Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are ...limited.
In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest.
The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% 48 of 133 patients and 39% 48 of 124 patients, respectively; relative risk, 0.92; 95% confidence interval CI, 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% 81 of 166 patients and 46% 74 of 161 patients, respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups.
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. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).
To describe neurobehavioral outcomes and investigate factors associated with survival and survival with good neurobehavioral outcome 1 year after in-hospital cardiac arrest for children who received ...extracorporeal cardiopulmonary resuscitation.
Secondary analysis of the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital trial.
Thirty-seven PICUs in the United States, Canada, and the United Kingdom.
Children (n = 147) resuscitated with extracorporeal cardiopulmonary resuscitation following in-hospital cardiac arrest.
Neurobehavioral status was assessed using the Vineland Adaptive Behavior Scales, Second Edition, at prearrest baseline and 12 months postarrest. Norms for Vineland Adaptive Behavior Scales, Second Edition, are 100 (mean) ± 15 (SD). Higher scores indicate better functioning. Outcomes included 12-month survival, 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70.
Of 147 children receiving extracorporeal cardiopulmonary resuscitation, 125 (85.0%) had a preexisting cardiac condition, 75 (51.0%) were postcardiac surgery, and 84 (57.1%) were less than 1 year old. Duration of chest compressions was greater than 30 minutes for 114 (77.5%). Sixty-one (41.5%) survived to 12 months, 32 (22.1%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 39 (30.5%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. On multivariable analyses, open-chest cardiac massage was independently associated with greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. Higher minimum postarrest lactate and preexisting gastrointestinal conditions were independently associated with lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70.
About one third of children survived with good neurobehavioral outcome 1 year after receiving extracorporeal cardiopulmonary resuscitation for in-hospital arrest. Open-chest cardiac massage and minimum postarrest lactate were associated with survival with good neurobehavioral outcome at 1 year.
To describe one-year cognitive and neurologic outcomes among extracorporeal cardiopulmonary resuscitation (ECPR) survivors enrolled in the Therapeutic Hypothermia after Paediatric Cardiac Arrest ...In-Hospital (THAPCA-IH) trial; and compare outcomes between survivors who received ECPR, later extracorporeal membrane oxygenation (ECMO), or no ECMO.
All children recruited to THAPCA-IH were comatose post-arrest. Neurobehavioral function was assessed by caregivers using the Vineland Adaptive Behaviour Scales, 2nd edition (VABS-II) at pre-arrest baseline and 12 months post-arrest. Age-appropriate cognitive performance measures (Mullen Scales of Early Learning or Wechsler Abbreviated Scale of Intelligence) and neurologic examinations were obtained 12 months post-arrest. VABS-II and cognitive performance measures were transformed to standard scores (mean = 100, SD = 15) with higher scores representing better performance. Only children with broadly normal pre-arrest function (VABS-II ≥70) were included in this analysis.
One-year follow-up was attained for 127 survivors with pre-arrest VABS-II ≥70. Of these, 57 received ECPR, 14 received ECMO later in their course, and 56 did not receive ECMO. VABS-II assessments were completed at 12 months for 55 (96.5%) ECPR survivors, cognitive testing for 44 (77.2%) and neurologic examination for 47 (82.5%). At 12 months, 39 (70.9%) ECPR survivors had VABS-II scores ≥70. On cognitive testing, 24 (54.6%) had scores ≥70, and on neurologic examination, 28 (59.5%) had no/minimal to mild impairment. Cognitive and neurologic score distributions were similar between ECPR, later ECMO and no ECMO groups.
Many ECPR survivors had favourable outcomes although impairments were common. ECPR survivors had similar outcomes to other survivors who were initially comatose post-arrest.
Approximately 40% of children who have an in-hospital cardiac arrest (IHCA) in the US survive to discharge. We aimed to evaluate the impact of post-cardiac arrest hypotension during targeted ...temperature management following IHCA on survival to discharge.
This is a secondary analysis of the therapeutic hypothermia after pediatric cardiac arrest in-hospital (THAPCA-IH) trial. “Early hypotension” was defined as a systolic blood pressure less than the fifth percentile for age and sex for patients not treated with extracorporeal membrane oxygenation (ECMO) or a mean arterial pressure less than fifth percentile for age and sex for patients treated with ECMO during the first 6 h of temperature intervention. The primary outcome was survival to hospital discharge.
Of 299 children, 142 (47%) patients did not receive ECMO and 157 (53%) received ECMO. Forty-two of 142 (29.6%) non-ECMO patients had systolic hypotension. Twenty-three of 157 (14.7%) ECMO patients had mean arterial hypotension. After controlling for confounders of interest, non-ECMO patients who had early systolic hypotension were less likely to survive to hospital discharge (40.5% vs. 72%; adjusted OR aOR 0.34; 95%CI, 0.12–0.93). There was no difference in survival to discharge by blood pressure groups for children treated with ECMO (30.4% vs. 49.3%; aOR = 0.60; 95%CI, 0.22–1.63).
In this secondary analysis of the THAPCA-IH trial, in patients not treated with ECMO, systolic hypotension within 6 h of temperature intervention was associated with lower odds of discharge survival. Blood pressure groups in patients treated with ECMO were not associated with survival to discharge.
Multiple sclerosis and other demyelinating diseases in the pediatric population have received an increasing level of attention by clinicians and researchers. The low incidence of these diseases in ...children creates a need for the involvement of multiple clinical centers in research efforts. The Network of Pediatric Multiple Sclerosis Centers was created initially in 2006 to improve the diagnosis and care of children with demyelinating diseases. In 2010, the Network shifted its focus to multicenter research while continuing to advance the care of patients. The Network has obtained support from the National Multiple Sclerosis Society, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. The Network will continue to serve as a platform for conducting impactful research in pediatric demyelinating diseases of the central nervous system. This article provides a description of the history and development, organization, mission, research priorities, current studies, and future plans of the Network.
To 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.
Randomized controlled trial.
Pediatric intensive care and pediatric cardiac care units in 15 clinical sites in the United States and Canada.
Children aged 48 hrs to 18 yrs of age, with return of circulation after cardiac arrest.
Therapeutic hypothermia vs. therapeutic normothermia.
The 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.
The 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.
To describe the rationale, timeline, study design, and protocol overview of the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials.
Multicenter randomized controlled trials.
Pediatric ...intensive care and cardiac ICUs in the United States and Canada.
Children from 48 hours to 18 years old, who have return of circulation after cardiac arrest, who meet trial eligibility criteria, and whose guardians provide written consent.
Therapeutic hypothermia or therapeutic normothermia.
From concept inception in 2002 until trial initiation in 2009, 7 years were required to plan and operationalize the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Two National Institute of Child Health and Human Development clinical trial planning grants (R21 and R34) supported feasibility assessment and protocol development. Two clinical research networks, Pediatric Emergency Care Applied Research Network and Collaborative Pediatric Critical Care Research Network, provided infrastructure resources. Two National Heart Lung Blood Institute U01 awards provided funding to conduct separate trials of in-hospital and out-of-hospital cardiac arrest. A pilot vanguard phase that included half the clinical sites began on March 9, 2009, and this was followed by full trial funding through 2015.
Over a decade will have been required to plan, design, operationalize, and conduct the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Details described in this report, such as participation of clinical research networks and clinical trial planning grants utilization, may be of utility for individuals who are planning investigator-initiated, federally supported clinical trials.
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.
Childhood obesity has more than tripled in the past 30 years. The prevalence of overweight and obese children has also increased in the pediatric cancer setting, causing substantial concern over ...proper chemotherapeutic dosing in this population. The purpose of this study was to determine if children with an increased body mass index (BMI) have an alteration in busulfan pharmacokinetics during hematopoietic stem cell transplant (HSCT) conditioning. We retrospectively reviewed data on busulfan pharmacokinetics (PK) on HSCT subjects (subjects were part of a prospective study previously reported by our group at Children’s Memorial Hospital) to determine appropriateness of dosing. Subjects were divided into appropriate BMI categories (<25th percentile, 25th-85th percentile, ≥85th percentile) and busulfan PK dosing was analyzed (test dose, regimen dose, area under the curve AUC, and clearance). The dosing based on PK test dose data of children with BMI ≥85% was compared against the package insert dosing recommendations of using adjusted ideal body weight (AIBW) in obese patients to determine which dosing schema was most accurate. Children with high BMIs had higher AUCs when dosing on actual weight then their normal or low BMI counterparts. This indicates that children with a high BMI require less drug (2.9 mg/kg using actual body weight) to achieve the same AUC as children with normal BMI (4.0 mg/kg) or low BMI (3.6 mg/kg). Using the recommended AIBW dosing schema, 53% of the patients with high BMIs would have had regimen dose AUCs ≥20% over/under the target; whereas with the PK test dose method, only 16% of the patients with high BMIs had regimen dose AUCs ≥20% over/under the target. PK testing continues to be the gold standard for busulfan dosing in children. Particular vigilance should be paid to PK monitoring in high BMI categories because of the potential risk of imprecise dosing when using the AIBW schema.
Pentostatin, one of the purine nucleoside analogues, is known to decrease lymphocyte number and function. We are currently investigating pentostatin for refractory chronic graft-vs.-host disease ...(cGVHD). Within an adult/pediatric phase II study, 16 patients under age 20 are evaluable. All children presented here failed at least two immunosuppressive regimens (including steroids at a dose equivalent to at least 1 mg/kg/day prednisone for one month) before enrollment. The treatment protocol consists of adding pentostatin 4 mg/m2/dose IV every 2 weeks for 6 months. Patients with improving disease are permitted to continue pentostatin therapy at a 3 to 4 week interval. To reduce the risk of infection, steroids are tapered early in all patients. At the end of 3 months, patients with stable or improving cGVHD are weaned off their other medications but maintained on calcineurin inhibitor. Pentostatin is stopped at 6 months if complete response (CR) is achieved or continued if partial response (PR). Patients are followed for improvement in the skin, mouth, and liver. The severity of GVHD is scored for each system on a scale from 0 to 4. Major response is defined as an improvement in symptom score of 2 points or more without worsening in any system. Minor response is a 1 point improvement. Mixed response is improvement in 1 system but worsening in another. Patients have received a median of 15 doses (range 5–30). Median age of the pediatric cohort is 14.5 years (range 5 to 19). Diagnoses include AML/MDS (6), ALL (5), hemoglobinopathy (2), T-cell leukemia (1), aplastic anemia (1), and lymphohistiocytosis (1). Ten had HLA-identical sibling donors (7 BM/3 PBSC) and 6 had HLA-matched unrelated donors (4 BM/2 PBSC). Median time since transplant to start of Pentostatin is 20.5 months (range 8–72). Most patients were on calcineurin inhibitor, eleven on prednisone, seven on MMF, one on rapamycin, and one was receiving ECP at entry on the study. Five patients attained a CR, eight a major response, and three patients have progressed. The overall response rate is 81%. Since some patients had multiple organ involvement, response rate by organ (PR or CR for individual organ) is below. Therapy has been well-tolerated. There has been only one toxicity likely due to pentostatin (creatinine elevation to 4.8 in a patient with a single kidney), and this required the patient to withdraw from the study. There have been no severe infections. There have been 2 deaths, both cGVHD-related, in patients who did not respond. Of the 11 patients on prednisone, 8 were weaned completely off steroids or to <1/4 of original dose at the end of the course of pentostatin. The results suggest that pentostatin has activity in the treatment of cGVHD and may be especially beneficial in children and adolescents. These data form the basis for an ongoing phase II, pediatric-only study through the Pediatric Blood and Marrow Transplant Consortium.
Response by specific organs involved
SystemPartial ResponseComplete ResponseProgressionTotalSkin73212--Mainly lichenoid--1--1--0--2--Mainly scleroderma--5--2--1--8--Mainly fasciitis--1--0--1--2Oral5117Liver0314
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