Blood glucose level as a predictor of Neonatal HIE

Treatment of neonatal hypoxic-ischemic encephalopathy (HIE) using therapeutic hypothermia (TH) beginning less than 6 hours after birth and extending for 72 hours has been shown to significantly increase the number of infants surviving without moderate-to-severe neurodevelopmental impairment (NDI). Although this strategy is effective in improving outcomes out to 18 months of age, with the number needed to treat being 6 (95% confidence interval, 5 to 10), a significant fraction of treated individuals either succumb or are left with severe NDI.  Factors that may contribute to greater risk from HIE and/or ineffectiveness of treatment can be considered when evaluating individual cases. The time interval from insult to onset of TH is particularly critical. Experimental data on HIE using animal models generally employ an acute asphyxia (hypoxia and/or ischemia) event wherein timing of the insult is exact. Consistent with the understanding of the transition from primary to secondary energy failure from animal observations and from clinical observations, the onset of TH needs to occur within a therapeutic window of 6 hours following the initial insult in order to block the cascade of events of secondary energy failure and thus to improve long-term outcomes. Clinically, once HIE is suspected and the clinical course suggests moderate (or greater) severity, TH should be initiated as promptly as feasible within 6 hours. Likewise, TH needs to be continued to 72 hours for a lasting effect. Trials using lower body temperature and shortening or extending the duration of hypothermia have not yielded better outcomes. For the case in the vignette, the time of the insult is known, leading to the diagnosis of moderate HIE, and TH is initiated within the prescribed window.  In some clinical cases associated with hypoxic or ischemic insults to the fetus, the insult may have occurred before the perinatal period or it may extend over time in utero before the mother and fetus present for healthcare. When the timing of the insult to the brain is inexact and may not be determinable, even prompt initiation of TH after birth may result in poor outcome because the therapeutic window had closed before the neonate was born. In the case in the vignette, the history of umbilical cord prolapse at the time of membrane rupture in an otherwise healthy situation suggests that TH was initiated well within the 6-hour time frame, thus this history would lead to optimism rather than pessimism regarding predicted outcomes. Amplitude-integrated electroencephalography (aEEG) or continuous EEG (cEEG) can be employed to assist in assessing and following neurologic status.  A discontinuous aEEG  or one having cyclicity (sleep-wake cycles) is consistent with an HIE-causing insult, likely to be mild-to-moderate. In severe HIE features of extremely low baseline, burst-suppression, or seizures are  seen. Infants who presented to the Cool Cap study with severe aEEG abnormalities, as compared with those having less severe aEEG findings, were 2 to 3 times more likely to have the primary outcome of death or severe neurodevelopmental impairments by 18 months of age. http://pediatrics.aappublications.org/content/119/5/912?sso=1&sso_redirect_count=1&nfstatus=200&nftoken=3bc9fb63-2530-496d-b914-51533a95da12&nfstatusdescription=SUCCESS%3a+Local+token+is+valid Seizures in patients with HIE are often subclinical, and continued use of monitoring can help in their detection. It is also helpful to note that seizures have not yet begun, in that they are more likely to occur beyond 6 hours post-insult. When seizures are present shortly after birth and resuscitation, the window of opportunity may have been missed, and thus early seizures make for greater concern as to the effectiveness of TH to improve neurodevelopmental outcome.  Animal studies show less of an increase in anaerobic glycolysis in the face of asphyxia when hypoglycemia is present (dogs); hypoglycemia may also impair cerebrovascular autoregulation (piglets). Hyperglycemia during hypoxia has been shown to increase brain injury (piglets, fetal sheep, adult rodents) and hyperglycemia during asphyxia lowers cerebral oxygen consumption and increases acidosis (fetal sheep). Earlier studies of hypoglycemia and HIE mostly reflect only short-term outcomes and they are inconsistent regarding the association of hypoglycemia with outcome. Similarly, conflicting results of the association between hyperglycemia and long-term outcomes have been reported. Furthermore, most of these studies did not assess the impact of TH. Of the metabolic data evaluated among infants with HIE, recent analysis of data from the original CoolCap study demonstrates that aberrations in glucose metabolism discovered within 12 hours of randomization, whether hypoglycemia (< 40 mg/dL [2.2 mmol/L]) or hyperglycemia (> 150 mg/dL [ 8.3 mmol/L]), are associated with increase in the risk of the outcome death or severe NDI among survivors (Figure). Of infants who subsequently had unfavorable outcomes, 9% had hypoglycemia and 41% had hyperglycemia on study entry, significantly greater than the 5% hypoglycemia and 24% hyperglycemia noted among infants with favorable outcomes (p = 0.011). Of the 120 infants in this study with a normal glucose on study entry, 59 (49%) have a favorable outcome, whereas a favorable outcome is seen only among 24 (28%) of the 85 infants with either high or low blood sugar. Glucose abnormalities persisting to 4 and 8 hours in the study were more prominent among infants with poorer outcomes at 18 months of age. These data are of interest in that the patients all were in a closely monitored clinical situation and long-term outcomes are known. The relationship between glucose aberrations and poorer outcome remain intact when data are corrected for birth weight, Sarnat score, 5-min Apgar, initial pH, and use of TH. At the time of this publication, sufficient data are not published to determine whether aberrations of glucose metabolism among patients with HIE are causes of long-term injury, markers of more extensive insult or of injuries from other causes, or coincidental findings. Nevertheless, observance of hyperglycemia, as in the vignette, can be cause for heightened concern about long-term development among patients receiving TH for HIE.