Neuroprotective treatment for perinatal asphyxia

Anne Lee Solevåg, Britt Nakstad About the authors

Perinatal asphyxia is caused by a number of conditions that occur during the perinatal period and which lead to hypoxia, ischaemia, hypercapnia and metabolic acidosis (1). Symptoms and findings that indicate perinatal asphyxia include hypoxic ischaemic encephalopathy (HIE) with (sub-)clinical seizures and reduced level of consciousness. Some causes of perinatal asphyxia are shown in Table 1. Perinatal asphyxia occurs in 1 – 10 of 1 000 births, with a different incidence in different parts of the world. The condition causes more than 800 000 deaths in the neonatal period per year worldwide and a substantial proportion of the children that survive suffer late effects such as cerebral palsy and epilepsy (3).

Table 1  Some causes of perinatal asphyxia, grouped into conditions before (antepartum), during (intrapartum) and after birth (postpartum) (2)




Umbilical cord compression

Umbilical cord compression

Respiratory depression due to opiates in mother’s circulatory system



Obstructed airway



Congenital sepsis

Uterine hyperactivity

Uterine hyperactivity (for example as a result of over-stimulation)

Congenital heart defect and / or lung anomalies

Placental abruption

Placental abruption

Placental dysfunction

Uterine rupture

Birth dystocia

Traumatic delivery/birth trauma

The mechanisms that cause neurological damage after perinatal asphyxia are divided schematically into three metabolic phases (4) (Fig. 1) (5, 6), and the objective of the treatment is to limit ongoing damage to cells. Hypoxia leads to primary energy failure (phase 1), but a short time after reoxygenation, aerobic metabolism and cell functions are re-established (phase 2). However, as a result of a cascade of cellular mechanisms (7, 8), after this «latent phase» of 6 – 24 hours mitochondrial energy production again begins to fail. This secondary energy failure (phase 3) lasts for 24 – 48 hours after the hypoxic event. The damage that occurs during this phase is considerable (9). Neuroprotective treatment targeting the «latent phase» may limit the secondary neuron damage due to perinatal asphyxia (5) (Fig. 1). New knowledge about cellular repair mechanisms can also pave the way for types of treatment that not merely limit damage, but can also repair defects in the immature nervous system (10).

Figure 1  The three metabolic phases after perinatal asphyxia. The secondary energy failure with subsequent damage can be limited by applying measures during the latent phase. The latent phase is therefore also called «the window of opportunity» (5, 6)

The purpose of this article is to provide an overview of established measures to limit neurological damage after perinatal asphyxia. Since these are limited in number, a selection of proposed strategies that appear promising for the future treatment of perinatal asphyxia is also presented.


We searched in the Medline and Cochrane Library databases on the search terms «perinatal asphyxia», «asphyxia neonatorum», «hypoxic ischemic encephalopathy» OR «hypoxia-ischemia, brain»; «treatment», «therapeutics» OR «neuroprotective agents» AND «infant, newborn». No restrictions were placed on the age of the publications. Only publications in English were included. The search was concluded on 9 December 2011. An overwhelming number of potential treatments were identified. On the basis of discussions with leading specialists in neonatal research, published abstracts from international paediatrics congresses in 2011 and publications from our own research group, we are presenting the interventions that appear most promising following a discretionary appraisal. We have also included more innovative methods based on research at our own institute, such as cell-based treatment and DNA repair mechanisms. These methods are discussed in 44 Medline-indexed articles and a Cochrane overview from our literature search. The remaining references in this article are about asphyxia and mechanisms generally and do not deal with neuroprotection in particular.


Mechanisms that lead to cell damage after perinatal asphyxia are presented schematically in Fig. 2 (11). In the following, neuroprotective strategies are grouped according to where in this chain they act. For the sake of simplicity, each strategy is presented under a single heading, even though many treatments have more than one mechanism. The strategies are also classified as non-medicinal, medicinal or cell-based.

Figure 2  Schematic presentation of some of the mechanisms underlying neurological damage after perinatal asphyxia. During hypoxia, iron is released from its binding to proteins. Free iron (Fe2+) reacts with hydrogen peroxide (H₂O₂) and forms the toxic hydroxyl radical (OH.) (Fenton reaction) (11). NMDA = N-methyl-D-aspartate

Non-medicinal treatment

General. Prevention through good perinatal care and appropriate treatment and stabilisation immediately after birth are important. Experimental and clinical studies have shown that hyperoxia after perinatal asphyxia exacerbates damage in both animals and humans (12, 13). Since the use of extra oxygen in resuscitation after asphyxia does not improve the short-term outcome clinically or experimentally either (14, 15), hyperoxia should be avoided and moderate hypoxaemia should possibly even be sought (16).

Hypothermia. Therapeutic hypothermia for moderate to severe perinatal asphyxia has become established treatment (17). Studies have shown that hypothermia reduces cellular energy utilisation (18), anaerobic metabolism and the formation of free radicals (19). Hypothermia also reduces the release of glutamate (19) and proapoptotic factors (6). In Norway, hypothermia treatment of newborns is a centralised task, and is performed according to a standardised protocol from the large, randomised clinical hypothermia trials (20 – 22). All maternity units are to have routines for transfer to regional cooling centres of newborns with a gestation age ≥ 36 weeks with moderate to severe perinatal asphyxia, even though randomised clinical trials have shown hypothermia to be the most effective for moderate asphyxia (23). Cooling must be initiated within six hours of the hypoxic event (in practice most often from the time of birth) and may take the form of whole body hypothermia or selective cooling of the head. With whole body hypothermia as practised in Norway, moderate hypothermia is sought, defined as rectal temperature of 33.5°C for 72 hours before gradual re-warming.

Medicinal treatment

Antioxidant effect. Allopurinol is used to treat gout and inhibits hypoxanthine catabolism, which generates free radicals after hypoxia/ischaemia (24) (Fig. 2). Allopurinol also acts by directly neutralising free radicals and binds free iron which is released from proteins by hypoxia (25). Free iron reacts with hydrogen peroxide and forms toxic hydroxyl radicals (11).

A Cochrane review from 2010 (26) included three randomised clinical trials (24, 27, 28). In these trials, allopurinol administered intravenously within two and four hours of birth in a total dose of 40 mg/kg did not result in a reduction in mortality, seizure frequency or number of pathological findings in cerebral imaging in the neonatal period. However, allopurinol treatment reduced the incidence of the combined outcome of death and severe handicap at the age of four to eight years when the children with the most severe asphyxia were excluded from the analysis (29). A clinical trial of antenatal allopurinol is in progress (30).

N-acetyl cysteine is used as a mucous-clearing treatment and for paracetamol overdose. N-acetyl cysteine is claimed to traverse the placenta and blood-brain barrier (31), can be safely used during pregnancy (32) and is a source of L-cysteine which is necessary for the formation of the endogenous antioxidant glutathione (31). Studies of neonatal pigs have shown that N-acetyl cysteine administered as an intravenous bolus of 150 mg/kg or 30 mg/kg ten or five minutes after the start of reoxygenation, followed by 100 mg/kg/hour or 20 mg/kg/hour reduces oxidative stress after hypoxia/ischaemia and improves systemic and cerebral haemodynamics (33, 34).

Glutamate antagonists. Xenon is a glutamate N-methyl-D-aspartate receptor antagonist (NMDA receptor antagonist) and has neuroprotective effects both in vitro (35) and in vivo (7). Inhalation of 5011% xenon for 18 hours combined with therapeutic hypothermia is undergoing clinical testing (Marianne Thoresen, unpublished lecture, Pediaterdagene [Paediatric days] 2012).

In addition to neuroprotection, xenon stabilises cardiovascular functions (36) and protects the myocardium (37).

One major disadvantage of xenon is that the gas is rare and expensive. Researchers who study xenon inhalation in newborns have therefore developed systems for recycling the gas in a closed system (38).

Anti-inflammatory treatment. Erythropoietin (EPO) is a haematopoietic hormone that also has receptors elsewhere than in haematopoietic tissue, including the brain (39).

As well as having an anti-inflammatory effect, EPO can reduce brain damage after hypoxia through reduced nitric oxide (NO) production (40), inhibited glutamate toxicity (41) and reduced lipid peroxidation (42). Neuronal anti-apoptotic mechanisms, angiogenesis and neurogenesis are also stimulated and modulated (43).

300 units/kg or 500 units/kg recombinant EPO administered subcutaneously within 48 hours of birth have been shown to improve the neurological outcome after perinatal asphyxia, with the most pronounced effect on girls (44). Higher doses (2 500 units/kg) given within 4 – 6 hours to newborns with mild/moderate hypoxic ischaemic encephalopathy have also had a positive effect on seizure control, EEG background activity and neurological development at the age of six months (45). Trials are now being conducted on EPO combined with hypothermia treatment.

Cell-based treatment

Stem cell treatment. Stem cell treatment can be administered by stimulating endogenous stem cells or by transplanting exogenous stem cells. There is a theoretical rationale supported by experimental animal studies to the effect that the administration or stimulation of neurotrophic factors/growth factors such as EPO, insulin-like growth factors and brain-derived neurotrophic factors can reduce brain damage after perinatal asphyxia (46 – 49). Mesenchymal stem cells from umbilical cord blood are possibly the most promising option for exogenous stem cell treatment of brain damage after perinatal asphyxia (50).

DNA repair enzymes. Hypoxia leads to damage to DNA bases. Endogenous repair mechanisms involve DNA repair enzymes including DNA glycosylases. Sejersted et al. recently published a study of the DNA glycosylase Neil-3 (endonuclease VIII-like 3) (10). In this study, Neil-3 knockout mice had a reduced ability to regenerate damaged brain tissue, probably as a result of both reduced proliferation of neuronal progenitors and inhibition of the ability to differentiate into mature neurons. The knowledge yielded by these findings provides a basis for treatment targeting endogenous repair mechanisms.


Hypothermia is currently the only neuroprotective treatment with a documented efficacy and safety profile in randomised clinical trials (20 – 22). However, the number needed to treat in order for one to survive without moderate to severe sequelae is 8 – 9, and almost half of all children treated with hypothermia suffer permanent neurological damage (23). There is therefore a need to optimise this form of treatment, for example by starting cooling earlier, changing the depth (temperature) of cooling and/or giving supplements of potentiating drugs.

Preclinical and clinical research now focuses on the additive or synergistic effects of hypothermia in combination with other neuroprotective treatment options (51, 52). Hypothermia changes the mechanisms of injury after perinatal asphyxia, as well as the pharmacokinetics and pharmacodynamics of drugs. It is therefore necessary to make a thorough study of the optimal time window, doses and any side effects both in vitro and in animals before clinical trials take place.

A combination of treatment methods targeting different mechanisms of injury may be necessary for achieving the best possible outcome after perinatal asphyxia. Today xenon, EPO and allopurinol treatment are the most convincing, and randomised clinical trials are on the way. Cell-based treatment methods and treatment targeting antioxidant defence also appear promising and may be important in future treatment of infants affected by asphyxia.


Measures to limit neurological damage after perinatal asphyxia focus on the «latent phase» 6 – 24 hours after the time when the damage occurred

Therapeutic hypothermia is currently the only established treatment for perinatal asphyxia

Xenon gas, allopurinol and erythropoietin may possibly reinforce the neuroprotective effect of therapeutic hypothermia

The article is based on a trial lecture by a doctoral candidate at the Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 9 December 2011.


Rennie JM. Roberton’s textbook of neonatology. London: Churchill Livingstone, 2005: 1128.


McGuire W. Perinatal asphyxia. Clin Evid 2006; nr. 15: 511 – 9. [PubMed]


Black RE, Cousens S, Johnson HL et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375: 1969 – 87. [PubMed] [CrossRef]


Lorek A, Takei Y, Cady EB et al. Delayed («secondary») cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res 1994; 36: 699 – 706. [PubMed] [CrossRef]


Gunn AJ, Gunn TR, de Haan HH et al. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997; 99: 248 – 56. [PubMed] [CrossRef]


Roelfsema V, Bennet L, George S et al. Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep. J Cereb Blood Flow Metab 2004; 24: 877 – 86. [PubMed] [CrossRef]


Hobbs C, Thoresen M, Tucker A et al. Xenon and hypothermia combine additively, offering long-term functional and histopathologic neuroprotection after neonatal hypoxia/ischemia. Stroke 2008; 39: 1307 – 13. [PubMed] [CrossRef]


Kittaka M, Giannotta SL, Zelman V et al. Attenuation of brain injury and reduction of neuron-specific enolase by nicardipine in systemic circulation following focal ischemia and reperfusion in a rat model. J Neurosurg 1997; 87: 731 – 7. [PubMed] [CrossRef]


Vannucci RC, Towfighi J, Vannucci SJ. Secondary energy failure after cerebral hypoxia-ischemia in the immature rat. J Cereb Blood Flow Metab 2004; 24: 1090 – 7. [PubMed] [CrossRef]


Sejersted Y, Hildrestrand GA, Kunke D et al. Endonuclease VIII-like 3 (Neil3) DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia. Proc Natl Acad Sci U S A 2011; 108: 18802 – 7. [PubMed] [CrossRef]


Bolann BJ, Ulvik RJ. Release of iron from ferritin by xanthine oxidase. Role of the superoxide radical. Biochem J 1987; 243: 55 – 9. [PubMed]


Vento M, Asensi M, Sastre J et al. Oxidative stress in asphyxiated term infants resuscitated with 10011% oxygen. J Pediatr 2003; 142: 240 – 6. [PubMed] [CrossRef]


Munkeby BH, Børke WB, Bjørnland K et al. Resuscitation with 10011% O2 increases cerebral injury in hypoxemic piglets. Pediatr Res 2004; 56: 783 – 90. [PubMed] [CrossRef]


Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: the Resair 2 study. Pediatrics 1998; 102: e1. [PubMed] [CrossRef]


Solevåg AL, Dannevig I, Nakstad B et al. Resuscitation of severely asphyctic newborn pigs with cardiac arrest by using 2111% or 10011% oxygen. Neonatology 2010; 98: 64 – 72. [PubMed] [CrossRef]


Niatsetskaya ZV, Charlagorla P, Matsukevich DA et al. Mild hypoxemia during initial reperfusion alleviates the severity of secondary energy failure and protects brain in neonatal mice with hypoxic-ischemic injury. J Cereb Blood Flow Metab 2012; 32: 232 – 41. [PubMed] [CrossRef]


Perlman JM, Wyllie J, Kattwinkel J et al. Part 11: Neonatal resuscitation: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010; 122 (suppl 2): S516 – 38. [PubMed] [CrossRef]


Laptook AR, Corbett RJ, Sterett R et al. Quantitative relationship between brain temperature and energy utilization rate measured in vivo using 31P and 1H magnetic resonance spectroscopy. Pediatr Res 1995; 38: 919 – 25. [PubMed] [CrossRef]


Thoresen M, Satas S, Puka-Sundvall M et al. Post-hypoxic hypothermia reduces cerebrocortical release of NO and excitotoxins. Neuroreport 1997; 8: 3359 – 62. [PubMed] [CrossRef]


Azzopardi DV, Strohm B, Edwards AD et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009; 361: 1349 – 58. [PubMed] [CrossRef]


Gluckman PD, Wyatt JS, Azzopardi D et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365: 663 – 70. [PubMed]


Shankaran S, Laptook AR, Ehrenkranz RA et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353: 1574 – 84. [PubMed] [CrossRef]


Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med 2007; 161: 951 – 8. [PubMed] [CrossRef]


Benders MJ, Bos AF, Rademaker CM et al. Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Arch Dis Child Fetal Neonatal Ed 2006; 91: F163 – 5. [PubMed] [CrossRef]


Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 2006; 58: 87 – 114. [PubMed] [CrossRef]


Chaudhari T, McGuire W. Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy. Cochrane Database Syst Rev 2008; nr. 2: CD006817. [PubMed]


Gunes T, Ozturk MA, Koklu E et al. Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns. Pediatr Neurol 2007; 36: 17 – 24. [PubMed] [CrossRef]


Van Bel F, Shadid M, Moison RM et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics 1998; 101: 185 – 93. [PubMed] [CrossRef]


Kaandorp JJ, van Bel F, Veen S et al. Long-term neuroprotective effects of allopurinol after moderate perinatal asphyxia: follow-up of two randomised controlled trials. Arch Dis Child Fetal Neonatal Ed 2012; 97: F162 – 6. [PubMed] [CrossRef]


Kaandorp JJ, Benders MJ, Rademaker CM et al. Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study. BMC Pregnancy Childbirth 2010; 10: 8. [PubMed] [CrossRef]


Farr SA, Poon HF, Dogrukol-Ak D et al. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 2003; 84: 1173 – 83. [PubMed] [CrossRef]


Horowitz RS, Dart RC, Jarvie DR et al. Placental transfer of N-acetylcysteine following human maternal acetaminophen toxicity. J Toxicol Clin Toxicol 1997; 35: 447 – 51. [PubMed] [CrossRef]


Johnson ST, Bigam DL, Emara M et al. N-acetylcysteine improves the hemodynamics and oxidative stress in hypoxic newborn pigs reoxygenated with 10011% oxygen. Shock 2007; 28: 484 – 90. [PubMed] [CrossRef]


Lee TF, Tymafichuk CN, Bigam DL et al. Effects of postresuscitation N-acetylcysteine on cerebral free radical production and perfusion during reoxygenation of hypoxic newborn piglets. Pediatr Res 2008; 64: 256 – 61. [PubMed] [CrossRef]


Ma D, Hossain M, Rajakumaraswamy N et al. Combination of xenon and isoflurane produces a synergistic protective effect against oxygen-glucose deprivation injury in a neuronal-glial co-culture model. Anesthesiology 2003; 99: 748 – 51. [PubMed] [CrossRef]


Coburn M, Kunitz O, Baumert JH et al. Randomized controlled trial of the haemodynamic and recovery effects of xenon or propofol anaesthesia. Br J Anaesth 2005; 94: 198 – 202. [PubMed] [CrossRef]


Preckel B, Schlack W, Heibel T et al. Xenon produces minimal haemodynamic effects in rabbits with chronically compromised left ventricular function. Br J Anaesth 2002; 88: 264 – 9. [PubMed] [CrossRef]


Chakkarapani E, Thoresen M, Hobbs CE et al. A closed-circuit neonatal xenon delivery system: a technical and practical neuroprotection feasibility study in newborn pigs. Anesth Analg 2009; 109: 451 – 60. [PubMed] [CrossRef]


van der Kooij MA, Groenendaal F, Kavelaars A et al. Neuroprotective properties and mechanisms of erythropoietin in in vitro and in vivo experimental models for hypoxia/ischemia. Brain Res Brain Res Rev 2008; 59: 22 – 33. [PubMed] [CrossRef]


Sakanaka M, Wen TC, Matsuda S et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 1998; 95: 4635 – 40. [PubMed] [CrossRef]


Morishita E, Masuda S, Nagao M et al. Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 1997; 76: 105 – 16. [PubMed] [CrossRef]


Sun Y, Calvert JW, Zhang JH. Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration. Stroke 2005; 36: 1672 – 8. [PubMed] [CrossRef]


Sola A, Wen TC, Hamrick SE et al. Potential for protection and repair following injury to the developing brain: a role for erythropoietin? Pediatr Res 2005; 57: 110R-7R. [PubMed] [CrossRef]


Zhu C, Kang W, Xu F et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics 2009; 124: e218 – 26. [PubMed] [CrossRef]


Elmahdy H, El-Mashad AR, El-Bahrawy H et al. Human recombinant erythropoietin in asphyxia neonatorum: pilot trial. Pediatrics 2010; 125: e1135 – 42. [PubMed] [CrossRef]


Galvin KA, Oorschot DE. Continuous low-dose treatment with brain-derived neurotrophic factor or neurotrophin-3 protects striatal medium spiny neurons from mild neonatal hypoxia/ischemia: a stereological study. Neuroscience 2003; 118: 1023 – 32. [PubMed] [CrossRef]


Gonzalez FF, McQuillen P, Mu D et al. Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Dev Neurosci 2007; 29: 321 – 30. [PubMed] [CrossRef]


Lin S, Fan LW, Rhodes PG et al. Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats. Exp Neurol 2009; 217: 361 – 70. [PubMed] [CrossRef]


Wang L, Zhang Z, Wang Y et al. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004; 35: 1732 – 7. [PubMed] [CrossRef]


van Velthoven CT, Kavelaars A, van Bel F et al. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun 2010; 24: 387 – 93. [PubMed] [CrossRef]


Cilio MR, Ferriero DM. Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med 2010; 15: 293 – 8. [PubMed] [CrossRef]


Fan X, van Bel F. Pharmacological neuroprotection after perinatal asphyxia. J Matern Fetal Neonatal Med 2010; 23 (suppl 3): 17 – 9. [PubMed] [CrossRef]


This article was published more than 12 months ago and we have therefore closed it for new comments.

Anbefalte artikler