24 vs. 72 hours of hypothermia for pediatric cardiac arrest: A pilot, randomized controlled trial.
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ABSTRACT:
SUBMITTER: Fink EL
PROVIDER: S-EPMC5899619 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
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24 vs. 72 hours of hypothermia for pediatric cardiac arrest: A pilot, randomized controlled trial.
Fink Ericka L EL Clark Robert S B RSB Berger Rachel P RP Fabio Anthony A Angus Derek C DC Watson R Scott RS Gianakas John J JJ Panigrahy Ashok A Callaway Clifton W CW Bell Michael J MJ Kochanek Patrick M PM
Resuscitation 20180214
<h4>Aim</h4>Children surviving cardiac arrest (CA) lack proven neuroprotective therapies. The role of biomarkers in assessing response to interventions is unknown. We hypothesized that 72 versus 24 h of hypothermia (HT) would produce more favorable biomarker profiles after pediatric CA.<h4>Methods</h4>This single center pilot randomized trial tested HT (33 ± 1 °C) for 24 vs. 72 h in 34 children with CA. Children comatose after return of circulation aged 1 week to 17 years and treated with HT by ...[more]
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Project description:ImportanceInternational resuscitation guidelines recommend targeted temperature management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain.ObjectiveTo determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM.Design, setting, and participantsThis was an international, investigator-initiated, blinded-outcome-assessor, parallel, pragmatic, multicenter, randomized clinical superiority trial in 10 intensive care units (ICUs) at 10 university hospitals in 6 European countries. Three hundred fifty-five adult, unconscious patients with out-of-hospital cardiac arrest were enrolled from February 16, 2013, to June 1, 2016, with final follow-up on December 27, 2016.InterventionsPatients were randomized to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C.Main outcomes and measuresThe primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, including time to death, the occurrence of adverse events, and intensive care unit resource use.ResultsIn 355 patients who were randomized (mean age, 60 years; 295 [83%] men), 351 (99%) completed the trial. Of these patients, 69% (120/175) in the 48-hour group had a favorable outcome at 6 months compared with 64% (112/176) in the 24-hour group (difference, 4.9%; 95% CI, -5% to 14.8%; relative risk [RR], 1.08; 95% CI, 0.93-1.25; P = .33). Six-month mortality was 27% (48/175) in the 48-hour group and 34% (60/177) in the 24-hour group (difference, -6.5%; 95% CI, -16.1% to 3.1%; RR, 0.81; 95% CI, 0.59-1.11; P = .19). There was no significant difference in the time to mortality between the 48-hour group and the 24-hour group (hazard ratio, 0.79; 95% CI, 0.54-1.15; P = .22). Adverse events were more common in the 48-hour group (97%) than in the 24-hour group (91%) (difference, 5.6%; 95% CI, 0.6%-10.6%; RR, 1.06; 95% CI, 1.01-1.12; P = .04). The median length of intensive care unit stay (151 vs 117 hours; P < .001), but not hospital stay (11 vs 12 days; P = .50), was longer in the 48-hour group than in the 24-hour group.Conclusions and relevanceIn unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU, targeted temperature management at 33°C for 48 hours did not significantly improve 6-month neurologic outcome compared with targeted temperature management at 33°C for 24 hours. However, the study may have had limited power to detect clinically important differences, and further research may be warranted.Trial registrationclinicaltrials.gov Identifier: NCT01689077.
| S-EPMC5541324 | biostudies-literature
Project description:BackgroundSeparate trials to evaluate therapeutic hypothermia after paediatric cardiac arrest for out-of-hospital and in-hospital settings reported no statistically significant differences in survival with favourable neurobehavioral outcome or safety compared to therapeutic normothermia. However, larger sample sizes might detect smaller clinical effects. Our aim was to pool data from identically conducted trials to approximately double the sample size of the individual trials yielding greater statistical power to compare outcomes.MethodsCombine individual patient data from two clinical trials set in forty-one paediatric intensive care units in USA, Canada and UK. Children aged at least 48 h up to 18 years old, who remained comatose after resuscitation, were randomized within 6 h of return of circulation to hypothermia or normothermia (target 33.0 °C or 36.8 °C). The primary outcome, survival 12 months post-arrest with Vineland Adaptive Behaviour Scales, Second Edition (VABS-II) score at least 70 (scored from 20 to 160, higher scores reflecting better function, population mean = 100, SD = 15), was evaluated among patients with pre-arrest scores ≥70.Results624 patients were randomized. Among 517 with pre-arrest VABS-II scores ≥70, the primary outcome did not significantly differ between hypothermia and normothermia groups (28% [75/271] and 26% [63/246], respectively; relative risk, 1.08; 95% confidence interval [CI], 0.81 to 1.42; p = 0.61). Among 602 evaluable patients, the change in VABS-II score from baseline to 12 months did not differ significantly between groups (p = 0.20), nor did, proportion of cases with declines no more than 15 points or improvement from baseline [22% (hypothermia) and 21% (normothermia)]. One-year survival did not differ significantly between hypothermia and normothermia groups (44% [138/317] and 38% [113/ 297], respectively; relative risk, 1.15; 95% CI, 0.95 to 1.38; p = 0.15). Incidences of blood-product use, infection, and serious cardiac arrhythmia adverse events, and 28-day mortality, did not differ between groups.ConclusionsAnalysis of combined data from two paediatric cardiac arrest targeted temperature management trials including both in-hospital and out-of-hospital cases revealed that hypothermia, as compared with normothermia, did not confer a significant benefit in survival with favourable functional outcome at one year.
| S-EPMC6361524 | biostudies-literature
Project description:The Therapeutic Hypothermia After Pediatric Cardiac Arrest trials will determine whether therapeutic hypothermia improves survival with good neurobehavioral outcome, as assessed by the Vineland Adaptive Behavior Scales Second Edition, in children resuscitated after cardiac arrest in the in-hospital and out-of-hospital settings. We describe the innovative efficacy outcome selection process during Therapeutic Hypothermia After Pediatric Cardiac Arrest protocol development.Consensus assessment of potential outcomes and evaluation timepoints.None.We evaluated practical and technical advantages of several follow-up timepoints and continuous/categorical outcome variants. Simulations estimated power assuming varying hypothermia benefit on mortality and on neurobehavioral function among survivors. Twelve months after arrest was selected as the optimal assessment timepoint for pragmatic and clinical reasons. Change in Vineland Adaptive Behavior Scales Second Edition from prearrest level, measured as quasicontinuous with death and vegetative status being worst-possible levels, yielded optimal statistical power. However, clinicians preferred simpler multicategorical or binary outcomes because of easier interpretability and favored outcomes based solely on postarrest status because of concerns about accurate parental assessment of prearrest status and differing clinical impact of a given Vineland Adaptive Behavior Scales Second Edition change depending on prearrest status. Simulations found only modest power loss from categorizing or dichotomizing quasicontinuous outcomes because of high expected mortality. The primary outcome selected was survival with 12-month Vineland Adaptive Behavior Scales Second Edition no less than two SD below a reference population mean (70 points), necessarily evaluated only among children with prearrest Vineland Adaptive Behavior Scales Second Edition greater than or equal to 70. Two secondary efficacy outcomes, 12-month survival and quasicontinuous Vineland Adaptive Behavior Scales Second Edition change from prearrest level, will be evaluated among all randomized children, including those with compromised function prearrest.Extensive discussion of optimal efficacy assessment timing, and of the advantages versus drawbacks of incorporating prearrest status and using quasicontinuous versus simpler outcomes, was highly beneficial to the final Therapeutic Hypothermia After Pediatric Cardiac Arrest design. A relatively simple, binary primary outcome evaluated at 12 months was selected, with two secondary outcomes that address the potential disadvantages of primary outcome.
| S-EPMC4396179 | biostudies-literature
Project description:Therapeutic hypothermia is largely used to protect the brain following return of spontaneous circulation (ROSC) after cardiac arrest (CA), but it is unclear whether we should start therapeutic hypothermia earlier, that is, before ROSC.We performed a systematic search of PubMed, EMBASE, CINAHL, the Cochrane Library and Ovid/Medline databases using "arrest" OR "cardiac arrest" OR "heart arrest" AND "hypothermia" OR "therapeutic hypothermia" OR "cooling" as keywords. Only studies using intra-arrest therapeutic hypothermia (IATH) were selected for this review. Three authors independently assessed the validity of included studies and extracted data regarding characteristics of the studied cohort (animal or human) and the main outcomes related to the use of IATH: Mortality, neurological status and cardiac function (particularly, rate of ROSC).A total of 23 animal studies (level of evidence (LOE) 5) and five human studies, including one randomized controlled trial (LOE 1), one retrospective and one prospective controlled study (LOE 3), and two prospective studies without a control group (LOE 4), were identified. IATH improved survival and neurological outcomes when compared to normothermia and/or hypothermia after ROSC. IATH was also associated with improved ROSC rates and with improved cardiac function, including better left ventricular function, and reduced myocardial infarct size, when compared to normothermia.IATH improves survival and neurological outcome when compared to normothermia and/or conventional hypothermia in experimental models of CA. Clinical data on the efficacy of IATH remain limited.
| S-EPMC3681365 | biostudies-literature
Project description:To understand factors affecting nurses' attitudes toward the Therapeutic Hypothermia After Pediatric Cardiac Arrest trials and association with approach/consent rates.Cross-sectional survey of pediatric/cardiac intensive care nurses' perceptions of the trials.Study was conducted at 16 of 38 self-selected study sites.Pediatric and cardiac intensive care nurses.The primary outcome was the proportion of nurses with positive perceptions, as defined by agree or strongly agree with the statement "I am happy to take care of a Therapeutic Hypothermia after Pediatric Cardiac Arrest patient". Associations between perceptions and study approach/consent rates were also explored. Of 2,241 nurses invited, 1,387 (62%) completed the survey and 77% reported positive perceptions of the trials. Nurses, who felt positively about the scientific question, the study team, and training received, were more likely to have positive perceptions of the trials (p < 0.001). Nurses who had previously cared for a research patient had significantly more positive perceptions of Therapeutic Hypothermia After Pediatric Cardiac Arrest compared with those who had not (79% vs 54%; p < 0.001). Of the 754 nurses who cared for a Therapeutic Hypothermia After Pediatric Cardiac Arrest patient, 82% had positive perceptions, despite 86% reporting it required more work. Sixty-nine percent believed that hypothermia reduces brain injury and mortality; sites had lower consent rates when their nurses believed that hypothermia was beneficial. Institution-specific approach rates were positively correlated with nurses' perceptions of institutional support for the trial (r = 0.54; p = 0.04), ICU support (r = 0.61; p = 0.02), and the importance of conducting the trial in children (r = 0.61; p = 0.01).The majority of nurses had positive perceptions of the Therapeutic Hypothermia After Pediatric Cardiac Arrest trials. Institutional, colleague, and study team support and training were contributing factors. Despite increased work, nurses remained enthusiastic demonstrating that studies with intensive bedside nursing procedures are feasible. Institutions whose nurses believed hypothermia was beneficial had lower consent rates, suggesting that educating nurses on study rationale and equipoise may enhance study participation.
| S-EPMC4779735 | biostudies-literature
Project description:AimImproved survival after cardiac arrest has placed greater emphasis on neurologic resuscitation. The purpose of this pilot study was to evaluate the relationship between cerebrovascular autoregulation and neurologic outcomes after pediatric cardiac arrest.MethodsChildren resuscitated from cardiac arrest had autoregulation monitoring during the first 72h after return of circulation with an index derived from near-infrared spectroscopy in a pilot study. The range of mean arterial blood pressure (MAP) with optimal vasoreactivity (MAPOPT) was identified. The area under the curve (AUC) of the time spent with MAP below MAPOPT and MAP deviation below MAPOPT was calculated. Neurologic outcome measures included placement of a new tracheostomy or gastrostomy, death from a primary neurologic etiology (brain death or withdrawal of support for neurologic futility), and change in the Pediatric Cerebral Performance Category score (ΔPCPC).ResultsThirty-six children were monitored. Among children who did not require extracorporeal membrane oxygenation (ECMO), children who received a tracheostomy/gastrostomy had greater AUC during the second 24h after resuscitation than those who did not (P=0.04; n=19). Children without ECMO who died from a neurologic etiology had greater AUC during the first 48h than did those who lived or died from cardiovascular failure (P=0.04; n=19). AUC below MAPOPT was not associated with ΔPCPC when children with or without ECMO were analyzed separately.ConclusionsDeviation from the blood pressure with optimal autoregulatory vasoreactivity may predict poor neurologic outcomes after pediatric cardiac arrest. This experimental autoregulation monitoring technique may help individualize blood pressure management goals after resuscitation.
| S-EPMC4164565 | biostudies-literature
Project description:To determine whether hypothermia within 24 hours of sepsis diagnosis is associated with development of persistent lymphopenia, a feature of sepsis-induced immunosuppression.Retrospective cohort study.A 1,200-bed university-affiliated tertiary care hospital.Adult patients diagnosed with bacteremia and sepsis within 5 days of hospital admission between January 1, 2010, and July 31, 2012.None.Leukocyte counts were recorded during the first 4 days following sepsis diagnosis. Persistent lymphopenia was defined as an absolute lymphocyte count less than 1.2 cells/?L×10(3) present on the fourth day after diagnosis. Of the 445 patients with sepsis included, hypothermia developed in 64 patients (14.4%) (defined as a body temperature<36.0°C) within 24 hours of sepsis diagnosis. Hypothermia was a significant independent predictor of persistent lymphopenia (adjusted odds ratio, 2.70 [95% CI, 1.10, 6.60]; p=0.03) after accounting for age, disease severity, comorbidities, source of bacteremia, and type of organism. Compared with the nonhypothermic patients, hypothermic patients had higher 28-day (50.0% vs 24.9%, p<0.001) and 1-year mortality (60.9% vs 47.0%, p=0.001).Hypothermia is associated with higher mortality and an increased risk of persistent lymphopenia in patients with sepsis, and it may be an early clinical predictor of sepsis-induced immunosuppression.
| S-EPMC4700928 | biostudies-literature
Project description:The determination of coma patient prognosis after cardiac arrest has clinical, ethical and social implications. Neurological examination, imaging and biochemical markers are helpful tools accepted as reliable in predicting recovery. With the advent of therapeutic hypothermia, these data need to be reconfirmed. In this study, we attempted to determine the validity of different markers, which can be used in the detection of patients with poor prognosis under hypothermia.Data from adult patients admitted to our intensive care unit for a hypothermia protocol after cardiac arrest were recorded prospectively to generate a descriptive and analytical study analyzing the relationship between clinical, neurophysiological, imaging and biochemical parameters with 6-month outcomes defined according to the Cerebral Performance Categories scale (good 1-2, poor 3-5). Neuron-specific enolase was collected at 72 hours. Imaging and neurophysiologic exams were carried out in the 24 hours after the rewarming period.Sixty-seven patients were included in the study, of which 12 had good neurological outcomes. Ventricular fibrillation and electroencephalographic theta activity were associated with increased likelihood of survival and improved neurological outcomes. Patients who had more rapid cooling (mean time of 163 versus 312 minutes), hypoxic-ischemic brain injury on magnetic resonance imaging or neuron-specific enolase > 58ng/mL had poor neurological outcomes (p < 0.05).Hypoxic-ischemic brain injury on magnetic resonance imaging and neuron-specific enolase were strong predictors of poor neurological outcomes. Although there is the belief that early achievement of target temperature improves neurological prognoses, in our study, there were increased mortality and worse neurological outcomes with earlier target-temperature achievement.
| S-EPMC4738817 | biostudies-other
Project description:To assess the feasibility, effectiveness, side effects, and adverse events associated with a standardized surface cooling protocol. Induced therapeutic hypothermia after pediatric cardiac arrest is an important intervention.Prospective intervention trial.Urban, tertiary care children's hospital.Twelve pediatric cardiac arrest survivors.Standardized surface cooling protocol.Patients (age: median, 1.5 yrs; interquartile range, 0.5-6.25; cardiopulmonary resuscitation duration: median, 18 mins; interquartile range, 10-45) were cooled by a standard surface cooling protocol for rapid induction and maintenance of goal rectal temperature (T) 32°C-34°C for 24 hrs, with prospectively defined rescue protocols. Side effects and clinical interventions were recorded. Median time to rectal T ?34°C was 1.5 (1, 1.5) hrs from cooling initiation and 6 (5, 6.5) hrs from arrest. T was documented every 30 mins. Maintenance target T 32°C-34°C was attained in 78% (414 of 531) of measurements, overshoot hypothermia <32°C in 15% (81 of 531), and overshoot hyperthermia >34°C in 7% (36 of 531). Mean bias between rectal vs. esophageal T was -0.42°C (95% confidence interval, -0.49 to -0.35), and between rectal and bladder T was 0.16°C (95% confidence interval, 0.11-0.22). Side effects observed included: hypokalemia <3.0 mEq/L in 67% of patients and bradycardia <2% for age in 58%. There were no episodes of bleeding or ventricular tachyarrhythmia that required treatment. Six (50%) of 12 patients survived to discharge.A standard surface cooling protocol achieved rapid induction of hypothermia after pediatric cardiac arrest. During maintenance of hypothermia, 78% of measures were within target T 32°C-34°C. Commonly employed temperature sites (esophageal, rectal, and bladder) were similar. Overshoot hypothermia and associated side effects were common, but there were no serious adverse events attributable to induced therapeutic hypothermia in this case series. Surface cooling protocols to induce and maintain therapeutic hypothermia after pediatric cardiac arrest are potentially feasible.
| S-EPMC3740551 | biostudies-literature
Project description:ObjectiveTo determine whether an 18-month vanguard phase, in the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials, confirmed study feasibility and patient safety, a prerequisite to continued funding by the sponsor.DesignRandomized controlled trial.SettingPediatric intensive care and pediatric cardiac care units in 15 clinical sites in the United States and Canada.PatientsChildren aged 48 hrs to 18 yrs of age, with return of circulation after cardiac arrest.InterventionsTherapeutic hypothermia vs. therapeutic normothermia.Measurements and main resultsThe first 15 of 20 potential sites to obtain Institutional Review Board and subcontract approvals were selected as vanguard sites. Institutional Review Board approvals were obtained 92 days (median, interquartile range 65-114) and subcontracts signed 34 days (interquartile range 20-48) after distribution. Sites screened subjects at 13 days (interquartile range 9-21) and enrolled the first subjects 64 days (interquartile range 13-154) after study launch. The recruitment milestone was reached 4 months ahead of schedule, with no safety concerns identified. Overall recruitment in this ongoing trial remains on target.ConclusionsThe Therapeutic Hypothermia after Pediatric Cardiac Arrest vanguard phase proved beneficial for the investigators and funding agency. Because complex multicenter trials are rarely ready to launch when grant funds are received, the vanguard allowed time to refine the protocol and recruitment approaches. Competition for vanguard positions led to expedient Institutional Review Board and subcontract completion. Early success and sustained momentum contributed to recruitment at or above goals. Financial risks to the sponsor were minimized by tying funding for the full trial to achieving prespecified milestones. A vanguard phase may be a desirable strategy for the successful conduct of other complex clinical trials.
| S-EPMC3540393 | biostudies-literature