Efficacy of Targeted Temperature Management after Pediatric Cardiac Arrest: A Meta-Analysis of 2002 Patients

Cardiac arrest (CA) is associated with high mortality and poor life quality. Targeted temperature management (TTM) or therapeutic hypothermia is a therapy increasing the survival of adult patients after CA. The study aim was to assess the feasibility of therapeutic hypothermia after pediatric CA. We performed a systematic review and meta-analysis of randomized controlled trials and observational studies evaluating the use of TTM after pediatric CA. The primary outcome was survival to hospital discharge or 30-day survival. Secondary outcomes included a one-year survival rate, survival with a Vineland adaptive behavior scale (VABS-II) score ≥ 70, and occurrence of adverse events. Ten articles (n = 2002 patients) were included, comparing TTM patients (n = 638) with controls (n = 1364). In a fixed-effects meta-analysis, survival to hospital discharge in the TTM group was 49.7%, which was higher than in the non-TTM group (43.5%; odds ratio, OR = 1.22; 95% confidence interval, CI: 1.00, 1.50; p = 0.06). There were no differences in the one-year survival rate or the occurrence of adverse events between the TTM and non-TTM groups. Altogether, the use of TTM was associated with a higher survival to hospital discharge; however, it did not significantly increase the annual survival. Additional high-quality prospective studies are necessary to confer additional TTM benefits.

. Inclusion and exclusion criteria of included studies.

Study Inclusion Criteria Exclusion Criteria Outcome(s) Colling Method Rewarming Setting Findings
Chang et al. 2016 EMS-assessed OHCA patients who survived to admission and were 18 years of age or younger, regardless of the cause (presumed cardiac or non-cardiac origin) (1) unknown neurological status at hospital discharge; (2) an alert mental status after resuscitation at the ED.
Survival to discharge. Good neurological status, defined as having a Cerebral Performance Category (CPC) score of 1 (good performance, no neurological disability) or 2 (moderate disability, can work).
Core temperature 32-34•C for at least 12h NS MTH and the effect of MTH across the initial ECG at the scene were not significantly associated with survival or good neurologic recovery in pediatric OHCA survivors.

Cheng et al. 2018
Patients treated under the TH protocol in the first 18 months of its initiation Age from 2 months to 18 years; cardiac arrest of at least 3 minutes' duration; survival for at least 12 hours after return of spontaneous circulation; and admission to the intensive care unit after resuscitation Children with congenital heart diseases. If a patient experienced more than one resuscitation during the study period, only the first resuscitation meeting the eligibility criteria was included.
The primary outcomes included survival and Pediatric Cerebral Performance Category (PCPC) scores at hospital discharge. The secondary outcomes were related to the application of therapeutic hypothermia and the hypothermia-related adverse events. in a coma after resuscitation (GCS > 8); 4) known to have pre-existing degenerative neurological diseases; 5) with traumatic brain injury; and 6) with ventricular fibrillation and a history of congenital heart disease.
days following cardiac arrest, duration of hospitalization, and the prevalence of therapeutic hypothermia-related adverse events. Adverse events included hemodynamic changes, intermittent arrhythmia, coagulopathy, electrolyte imbalance and infection during hypothermia, and rebounding increased intracranial pressure and seizures after rewarming.
the patient reached 36 °C.
hypothermia was associated with a better 1-month survival rate and 6month neurological outcomes than normothermia in our pediatric patients with asphyxial OHCA.

Moler et al. 2015
Children older than 48 hours and younger than 18 years of age were eligible for inclusion in the study if they had a cardiac arrest requiring chest compressions for at least 2 minutes and remained dependent on mechanical ventilation after the return of circulation.
The inability to undergo randomization for any reason within 6 hours after the return of circulation, a score of 5 or 6 on the Glasgow Coma Scale motorresponse subscale (on which scores range from 1 to 6, with lower scores indicating reduced levels of function), the decision by the clinical team to withhold aggressive treatment, and major trauma associated with the cardiac arrest.
The primary outcome was survival with a good neurobehavioral outcome at 12 months of follow-up. Secondary outcomes were survival 12 months after cardiac arrest and change in neurobehavioral function, measured as the difference be-tween the baseline level before cardiac arrest and the 12-month measurement on the VABS-II.
The children were then rewarmed over a period of 16 hours or longer to a target temperature of 36.8°C (range, 36.0 to 37.5).
In comatose children who survived outof-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year Moler et al. 2017 Children older than 48 hours and younger than 18 years of age were eligible for inclusion if they had a cardiac arrest that began within the walls of a hospital, received chest compressions for at least 2 minutes, and remained dependent on mechanical ventilation after the return of circulation.
A score of 5 or 6 on the Glasgow Coma Scale motor-response subscale (on which scores range from 1 to 6, with lower scores indicating worse function), the inability to undergo randomization within 6 hours after the return of circulation, active and refractory severe bleeding, a preexisting illness associated with a life expectancy of less than 12 months, and a decision by the clinical team to withhold aggressive treatment.
The primary outcome was survival with a favorable neurobehavioral outcome at 12 months of follow-up. Secondary outcomes were survival at 12 months after cardiac arrest and change in neurobehavioral function, which was measured as the difference between the baseline measurement (before cardiac arrest) and the 12month measurement on the VABS-II.
The patients were then rewarmed over a period of 16 hours or longer to a target temperature of 36.8°C (range, 36.0 to 37.5) Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year.

Scholefield et al. 2015
Aged between at least one day and 16 years, admitted to ICU after an OHCA with return of spontaneous circulation (ROSC).

NS
Primary outcome was survival to hospital discharge; efficacy and safety outcomes included: application of TTM, physiological, hematological and biochemical side effects.
Secondly, the proportions with abnormal values or adverse events within 72 h of ICU admission were compared.

32-34•C for 24 h
controlled rewarming, by 0.5 • C every 2 h, and 37 • C TTM (32-34•C) was feasible but associated with bradycardia, hypotension, and increased length of stay in ICU. Temperature <32 • C had a universally grave prognosis. Larger studies are required to assess effect on survival.
van Zellem et al. 2015 Patients aged >28 days and <18 years with documented CA.
(1) all children resuscitated in-hospital (e.g. emergency department, ward, or ICU) and out-of-hospital, and consecutively admitted to our ICU, and (2) children resuscitated in a regional hospital or other university hospital, and after ROSC consecutively admitted to our ICU.
Neonatal resuscitations, children with cyanotic congenital heart disease, and children without an arterial line.
The primary outcome measure was IH mortality.
In the second analysis of the first research question, the "area under the curve" (AUC) of PaO 2 was calculated for each patient to determine the influence of the cumulative PaO 2 on in-hospital mortality.
Target temperature is 32-34 • C for 24 h following ROSC.
Rewarmed passively at a rate of 0.5 • C per 2 h.
Cumulative PaO2 analysis showed that the IH mortality is significantly lower in MTH-treated children with high PaO2 levels.  Case in which patients received therapeutic hypothermia (core temperature 32-34•C) after recovering spontaneous circulation (ROSC) by using a method such as external cooling (water, fanning, or ice padding), internal cooling (gastric lavage, bladder cooling, or intravascular cooling using a catheter) or mixed cooling.

Cheng et al. 2018
Temperature was targeted to be 33.5°C for either 72h (<1year of age) or 48h (1year of age). Patients < 1 year of age were cooled for 72 h based on published neo-natal trials, while patients 1 year of age were cooled 48 h. Cooling was managed via the ECMO circuit or via cooling blanket for those not on ECMO. Per protocol, patients were rewarmed at a rate of 0.5 °C every 2 h to a goal temperature of 36.5 °C, although goal temperature was set by the medical care team.
For control patients, data were collected over a "therapeutic window" time period which paralleled the data collection time period for TTM patients. The "therapeutic window" consisted of either 72 h (< 1 year of age) or 48 h (1 year of age) to represent the TTM time period post-arrest, plus 12 h to represent rewarming.
Thus, control patients had temperature and monitoring data collected for 84 h post-arrest if < 1 year of age and 60 h if ≥1 year of age.

Doherty et al. 2009
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 Normothermia.

Fink et al. 2010
Induction of HT was accomplished with multiple modalities. Most commonly, we used a cooling blanket (Cincinnati SubZero Plastipad, Cincinnati, OH) positioned under the patient and controlled by an automated cooling system (Gaymar Medi-Therm III, Orchard Park, NY) set to the target temperature. Other methods included surface cooling with ice packets, bath and fan, lowering of the room and ventilator humidifier thermostat, and, occasionally, gastric lavage with iced saline. One patient received 40 mL/kg of intravenous iced saline to induce HT. Re-warming was achieved by increasing the set point of the cooling blanket gradually until the patient reached 36°C, at which time the blanket was turned off to prevent over-warming. Normothermia.

Lin et al. 2013
Patients who were cooled to a temperature of 33 o C within 6 hours of cardiac arrest for a continuous period of 24 or 72 hours. Induction of therapeutic hypothermia was accomplished with thermal heat-exchange cooling pads attached to the patient and controlled by an automated temperature management system (Arctic SunTM, Medivance, Inc.) set to the target temperature. Neuromuscular blockers were used to prevent shivering during induction of therapeutic hypothermia. Hyperthermia was prevented in both groups as recommended by the current International Liaison Committee on Resuscitation guidelines. Rewarming was achieved by increasing the set point of the temperature management system gradually at 1 o C per day until the patient reached 36 o C Normothermia.

Lin et al. 2018
Induction of therapeutic hypothermia was accomplished with thermal heat-exchange cooling pads according to the patient's age and size, and controlled using an automated temperature management system (Arctic Sun, Medivance Inc. Louisville, CO, USA) set to a target temperature of 33 °C. From our past experience of critical care for neonatal asphyxia, we used a cooling duration of the maintenance phase of 72 h for the children with asphyxial aetiologies. Rewarming was achieved by gradually increasing the Normothermia.
temperature on the management system by 1 °C per day until the patient reached 36 °C.

Moler et al. 2015
Children who were assigned to therapeutic hypothermia were pharmacologically paralyzed and sedated, and a Blanketrol III temperature management unit (Cincinnati Sub-Zero) was used, with blankets applied anteriorly and posteriorly, to achieve and maintain a core temperature of 33.0°C (range, 32.0 to 34.0) for 48 hours. The children were then rewarmed over a period of 16 hours or longer to a target temperature of 36.8°C (range, 36.0 to 37.5); this temperature was actively maintained throughout the remainder of the 120-hour intervention period.
Identical care except that the core temperature was actively maintained with the cooling unit at 36.8°C (range, 36.0 to 37.5) for 120 hours.

Moler et al. 2017
Targeted temperature management was active-ly maintained for 120 hours in each group. Pa-tients who were assigned to therapeutic hypo-thermia were pharmacologically paralyzed and sedated, and a Blanketrol III temperature-man-agement unit (Cincinnati Sub-Zero) was used, with blankets applied anteriorly and posteriorly, to achieve and maintain a core temperature of 33.0°C (range, 32.0 to 34.0) for 48 hours. The patients were then rewarmed over a period of 16 hours or longer to a target temperature of 36.8°C (range, 36.0 to 37.5); this temperature was actively maintained throughout the remainder of the 120-hour intervention period.
Identical care except that the core temperature was actively maintained with the temperature-management unit at 36.8°C (range, 36.0 to 37.5) for 120 hours.

Scholefield et al. 2015
TTM (32-34•C) was initiated in the PICU with the use of servocontrolled water blanket cooling mattresses (Blanketroll II, Cincinnati Sub Zero, OH, USA) to reduce temperature between 32 and 34 • C for 24 h followed by controlled rewarming, by 0.5 • C every 2 h, and 37 • C.
van Zellem et al. 2015 Hypothermia was achieved by administering a bolus of cold fluids and applying external cooling using a mattress with Blanketrol® III (Cincinnati Sub-Zero Products, Inc., Sharonville, OH, USA). The target temperature is 32-34 • C for 24 h following ROSC, after which they were rewarmed passively at a rate of 0.5 • C per 2 h. The target temperature must have been reached for MTH to be effective.
Children in whom the target temperature range was not reached Legend: ECMO, ExtraCorporeal Membrane Oxygenation; NS, not specified; ROSC, return of spontaneous circulation; TTM, Targeted temperature management.   . Figure S1. Forest plot of patients age in TTM and not TTM group. The center of each square represents the weighted mean differences for individual trials, and the corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled results. Figure S2. Forest plot of patients gender (male) in TTM and not TTM group. The center of each square represents the weighted odds ratios for individual trials, and the corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled results. Figure S3. Forest plot of cardiac etiology of cardiac arrest in TTM and not TTM group. The center of each square represents the weighted odds ratios for individual trials, and the corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled results. Figure S4. Forest plot of witnessed cardiac arrest in TTM and not TTM group. The center of each square represents the weighted odds ratios for individual trials, and the corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled results. Figure S5. Forest plot of bystander cardiopulmonary resuscitation in TTM and not TTM group. The center of each square represents the weighted odds ratios for individual trials, and the corresponding horizontal line stands for a 95% confidence interval. The diamonds represent pooled results. Figure S6. Funnel plot of odds ratio (OR) with standard error: (A) survival to hospital discharge, (B) survival rate in 6months follow-up; (C) survival rate in 1-year follow-up; (D) survival with VABS-II score ≥ 70 points at 1-year follow-up. Data from each modality are plotted against their standard error (SE). Solid line = summary estimate of the odds ratio; dashed line = 95%CI confidence limits around the OR. Figure S7. A summary table of review authors' judgements for each risk of bias item for each randomized study. Figure S8. A plot of the distribution of review authors' judgements across randomized studies for each risk of bias item. Figure S9. A summary table of review authors' judgements for each risk of bias item for each non-randomized study. Figure S10. A summary table of review authors' judgements for each risk of bias item for each non-randomized study.