Hypothermia For Hypoxic-ischemic Encephalopathy Research Articles

Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy - Part 1

Induced Hypothermia for Hypoxic-Ischaemic Encephalopathy - Part 1

Early predictors of outcome in infants treated with hypothermia for hypoxic-ischaemic encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of acquired neonatal brain injury. Assessment of the severity of cerebral injury and likely neurological outcome in infants with HIE is important for determining management and prognosis, for counselling parents, and for selection for neuroprotective trials. The condition of the infant at birth, the severity of HIE, neurophysiological tests, including amplitude-integrated electroencephalography (aEEG), biochemical markers, and neuroimaging have been used to assess prognosis and predict long-term outcome. The predictive accuracy of these indicators in the early postnatal period is modest. Neurophysiological assessment seems to be most helpful during the first 24 to 48 hours after birth whilst magnetic resonance imaging (MRI) seems most informative later. Several biochemical markers, including serum S100β and neuron-specific enolase (NSE), are also associated with HIE but their levels depend on the timing of sampling and their prognostic value is uncertain. Comprehensive neurophysiological assessment and neuroimaging may be limited to specialist centres. Therapeutic hypothermia is now standard care in infants with moderate to severe HIE so it is important to examine the influence of hypothermia on the assessment of prognosis in these infants.

Erythropoietin: a novel therapy for hypoxic-ischaemic encephalopathy?

Perinatal hypoxic-ischaemic encephalopathy (HIE) occurs in 1 to 3 per 1000 term births. HIE is not preventable in most cases, and therapies are limited. Hypothermia improves outcomes and is the current standard of care. Yet, clinical trials suggest that 44-53% of infants who receive hypothermia will die or suffer moderate to severe neurological disability. In this article, we review the preclinical and clinical evidence for erythropoietin (EPO) as a potential novel neuroprotective agent for the treatment of HIE. EPO is a novel neuroprotective agent, with remarkable neuroprotective and neuroregenerative effects in animals. Rodent and primate models of neonatal brain injury support the safety and efficacy of multiple EPO doses for improving histological and functional outcomes after hypoxia-ischaemia. Small clinical trials of EPO in neonates with HIE have also provided evidence supporting safety and preliminary efficacy in humans. There is currently insufficient evidence to support the use of high-dose EPO in newborns with HIE. However, several on-going trials will provide much needed data regarding the safety and efficacy of this potential new therapy when given in conjunction with hypothermia for HIE. Novel neuroprotective therapies are needed to further reduce the rate and severity of neurodevelopmental disabilities resulting from HIE. High-dose EPO is a promising therapy that can be administered in conjunction with hypothermia. However, additional data are needed to determine the safety and efficacy of this adjuvant therapy for HIE.

Phase Changing Material: An Alternative Method for Cooling Babies with Hypoxic Ischaemic Encephalopathy

Background: Therapeutic hypothermia for hypoxic ischaemic encephalopathy (HIE) has been proved effective. Standard equipment is expensive, while ice packs used in low resource settings are labour intensive and associated with wider temperature fluctuations. Objectives: To assess the feasibility of using phase changing material (PCM) as an alternative method for providing therapeutic hypothermia. Methods: We retrospectively analysed 41 babies with HIE who had been cooled with PCM (OM 32™ or HS 29™) to a target rectal temperature of 33-34°C. Rectal temperature was continuously monitored and recorded every hour. If the rectal temperature was >33.8°C, cool gel packs were applied, and if the temperature was <33.2°C, the baby was covered with sheets and the warmer output turned on till the temperature stabilized at 33.5°C. The unit's standard protocol for cooling was followed for monitoring and treatment. The outcome measures were stability and fluctuation of the rectal temperature and the need for interventions to maintain the target temperature. Results: The mean (±SD) temperature during the cooling phase was 33.45 ± 0.26°C. Throughout the cooling phase, the target temperature range was maintained in 96.2% of the time. There was no temperature reading <32°C. With HS 29, ice packs were not used in any baby, and the warmer was used for a median of 7 h (interquartile range 1.5-14). Conclusions: PCM provides a low cost and effective method to maintain therapeutic hypothermia. However, careful monitoring is required during induction and the rewarming phase to avoid hypothermia outside the therapeutic range.

Neuro protection for infants

Infants receive a variety of brain injuries—intraventricular hemorrhage in preterm infants, hypoxic ischemic encephalopathy in term infants, and often poorly defined events resulting in cerebral palsy and other neurodevelopmental abnormalities. Recently, specific neuroprotective therapies have been tested to improve, including antenatal magnesium treatment for preterm deliveries and therapeutic hypothermia for hypoxic ischemic encephalopathy. Numerous other neuroprotective treatments, including stem cell treatments and erythropoietin treatments, are being tested in animal models and erythropoietin treatments. In this issue of The Journal, Benders et al report that the treatment of term infants with perinatal arterial ischemic strokes with erythropoietin is safe and feasible. This pilot study should result in formal therapeutic trials. Such interventions are gaining traction as a number of neonatologists are teaming up with pediatric neurologists to develop neurologic neonatal intensive care units to better diagnose and develop treatments for infants at high-risk of brain injury. The use of newer imaging and monitoring tools makes these efforts very likely to succeed. Article page 481▶ Feasibility and Safety of Erythropoietin for Neuroprotection after Perinatal Arterial Ischemic StrokeThe Journal of PediatricsVol. 164Issue 3PreviewTo perform a feasibility and safety study with recombinant human erythropoietin (rhEPO) in neonates with perinatal arterial ischemic stroke. Full-Text PDF

Impact of therapeutic hypothermia on coronary flow

Mild hypothermia therapy (HT) improves survival and neurologic outcome after sudden cardiac death (SCD) [1]. Despite the controversy between the relation of HT and stent thrombosis (ST) [2], our group reported an increased risk of ST in patients treated with HT [3]. Increased platelet activation and a potential inefficiency of antiplatelet therapy may explain the increased riskof ST inHT.Nonetheless, recentdata suggest that other etiologic mechanisms may play a role in the occurrence of thrombotic events. Experimental models have demonstrated a relationship between HT and endothelial dysfunction [4]. Endothelial disorders have been associated with coronary-flow impairment and therefore thrombotic events [5,6]. The objective of our study was to analyze the impact of HT on coronary microcirculation by comparing the coronary flow measured by thrombolysis in Myocardial Infarction frame count (TFC) with and without HT. From January 2010 to March 2013, 55 patients with out-of-hospital SCD were admitted in our institution and treated with HT (mean age 55.4 ± 15 years, 67% male). Of them, 39 (70.9%) patients had STsegment elevation myocardial infarction (STEMI) and underwent primary PCI. The HT protocol was accomplished as previously described [2]. We selected those patients in whom two coronary angiographies (with and without HT) were performed (see Table 1). Five patients (12.9%) were included in the analysis. In every patient, a clear distal anatomic landmarkwas selected as the region of interest to quantify the TFC, andmeasurementswere repeated in both normothermia andHT. In case of STEMI or ST, the coronary flow was always measured in a noninfarct related artery. Coronary angiography technique including catheter shape, catheter diameter, automatic contrast injection flow, and projection were the same for every paired angiography. An experienced reviewer blinded to the temperature condition assessed the TFC. TFC values were compared using t-test for repeated measures with SPSS ® v.18.0 (IBM Corp., Armonk, NY, USA). Patient characteristics, clinical status and TFC are summarized in Table 1. Patients with cardiogenic shock were treated with IV norepinephrine and/or dobutamine infusion according to guidelines. Coronary angiography in normothermiawas performed after SCDwith a diagnosis of STEMI in 80% of patients. Coronary angiography in HT was indicated in 80% of patients because a suspicion of ST. Despite the small number of patients, a noteworthy trend towards a higher TFCwas observed in hypothermia compared to normothermia (11.6 vs. 8.0; p = 0.066) (Fig. 1). VanGenderen et al. [7] reporteda significantmicrocirculatory disorder after HTas a result of changes in body temperature rather than changes in systemic hemodynamic variables. Accordingly, Ergenekon observed that newborn patients treated with hypothermia for hypoxic ischemic encephalopathy presented a sluggish peripheral flow when compared to controls [8]. Recently, Zoerner et al. [4] demonstrated that mild HT is associated with higher plasmatic levels of endothelin-1 (ET-1). ET-1, a potent vasoconstrictor isolated from endothelial cells, has a biological effect that includes platelet activation and vascular dysfunction and is associated with a lower endothelial progenitor cell mobilization after myocardial infarction [9]. High ET-1 levels have been linked to impaired coronary circulation including slow coronary flow and even no-reflow. Slow coronary flow is a recognized predictor of thrombotic events, althoughother factorsmayalsoplaya role. The results of our studysuggest thatmildHTmight slowdown coronaryflowand endothelial dysfunction seems to be the most plausible explanation considering the previous published data [4,7]. The identification of other potential pro-thrombotic mechanisms besides the coagulation and platelet disorders seems to be of pivotal importance when designing strategies for preventing thrombotic events. In this sense, the present manuscript should be considered as hypothesis generating and encourage future research. Although the small number of patients is the main limitation of the study, the strong trend towards a reduced TFC despite the limited sample and the difficulties finding patients with SCD with two coronary angiographies (with and without HT) should be taken into consideration.

The Combined Therapy with Resveratrol and Hypothermia Prevents Apoptosis in a Neonatal Rat Model of Global Hypoxic-Ischemic Encephalopathy

Birth asphyxia and newborn prematurity are the two major causes of perinatal mortality resulting in central nervous system (CNS) injury by hypoxia and ischemia. Hypoxia and ischemia produce massive brain damage following a typical pattern which is defined by selective vulnerability of the brain regions.The main objective of this study was to test the possible protective effect of resveratrol and hypothermia in hypoxic-ischemic encephalopathy in newborn rats. The changes in terms of histology and apoptosis were determined in brain so as to assess the local damages induced by hypoxic ishemia. The experiment was performed on 17 newborn Wistar rats that were given resveratrol in a dose of 20 mg/kg/day for seven days as premedication. At the end of this period the animals were exposed to hypobaric hypoxia (9% O+2 for 90 minutes) and ischemia (by clamping the right carotid artery). In global hypoxic-ischemic encephalopathy the resveratrol at a dose of 20 mg/kg/day as premedication offers neuroprotection by reducing the number of cells expressing apoptosis in CA1, CA2, CA3 and dentate gyrus of the hippocampus under the conditions of conjugation with post-injury hypothermia. In the cerebral cortex the resveratrol protective effects were not hypothermia dependent. No protective effect of resveratrol was observed in thalamus after global hypoxic-ischemic encephalopathy. The results of this study prove that resveratrol offers neuroprotection in hypobaric hypoxic brain injuries, but the protection is conditioned in most of the brain regions (excepting cerebral cortex) by conjugation of the protective therapy with post-injury hypothermia treatment

Therapeutic hypothermia during neonatal transport: data from the California Perinatal Quality Care Collaborative (CPQCC) and California Perinatal Transport System (CPeTS) for 2010

To evaluate cooling practices and neonatal outcomes in the state of California during 2010 using the California Perinatal Quality Care Collaborative and California Perinatal Transport System databases. Database analysis to determine the perinatal and neonatal demographics and outcomes of neonates cooled in transport or after admission to a cooling center. Of the 223 infants receiving therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE) in California during 2010, 69% were cooled during transport. Despite the frequent use of cooling in transport, cooling center admission temperature was in the target range (33-34 °C) in only 62 (44%). Among cooled infants, gestational age was <35 weeks in 10 (4.5%). For outborn and transported infants, chronologic age at the time of cooling initiation was >6 h in 20 (11%). When initiated at the birth hospital, cooling was initiated at <6 h of age in 131 (92.9%). More than half of the infants cooled in transport do not achieve target temperature by the time of arrival at the cooling center. The use of cooling devices may improve temperature regulation on transport.

Therapeutic Hypothermia for Hypoxic Ischaemic Encephalopathy in Singapore General Hospital: Two Patient Case Series and Review of Literature

Neonatal encephalopathy affects 2–5/1000 live births and hypoxic ischaemic encephalopathy (HIE) is the major cause1. Therapeutic hypothermia reduces brain injury and improves the neurodevelopmental outcome.We are sharing our local experience in therapeutic hypothermia in the form of a case series of two patients. Our incidence of moderate to severe HIE is 0.6/1000 live births. Both patients were cooled for 72 hours.The challenges faced were mainly in the time taken for achieving the target temperature and the time needed for re-warming, which varied from one to six hours and 4–24 hours, respectively. Complications like hyponatremia, hypokalemia, sinus bradycardia and thrombocytopenia were noted. Amplitude integrated electroencephalogram (aEEG) remained abnormal post cooling for both babies. Clinical markers, aEEG and MRI head findings combine to prognosticate well for the neurodevelopmental outcomes.We need to be familiar with the protocol for timely implementation of cooling, whichever the cooling method. Concentrating these high-risk cases in selected tertiary centres capable of instituting cooling as well as long-term follow-up will ensure better outcomes.

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000-10000 U/L; area under the curve = 117000-140000 U*h/L). In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13780, and 33316 U/L, and total Epo exposure (area under the curve) was 50306, 131054, and 328002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

Recooling for Rebound Seizures After Rewarming in Neonatal Encephalopathy

Infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy are at risk for rebound seizures during and after the rewarming phase. We report a term male infant who was cooled for hypoxic ischemic encephalopathy. He developed electrographic seizures for the first time during the warming phase, which continued in the hours after rewarming. The seizures stopped within 30 minutes of recooling to 33.5°C without anticonvulsant medication. He was uneventfully cooled for an additional 24 hours and then rewarmed with no recurrence of seizures. Hypothermia appeared to have an antiepileptic effect in this case and may be worthy of additional investigation as an adjunct to antiepileptic drug therapy in newborns.

Pharmacokinetics and pharmacodynamics of medication in asphyxiated newborns during controlled hypothermia. The PharmaCool multicenter study

BackgroundIn the Netherlands, perinatal asphyxia (severe perinatal oxygen shortage) necessitating newborn resuscitation occurs in at least 200 of the 180–185.000 newly born infants per year. International randomized controlled trials have demonstrated an improved neurological outcome with therapeutic hypothermia. During hypothermia neonates receive sedative, analgesic, anti-epileptic and antibiotic drugs. So far little information is available how the pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs are influenced by post resuscitation multi organ failure and the metabolic effects of the cooling treatment itself. As a result, evidence based dosing guidelines are lacking. This multicenter observational cohort study was designed to answer the question how hypothermia influences the distribution, metabolism and elimination of commonly used drugs in neonatal intensive care.Methods/DesignMulticenter cohort study. All term neonates treated with hypothermia for Hypoxic Ischemic Encephalopathy (HIE) resulting from perinatal asphyxia in all ten Dutch Neonatal Intensive Care Units (NICUs) will be eligible for this study. During hypothermia and rewarming blood samples will be taken from indwelling catheters to investigate blood concentrations of several antibiotics, analgesics, sedatives and anti-epileptic drugs. For each individual drug the population PK will be characterized using Nonlinear Mixed Effects Modelling (NONMEM). It will be investigated how clearance and volume of distribution are influenced by hypothermia also taking maturation of neonate into account. Similarly, integrated PK-PD models will be developed relating the time course of drug concentration to pharmacodynamic parameters such as successful seizure treatment; pain assessment and infection clearance.DiscussionOn basis of the derived population PK-PD models dosing guidelines will be developed for the application of drugs during neonatal hypothermia treatment. The results of this study will lead to an evidence based drug treatment of hypothermic neonatal patients. Results will be published in a national web based evidence based paediatric formulary, peer reviewed journals and international paediatric drug references.Trial registrationNTR2529.

The Efficacy of Hypothermia in Hypoxic-Ischemic Encephalopathy at 18 Mo or More

To evaluate the efficacy of hypothermia in the treatment of hypoxic-ischemic encephalopathy (HIE) in neonates at 18 mo of age or more. Also to examine whether the severity of encephalopathy affects the efficacy of hypothermia on mortality and neurodevelopmental disability. The authors recruited the trials that assessed the efficacy of therapeutic hypothermia in the treatment of HIE in neonates at 18 mo of age or older up to April 2011. The meta- analysis was performed using a fixed effect model. Hypothermia significantly reduced the combined rate of death or neurodevelopmental disability (RR = 0.74, 95% CI: 0.67 to 0.82; RD = -0.13, 95% CI: -0.18 to -0.08; NNT = 7, 95% CI: 6 to 9) among infants at 18 mo of age or older. Hypothermia reduced the rate of death (RR = 0.75, 95% CI: 0.64 to 0.88), neurodevelopmental disability (RR = 0.65, 95% CI: 0.54 to 0.79), cerebral palsy (RR = 0.65, 95% CI: 0.53 to 0.80), developmental delay (RR = 0.72, 95% CI: 0.57 to 0.92), neuromotor delay (RR = 0.78, 95% CI: 0.61 to 0.99) and visual deficit (RR = 0.59, 95% CI: 0.36 to 0.99). Analysis of the severity of disease showed that hypothermia reduced the combined rate of death or neurodevelopmental disability not only in moderate encephalopathy infants (RR = 0.63, 95% CI: 0.53 to 0.76) but also in severe encephalopathy infants (RR = 0.82, 95% CI: 0.74 to 0.92). Hypothermia has a beneficial effect in the treatment of HIE in neonates at 18 mo of age or older.

Phenobarbital and Temperature Profile During Hypothermia for Hypoxic-Ischemic Encephalopathy

Data from the whole-body hypothermia trial was analyzed to examine the effects of phenobarbital administration prior to cooling (+PB) on the esophageal temperature (T (e)) profile, during the induction phase of hypothermia. A total of 98 infants were analyzed. At enrollment, +PB infants had a higher rate of severe hypoxic-ischemic encephalopathy and clinical seizures and lower T (e) and cord pH than infants that have not received phenobarbital (-PB). There was a significant effect of phenobarbital itself and an interaction between phenobarbital and time in the T (e) profile. Mean T (e) in the +PB group was lower than in the -PB group, and the differences decreased over time. In +PB infants, the time to surpass target T (e) of 33.5°C and to reach the minimum T (e) during overshoot were shorter. In conclusion, the administration of phenobarbital before cooling was associated with changes that may reflect a reduced thermogenic response associated with barbiturates.

Hypothermia: Novel approaches for premature infants

Hypothermia for hypoxic ischemic encephalopathy has recently permeated clinical practice for term infants. Speculation regarding a neuroprotective benefit of hypothermia for premature infants with HIE has been raised as a need for further research. Hypothermia for other indications including necrotizing enterocolitis with the hope of tissue preservation following injury is less well studied. A summary of evidence for hypothermia and premature infants is presented in this brief report.

Perinatal hypoxic-ischemic encephalopathy.

Perinatal hypoxic-ischemic encephalopathy (HIE) is an important cause of brain injury in the newborn and can result in long-term devastating consequences. Perinatal hypoxia is a vital cause of long-term neurologic complications varying from mild behavioural deficits to severe seizure, mental retardation, and/or cerebral palsy in the newborn. In the mammalian developing brain, ongoing research into pathophysiological mechanism of neuronal injury and therapeutic strategy after perinatal hypoxia is still limited. With the advent of promising therapy of hypothermia in HIE, this paper reviews the pathophysiology of HIE and the future potential neuroprotective strategies for clinical potential for hypoxia sufferers.

Selective Head Cooling with Mild Systemic Hypothermia after Neonatal Hypoxic-Ischemic Encephalopathy: A Multicenter Randomized Controlled Trial in China

To investigate the efficacy and safety of selective head cooling with mild systemic hypothermia in hypoxic-ischemic encephalopathy (HIE) in newborn infants. Infants with HIE were randomly assigned to the selective head cooling or control group. Selective head cooling was initiated within 6 hours after birth to a nasopharyngeal temperature of 34 degrees+/-0.2 degrees C and rectal temperature of 34.5 degrees to 35.0 degrees C for 72 hours. Rectal temperature was maintained at 36.0 degrees to 37.5 degrees C in the control group. Neurodevelopmental outcome was assessed at 18 months of age. The primary outcome was a combined end point of death and severe disability. One hundred ninety-four infants were available for analysis (100 and 94 infants in the selective head cooling and control group, respectively). For the selective head cooling and control groups, respectively, the combined outcome of death and severe disability was 31% and 49% (OR: 0.47; 95% CI: 0.26-0.84; P=.01), the mortality rate was 20% and 29% (OR:0.62; 95% CI: 0.32-1.20; P=.16), and the severe disability rate was 14% (11/80) and 28% (19/67) (OR: 0.40; 95% CI: 0.17-0.92; P=.01). Selective head cooling combined with mild systemic hypothermia for 72 hours may significantly decrease the combined outcome of severe disability and death, as well as severe disability.

Pulmonary Hypertensive Crisis Requiring ECMO Associated with Re-warming from whole Body Hypothermia for Hypoxic Ischemic Encephalopathy: Clinical Observations from a Case Series

Pulmonary Hypertensive Crisis Requiring ECMO Associated with Re-warming from whole Body Hypothermia for Hypoxic Ischemic Encephalopathy: Clinical Observations from a Case Series

Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy

Therapeutic hypothermia reduces mortality and neurologic impairment in neonates with hypoxic-ischemic encephalopathy. Topiramate exerts a neuroprotective effect in asphyxiated neonatal animal models. However, no studies have investigated the association of hypothermia and topiramate, because topiramate pharmacokinetics during hypothermia and the optimal administration schedule are unknown. The influence of hypothermia on topiramate pharmacokinetics was evaluated in asphyxiated neonates treated with prolonged whole-body hypothermia and topiramate. Thirteen term newborns were treated with mild or deep whole body hypothermia for 72 h; all received oral topiramate, 5 mg/kg once a day for the first 3 days of life, and seven had concomitant phenobarbital treatment. Topiramate concentrations were measured on serial dried blood spots. Topiramate concentrations were within the reference range in 11 of 13 newborns, whereas concentrations exceeded the upper limit in 2 of 13, both newborns on deep hypothermia. Topiramate concentrations reached a virtual steady state in nine newborns, for whom pharmacokinetic parameters were calculated. Values of topiramate maximal and minimal concentration, half-life, average concentration, and area under the time-concentration curve resulted in considerably higher values than those reported in normothermic infants. With respect to normothermic infants, time of maximal concentration was mildly delayed and apparent total body clearance was lower, suggesting slower absorption and elimination. Pharmacokinetic parameters did not differ significantly between infants on deep versus mild hypothermia and in those on topiramate monotherapy versus add-on phenobarbital. Most neonates on prolonged hypothermia treated with topiramate 5 mg/kg once a day exhibited drug concentrations within the reference range for the entire treatment duration.

HYPOXIC-ISCHEMIC BRAIN INJURY IN THE NEONATALPERIOD – CURRENT CONCEPTS, NOVEL DIAGNOSTICAPPROACHES AND NEUROPROTECTIVE STRATEGIES*

In the presenting paper, we describe mechanisms of brain injury following a hypoxicischemic event in the neonatal period. Neuronal death occurs in two major phases, theprimary neuronal cell loss at the time of the insult and the delayed neuronal cell loss, occurring about 6 hours – 4 days after the injury. We describe different cellular mechanismsresponsible for the neuronal death. The main patterns of brain injury that can be readilyrecognized with the newer neuroimaging techniques are dependent on the gestationalage of the newborn. In order to apply novel neuroprotective treatments to the newbornswith hypoxic-ischemic encephalopathy (HIE), the newborns at risk have to be identified asearly as possible. Among the most useful diagnostic methods are amplitude-integrated EEG,new markers of brain lesions and different modalities of magnetic-resonance imaging.During resuscitation of neonates with HIE the importance of prevention of hyperoxia,and, during intensive care, of hypocapnia and hyperglycemia is stressed. In the treatmentof newborns with HIE hypothermia, by means of both selective head cooling or whole bodyhypothermia, reduced the risk of death and disability according to three multicenterrandomized controlled studies. It is therefore recommended for treatment of HIE in thenewborn. One of the potentially beneficial effects of therapeutic hypothermia is also widening of the therapeutic window for intervention with other neuroprotective regimens. Amongthese, treatments with erythropoietin or minocycline seem to be clinically promising.