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
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
There is now convincing evidence that in industrialized countries therapeutic hypothermia for perinatal asphyxial encephalopathy increases survival with normal neurological function. However, the greatest burden of perinatal asphyxia falls in low and mid-resource settings where it is unclear whether therapeutic hypothermia is safe and effective.
Under the UCL Uganda Women's Health Initiative, a pilot randomized controlled trial in infants with perinatal asphyxia was set up in the special care baby unit in Mulago Hospital, a large public hospital with ~20,000 births in Kampala, Uganda to determine:
(i) The feasibility of achieving consent, neurological assessment, randomization and whole body cooling to a core temperature 33-34°C using water bottles
(ii) The temperature profile of encephalopathic infants with standard care
(iii) The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome
(iv) The feasibility of neurodevelopmental follow-up at 18-22 months of age
Ethical approval was obtained from Makerere University and Mulago Hospital. All infants were in-born. Parental consent for entry into the trial was obtained. Thirty-six infants were randomized either to standard care plus cooling (target rectal temperature of 33-34°C for 72 hrs, started within 3 h of birth) or standard care alone. All other aspects of management were the same. Cooling was performed using water bottles filled with tepid tap water (25°C). Rectal, axillary, ambient and surface water bottle temperatures were monitored continuously for the first 80 h. Encephalopathy scoring was performed on days 1-4, a structured, scorable neurological examination and head circumference were performed on days 7 and 17. Cranial ultrasound was performed on days 1, 3 and 7 and scored. Griffiths developmental quotient, head circumference, neurological examination and assessment of gross motor function were obtained at 18-22 months.
We will highlight differences in neonatal care and infrastructure that need to be taken into account when considering a large safety and efficacy RCT of therapeutic hypothermia in low and mid resource settings in the future.
Current controlled trials ISRCTN92213707
All infants have some degree of hypoxia and respiratory acidosis at birth, but these conditions are more profound in the asphyxiated newborn. The newborn infant is very susceptible to cooling and may require warming. Skin temperature should be maintained between 36-36.5°.2 Resuscitation of the asphyxiated newborn must include both ventilatory and metabolic correction.
Newborn infants may have cardiorespiratory problems due to asphyxia, drugs given to the mother, intrathoracic disease, anemia, hypovolemia (due to antepartum hemorrhage), hypotension, etc. There is no substitute for oxygen which is the drug of choice in respiratory depression of the newborn. The use of stimulating drugs like Coramine, picrotoxin, alphalobectine, and Megamide has no place in the resuscitation of the asphyxiated newborn.
Speckle tracking echocardiography is increasingly being used to assess cardiac function in neonates. The objective was to compare speckle tracking strain indices between asphyxiated infants and healthy controls and to ascertain correlations between strain and 2D Doppler derived indices and cardiac troponin (biochemical marker of myocardial injury).
Clinical and echocardiographic data from severely asphyxiated infants undergoing therapeutic hypothermia was evaluated retrospectively. This was compared with prospective data from healthy infants. Correlations between variables were assessed using Pearson’s coefficient of correlation.
Twenty four infants with severe perinatal asphyxia were admitted during the study period of which 3 were not cooled and were excluded. The gestational age and birth weights of cases and controls were comparable. The mean left ventricular global longitudinal strain (GLS) from apical 4 chamber view was noted to be significantly impaired in the asphyxiated infants (– 11.01% ± 2.48 vs – 21.45% ± 2.74, p <0.001). Cardiac output was significantly lower in the asphyxiated infants (97 ± 26 vs 230 ± 60 ml/kg/min). In asphyxiated infants, GLS correlated positively with cardiac output (r2 = 0.86, p< 0.001) and negatively with serum troponin levels (r2 = 0.64, p< 0.001). GLS was less impaired in infants on inotropes compared to those not on inotropic support, -12.55% (1.9) vs -10.2% (1.3), p= 0.018. Infants who died had a lower global strain value compared to survivors, – 9.7% (1.6) vs – 12.8% (2.6), p = 0.02.
2D Speckle derived strain was impaired in asphyxiated infants. Significant correlations between GLS and cardiac output and troponin were noted.
Asphyxia; Neonates; Speckle tracking; Strain
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.
Whole-body deep hypothermia (DH) could be a new therapeutic strategy for asphyxiated newborn. This retrospective study describes how DH modified the heart rate and arterial blood pressure if compared to mild hypothermia (MH). Fourteen in DH and 17 in MH were cooled within the first six hours of life and for the following 72 hours. Hypothermia criteria were gestational age ≥36 weeks; birth weight ≥1800 g; clinical signs of moderate/severe hypoxic-ischemic encephalopathy. Rewarming was obtained in the following 6–12 hours (0.5°C/h) after cooling. Heart rates were the same between the two groups; there was statistically significant difference at the beginning of hypothermia and during rewarming. Three babies in the DH group and 2 in the MH group showed HR < 80 bpm and QTc > 520 ms. Infant submitted to deep hypothermia had not bradycardia or Qtc elongation before cooling and after rewarming. Blood pressure was significantly lower in DH compared to MH during the cooling, and peculiar was the hypotension during rewarming in DH group. Conclusion. The deeper hypothermia is a safe and feasible, only if it is performed by a well-trained team. DH should only be associated with a clinical trial and prospective randomized trials to validate its use.
Resuscitation of a neonate requires both immediate cardiopulmonary resuscitation and extended intensive care. Initial resuscitation of the neonate, as for adults, must include support of the airway, breathing and circulation. Because of the unique physiology of a newborn infant, some aspects of drug therapy differ significantly from their counterparts in the resuscitation of adults, and hypoglycemia and hypothermia pose special threats to a distressed neonate. Epinephrine and atropine can be administered via an endotracheal tube, but vascular access, which is most easily obtained by cannulating an umbilical vessel, is required for administering other drugs. Initial drug therapy, including glucose, oxygen and bicarbonate, is intended to restore metabolic homeostasis. Bicarbonate administration must be preceded by adequate alveolar ventilation. Drugs used to increase cardiac output early in resuscitation include those that increase heart rate, increase preload or improve myocardial function. Other drugs used in extended intensive care may also improve cardiac output, alter the distribution of the circulation or alter pulmonary function or gas exchange. These agents will be reviewed in a subsequent article.
Subcutaneous fat necrosis (SCFN) is an inflammatory disorder of adipose tissue. The main risk factors for the development of SCFN are perinatal asphyxia and hypothermia. Presented here is a case of a newborn who developed SCFN in association with polycythemia and hypocalcemia following treatment by passive cooling. Neonates who undergo passive or whole body cooling therapy should be closely monitored for any signs of SCFN.
There is a rich history for the use of therapeutic hypothermia after cardiac arrest in neonatology and pediatrics. Laboratory reports date back to 1824 in experimental perinatal asphyxia. Similarly, clinical reports in pediatric cold water drowning victims represented key initiating work in the field. The application of therapeutic hypothermia in pediatric drowning victims represented some of the seminal clinical use of this modality in modern neurointensive care. Uncontrolled application (too deep and too long) and unique facets of asphyxial cardiac arrest in children (a very difficult insult to affect any benefit) likely combined to result in abandonment of therapeutic hypothermia in the mid to late 1980s. Important studies in perinatal medicine have built upon the landmark clinical trials in adults, and are once again bringing therapeutic hypothermia into standard care for pediatrics. Although more work is needed, particularly in the use of mild therapeutic hypothermia in children, there is a strong possibility that this important therapy will ultimately have broad applications after cardiac arrest and CNS insults in the pediatric arena.
Asphyxia; cooling; neonate; newborn; drowning; resuscitation
There is a rich history for the use of therapeutic hypothermia after cardiac arrest in neonatology and pediatrics. Laboratory reports date back to 1824 in experimental perinatal asphyxia. Similarly, clinical reports in pediatric cold water drowning victims represented key initiating work in the field. The application of therapeutic hypothermia in pediatric drowning victims represented some of the seminal clinical use of this modality in modern neurointensive care. Uncontrolled application (too deep and too long) and unique facets of asphyxial cardiac arrest in children (a very difficult insult to affect any benefit) likely combined to result in abandonment of therapeutic hypothermia in the mid to late 1980s. Important studies in perinatal medicine have built upon the landmark clinical trials in adults, and are once again bringing therapeutic hypothermia into standard care for pediatrics. Although more work is needed, particularly in the use of mild therapeutic hypothermia in children, there is a strong possibility that this important therapy will ultimately have broad applications after cardiac arrest and central nervous system (CNS) insults in the pediatric arena.
asphyxia; cooling; drowning; neonate; newborn; resuscitation
Moderate hypothermia in neonates with hypoxic–ischaemic encephalopathy might improve survival and neurological outcomes at up to 18 months of age, although complete neurological assessment at this age is difficult. To ascertain more precisely the effect of therapeutic hypothermia on neonatal cerebral injury, we assessed cerebral lesions on MRI scans of infants who participated in the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial.
In the TOBY trial hypoxic–ischaemic encephalopathy was graded clinically according to the changes seen on amplitude integrated EEG, and infants were randomly assigned to intensive care with or without cooling by central telephone randomisation. The relation between allocation to hypothermia or normothermia and cerebral lesions was assessed by logistic regression with perinatal factors as covariates, and adjusted odds ratios (ORs) were calculated. The TOBY trial is registered, number ISRCTN 89547571.
325 infants were recruited in the TOBY trial between 2002 and 2006. Images were available for analysis from 131 infants. Therapeutic hypothermia was associated with a reduction in lesions in the basal ganglia or thalamus (OR 0·36, 95% CI 0·15–0·84; p=0·02), white matter (0·30, 0·12–0·77; p=0·01), and abnormal posterior limb of the internal capsule (0·38, 0·17–0·85; p=0·02). Compared with non-cooled infants, cooled infants had fewer scans that were predictive of later neuromotor abnormalities (0·41, 0·18–0·91; p=0·03) and were more likely to have normal scans (2·81, 1·13–6·93; p=0·03). The accuracy of prediction by MRI of death or disability to 18 months of age was 0·84 (0·74–0·94) in the cooled group and 0·81 (0·71–0·91) in the non-cooled group.
Therapeutic hypothermia decreases brain tissue injury in infants with hypoxic–ischaemic encephalopathy. The predictive value of MRI for subsequent neurological impairment is not affected by therapeutic hypothermia.
UK Medical Research Council; UK Department of Health.
Pulseless electrical activity is an important cause of cardiac arrest. Our purpose was to determine if induction of hypothermia with a cold perfluorocarbon-based total liquid ventilation system (TLV) would improve resuscitation success in a swine model of asphyxial cardiac arrest/PEA.
Twenty swine were randomly assigned to control (C, no ventilation, n=11) or TLV with pre-cooled PFC (n=9) groups. Asphyxia was induced by insertion of a stopper into the endotracheal tube, and continued in both groups until loss of aortic pulsations (LOAP) was reached, defined as a pulse pressure less than 2mmHg. The TLV animals underwent asphyxial arrest for an additional 2 minutes after LOAP, followed by 3 minutes of hypothermia, prior to starting CPR. The C animals underwent 5 minutes of asphyxia beyond LOAP. Both groups then underwent CPR for at least 10 minutes. The endpoint was the resumption of spontaneous circulation maintained for 10 minutes.
Seven of 9 animals achieved resumption of spontaneous circulation (ROSC) in the TLV group vs. 5 of 11 in the C group (p=0.2). The mean pulmonary arterial temperature was lower in total liquid ventilation animals starting 4 minutes after induction of hypothermia (TLV 36.3 ± SE 0.2 vs. C 38.1±0.2°C, p<0.0001). Arterial pO2 was higher in total liquid ventilation animals at 2.5 minutes of CPR (TLV 76±12 vs. C 44±2 mmHg; p=0.03).
Induction of moderate hypothermia using perfluorocarbon-based total liquid ventilation did not improve ROSC success in this model of asphyxial cardiac arrest.
CPR; resuscitation; cardiac arrest; asphyxia; defibrillation; perfluorocarbons; liquid ventilation
Induced hypothermia after ischemic stroke is a promising neuroprotective therapy, and is the most potent in pre-clinical models. Technological limitations and homeostatic mechanisms that maintain core body temperature, however, have limited the clinical application of hypothermia. Advances in intravascular cooling and successful trials of hypothermia after global cerebral ischemia, such as in cardiac arrest and neonatal asphyxia, renewed interest in hypothermia for stroke.
Induced hypothermia after ischemic stroke is a promising neuroprotective therapy and is the most potent in pre-clinical models. Technological limitations and homeostatic mechanisms that maintain core body temperature, however, have limited the clinical application of hypothermia. Advances in intravascular cooling and successful trials of hypothermia after global cerebral ischemia, such as in cardiac arrest and neonatal asphyxia, have renewed interest in hypothermia for stroke.
cerebral vascular disease; hypothermia; regeneration; stem cells; stroke; traumatic brain injury; traumatic spinal cord injury
To assess whether continuous consent, a process in which information is given to research participants at different stages in a trial, and clinician training in that process were effective when used by clinicians while gaining consent to the Total Body Hypothermia (TOBY) trial. The TOBY trial is a randomised controlled trial (RCT) investigating the use of whole‐body cooling for neonates with evidence of perinatal asphyxia. Obtaining valid informed consent for the TOBY trial is difficult, but is a good test of the effectiveness of continuous consent.
Semistructured interviews were conducted with 30 sets of parents who consented to the TOBY trial and with 10 clinicians who sought it by the continuous consent process. Analysis was focused on the validity of parental consent based on the consent components of competence, information, understanding and voluntariness.
No marked problems with consent validity at the point of signature were observed in 19 of 27 (70%) couples. Problems were found mainly to lie with the competence and understanding of the parents: mothers, particularly, had problems with competence in the early stages of consent. Problems in understanding were primarily to do with side effects. Problems in both competence and understanding were observed to reduce markedly, particularly for mothers, in the post‐signature phase, when further discussion took place. Randomisation was generally understood but unpopular. Information was not always given by clinicians in stages during the short period available before parents gave consent. Most clinicians, however, were able to give follow‐up information.
Consent validity was found to compare favourably with similar trials examined in the Euricon study.
Adopting the elements of the continuous consent process and clinician training in RCTs should be considered by researchers, particularly when they have concerns about the quality of consent they are likely to obtain by using a conventional process.
The purposes of this feasibility study are to assess: (1) the potential utility of early brain magnetic resonance imaging (MRI) in asphyxiated newborns treated with hypothermia; (2) whether early MRI predicts later brain injury observed in these newborns after hypothermia is completed; and (3) whether early MRI indicators of brain injury in these newborns represent reversible changes.
Patients and Methods
All consecutive asphyxiated term newborns meeting the criteria for therapeutic hypothermia were enrolled prospectively. Each of them underwent 1–2 “early” MRI scans while receiving hypothermia, on day of life (DOL) 1 and DOL 2–3, and also 1–2 “late” MRI scans on DOL 8–13 and at 1 month of age.
Thirty-seven MRI scans were obtained in twelve asphyxiated neonates treated with induced hypothermia. Four newborns did develop MRI evidence of brain injury, already visible on early MRI scans. The remaining eight newborns did not develop significant MRI evidence of brain injury on any of the MRI scans. In addition, two patients displayed unexpected findings on early MRIs, leading to early termination of hypothermia treatment.
MRI scans obtained on DOL 2–3 during hypothermia seem to predict later brain injuries in asphyxiated newborns in this feasibility study. Brain injuries identified during this early time appear to represent irreversible changes. Early MRI scans might also be useful to demonstrate unexpected findings not related to hypoxic-ischemic encephalopathy, which could potentially be exacerbated by induced hypothermia. Additional studies with larger numbers of patients will be useful to more definitively confirm these results.
hypoxic-ischemic encephalopathy; newborn brain; hypothermia; magnetic resonance imaging
To investigate one-segment strain and strain rate indices as measures of myocardial performance in asphyxiated term neonates.
Quality improvement cohort study.
Newborns admitted to a neonatal intensive care unit at a Norwegian University Hospital for perinatal asphyxia and non-asphyxiated newborn recruited from the maternity ward at the same hospital.
Twenty asphyxiated and 48 non-asphyxiated term neonates.
Primary outcome measure
Strain and strain rate indices and repeatability measures. One-segment longitudinal strain and strain rate by tissue Doppler were assessed on days 1, 2 and 3 of life in nine heart walls. Repeatability was compared against measurements from two-segment analyses previously performed in the same images.
The 95% limits of agreement were significantly better for the one-segment than two-segment repeatability analyses, the inter-rater peak systolic strain (PSS) was (−3.1, 3.3) vs (−11.4, 18.3)%, the inter-rater peak systolic strain rate (PSSR) was (−0.38, 0.40) vs (−0.79, 1.15)/s, the intra-rater PSS was (−2.5, 2.6) vs (−8.0, 9.8)% and the intra-rater PSSR was (−0.23, 0.25) vs (−0.75, 0.80)/s (p<0.05). The myocardial performance was lower in the asphyxiated neonates (indices closer to zero) than in the non-asphyxiated neonates, PSS was −17.8 (0.6) (mean (SEM)) vs −21.2 (0.3)%, PSSR −1.43 (0.08) vs −1.61 (0.03)/s, early diastolic strain rate 1.72 (0.11) vs 2.00 (0.11)/s and strain rate during the atrial systole 1.92 (0.17) vs 2.27 (0.10)/s (p<0.05), despite no difference in fractional shortening (29.0 (0.5) vs 29.1 (1.0)%) (p>0.05).
One-segment strain and strain rate assessed the reduced myocardial performance in asphyxiated neonates with significantly improved reproducibility as compared with two-segment analysis and was therefore more feasible than two-segment analyses for assessment of myocardial performance after perinatal asphyxia.
Cardiology; Echocardiography; Neonatology; Paediatrics; Paediatric cardiology
Therapeutic hypothermia is a means of neuroprotection well established in the management of acute ischemic brain injuries such as anoxic encephalopathy after cardiac arrest and perinatal asphyxia. As such, it is the only neuroprotective strategy for which there is robust evidence for efficacy. Although there is overwhelming evidence from animal studies that cooling also improves outcome after focal cerebral ischemia, this has not been adequately tested in patients with acute ischemic stroke. There are still some uncertainties about crucial factors relating to the delivery of hypothermia, and the resolution of these would allow improvements in the design of phase III studies in these patients and improvements in the prospects for successful translation. In this study, we discuss critical issues relating first to the targets for therapy including the optimal depth and duration of cooling, second to practical issues including the methods of cooling and the management of shivering, and finally, of factors relating to the design of clinical trials. Consideration of these factors should inform the development of strategies to establish beyond doubt the place of hypothermia in the management of acute ischemic stroke.
acute stroke; animal models; clinical trials; hypothermia; shivering MR spectroscopy
Neuroprotection is a major health care priority, given the enormous burden of human suffering and financial cost caused by perinatal brain damage. With the advent of hypothermia as therapy for term hypoxic–ischemic encephalopathy, there is hope for repair and protection of the brain after a profound neonatal insult. However, it is clear from the published clinical trials and animal studies that hypothermia alone will not provide complete protection or stimulate the repair that is necessary for normal neurodevelopmental outcome. This review critically discusses drugs used to treat seizures after hypoxia–ischemia in the neonate with attention to evidence of possible synergies for therapy. In addition, other agents such as xenon, N-acetylcysteine, erythropoietin, melatonin and cannabinoids are discussed as future potential therapeutic agents that might augment protection from hypothermia. Finally, compounds that might damage the developing brain or counteract the neuroprotective effects of hypothermia are discussed.
Anticonvulsants; Hypoxia; Ischemia; Neuroprotection; Repair; Seizures
To compare the association between perinatal events and the pattern and extent of brain injury on early MRI in newborns with and without therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE).
We performed a cohort study of 35 treated and 25 non-treated neonates who underwent MRI. The injury patterns were defined a priori as: normal (N), watershed (WS) or basal ganglia/thalamus (BG/T) predominant, as well as a dichotomous outcome of moderate-to-severe versus mild-no injury.
Neonates with hypothermia had less extensive WS and BG/T injuries, and a greater proportion had normal imaging. Therapeutic hypothermia was associated with a decreased risk of both BG/T injury (RR 0.29, 95% CI 0.10-0.81, p = 0.01) and moderate-severe injury. Neonates with sentinel events showed a decrease in BG/T predominant injury and increase in normal imaging. All neonates with decreased fetal movements had injury, predominantly WS, regardless of therapeutic hypothermia.
These results validate reports of reduced brain injury following therapeutic hypothermia, and suggest that perinatal factors are important indicators of response to treatment.
Neonatal; MRI; Hypoxia-ischemia; Hypothermia therapy
Providing safe and effective drug therapy to neonates requires knowledge of the impact of development on the pharmacokinetics and pharmacodynamics of drugs. Although maturational changes are observed throughout childhood, they are most prominent during the first year of life. Several of these processes overlap, making development an extremely dynamic system in the newborn compared with that in infants, children, or adults. Changes in body composition and porportions, liver mass, metabolic activity, and renal function collectively affect the pharmacokinetic behavior of medications. Instead of simply adapting doses by scaling adult or pediatric doses on the basis of a patient's weight and/or body surface area, integrated knowledge of clinical maturation and developmental pharmacology is critical to the safe and effective use of medications in neonates. Unfortunately, the effects of human ontogeny on both pharmacokinetics and pharmacodynamics have not been well established in these early stages of life, and information regarding the influence of developmental changes on the pharmacodynamics of medications is even more limited. Theoretically, age-dependent variations in receptor number and affinity for drugs have significant potential to influence an individual's response to drug therapy. In this review, some of the relevant covariates of pharmacokinetics and pharmacodynamics in neonates are reviewed and illustrated based on the published literature.
developmental pharmacology; neonate; pharmacodynamic; pharmacokinetic
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.
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