PEDIATRICS Vol. 122 No. 3 September 2008, pp. 491-499 (doi:10.1542/peds.2007-1673)
ARTICLE |
Elevated Temperature After Hypoxic-Ischemic Encephalopathy: Risk Factor for Adverse Outcomes
a Department of Pediatrics, Women and Infants' Hospital of Rhode Island, Providence, Rhode Island
b Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas
c Department of Pediatrics, Wayne State University, Detroit, Michigan
d Department of Statistics and Epidemiology, RTI International, Research Triangle Park, North Carolina
e Department of Pediatrics, Yale University, New Haven, Connecticut
f Department of Pediatrics, Case Western University, Cleveland, Ohio
g Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
h Department of Pediatrics, Duke University, Durham, North Carolina
i Department of Pediatrics, Wake Forest University, Winston-Salem, North Carolina
j National Institute of Child Health and Human Development, Bethesda, Maryland
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. The goal was to determine whether the risk of death or moderate/severe disability in term infants with hypoxic-ischemic encephalopathy increases with relatively high esophageal or skin temperature occurring between 6 and 78 hours after birth.
METHODS. This was an observational secondary study within the National Institute of Child Health and Human Development Neonatal Research Network randomized trial comparing whole-body cooling and usual care (control) for term infants with hypoxic-ischemic encephalopathy. Esophageal and skin temperatures were recorded serially for 72 hours. Each infant's temperatures for each site were rank ordered. The high temperature was defined for each infant as the mean of all temperature measurements in the upper quartile. The low temperature was similarly defined as the mean of the lower quartile. Outcomes were related to temperatures in 3 logistic regression analyses for the high, median, and low temperatures at each temperature site for each group, with adjustment for the level of encephalopathy, gender, gestational age, and race.
RESULTS. In control infants, the mean esophageal temperature was 37.2 ± 0.7°C over the 72-hour period, and 63%, 22%, and 8% of all temperatures were >37°C, >37.5°C, and >38°C, respectively. The mean skin temperature was 36.5 ± 0.8°C, and 12%, 5%, and 2% of all temperatures were >37°C, >37.5°C, and >38°C, respectively. The odds of death or disability were increased 3.6–4 fold for each 1°C increase in the highest quartile of skin or esophageal temperatures. There were no associations between temperatures and outcomes in the cooling-treated group.
CONCLUSIONS. Relatively high temperatures during usual care after hypoxia-ischemia were associated with increased risk of adverse outcomes. The results may reflect underlying brain injury and/or adverse effects of temperature on outcomes.
Key Words: hypoxic-ischemic encephalopathy • neurologic outcome • temperature
Abbreviations: OR—odds ratio • CI—confidence interval • IL—interleukin
Perinatal hypoxia-ischemia represents the cause of newborn encephalopathy in up to 30% of affected infants and can result in death, cerebral palsy, mental impairment, and seizures.1,2 Treatment of infants with hypoxic-ischemic encephalopathy has been limited to supportive intensive care, without any specific brain-oriented therapy. This approach is changing with the recognition that brain temperature during and/or after hypoxia-ischemia may modulate the extent of injury. Small reductions in brain temperature (as little as 2°C) in neonatal animals attenuated damaging processes involved in the pathogenesis of brain injury (eg, energy depletion, excitotoxicity, nitric oxide production, and apoptosis) and decreased the extent of clinical and histologic brain injury.3 Conversely, small increases in brain temperature in neonatal animals during and/or after hypoxia-ischemia increased the extent of injury.4,5
In humans, beneficial effects of reducing brain temperature were noted in 2 large, randomized, clinical trials in near-term and term infants with hypoxia-ischemia.6,7 In contrast, harmful effects of elevated temperature on human brain are uncertain and extremely complex. Observations that intrapartum maternal fever was associated with increased risks of seizures,8 neonatal encephalopathy,9 and subsequent cerebral palsy10 in term infants yielded little direct information on the extent, timing, and duration of elevated temperature and possible associated brain injury. Brain injury in adults may increase brain temperature, and the temperatures of the brain and body may be either concordant or discordant.11 In human neonates, heat flux measurements, to derive brain temperatures indirectly, support the potential for dissociation of brain and body temperatures.12 Our randomized trial of whole-body hypothermia provided an opportunity to examine the hypothesis that elevated body temperature is associated with worse outcomes among term infants with encephalopathy presumed to be attributable to hypoxia-ischemia.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Infants
This was an observational study using data from the National Institute of Child Health and Human Development Neonatal Research Network randomized trial comparing whole-body hypothermia and current usual care (representing a control group).7 The trial was performed after informed consent was obtained. Eligibility criteria included gestational age of
36 weeks, postnatal age of 
6 hours, and sequential fulfillment of specific physiologic and/or clinical criteria (acute perinatal event, acidemia, low Apgar scores, and need for ventilation), followed by demonstration of moderate/severe encephalopathy with modified Sarnat criteria.7
Temperature Control
Control infants were treated by using a radiant warmer that was initially servo-controlled to maintain abdominal skin temperature between 36.5°C and 37.0°C and to maintain core temperature. Subsequent adjustments of the servo-control in response to relatively high or low axillary temperatures were made according to guidelines within participating network NICUs. All infants had an esophageal temperature probe positioned in the lower one third of the esophagus, with subsequent verification of positioning with radiographs. Esophageal temperatures were recorded by using either a Blanketrol II Hyper-Hypothermia system (Cincinnati Sub-Zero, Cincinnati, OH) in the monitoring mode or an independent temperature-monitoring unit (Mon-a-therm; Mallinckrodt Medical, St Louis, MO). Esophageal temperatures were not used for patient treatment in the randomized, controlled trial because this did not represent usual care. Control infants had esophageal and skin temperatures recorded at 4-hour intervals for 72 hours (total of 19 values per patient), during which whole-body hypothermia was performed in the experimental group.
Network centers were surveyed to identify hospital-specific care practices for temperature regulation in near-term and term infants with hypoxic-ischemic encephalopathy during the randomized trial (July 2000 to May 2003). Network research coordinators identified whether such infants were routinely nursed under a radiant warmer or incubator, whether and how temperature was servo-controlled, acceptable skin and axillary temperature ranges, and what information was documented in the medical chart.
Infants assigned randomly to whole-body cooling were positioned on a cooling/heating blanket that was attached to a Blanketrol II Hyper-Hypothermia system (Cincinnati Sub-Zero). The automatic control mode was used to maintain an esophageal temperature of 33.5°C for 72 hours, followed by rewarming and subsequent temperature regulation according to local practice (see ref 7 for details). Esophageal and skin temperatures were recorded at 15-minute intervals during the first 4 hours of cooling, at 1-hour intervals until 12 hours of cooling, and at 4-hour intervals until 72 hours of cooling. Temperatures between 2 and 72 hours (26 values per patient) were used in this analysis and represented temperatures after equilibration during cooling.
Outcomes
The primary outcome was death or moderate/severe disability at 18 to 22 months of age. Trained assessors who were blinded to treatment group assessed outcomes by using standardized assessments. Disability was predefined as either severe or moderate. Severe disability included any of the following: Bayley II Mental Developmental Index score of <70, Gross Motor Functional Classification System score of 3 to 5, blindness, or hearing deficit with amplification. Criteria for moderate disability were Mental Developmental Index score of 70 to 84 with any of the following: Gross Motor Functional Classification System score of 2, persistent seizure disorder, or hearing deficit without amplification.
Data Analyses
For analysis of the relationship between temperatures and outcomes, temperature values representing the extremes and midpoint of the multiple temperatures recorded for each infant were derived. Esophageal and skin temperatures for each infant were rank ordered. For each infant, we defined the high temperature as the mean temperature of the highest quartile and the low temperature as the mean temperature of the lowest quartile. Each infant's high temperature, as just defined, was used in a logistic regression analysis to relate temperatures to the outcomes described above for each group separately (hypothermic and control groups). Separate analyses were performed for the high temperatures of esophageal and skin sites, and each regression was adjusted for level of encephalopathy, gender, race, and gestational age. Similar analyses were performed for the low and median temperatures. The duration of elevated temperature was related to outcomes through adjusted logistic regression analyses using the total time and longest continuous time above threshold temperatures for esophageal and skin temperatures. Threshold temperatures were explored by examining esophageal temperatures of >37.5°C and skin temperatures of >37°C by increments of 0.5°C for each temperature site. Of the 106 control infants, 7 were excluded from these analyses because of missing temperature (n = 4) or outcome (n = 3) data. Of 102 infants who underwent cooling, 5 were excluded because of missing temperature data (n = 3), missing data on level of encephalopathy (n = 1), or protocol violation (n = 1). Associations between temperatures and outcomes are expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Results are expressed as mean ± SD where appropriate.
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RESULTS |
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Maternal and infant characteristics of the 99 control infants and 97 cooling-treated infants analyzed for this study were similar to those of the entire study cohort (N = 208).7 At least 1 intrapartum complication (fetal heart rate decelerations, cord prolapse, uterine rupture, maternal pyrexia, shoulder dystocia, or maternal hemorrhage) occurred in 86% and 89% of mothers of control and cooling-treated infants, respectively. Transfer from birth hospitals to network centers occurred for 41% and 47% of control and cooling-treated infants, respectively. Intubation was performed for 92% and 95% of control and cooling-treated infants, respectively; cord pH values were 6.8 ± 0.2 and 6.9 ± 0.2 and base deficits were 20 ± 9 mmol/L and 19 ± 7 mmol/L, respectively. Characteristics that were adjusted for in regression analyses were as follows: maternal race: control: black, 37%; white, 31%; other, 31%; cooling-treated: black, 31%; white, 40%; other, 29%; male gender: control: 64%; cooling-treated: 49%; gestational age: 39 ± 2 weeks in both groups; moderate encephalopathy: control: 63%; cooling-treated: 69%; severe encephalopathy: control: 37%; cooling-treated: 31%.
As verified in the coordinator survey, control infants were cared for initially under a radiant warmer with servo-control of the abdominal skin temperature. The initial servo set-point temperature was 36.5°C in 15 of the 20 hospitals participating in the study (4 network sites enrolled infants from 2 hospitals). The remaining 5 hospitals used initial servo set-point temperatures of 36°C (n = 3), 36.6°C (n = 1), and 36°C to 36.5°C (n = 1). Temperatures from the axilla and skin were monitored as part of usual care at all hospitals. The minimal and maximal acceptable temperatures were 36.0°C and 37.5°C, respectively, and ranges of up to 1°C were acceptable in some hospitals. The frequency with which temperatures were recorded ranged from 1 to 4 hours.
Figure 1 presents the esophageal and skin temperatures for each group during the 72-hour study period. The mean esophageal temperature over the 72-hour period for all control infants was 37.2 ± 0.7°C, with 25th and 75th percentile values of 36.9°C and 37.5°C, respectively. For control infants, 63%, 22%, and 8% of all esophageal temperature values (N = 1690; 191 missing values) were >37°C, >37.5°C, and >38°C, respectively. Corresponding values for skin temperatures (N = 1731; 150 missing values) were a mean temperature of 36.5°C ± 0.8°C, with 12%, 5%, and 2% of values being >37°C, >37.5°C, and >38°C, respectively. The correlation between esophageal and skin temperatures for the control infants was 0.36 (P < .0001). The distribution of control infants among the high, median, and low esophageal temperatures is indicated in Fig 2. The high esophageal temperatures (mean of the highest quartile) ranged from a minimum of 36.5°C to a maximum of 40°C, and 23 infants had high temperatures of 38°C. The median values ranged from 36.3°C to 38.9°C, and 5 infants had median temperatures of >38°C. The low temperatures (mean of the lowest quartile) ranged from 33.8°C to 37.8°C, and no infants had low temperatures of >38°C. Overlap was present among the high, low, and median temperatures, which indicated that some infants' high temperatures were equal to or less than other infants' low temperatures.
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Logistic regression analyses relating each of the 3 esophageal temperature measurements to the primary outcome indicated significant associations for the high and median temperatures (Table 1). For the mean of the highest quartile of esophageal temperatures, the odds of death or moderate/severe disability were increased fourfold and the odds of death alone were increased 6.2-fold for each 1°C increase. For the median esophageal temperature, the odds of death alone were increased 5.9-fold for each 1°C increase. There was no association between the mean of the lowest quartile and the primary outcome or its components.
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The distribution of control infants among the high, median, and low skin temperatures is presented in Fig 3. The high temperatures (mean of the highest quartile) ranged from a minimum of 35.7°C to a maximum of 39.3°C, and 6 infants had high temperatures of >38°C. The median values ranged from 34.3°C to 38.6°C, and 2 infants had median temperatures of >38°C. The low temperatures (mean of the lowest quartile) ranged from 32.1°C to 37.9°C, and no temperature was >38°C. Logistic regression analyses relating each of the 3 skin temperature measurements to the primary outcome indicated significant associations for the high temperature (Table 2). The mean of the highest quartile of skin temperatures was associated with 3.6-fold and 3.2-fold increased odds of death or moderate/severe disability or death alone, respectively, for each 1°C increase.
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The duration of elevated temperature was also examined. Death or moderate/severe disability was associated with the total time of esophageal temperatures of >38°C (OR: 1.13; 95% CI: 1.04–1.24) and the longest continuous time with values of >38°C (OR: 1.16; 95% CI: 1.04–1.29). Death or moderate/severe disability was associated with the longest continuous time with skin temperatures of >37.5°C (OR: 1.25; 95% CI: 1.03–1.51) but not with the total time above this threshold temperature (OR: 1.09; 95% CI: 0.99–1.20). There were 22 infants with
2 consecutive esophageal temperatures of >38°C (>4 consecutive hours), and the median duration for each infant ranged from 8 to 28 hours, with an overall median value of 12 hours for all 22 infants. Approximately one half of the esophageal temperatures of >38°C occurred in the first 24 hours of the intervention interval, with the remainder occurring equally among the second and third days. The mean esophageal temperature over the 72-hour intervention for cooling-treated infants was 33.3 ± 0.4°C. The distribution of temperatures among cooling-treated infants was narrower than that in the control group, with 25th and 75th percentile values of 33.2°C and 33.5°C, respectively; 89.7% of all esophageal temperatures (2334 measurements, with 188 missing values) were between 33.1°C and 34.0°C (inclusive). The narrower temperature distribution for cooling-treated infants, compared with control infants, resulted in greater overlap between predefined high (range: 33.2–34.4°C), low (range: 29.6–33.6°C), and median (range: 30.2–33.8°C) temperatures for this group. The mean skin temperature over the 72-hour intervention was 31.8 ± 1.1°C, with 25th and 75th percentile values of 31.3°C and 32.2°C, respectively. The correlation between esophageal and skin temperatures for the cooling-treated infants was 0.69 (P < .0001). No associations between esophageal or skin temperatures and death or moderate/severe disability were found in the logistic regression analyses for the cooling-treated group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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There are 2 principal findings of this observational study. First, broad ranges of esophageal and skin temperatures were observed among control infants given usual care in contemporary NICU environments. Second, within this range, relatively high esophageal and skin temperatures were associated with increases in the odds of death and death or moderate/severe disability in analyses controlling for the degree of encephalopathy as well as gender, race, and gestational age. The risk of death or moderate/severe disability was increased 3.6-fold to fourfold for every 1°C increase in the mean of the highest quartile of skin or esophageal temperature. The risk of death alone was increased 5.9-fold for every 1°C increase in the median esophageal temperature. The risk of death or moderate/severe disability was increased with the duration of elevated temperature, but the ORs were less prominent.
The association between elevated temperature and death or disability has at least 3 equally plausible explanations, that is, brain injury raises body temperature, elevated body temperature results in brain injury, or elevated temperature is a marker for an underlying process of which a component is encephalopathy. These possibilities are not mutually exclusive. Similar observations were made for adults with stroke, for whom there were associations between hyperthermia, initial stroke severity, infarction size, and mortality rates.13–15
In support of brain injury resulting in elevated body temperature are the observations that the extent and region of brain lesions trigger mechanisms involved in the pathogenesis of elevated temperature. For example, interleukin (IL)-6 protein is expressed in neurons and microglia within hours after focal ischemia, and expression is upregulated predominantly in the penumbra, with less expression in the contralateral cortex associated with spreading depression.16 IL-6 is an endogenous pyrogen, based on systemic or central intraventricular application of this cytokine evoking fever.17,18 Studies with IL-6–knockout mice have demonstrated that IL-6 expression within the brain is necessary for febrile responses to exogenous (lipopolysaccharide) and downfield endogenous (IL-1β) pyrogens.19 Site-specific injury associated with elevated temperature was assessed by correlating thermoregulatory responses and histologic injury in rodents undergoing fluid percussion injury.20 This model is associated with posttraumatic hyperthermia, blunting or loss of circadian temperature rhythms, and diffuse brain injury involving the cortex, thalamus, and hippocampus. Animals with posttraumatic hyperthermia had similar extents of cell loss, compared with animals without hyperthermia, but were distinguished by infiltration of astrocytes and microglia in 4 areas of the brain involved in temperature control (ventromedial preoptic nucleus, paraventricular nucleus, suprachiasmatic nucleus, and anterior perifornical nucleus). Data on localization of pathologic lesions in animals share interesting parallels with specific MRI patterns of injury in term infants after neonatal encephalopathy. Of the multiple observed injury patterns, injury dominated by changes in the basal ganglia and thalamus was associated with the most-severe neonatal signs and the greatest impairment of motor and cognitive function at 30 months of age.21
Alternatively, there is experimental support for elevated temperature resulting in brain injury. Elevated intraischemic temperature exacerbated the extent of neuronal damage in adult dogs and rodents.22–26 Similar observations were reported for 7-day rat pups, in whom an increase in brain temperature of 1°C to 2°C during hypoxia-ischemia aggravated behavioral deficits and neuronal injury, compared with normothermic animals.4 There are fewer data to demonstrate that an elevation of temperature remote from brain ischemia exacerbates injury. In adult rats, 3 hours of hyperthermia (39–40°C) initiated 24 hours after brain ischemia increased ischemic neurons of the CA1 sector 2.5-fold, compared with 38°C.27 In 10-day rat pups, an increase in core body temperature (37.5°C, compared with 36.0°C) for 4 hours immediately after hypoxia-ischemia increased the extent of neuronal injury.5 Intraischemic hyperthermia acts through several mechanisms to worsen brain injury, including enhanced release of neurotransmitters, exaggerated oxygen radical production, greater blood-brain barrier breakdown, enhanced inflammatory responses, impaired recovery of energy metabolism and protein synthesis, and worsening of cytoskeletal proteolysis.28–30 It remains unclear to what extent these processes are activated when temperature is elevated remote from an hypoxic-ischemic event.
There is little direct evidence to support elevated temperature representing a marker of a currently undiagnosed underlying process. Of newborns with encephalopathy, 69% have only antepartum risk factors, without evidence of impaired intrapartum gas exchange.2 The causal path to newborn encephalopathy may involve intrapartum events alone or interactions among multiple antepartum or antepartum and intrapartum variables. Inflammation modulating the effects of acute hypoxia-ischemia represents a potential example of such interactions.31 In this context, fever could be a marker for the underlying process and its severity. Given these considerations, the current study used enrollment criteria that reflected intrapartum events.7
Thermoregulatory practices for term infants are largely extrapolated from those for preterm infants, among whom neonatal mortality rates were lower if infants were nursed in warmer, compared with cooler, environmental temperatures.32,33 Differences in survival rates reflect the relationship between temperature and oxygen consumption, and thermoregulatory practices have evolved to care for infants in environments that minimize oxygen consumption. In preterm infants, oxygen consumption increases with changes in skin temperature before core temperature is altered, and servo-control of skin temperature can be used to minimize oxygen consumption more effectively than servo-control of core temperature.34 Servo-control of abdominal skin temperature by using a radiant warmer and an initial set point of 36.5°C approximates conditions associated with a minimal metabolic rate in preterm infants35 and is readily used for term infants in the absence of other available data. However, it is unclear how oxygen consumption would be best regulated in term infants and whether the skin or axillary temperatures needed to minimize oxygen consumption and to reduce adverse outcomes are the same in healthy term infants and those with hypoxic-ischemic encephalopathy. Although the temperature display was not shielded from bedside providers, the esophageal temperature was not used to guide clinical care, because it is rarely measured in newborns. Simultaneous esophageal and axillary temperatures were not recorded, and other documentation of changes in the automatic control set point or other measures to limit the extent of elevated temperature were not systematically collected. Other causes of elevated temperature, such as infection, are unlikely, because there were only 2 infants in each group with positive blood culture results.36
There were no associations between high, low, and median temperatures of infants undergoing whole-body cooling and outcomes. This may reflect the fact that the majority of esophageal temperatures were within a relatively narrow range (90% of the 2334 values were between 33.1°C and 34.0°C). Circulation of water through 2 blankets simultaneously (a pediatric-size blanket for the infant to lie on and a suspended adult-size blanket), in conjunction with the automatic control mode of the Blanketrol device, contributed to maintaining 90% of all esophageal temperatures within 0.5°C of the set point.7
The results of this study should be viewed as hypothesis-generating. This was an observational secondary study that demonstrated an association between elevated temperature and death or moderate/severe disability. The association could be attributable to the severity of the brain lesion, specific adverse effects of an elevated temperature, or both. Whether this association is causal is not clear. A randomized, controlled trial would be needed to determine whether prevention of the elevated esophageal or skin temperatures associated with adverse outcomes in our study would reduce the rates of death or moderate/severe disability for infants treated without active cooling.
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ACKNOWLEDGMENTS |
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This work was supported in part by National Institutes of Health grants U10 HD34216, U10 HD27853, U10 HD27871, U10 HD40461, U10 HD40689, U10 HD27856, U10 HD27904, U10 HD40498, U10 HD40521, U10 HD36790, U10 HD21385, U10 HD27880, U10 HD27851, and U10 HD 21373 and General Clinical Research Center grants M01 RR 08084, M01 RR 00125, M01 RR 00750, M01 RR 00070, M01 RR 0039–43, M01RR 00039, and 5 M01 RR00044.
The Hypothermia Study Group was as follows: Case Western Reserve University: Rainbow Children's Hospital principal investigator: Avroy A. Fanaroff, MD; co-principal investigator: Michele C. Walsh, MD; study coordinator: Nancy Newman, RN; follow-up principal investigator: DeeAnne Wilson-Costello, MD; follow-up coordinator: Bonnie Siner, RN; Brown University: Women & Infant's Hospital principal investigator: William Oh, MD; study coordinator: Angelita Hensman, RNC; follow-up principal investigator: Betty Vohr, MD; follow-up coordinator: Lucy Noel, RN; Duke University: principal investigator: C. Michael Cotten, MD; study coordinator: Kathy Auten, BS; follow-up principal investigator: Ricki Goldstein, MD; follow-up coordinator: Melody Lohmeyer, RN; Emory University: Grady Memorial Hospital and Crawford Long Hospital principal investigator: Barbara J. Stoll, MD; co-principal investigator: Lucky Jain, MD; study coordinator: Ellen Hale, RN; Indiana University: Riley Hospital for Children and Methodist Hospital principal investigator: James A. Lemons, MD; study coordinators: Diana Dawn Appel, RN, and Lucy Miller, RN; follow-up principal investigator: Anna Dusick, MD; follow-up coordinator: Leslie Richard, RN; Stanford University: principal investigator: David K. Stevenson, MD; co-principal investigator: Krisa VanMeurs, MD; study coordinator: M. Bethany Ball, CCRC; follow-up principal investigator: Susan R. Hintz, MD; University of Alabama at Birmingham: University Hospital-UAB principal investigator: Waldemar A. Carlo, MD; study coordinators: Monica Collins, RN, and Shirley Cosby, RN; follow-up principal investigator: Myriam Peralta-Carcelen, MD; follow-up coordinator: Vivien Phillips, RN; University of Cincinnati: University Hospital, Cincinnati Children's Hospital Medical Center, principal investigator: Edward F. Donovan, MD; study coordinators: Cathy Grisby, RN, Barb Alexander, RN, Jody Shively, RN, and Holly Mincey, RN; follow-up principal investigator: Jean Steichen, MD; follow-up coordinator: Teresa Gratton, PA; University of California, San Diego: UCSD Medical Center and Sharp Mary Birch Hospital for Women principal investigator: Neil N. Finer, MD; co-principal investigator: David Kaegi, MD; study coordinators: Chris Henderson, CRTT, Wade Rich, RRT-NPS, and Kathy Arnell, RN; follow-up principal investigator: Yvonne E. Vaucher, MD, MPH; follow-up coordinator: Martha Fuller, RN, MSN; University of Miami: principal investigator: Shahnaz Duara, MD; study coordinator: Ruth Everett, BSN; follow-up principal investigator: Charles R. Bauer, MD; University of Rochester: Golisano Children's Hospital at Strong principal investigator: Ronnie Guillet, MD, PhD; study coordinator: Linda Reubens, RN; follow-up principal investigator: Gary Myers, MD; follow-up coordinator: Diane Hust, RN; University of Texas Southwestern Medical Center at Dallas: Parkland Hospital principal investigator: Abbot R. Laptook, MD; study coordinators: Susie Madison, RN, Gay Hensley, RN, and Nancy Miller, RN; follow-up principal investigators: Roy Heyne, MD, and Sue Broyles, MD; follow-up coordinator: Jackie Hickman, RN; University of Texas: Houston Memorial Hermann Children's Hospital principal investigator: Jon E. Tyson, MD, MPH; study coordinators: Georgia McDavid, RN, Esther G. Akpa, RN, Claudia Y. Franco, RN, MSN, NNP, Patty A. Cluff, RN, and Anna E. Lis, RN; follow-up principal investigators: Brenda H. Morris, MD, and Pamela J. Bradt, MD, MPH; Wayne State University: Hutzel Women's Hospital & Children's Hospital of Michigan principal investigator: Seetha Shankaran, MD; study coordinators: Rebecca Bara, RN, and Geraldine Muran, RN; follow-up principal investigator: Yvette Johnson, MD; follow-up coordinator: Debbie Kennedy, RN; Yale University: New Haven Children's Hospital principal investigator: Richard A. Ehrenkranz, MD; study coordinator: Patricia Gettner, RN; follow-up coordinator: Elaine Romano, RN; National Institute of Child Health and Human Development: Neonatal Research Steering Committee: Brown University: William Oh, MD; Case Western University: Avroy A. Fanaroff, MD; Duke University: Ronald N. Goldberg, MD; Emory University: Barbara J. Stoll, MD; Indiana University: James A. Lemons, MD; Stanford University: David K. Stevenson, MD; University of Alabama at Birmingham: Waldemar A. Carlo, MD; University of Cincinnati: Edward F. Donovan, MD; University of California, San Diego: Neil N. Finer, MD; University of Miami: Shahnaz Duara, MD; University of Rochester: Dale L. Phelps, MD; University of Texas at Dallas: Abbot R. Laptook, MD; University of Texas at Houston: Jon E. Tyson, MD, MPH; Wake Forest University: T. Michael O'Shea, MD, MPH; Wayne State University: Seetha Shankaran, MD; Yale University: Richard A. Ehrenkranz, MD; University of Cincinnati: chair: Alan Jobe, MD, PhD; Data Coordinating Center: RTI International: principal investigator: W. Kenneth Poole, PhD; coordinators: Betty Hastings and Carolyn M. Petrie, MS; National Institute of Child Health and Human Development: program scientists: Rosemary D. Higgins, MD, and Linda L. Wright, MD; coordinator: Elizabeth McClure, MEd; Data Safety and Monitoring Committee: Children's National Medical Center: Gordon Avery, MD; Columbia University: Mary D'Alton, MD; RTI International: W. Kenneth Poole, PhD (ex officio); University of Virginia: John C. Fletcher, PhD (deceased); University of Washington: Christine A. Gleason, MD; University of Pittsburgh: Carol Redmond, PhD.
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FOOTNOTES |
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Accepted Dec 13, 2007.
Address correspondence to Abbot Laptook, MD, Department of Pediatrics, Women and Infants' Hospital of Rhode Island, 101 Dudley St, Providence, RI 02906. E-mail: alaptook{at}wihri.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Elevated brain temperature exacerbates hypoxic-ischemic brain injury in animals, but there are few data for human infants.
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| What This Study Adds This study establishes an association between elevated body temperature and exacerbation of hypoxic-ischemic brain injury in newborn infants.
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