Search

OBJECTIVE To test the hypothesis that an Apgar score at 10 minutes is independently predictive for death or moderate or severe disability. METHODS A secondary analysis of the Optimizing Cooling Trial (NCT01192776) including 347 infants with ≥36 weeks’ gestational age at birth and hypoxic-ischemic encephalopathy and 18- to 22-month outcomes from 18 US centers in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome was the composite of death or moderate/severe disability at 18 to 22 months of age. Generalized estimating equation models were used to examine the relationship between Apgar scores and outcomes, controlling for center, hypothermia treatment, and severity of hypoxic-ischemic encephalopathy (HIE). Classification and regression tree analyses were conducted to identify combinations of variables available during resuscitation that were most predictive for the composite outcome and death. RESULTS The study revealed that 50% (13 of 26) of infants with a 10-minute Apgar score of 0 survived; 46% (6 of 13) had no disability, 16% (2 of 13) had mild disability, and 38% (5 of 13) had moderate or severe disability. The 10-minute Apgar score of 0 was independently associated with death or moderate or severe disability (adjusted relative risk = 1.72, 95% confidence interval 1.11–2.68, P value = .016), but the area under the curve analysis (AUC) was low (AUC = 0.56). The predictive accuracy improved when the 10-minute Apgar score was combined with other risk variables available during resuscitation by using a classification and regression tree analysis (AUC = 0.66). CONCLUSIONS A 10-minute Apgar score of 0 alone does not predict the risk of death or moderate or severe disability well. The current study provides evidence in support of the 2020 American Heart Association/International Liaison Committee on Resuscitation recommendation for continuing resuscitative efforts for infants who need cardiopulmonary resuscitation at 10 minutes after birth.

In this state-of-the-art review, we highlight the major advances over the last 5 years in neonatal acute kidney injury (AKI). Large multicenter studies reveal that neonatal AKI is common and independently associated with increased morbidity and mortality. The natural course of neonatal AKI, along with the risk factors, mitigation strategies, and the role of AKI on short- and long-term outcomes, is becoming clearer. Specific progress has been made in identifying potential preventive strategies for AKI, such as the use of caffeine in premature neonates, theophylline in neonates with hypoxic-ischemic encephalopathy, and nephrotoxic medication monitoring programs. New evidence highlights the importance of the kidney in “crosstalk” between other organs and how AKI likely plays a critical role in other organ development and injury, such as intraventricular hemorrhage and lung disease. New technology has resulted in advancement in prevention and improvements in the current management in neonates with severe AKI. With specific continuous renal replacement therapy machines designed for neonates, this therapy is now available and is being used with increasing frequency in NICUs. Moving forward, biomarkers, such as urinary neutrophil gelatinase–associated lipocalin, and other new technologies, such as monitoring of renal tissue oxygenation and nephron counting, will likely play an increased role in identification of AKI and those most vulnerable for chronic kidney disease. Future research needs to be focused on determining the optimal follow-up strategy for neonates with a history of AKI to detect chronic kidney disease.

The transition from intrauterine life to extrauterine existence encompasses significant cardiorespiratory adaptations. These include rapid lung aeration and increase in pulmonary blood flow (PBF). Perinatal asphyxia and fetal growth restriction can severely hamper this transition. Hypoxia is the common denominator in these 2 disease states, with the former characterized by acute insult and the latter by utero-placental insufficiency and a chronic hypoxemic state. Both may manifest as hemodynamic instability. In this review, we emphasize the role of physiologic-based cord clamping in supplementing PBF during transition. The critical role of lung aeration in initiating pulmonary gas exchange and increasing PBF is discussed. Physiologic studies in animal models have enabled greater understanding of the mechanisms and effects of various therapies on transitional circulation. With data from sheep models, we elaborate instrumentation for monitoring of cardiovascular and pulmonary physiology and discuss the combined effect of chest compressions and adrenaline in improving transition at birth. Lastly, physiologic adaptation influencing management in human neonatal cohorts with respect to cardiac and vascular impairments in hypoxic-ischemic encephalopathy and growth restriction is discussed. Impairments in right ventricular function and vascular mechanics hold the key to prognostication and understanding of therapeutic rationale in these critically ill cohorts. The right ventricle and pulmonary circulation seem to be especially affected and may be explored as therapeutic targets. The role of comprehensive assessments using targeted neonatal echocardiography as a longitudinal, reliable, and easily accessible tool, enabling precision medicine facilitating physiologically appropriate treatment choices, is discussed.

OBJECTIVES: To develop predictive models for death or neurodevelopmental impairment (NDI) after neonatal hypoxic-ischemic encephalopathy (HIE) from data readily available at the time of NICU admission (“early”) or discharge (“cumulative”). METHODS: In this retrospective cohort analysis, we used data from the Children’s Hospitals Neonatal Consortium Database (2010–2016). Infants born at ≥35 weeks’ gestation and treated with therapeutic hypothermia for HIE at 11 participating sites were included; infants without Bayley Scales of Infant Development scores documented after 11 months of age were excluded. The primary outcome was death or NDI. Multivariable models were generated with 80% of the cohort; validation was performed in the remaining 20%. RESULTS: The primary outcome occurred in 242 of 486 infants; 180 died and 62 infants surviving to follow-up had NDI. HIE severity, epinephrine administration in the delivery room, and respiratory support and fraction of inspired oxygen of 0.21 at admission were significant in the early model. Severity of EEG findings was combined with HIE severity for the cumulative model, and additional significant variables included the use of steroids for blood pressure management and significant brain injury on MRI. Discovery models revealed areas under the curve of 0.852 for the early model and of 0.861 for the cumulative model, and both models performed well in the validation cohort (goodness-of-fit χ2: P = .24 and .06, respectively). CONCLUSIONS: Establishing reliable predictive models will enable clinicians to more accurately evaluate HIE severity and may allow for more targeted early therapies for those at highest risk of death or NDI.

Although parents are typically the most appropriate decision-makers for their children, there are limits to this authority. Medical providers may be ethically obligated to seek state intervention against a parental decision if the parent places a child at significant and imminent risk of serious harm. When parents make medical decisions for their children, they assess both the projected benefits and risks of their choices for their family. These assessments are impacted by uncertainty, which is a common feature of neonatal intensive care. The relative presence or absence of uncertainty may impact perceptions of parental decisions and a medical provider’s decision to seek state intervention to overrule parents. In this article, we propose a model integrating prognostic uncertainty into pediatric decision-making that may aid providers in such assessments. We will demonstrate how to apply this model to 3 neonatal cases and propose that the presence of greater uncertainty ought to permit parents greater latitude to incorporate family values into their decision-making even if these decisions are contradictory to the recommendations of the medical team.

* Abbreviations: CMC — : children with medical complexity ED — : emergency department PCP — : primary care provider Children with medical complexity (CMC) are traditionally defined as those who have health conditions that are expected to last at least 12 months and affect multiple body systems or 1 system severely enough that specialty care and hospitalization are necessary.1 This definition has been refined recently to reflect the necessary multifaceted approach to address increasing prevalence, cost, and challenges of caring for this population in the community and the hospital setting.2–5 Most of the current literature on CMC focuses specifically on the strengthening of the medical home (and more recently, the medical neighborhood) and highlights the importance of preventing inpatient hospitalization and emergency care.6 The importance of this work is irrefutable for CMC, but in regard to their emergency needs, we would like to propose a flip in the current script. George, a 6-year-old boy who suffered an anoxic brain injury at birth, is tracheostomy and ventilator dependent, with gastrojejunal feeds, and seizure disorder presents to his local emergency department (ED) at 6:00 pm with increased seizure frequency, rhinorrhea, and cough. His family called the primary care office and spoke to the on-call provider, who understood that care was needed, but the office was closed. The local ED was suggested. At the local ED, a chest radiograph and basic metabolic profile are … Address correspondence to Christian D. Pulcini, MD, MEd, MPH, Division of Emergency Medicine, Children’s Hospital of Philadelphia, Colket Translational Research Building, 2nd Floor, 3501 Civic Center Blvd, Philadelphia, PA 19104. E-mail: pulcinic{at}email.chop.edu

BACKGROUND: Neuromotor impairments are common after pediatric stroke, but little is known about functional motor outcomes. We evaluated motor function and how it changed over the first 12 months after diagnosis. We also examined differences in outcome according to age at diagnosis and whether fine motor (FM) or gross motor (GM) function at 12 months was associated with adaptive behavior. METHODS: This prospective, longitudinal study recruited children (N = 64) from The Royal Children’s Hospital, Melbourne who were diagnosed with acute arterial ischemic stroke (AIS) between December 2007 and November 2013. Motor assessments were completed at 3 time points after the diagnosis of AIS (1, 6, and 12 months). Children were grouped as follows: neonates (n = 27), preschool-aged (n = 19), and school-aged (n = 18). RESULTS: A larger lesion size was associated with poorer GM outcomes at 12 months (P = .016). Neonatal AIS was associated with better FM and GM function initially but with a reduction in z scores over time. For the preschool- and school-aged groups, FM remained relatively stable over time. For GM outcomes, the preschool- and the school-aged age groups displayed similar profiles, with gradual recovery over time. Overall, poor FM and GM outcomes at 12 months were associated with poorer adaptive behavior scores. CONCLUSIONS: Motor outcomes and the trajectory of recovery post-AIS differed according to a child’s age at stroke onset. These findings indicate that an individualized approach to surveillance and intervention may be needed that is informed in part by age at diagnosis.

Data from large randomized clinical trials indicate that therapeutic hypothermia, using either selective head cooling or systemic cooling, is an effective therapy for neonatal encephalopathy. Infants selected for cooling must meet the criteria outlined in published clinical trials. The implementation of cooling needs to be performed at centers that have the capability to manage medically complex infants. Because the majority of infants who have neonatal encephalopathy are born at community hospitals, centers that perform cooling should work with their referring hospitals to implement education programs focused on increasing the awareness and identification of infants at risk for encephalopathy, and the initial clinical management of affected infants.

OBJECTIVE: To determine whether antepartum factors alone, intrapartum factors alone, or both in combination, are associated with term neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: A total of 405 infants ≥35 weeks’ gestation with early encephalopathy, born between 1992 and 2007, were compared with 239 neurologically normal infants born between 1996 and 1997. All cases met criteria for perinatal asphyxia, had neuroimaging findings consistent with acute hypoxia-ischemia, and had no evidence for a non–hypoxic-ischemic cause of their encephalopathy. RESULTS: Both antepartum and intrapartum factors were associated with the development of HIE on univariate analysis. Case infants were more often delivered by emergency cesarean delivery (CD; 50% vs 11%, P < .001) and none was delivered by elective CD (vs 10% of controls). On logistic regression analysis only 1 antepartum factor (gestation ≥41 weeks) and 7 intrapartum factors (prolonged membrane rupture, abnormal cardiotocography, thick meconium, sentinel event, shoulder dystocia, tight nuchal cord, failed vacuum) remained independently associated with HIE (area under the curve 0.88; confidence interval 0.85–0.91; P < .001). Overall, 6.7% of cases and 43.5% of controls had only antepartum factors; 20% of cases and 5.8% of controls had only intrapartum factors; 69.5% of cases and 31% of controls had antepartum and intrapartum factors; and 3.7% of cases and 19.7% of controls had no identifiable risk factors (P < .001). CONCLUSIONS: Our results do not support the hypothesis that HIE is attributable to antepartum factors alone, but they strongly point to the intrapartum period as the necessary factor in the development of this condition.

OBJECTIVE: More than half of all infants with neonatal hypoxic ischemic encephalopathy (HIE) are graded as mild and do not meet current criteria for therapeutic hypothermia. These infants are often not enrolled in follow-up, and hence our knowledge of their long-term outcome is sparse. We wished to compare 5-year outcomes in a group of infants with mild, moderate, and severe HIE, graded with both early EEG and clinical assessment, none of whom were treated with therapeutic hypothermia. METHODS: Term infants with HIE and a healthy comparison group were recruited at birth. Both groups had early continuous EEG recordings. Cognitive and motor outcome was assessed at 5 years. RESULTS: Outcome was available in 53 infants with HIE and 30 infants in the comparison group at 5 years. Infants with mild HIE at birth (n = 22) had significantly lower full-scale IQ, verbal IQ, and performance IQ than comparison infants (n = 30) at 5 years (P = .001, .001, and 0.004, respectively). No difference in cognitive measures was seen between infants with mild and moderate grades HIE. Intact survival at 5 years varied across EEG grade HIE at 6 hours after birth; 75% in mild, 46% in moderate, 43% in major abnormalities, and 0% with inactive EEGs, compared with 97% in the comparison group. CONCLUSIONS: Survivors of mild HIE, graded clinically or by early EEG, have higher rates of disability than their peers and have cognitive outcomes similar to that of children with moderate encephalopathy in an uncooled HIE cohort.

OBJECTIVE: To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy. METHODS: In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar RESULTS: The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05). CONCLUSIONS: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function.

OBJECTIVES: To examine the association of intrapartum temperature elevation with adverse neonatal outcome among low-risk women receiving epidural analgesia and evaluate the association of epidural with adverse neonatal outcome without temperature elevation. METHODS: We studied all low-risk nulliparous women with singleton pregnancies ≥37 weeks delivering at our hospital during 2000, excluding pregnancies where infants had documented sepsis, meningitis, or a major congenital anomaly. Neonatal outcomes were compared between women receiving (n = 1538) and not receiving epidural analgesia (n = 363) in the absence of intrapartum temperature elevation (≤99.5°F) and according to the level of intrapartum temperature elevation within the group receiving epidural (n = 2784). Logistic regression was used to evaluate neonatal outcome while controlling for confounders. RESULTS: Maternal temperature >100.4°F developed during labor in 19.2% (535/2784) of women receiving epidural compared with 2.4% (10/425) not receiving epidural. In the absence of intrapartum temperature elevation (≤99.5°F), no significant differences were observed in adverse neonatal outcomes between women receiving and not receiving epidural. Among women receiving epidural, a significant linear trend was observed between maximum maternal temperature and all neonatal outcomes examined including hypotonia, assisted ventilation, 1- and 5-min Apgar scores 101°F had a two- to sixfold increased risk of all adverse outcomes examined. CONCLUSIONS: The proportion of infants experiencing adverse outcomes increased with the degree of epidural-related maternal temperature elevation. Epidural use without temperature elevation was not associated with any of the adverse outcomes we studied.

OBJECTIVE: 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. DESIGN: Neonates were eligible for this prospective study if moderate or severe HIE occurred at RESULTS: 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). CONCLUSIONS: 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.

The death or near death of a presumably healthy newborn in the delivery room is uncommon. We report here 6 cases of apparent life-threatening events (ALTEs) in the delivery room during the first 2 hours of life. In each case, the incident occurred in a healthy infant who was in a prone position on his or her mother's abdomen during early skin-to-skin contact. In most cases, the mother was primiparous, and in all cases the mother and infant were not observed during the initiation of skin-to-skin contact and breastfeeding. There are many benefits of early skin-to-skin contact and breastfeeding in the delivery room. However, in view of the risk of a rare but significant ALTE, we suggest that surveillance of newborns is needed. Although many ALTEs are apparently caused by obstruction, we suggest that a standardized investigational workup be performed after an ALTE.

The majority of deaths in infants with hypoxic-ischemic encephalopathy (HIE) follow decisions to withdraw life-sustaining treatment. Clinicians use prognostic tests including MRI to help determine prognosis and decide whether to consider treatment withdrawal. A recently published meta-analysis provided valuable information on the prognostic utility of magnetic resonance (MR) biomarkers in HIE and suggested, in particular, that proton MR spectroscopy is the most accurate predictor of neurodevelopmental outcome. How should this evidence influence treatment-limitation decisions? In this article I outline serious limitations in existing prognostic studies of HIE, including small sample size, selection bias, vague and overly inclusive outcome assessment, and potential self-fulfilling prophecies. Such limitations make it difficult to answer the most important prognostic question. Reanalysis of published data reveals that severe abnormalities on conventional MRI in the first week have a sensitivity of 71% (95% confidence interval: 59%–91%) and specificity of 84% (95% confidence interval: 68%–93%) for very adverse outcome in infants with moderate encephalopathy. On current evidence, MR biomarkers alone are not sufficiently accurate to direct treatment-limitation decisions. Although there may be a role for using MRI or MR spectroscopy in combination with other prognostic markers to identify infants with very adverse outcome, it is not possible from meta-analysis to define this group clearly. There is an urgent need for improved prognostic research into HIE.

OBJECTIVES: The goals were to investigate how many subclinical seizures in full-term neonates with hypoxic-ischemic encephalopathy (HIE) would be missed without continuous amplitude-integrated electroencephalography (aEEG) and whether immediate treatment of both clinical and subclinical seizures would result in a reduction in the total duration of seizures and a decrease in brain injury, as seen on MRI scans. METHODS: In this multicenter, randomized, controlled trial, term infants with moderate to severe HIE and subclinical seizures were assigned randomly to either treatment of both clinical seizures and subclinical seizure patterns (group A) or blinding of the aEEG registration and treatment of clinical seizures only (group B). All recordings were reviewed with respect to the duration of seizure patterns and the use of antiepileptic drugs (AEDs). MRI scans were scored for the severity of brain injury. RESULTS: Nineteen infants in group A and 14 infants in group B were available for comparison. The median duration of seizure patterns in group A was 196 minutes, compared with 503 minutes in group B (not statistically significant). No significant differences in the number of AEDs were seen. Five infants in group B received AEDs when no seizure discharges were seen on aEEG traces. Six of 19 infants in group A and 7 of 14 infants in group B died during the neonatal period. A significant correlation between the duration of seizure patterns and the severity of brain injury in the blinded group, as well as in the whole group, was found. CONCLUSIONS: In this small group of infants with neonatal HIE and seizures, there was a trend for a reduction in seizure duration when clinical and subclinical seizures were treated. The severity of brain injury seen on MRI scans was associated with a longer duration of seizure patterns.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of erythropoietin in neonatal hypoxic-ischemic encephalopathy (HIE), by using a randomized, prospective study design. METHODS: A total of 167 term infants with moderate/severe HIE were assigned randomly to receive either erythropoietin (N = 83) or conventional treatment (N = 84). Recombinant human erythropoietin, at either 300 U/kg (N = 52) or 500 U/kg (N = 31), was administered every other day for 2 weeks, starting RESULTS: Complete outcome data were available for 153 infants. Nine patients dropped out during treatment, and 5 patients were lost to follow-up monitoring. Death or moderate/severe disability occurred for 35 (43.8%) of 80 infants in the control group and 18 (24.6%) of 73 infants in the erythropoietin group (P = .017) at 18 months. The primary outcomes were not different between the 2 erythropoietin doses. Subgroup analyses indicated that erythropoietin improved long-term outcomes only for infants with moderate HIE (P = .001) and not those with severe HIE (P = .227). No negative hematopoietic side effects were observed. CONCLUSION: Repeated, low-dose, recombinant human erythropoietin treatment reduced the risk of disability for infants with moderate HIE, without apparent side effects.

BACKGROUND. Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. OBJECTIVE. Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. DESIGN/METHODS. A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. RESULTS. Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non–central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5°C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. CONCLUSIONS. Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.

OBJECTIVES. The purpose of this work was to evaluate the extent of free radical injury in newborns with hypoxic ischemic encephalopathy by measuring plasma levels of malondialdehyde and nitric oxide and to assess the blood-brain barrier permeability by measuring the cerebrospinal fluid albumin/plasma albumin ratio.METHODS. This prospective observational study was conducted over a period of 2 years at Sir Sundarlal Hospital, Banaras Hindu University. The study population consisted of 43 term neonates with perinatal asphyxia who subsequently developed hypoxic ischemic encephalopathy. Twenty normal gestational age- and gender-matched healthy infants without any perinatal asphyxia served as control subjects. Peripheral venous blood samples were analyzed for malondialdehyde, total plasma nitrates/nitrites, and albumin levels between 12 and 24 hours of life. To assess the blood-brain barrier permeability, the cerebrospinal fluid albumin/plasma albumin ratio was measured. Correlation among the levels of malondialdehyde, nitrates/nitrites, and blood-brain barrier permeability was calculated. Data were analyzed by using SPSS 10 software.RESULTS. Plasma malondialdehyde and nitrate/nitrite levels were significantly higher in infants with hypoxic ischemic encephalopathy compared with control subjects. Although there was a progressive increment in plasma levels of malondialdehyde with increasing severity of hypoxic ischemic encephalopathy, the differences were not statistically significant. Plasma nitrate/nitrite levels were almost similar in all stages of hypoxic ischemic encephalopathy. Plasma albumin levels were comparable in infants with hypoxic ischemic encephalopathy and control subjects, whereas cerebrospinal fluid albumin levels and blood-brain barrier permeability were significantly higher in infants with hypoxic ischemic encephalopathy. Significant correlation was observed between plasma malondialdehyde and nitrate/nitrite levels with blood-brain barrier permeability.CONCLUSIONS. Increased plasma levels of malondialdehyde and nitrates/nitrites are found to be associated with hypoxic ischemic encephalopathy, indicating the possible role of free radical injury in its causation. Increased blood-brain barrier permeability may be another contributory factor to the progression of the disease.

OBJECTIVES. We studied (1) the pattern of brain injury in term neonates with encephalopathy with evidence of a preceding hypoxic sentinel event, (2) prenatal and perinatal risk factors, and (3) the correlation between neuroimaging findings and developmental outcomes. METHODS. We identified, among 500 term neonates with encephalopathy who were studied with MRI between 1992 and 2005, 48 infants with evidence of a preceding acute hypoxic event, and we reviewed their MRI scans retrospectively. Prenatal and perinatal data were compared with those for term normal low-risk infants. Neurodevelopmental outcomes were assessed at a minimum of 12 months. RESULTS. Five patterns of brain injury were identified, as follows: pattern I, basal ganglia and thalami lesions associated with severe white matter damage (n = 6; 14%); pattern II, basal ganglia and thalami lesions with mild or moderate white matter changes (n = 24; 56%); pattern III, isolated thalamic injury (n = 2; 5%); pattern IV, moderate white matter damage only (n = 1; 2%); pattern V, mild white matter changes or normal findings (n = 10; 23%). No scan showed evidence of long-standing injury. The internal capsule was abnormal in 93% of infants with patterns I and II, and 86% of those infants died or developed cerebral palsy. Infants with patterns III and IV had developmental delay and diplegic cerebral palsy, respectively. Pattern V was associated with normal outcomes. Case infants were significantly more often of African descent, born to pluriparous or hypertensive mothers. Uterine rupture followed previous cesarean section in 8 of 11 cases. Cord prolapse accompanied undiagnosed breech presentation in 4 of 9 cases. CONCLUSIONS. Basal ganglia and thalami lesions are the imaging signature in term neonates exposed to hypoxic-ischemic sentinel events. Patterns of central gray matter and secondary white matter injury were associated with higher risks of severe morbidity and death. Affected infants did not seem intrinsically different from our low-risk population. These data support the need for anticipating sentinel events and expediting delivery.

OBJECTIVES. Asphyxia and hypothermia may modify drug pharmacokinetics. We investigated whether analgesia with morphine in neonates with hypoxic ischemic encephalopathy undergoing prolonged moderate systemic hypothermia resulted in elevated serum morphine concentrations compared with normothermic infants. PATIENTS AND METHODS. Infants from 1 center participating in a multicenter randomized study of moderate whole-body hypothermia after perinatal asphyxia (the Total Body Hypothermia Study) were randomly selected for treatment with hypothermia (n = 10) or for standard care on normothermia (n = 6). Hypothermia (33°C to 34°C) was started before 6 hours of age and maintained for 72 hours. All of the infants were treated with a continuous infusion of morphine-hydrochloride, with the rate adjusted according to clinical status. Serum morphine concentrations were determined at 6, 12, 24, 48, and 72 hours after birth. RESULTS. Serum morphine concentrations at 24 to 72 hours after birth were (median [range]) 292 ng/mL (137–767 ng/mL) in the hypothermia-treated infants and 206 ng/mL (88–327 ng/mL) in the infants on normothermia, despite similar morphine infusion rates and cumulative doses. Morphine concentrations correlated with morphine infusion rate, cumulative dose, and treatment with hypothermia. Serum morphine concentrations reached a steady state after 24 hours in the normothermic infants but continued to increase throughout the assessment period in the hypothermia group. Morphine clearance was low in both groups: (median [range]) morphine clearance estimated from area under the curve was 0.69 mL/min per kg (0.58–1.21 mL/min per kg) in hypothermic group and 0.89 mL/min per kg (0.65–1.33 mL/min per kg) in infants on normothermia. Serum morphine concentrations >300 nL/mL occurred more often in the hypothermia group and when the morphine infusion rate was >10 μg/kg per h. CONCLUSIONS. Infants with hypoxic ischemic encephalopathy have reduced morphine clearance and elevated serum morphine concentrations when morphine infusion rates are based on clinical state. Potentially toxic serum concentrations of morphine may occur with moderate hypothermia and infusion rates >10 μg/kg per h.

OBJECTIVE. The goals were to identify predictor variables and to develop scoring systems and classification trees to predict death/disability or death in infants with hypoxic-ischemic encephalopathy.METHODS. Secondary analysis of data from the multicenter, randomized, controlled, National Institute of Child Health and Human Development Neonatal Research Network trial of hypothermia in hypoxic-ischemic encephalopathy was performed. Data for 205 neonates diagnosed as having hypoxic-ischemic encephalopathy were studied. Logistic regression analysis was performed by using clinical and laboratory variables available within 6 hours of birth, with death or moderate/severe disability at 18 to 22 months or death as the outcomes. By using the identified variables and odds ratios, scoring systems to predict death/disability or death were developed, weighting each predictor in proportion to its odds ratio. In addition, classification and regression tree analysis was performed, with recursive partitioning and automatic selection of optimal cutoff points for variables. Correct classification rates for the scoring systems, classification and regression tree models, and early neurologic examination were compared.RESULTS. Correct classification rates were 78% for death/disability and 71% for death with the scoring systems, 80% and 77%, respectively, with the classification and regression tree models, and 67% and 73% with severe encephalopathy in early neurologic examination. Correct classification rates were similar in the hypothermia and control groups.CONCLUSIONS. Among neonates diagnosed as having hypoxic-ischemic encephalopathy, the classification and regression tree model, but not the scoring system, was superior to early neurologic examination in predicting death/disability. The 3 models were comparable in predicting death. Only a few components of the early neurologic examination were associated with poor outcomes. These scoring systems and classification trees, if validated, may help in assessments of prognosis and may prove useful for risk-stratification of infants with hypoxic-ischemic encephalopathy for clinical trials.

BACKGROUND. After perinatal asphyxia, predicting which infants will develop significant hypoxic-ischemic encephalopathy and neonatal seizures remains a difficult task. High-risk markers (Apgar score, acidosis, nucleated red blood cells, and resuscitation) have been used to predict neonatal seizures with varying success. The “3 strikes” of Apgar score of METHOD. We recruited term infants with perinatal asphyxia. Continuous video electroencephalography was commenced soon after birth and continued for 24 to 72 hours. The abilities of high-risk markers to predict electroencephalographic seizurs, background electroencephalographic activity, and Sarnat grade were examined.RESULTS. Forty-nine infants were suitable for analysis. Electrographic seizures occurred in 11 of the 49 infants. Encephalopathy was scored by using Sarnat grade (6, severe; 18, moderate; 25, mild) and electroencephalographic findings (4 inactive, 4 major abnormalities, 16 moderate abnormalities, and 25 normal/mildly abnormal). Apgar score of CONCLUSION. After perinatal asphyxia, neither the condition at birth nor the degree of metabolic acidosis reliably predict neonatal seizures.

OBJECTIVE. Single-channel amplitude-integrated electroencephalography has been shown to be predictive of neurodevelopmental outcome in term infants with hypoxic-ischemic encephalopathy. We describe the relationship of quantifiable electroencephalogram (EEG) measures, obtained using a 2-channel digital bedside EEG monitor from term newborn infants with encephalopathy and/or seizures, to cerebral injury defined qualitatively by MRI. METHODS. Median values of minimum, mean, and maximum EEG amplitude were obtained from term-born encephalopathic infants during a 2-hour seizure-free period obtained within 72 hours of admission. Infants underwent MRI with images qualitatively scored for abnormalities of cortex, white matter, deep nuclear gray matter, and posterior limb of the internal capsule. Eighty-six infants had EEG measures related to qualitative MRI outcomes. RESULTS. The most common diagnosis was hypoxic ischemic encephalopathy (n = 40). For all infants there was a negative relationship between EEG amplitude measures and MRI abnormality scores assessed on a scale from 4 to 15, with a higher score indicating more abnormalities. This relationship was strongest for the minimum amplitude measures in both hemispheres; that is, for every unit increase in score there was a mean drop of 0.41 μv for the left cerebral hemisphere, with 35% of variance explained. This relationship persisted on sub-group analyses for infants with hypoxic-ischemic encephalopathy, infants with other diagnoses and infants monitored after the first 24 hours of life. Using an MRI abnormality score cutoff of 8 or worse for cerebral injury in infants with hypoxic-ischemic encephalopathy, a minimum amplitude of 4 μV showed a higher specificity (80%: left hemisphere), whereas a minimum amplitude of 6 μV showed a higher sensitivity (92%: left hemisphere). CONCLUSIONS. Bedside EEG measures in term-born encephalopathic infants are related to the severity of cerebral injury as defined by qualitative MRI. A minimum amplitude of

OBJECTIVE. Apparent diffusion coefficients (ADC) that are measured by diffusion-weighted imaging are reduced in severe white matter (WM) and in some severe basal ganglia and thalamic (BGT) injury in infants who present with hypoxic-ischemic encephalopathy (HIE). However, ADC values may pseudonormalize or even be high during this time in some less severe but clinically significant injuries. We hypothesized that fractional anisotropy (FA), a measure of the directional diffusivity of water made using diffusion tensor imaging, may be abnormal in these less severe injuries; therefore, the objective of this study was to use diffusion tensor imaging to measure ADC and FA in infants with moderate and severe hypoxic-ischemic brain injury. METHODS. Twenty infants with HIE and 7 normal control infants were studied. All infants were born at >36 weeks' gestational age, and MRI scans were obtained within 3 weeks of delivery. Data were examined for normality, and comparisons were made using analysis of variance or Kruskal-Wallis as appropriate. RESULTS. During the first week, FA values were decreased with both severe and moderate WM and BGT injury as assessed by conventional imaging, whereas ADC values were reduced only in severe WM injury and some severe BGT injury. Abnormal ADC values pseudonormalized during the second week, whereas FA values continued to decrease. CONCLUSION. FA is reduced in moderate brain injury after HIE. A low FA may reflect a breakdown in WM organization. Moderate BGT injury may result in atrophy but not overt infarction; it is possible that delayed apoptosis is more marked than immediate necrosis, and this may account for normal early ADC values. The accompanying low FA within some severe and all moderate gray matter lesions, which is associated with significant later impairment, may help to confirm clinically significant abnormality in infants with normal ADC values.

OBJECTIVE. To determine the value of regional cerebral oxygen saturation (rSo2), fractional cerebral tissue oxygen extraction (FTOE) measured by near-infrared spectroscopy (NIRS), and amplitude integrated electroencephalogram (aEEG) after birth asphyxia in relation to neurodevelopmental outcome.METHODS. NIRS measured rSo2, FTOE, and aEEG were monitored simultaneously, together with arterial oxygen saturation (Sao2) and blood pressure during the first 48 hours after severe birth asphyxia in 18 term infants. FTOE was calculated as [Sao2 − rSo2]/Sao2. Neurodevelopmental outcome was assessed at 3, 9, and 18 months and 3 and 5 years of age. At the time points 6, 12, 18, 24, 30, 36, 42, and 48 hours after birth, the mean values of Sao2, rSo2, FTOE, and mean arterial blood pressure were calculated over a 1-hour period. A stepwise-regression model was used to investigate the relative contribution of rSo2, FTOE, or aEEG to developmental outcome.RESULTS. Nine Infants died during the neonatal period as a result of neurologic deterioration, and 8 infants had a normal outcome at 5 years of age. One child developed learning disabilities and a mild diplegia. The rSo2 and FTOE remained stable in infants with a normal outcome. The rSo2 increased and the FTOE decreased after 24 hours in the infants with an adverse outcome. (rSo2: 65% vs 84% at 12 and 48 hours, respectively; FTOE: 0.32 vs 0.12 at 12 and 48 hours, respectively). aEEG showed the closest relationship with outcome, but also rSo2 showed a significant correlation 24 hours after birth.CONCLUSIONS. rSo2 and FTOE seem to reflect secondary energy failure. aEEG showed the closest relationship with outcome after severe birth asphyxia.

Hypothermia induced by whole-body cooling (WBC) and selective head cooling (SHC) both reduce brain injury after hypoxia-ischemia in newborn animals, but it is not known how these treatments affect the incidence or pattern of brain injury in human newborns. To assess this, 14 term infants with hypoxic-ischemic encephalopathy (HIE) treated with SHC, 20 infants with HIE treated with WBC, and 52 noncooled infants with HIE of similar severity were studied with magnetic resonance imaging in the neonatal period. Infants fulfilling strict criteria for HIE were recruited into the study after assessment of an amplitude-integrated electroencephalography (aEEG). Cooling was commenced within 6 hours of birth and continued for 48 to 72 hours. Hypothermia was not associated with unexpected or unusual lesions, and the prevalence of intracranial hemorrhage was similar in all 3 groups. Both modes of hypothermia were associated with a decrease in basal ganglia and thalamic lesions, which are predictive of abnormal outcome. This decrease was significant in infants with a moderate aEEG finding but not in those with a severe aEEG finding. A decrease in the incidence of severe cortical lesions was seen in the infants treated with SHC.

Objective. The aim of this study was to establish a more objective method for confirming tissue injury in term neonates who present with early seizures that are believed to be hypoxic-ischemic in origin. Methods. We studied the relationship between contemporaneous diffusion-weighted magnetic resonance imaging and conventional magnetic resonance imaging in 63 symptomatic term-born neonates and 15 control term infants performed in the neonatal period. Apparent diffusion coefficients (ADC) were obtained for multiple regions of the brain. Results. ADC values in the 15 control infants were 1 (1–1.15) (median [range]) × 10−3/mm2/second in the thalami and 1.1 (1–1.3) × 10−3/mm2/second in the lentiform nuclei, 1.5 (1.3–1.7) × 10−3/mm2/second in the centrum semiovale, 1.6 (1.46–1.7) × 10−3/mm2/second in the anterior white matter (WM), and 1.55 (1.35–1.85) × 10−3/mm2/second in the posterior WM with little variation over time. ADC values were significantly reduced in the first week after severe injury to either WM or basal ganglia and thalami (BGT), but values normalized at the end of the first week and then increased during week 2. ADC values were either normal or increased in moderate BGT and WM lesions when compared with controls. ADC values < 1.1 × 10−3/mm2/second were always associated with WM infarction and values Conclusion. A reduced ADC soon after delivery allows the presence of tissue infarction to be confirmed at a time when conventional imaging changes may be subtle. However, as both moderate WM and BGT lesions may have normal or increased ADC values, a normal ADC value during the first week does not signify normal tissue. ADC values should always be measured in combination with visual analysis of both conventional and diffusion-weighed images for maximum detection of pathologic tissue, and the timing of the scan needs to be taken into account when interpreting the results.

Brain injury in the premature infant consists of multiple lesions, principally germinal matrix-intraventricular hemorrhage, posthemorrhagic hydrocephalus, and periventricular leukomalacia (PVL). The last of these now appears to be the most important determinant of the neurologic morbidity observed in survivors of birth weight

Objectives. To determine the initial inflammatory cytokine response in term infants born to mothers with clinical chorioamnionitis and to assess whether the cytokine response is associated with birth depression, abnormal neurologic examination, and hypoxic-ischemic encephalopathy (HIE).Methods. Infants who were exposed to chorioamnionitis and admitted to the neonatal intensive care unit (n = 61) were studied prospectively. Cytokine concentrations were measured from umbilical cord blood and at 6 and 30 hours after birth. Control values (n = 50) were determined from cord blood of healthy term infants. Enzyme-linked immunosorbent assays were performed for interleukin (IL)-1β; IL-6; IL-8; regulated on activation, normal T-cell expressed and secreted (RANTES); macrophage inflammatory protein-1α; and tumor necrosis factor-α. Serial blinded neurologic examinations using a modified Dubowitz score were performed simultaneously at 6 and 30 hours.Results. Cord IL-6 (1071 ± 1517 vs 65 ± 46 pg/mL), IL-8 (2580 ± 9834 vs 66 ± 57 pg/mL), and RANTES (95 917 ± 16 518 vs 54 000 ± 14 306 pg/mL) concentrations only were higher in infants with chorioamnionitis versus control infants. IL-6 increased at 6 hours to 1451 ± 214 pg/mL, followed by a 5-fold decline at 30 hours in contrast to progressive decreases over time in IL-8 and RANTES. There was no relationship between cytokines and birth depression. Modified Dubowitz score correlated with IL-6 at 6 hours (r = 0.5). Infants with HIE/seizures (n = 5) had significantly higher cytokine concentrations at 6 hours versus infants without either (n = 56): IL-6 (3130 vs 1219 pg/mL), IL-8 (5433 vs 780 pg/mL), and RANTES (97 396 vs 46 914 pg/mL).Conclusions. There was a significant association between abnormalities in the neurologic examination and cytokine concentrations, with the highest cytokines concentrations observed in infants who developed HIE/seizures.

Objective: To assess the value and the limitations of amplitude integrated electroencephalogram (EEG) using the cerebral function monitor (CFM) in comparison with standard EEG in neonates who have hypoxic ischemic encephalopathy or were suspected of having convulsions. Methods. In 36 neonates with a gestational age ≥36 weeks, CFM and simultaneously recorded EEG traces were analyzed off-line and independently classified. CFM background activity: continuous normal voltage; continuous normal voltage, slightly discontinuous (DNV); burst-suppression (BS); continuous extremely low voltage; flat tracing. CFM epileptiform activity: suspected epileptic activity, single seizure (SS), repetitive seizures (RS), status epilepticus (SE). EEG background activity: normal, depressed, low voltage undifferentiated, excessive discontinuity, BS, no activity. Epileptiform activity: interictal unifocal, interictal multifocal, ictal unifocal, ictal multifocal, SE. Results. A total of 33 traces were suitable for analysis. Interobserver agreement on background activity was reached in 31 cases (κ = 0.92) for CFM and in 27 cases (κ = 0.74) for EEG. There was full agreement on CFM ictal activity (RS, SS, or SE) and EEG ictal activity. A normal CFM (continuous normal voltage) corresponded with a normal or a depressed EEG in 90% of the cases. The positive predictive value for a severely abnormal CFM (BS, continuous extremely low voltage, flat tracing) to correspond with a severely abnormal EEG (excessive discontinuity, BS, low voltage undifferentiated, no activity) was 100% (negative predictive value, 80%; sensitivity, 76%; specificity, 100%). DNV (10) on CFM corresponded either with depressed (6) or excessive discontinuity (4) on EEG. Ictal activity on EEG corresponded with SS, RS, or SE on CFM in 8 cases (sensitivity, 80%; specificity, 100%; positive predictive value, 100%; negative predictive value, 92%). Conclusion. CFM is a reliable tool for monitoring both background patterns (especially normal and severely abnormal) and ictal activity. Certain focal, low amplitude, and very short periods of seizure discharges can be missed. We recommend using CFM as a monitoring device and performing intermittent standard EEG whenever there is any doubt about the classification of the CFM (ie, DNV pattern or suspected epileptiform activity).

Objective Selective head cooling (SHC) combined with mild body cooling is currently being evaluated as a potentially therapeutic option in the management of neonatal hypoxic-ischemic encephalopathy. It is proposed that SHC enables local hypothermic neuroprotection while minimizing the deleterious side effects of systemic hypothermia. However, there is little evidence that it is possible to cool the brain more than the body for a prolonged period of time. The aim of this study was to examine whether the brain (T(deep brain)) could be cooled to below the rectal temperature (T(rectal)) in our piglet hypoxia ischemia (HI) model for a period of 24 hours, using a head-cooling cap. Methods Eight anesthetized piglets (median age: 15 hours) had subdural and intracerebral basal ganglia temperature probes inserted. After a 45-minute global HI insult (known to produce permanent brain damage), SHC using a cap perfused with cold water (5 degrees C-24 degrees C) combined with overhead body heating to maintain T(rectal) at 34 to 35 degrees C was performed for 24 hours. Results The piglets were cooled to a median T(rectal) of 35.0 degrees C (interquartile range [IQR]: 34.7-35.3) for 24 hours. During this time, the median T(deep brain) was 31.4 degrees C (IQR: 30 degrees C-32.2 degrees C), with a median T(rectal) to T(deep brain) gradient of 3.4 degrees C (IQR: 2.7 degrees C-4.8 degrees C). At the end of the cooling period, this gradient was still maintained at a median of 3.3 degrees C (IQR: 2.9 degrees C-3.7 degrees C). The ability to obtain the gradient was not influenced by the size of the piglet (1300-1840 g). Cap cooling lowered scalp temperature (T(scalp)) to a median of 24.9 degrees C (IQR: 22.2 degrees C-29.2 degrees C) and subdural temperature to a median of 28.1 degrees C (IQR: 25.8 degrees C-29.5 degrees C) but did not result in either skin injury or superficial brain hemorrhage. There was no clinically useful correlation between T(scalp) and T(deep brain) or between T(scalp) and T(subdural). Conclusions This study using our piglet HI model shows that it is possible by means of a head-cooling cap to cool the brain more than the body for a 24-hour period while keeping the core temperature mildly hypothermic. However, we were unable to predict temperatures inside the brain using surface temperature probes on the head.

* Abbreviation: CT — : computed tomography What and why? As health care professionals, we must address both of these questions in scientific inquiry as well as in clinical practice. Most times, facts (the “what”) are relatively easy to come by. The reasons (the “why”) behind these events are usually more difficult to discover and understand. Let us look at the example of head computed tomography (CT) in a group of neonates. There are 2 facts here. First, in an investigation of 4107 term infants diagnosed with encephalopathy by Barnette et al1 in this issue of Pediatrics , CT examinations were performed in 22.7%, with 2.4% of this population having >1 CT examination. Second, the investigators remind us that MRI is better than CT at prognostic evaluation in this scenario. From these facts, the investigators concluded that a preferred imaging strategy would be ultrasonography followed by MRI, without a CT examination. There are a few other relevant facts we know. First, a CT scan is easier … Address correspondence to Donald P. Frush, MD, FACR, FAAP, Department of Radiology, 1905 McGovern-Davison Children’s Health Center, Duke University Medical Center, Durham, NC 27710. E-mail: donald.frush{at}duke.edu

BACKGROUND AND OBJECTIVE: Computed tomography (CT) is still used for neuroimaging of infants with known or suspected neurologic disorders. Alternative neuroimaging options that do not expose the immature brain to radiation include MRI and cranial ultrasound. We aim to characterize and compare the use and findings of neuroimaging modalities, especially CT, in infants with neonatal encephalopathy. METHODS: The Vermont Oxford Network Neonatal Encephalopathy Registry enrolled 4171 infants (≥36 weeks’ gestation or treated with therapeutic hypothermia) between 2006 and 2010 who were diagnosed with encephalopathy in the first 3 days of life. Demographic, perinatal, and medical conditions were recorded, along with treatments, comorbidities, and outcomes. The modality, timing, and results of neuroimaging were also collected. RESULTS: CT scans were performed on 933 of 4107 (22.7%) infants, and 100 of 921 (10.9%) of those received multiple CT scans. Compared with MRI, CT provided less detailed evaluation of cerebral injury in areas of prognostic significance, but was more sensitive than cranial ultrasound for hemorrhage and deep brain structural abnormalities. CONCLUSIONS: CT is commonly used for neuroimaging in newborn infants with neonatal encephalopathy despite concerns over potential harm from radiation exposure. The diagnostic performance of CT is inferior to MRI in identifying neonatal brain injury. Our data suggest that using cranial ultrasound for screening, followed by MRI would be more appropriate than CT at any stage to evaluate infants with neonatal encephalopathy.

Objectives.The aims of the study were to establish the relationship between head growth in the first year of life with the pattern on injury on neonatal magnetic resonance imaging (MRI) in infants with hypoxic–ischemic encephalopathy (HIE) and to relate these to the neurodevelopmental outcome.Methods.Fifty-two term infants who presented at birth with a neonatal encephalopathy consistent with HIE and who had neonatal brain MRI were entered into the study. Head circumference charts were evaluated retrospectively and the head growth over the first year of life compared with the pattern of brain lesions on MRI and with the neurodevelopmental outcome at 1 year of age. Suboptimal head growth was classified as a drop of >2 standard deviations across the percentiles with or without the development of microcephaly, which was classified as a head circumference below the third percentile.Results.There was no statistical difference between the neonatal head circumferences of the infants presenting with HIE and control infants. At 12 months, microcephaly was present in 48% of the infants with HIE, compared with 3% of the controls. Suboptimal head growth was documented in 53% of the infants with HIE, compared with 3% of the controls. Suboptimal head growth was significantly associated with the pattern of brain lesions, in particular to involvement of severe white matter and to severe basal ganglia and thalamic lesions. Suboptimal head growth predicted abnormal neurodevelopmental outcome with a sensitivity of 79% and a specificity of 78%, compared with the presence of microcephaly at 1 year of age, which had a sensitivity of only 65% and a specificity of 73%. The exceptions were explained by infants with only moderate white matter abnormalities who had suboptimal head growth but normal outcome at 1 year of age and by infants with moderate basal ganglia and thalamic lesions only who had normal head growth but significant motor abnormality.

Background. Clinical trials of mild cooling to 35°C or below in infants with early hypoxic–ischemic encephalopathy are under way. The objective of this study was to systematically document cardiovascular changes associated with mild therapeutic hypothermia and rewarming in such infants. Patients and Methods. Nine infants with gestational ages of 36 to 42 weeks, with 10-minute Apgar scores of 5 or less, clinical encephalopathy, and an abnormal electroencephalogram before 6 hours were cooled by surface cooling the trunk (n = 3) or by applying a cap perfused with cooled water (n = 6) for a median of 72 hours. The target core temperature was 34.0°C to 35.0°C for head-cooled infants and 33.0°C to 34.0°C for surface-cooled infants. Maintenance heating and rewarming were provided by an overhead heater. Results. Mean arterial blood pressure increased by a median of 10 mm Hg during cooling and fell by a median of 8 mm Hg on rewarming. Heart rate decreased by a median of 34 beats/minute on cooling and increased by a median of 32 beats/minute on rewarming. A large increase in the output of the overhead heater decreased mean arterial blood pressure in 5 infants. Anticonvulsant drugs, sedatives, or intercurrent hypoxemia also produced falls in temperature. The inspired oxygen fraction had to be increased by a median of .14 to maintain oxygenation during cooling with 2 infants requiring 100% oxygen, an effect probably attributable to pulmonary hypertension, which was reversible with rewarming. Conclusions. Therapeutic cooling produces changes in heart rate and blood pressure that are not hazardous, but the combination of inadvertent overcooling and inappropriately rapid rewarming, together with sedative drugs that can impair normal thermoregulatory vasoconstriction, can cause hypotension in posthypoxic newborn infants. Infants who already require 50% oxygen should be cooled cautiously because pulmonary hypertension may develop. Knowledge of these cardiovascular changes, careful monitoring, anticipation, and correction should help to avoid potential adverse effects in the upcoming clinical trials.

On the basis of opinions of problematic evidence, Kirpalani et al1 stated that the “standard of care” criteria for adopting hypothermia for neonatal hypoxic-ischemic encephalopathy (HIE) had not been met. They argued for a “conservative approach.” Clinicians who are “impressed” by their evidence are not mandated to offer cooling and can ethically continue to randomly assign patients “into ongoing, or new trials.” Yet, the authors considered the evidence to be “certainly” sufficiently strong for cautious use of this treatment by clinicians who are “impressed with the results.” These apparently conflicting statements are reinforced by previous confusing statements by co-author Barks2: “Many of us, including this author and the lead author [Dr Shankaran] of the Network trial,[3] who caution against uncontrolled adoption of cooling, have lost equipoise, and we are now cooling babies who meet the eligibility criteria of our original trials,” and the semantically elusive, “In a small number of experienced centers, it is a novel therapy that has become ‘standard care’ (without randomization), but it is not yet the ‘standard of care’ (emphasis in the original). Evolution in this field has outdated this conservative approach. One cooling trial (Infant Cooling Evaluation [ICE])4 was stopped prematurely, the research protocol of another has been altered,5 a third trial (Trial of Whole Body Hypothermia for Perinatal Asphyxia [TOBY])6 was stopped at the end of the funding period before achieving its revised sample size, and 3 independent systematic reviews4,7,8 have confirmed the efficacy and safety of cooling. Today's question is whether it is acceptable for individual hospitals or physicians to withhold from parents … Address correspondence to Max Perlman, MB, BS, FRCPC, FRCP, 1711/175 Cumberland St, Toronto, Ontario, Canada M5R 3M9. E-mail: max.perlman{at}sympatico.ca

OBJECTIVE: To evaluate the association between severity of cerebral palsy (CP) and growth to 6 to 7 years of age among children with moderate to severe (Mod/Sev) hypoxic ischemic encephalopathy (HIE). It was hypothesized that children with Mod/Sev CP would have poorer growth, lower cognitive scores, and increased rehospitalization rates compared with children with no CP (No CP). METHODS: Among 115 of 122 surviving children followed in the hypothermia trial for neonatal HIE, growth parameters and neurodevelopmental status at 18 to 22 months and 6 to 7 years were available. Group comparisons (Mod/Sev CP and No CP) with unadjusted and adjusted analyses for growth RESULTS: Children with Mod/Sev CP had high rates of slow growth and cognitive and motor impairment and rehospitalizations at 18 to 22 months and 6 to 7 years. At 6 to 7 years of age, children with Mod/Sev CP had increased rates of growth parameters CONCLUSIONS: Term children with HIE who develop Mod/Sev CP have high and increasing rates of growth

OBJECTIVE: To examine the association between ischemic-hypoxic conditions (IHCs) and attention-deficit/hyperactivity disorder (ADHD) by gestational age and race/ethnicity. METHODS: Nested case-control study using the Kaiser Permanente Southern California (KPSC) medical records. The study cohort included children aged 5 to 11 years who were delivered and cared for in the KPSC between 1995 and 2010 ( N = 308 634). Case children had a diagnosis of ADHD and received ≥2 prescriptions specific to ADHD during the follow-up period. For each case, 5 control children were matched by age at diagnosis. Exposures were defined by using International Classification of Diseases, Ninth Revision codes. A conditional regression model was used to estimate adjusted odds ratios (ORs). RESULTS: Among eligible children, 13 613 (4.3%) had a diagnosis of ADHD. Compared with control children, case children were more likely to be male and of white or African American race/ethnicity. Case children were more likely to be exposed to IHCs (OR = 1.16, 95% confidence interval [CI] 1.11–1.21). When stratified by gestational age, cases born at 28 to 33, 34 to 36, and 37 to 42 weeks of gestation, were more likely to be exposed to IHCs (ORs, 1.6 [95% CI 1.2–2.1], 1.2 [95% CI 1.1–1.3], and 1.1 [95% CI 1.0–1.2], respectively) compared with controls. IHC was associated with increased odds of ADHD across all race/ethnicity groups. CONCLUSIONS: These findings suggest that IHCs, especially birth asphyxia, respiratory distress syndrome, and preeclampsia, are independently associated with ADHD. This association was strongest in preterm births. * Abbreviations: ADHD — : attention-deficit/hyperactivity disorder IHC — : ischemic-hypoxic condition ICD-9-CM — : International Classification of Diseases, Ninth Revision, Clinical Modification KPSC — : Kaiser Permanente Southern California OR — : odds ratio RDS — : respiratory distress syndrome

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.

Therapeutic moderate hypothermia in newborns with hypoxic-ischemic encephalopathy is rapidly becoming standard clinical practice. We report here 12 cases of subcutaneous fat necrosis among 1239 cases registered with a national registry of newborns treated with moderate whole-body hypothermia. All the infants suffered from perinatal asphyxia and hypoxic-ischemic encephalopathy. Moderate-to-severe hypercalcemia was identified in 8 of 10 infants with blood calcium measurements. In all cases the skin lesions appeared after completion of the cooling treatment. Our data suggest that prolonged moderate hypothermia is an actual risk factor for subcutaneous fat necrosis. Because the lesions often develop several days after birth, physicians need to be aware of this condition as a possible complication in infants treated with moderate hypothermia after asphyxia. Blood calcium levels need to be monitored in affected infants.

OBJECTIVE: Mild hypothermia after perinatal hypoxic-ischemic encephalopathy (HIE) reduces neurologic sequelae without significant adverse effects, but studies are needed to determine the most-efficacious methods. METHODS: In the neo.nEURO.network trial, term neonates with clinical and electrophysiological evidence of HIE were assigned randomly to either a control group, with a rectal temperature of 37°C (range: 36.5–37.5°C), or a hypothermia group, cooled and maintained at a rectal temperature of 33.5°C (range: 33–34°C) with a cooling blanket for 72 hours, followed by slow rewarming. All infants received morphine (0.1 mg/kg) every 4 hours or an equivalent dose of fentanyl. Neurodevelopmental outcomes were assessed at the age of 18 to 21 months. The primary outcome was death or severe disability. RESULTS: A total of 129 newborn infants were enrolled, and 111 infants were evaluated at 18 to 21 months (53 in the hypothermia group and 58 in the normothermia group). The rates of death or severe disability were 51% in the hypothermia group and 83% in the normothermia group (P = .001; odds ratio: 0.21 [95% confidence interval [CI]: 0.09–0.54]; number needed to treat: 4 [95% CI: 3–9]). Hypothermia also had a statistically significant protective effect in the group with severe HIE (n = 77; P = .005; odds ratio: 0.17 [95% CI: 0.05–0.57]). Rates of adverse events during the intervention were similar in the 2 groups except for fewer clinical seizures in the hypothermia group. CONCLUSION: Systemic hypothermia in the neo.nEURO.network trial showed a strong neuroprotective effect and was effective in the severe HIE group.

OBJECTIVES: Amplitude-integrated electroencephalogram (aEEG) at METHODS: Seventy-four infants were recruited by using the CoolCap entry criteria, and their outcomes were assessed by using the Bayley Scales of Infant Development II at 18 months. The aEEG was recorded for 72 hours. Patterns and voltages of aEEG backgrounds were assessed. RESULTS: The positive predictive value of an abnormal aEEG pattern at the age of 3 to 6 hours was 84% for normothermia and 59% for hypothermia. Moderate abnormal voltage background at 3 to 6 hours of age did not predict outcome. The recovery time to normal background pattern was the best predictor of poor outcome (96.2% in hypothermia, 90.9% in normothermia). Never developing SWC always predicted poor outcome. Time to SWC was a better outcome predictor for infants who were treated with hypothermia (88.5%) than with normothermia (63.6%). CONCLUSIONS: Early aEEG patterns can be used to predict outcome for infants treated with normothermia but not hypothermia. Infants with good outcome had normalized background pattern by 24 hours when treated with normothermia and by 48 hours when treated with hypothermia.

OBJECTIVE: The goal was to examine biochemical, neurophysiologic, anatomic, and clinical changes associated with erythropoietin administration to neonates with hypoxic-ischemic encephalopathy (HIE). METHODS: We conducted a prospective case-control study with 45 neonates in 3 groups, a normal healthy group (N = 15), a HIE-erythropoietin group (N = 15; infants with mild/moderate HIE who received human recombinant erythropoietin, 2500 IU/kg, subcutaneously, daily for 5 days), and a HIE-control group (N = 15; did not receive erythropoietin). Serum concentrations of nitric oxide (NO) were measured at enrollment for the normal healthy neonates and at enrollment and after 2 weeks for the 2 HIE groups. The 2 HIE groups underwent electroencephalography at enrollment and at 2 to 3 weeks. Brain MRI was performed at 3 weeks. Neurologic evaluations and Denver Developmental Screening Test II assessments were performed at 6 months. RESULTS: Compared with normal healthy neonates, the 2 HIE groups had greater blood NO concentrations (P < .001). At enrollment, the 2 HIE groups did not differ in clinical severity, seizure incidence, NO concentrations, or electroencephalographic findings. At 2 weeks of age, electroencephalographic backgrounds improved significantly (P = .01) and NO concentrations decreased (P < .001) in the HIE-erythropoietin group, compared with the HIE-control group; MRI findings did not differ between groups. At 6 months of age, infants in the HIE-erythropoietin group had fewer neurologic (P = .03) and developmental (P = .03) abnormalities. CONCLUSION: This study demonstrates the feasibility of early administration of human recombinant erythropoietin to term neonates with HIE, to protect against encephalopathy.

OBJECTIVE: Accurate prediction of neurodevelopmental outcome in neonatal encephalopathy (NE) is important for clinical management and to evaluate neuroprotective therapies. We undertook a meta-analysis of the prognostic accuracy of cerebral magnetic resonance (MR) biomarkers in infants with neonatal encephalopathy. METHODS: We reviewed all studies that compared an MR biomarker performed during the neonatal period with neurodevelopmental outcome at ≥1 year. We followed standard methods recommended by the Cochrane Diagnostic Accuracy Method group and used a random-effects model for meta-analysis. Summary receiver operating characteristic curves and forest plots of each MR biomarker were calculated. χ2 tests examined heterogeneity. RESULTS: Thirty-two studies (860 infants with NE) were included in the meta-analysis. For predicting adverse outcome, conventional MRI during the neonatal period (days 1–30) had a pooled sensitivity of 91% (95% confidence interval [CI]: 87%–94%) and specificity of 51% (95% CI: 45%–58%). Late MRI (days 8–30) had higher sensitivity but lower specificity than early MRI (days 1–7). Proton MR spectroscopy deep gray matter lactate/N-acetyl aspartate (Lac/NAA) peak-area ratio (days 1–30) had 82% overall pooled sensitivity (95% CI: 74%–89%) and 95% specificity (95% CI: 88%–99%). On common study analysis, Lac/NAA had better diagnostic accuracy than conventional MRI performed at any time during neonatal period. The discriminatory powers of the posterior limb of internal capsule sign and brain-water apparent diffusion coefficient were poor. CONCLUSIONS: Deep gray matter Lac/NAA is the most accurate quantitative MR biomarker within the neonatal period for prediction of neurodevelopmental outcome after NE. Lac/NAA may be useful in early clinical management decisions and counseling parents and as a surrogate end point in clinical trials that evaluate novel neuroprotective therapies.

OBJECTIVE: We examined the evolution of electroencephalographic (EEG) changes after hypoxic injury. METHODS: Continuous, multichannel, video-EEG was recorded for term infants with hypoxic-ischemic encephalopathy, from RESULTS: Forty-four infants completed neurodevelopmental follow-up. Of those, 20 (45%) had abnormal outcomes. The EEG grade assigned correlated significantly with outcome. EEG abnormalities improved with time, with the worst EEG grade seen on the earliest recording in all cases. The best predictive ability was seen at 6 hours of age (area under the receiver operator characteristic curve: 0.958 [95% confidence interval: 0.88–1.04]; P = .000). Normal/mildly abnormal EEG results at 6, 12, or 24 hours had 100% positive predictive values for normal outcomes and negative predictive values of 67% to 76%. By 48 hours, many of the EEG findings had improved significantly. This led to the positive predictive value of abnormal EEG results being greater at 48 hours (93%), with a concurrent negative predictive value of 71%. EEG features that were associated with abnormal outcomes were background amplitude of 30 seconds, electrographic seizures, and absence of sleep-wake cycling at 48 hours. CONCLUSIONS: Early EEG is a reliable predictor of outcome in HIE. A normal or mildly abnormal EEG results within 6 hours after birth were associated with normal neurodevelopmental outcomes at 24 months.

OBJECTIVE. Several trials suggest that hypothermia is beneficial in selected infants with hypoxic-ischemic encephalopathy. However, the cooling methods used required repeated interventions and were either expensive or reported significant temperature variation. The objective of this pilot study was to describe the use, efficacy, and physiologic impact of an inexpensive servo-controlled cooling fan blowing room-temperature air. PATIENTS AND METHODS. A servo-controlled fan was manufactured and used to cool 10 infants with hypoxic-ischemic encephalopathy to a rectal temperature of 33°C to 34°C. The infants were sedated with phenobarbital, but clonidine was administered to some infants if shivering or discomfort occurred. A servo-controlled radiant warmer was used simultaneously with the fan to prevent overcooling. The settings used on the fan and radiant warmer differed slightly between some infants as the technique evolved. RESULTS. A rectal temperature of 34°C was achieved in a median time of 58 minutes. Overcooling did not occur, and the mean temperature during cooling was 33.6°C ± 0.2°C. Inspired oxygen requirements increased in 6 infants, and 5 infants required inotropic support during cooling, but this was progressively reduced after 1 to 2 days. Dehydration did not occur. Five infants shivered when faster fan speeds were used, but 4 of the 5 infants had hypomagnesemia. Shivering was controlled with clonidine in 4 infants, but 1 infant required morphine. CONCLUSIONS. Servo-controlled fan cooling with room-temperature air, combined with servo-controlled radiant warming, was an effective, simple, and safe method of inducing and maintaining rectal temperatures of 33°C to 34°C in sedated infants with hypoxic-ischemic encephalopathy. After induction of hypothermia, a low fan speed facilitated accurate temperature control, and warmer-controlled rewarming at 0.2°C increments every 30 minutes resulted in more appropriate rewarming than when 0.5°C increments every hour were used.

OBJECTIVE. Our goal was to compare the patterns of brain injury detected by computed tomography, conventional MRI (T1- and T2-weighted sequences), and diffusion-weighted MRI in a cohort of term newborns with neonatal encephalopathy studied uniformly with all 3 modalities on the third day of life.METHODS. Term newborns (≥36 weeks' gestation) admitted to our center with neonatal encephalopathy were scanned with computed tomography, MRI, and diffusion-weighted MRI at 72 (±12) hours of life (n = 48). Each modality was scored independently of the other with previously validated scoring systems. The predominant pattern of brain injury was classified as: normal, watershed, basal nuclei, total (maximal basal nuclei and watershed), and focal-multifocal (presence of strokes and/or white matter injury alone).RESULTS. The agreement for the predominant pattern of injury was excellent between MRI and diffusion-weighted MRI (77% agreement). The agreement for the pattern of injury was also good for computed tomography and diffusion-weighted MRI (67% agreement). The extent of cortical injury and focal-multifocal lesions, such as strokes and white matter injury, were less apparent on computed tomography than diffusion-weighted MRI. In 19 newborns with a repeat MRI in the second week of life, the predominant pattern seen on the day 3 diffusion-weighted MRI was confirmed.CONCLUSIONS. Diffusion-weighted MRI is the most sensitive technique with which to assess brain injury on day 3 of life in term newborns with neonatal encephalopathy, particularly for cortical injury and focal-multifocal lesions such as stroke and white matter injury. All 3 modalities identify the most serious patterns of brain injury similarly.

The neonatal community deserves congratulations for responding vigorously to Silverman's1 call for randomized controlled trials (RCTs) to evaluate neonatal therapies. Although more trials are still needed,2 existing RCTs present new challenges in interpretation. One of the most vexing is when to proclaim innovative therapies as “standard of care.” The neonatal critical care community faces this challenge in evaluation of hypothermia as treatment for hypoxemic-ischemic encephalopathy (HIE).3–5 National bodies have made declarations that the neonatal community should consider hypothermia experimental pending completion of current ongoing trials.6–9 Although the influence of these bodies is considerable, individual physicians and sites apparently feel pressure to “do something” in the very dire circumstances of HIE in the newborn. In an informal sample of convenience, we have found that some centers are performing cooling, either with or without informed consent. Although many clinicians concur with the leading bodies that state there is a need for additional trials, it is confusing for practicing neonatologists when some members of these bodies also publicly state that they are actively providing cooling therapy. If leading centers are promoting active cooling, they have, in effect, adopted cooling as a standard of care. This may not only have legal implications but also raises ethical issues for those who believe the right thing to do currently is to continue performing RCTs. The countervailing argument is that to not offer cooling as standard therapy for such a devastating disease as HIE is itself, unethical. These opposing viewpoints are not easily resolvable except by considering what the overall benefit of eliminating residual doubt, one way or the other, would be. Our concern is that advocacy of hypothermia as a standard of care represents an excessively low threshold for accepting promising therapies and will ultimately lead to resources … Address correspondence to Haresh Kirpalani, BM, MSc, Division of Neonatology, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mail: kirpalanih{at}email.chop.edu