Therapeutic hypothermia instituted within 6 h of birth has been shown to improve neurodevelopmental outcomes in term newborns with moderate–to–severe hypoxic–ischemic encephalopathy (HIE). The majority of infants who would benefit from cooling are born at centers that do not offer the therapy, and adding the time for transport will result in delays in therapy, that may lead to suboptimal or no neuroprotection for some patients. Our objective was to evaluate the effect of our center's experience with therapeutic hypothermia on neonatal transport.
Retrospective review of all cases of therapeutic hypothermia at a single neonatal intensive care unit from 2005 to 2009.
Of 50 infants with HIE treated with hypothermia, 40 were outborn and 35 were cooled on transport. The majority of patients were passively cooled by the referring clinicians, then actively cooled by our transport team. Overcooling to <32 °C occurred in 34% of patients, but there were no significant differences in admission vital signs or laboratory values between overcooled and appropriately cooled infants. The average time after birth of initiation of passive cooling was 1.4 h and active cooling was 2.7 h compared with the time of admission to our unit of 5.9 h.
We discuss the important aspects of our program, including the education of referring and receiving clinicians and avoidance of overcooling.
hypothermia; hypoxic-ischemic encephalopathy; neontal transport; neuroprotection; birth asphyxia
Knowledge of the nature, prognosis, and ways to treat brain lesions in neonatal infants has increased remarkably. Neonatal hypoxic-ischaemic encephalopathy (HIE) in term infants, mirrors a progressive cascade of excito-oxidative events that unfold in the brain after an asphyxial insult. In the laboratory, this cascade can be blocked to protect brain tissue through the process of neuroprotection. However, proof of a clinical effect was lacking until the publication of three positive randomised controlled trials of moderate hypothermia for term infants with HIE. These results have greatly improved treatment prospects for babies with asphyxia and altered understanding of the theory of neuroprotection. The studies show that moderate hypothermia within 6 h of asphyxia improves survival without cerebral palsy or other disability by about 40% and reduces death or neurological disability by nearly 30%. The search is on to discover adjuvant treatments that can further enhance the effects of hypothermia.
Despite major advances in monitoring technology and knowledge of fetal and neonatal pathophysiology, neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the main causes of severe adverse neurological outcome in children. Until recently, there were no therapies other than supportive measures. Over the past several years, mild hypothermia has been proven to be safe to treat HIE. Unfortunately, this neuroprotective strategy seems efficient in preventing brain injury in some asphyxiated newborns, but not in all of them. Thus, there is increasing interest to rapidly understand how to refine hypothermia therapy and add neuroprotective or neurorestorative strategies. Several promising newer treatments to treat birth asphyxia and prevent its devastating neurological consequences are currently being tested. In this paper, the physiopathology behind HIE, the currently available treatment, the potential alternatives, and the next steps before implementation of these other treatments are reviewed.
To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.
Stage of encephalopathy was evaluated at <6 hr of age, during study intervention and at discharge among 204 participants in the NICHD Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.
Moderate and severe HIE occurred at <6 hrs of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hrs of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hrs increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at < 6hrs for death/disability.
On serial neurological examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurological exam at discharge was associated with a greater risk of death or disability.
Neurological examinations; neonates; clinical biomarker; death; disability
Little is known about the effects of hypothermia therapy and subsequent rewarming on the PQRST intervals and heart rate variability (HRV) in term newborns with hypoxic-ischemic encephalopathy (HIE).
This study describes the changes in the PQRST intervals and HRV during rewarming to normal core body temperature of 2 newborns with HIE after hypothermia therapy.
Within 6 h after birth, 2 newborns with HIE were cooled to a core body temperature of 33.5°C for 72 h using a cooling blanket, followed by gradual rewarming (0.5°C per hour) until the body temperature reached 36.5°C. Custom instrumentation recorded the electrocardiogram from the leads used for clinical monitoring of vital signs. Generalized linear mixed models were calculated to estimate temperature-related changes in PQRST intervals and HRV.
For every 1°C increase in body temperature, the heart rate increased by 9.2 bpm (95% CI 6.8–11.6), the QTc interval decreased by 21.6 ms (95% CI 17.3–25.9), and low and high frequency HRV decreased by 0.480 dB (95% CI 0.052–0.907) and 0.938 dB (95% CI 0.460–1.416), respectively.
Hypothermia-induced changes in the electrocardiogram should be monitored carefully in future studies.
Hypoxic-ischemic encephalopathy; Hypothermia therapy; Electrocardiogram; QT interval; Heart rate variability
Hypoxic-Ischemic Encephalopathy (HIE) is the consequence of systemic asphyxia occurring at birth. Twenty five percent of neonates with HIE develop severe and permanent neuropsychological sequelae, including mental retardation, cerebral palsy, and epilepsy. The outcomes of HIE are devastating and permanent, making it critical to identify and develop therapeutic strategies to reduce brain injury in newborns with HIE. To that end, the neonatal rat model for hypoxic-ischemic brain injury has been developed to model this human condition. The HIE model was first validated by Vannucci et al 1 and has since been extensively used to identify mechanisms of brain injury resulting from perinatal hypoxia-ischemia 2 and to test potential therapeutic interventions 3,4. The HIE model is a two step process and involves the ligation of the left common carotid artery followed by exposure to a hypoxic environment. Cerebral blood flow (CBF) in the hemisphere ipsilateral to the ligated carotid artery does not decrease because of the collateral blood flow via the circle of Willis; however with lower oxygen tension, the CBF in the ipsilateral hemisphere decreases significantly and results in unilateral ischemic injury. The use of 2,3,5-triphenyltetrazolium chloride (TTC) to stain and identify ischemic brain tissue was originally developed for adult models of rodent cerebral ischemia 5, and is used to evaluate the extent of cerebral infarctin at early time points up to 72 hours after the ischemic event 6. In this video, we demonstrate the hypoxic-ischemic injury model in postnatal rat brain and the evaluation of the infarct size using TTC staining.
With mounting evidence that hypothermia is neuroprotective in newborns with hypoxic-ischemic encephalopathy (HIE), an increasing number of centers are offering this therapy. Hypothermia is associated with a wide range of physiologic changes affecting every organ system, and awareness of these effects is essential for optimum patient management. Lowering the core temperature also alters pharmacokinetic and pharmacodynamic properties of medications commonly used in asphyxiated neonates, necessitating close attention to drug efficacy and side effects. Rewarming introduces additional risks and challenges as the hypothermia-associated physiologic and pharmacologic changes are reversed. In this review we provide an organ system-based assessment of physiologic changes associated with hypothermia. We also summarize evidence from randomized controlled trials showing lack of serious adverse effects of moderate hypothermia therapy in term and near-term newborns with moderate-to-severe HIE. Finally, we review the effects of hypothermia on drug metabolism and clearance based on studies in animal models and human adults, and limited data from neonates.
hypothermia; hypoxic-ischemic encephalopathy; neonate; pharmacologic effect; physiology effect; rewarming
Hypoxic ischemic encephalopathy is a serious condition affecting infants which can result in death and disability. This is a summary of pathogenesis of HIE, animal studies of cooling for hypoxic and ischemic models, human hypothermia trials, and the American Academy of Pediatrics publication on hypothermia for HIE. Hypothermia for neonatal HIE is continuing to evolve as a therapy. Studies, gaps in knowledge and opportunities for research are presented herein.
To evaluate the association between early hypocarbia and 18-22 month outcome among neonates with hypoxic-ischemic encephalopathy (HIE).
Data from the NICHD NRN randomized controlled trial of whole body hypothermia for neonatal HIE were used for this secondary observational study. Infants (n=204) had multiple blood gases recorded from birth-12h of study intervention (hypothermia vs. intensive care alone). The relationship between hypocarbia and outcome (death/disability at 18-22 months) was evaluated by unadjusted and adjusted analyses examining minimum PCO2 and cumulative exposure to PCO2 <35 mmHg. The relationship between cumulative PCO2 <35 mmHg (calculated as the difference between 35mmHg and the sampled PCO2 multiplied by the duration of time spent <35 mmHg) and outcome was evaluated by level of exposure (none-high) using a multiple logistic regression analysis with adjustments for pH, level of encephalopathy, treatment group (± hypothermia), time to spontaneous respiration and ventilator days; results were expressed as OR and 95% confidence intervals. Alternative models of CO2 concentration were explored to account for fluctuations in CO2.
Both minimum PCO2 and cumulative PCO2 <35mmHg were associated with poor outcome (P<0.05). Moreover, death/disability increased with greater cumulative exposure to PCO2 <35mmHg.
Hypocarbia is associated with poor outcome following HIE.
hypocarbia; hypoxic ischemic encephalopathy; whole body hypothermia; outcome; neurodevelopmental impairment
Despite recent advances in neonatal care and monitoring, asphyxia globally accounts for 23% of the 4 million annual deaths of newborns, and leads to hypoxic-ischemic encephalopathy (HIE). Occurring in five of 1000 live-born infants globally and even more in developing countries, HIE is a serious problem that causes death in 25%–50% of affected neonates and neurological disability to at least 25% of survivors. In order to prevent the damage caused by HIE, our invention provides an effective whole-body cooling of the neonates by utilizing evaporation and an endothermic reaction. Our device is composed of basic electronics, clay pots, sand, and urea-based instant cold pack powder. A larger clay pot, lined with nearly 5 cm of sand, contains a smaller pot, where the neonate will be placed for therapeutic treatment. When the sand is mixed with instant cold pack urea powder and wetted with water, the device can extract heat from inside to outside and maintain the inner pot at 17°C for more than 24 hours with monitoring by LED lights and thermistors. Using a piglet model, we confirmed that our device fits the specific parameters of therapeutic hypothermia, lowering the body temperature to 33.5°C with a 1°C margin of error. After the therapeutic hypothermia treatment, warming is regulated by adjusting the amount of water added and the location of baby inside the device. Our invention uniquely limits the amount of electricity required to power and operate the device compared with current expensive and high-tech devices available in the United States. Our device costs a maximum of 40 dollars and is simple enough to be used in neonatal intensive care units in developing countries.
therapeutic hypothermia; evaporative cooling; hypoxic ischemic encephalopathy; birth asphyxia; neuroprotection
The objective of this work was to determine the impact of therapeutic hypothermia (TH) on the magnitude and time course of mean diffusivity (MD) changes following hypoxic-ischemic encephalopathy (HIE) in newborns.
Cerebral MRI scans of infants undergoing whole body TH for HIE from 2007 to 2010 were retrospectively reviewed. The data were analyzed identically to a control group of newborns with HIE previously published, prior to the development of TH. Anatomic injury was defined on T1- and T2-weighted (“late”) MRI obtained after the fifth day of life. Since MD values vary regionally, the ratios of MD values for injured and normal tissue were calculated for areas of injury. Normal values were obtained from corresponding brain regions of 12 infants undergoing TH who had no injury on MRI studies.
Twenty-three of 59 infants who underwent TH and MRI displayed cerebral injury on late MRI and were included in the study. MD ratios were decreased in all injured infants within the first 7 days of life. The return of MD to normal (pseudonormalization) occurred after the tenth day as compared to 6–8 days in the control group. Infants with severest injury demonstrated greater reduction in MD, but no difference in time to pseudonormalization.
TH slows the evolution of diffusion abnormalities on MRI following HIE in term infants.
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.
Therapeutic hypothermia (TH) is the first intervention to consistently show improved neurological outcomes in neonates with hypoxic ischemic encephalopathy (HIE). Since the recent introduction of TH for HIE in many centres, reviews of practices during the implementation of TH in Canada have not been published.
To determine if eligible neonates are being offered TH and to identify any barriers to the effective implementation of TH.
A retrospective review of neonates referred to a regional tertiary centre at a gestational age of 35 weeks or more with HIE was conducted.
Among 41 neonates referred, 29 (71%) were eligible for TH; among eligible patients, five were moribund and excluded, and TH was initiated in 16 (67%) of the remaining 24. Reasons for not cooling in eight eligible patients included a delay in referral (n=5, median age at referral was 14 h) and a failure to recognize the severity of HIE (n=3). Among cooled patients, median times were the following: 116 min for age at referral; 80 min for time from referral to transport team arrival; and 358 min for age at initiation of cooling. Seven (44%) patients had cooling initiated after 6 h of age.
A significant proportion of eligible patients were not offered TH, and in many cooled patients, initiation of cooling was delayed beyond the recommended 6 h. For eligible patients to benefit from TH, it is imperative that all birthing centres be made aware that TH is now widely available as an important treatment option, but also that TH is a time-sensitive therapy requiring rapid identification and referral. In the region studied, for eligible patients, referring hospitals should initiate passive cooling before arrival of the transport team. Referring hospitals should be prepared to provide early, yet safe initiation of passive cooling by having the appropriate equipment, and having staff trained in the use and monitoring of rectal temperatures.
Hypoxic ischemic encephalopathy; Infant; Newborn; Therapeutic hypothermia
Hypoxic ischaemic encephalopathy (HIE) in newborns can cause significant long-term neurological disability. The insult is a complex injury characterised by energy failure and disruption of cellular homeostasis, leading to mitochondrial damage. The importance of individual metabolic pathways, and their interaction in the disease process is not fully understood. The aim of this study was to describe and quantify the metabolomic profile of umbilical cord blood samples in a carefully defined population of full-term infants with HIE.
Methods and Findings
The injury severity was defined using both the modified Sarnat score and continuous multichannel electroencephalogram. Using these classification systems, our population was divided into those with confirmed HIE (n = 31), asphyxiated infants without encephalopathy (n = 40) and matched controls (n = 71). All had umbilical cord blood drawn and biobanked at −80°C within 3 hours of delivery. A combined direct injection and LC-MS/MS assay (AbsolutIDQ p180 kit, Biocrates Life Sciences AG, Innsbruck, Austria) was used for the metabolomic analyses of the samples. Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). 9 of these metabolites were only significantly altered between neonates with Hypoxic ischaemic encephalopathy and matched controls, while 14 were significantly altered in both study groups. Multivariate Discriminant Analysis models developed showed clear multifactorial metabolite associations with both asphyxia and HIE. A logistic regression model using 5 metabolites clearly delineates severity of asphyxia and classifies HIE infants with AUC = 0.92. These data describe wide-spread disruption to not only energy pathways, but also nitrogen and lipid metabolism in both asphyxia and HIE.
This study shows that a multi-platform targeted approach to metabolomic analyses using accurately phenotyped and meticulously biobanked samples provides insight into the pathogenesis of perinatal asphyxia. It highlights the potential for metabolomic technology to develop a diagnostic test for HIE.
To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia.
Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.
There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n = 12) or discontinuous normal voltage (n = 12), or abnormal, with burst suppression (n = 22), continuous low voltage (n = 26), or flat tracing (n = 36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P = .19).
The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.
neonatal hypoxic-ischemic encephalopathy; amplitude integrated EEG
To determine the frequency of hypoxic-ischemic encephalopathy (HIE) in preterm infants of 33 to 35 weeks’ gestational age on the basis of physiological screening for perinatal acidosis and neurological assessment of encephalopathy and to correlate neurodevelopmental outcomes with brain magnetic resonance imaging findings.
This retrospective cohort study included all inborn infants of 33 to 35 weeks’ gestation admitted to the neonatal intensive care unit at Parkland Memorial Hospital with perinatal acidosis from October 2005 to September 2008. Their medical records were reviewed, and pertinent data were recorded.
Of 1305 newborns, 2.5% (n = 33) had perinatal acidosis, and 27% (n = 9) of these had HIE (2, mild; 4, moderate; 3, severe). Persistence of metabolic acidosis on the first arterial blood gas obtained in the first hour of age was significantly associated with HIE (P < .005). Magnetic resonance imaging results were abnormal in 3 of 4 infants with moderate HIE and in both survivors with severe HIE. Death or disability occurred in no infants with mild or moderate HIE, but in all infants with severe HIE.
Screening criteria for HIE that use biochemical and neurological assessments as performed in term newborns can be applied to preterm infants of 33 to 35 weeks’ gestation.
Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 106 MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.
Perinatal asphyxia leading to hypoxic-ischemic encephalopathy (HIE) is a common problem causing multi organ dysfunction including myocardial involvement which can affect the outcome.
To evaluate the myocardial dysfunction in neonates having HIE by electrocardiographic(ECG) and cardiac enzymes (CK Total, CK-MB and Troponin I) and find out the relationship with HIE and outcome.
This was a hospital based prospective study. Sixty term neonates who had suffered perinatal asphyxia and developed HIE were enrolled. Myocardial involvement was assessed by clinical, ECG, and CK Total, CK-MB and Troponin I measurements.
Of 60 cases, 13(21.7%) were in mild, 27(45%) in moderate and 20(33.3%) belonged to severe,HIE. ECG was abnormal in 46 (76.7%); of these 19 (41.3%) had grade I, 13 (28.2%) grades II and III each and 1 (2.1%) with grade IV changes. Serum levels of CK Total, CK- MB and Troponin I were raised in 54 (90%), 52 (86.6%) and 48 (80%) neonates, respectively. ECG changes and enzymatic levels showed increasing abnormalities with severity of HIE, and the differences among different grades were significant (p = 0.002, 0.02, <0.001 and 0.004, respectively). Nineteen (32%) cases died during hospital stay. The non- survivors had high proportion of abnormal ECG (p = 0.024), raised levels of CK-MB (p = 0.018) and Troponin I (p = 0.008) in comparison to survivors.
Abnormal ECG and cardiac enzymes levels are found in HIE and can lead to poor outcome due to myocardial damage Early detection can help in better management and survival of these neonates.
Perinatal asphyxia; HIE; Myocardial dysfunction
An early clinical score predicting an abnormal amplitude-integrated electroencephalogram (aEEG) or moderate-severe hypoxic ischemic encephalopathy (HIE) may allow rapid triage of infants for therapeutic hypothermia. We aimed to determine if early clinical examination could predict either an abnormal aEEG at age 6 hours or moderate-severe HIE presenting within 72 hours of birth.
Sixty infants ≥ 36 weeks gestational age were prospectively enrolled following suspected intrapartum hypoxia and signs of encephalopathy. Infants who were moribund, had congenital conditions that could contribute to the encephalopathy or had severe cardio-respiratory instability were excluded. Predictive values of the Thompson HIE score, modified Sarnat encephalopathy grade (MSEG) and specific individual signs at age 3–5 hours were calculated.
All of the 60 infants recruited had at least one abnormal primitive reflex. Visible seizures and hypotonia at 3–5 hours were strongly associated with an abnormal 6-hour aEEG (specificity 88% and 92%, respectively), but both had a low sensitivity (47% and 33%, respectively). Overall, 52% of the infants without hypotonia at 3–5 hours had an abnormal 6-hour aEEG. Twelve of the 29 infants (41%) without decreased level of consciousness at 3–5 hours had an abnormal 6-hour aEEG (sensitivity 67%; specificity 71%). A Thompson score ≥ 7 and moderate-severe MSEG at 3–5 hours, both predicted an abnormal 6-hour aEEG (sensitivity 100 vs. 97% and specificity 67 vs. 71% respectively). Both assessments predicted moderate-severe encephalopathy within 72 hours after birth (sensitivity 90%, vs. 88%, specificity 92% vs. 100%). The 6-hour aEEG predicted moderate-severe encephalopathy within 72 hours (sensitivity 75%, specificity 100%) but with lower sensitivity (p = 0.0156) than the Thompson score (sensitivity 90%, specificity 92%). However, all infants with a normal 3- and 6-hour aEEG with moderate-severe encephalopathy within 72 hours who were not cooled had a normal 24-hour aEEG.
The encephalopathy assessment described by the Thompson score at age 3–5 hours is a sensitive predictor of either an abnormal 6-hour aEEG or moderate-severe encephalopathy presenting within 72 hours after birth. An early Thompson score may be useful to assist with triage and selection of infants for therapeutic hypothermia.
Asphyxia; Neonate; Hypoxic ischemic encephalopathy; Electroencephalogram; aEEG; Prognostic
We assessed the effects of hypoxic-ischemic encephalopathy (HIE) and whole-body hypothermia therapy on auditory brain stem evoked responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We performed serial assessments of ABRs and DPOAEs in newborns with moderate or severe HIE, randomized to hypothermia (n = 4) or usual care (n = 5). Participants were five boys and four girls with mean gestational age (standard deviation) of 38.9 (1.8) weeks. During the first week of life, peripheral auditory function, as measured by the DPOAEs, was disrupted in all nine subjects. ABRs were delayed but central transmission was intact, suggesting a peripheral rather than a central neural insult. By 3 weeks of age, peripheral auditory function normalized. Hypothermia temporarily prolonged the ABR, more so for waves generated higher in the brain stem but the effects reversed quickly on rewarming. Neonatal audiometric testing is feasible, noninvasive, and capable of enhancing our understanding of the effects of HIE and hypothermia on auditory function.
Hypoxia-ischemia; hypothermia; auditory evoked potentials; otoacoustic emissions
Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2–3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment.
Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests.
This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.
Current Controlled Trials ISRCTN62175998; ClinicalTrials.gov Identifier NCT01241019; EudraCT Number 2010-018627-25
Neonatal hypoxic-ischemic encephalopathy; Therapeutic hypothermia; Topiramate
Moderate to severe hypoxic–ischemic injury in newborn infants, manifested as encephalopathy immediately or within hours after birth, is associated with a high risk of either death or a lifetime with disability. In recent multicenter clinical trials, hypothermia initiated within the first 6 postnatal hours has emerged as a therapy that reduces the risk of death or impairment among infants with hypoxic–ischemic encephalopathy. Prior to hypothermia, no therapies directly targeting neonatal encephalopathy secondary to hypoxic–ischemic injury had convincing evidence of efficacy. Hypothermia therapy is now becoming increasingly available at tertiary centers. Despite the deserved enthusiasm for hypothermia, obstetric and neonatology caregivers, as well as society at large, must be reminded that in the clinical trials more than 40% of cooled infants died or survived with impairment. Although hypothermia is an evidence-based therapy, additional discoveries are needed to further improve outcome after HIE. In this article, we briefly present the epidemiology of neonatal encephalopathy due to hypoxic–ischemic injury, describe the rationale for the use of hypothermia therapy for hypoxic–ischemic encephalopathy, and present results of the clinical trials that have demonstrated the efficacy of hypothermia. We also present findings noted during and after these trials that will guide care and direct research for this devastating problem.
HIE; hyperthermia; hypothermia; hypoxic–ischemic encephalopathy; neonate; perinatal asphyxia
Hypoxic ischemic encephalopathy (HIE) remains a significant cause of mortality and long-term disability in late preterm and term infants. Mild therapeutic hypothermia to a rectal temperature of 34±0.5°C initiated as soon as possible within the first 6 h of life decreases mortality and severe long-term neurodevelopmental disabilities in infants with moderate HIE who are ≥36 weeks’ gestational age. There are minimal side effects, and the incidence of disability in survivors is not increased. Infants with severe encephalopathy are less likely to benefit from treatment. Cooling may be achieved by either total body or selective head cooling. As cooling is now considered a standard of care, infants ≥36 weeks’ gestational age who are depressed at birth should be assessed to determine whether they meet the criteria for cooling. There is currently no evidence that therapeutic hypothermia offers any benefit to infants <36 weeks’ gestational age.
Asphyxia; Cooling; Hypothermia; Hypoxic ischemic encephalopathy; Outcome
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.
Infant; premature; hypoxic-ischemic encephalopathy; hypothermia; necrotizing enterocolitis
Perinatal brain injury is the leading cause of subsequent neurological disability in both term and preterm baby. Glutamate excitotoxicity is one of the major factors involved in perinatal hypoxic-ischemic encephalopathy (HIE). Glutamate transporter GLT1, expressed mainly in mature astrocytes, is the major glutamate transporter in the brain. HIE induced excessive glutamate release which is not reuptaked by immature astrocytes may induce neuronal damage. Compounds, such as ceftriaxone, that enhance the expression of GLT1 may exert neuroprotective effect in HIE.
We used a neonatal rat model of HIE by unilateral ligation of carotid artery and subsequent exposure to 8% oxygen for 2 hrs on postnatal day 7 (P7) rats. Neonatal rats were administered three dosages of an antibiotic, ceftriaxone, 48 hrs prior to experimental HIE. Neurobehavioral tests of treated rats were assessed. Brain sections from P14 rats were examined with Nissl and immunohistochemical stain, and TUNEL assay. GLT1 protein expression was evaluated by Western blot and immunohistochemistry.
Pre-treatment with 200 mg/kg ceftriaxone significantly reduced the brain injury scores and apoptotic cells in the hippocampus, restored myelination in the external capsule of P14 rats, and improved the hypoxia-ischemia induced learning and memory deficit of P23-24 rats. GLT1 expression was observed in the cortical neurons of ceftriaxone treated rats.
These results suggest that pre-treatment of infants at risk for HIE with ceftriaxone may reduce subsequent brain injury.
β-lactam antibiotics; ceftriaxone; hypoxic-ischemic injury; neonatal rat; GLT1; EAAT2