Todd J. Kilbaugh

Cyclosporin A Preserves Mitochondrial Function after Traumatic Brain Injury in the Immature Rat and Piglet

Cyclosporin A (CsA) has been shown to be neuroprotective in mature animal models of traumatic brain injury (TBI), but its effects on immature animal models of TBI are unknown. In mature animal models, CsA inhibits the opening of the mitochondrial permeability transition pore (MPTP), thereby maintaining mitochondrial homeostasis following injury by inhibiting calcium influx and preserving mitochondrial membrane potential. The aim of the present study was to evaluate CsAs ability to preserve mitochondrial bioenergetic function following TBI (as measured by mitochondrial respiration and cerebral microdialysis), in two immature models (focal and diffuse), and in two different species (rat and piglet). Three groups were studied: injured+CsA, injured+saline vehicle, and uninjured shams. In addition, we evaluated CsAs effects on cerebral hemodynamics as measured by a novel thermal diffusion probe. The results demonstrate that post-injury administration of CsA ameliorates mitochondrial dysfunction, preserves cerebral blood flow (CBF), and limits neuropathology in immature animals 24 h post-TBI. Mitochondria were isolated 24 h after controlled cortical impact (CCI) in rats and rapid non-impact rotational injury (RNR) in piglets, and CsA ameliorated cerebral bioenergetic crisis with preservation of the respiratory control ratio (RCR) to sham levels. Results were more dramatic in RNR piglets than in CCI rats. In piglets, CsA also preserved lactate pyruvate ratios (LPR), as measured by cerebral microdialysis and CBF at sham levels 24 h after injury, in contrast to the significant alterations seen in injured piglets compared to shams (p<0.01). The administration of CsA to piglets following RNR promoted a 42% decrease in injured brain volume (p<0.01). We conclude that CsA exhibits significant neuroprotective activity in immature models of focal and diffuse TBI, and has exciting translational potential as a therapeutic agent for neuroprotection in children.

Differences in medical therapy goals for children with severe traumatic brain injury-an international study.

Objectives: To describe the differences in goals for their usual practice for various medical therapies from a number of international centers for children with severe traumatic brain injury. Design: A survey of the goals from representatives of the international centers. Setting: Thirty-two pediatric traumatic brain injury centers in the United States, United Kingdom, France, and Spain. Patients: None. Interventions: None. Measurements and Main Results: A survey instrument was developed that required free-form responses from the centers regarding their usual practice goals for topics of intracranial hypertension therapies, hypoxia/ischemia prevention and detection, and metabolic support. Cerebrospinal fluid diversion strategies varied both across centers and within centers, with roughly equal proportion of centers adopting a strategy of continuous cerebrospinal fluid diversion and a strategy of no cerebrospinal fluid diversion. Use of mannitol and hypertonic saline for hyperosmolar therapies was widespread among centers (90.1% and 96.9%, respectively). Of centers using hypertonic saline, 3% saline preparations were the most common but many other concentrations were in common use. Routine hyperventilation was not reported as a standard goal and 31.3% of centers currently use PbO2 monitoring for cerebral hypoxia. The time to start nutritional support and glucose administration varied widely, with nutritional support beginning before 96 hours and glucose administration being started earlier in most centers. Conclusions: There were marked differences in medical goals for children with severe traumatic brain injury across our international consortium, and these differences seemed to be greatest in areas with the weakest evidence in the literature. Future studies that determine the superiority of the various medical therapies outlined within our survey would be a significant advance for the pediatric neurotrauma field and may lead to new standards of care and improved study designs for clinical trials.

Extracorporeal Cardiopulmonary Resuscitation (E-CPR) During Pediatric In-Hospital Cardiopulmonary Arrest Is Associated With Improved Survival to Discharge: A Report from the American Heart Association's Get With The Guidelines-Resuscitation (GWTG-R) Registry.

Background— Although extracorporeal cardiopulmonary resuscitation (E-CPR) can result in survival after failed conventional CPR (C-CPR), no large, systematic comparison of pediatric E-CPR and continued C-CPR has been reported. Methods and Results— Consecutive patients <18 years old with CPR events ≥10 minutes in duration reported to the Get With the Guidelines–Resuscitation registry between January 2000 and December 2011 were identified. Hospitals were grouped by teaching status and location. Primary outcome was survival to discharge. Regression modeling was performed, conditioning on hospital groups. A secondary analysis was performed with the use of propensity score matching. Of 3756 evaluable patients, 591 (16%) received E-CPR and 3165 (84%) received C-CPR only. Survival to hospital discharge and survival with favorable neurological outcome (Pediatric Cerebral Performance Category score of 1–3 or unchanged from admission) were greater for E-CPR (40% [237 of 591] and 27% [133 of 496]) versus C-CPR patients (27% [862 of 3165] and 18% [512 of 2840]). Odds ratios (ORs) for survival to hospital discharge and survival with favorable neurological outcome were greater for E-CPR versus C-CPR. After adjustment for covariates, patients receiving E-CPR had higher odds of survival to discharge (OR, 2.80; 95% confidence interval, 2.13–3.69; P<0.001) and survival with favorable neurological outcome (OR, 2.64; 95% confidence interval, 1.91–3.64; P<0.001) than patients who received C-CPR. This association persisted when analyzed by propensity score–matched cohorts (OR, 1.70; 95% confidence interval, 1.33–2.18; P<0.001; and OR, 1.78; 95% confidence interval, 1.31–2.41; P<0.001, respectively]. Conclusion— For children with in-hospital CPR of ≥10 minutes duration, E-CPR was associated with improved survival to hospital discharge and survival with favorable neurological outcome compared with C-CPR.

Nonconvulsive Electrographic Seizures are Common in Children With Abusive Head Trauma

Objective: To determine the prevalence of nonconvulsive seizures in children with abusive head trauma. Design: Retrospective study of children with abusive head trauma undergoing clinically indicated continuous electroencephalographic monitoring. Setting: PICU of a tertiary care hospital. Subjects: Children less than or equal to 2 years old with evidence of abusive head trauma determined by neuroimaging, physical examination, and determination of abuse by the Child Protection Team. Interventions: None. Measurements and Main Results: Thirty-two children with abusive head trauma were identified with a median age of 4 months (interquartile range 3, 5.5 months). Twenty-one of 32 children (66%) underwent electroencephalographic monitoring. Those monitored were more likely to have a lower admission Glasgow Coma Scale (8 vs 15, p = 0.05) and be intubated (16 vs 2, p = 0.002). Electrographic seizures occurred in 12 of 21 children (57%) and constituted electrographic status epilepticus in 8 of 12 children (67%). Electrographic seizures were entirely nonconvulsive in 8 of 12 children (67%). Electroencephalographic background category (discontinuous and slow-disorganized) (p = 0.02) and neuroimaging evidence of ischemia were associated with the presence of electrographic seizures (p = 0.05). Subjects who had electrographic seizures were no more likely to have clinical seizures at admission (67% electrographic seizures vs 33% none, p = 0.6), parenchymal imaging abnormalities (61% electrographic seizures vs 39% none, p = 0.40), or extra-axial imaging abnormalities (56% electrographic seizures vs 44% none, p = 0.72). Four of 21 (19%) children died prior to discharge; none had electrographic seizures, but all had attenuated-featureless electroencephalographic backgrounds. Follow-up outcome data were available for 16 of 17 survivors at a median duration of 9.5 months following PICU admission, and the presence of electrographic seizures or electrographic status epilepticus was not associated with the Glasgow Outcome Scale score (p = 0.10). Conclusions: Electrographic seizures and electrographic status epilepticus are common in children with abusive head trauma. Most seizures have no clinical correlate. Further study is needed to determine whether seizure identification and management improves outcome.

Outcome of pediatric acute myeloid leukemia patients receiving intensive care in the United States.

Objective: Children with acute myeloid leukemia are at risk for sepsis and organ failure. Outcomes associated with intensive care support have not been studied in a large pediatric acute myeloid leukemia population. Our objective was to determine hospital mortality of pediatric acute myeloid leukemia patients requiring intensive care. Design: Retrospective cohort study of children hospitalized between 1999 and 2010. Use of intensive care was defined by utilization of specific procedures and resources. The primary endpoint was hospital mortality. Setting: Forty-three children’s hospitals contributing data to the Pediatric Health Information System database. Patients: Patients who are newly diagnosed with acute myeloid leukemia and who are 28 days through 18 years old (n = 1,673) hospitalized any time from initial diagnosis through 9 months following diagnosis or until stem cell transplant. A reference cohort of all nononcology pediatric admissions using the same intensive care resources in the same time period (n = 242,192 admissions) was also studied. Interventions: None. Measurements and Main Results: One-third of pediatric patients with acute myeloid leukemia (553 of 1,673) required intensive care during a hospitalization within 9 months of diagnosis. Among intensive care admissions, mortality was higher in the acute myeloid leukemia cohort compared with the nononcology cohort (18.6% vs 6.5%; odds ratio, 3.23; 95% CI, 2.64–3.94). However, when sepsis was present, mortality was not significantly different between cohorts (21.9% vs 19.5%; odds ratio, 1.17; 95% CI, 0.89–1.53). Mortality was consistently higher for each type of organ failure in the acute myeloid leukemia cohort versus the nononcology cohort; however, mortality did not exceed 40% unless there were four or more organ failures in the admission. Mortality for admissions requiring intensive care decreased over time for both cohorts (23.7% in 1999–2003 vs 16.4% in 2004–2010 in the acute myeloid leukemia cohort, p = 0.0367; and 7.5% in 1999–2003 vs 6.5% in 2004–2010 in the nononcology cohort, p < 0.0001). Conclusions: Pediatric patients with acute myeloid leukemia frequently required intensive care resources, with mortality rates substantially lower than previously reported. Mortality also decreased over the time studied. Pediatric acute myeloid leukemia patients with sepsis who required intensive care had a mortality comparable to children without oncologic diagnoses; however, overall mortality and mortality for each category of organ failure studied was higher for the acute myeloid leukemia cohort compared with the nononcology cohort.

Official american thoracic society technical standards: Flexible airway endoscopy in children

BACKGROUND Flexible airway endoscopy (FAE) is an accepted and frequently performed procedure in the evaluation of children with known or suspected airway and lung parenchymal disorders. However, published technical standards on how to perform FAE in children are lacking. METHODS The American Thoracic Society (ATS) approved the formation of a multidisciplinary committee to delineate technical standards for performing FAE in children. The committee completed a pragmatic synthesis of the evidence and used the evidence synthesis to answer clinically relevant questions. RESULTS There is a paucity of randomized controlled trials in pediatric FAE. The committee developed recommendations based predominantly on the collective clinical experience of our committee members highlighting the importance of FAE-specific airway management techniques and anesthesia, establishing suggested competencies for the bronchoscopist in training, and defining areas deserving further investigation. CONCLUSIONS These ATS-sponsored technical standards describe the equipment, personnel, competencies, and special procedures associated with FAE in children.

The anesthetic effects on vasopressor modulation of cerebral blood flow in an immature swine model.

BACKGROUND:The effect of various sedatives and anesthetics on vasopressor modulation of cerebral blood flow (CBF) in children is unclear. In adults, isoflurane has been described to decrease CBF to a lesser extent than fentanyl and midazolam. Most large-animal models of neurocritical care use inhaled anesthetics for anesthesia. Investigations involving modulations of CBF would have improved translatability within a model that more closely approximates the current practice in the pediatric intensive care unit. METHODS:Fifteen 4-week-old piglets were given 1 of 2 anesthetic protocols: total IV anesthesia (TIVA) (midazolam 1 mg/kg/h and fentanyl 100 &mgr;g/kg/h, n = 8) or ISO (isoflurane 1.5%–2% and fentanyl 100 &mgr;g/kg/h, n = 7). Mean arterial blood pressure, intracranial pressure (ICP), CBF, and brain tissue oxygen tension were measured continuously as piglets were exposed to escalating doses of arginine vasopressin, norepinephrine (NE), and phenylephrine (PE). RESULTS:Baseline CBF was similar in the 2 groups (ISO 38 ± 10 vs TIVA 35 ± 26 mL/100 g/min) despite lower baseline cerebral perfusion pressure in the ISO group (45 ± 11 vs 71 ± 11 mm Hg; P < 0.0005). Piglets in the ISO group displayed increases in ICP with PE and NE (11 ± 4 vs 16 ± 4 mm Hg and 11 ± 8 vs 18 ± 5 mm Hg; P < 0.05), but in the TIVA group, only exposure to PE resulted in increases in ICP when comparing maximal dose values with baseline data (11 ± 4 vs 15 ± 5 mm Hg; P < 0.05). Normalized CBF displayed statistically significant increases regarding anesthetic group and vasopressor dose when piglets were exposed to NE and PE (P < 0.05), suggesting an impairment of autoregulation within ISO, but not TIVA. CONCLUSION:The vasopressor effect on CBF was limited when using a narcotic-benzodiazepine–based anesthetic protocol compared with volatile anesthetics, consistent with a preservation of autoregulation. Selection of anesthetic drugs is critical to investigate mechanisms of cerebrovascular hemodynamics, and in translating critical care investigations between the laboratory and bedside.

Persistently Altered Brain Mitochondrial Bioenergetics After Apparently Successful Resuscitation From Cardiac Arrest.

Background Although advances in cardiopulmonary resuscitation have improved survival from cardiac arrest (CA), neurologic injury persists and impaired mitochondrial bioenergetics may be critical for targeted neuroresuscitation. The authors sought to determine if excellent cardiopulmonary resuscitation and postresuscitation care and good traditional survival rates result in persistently disordered cerebral mitochondrial bioenergetics in a porcine pediatric model of asphyxia-associated ventricular fibrillation CA. Methods and Results After 7 minutes of asphyxia, followed by ventricular fibrillation, 5 female 1-month-old swine (4 sham) received blood pressure–targeted care: titration of compression depth to systolic blood pressure of 90 mm Hg and vasopressor administration to a coronary perfusion pressure >20 mm Hg. All animals received protocol-based vasopressor support after return of spontaneous circulation for 4 hours before they were killed. The primary outcome was integrated mitochondrial electron transport system (ETS) function. CA animals displayed significantly decreased maximal, coupled oxidative phosphorylating respiration (OXPHOSCI+CII) in cortex (P<0.02) and hippocampus (P<0.02), as well as decreased phosphorylation and coupling efficiency (cortex, P<0.05; hippocampus, P<0.05). Complex I– and complex II–driven respiration were both significantly decreased after CA (cortex: OXPHOSCI P<0.01, ETSCII P<0.05; hippocampus: OXPHOSCI P<0.03, ETSCII P<0.01). In the hippocampus, there was a significant decrease in maximal uncoupled, nonphosphorylating respiration (ETSCI+CII), as well as a 30% reduction in citrate synthase activity (P<0.04). Conclusions Mitochondria in both the cortex and hippocampus displayed significant alterations in respiratory function after CA despite excellent cardiopulmonary resuscitation and postresuscitation care in asphyxia-associated ventricular fibrillation CA. Analysis of integrated ETS function identifies mitochondrial bioenergetic failure as a target for goal-directed neuroresuscitation after CA. IACUC Protocol: IAC 13-001023.

Influences of developmental age on the resolution of diffuse traumatic intracranial hemorrhage and axonal injury

This study investigated the age-dependent injury response of diffuse traumatic axonal injury (TAI) and regional subdural and subarachnoid intracranial hemorrhage (ICH) in two pediatric age groups using a porcine head injury model. Fifty-five 5-day-old and 40 four-week-old piglets-which developmentally correspond to infants and toddlers, respectively-underwent either a sham injury or a single rapid non-impact rotational injury in the sagittal plane and were grouped by post-TBI survival time (sham, 3-8 h, one day, 3-4 days, and 5-6 days). Both age groups exhibited similar initial levels of ICH and a significant reduction of ICH over time (p<0.0001). However, ICH took longer to resolve in the five-day-old age group. At 5-6 days post-injury, ICH in the cerebrum had returned to sham levels in the four-week-old piglets, while the five-day-olds still had significantly elevated cerebral ICH (p=0.012). Both ages also exhibited similar resolution of axonal injury with a peak in TAI at one day post-injury (p<0.03) and significantly elevated levels even at 5-6 days after the injury (p<0.008), which suggests a window of vulnerability to a second insult at one day post-injury that may extend for a prolonged period of time. However, five-day-old piglets had significantly more TAI than four-week-olds overall (p=0.016), which presents some evidence for an increased vulnerability to brain injury in this age group. These results provide insight into an optimal window for clinical intervention, the period of increased susceptibility to a second injury, and an age dependency in brain injury tolerance within the pediatric population.

Blood Pressure- and Coronary Perfusion Pressure-Targeted Cardiopulmonary Resuscitation Improves 24-Hour Survival From Ventricular Fibrillation Cardiac Arrest.

Objectives:Treatment algorithms for cardiac arrest are rescuer centric and vary little from patient to patient. The objective of this study was to determine if cardiopulmonary resuscitation–targeted to arterial blood pressure and coronary perfusion pressure rather than optimal guideline care would improve 24-hour survival in a porcine model of ventricular fibrillation cardiac arrest. Data Sources:Preclinical animal laboratory using female 3-month-old swine. Study Selection:A randomized interventional study. Data Extraction:After induction of anesthesia and 7 minutes of untreated ventricular fibrillation, 16 female 3-month-old swine were randomized to 1) blood pressure care: titration of chest compression depth to a systolic blood pressure of 100 mm Hg and vasopressor dosing to maintain coronary perfusion pressure of greater than 20 mm Hg or 2) guideline care: chest compression depth targeted to 51 mm and standard guideline vasopressor dosing. Animals received manual cardiopulmonary resuscitation for 10 minutes before the first defibrillation attempt and standardized postresuscitation care for 24 hours. Data Synthesis:Twenty-four–hour survival was more likely with blood pressure care versus guideline care (0/8 vs 5/8; p < 0.03), and all survivors had normal neurologic examinations. Mean coronary perfusion pressure prior to defibrillation was significantly higher with blood pressure care (28 ± 3 vs 10 ± 6 mm Hg; p < 0.01). Chest compression depth was lower with blood pressure care (48 ± 0.4 vs 44 ± 0.5 mm Hg; p < 0.05), and the number of vasopressor doses was higher with blood pressure care (median, 3 [range, 1–7] vs 2 [range, 2–2]; p < 0.01). Conclusions:Individualized goal-directed hemodynamic resuscitation targeting systolic blood pressure of 100 mm Hg and coronary perfusion pressure of greater than 20 mm Hg improved 24-hour survival compared with guideline care in this model of ventricular fibrillation cardiac arrest.