Kimberly Statler Bennett

Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children

BACKGROUND Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS We conducted this trial of two targeted temperature interventions at 38 childrens hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days 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 Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS In comatose children who survived out-of-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. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children

Background 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. Methods In a trial conducted at 37 childrens 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. Results 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. Conclusions 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.)

Early oxygenation and ventilation measurements after pediatric cardiac arrest: lack of association with outcome.

Objectives:To explore oxygenation and ventilation status early after cardiac arrest in infants and children. We hypothesize that hyperoxia is common and associated with worse outcome after pediatric cardiac arrest. Design:Retrospective cohort study. Setting:Fifteen hospitals within the Pediatric Emergency Care Applied Research Network. Patients:Children who suffered a cardiac arrest event and survived for at least 6 hours after return of circulation. Interventions:None. Measurements and Main Results:Analysis of 195 events revealed that abnormalities in oxygenation and ventilation are common during the initial 6 hours after pediatric cardiac arrest. Hyperoxia was frequent, affecting 54% of patients. Normoxia was documented in 34% and hypoxia in 22% of patients. These percentages account for a 10% overlap of patients who had both hyperoxia and hypoxia. Ventilation status was more evenly distributed with hyperventilation observed in 38%, normoventilation in 29%, and hypoventilation in 46%, with a 13% overlap of patients who had both hyperventilation and hypoventilation. Derangements in both oxygenation and ventilation were common early after cardiac arrest such that both normoxia and normocarbia were documented in only 25 patients (13%). Neither oxygenation nor ventilation status was associated with outcome. After controlling for potential confounders, arrest location and rhythm were significantly associated with worse outcome; however, hyperoxia was not (odds ratio for good outcome, 1.02 [0.46, 2.84]; p = 0.96). Conclusions:Despite recent resuscitation guidelines that advocate maintenance of normoxia and normoventilation after pediatric cardiac arrest, this is uncommonly achieved in practice. Although we did not demonstrate an association between hyperoxia and worse outcome, the small proportion of patients kept within normal ranges limited our power. Preclinical data suggesting potential harm with hyperoxia remain compelling, and further investigation, including prospective, large studies involving robust recording of physiological derangements, is necessary to further advance our understanding of this important topic.

High-dose barbiturates for refractory intracranial hypertension in children with severe traumatic brain injury

Objectives: To evaluate high-dose barbiturates as a second-tier therapy for pediatric refractory intracranial hypertension complicating severe traumatic brain injury. Design: This is a retrospective cohort study of children with refractory intracranial hypertension treated with high-dose barbiturates. Setting: A single center level I pediatric trauma from 2001 to 2010. Patients: Thirty-six children with refractory intracranial hypertension defined as intracranial pressure greater than 20 mm Hg despite standard management treated with high-dose barbiturates after severe traumatic brain injury. Interventions: High-dose barbiturates were administered for refractory intracranial hypertension for a minimum duration of 6 hours and monitored by continuous electroencephalography. Measurements and Main Results: Exposure was control of refractory intracranial hypertension defined as > 20 mm Hg within 6 hours after starting barbiturates. Pediatric cerebral performance category scores at hospital discharge and at 3 months (or longer) follow-up were the primary outcomes. Ten of 36 patients (28%) had control of refractory intracranial hypertension. Neither demographic nor injury characteristics were associated with refractory intracranial hypertension control. Children who responded received barbiturates significantly later after injury (76 vs. 29 median hours). Overall, 14 children died, 13 without control of intracranial pressure. Survival was more common in those who responded compared with those who did not respond to high-dose barbiturates, although this did not reach statistical significance (relative risk of death 0.2; 95% confidence interval; [0.03–1.3]). Of the 22 survivors, 19 had an acceptable survival (pediatric cerebral performance category less than 3) at 3 months or longer after injury; however, only three returned to normal function. Among survivors, control of refractory intracranial hypertension was associated with significantly better pediatric cerebral performance category scores and over two-fold likelihood of acceptable long-term outcome (relative risk 2.3; 95% confidence interval [1.4–4.0]) compared with uncontrolled refractory intracranial hypertension despite high-dose barbiturates. Conclusions: Addition of high-dose barbiturates achieved control of refractory intracranial hypertension in almost 30% of treated children. Control of refractory intracranial hypertension was associated with increased likelihood of an acceptable long-term outcome.

Use of Rotterdam CT Scores for Mortality Risk Stratification in Children with Traumatic Brain Injury

Objectives: The Rotterdam CT score refined features of the Marshall score and was designed to categorize traumatic brain injury type and severity in adults. The objective of this study was to determine whether the Rotterdam CT score can be used for mortality risk stratification after pediatric traumatic brain injury. Design: In children with moderate to severe traumatic brain injury, a comparison of observed versus predicted mortality was calculated using published model probabilities of adult mortality. Development and validation of a new pediatric mortality model using randomly selected prediction and validation samples from our cohort. Setting: A single level 1 pediatric trauma center. Subjects: Six hundred thirty-two children with moderate or severe traumatic brain injury. Interventions: None. Measurements and Main Results: Sixteen percent of the patients (101 of 632) died prior to hospital discharge. The predicted mortality based on Rotterdam score for adults with moderate or severe traumatic brain injury discriminated pediatric observed mortality well (area under the curve = 0.85; 95% CI, 0.80–0.89) but had poor calibration, overestimating or underestimating mortality for children in several Rotterdam categories. A predictive model based on children with moderate or severe traumatic brain injury from the single center discriminated mortality well (area under the curve, 0.80; 95% CI, 0.68–0.91) and showed good calibration and overall fit. Conclusions: Children with traumatic brain injury have better survival than adults in Rotterdam CT score categories representing less severe injuries but worse survival than adults in higher score categories. A novel, validated pediatric mortality model based on the Rotterdam score is accurate in children with moderate or severe traumatic brain injury and can be used for risk stratification.

Alpha II Spectrin breakdown products in immature Sprague Dawley rat hippocampus and cortex after traumatic brain injury

After traumatic brain injury (TBI), proteolysis of Alpha II Spectrin by Calpain 1 produces 145 Spectrin breakdown products (SBDPs) while proteolysis by Caspase 3 produces 120 SBDPs. 145 and 120 SBDP immunoblotting reflects the relative importance of caspase-dependent apoptosis or calpain-dependent excitotoxic/necrotoxic cell death in brain regions over time. In the adult rat, controlled cortical impact (CCI) increased 120 SBDPs in the first hours, lasting a few days, and increased 145 SBDPs within the first few days lasting up to 14 days after injury. Little is known about SBDPs in the immature brain after TBI. Since development affects susceptibility to apoptosis after TBI, we hypothesized that CCI would increase 145 and 120 SBDPs in the immature rat brain relative to SHAM during the first 3 and 5 days, respectively. SBDPs were measured in hippocampi and cortices at post injury days (PID) 1, 2, 3, 5, 7 and 14 after CCI or SHAM surgery in the 17 day old Sprague Dawley rat. 145 SBDPs increased in both brain tissues ipsilateral to injury during the first 3 days, while changes in contralateral tissues were limited to PID2 cortex. 145 SBDPs elevations were more marked and enduring in hippocampus than in cortex. Against expectations, 120 SBDPs only increased in PID1 hippocampus and PID2 cortex. 145 SBDPs elevations occurred early after CCI, similar to previous studies in the adult rat, but resolved more quickly. The minimal changes in 120 SBDPs suggest that calpain-dependent, but not caspase-dependent, cell death predominates in the 17 day old rat after CCI.

Association of early postresuscitation hypotension with survival to discharge after targeted temperature management for pediatric out-of-hospital cardiac arrest secondary analysis of a randomized clinical trial

Importance Out-of-hospital cardiac arrest (OHCA) occurs in more than 6000 children each year in the United States, with survival rates of less than 10% and severe neurologic morbidity in many survivors. Post–cardiac arrest hypotension can occur, but its frequency and association with survival have not been well described during targeted temperature management. Objective To determine whether hypotension is associated with survival to discharge in children and adolescents after resuscitation from OHCA. Design, Setting, and Participants This post hoc secondary analysis of the Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) trial included 292 pediatric patients older than 48 hours and younger than 18 years treated in 36 pediatric intensive care units from September 1, 2009, through December 31, 2012. Participants underwent therapeutic hypothermia (33.0°C) vs therapeutic normothermia (36.8°C) for 48 hours. All participants had hourly systolic blood pressure measurements documented during the initial 6 hours of temperature intervention. Hourly blood pressures beginning at the time of temperature intervention (time 0) were normalized for age, sex, and height. Early hypotension was defined as a systolic blood pressure less than the fifth percentile during the first 6 hours after temperature intervention. With use of forward stepwise logistic regression, covariates of interest (age, sex, initial cardiac rhythm, any preexisting condition, estimated duration of cardiopulmonary resuscitation [CPR], primary cause of cardiac arrest, temperature intervention group, night or weekend cardiac arrest, witnessed status, and bystander CPR) were evaluated in the final model. Data were analyzed from February 5, 2016, through June 13, 2017. Exposures Hypotension. Main Outcomes and Measure Survival to hospital discharge. Results Of 292 children (194 boys [66.4%] and 98 girls [33.6%]; median age, 23.0 months [interquartile range, 5.0-105.0 months]), 78 (26.7%) had at least 1 episode of early hypotension. No difference was observed between the therapeutic hypothermia and therapeutic normothermia groups in the prevalence of hypotension during induction and maintenance (73 of 153 [47.7%] vs 72 of 139 [51.8%]; P = .50) or rewarming (35 of 118 [29.7%] vs 19 of 95 [20.0%]; P = .10) during the first 72 hours. Participants who had early hypotension were less likely to survive to hospital discharge (20 of 78 [25.6%] vs 93 of 214 [43.5%]; adjusted odds ratio, 0.39; 95% CI, 0.20-0.74). Conclusions and Relevance In this post hoc secondary analysis of the THAPCA trial, 26.7% of participants had hypotension within 6 hours after temperature intervention. Early post–cardiac arrest hypotension was associated with lower odds of discharge survival, even after adjusting for covariates of interest.

Adherence to the guidelines for management of severe pediatric traumatic brain injury: enough evidence to support benefit?

2308 www.ccmjournal.org October 2014 • Volume 42 • Number 10 13. Cifra CL, Bembea MM, Fackler JC, et al: The Morbidity and Mortality Conference in PICUs in the United States: A National Survey. Crit Care Med 2014; 42:2252–2257 14. Odetola FO, Clark SJ, Freed GL, et al: A national survey of pediatric critical care resources in the United States. Pediatrics 2005; 115:e382–e386 15. Antonacci AC, Lam S, Lavarias V, et al: A report card system using error profile analysis and concurrent morbidity and mortality review: Surgical outcome analysis, part II. J Surg Res 2009; 153: 95–104 16. Epstein NE: Are morbidity and mortality conferences DNR (Do Not Resuscitate) or can they be revived? Surg Neurol Int 2012; 3:114

Drugs in pediatric ischemic stroke.

Traditionally, drug therapy for pediatric ischemic stroke has been extrapolated from adult guidelines and studies. This approach is not optimal due to important differences between adult and pediatric stroke (e.g. etiologies, maturation changes in hemostasis). Research in pediatric stroke is increasing, and pediatric specific management guidelines have recently become available. This manuscript summarizes available drug therapy recommendations for pediatric ischemic stroke. Both acute management and secondary stroke prevention are discussed, including antiplatelet, anticoagulant, and thrombolytic drugs. When relevant, recommendations from adult ischemic stroke guidelines and data from pediatric stroke studies are incorporated.

Temporal response profiles of serum ubiquitin C-terminal hydrolase-L1 and the 145-kDa alpha II-spectrin breakdown product after severe traumatic brain injury in children

OBJECTIVE Traumatic brain injury (TBI) is the leading cause of acquired disability among children. Brain injury biomarkers may serve as useful diagnostic and prognostic indicators for TBI. Levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and the 145-kDa alpha II-spectrin breakdown product (SBDP-145) correlate with outcome in adults after severe TBI. The authors conducted a pilot study of these biomarkers in children after severe TBI to inform future research exploring their utility in this population. METHODS The levels of UCH-L1 and SBDP-145 were measured in serum, and UCH-L1 in CSF from pediatric patients after severe TBI over 5 days after injury. Both biomarkers were also measured in age-matched control serum and CSF. RESULTS Adequate numbers of samples were obtained in serum, but not CSF, to assess biomarker temporal response profiles. Using patients with samples from all time points, UCH-L1 levels increased rapidly and transiently, peaking at 12 hours after injury. SBDP-145 levels showed a more gradual and sustained response, peaking at 48 hours. The median serum UCH-L1 concentration was greater in patients with TBI than in controls (median [IQR] = 361 [187, 1330] vs 147 [50, 241] pg/ml, respectively; p < 0.001). Receiver operating characteristic (ROC) analysis revealed an AUC of 0.77. Similarly, serum SBDP-145 was greater in children with TBI than in controls (median [IQR] = 172 [124, 257] vs 69 [40, 99] pg/ml, respectively; p < 0.001), with an ROC AUC of 0.85. When only time points of peak levels were used for ROC analysis, the discriminability of each serum biomarker increased (AUC for UCH-L1 at 12 hours = 1.0 and for SBDP-145 at 48 hours = 0.91). Serum and CSF UCH-L1 levels correlated well in patients with TBI (r = 0.70, p < 0.001). CONCLUSIONS Findings from this exploratory study reveal robust increases of UCH-L1 and SBDP-145 in serum and UCH-L1 in CSF obtained from children after severe TBI. In addition, important temporal profile differences were found between these biomarkers that can help guide optimal time point selection for future investigations of their potential to characterize injury or predict outcomes after pediatric TBI.