important sensory inputs during this critical window, a condition that is perhaps not dissimilar from maternal separation.65 Repetitive pain and maternal separation in newborn rat pups lead to long-term changes in behavior,20,66,67 some of which are prevented by analgesic therapy.68,69 These data suggest that the long-term effects of analgesic/anesthetic drugs would depend on whether they are given in the presence or absence of painful stimulation. The clinical use of anesthetic agents occurs during painful stimulation, but Olney et al.  administered anesthesia without any painful stimulation. Based on the neuronal stimulation hypothesis,42 we speculate that painful stimuli during surgery activate N  -methyl-d-aspartate and other excitatory receptors in the immature brain and that therapeutic doses of anesthetic drugs will reduce extreme degrees of neuronal excitation.40,70 Thus, the effects of surgery without anesthesia as well as the effects of anesthesia without surgery may be detrimental to the developing brain. Clinical extrapolation from these rodent models2,5,6 requires that the experimental conditions should be similar to those associated with surgical anesthesia in human neonates.
Consequences of Withholding Anesthesia/Analgesia
In addition to humanitarian concerns, multiple lines of evidence support the necessity of adequate anesthesia in term or preterm neonates undergoing surgery. Short-term consequences of withholding anesthetic agents during neonatal surgery include an increased incidence of intraoperative and postoperative complications,23–25,71 leading to poor surgical outcomes.71–75 Long-term consequences of repetitive and prolonged pain in the neonatal period include prolonged changes in pain sensitivity and pain processing,76–79 as well as a variety of neurodevelopmental, behavioral, and cognitive deficits manifesting in later childhood.40,74,80–82 The evidence for improved clinical and developmental outcomes highlighting the importance of adequate anesthesia and pain control in the surgical neonate continues to mount, which must be weighed carefully against the recent experimental data showing the neurotoxic effects of anesthetic agents.
There is no doubt that prolonged exposure of newborn rat pups to anesthetic and anticonvulsant drugs leads to accelerated neurodegeneration and long-term behavioral deficits. Similarly, preterm and term neonates subjected to prolonged pain and surgical stress are also at risk for long-term adverse outcomes. Further investigations in this area may consider an experimental design in which the neurobiological and clinical effects of anesthesia with and without surgery are compared to increase its relevance to the clinical situation. Clearer understanding of the mechanisms by which exposures to pain/stress or prolonged anesthesia in the perinatal period can alter the survival or development of immature neurons and glia may prevent some long-term neurobehavioral abnormalities in humans. In the meantime, clinicians should administer anesthetic agents to newborn infants or pregnant mothers but avoid prolonged periods of anesthetic exposure. The experimental findings of Olney et al.  are certainly sound but it may be premature to apply them to clinical settings at this time. Alleviation of pain and stress during the perinatal period should remain an essential clinical goal until further research defines the clinical importance of these results.
AHRQ: HCUPnet: Healthcare Cost and Utilization Project. Rockville, MD, Agency for Healthcare Research and Quality, 2001AHRQ, Rockville, MD Agency for Healthcare Research and Quality
Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW: Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283:70–4Ikonomidou, C Bosch, F Miksa, M Bittigau, P Vockler, J Dikranian, K Tenkova, TI Stefovska, V Turski, L Olney, JW
Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF: Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23:876–82Jevtovic-Todorovic, V Hartman, RE Izumi, Y Benshoff, ND Dikranian, K Zorumski, CF Olney, JW Wozniak, DF
Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price MT, Stefovska V, Horster F, Tenkova T, Dikranian K, Olney JW: Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287:1056–60Ikonomidou, C Bittigau, P Ishimaru, MJ Wozniak, DF Koch, C Genz, K Price, MT Stefovska, V Horster, F Tenkova, T Dikranian, K Olney, JW
Ikonomidou C, Bittigau P, Koch C, Genz K, Hoerster F, Felderhoff-Mueser U, Tenkova T, Dikranian K, Olney JW: Neurotransmitters and apoptosis in the developing brain. Biochem Pharmacol 2001; 62:401–5Ikonomidou, C Bittigau, P Koch, C Genz, K Hoerster, F Felderhoff-Mueser, U Tenkova, T Dikranian, K Olney, JW
Olney JW, Wozniak DF, Jevtovic-Todorovic V, Farber NB, Bittigau P, Ikonomidou C: Drug-induced apoptotic neurodegeneration in the developing brain. Brain Pathol 2002; 12:488–98Olney, JW Wozniak, DF Jevtovic-Todorovic, V Farber, NB Bittigau, P Ikonomidou, C
Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, Dzietko M, Pesditschek S, Mai I, Dikranian K, Olney JW, Ikonomidou C: Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A 2002; 99:15089–94Bittigau, P Sifringer, M Genz, K Reith, E Pospischil, D Govindarajalu, S Dzietko, M Pesditschek, S Mai, I Dikranian, K Olney, JW Ikonomidou, C
Morgan K: Mind numbing: Anesthesia in baby rats stunts brain development, Science News 2003; 163:87Morgan, K
Dryden J, Beard B: Common pediatric anesthesia drugs cause brain damage and learning and memory problems in infant rats. St. Louis: Washington University News Release 075FAD9, January 31, 2003
Carey J: Common general anesthetics given at an early age may cause brain damage, other neurologic problems. Washington, D.C.: Society for Neuroscience News Release (NR-03–03), February 10, 2003.
Dryden J: Common anesthetics and drugs of abuse damage the developing brain. St. Louis: Washington University News Release, January 1, 1999
Dryden J: Small amounts of alcohol or anesthetics may damage the developing brain. St. Louis: Washington University News Release, February 13, 2004
Kong D: Study renews debate on psychosis-inducing research. Boston Globe February 22, 1999, Health & Science Section, pp. E1
Betts EK, Downes JJ: Anesthetic considerations in newborn surgery. Semin Anesth 1984; 3:59–74Betts, EK Downes, JJ
Anand KJS, Hickey PR: Special Article: Pain and its effects in the human neonate and fetus. N Engl J Med 1987; 317:1321–9Anand, KJS Hickey, PR
Fitzgerald M: Cutaneous primary afferent properties in the hind limb of the neonatal rat. J Physiol 1987; 383:79–92Fitzgerald, M
Fitzgerald M, Shaw A, MacIntosh N: The postnatal development of the cutaneous flexor reflex: a comparative study in premature infants and newborn rat pups. Dev Med Child Neurol 1988; 30:520–6Fitzgerald, M Shaw, A MacIntosh, N
Fitzgerald M, McIntosh N: Pain and analgesia in the newborn. Arch Dis Child 1989; 64:441–3Fitzgerald, M McIntosh, N
Fitzgerald M: The development of activity evoked by fine diameter cutaneous fibres in the spinal cord of the newborn rat. Neurosci Lett 1988; 86:161–6Fitzgerald, M
Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ: Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 1997; 277:1659–62Liu, D Diorio, J Tannenbaum, B Caldji, C Francis, D Freedman, A Sharma, S Pearson, D Plotsky, PM Meaney, MJ
Meaney MJ, Bhatnagar S, Diorio J, Larocque S, Francis D, O’Donnell D, Shanks N, Sharma S, Smythe J, Viau V: Molecular basis for the development of individual differences in the hypothalamic-pituitary-adrenal stress response. Cell Mol Neurobiol 1993; 13:321–47Meaney, MJ Bhatnagar, S Diorio, J Larocque, S Francis, D O’Donnell, D Shanks, N Sharma, S Smythe, J Viau, V
Plotsky PM, Meaney MJ: Early postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats. Molecular Brain Res 1993; 18:195–200Plotsky, PM Meaney, MJ
Anand KJS, Sippell WG, Aynsley-Green A: Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987; 1:243–8Anand, KJS Sippell, WG Aynsley-Green, A
Anand KJS, Sippell WG, Schofield NM, Aynsley-Green A: Does halothane anaesthesia decrease the metabolic and endocrine stress responses of newborn infants undergoing operation? Br Med J (Clin Res Ed) 1988; 296:668–72Anand, KJS Sippell, WG Schofield, NM Aynsley-Green, A
Anand KJS, Hickey PR: Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992; 326:1–9Anand, KJS Hickey, PR
Menon G, Anand KJS, McIntosh N: Practical approach to analgesia and sedation in the neonatal intensive care unit. Semin Perinatol 1998; 22:417–24Menon, G Anand, KJS McIntosh, N
Berde CB, Sethna NF: Analgesics for the treatment of pain in children. N Engl J Med 2002; 347:1094–103Berde, CB Sethna, NF
Rabinowicz T, de Courten-Myers GM, Petetot JM, Xi G, de los Reyes E: Human cortex development: estimates of neuronal numbers indicate major loss late during gestation. J Neuropathol Exp Neurol 1996; 55:320–8Rabinowicz, T de Courten-Myers, GM Petetot, JM Xi, G de los Reyes, E
Kuan CY, Roth KA, Flavell RA, Rakic P: Mechanisms of programmed cell death in the developing brain. Trends Neurosci 2000; 23:291–7Kuan, CY Roth, KA Flavell, RA Rakic, P
Dikranian K, Ishimaru MJ, Tenkova T, Labruyere J, Qin YQ, Ikonomidou C, Olney JW: Apoptosis in the in vivo  mammalian forebrain. Neurobiol Dis 2001; 8:359–79Dikranian, K Ishimaru, MJ Tenkova, T Labruyere, J Qin, YQ Ikonomidou, C Olney, JW
Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA: Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 1998; 18:3659–68Namura, S Zhu, J Fink, K Endres, M Srinivasan, A Tomaselli, KJ Yuan, J Moskowitz, MA
Mooney S, Miller M: Expression of bcl-2, bax, and caspase-3 in the brain of the developing rat. Dev Brain Res 2000; 123:103–17Mooney, S Miller, M
Volpe JJ: Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res 2001; 50:553–62Volpe, JJ
Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ: Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci 1998; 18:6241–53Back, SA Gan, X Li, Y Rosenberg, PA Volpe, JJ
Rao H, Jean A, Kessler JP: Postnatal ontogeny of glutamate receptors in the rat nucleus tractus solitarii and ventrolateral medulla. J Auton Nerv Syst 1997; 65:25–32Rao, H Jean, A Kessler, JP
Chahal H, D’Souza SW, Barson AJ, Slater P: Modulation by magnesium of N-methyl-D-aspartate receptors in developing human brain. Arch Dis Child Fetal Neonatal Ed 1998; 78:F116–20Chahal, H D’Souza, SW Barson, AJ Slater, P
Ritter LM, Unis AS, Meador-Woodruff JH: Ontogeny of ionotropic glutamate receptor expression in human fetal brain. Brain Res Dev Brain Res 2001; 127:123–33Ritter, LM Unis, AS Meador-Woodruff, JH
McDonald JW, Silverstein FS, Johnston MV: Neurotoxicity of N  -methyl-d-aspartate is markedly enhanced in developing rat central nervous system. Brain Res 1988; 459:200–3McDonald, JW Silverstein, FS Johnston, MV
Mitani A, Watanabe M, Kataoka K: Functional change of NMDA receptors related to enhancement of susceptibility to neurotoxicity in the developing pontine nucleus. J Neurosci 1998; 18:7941–52Mitani, A Watanabe, M Kataoka, K
Bhutta AT, Anand KJS: Vulnerability of the developing brain: Neuronal mechanisms. Clin Perinatol 2002; 29:357–72Bhutta, AT Anand, KJS
Rakic P, Komuro H: The role of receptor/channel activity in neuronal cell migration. J Neurobiol 1995; 26:299–315Rakic, P Komuro, H
Lipton SA, Nakanishi N: Shakespeare in love—with NMDA receptors? Nat Med 1999; 5:270–1Lipton, SA Nakanishi, N
Rozza A, Masoero E, Favalli L, Lanza E, Govoni S, Rizzo V, Montalbetti L: Influence of different anesthetics on extracellular amino acids in rat brain. J Neurosci Methods 2000; 101:165–9Rozza, A Masoero, E Favalli, L Lanza, E Govoni, S Rizzo, V Montalbetti, L
Clancy B, Darlington RB, Finlay BL: Translating developmental time across mammalian species. Neuroscience 2001; 105:7–17Clancy, B Darlington, RB Finlay, BL
Berde CB, Cairns B: Developmental pharmacology across species: Promise and problems. Anesth Analg 2000; 91:1–5Berde, CB Cairns, B
Griesbach GS, Amsel A: Immediate and long-term effects of neonatal MK-801 treatment on non-spatial learning. Proc Natl Acad Sci U S A 1998; 95:11435–9Griesbach, GS Amsel, A
Uemura E, Levin ED, Bowman RE: Effects of halothane on synaptogenesis and learning behavior in rats. Exp Neurol 1985; 89:520–9Uemura, E Levin, ED Bowman, RE
Hayashi H, Dikkes P, Soriano SG: Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain. Paediatr Anaesth 2002; 12:770–4Hayashi, H Dikkes, P Soriano, SG
Olney JW, Streissguth A, Susser E, Zorumski C: Pediatric medicines and alcohol cause developing neurons to commit suicide. American Association for the Advancement of Science (AAAS) Annual Meeting. Seattle: American Association for the Advancement of Science (AAAS), 2004, pp 1073Olney, JW Streissguth, A Susser, E Zorumski, C Seattle American Association for the Advancement of Science (AAAS)
Olney JW: Perinatal drug/alcohol exposure and neuronal suicide—Public health implications. American Association for the Advancement of Science (AAAS) Annual Meeting. Seattle: American Association for the Advancement of Science (AAAS), 2004, pp 1073Olney, JW Seattle American Association for the Advancement of Science (AAAS)
Dobbing J: Undernutrition and the developing brain: the relevance of animal models to the human problem. Am J Dis Child 1970; 120:411–5Dobbing, J
Lucas A, Morley R, Cole TJ, Gore SM, Lucas PJ, Crowle P, Pearse R, Boon AJ, Powell R: Early diet in preterm babies and developmental status at 18 months. Lancet 1990; 335:1477–81Lucas, A Morley, R Cole, TJ Gore, SM Lucas, PJ Crowle, P Pearse, R Boon, AJ Powell, R
Lucas A, Morley R, Cole TJ: Randomised trial of early diet in preterm babies and later intelligence quotient. Br Med J 1998; 317:1481–7Lucas, A Morley, R Cole, TJ
Litman RS, Wu CL, Quinlivan JK: Gastric volume and pH in infants fed clear liquids and breast milk prior to surgery. Anesth Analg 1994; 79:482–5Litman, RS Wu, CL Quinlivan, JK
Nagata N, Saji M, Ito T, Ikeno S, Takahashi H, Terakawa N: Repetitive intermittent hypoxia-ischemia and brain damage in neonatal rats. Brain Dev 2000; 22:315–20Nagata, N Saji, M Ito, T Ikeno, S Takahashi, H Terakawa, N
Otoya RE, Seltzer AM, Donoso AO: Acute and long-lasting effects of neonatal hypoxia on (+)-3-[125I]MK-801 binding to NMDA brain receptors. Exp Neurol 1997; 148:92–9Otoya, RE Seltzer, AM Donoso, AO
Delivoria-Papadopoulos M, Mishra OP: Mechanisms of cerebral injury in perinatal asphyxia and strategies for prevention. J Pediatr 1998; 132:S30–4Delivoria-Papadopoulos, M Mishra, OP
Zilberstein G, Levy R, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Appelbaum A, Roytblat L: Ketamine attenuates neutrophil activation after cardiopulmonary bypass. Anesth Analg 2002; 95:531–6Zilberstein, G Levy, R Rachinsky, M Fisher, A Greemberg, L Shapira, Y Appelbaum, A Roytblat, L
Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, Gurman GM, Shapira Y, Duvdenani A: Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998; 87:266–71Roytblat, L Talmor, D Rachinsky, M Greemberg, L Pekar, A Appelbaum, A Gurman, GM Shapira, Y Duvdenani, A
Lewis E, Rogachev B, Shaked G, Douvdevani A: The in vitro  effects of Ketamine at large concentrations can be attributed to a nonspecific cytostatic effect. Anesth Analg 2001; 92:927–9Lewis, E Rogachev, B Shaked, G Douvdevani, A
Lees GJ: Influence of ketamine on the neuronal death caused by NMDA in the rat hippocampus. Neuropharmacology 1995; 34:411–7Lees, GJ
Roytblat L, Bear R, Gesztes T: Seizures after pentazocine overdose. Isr J Med Sci 1986; 22:385–6Roytblat, L Bear, R Gesztes, T
Jensen FE: The role of glutamate receptor maturation in perinatal seizures and brain injury. Int J Dev Neurosci 2002; 20:339–47Jensen, FE
Wasterlain CG, Shirasaka Y: Seizures, brain damage and brain development. Brain Dev 1994; 16:279–95Wasterlain, CG Shirasaka, Y
Anand KJS, Scalzo FM: Can adverse neonatal experiences alter brain development and subsequent behavior? Biol Neonate 2000; 77:69–82Anand, KJS Scalzo, FM
Ruda MA, Ling Q-D, Hohmann AG, Peng YB, Tachibana T: Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science 2000; 289:628–31Ruda, MA Ling, Q-D Hohmann, AG Peng, YB Tachibana, T
Anand KJS, Coskun V, Thrivikraman KV, Nemeroff CB, Plotsky PM: Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav 1999; 66:627–37Anand, KJS Coskun, V Thrivikraman, KV Nemeroff, CB Plotsky, PM
Bhutta AT, Rovnaghi CR, Simpson PM, Gosset JM, Scalzo FM, Anand KJS: Interactions of inflammatory pain and morphine treatment in infant rats: Long-term behavioral effects. Physiol Behav 2001; 73:51–8Bhutta, AT Rovnaghi, CR Simpson, PM Gosset, JM Scalzo, FM Anand, KJS
Rahman W, Fitzgerald M, Aynsley-Green A, Dickenson AH: The effects of neonatal exposure to inflammation and/or morphine on neuronal responses and morphine analgesia in adult rats. Proceedings of the 8th World Congress on Pain. Edited by Jensen TS, Turner JA, Wiesenfeld-Hallin Z. Seattle: IASP Press, 1997, pp 783–794Rahman, W Fitzgerald, M Aynsley-Green, A Dickenson, AH The effects of neonatal exposure to inflammation and/or morphine on neuronal responses and morphine analgesia in adult rats.Jensen TS, Turner JA, Wiesenfeld-Hallin Z Seattle IASP Press
Bhutta AT, Anand KJS: Abnormal cognition and behavior in preterm neonates linked to smaller brain volumes. Trends Neurosci 2001; 24:129–130Bhutta, AT Anand, KJS
Anand KJS: Relationships between stress responses and clinical outcome in newborns, infants, and children. Crit Care Med 1993; 21:S358–9Anand, KJS
Bouwmeester NJ, Anand KJS, van Dijk M, Hop WC, Boomsma F, Tibboel D: Hormonal and metabolic stress responses after major surgery in children aged 0–3 years: A double-blind, randomized trial comparing the effects of continuous versus intermittent morphine. Br J Anaesth 2001; 87:390–9Bouwmeester, NJ Anand, KJS van Dijk, M Hop, WC Boomsma, F Tibboel, D
Furdon SA, Eastman M, Benjamin K, Horgan MJ: Outcome measures after standardized pain management strategies in postoperative patients in the neonatal intensive care unit. J Perinat Neonatal Nurs 1998; 12:58–69Furdon, SA Eastman, M Benjamin, K Horgan, MJ
Rossi AF, Seiden HS, Sadeghi AM, Nguyen KH, Quintana CS, Gross RP, Griepp RB: The outcome of cardiac operations in infants weighing two kilograms or less. J Thorac Cardiovasc Surg 1998; 116:28–35Rossi, AF Seiden, HS Sadeghi, AM Nguyen, KH Quintana, CS Gross, RP Griepp, RB
van Lingen RA, Simons SH, Anderson BJ, Tibboel D: The effects of analgesia in the vulnerable infant during the perinatal period. Clin Perinatol 2002; 29:511–34van Lingen, RA Simons, SH Anderson, BJ Tibboel, D
Whitfield MF, Grunau RE: Behavior, pain perception, and the extremely low-birth weight survivor. Clin Perinatol 2000; 27:363–79Whitfield, MF Grunau, RE
Taddio A, Shah V, Gilbert-MacLeod C, Katz J: Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA 2002; 288:857–61Taddio, A Shah, V Gilbert-MacLeod, C Katz, J
Mitchell A, Boss BJ: Adverse effects of pain on the nervous systems of newborns and young children: A review of the literature. J Neurosci Nurs 2002; 34:228–36Mitchell, A Boss, BJ
Anand KJS: Pain, plasticity, and premature birth: A prescription for permanent suffering? Nat Med 2000; 6:971–3Anand, KJS
Tobiansky R, Lui K, Roberts S, Veddovi M: Neurodevelopmental outcome in very low birthweight infants with necrotizing enterocolitis requiring surgery. J Paediatr Child Health 1995; 31:233–6Tobiansky, R Lui, K Roberts, S Veddovi, M
Chacko J, Ford WD, Haslam R: Growth and neurodevelopmental outcome in extremely-low-birth-weight infants after laparotomy. Pediatr Surg Int 1999; 15:496–9Chacko, J Ford, WD Haslam, R
McLendon D, Check J, Carteaux P, Michael L, Moehring J, Secrest JW, Clark SE, Cohen H, Klein SA, Boyle D, George JA, Okuno-Jones S, Buchanan DS, McKinley P, Whitfield JM: Implementation of potentially better practices for the prevention of brain hemorrhage and ischemic brain injury in very low birth weight infants. Pediatrics 2003; 111:e497–503McLendon, D Check, J Carteaux, P Michael, L Moehring, J Secrest, JW Clark, SE Cohen, H Klein, SA Boyle, D George, JA Okuno-Jones, S Buchanan, DS McKinley, P Whitfield, JM