REVIEW ARTICLE. Hypothermia to Treat Neonatal Hypoxic Ischemic Encephalopathy

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1 REVIEW ARTICLE Hypothermia to Treat Neonatal Hypoxic Ischemic Encephalopathy Systematic Review Prakesh S. Shah, MD, MSc, FRCPC; Arne Ohlsson, FRCPC, MSc; Max Perlman, FRCPC Objectives: To systematically review the effectiveness, as determined by survival without moderate to severe neurodevelopmental disability in infancy and childhood, and the safety of hypothermia vs normothermia in neonates with postintrapartum hypoxic-ischemic encephalopathy and to perform subgroup analyses based on severity of encephalopathy (moderate or severe), type of hypothermia (systemic or selective head cooling), and degree of hypothermia (moderate [ C] or mild [ 33.6 C]). Data Sources: MEDLINE, EMBASE, CINAHL (Cumulative Index for Nursing and Allied Health Literature), the Cochrane Library, abstracts of annual meetings of the Pediatric Academic Societies, and bibliographies of identified articles. Study Selection: Randomized and quasi-randomized controlled trials without language restriction were assessed by 2 reviewers independently and discrepancies were resolved by involving a third reviewer. Quality of the trials was assessed on the basis of concealment of allocation, method of randomization, masking of outcome assessment, and completeness of follow-up. Intervention: Systemic or selective head hypothermia compared with normothermia. Main Outcome Measure: Death or moderate to severe neurodevelopmental disability. Results: Eight studies of acceptable quality were included. The combined outcome of death or neurodevelopmental disability in childhood was reduced in infants receiving hypothermia compared with control infants (4 studies including 497 infants; relative risk, 0.76, 95% confidence interval, ; number needed to treat, 6; 95% confidence interval, 4-14), as were death and moderate to severe neurodevelopmental disability when analyzed separately. Cardiac arrhythmias and thrombocytopenia were more common with hypothermia; however, they were clinically benign. Conclusions: In neonates with postintrapartum asphyxial hypoxic-ischemic encephalopathy, hypothermia is effective in reducing death and moderate to severe neurodevelopmental disability either in combination or separately and is a safe intervention. Arch Pediatr Adolesc Med. 2007;161(10): Author Affiliations: Departments of Pediatrics, Mount Sinai Hospital (Drs Shah and Ohlsson) and University of Toronto (Drs Shah, Ohlsson, and Perlman), Toronto, Ontario, Canada. ASPHYXIA ACCOUNTS FOR 23% of the 4 million annual global neonatal deaths. 1 In developed countries, the incidence of postintrapartum asphyxial hypoxicischemic encephalopathy (HIE) is 1 to 2 in 1000 live births. 2 Pathologic and imaging investigations in the last 2 decades have clarified cellular injury mechanisms occurring after asphyxia. 3 The secondary neuronal damage that follows the primary insult is the target for preventive interventions. Hypothermia, both systemic (whole body) and selective (head cooling), has shown promise in studies in animals, neonates, and adults. 4-9 Possible mechanisms of action of hypothermia include reduced neuronal metabolic demand, reduced cytotoxin accumulation, and prevention of apoptosis during secondary energy failure. 10 A systematic review of hypothermia (2 studies reported in 4 publications ) used to treat neonatal HIE found a lack of evidence to support this intervention. 15 Since then, several randomized controlled trials (RCTs) have been performed. Higgins 16 reviewed only 2 large multicenter trials and identified deficiencies in our knowledge of this intervention. Speer and Perlman 17 reviewed experimental studies, pilot (feasibility and safety) studies, and multicenter studies. Their review included both randomized and nonrandomized studies and excluded non English literature studies, and several studies, including RCTs, were not assessed for safety. No meta-analytic techniques were used to describe either safety or efficacy. 951

2 Our primary objectives were to assess the effectiveness, as determined by survival without moderate to severe disability in infancy and childhood, and the safety of hypothermia vs normothermia in neonates with postintrapartum asphyxial HIE. Secondary objectives were to perform subgroup analyses based on severity of encephalopathy (moderate or severe), type of hypothermia (systemic or selective head cooling), and degree of hypothermia (moderate [ C] or mild [ 33.6 C]). METHODS DATA SOURCES MEDLINE ( January 1, 1966, to December 31, 2006), EMBASE ( January 1, 1980, to December 31, 2006), CINAHL (Cumulative Index to Nursing and Allied Health Literature; January 1, 1982, to December 31, 2006), the Cochrane Library (2006, issue 4), abstracts of the annual meetings of the Pediatric Academic Societies and the European Society of Pediatric Research ( ), and bibliographies of identified articles were searched (December 2006). No language restrictions were applied. MeSH terms and text words for search used included the following: infant-newborn; infant, newborn, diseases; newborn infant; neonate (population); hypothermia; hypothermias; hypothermia, induced; cerebral hypothermia; circulatory arrest; deep hypothermia, induced; cooling; head cooling; whole body cooling (intervention); clinical trials; controlled clinical trials; randomized controlled trials; random allocation; multicenter studies; control groups; and evaluation studies (comparison). These were adjusted according to database-specific terms. STUDY SELECTION Randomized and quasi-randomized (eg, randomization on the basis of day, date, and hospital number) controlled trials of hypothermia (systemic or selective head cooling) were included. Retrospective studies, before-and-after comparisons, case series, case reports, letters to the editor not containing primary data, editorials, review articles, and commentaries were excluded but were read to identify potential studies. Duplicate reports not providing additional information were excluded. Randomized controlled trials in which neonates had clinical (including, but not limited to, low Apgar score, need for resuscitation, neurologic examination demonstrating evidence of encephalopathy with or without preceding intrapartum history indicative of the possibility of asphyxia), biochemical (umbilical arterial or immediate postnatal blood gas analyses revealing ph or acid-base deficit below a set cut-off point as defined in the study), and electrophysiologic evidence of HIE (amplitudeintegrated electroencephalogram showing patterns indicative of moderate or severe encephalopathy) were included. Patients in the intervention arm must have received hypothermia (systemic or selective head cooling) for at least 24 hours. DATA EXTRACTION Identified studies were reviewed and data from eligible studies were abstracted independently by 2 of us (P.S.S. and A.O.) and compared. Discrepancies were resolved by consensus and involvement of a third author (M.P.). Methodological quality was assessed using the information in the original publications. Quality was assessed for allocation concealment (yes, no, or cannot tell), method of randomization (randomized or quasirandomized), and masking of outcome assessment (yes, no, or cannot tell). The intervention could not be masked. A typical effect size was calculated and reported as relative risk (RR), risk difference, and number-needed-to-treat, as appropriate, with 95% confidence interval (CI). All analyses (fixed-effects model) were performed using Revman software (Cochrane Collaboration, Oxford, England, and the University of Maryland Center for Integrative Medicine, Baltimore). The 2 test was applied to detect between-study heterogeneity, and the I 2 statistic was applied to assess the appropriateness of combining study results. 18 No statistical corrections were used to adjust for multiple analyses. Publication bias was assessed by checking funnel plots. OUTCOMES OF INTEREST The primary outcome was survival without moderate to severe neurodevelopmental disability in infancy and childhood. Secondary outcomes assessed included (1) effectiveness outcomes including neurodevelopmental disability among survivors, severe visual deficit, severe hearing deficit, epilepsy, and cognitive or psychomotor delay, and (2) safety outcomes including death and cardiovascular (arrhythmia and hypotension), hematologic (platelet count 100, and clinical and laboratory evidence of altered coagulation), neurologic (seizures after enrollment), infectious (sepsis), renal (oliguria, defined as urine output 1 ml/kg/h; renal failure, defined as oliguria or anuria with rising creatinine level), hepatic (elevated liver enzyme levels), and electrolyte (hypoglycemia, defined as serum glucose concentration 47 mg/dl [to convert to millimoles per liter, multiply by ]; or hypokalemia, defined as serum potassium concentration 3.5 meq/l [to convert to millimoles per liter, multiply by 1.0]) disorders. Severe neurodevelopmental disability was considered when cerebral palsy (nonambulatory, severe spasticity, or Gross Motor Functional Classification System 19 class 3 or higher), Mental Developmental Index or Psychomotor Developmental Index of less than 70 for age, hearing deficit requiring hearing aids, or visual acuity less than 6/60 (Snellen 20/200) in either eye was present. Moderate neurodevelopmental disability was considered when moderate motor dysfunction (ambulatory cerebral palsy, moderate spasticity, or Gross Motor Functional Classification System class 2), Mental Developmental Index or Psychomotor Developmental Index 70 to 84 for age, or moderate hearing or visual deficit was present. DATA ANALYSES Inasmuch as this therapy is in the evaluation phase, we included data on efficacy from studies that reported childhood (age 12 months) outcomes only and data on safety from all studies that reported safety outcomes including death. Subgroup analyses were planned a priori on the basis of comparisons between patients with moderate or severe HIE (Sarnat and Sarnat 20 or similar staging system or amplitude-integrated electroencephalographic findings suggestive of moderate to severe involvement 21 ). RESULTS Sixteen studies were assessed for eligibility. Three retrospective studies, case series, 4,25,26 1 interim report of an ongoing RCT, 27 and 1 study that reported only echocardiographic findings 28 were excluded (Figure 1). Battin et al 11,12 and Gunn et al 13 published their results in 3 different reports. The last report 11 comprised 9 nonrandomized infants, 7 who received hypothermia and 2 control infants. Data for the nonrandomized infants could not be separated out; thus, we only analyzed data pub- 952

3 lished in 1 of the reports that randomized patients to hypothermia or normothermia. 13 For efficacy evaluation, 4 studies provided data on infancy or childhood outcomes, 9,13,29,30 and for safety evaluation, data from all 8 studies were included. 9,13,14,29-33 Of the 650 patients in these studies, only 19 patients with mild HIE were included in 4 studies. 13,29,31,33 Two patients in the study by Eicher et al 29 had postnatal asphyxia; 1 died and the data for the other infant were not reported separately. Four studies used systemic hypothermia 8,9,14,29,32 and 4 used selective head cooling ,30,31,33 Intervention began within the first 6 hours after birth in all studies. The goal in the intervention group was moderate hypothermia ( C) in 4 studies 9,29,31,32 and moderate hypothermia ( 33.6 C) in 4 studies. 13,14,30,33 Systemic hypothermia was achieved using a plastic bag containing water and a cooling blanket in 1 study 8,29 and precooled blankets in 1 study. 9,14 The method of cooling was not reported in 1 study. 32 Head cooling (which causes systemic hypothermia as well as head cooling) was achieved using a cap containing circulating cold water. 11,12,30,31,33,34 The intervention period was 72 hours in 7 studies and 48 hours in 1 study. 8,29 Infants were gradually rewarmed at 0.5 C per hour or allowed to warm passively in nursery temperature. No adverse effects were observed during rewarming. Overall methodological quality of the studies was acceptable (Table 1). Concealed allocation was performed in 6 studies, not reported in 1 study, and not done in 1 study. Seven studies were randomized trials and 1 was quasi-randomized 33 ; randomization was based on the day of admission. In all studies, the intervention was unmasked. Assessment of survivors at follow-up during childhood was reported in 4 studies, 9,11,29,30 with 32% patients lost to follow-up in 1 study. 29 Funnel plot assessment revealed a lack of studies at the extremes of point estimates and clustering of the studies at the point estimate, indicating minor heterogeneity in reported outcomes. PRIMARY OUTCOME There was a significant reduction in the risk of death or of moderate to severe neurodevelopmental disability (Figure 2) in infants who received hypothermia compared with control infants (RR, 0.76 [95% CI, ]; risk difference, 0.16 [95% CI, 0.24 to 0.07]; number needed to treat, 6 [95% CI, 4-14]; test of heterogeneity, P=.54 and I 2 =0). EFFECTIVENESS OUTCOMES Compared with the control group, the hypothermia group showed a significant reduction in severe neurodevelopmental disability rate, severe cerebral palsy, and number of infants with a Mental Developmental Index or a Psychomotor Developmental Index less than 70 (Table 2). More infants in the control group died after withdrawal of life support. SAFETY OUTCOMES Mortality was reduced in the hypothermia group (RR, 0.74 [95% CI, ]; risk difference, 0.09 [95% CI, Efficacy outcomes, 4 studies 8 Studies included (11 publications) Safety outcomes, 8 studies 10 Studies assessed (13 publications) Figure 1. Flow diagram of study selection. 2 Studies excluded 0.15 to 0.02]; number needed to treat, 11 [95% CI, 7-50]; test of heterogeneity, P=.91 and I 2 =0) (Table 2). Most studies reported associations between hypothermia (systemic and head cooling) and bradycardia. The rates of arrhythmia and thrombocytopenia were higher in the hypothermia group. Eicher et al 8 noted a higher incidence of bradycardia (heart rate 80 beats/min) in the hypothermia group compared with the normothermia group (11 vs 2 patients; P=.005). One study 30 that reported a higher incidence of arrhythmia also reported that none of the infants had major arrhythmia (requiring intervention). Thrombocytopenia did not result in adverse consequences in any infant. No significant between-group differences were observed in adverse effects or organ dysfunction. SECONDARY OUTCOMES Subgroup analyses based on severity of encephalopathy (moderate or severe) revealed significant reduction in the risk of the combined outcomes of death or moderate to severe neurodevelopmental disability and severe cerebral palsy in patients with moderate encephalopathy in the hypothermia group compared with the control group (Table 3). In patients with severe encephalopathy, the trends were similar but did not reach statistical significance. Other a priori planned subgroup analyses were not performed at this stage because of the small number of studies and almost similar division of studies as subgroup analyses based on severity of insult. The absolute number of patients contributing to each meta-analysis from individual studies is given in Table 4. COMMENT 16 Studies identified 1 Interim report of ongoing study 6 Studies excluded 3 Retrospective studies 3 Case series 1 Study that reported only echocardiographic findings In this systematic review of 8 eligible trials of acceptable quality, we identified that for neonatal postintrapartum asphyxial HIE, therapeutic hypothermia reduces the risk of the combined outcome of death or moderate to severe neurodevelopmental disability in infancy or childhood and individual outcomes of death, severe neurodevelopmental disability, severe cerebral palsy, and 953

4 Table 1. Characteristics of Included Studies Characteristic Akisu et al 31 Gunn et al 13 Gluckman et al 30 Lin et al 33 Bhat 32 Eicher et al 8,29 Shankaran et al 14 Shankaran et al 9 No. of infants, 11/10 12/10 108/110 32/30 20/15 32/33 9/10 102/106 treatment/control Inclusion criteria a Apgar score 5at5min 6at5min 5at10min 5at5min 5at10min 5at10min 5at10min 5at10min Resuscitation NA NA NA NA At 10 min For 5 min Mechanical ventilation at 10 min Mechanical ventilation at 10 min Cord arterial ph/bd Postnatal ph/bd Exclusion criteria c Hypothermia Temperature goal, C ph 7.1 or BD 10 ph 7.1 or BD 10 Metabolic disease, congenital infection Selective head cooling ph 7.09 ph 7.09 Metabolic disease Selective head cooling (n = 6), (n=6) ph 7or BD 16 ph 7or BD 16 Administration of prophylactic anticonvulsant, birth weight 1800 g, infant in extremis Selective head cooling NA ph 7.10 or BD 15 Severe persistent fetal circulation Selective head cooling ph 7or BD 18 ph 7, BD 13 ph 7orBD 16, or, if ph and BD 10-16, additional criteria b NA ph 7.1 ph 7orBD 16, or, if ph and BD 10-16, additional criteria b NA Sepsis, chorioamnionitis, growth restriction Chromosomal anomaly, growth restriction, infant in extremis ph 7orBD 16, or, if ph and BD 10-16, additional criteria b ph 7orBD 16, or, if ph and BD 10-16, additional criteria b Chromosomal anomaly, growth restriction, infant in extremis Systemic Systemic Systemic Systemic ± Measurement site Left ear Rectal Rectal Rectal NA Rectal Esophageal Esophageal Allocation Cannot tell Yes Yes No Yes Yes Yes Yes concealment Randomization Yes Yes Yes Quasi Yes Yes Yes Yes Masking of Cannot tell Cannot tell Yes Yes (for NA Cannot tell Cannot tell Yes outcome assessment radiology) Completeness of follow-up Yes No No Yes Yes No Yes No Abbreviations: BD, base deficit; NA, data not available; NP, nasopharyngeal; UA, umbilical arterial. a All studies included infants with encephalopathy. b Additional criteria required including acute perinatal event, Apgar score less than 5 at 10 minutes, or need for mechanical ventilation at age more than 10 minutes. c All studies excluded infants with congenital anomalies. Study or Subcategory Gunn and Gunn 10 Eicher et al 8 Gluckman et al 30 Shankaran et al 9 Treatment Group 4/12 14/27 59/108 45/102 Control Group, n/n 3/10 21/25 73/110 64/103 Favors Treatment Group Favors Control Group Weight, % RR, Fixed 1.11 ( ) 0.62 ( ) 0.82 ( ) 0.71 ( ) Total 249 Total events: 122 (treatment group), (161 control group) Test for heterogeneity: χ 2 = 2.15; df = 3 (P =.54); I 2 = 0 Test for overall effect: Z = 3.53 (P =.004) ( ) RR Fixed, 2 Figure 2. Death or moderate to severe neurodevelopmental disability in survivors. CI indicates confidence interval; RR, relative risk. developmental indices (Mental Developmental Index and Psychomotor Developmental Index) less than 70, especially in patients with moderate encephalopathy. Patients in the hypothermia group had higher incidences of arrhythmia and thrombocytopenia; however, these were not clinically important. 954

5 Table 2. Secondary Effectiveness and Safety Outcomes: Hypothermia vs Control Groups Outcome No. of Studies Events in Treatment Group, No. (%) Events in Control Group, No. (%) RR a RD a No. Needed to Treat/Harm I 2 Test of Heterogeneity for RR (%) Neurodevelopmental disability 4 50/177 (28) 67/153 (44) 0.65 (0.48 to 0.87) 0.16 ( 0.26 to 0.05) 6 (4 to 20) 0 (0.55) in survivors 9,11,29,30 Severe cerebral palsy 9, /149 (19) 40/132 (30) 0.64 (0.42 to 0.98) 0.11 ( 0.21 to 0.01) 9 (5 to 100) 0 (0.92) Mental Developmental Index 3 44/162 (27) 53/135 (39) 0.69 (0.50 to 0.96) 0.12 ( 0.23 to 0.01) 8 (4 to 100) 0 (0.84) 70 9,29,30 Psychomotor Developmental 3 45/160 (28) 52/129 (40) 0.70 (0.50 to 0.96) 0.12 ( 0.23 to 0.01) 8 (4 to 100) 0 (0.40) Index 70 Severe visual deficit 27,29, /164 (9) 21/138 (15) 0.56 (0.30 to 1.07) 0.07 ( 0.14 to 0.01) NS 0 (0.73) Severe hearing deficit 9,29,30 3 9/158 (6) 8/130 (6) 0.92 (0.37 to 2.32) 0 ( 0.06 to 0.05) NS 0 (0.69) Epilepsy 14,29, /96 (13) 13/85 (15) 0.85 (0.42 to 1.72) 0.02 ( 0.13 to 0.08) NS 0 (0.52) Life support withdrawn 9,14,29, /175 (12) 37/179 (21) 0.59 (0.36 to 0.96) 0.09 ( 0.16 to 0.01) 11 (6 to 100) 9 (0.33) Death 9,11,14, /326 (24) 108/324 (33) 0.74 (0.58 to 0.94) 0.09 ( 0.15 to 0.02) 11 (7 to 50) 0 (0.91) Arrhythmia 9,13,30, /237 (4) 2/271 (1) 6.29 (1.43 to 27.75) 0.04 (0.01 to 0.07) 25 (14 to 100) 7 (0.30) Hypotension 8,9,13,14, /277 (41) 108/285 (35) 1.20 (0.99 to 1.44) 0.07 (0.00 to 0.15) NS 74 (0.009) Coagulopathy 8,9,14, /254 (23) 48/265 (18) 1.27 (0.92 to 1.74) 0.05 ( 0.02 to 0.11) NS 0 (0.77) Thrombocytopenia 8,13, /155 (38) 40/159 (25) 1.51 (1.09 to 2.10) 0.13 (0.03 to 0.23) 8 (4 to 33) 0 (0.90) Oliguria 8,9,14, /257 (50) 144/265 (54) 0.90 (0.78 to 1.04) 0.05 ( 0.12 to 0.02) NS 0 (0.54) Renal failure 8,9,14, /153 (10) 17/157 (11) 0.95 (0.53 to 1.70) 0.01 ( 0.07 to 0.06) NS 0 (0.76) Liver dysfunction 9,14, /223 (28) 79/234 (34) 0.84 (0.64 to 1.09) 0.05 ( 0.13 to 0.03) NS 38 (0.20) PPHN 8,9,14, /154 (25) 32/157 (20) 1.25 (0.83 to 1.88) 0.05 ( 0.04 to 0.14) NS 0 (0.79) Hypoglycemia 9,13,30, /237 (14) 40/244 (16) 0.84 (0.55 to 1.28) 0.03 ( 0.09 to 0.04) NS 0 (0.61) Hypokalemia 8,13, /155 (55) 87/159 (55) 1.02 (0.84 to 1.24) 0.01 ( 0.09 to 0.12) NS 0 (1.00) Seizures 8,9,13,14,30, /275 (50) 134/275 (49) 1.07 (0.93 to 1.23) 0.03 ( 0.04 to 0.10) NS 27 (0.22) Sepsis 8,9,13,30, /268 (4) 12/275 (4) 0.85 (0.39 to 1.85) 0.01 ( 0.04 to 0.03) NS 0 (0.85) Abbreviations: CI, confidence interval; NS, not significant; PPHN, persistent pulmonary hypertension of the newborn; RD, risk difference; RR, relative risk. a Calculated based on the inverse variance method (weight given to each study is chosen to be the inverse of the variance of the effect estimate) and not simply combined event rates. Table 3. Subgroup Analysis According to Severity of Encephalopathy Events in Treatment Group, No. (%) Events in Control Group, No. (%) Outcome Severity of Encephalopathy RR a RD a Death or moderate to severe neurodevelopmental disability Death Moderate 12,30 26/95 (27) 35/94 (37) 0.75 (0.49 to 1.15) 0.09 ( 0.22 to 0.04) Severe 12,30 13/26 (50) 10/24 (42) 1.21 (0.65 to 2.23) 0.09 ( 0.19 to 0.36) Moderate to severe neurodevelopmental Moderate 12,30 19/69 (28) 25/59 (42) 0.65 (0.40 to 1.07) 0.15 ( 0.31 to 0.02) disability Severe 12,30 7/12 (58) 7/14 (50) 1.17 (0.57 to 2.37) 0.08 ( 0.30 to 0.47) Moderate 9,12,30 67/164 (41) 90/157 (57) 0.72 (0.58 to 0.91) 0.16 ( 0.26 to 0.05) b Severe 9,12,30 43/58 (74) 51/64 (80) 0.93 (0.76 to 1.14) 0.05 ( 0.20 to 0.10) Severe cerebral palsy Moderate 30 7/60 (12) 15/54 (28) 0.42 (0.19 to 0.95) 0.16 ( 0.31 to 0.02) c Severe 30 7/12 (58) 6/14 (43) 1.36 (0.63 to 2.94) 0.15 ( 0.23 to 0.54) Mental Developmental Index 70 Moderate 30 15/60 (25) 20/50 (40) 0.63 (0.36 to 1.09) 0.15 ( to 0.02) Severe 30 6/11 (54) 4/14 (29) 1.91 (0.71 to 5.13) 0.26 ( 0.12 to 0.64) Psychomotor Developmental Moderate 30 14/60 (23) 18/50 (36) 0.65 (0.36 to 1.17) 0.13 ( 0.30 to 0.04) Index 70 Severe 30 7/11 (64) 5/10 (50) 1.27 (0.59 to 2.73) 0.14 ( 0.28 to 0.56) Severe visual deficit Moderate 30 4/57 (7) 7/50 (14) 0.50 (0.16 to 1.61) 0.07 ( 0.19 to 0.05) Severe 30 3/12 (25) 4/13 (31) 0.81 (0.23 to 2.91) 0.06 ( 0.41 to 0.29) Severe hearing deficit Moderate 30 3/50 (6) 1/50 (2) 3.00 (0.32 to 27.87) 0.04 ( 0.04 to 0.12) Severe 30 2/11 (18) 2/13 (15) 1.18 (0.20 to 7.06) 0.03 ( 0.27 to 0.33) Epilepsy Moderate 12,30 10/69 (14) 9/59 (15) 0.93 (0.40 to 2.14) 0.01 ( 0.13 to 0.11) Severe 30 3/12 (25) 3/14 (21) 1.17 (0.29 to 4.74) 0.04 ( 0.29 to 0.36) Abbreviations: CI, confidence interval; RD, risk difference; RR, relative risk. a Calculated based on the inverse variance method (weight given to each study is chosen to be the inverse of the variance of the effect estimate) and not simply combined event rates. b Number needed to treat: 6 (95% CI, 4 to 20). c Number needed to treat: 6 (95% CI, 3 to 50). A Cochrane review concluded that evidence is lacking to make recommendations based on the data available in At least 3 multicenter RCTs of this intervention are ongoing 27,35,36 but will not be completed for 3 years. Of these, the TOBY trial 35 had a planned sample size of 400 patients; however, recruitment was stopped after enrollment of 325 patients. Simbruner 36 has modified the protocol to include mildly asphyxiated patients (1-sided sample 955

6 Table 4. Number of Patients for Each Study Contributing to Outcomes a Outcome Akisu et al 31 Gunn et al 13 Gluckman et al 30 Lin Eicher et al 33 Bhat 32 et al 8,29 Shankaran et al 14 Shankaran et al 9 Moderate to severe NA 2/12 vs 1/10 23/72 vs 31/68 NA NA 4/17 vs 7/11 NA 21/78 vs 28/65 neurodevelopmental disability in survivor Severe cerebral palsy NA NA 14/72 vs 21/68 NA NA NA NA 15/77 vs 19/64 Mental Developmental N/A N/A 21/70 vs 24/61 NA NA 4/17 vs 5/12 NA 19/75 vs 24/62 Index 70 Psychomotor NA NA 21/69 vs 23/56 NA NA 4/17 vs 7/11 NA 20/74 vs 22/62 Developmental Index 70 Severe visual deficit NA NA 7/72 vs 11/64 NA NA 2/17 vs 1/11 NA 5/75 vs 9/63 Severe hearing deficit NA NA 5/64 vs 3/55 NA NA 1/17 vs 1/11 NA 3/77 vs 4/64 Epilepsy NA NA 11/72 vs 11/67 NA NA 1/17 vs 0/11 0/7 vs 2/7 NA Life support withdrawn NA NA NA 2/31 vs 2/30 NA 5/32 vs 7/33 2/9 vs 1/10 12/102 vs 27/106 Death 0/11 vs 2/10 2/12 vs 2/10 36/108 vs 42/110 2/31 vs 2/30 3/20 vs 5/15 10/32 vs 14/33 2/9 vs 3/10 24/102 vs 38/106 Arrhythmia 0/11 vs 0/10 0/12 vs 0/10 10/112 vs 1/118 NA NA NA NA 2/102 vs 1/106 Hypotension 0/11 vs 0/10 0/12 vs 0/10 62/112 vs 61/118 NA NA 11/31 vs 2/31 8/9 vs 10/10 42/102 vs 35/106 Coagulopathy NA NA 21/112 vs 17/118 NA NA 19/31 vs 18/31 1/9 vs 1/10 18/102 vs 12/106 Thrombocytopenia NA 3/12 vs 2/10 36/112 vs 26/118 NA NA 20/31 vs 12/31 NA NA Oliguria NA 12/12 vs 10/10 73/112 vs 83/118 NA NA 27/31 vs 28/31 NA 16/102 vs 23/106 Renal failure 5/11 vs 5/10 NA NA NA NA 2/31 vs 3/31 3/9 vs 5/10 6/102 vs 4/106 Liver dysfunction NA NA 42/112 vs 3/118 NA NA NA 1/9 vs 1/10 20/102 vs 16/106 PPHN NA 2/12 vs 2/10 NA NA NA 9/31 vs 5/31 3/9 vs 2/10 25/102 vs 23/106 Hypoglycemia 2/11 vs 2/10 5/12 vs 2/10 14/112 vs 20/118 NA NA NA NA 12/102 vs 16/106 Hypokalemia NA 6/12 vs 5/10 71/112 vs 73/118 NA NA 9/31 vs 9/31 NA NA Seizures 0/11 vs 3/10 7/12 vs 4/10 93/112 vs 96/118 NA NA 7/31 vs 1/31 0/7 vs 2/7 31/102 vs 28/106 Sepsis 1/11 vs 2/10 0/12 vs 1/10 3/112 vs 3/118 NA NA 1/31 vs 0/31 NA 5/102 vs 6/106 Abbreviations: NA, data not available; PPHN, persistent pulmonary hypertension of the newborn. a Values are given as treatment event rate/total in treatment group (assessed) vs control event rate/total in control group (assessed) for respective outcome. size of 150 patients). Since the study by Shankaran et al, 9 hypothermia is offered as the standard of care in centers (part of the National Institute of Health Child Health and Human Development [NIHCHD] network) that participated in the study. 37 Paradoxically, in a recently concluded consensus conference organized by the NIHCHD, the panel identified that the major limitation in the evaluation of hypothermia for neuroprotection was the lack of long-term safety and efficacy data and cautioned against the use of hypothermia. 17,38,39 In another review, Edwards and Azzopardi 40 performed a (speculative) meta-analysis of 3 studies 9,29,30 and identified similar estimates (RR, 0.76; 95% CI, ) for death or neurodevelopmental disability; however, they precluded generalized use sparing the result of their own and other trials. Thoresen and Whitelaw, 41 reviewing the same 3 studies, 9,29,30 questioned the equipoise of ongoing trials and suggested taking the next step in research, combining hypothermia with other neuroprotective interventions. Saugstad 42 indicated that plans are forthcoming for combining hypothermia with resuscitation in room air in infants with asphyxia. The pragmatic aspects of implementation of hypothermia need to be developed in the local context. The careful use of devices such as a cooling blanket may provide initial hypothermia until the arrival of a transport team for transfer where ongoing care can be provided in accordance with protocol. A meta-analysis is as good as the individual studies that it includes. 43 Failure to conduct meta-analyses can delay introduction of effective treatments; however, they are prone to several biases. Of the 8 studies included in our review, 2 were large, multicenter, international RCTs 9,30 ; 3 were moderate-sized national RCTs 8,29,33 ; and 3 were pilot single-unit studies. 13,14,32 There were clinical heterogeneities among these studies in inclusion criteria, severity of illness, degree of hypothermia, and outcomes assessment. However, all neonates had evidence of HIE. Only 1 study used amplitude-integrated encephalography for study enrollment, 30 which is not surprising because of the limited availability of the instrument and expertise. Combining outcomes from 2 methods of hypothermia (systemic and selective head cooling) may be criticized; however, our subgroup analyses reveal that the direction of effect in both interventions was toward improvement in the primary outcome. In addition, selective head cooling also induces mild systemic hypothermia. Outcome assessment is a concern in trials of hypothermia because of the inability to mask hypothermia therapy and the possible implications for decision making about life support. Common practice is to use combined outcomes in postasphyxial HIE because most deaths are secondary to withdrawal of life-sustaining medical treatment. Critics predicted, and it has been confirmed, that parents of infants in the intervention group would be less likely to be offered and less likely to accept withdrawal of life support than parents of infants in the control group. However, neurodevelopmental disability rate was reduced in the hypothermia group, refuting the notion of physician bias against withdrawal of life support. 956

7 The strengths of our meta-analysis include reports from 8 RCTs performed worldwide and an exhaustive literature search with no language restriction. We caution readers about interpretations of subgroup analyses. Inasmuch as these are only hypotheses generating, the differences observed could simply be the result of differences in the studies, and we have not performed any direct statistical comparisons. Our results reveal significant improvement in the composite outcome in survivors who received hypothermia. We examined how many more infants would be needed to nullify the positive effect (RR of death or moderate to severe neurodevelopmental disability, 0.76; 95% CI, ) and cause the upper margin of this CI to cross 1. Hypothetically, if all future trials produce a composite adverse outcome rate of 65% in both groups (similar to the control group of included studies), that is, no effect on hypothermia, then more than 1500 additional infants would be needed. This is not even close to the combined total number of patients planned in the ongoing 3 RCTs (approximately 800 infants). This theoretical analysis is not intended to limit recruitment in ongoing trials; however; it alerts those awaiting the results. The overall results of this meta-analysis and reported RCTs seriously question the equipoise of these trials and support the recent call for a review of the topic. 44 Possible reservations to these results are related to age at assessment of the outcome (12-24 months) and adverse effects. Shankaran et al 45 reported that in these patients, neurologic examination at 12 months can predict severe disability at age 5 years. We acknowledge that long-term safety data are lacking; however, reduction in mortality without increase in the number of infants with substantial early-onset neurodevelopmental disability is a finding difficult to ignore. Bradycardia is common with hypothermia, as tachycardia is with fever. Thrombocytopenia associated with hypothermia is in keeping with the physiologic response of reduced coagulability observed in hibernating animals; otherwise, their circulatory system would become clogged. 46 With a 16% risk reduction in primary outcome, we calculate that in the United States alone (4 million annual births), this could potentially prevent death or severe disability in 1200 neonates per year, or at least 3 neonates per day. On the basis of findings in this review, we suggest hypothermia for the treatment of postintrapartum asphyxial HIE within the first 6 hours after birth, in particular in infants with moderate encephalopathy being treated in centers with expertise and within the strict guidelines outlined in the protocols of these studies. Parents need to be informed about the known reductions in short-term adverse outcomes and the lack of longterm safety data. We strongly advocate continued follow-up of the infants enrolled in these trials to ascertain the long-term effects of hypothermia in survivors. Further research to answer questions such as ideal time of initiation of intervention, duration of intervention, degree of hypothermia, method of hypothermia, duration of rewarming, and ideal candidates for this intervention is needed. Accepted for Publication: March 3, Correspondence: Prakesh S. Shah, MD, MSc, FRCPC, Department of Paediatrics, Mount Sinai Hospital, Room 775A, 600 University Ave, Toronto, ON M5G 1X5, Canada (pshah@mtsinai.on.ca). Author Contributions: Dr Shah had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Shah and Ohlsson. Acquisition of data: Shah and Ohlsson. Analysis and interpretation of data: Shah, Ohlsson, and Perlman. Drafting of the manuscript: Shah. Critical revision of the manuscript for important intellectual content: Shah, Ohlsson, and Perlman. Statistical analysis: Shah. Administrative, technical, and material support: Ohlsson. Study supervision: Ohlsson and Perlman. Financial Disclosure: None reported. Additional Contributions: Meijian Zhao, MD, and Mss Li Chen and Carol Cheng translated the manuscript from Chinese to English. REFERENCES 1. Lawn JE, Cousens S, Zupan J; Lancet Neonatal Survival Steering Team. Four million neonatal deaths: when? where? why? Lancet. 2005;365(9462): Low JA, Lindsay BG, Derrick EJ. Threshold of metabolic acidosis associated with newborn complications. Am J Obstet Gynecol. 1997;177(6): Inder TE, Volpe JJ. Mechanisms of perinatal brain injury. Semin Neonatol. 2000; 5(1): Azzopardi D, Robertson NJ, Cowan FM, Rutherford MA, Rampling M, Edwards AD. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. 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