Published online before print March 9, 2009, doi: 10.1161/CIRCULATIONAHA.108.791384
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(Circulation. 2009;119:1492-1500.)
© 2009 American Heart Association, Inc.
Pediatric Cardiology |
Hypothermia Therapy After Pediatric Cardiac Arrest
From the Department of Anaesthesia, Division of Pediatric Intensive Care (D.R.D.), Children’s Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada; Department of Critical Care Medicine, The Hospital for Sick Children and Interdepartmental Division of Critical Care Medicine, University of Toronto (D.R.D., C.S.P., R.F., D.J.B., J.S.H.), Toronto, Ontario, Canada; Department of Anaesthesia (D.R.D., D.J.B.), The Hospital for Sick Children, Toronto, Ontario, Canada; Chalmers Research Group (I.G.), Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada; Cardiac Intensive Care Unit (A.H.), Great Ormond Street Hospital for Children, NHS Trust and the Institute of Child Health, London, United Kingdom; CHU mère-enfant Sainte-Justine (J.L., M.T.), Pediatric Intensive Care Division, Department of Pediatrics, Montréal, Québec, Canada; University of Alberta and Department of Pediatrics, Division of Pediatric Intensive Care (A.J.), Stollery Children’s Hospital, Edmonton, Alberta, Canada; Department of Pediatrics, Division of Pediatric Critical Care (K.C.), McMaster Children’s Hospital, Hamilton, Ontario, Canada; and Neuroscience and Mental Health Research Program (J.S.H.), Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Correspondence to James S. Hutchison, Department of Critical Care Medicine, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail jamie.hutchison{at}sickkids.ca
Received May 8, 2008; accepted December 8, 2008.
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Abstract |
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Background— Hypothermia therapy improves mortality and functional outcome after cardiac arrest and birth asphyxia in adults and newborns. The effect of hypothermia therapy in infants and children with cardiac arrest is unknown.
Methods and Results— A 2-year, retrospective, 5-center study was conducted, and 222 patients with cardiac arrest were identified. Seventy-nine (35.6%) of these patients met eligibility criteria for the study (age >40 weeks postconception and <18 years, cardiac arrest >3 minutes in duration, survival for 
12 hours after return of circulation, and no birth asphyxia). Twenty-nine (36.7%) of these 79 patients received hypothermia therapy and were cooled to 33.7±1.3°C for 20.8±11.9 hours. Hypothermia therapy was associated with higher mortality (P=0.009), greater duration of cardiac arrest (P=0.005), more resuscitative interventions (P<0.001), higher postresuscitation lactate levels (P<0.001), and use of extracorporeal membrane oxygenation (P<0.001). When adjustment was made for duration of cardiac arrest, use of extracorporeal membrane oxygenation, and propensity scores by use of a logistic regression model, no statistically significant differences in mortality were found (P=0.502) between patients treated with hypothermia therapy and those treated with normothermia. Also, no differences in hypothermia-related adverse events were found between groups.
Conclusions— Hypothermia therapy was used in resuscitation scenarios that are associated with greater risk of poor outcome. In an adjusted analysis, the effectiveness of hypothermia therapy was neither supported nor refuted. A randomized controlled trial is needed to rigorously evaluate the benefits and harms of hypothermia therapy after pediatric cardiac arrest.
Key Words: heart arrest • pediatrics • cerebral ischemia
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Introduction |
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Despite relative success in the initial resuscitation from pediatric cardiac arrest, with >60% of victims having return of circulation, the 1-year survival rate of children after cardiac arrest remains poor (<35%).1–5 Hypoxic-ischemic encephalopathy is the most important cause of morbidity and mortality after resuscitation, and its severity is affected by cardiac arrest duration and resuscitation effectiveness.3,6,7 Evidence exists of neurological insult in nearly half of all patients after successful resuscitation.7 Hypothermia therapy holds promise as a neuroprotective treatment after cardiac arrest, and its use is supported by strong basic scientific evidence over the last 15 years.8–14 On the basis of the results of randomized trials, the use of hypothermia therapy in survivors of adult cardiac arrest has been recommended in cardiac arrest treatment guidelines.15–17 Hypothermia therapy has also been reported to reduce the risk of death and disability in neonates with moderate hypoxic-ischemic encephalopathy.18,19 The limited evidence for the use of hypothermia therapy in pediatrics is reflected in the American Heart Association guidelines, which recommend that hypothermia therapy be considered in children who remain comatose after resuscitation.20,21 This recommendation is based on extrapolation from existing nonpediatric studies, because no current studies of hypothermia therapy in children after cardiac arrest are available.
Clinical Perspective p 1500
We hypothesized that hypothermia therapy would be associated with improved outcomes after cardiac arrest. Our objectives were to determine the effect of hypothermia therapy on mortality and functional outcome and to describe any adverse effects of hypothermia therapy.
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Methods |
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Study Design
A retrospective observational study was done and reported with modifications of the Utstein template.22,23 The study protocol was developed with critical appraisal by the Canadian Critical Care Trials Group. Four university-affiliated tertiary pediatric institutions in Canada and 1 in the United Kingdom participated in the study (The Hospital for Sick Children, Toronto, Ontario, Canada; McMaster Hospital, Hamilton, Ontario, Canada; Hôpital Sainte-Justine, Montreal, Quebec, Canada; Stollery Children’s Hospital, Edmonton, Alberta, Canada; and Great Ormond Street Children’s Hospital, London, United Kingdom). Research ethics committees approved the study at each center.
Patient Selection
Each participating center searched International Classification of Diseases, 9th Revision codes and institutional databases, including Pediatric Intensive Care Unit Evaluations, cardiac arrest, code blue, extracorporeal membrane oxygenation (ECMO), and death databases. The databases were searched from September 1, 2001, through August 31, 2003, for all patients admitted to the hospital who experienced an out-of-hospital or in-hospital cardiac arrest. The pediatric Utstein style was used to define and time events that related to the cardiac arrest.22 We included patients who had survived a cardiac arrest of sufficient duration to potentially cause a hypoxic-ischemic brain injury and who survived long enough after cardiac arrest for hypothermia therapy to be used. The inclusion criteria were as follows: Patients >40 weeks postconceptual age and <18 years of age; cardiac arrest of at least 3 minutes duration; survival for at least 12 hours after return of spontaneous circulation (or the commencement of rescue ECMO flow); and admission to the intensive care unit after resuscitation. We excluded patients if adequate data could not be extracted from the chart. We also excluded neonates admitted to the neonatal intensive care unit directly from the delivery room with a diagnosis of birth asphyxia, because this population has been studied previously.18,19
Data Collection
A case report form and a procedures manual were developed and pretested at The Hospital for Sick Children before implementation at the other centers. Research assistants at each institution were trained with regard to definitions relating to cardiac arrest, "good clinical practice" for case report form completion, and the scoring of outcome measurements before data collection. The following information was abstracted for all patients: Demographics, prearrest medical history, cause of arrest, duration and location of arrest, first-monitored rhythm during arrest, interventions performed during resuscitation, postresuscitative variables (physiological and supportive therapy), interventions performed to control temperature, complications, and outcomes.
Patients were divided into 2 groups, hypothermia therapy and normothermia. The hypothermia therapy group was defined a priori as all patients who were cooled to a temperature of 
35°C within 6 hours of cardiac arrest for a continuous period of at least 12 hours. This definition was based on reports from laboratory studies9,24,25 and a prospective study in adult humans.15 All other patients were considered as having received normothermia.
Outcomes
Mortality at 6 months was the primary outcome. Mortality at 30 days was also recorded. Other outcomes included the following: (1) Pediatric Cerebral Performance Category (PCPC) score,26,27 assessed at 6 months after cardiac arrest; (2) when the PCPC assessment was possible before cardiac arrest, the 
PCPC at 6 months was calculated; (3) duration of mechanical ventilation; (4) length of stay in the intensive care unit; (5) length of stay at an acute-care hospital (tertiary care facility); (6) multiorgan dysfunction scores28 and pediatric logistic organ dysfunction scores29 for 3 days; and (7) data on hypothermia-related adverse events (eg, infections, bleeding or thrombosis, and arrhythmias), recorded for 14 days after cardiac arrest. The decision to cool was recorded, as well as the cooling method(s), time to target temperature, and duration of cooling.
Data Management and Analysis
Patient characteristics for each study group are represented as descriptive statistics (unless otherwise noted), mean and SD, or median and interquartile range (IQR). Proportions were compared with 
2 tests (or Fisher exact test where appropriate). Temperature and blood pressure were compared between study groups with a linear mixed-effects model, including a fixed effect for time and an interaction term between time and study group. The admission pediatric logistic organ dysfunction score was compared between study groups with Student t test. Continuous variables with a skewed distribution were compared between study groups with Mann-Whitney tests. Differences between groups in the numbers of resuscitation drug doses were assessed with Poisson regression models.
Propensity scores were calculated to match case subjects with control subjects by use of a logistic regression model that included age group, primary cause of arrest, arresting rhythm, location of cardiac arrest (in or out of the hospital), duration of cardiac arrest, interventions performed during resuscitation (doses of epinephrine, atropine, calcium, and bicarbonate), and use of ECMO as covariates.30 The effect of hypothermia therapy on survival at 30 days and 6 months, as well as functional outcome (PCPC score 1 to 3 versus 4 to 6), was assessed with multivariate logistic regression models, adjusted for duration of cardiac arrest and use of ECMO (because these variables have been reported to modify the outcomes3,4), as well as propensity score.30
We also analyzed several important subgroups. We compared mortality between the hypothermia therapy and normothermia groups in patients with a primary cardiac cause of their cardiac arrest and in those who died unexpectedly versus expectedly in the regression models. We compared mortality in the out-of-hospital and in-hospital cardiac arrest cases across all 5 centers and in the centers that did and did not use hypothermia therapy. We also described covariables and mortality in the subgroup of patients who were overcooled to <32°C, because overcooling has been associated with worse outcome.31 Duration of cardiac arrest (from the time of onset of cardiac arrest until return of spontaneous circulation or start of ECMO flow), ventilator days, days in the pediatric intensive care unit, and hospital stay were compared with time-to-event analyses (log-rank test or Breslow test where appropriate).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Patient Characteristics
Within the 2-year time period of the study (September 1, 2001, until August 31, 2003), 222 patients were identified with a cardiac arrest from the databases at the 5 study hospitals (Figure 1). Seventy-nine (35.6%) of these 222 patients met the study entry criteria. The cause of cardiac arrest was cardiac in 55 cases, respiratory in 16, cardiorespiratory in 7 (6 cases of septic shock and 1 case of severe pulmonary hemorrhage), and unknown in 1. Twenty-nine (36.7%) of these 79 patients met our a priori definition of receiving hypothermia therapy. The remaining 50 patients (63.3%) were assigned to the control (normothermia) group.
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Four of the 5 hospitals included in the study had pediatric cardiovascular surgery programs. Three of the 5 hospitals had rescue ECMO programs for resuscitation from cardiac arrest. Demographic factors are shown in Table 1. The majority of the 79 patients included had a chronic illness before the cardiac arrest.
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Variables During Resuscitation
Duration of cardiac arrest was a median of 19.5 minutes (range 3 to 109 minutes). The duration of cardiac arrest in the hypothermia therapy group (median 30 minutes, IQR 22.75 to 42 minutes) was longer than in the normothermia group (median 10 minutes, IQR 5 to 29.5 minutes, P=0.002). The hypothermia therapy group also received more interventions (single-bolus doses) during resuscitation, including epinephrine (P=0.006), atropine, (P=0.076), sodium bicarbonate (P<0.001), and calcium (P=0.009; Figure 1) and had a higher serum lactate reading immediately after resuscitation than patients in the normothermia group (median 16.2 versus 7.5 mmol/L, P<0.001; Figure 2). The use of ECMO was also more frequent in the hypothermia therapy group (79.3%) than in the normothermia group (20.4%; P<0.001). Patients in the hypothermia therapy group also had significantly higher admission pediatric logistic organ dysfunction scores (33.33±11.74) than the normothermia group (22.34±12.14, P<0.001) which suggests a greater severity of illness before the arrest and resuscitation.
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Temperature Data
Temperature data are shown in Figure 2. A "decision to cool" was documented in 30 (38.0%) of 79 patients; however, 5 of these patients did not reach the target temperature for long enough or within the timeframe to fulfill our a priori definition of hypothermia therapy. An additional 4 patients received hypothermia therapy by our definition, even though no clinical plan was documented in the chart to use therapeutic cooling. The mean temperature for patients receiving hypothermia therapy was 33.7±1.3°C, and the mean duration of hypothermia therapy was 20.8±11.9 hours (range 12 to 69 hours). Temperature within the first 12 hours after cardiac arrest was significantly lower in the hypothermia therapy group than in the normothermia group (P<0.001; Figure 2). The methods used to cool patients in the hypothermia therapy group were ECMO in 22 (76%) of 29 patients, cooled fluid and forced air blankets in 2 (7%), and icepacks in 6 (21%). Neuromuscular blockade was used to prevent shivering during cooling in all patients. A greater proportion of patients <12 months of age received hypothermia therapy than patients 1 to 18 years old (Table 1). Hyperthermia was prevented in both groups as recommended by the current International Liaison Committee on Resuscitation guidelines,21 with 8 (16%) of 50 patients in the normothermia group recorded as receiving interventions to control temperature, by use of the temperature control device if the patient was placed on ECMO or active surface cooling in patients not on ECMO. Finally, significant variation was found in the use of hypothermia therapy between reporting centers (P=0.004), with 2 of 5 centers having no patient treated with hypothermia therapy.
Mortality
Mortality (unadjusted) was higher at 6 months in the hypothermia therapy group (69.0%) than in the normothermia group (38.0%; odds ratio [OR] 3.62, 95% confidence interval [CI] 1.37 to 9.62, P=0.009; Table 2). The association between hypothermia therapy and mortality declined and lost statistical significance when we adjusted for duration of cardiac arrest, use of ECMO, and propensity score (adjusted OR 1.99, 95% CI 0.45 to 8.85, P=0.502; Table 2). The 30-day mortality rate (unadjusted) was higher in the hypothermia therapy group (58.6%) than in the normothermia group (36.0%), but this did not reach statistical significance (P=0.054). For patients who had solely a cardiac origin of their cardiac arrest, after the removal of those patients who had either a respiratory or cardiorespiratory cause of their cardiac arrest from the analysis, no difference was found in mortality (unadjusted and adjusted) between the hypothermia and normothermia groups. Among those patients who died, no statistical difference was found between the 2 treatment groups in the number of patients who died unexpectedly at 6 months (deaths without do-not-resuscitate orders in place) or those whose deaths were expected (individuals with do-not-resuscitate orders placed, or those from whom life-sustaining supports were withdrawn; Figure 1; P=0.731). The mortality rate was 100% in patients with an out-of-hospital cardiac arrest and 46.7% in patients with an in-hospital cardiac arrest. Survival was inversely associated with duration of cardiac arrest, with a median duration of 29 minutes in nonsurvivors and 10 minutes in survivors (P=0.001). Mortality rates at 6 months varied between 24% and 100% across the 5 study centers (P=0.023). When the regression models were run on the subsample of patients coming from the 3 of 5 centers where hypothermia therapy was used, mortality (unadjusted) was found to be significantly higher in the hypothermia group than in the normothermia group (P=0.019). The difference did not remain significant once the model was adjusted for duration of cardiac arrest, use of ECMO, and propensity score (P=0.197). For normothermia patients, mortality in the 2 centers that did not use hypothermia therapy was 6 (60%) of 10 patients, whereas mortality in the sites that used hypothermia therapy was 13 (32.5%) of 40 patients, but this difference was not statistically significant (P=0.150).
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Functional and Other Outcomes
The proportion of patients with an unfavorable outcome (PCPC of 4 to 6) at 6 months after cardiac arrest was higher in the hypothermia therapy group (unadjusted OR 2.92, 95% CI 1.10 to 7.69, P=0.031; Table 2). When we adjusted for duration of cardiac arrest, use of ECMO, and propensity score, this association lost statistical significance (adjusted OR 2.00, 95% CI 0.45 to 9.01, P=0.364; Table 2). Similar results were found when participants recruited from centers where hypothermia was not offered were excluded. The proportion of patients with a PCPC score of 1 to 3 before cardiac arrest who had a PCPC score of 4 to 6 after cardiac arrest (PCPC) was higher in the hypothermia therapy group (13 of 20; 65%) than in the normothermia group (17 of 45; 37.8%), but this did not reach statistical significance (P=0.060). Nonsignificant trends were noted toward longer duration of mechanical ventilation (13.0 [IQR 4.0 to 28.0] days compared with 7.5 [IQR 4 to 17.25] days, P=0.217) and longer stay in the pediatric intensive care unit (16.0 [IQR 4.0 to 30.5] days compared with 9.0 [IQR 5.0 to 22.25] days, P=0.411) in the hypothermia therapy group than in the normothermia group. No difference was found in the duration of hospital stay (26.0 [IQR 6.5 to 72.5] days versus 26.0 [IQR 11.75 to 43.25] days, P=0.935) between the 2 groups.
Hypothermia-Related Adverse Events
The multiorgan dysfunction score was higher in the hypothermia therapy group on the first 3 days after cardiac arrest (P=0.004, P=0.011, and P<0.001 for day 1, 2, and 3, respectively; Figure 2). Mean arterial blood pressure was recorded for up to 72 hours after cardiac arrest. Data were analyzed by age group, and blood pressure was found to be significantly lower in the hypothermia therapy group in patients 1 to 12 months of age (P=0.002) and patients 1 to 18 years of age (P=0.017). No difference in blood pressure was found between groups for patients 1 to 4 weeks of age (P=0.343).
Five (17.2%) of the 29 hypothermia therapy patients were overcooled to <32°C. The duration of cardiac arrest in these 5 patients ranged from 12 to 79 minutes, postresuscitation lactate levels ranged from 13.4 to 35 mmol/L, and pediatric logistic organ dysfunction scores range from 22 to 52. Three of these 5 patients died. No statistically significant differences were found between the hypothermia therapy and normothermia groups in infectious complications or other hypothermia-related adverse events for 14 days after return of circulation (Table 3). Normothermic patients were more likely to receive nitroprusside than hypothermia therapy patients (56.0% versus 27.6%) on day 1 (P=0.019). No other differences were found for other inotropic supports (dopamine, epinephrine, or norepinephrine) or use of a phosphodiesterase inhibitor (milrinone) for 3 days after cardiac arrest (data not shown).
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Discussion |
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We report the use of hypothermia therapy after cardiac arrest in a cohort of pediatric patients from 5 university-affiliated centers. Hypothermia therapy was used after cardiac arrest in one third of these patients and in 3 of 5 study centers, and its use was associated with higher mortality and worse functional outcome than with normothermia. However, when regression modeling was used to adjust for duration of cardiac arrest, use of ECMO, and propensity scores, hypothermia therapy no longer had a statistically significant adverse impact on survival or functional outcome. The majority of patients in the present study, 75 (94.9%) of 79, had in-hospital cardiac arrests.
Therapeutic hypothermia was used more often in infants than in older children, and admission pediatric logistic organ dysfunction scores were higher than in the normothermia group. Many intraresuscitation and postresuscitation variables were associated with the use of hypothermia therapy, which included longer durations of cardiac arrest, more pharmacological interventions during resuscitation, greater postresuscitation lactic acid levels, higher multiorgan dysfunction scores, and more renal replacement therapies. These factors are known to be associated with worse outcome in cardiac arrest and may explain the worse outcome in the hypothermia therapy group.1,32–34 A greater proportion of patients in the hypothermia therapy group received ECMO. However, no statistical difference was found between the 2 groups relative to hypothermia-related adverse effects or use of inotropes. Also, no statistically significant differences were found in the median duration of days ventilated, pediatric intensive care unit days, or days spent in the hospital among survivors.
The American Heart Association and the International Liaison Committee on Resuscitation recommend that hypothermia therapy (32°C to 34°C for 12 to 24 hours) should be considered if the child remains comatose after resuscitation.21 This recommendation was extrapolated from adult data by an expert panel.20 Previous experience with therapeutic hypothermia in pediatrics apart from intraoperative hypothermia for congenital cardiac surgery is limited. Hypothermia (<32°C) on admission after ice-water near drowning has been associated with intact survival, but hypothermia therapy combined with hyperventilation and barbiturate coma was associated with a high rate of infectious complications with no clear improvement in outcome after near drowning.35,36
In the present study, during hypothermia therapy, patients were cooled to varying temperature ranges and for varying durations. Patients were also rewarmed at varying rates. Five of 29 patients were overcooled to <32°C, and this has been associated with adverse outcomes.31 Rewarming too rapidly after hypothermia therapy has also been associated with hypotension and with increased mortality after traumatic brain injury in children.37 It is clear that centers in the present study were not using guidelines for hypothermia therapy and rewarming. We recommend that guidelines for cooling and rewarming be used in the future to decrease variability in care and improve patient safety.38 Hyperthermia is common after return of spontaneous circulation and is associated with increased mortality.39 In the patients enrolled in the present study, hyperthermia was actively prevented as recommended by the current International Liaison Committee on Resuscitation guidelines.21
Therapeutic hypothermia has been reported to be safe in neonates after birth asphyxia.18,19,40–42 Whole-body hypothermia therapy has been shown to reduce the risk of death and disability in subgroups of infants after moderate to severe ischemic encephalopathy.18,19 One explanation for the different findings of the present study from other reports in adults and newborns is that pediatric patients with cardiac arrest are not a homogenous population. In the adult studies, patients were resuscitated after ventricular tachyarrhythmia, whereas the neonatal studies describe another relatively homogenous population with birth asphyxia. In-hospital pediatric patients with cardiac arrest often have chronic diseases, and usually, they have an insidious physiological deterioration that leads to cardiac arrest, which may affect the patient’s overall outcome.43,44
A recent survey of pediatric intensivists reported that many physicians were aware of the adult therapeutic hypothermia literature. Thirty-eight percent occasionally used hypothermia therapy and 9% always used hypothermia therapy after pediatric cardiac arrest.45 In the present study, use of hypothermia therapy for cardiac arrests was also variable across study sites, with 2 of 5 centers not using hypothermia therapy.
The present study has some limitations, such as its retrospective design. Our conclusion that no difference in outcome was found between the 2 intervention groups in the adjusted analysis might reflect a lack of statistical power. Given a mortality rate of 
40% in the normothermia group, we would need 165 patients in each of the hypothermia therapy and normothermia groups to detect an OR of 2.0 with 80% power and a 2-sided 
=0.05. Although we found no increase in adverse events associated with the use of hypothermia therapy, adverse event rates are typically underestimated in retrospective studies, because they are not recorded sometimes. Wide variability in resuscitation outcome was found among the 5 contributing centers. The subgroups varied in type of arrest and treatment, and these variations may have had substantial effects on outcome. The conclusions should be interpreted with caution in light of the heterogeneity of the patients and their treatment.
In conclusion, hypothermia therapy was associated with a worse mortality and functional outcome, but the association was lost when the analysis was adjusted for duration of cardiac arrest, ECMO, and propensity scores. No difference was found between the groups in adverse events for 14 days after return of circulation. The present study strongly supports the need for randomized controlled clinical trials before therapeutic hypothermia becomes a standard of care after resuscitation from pediatric cardiac arrest.
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Acknowledgments |
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We thank Rose Gaiteiro, the study research coordinator, and the research assistants at the study sites.
Sources of Funding
This study was supported by The Hospital for Sick Children Foundation seed grant No. 27 and the Heart and Stroke Foundation of Ontario grant No. NA5360. Dr Doherty was supported by an Ontario Ministry of Health Trauma Fellowship.
Disclosures
None.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Schindler MB, Bohn D, Cox PN, McCrindle BW, Jarvis A, Edmonds J, Barker G. Outcome of out-of-hospital cardiac or respiratory arrest in children. N Engl J Med. 1996; 335: 1473–1479.
2. Young KD, Seidel JS. Pediatric cardiopulmonary resuscitation: a collective review. Ann Emerg Med. 1999; 33: 195–205.[CrossRef][Medline] [Order article via Infotrieve]
3. Lopez-Herce J, Garcia C, Rodriguez-Nunez A, Domínguez P, Carrillo A, Calvo C, Delgado MA. Long-term outcome of paediatric cardiorespiratory arrest in Spain. Resuscitation. 2005; 64: 79–85.[CrossRef][Medline] [Order article via Infotrieve]
4. de Mos N, van Litsenburg RR, McCrindle B, Bohn DJ, Parshuram CS. Pediatric in-intensive-care-unit cardiac arrest: incidence, survival, and predictive factors. Crit Care Med. 2006; 34: 1209–1215.[CrossRef][Medline] [Order article via Infotrieve]
5. Nadkarni VM, Larkin GL, Peberdy MA, Carey SM, Kaye W, Mancini ME, Nichol G, Lane-Truitt T, Potts J, Ornato JP, Berg RA; for the National Registry of Cardiopulmonary Resuscitation Investigators. First documented rhythm and clinical outcome from in-hospital cardiac arrest among children and adults. JAMA. 2006; 295: 50–57.
6. Cantineau JP, Lambert Y, Merckx P, Reynaud P, Porte F, Bertrand C, Duvaldestin P. End-tidal carbon dioxide during cardiopulmonary resuscitation in humans presenting mostly with asystole: a predictor of outcome. Crit Care Med. 1996; 24: 791–796.[CrossRef][Medline] [Order article via Infotrieve]
7. Torbey MT, Geocadin R, Bhardwaj A. Brain arrest neurological outcome scale (BrANOS): predicting mortality and severe disability following cardiac arrest. Resuscitation. 2004; 63: 55–63.[CrossRef][Medline] [Order article via Infotrieve]
8. Lei B, Tan X, Cai H, Xu Q, Guo Q. Effect of moderate hypothermia on lipid peroxidation in canine brain tissue after cardiac arrest and resuscitation. Stroke. 1994; 25: 147–152.[Abstract]
9. Colbourne F, Sutherland G, Corbett D. Postischemic hypothermia: a critical appraisal with implications for clinical treatment. Mol Neurobiol. 1997; 14: 171–201.[Medline] [Order article via Infotrieve]
10. Corbett D, Nurse S, Colbourne F. Hypothermic neuroprotection: a global ischemia study using 18- to 20-month-old gerbils. Stroke. 1997; 28: 2238–2242.
11. Colbourne F, Li H, Buchan AM. Indefatigable CA1 sector neuroprotection with mild hypothermia induced 6 hours after severe forebrain ischemia in rats. J Cereb Blood Flow Metab. 1999; 19: 742–749.[CrossRef][Medline] [Order article via Infotrieve]
12. Corbett D, Thornhill J. Temperature modulation (hypothermic and hyperthermic conditions) and its influence on histological and behavioral outcomes following cerebral ischemia. Brain Pathol. 2000; 10: 145–152.[Medline] [Order article via Infotrieve]
13. Hicks SD, Parmele KT, DeFranco DB, Klann E, Callaway CW. Hypothermia differentially increases extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun terminal kinase activation in the hippocampus during reperfusion after asphyxial cardiac arrest. Neuroscience. 2000; 98: 677–685.[CrossRef][Medline] [Order article via Infotrieve]
14. Sutcliffe IT, Smith HA, Stanimirovic D, Hutchison JS. Effects of moderate hypothermia on IL-1 beta-induced leukocyte rolling and adhesion in pial microcirculation of mice and on proinflammatory gene expression in human cerebral endothelial cells. J Cereb Blood Flow Metab. 2001; 21: 1310–1319.[CrossRef][Medline] [Order article via Infotrieve]
15. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002; 346: 557–563.
16. The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002; 346: 549–556.
17. Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW, Kloeck WG, Billi J, Böttiger BW, Morley PT, Nolan JP, Okada K, Reyes C, Shuster M, Steen PA, Weil MH, Wenzel V, Hickey RW, Carli P, Vanden Hoek TL, Atkins D; International Liaison Committee on Resuscitation. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation. 2003; 108: 118–121.
18. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; for the National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005; 353: 1574–1584.
19. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005; 365: 663–670.[Medline] [Order article via Infotrieve]
20. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2005; 112: 1–203.
21. The International Liaison Committee on Resuscitation (ILCOR) consensus on science with treatment recommendations for pediatric and neonatal patients: pediatric basic and advanced life support. Pediatrics. 2006; 117: e955–e977.
22. Zaritsky A, Nadkarni V, Hazinski MF, Foltin G, Quan L, Wright J, Fiser D, Zideman D, O'Malley P, Chameides L. Recommended guidelines for uniform reporting of pediatric advanced life support: the pediatric Utstein Style: a statement for healthcare professionals from a task force of the American Academy of Pediatrics, the American Heart Association, and the European Resuscitation Council. Writing Group. Circulation. 1995; 92: 2006–2020.
23. Jacobs I, Nadkarni V, Bahr J, Berg RA, Billi JE, Bossaert L, Cassan P, Coovadia A, D'Este K, Finn J, Halperin H, Handley A, Herlitz J, Hickey R, Idris A, Kloeck W, Larkin GL, Mancini ME, Mason P, Mears G, Monsieurs K, Montgomery W, Morley P, Nichol G, Nolan J, Okada K, Perlman J, Shuster M, Steen PA, Sterz F, Tibballs J, Timerman S, Truitt T, Zideman D. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa). Circulation. 2004; 110: 3385–3397.
24. Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia is neuroprotective in the gerbil. Brain Res. 1994; 654: 265–272.[CrossRef][Medline] [Order article via Infotrieve]
25. Colbourne F, Corbett D. Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection. J Neurosci. 1995; 15: 7250–7260.[Abstract]
26. Fiser DH. Assessing the outcome of pediatric intensive care. J Pediatr. 1992; 121: 68–74.[CrossRef][Medline] [Order article via Infotrieve]
27. Fiser DH, Long N, Roberson PK, Hefley G, Zolten K, Brodie-Fowler M. Relationship of pediatric overall performance category and pediatric cerebral performance category scores at pediatric intensive care unit discharge with outcome measures collected at hospital discharge and 1- and 6-month follow-up assessments. Crit Care Med. 2000; 28: 2616–2620.[CrossRef][Medline] [Order article via Infotrieve]
28. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald WJ. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995; 23: 1638–1652.[CrossRef][Medline] [Order article via Infotrieve]
29. Leteurtre S, Martinot A, Duhamel A, Proulx F, Grandbastien B, Cotting J, Gottesman R, Joffe A, Pfenninger J, Hubert P, Lacroix J, Leclerc F. Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet. 2003; 362: 192–197.[CrossRef][Medline] [Order article via Infotrieve]
30. D'Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 1998; 17: 2265–2281.[CrossRef][Medline] [Order article via Infotrieve]
31. Merchant RM, Abella BS, Peberdy MA, Soar J, Ong ME, Schmidt GA, Becker LB, Vanden Hoek TL. Therapeutic hypothermia after cardiac arrest: unintentional overcooling is common using ice packs and conventional cooling blankets. Crit Care Med. 2006; 34: S490–S494.[CrossRef][Medline] [Order article via Infotrieve]
32. Herlitz J, Engdahl J, Svensson L, Young M, Angquist KA, Holmberg S. Characteristics and outcome among children suffering from out of hospital cardiac arrest in Sweden. Resuscitation. 2005; 64: 37–40.[CrossRef][Medline] [Order article via Infotrieve]
33. Abella BS, Sandbo N, Vassilatos P, Alvarado JP, O'Hearn N, Wigder HN, Hoffman P, Tynus K, Vanden Hoek TL, Becker LB. Chest compression rates during cardiopulmonary resuscitation are suboptimal: a prospective study during in-hospital cardiac arrest. Circulation. 2005; 111: 428–434.
34. Danciu SC, Klein L, Hosseini MM, Ibrahim L, Coyle BW, Kehoe RF. A predictive model for survival after in-hospital cardiopulmonary arrest. Resuscitation. 2004; 62: 35–42.[CrossRef][Medline] [Order article via Infotrieve]
35. Bohn DJ, Biggar WD, Smith CR, Conn AW, Barker GA. Influence of hypothermia, barbiturate therapy, and intracranial pressure monitoring on morbidity and mortality after near-drowning. Crit Care Med. 1986; 14: 529–534.[Medline] [Order article via Infotrieve]
36. Biggart MJ, Bohn DJ. Effect of hypothermia and cardiac arrest on outcome of near-drowning accidents in children. J Pediatr. 1990; 117: 179–183.[CrossRef][Medline] [Order article via Infotrieve]
37. Hutchison JS, Ward RE, Lacroix J, Hébert PC, Barnes MA, Bohn DJ, Dirks PB, Doucette S, Fergusson D, Gottesman R, Joffe AR, Kirpalani HM, Meyer PG, Morris KP, Moher D, Singh RN, Skippen PW; for the Hypothermia Pediatric Head Injury Trial Investigators and the Canadian Critical Care Trials Group. Hypothermia therapy after traumatic brain injury in children. N Engl J Med. 2008; 358: 2447–2456.
38. Hutchison JS, Doherty DR, Orlowski JP, Kissoon N. Hypothermia therapy for cardiac arrest in pediatric patients. Pediatr Clin North Am. 2008; 55: 529–544.[CrossRef][Medline] [Order article via Infotrieve]
39. Hickey RW, Kochanek PM, Ferimer H, Graham SH, Safar P. Hypothermia and hyperthermia in children after resuscitation from cardiac arrest. Pediatrics. 2000; 106: 118–122.
40. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study. Pediatrics. 1998; 102: 885–892.
41. Battin MR, Penrice J, Gunn TR, Gunn AJ. Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia. Pediatrics. 2003; 111: 244–251.
42. Wyatt JS, Gluckman PD, Liu PY, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thorensen M, Whitelaw A, Gunn AJ; for the CoolCap study group. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics. 2007; 119: 912–921.
43. Suominen P, Olkkola KT, Voipio V, Korpela R, Palo R, Räsänen J. Utstein style reporting of in-hospital paediatric cardiopulmonary resuscitation. Resuscitation. 2000; 45: 17–25.[CrossRef][Medline] [Order article via Infotrieve]
44. Reis AG, Nadkarni V, Perondi MB, Grisi S, Berg RA. A prospective investigation into the epidemiology of in-hospital pediatric cardiopulmonary resuscitation using the international Utstein reporting style. Pediatrics. 2002; 109: 200–209.
45. Haque IU, Latour MC, Zaritsky AL. Pediatric critical care community survey of knowledge and attitudes toward therapeutic hypothermia in comatose children after cardiac arrest. Pediatr Crit Care Med. 2006; 7: 7–14.[CrossRef][Medline] [Order article via Infotrieve]
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Footnotes |
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Presented in part at the Resuscitation Science Symposium, 78th Scientific Sessions of the American Heart Association, Dallas, Tex, November 11, 2005, and published in abstract form (Circulation. 2005;112:24–25).
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.791384/DC1.
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