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1.  Differing Effects when Using Phenylephrine and Norepinephrine To Augment Cerebral Blood Flow after Traumatic Brain Injury in the Immature Brain 
Journal of Neurotrauma  2015;32(4):237-243.
Abstract
Low cerebral blood flow (CBF) states have been demonstrated in children early after traumatic brain injury (TBI), and have been correlated with poorer outcomes. Cerebral perfusion pressure (CPP) support following severe TBI is commonly implemented to correct cerebral hypoperfusion, but the efficacy of various vasopressors has not been determined. Sixteen 4-week-old female swine underwent nonimpact inertial brain injury in the sagittal plane. Intraparenchymal monitors were placed to measure intracranial pressure (ICP), CBF, brain tissue oxygen tension (PbtO2), and cerebral microdialysis 30 min to 6 h post-injury. One hour after injury, animals were randomized to receive either phenylephrine (PE) or norepinephrine (NE) infusions titrated to a CPP >70 mm Hg for 5 h. Animals were euthanized 6 h post-TBI, and brains were fixed and stained to assess regions of cell and axonal injury. After initiation of CPP augmentation with NE or PE infusions, there were no differences in ICP between the groups or over time. Animals receiving NE had higher PbtO2 than those receiving PE (29.6±10.2 vs. 19.6±6.4 torr at 6 h post-injury, p<0.05). CBF increased similarly in both the NE and PE groups. CPP support with PE resulted in a greater reduction in metabolic crisis than with NE (lactate/pyruvate ratio 16.7±2.4 vs. 42.7±10.2 at 6 h post-injury, p<0.05). Augmentation of CPP to 70 mm Hg with PE resulted in significantly smaller cell injury volumes at 6 h post-injury than CPP support with NE (0.4% vs. 1.4%, p<0.05). Despite similar increases in CBF, CPP support with NE resulted in greater brain tissue oxygenation and hypoxic-ischemic injury than CPP support with PE. Future clinical studies comparing the effectiveness of various vasopressors for CPP support are warranted.
doi:10.1089/neu.2014.3468
PMCID: PMC4321769  PMID: 25072522
CBF; CPP; NE; PE; TBI
2.  An ounce of prevention but less than a pound of cure: seizure prophylaxis after intracranial hemorrhage 
doi:10.1097/PCC.0000000000000237
PMCID: PMC4185423  PMID: 25280151
intracranial hemorrhage; seizures; seizure prophylaxis; children; electroencephalogram monitoring
3.  Risk factors associated with infections and need for permanent cerebrospinal fluid diversion in pediatric intensive care patients with externalized ventricular drains 
Neurocritical care  2014;21(2):294-299.
Introduction
Externalized ventricular drains (EVDs) are commonly used in pediatric intensive care units (PICU) but few data are available regarding infection rates, infection risks, or factors associated with conversion to permanent cerebrospinal fluid (CSF) diversion.
Methods
Retrospective observational study of patients managed with EVDs admitted to a tertiary care PICU from January 2005 to December 2009
Results
Three hundred eighty patients were identified. Neurologic diagnostic groups were externalization of existing shunt (EXSHUNT) in 196 patients (52%), brain tumor in 122 patients (32%), intracranial hemorrhage (ICH) in 23 patients (6%), traumatic brain injury (TBI) in 17 patients (5%), meningitis in 9 patients (2%) or other in 13 patients (3%). Six percent of all patients (24/380) had new infections associated with EVD management for an infection rate of 8.6 per 1000 catheter days. The median time to positive cultures was 7 days (interquartile range 4.75, 9) after EVD placement. Patients with EVD infections had significantly longer EVD duration 6 vs. 11.5 days (p=0.0001), and higher maximum EVD outputs 1.9 vs. 1.5 mL/kg/hr (p=0.0017). Need for permanent CSF diversion was associated with higher maximum EVD drainage (1.3 vs. 1.6 mL/kg/hr p < 0.0001), longer EVD duration (5 vs. 4 days, p < 0.005), and younger age (4.5 vs. 8 years, p < 0.02) but not intracranial hypertension (72% vs. 82% of patients, p = 0.4).
Conclusion
In our large pediatric cohort, EVD infections were associated with longer EVD duration and higher maximum EVD output. Permanent CSF diversion was more likely in patients with higher maximum EVD drainage, longer EVD duration, and younger age.
doi:10.1007/s12028-013-9946-7
PMCID: PMC4133323  PMID: 24522759
externalized ventricular drain; ventricular catheter infection; pediatric intensive care unit; neurocritical care; ventriculoperitoneal shunt; pediatric
4.  Hemodynamic Directed CPR Improves Cerebral Perfusion Pressure and Brain Tissue Oxygenation 
Resuscitation  2014;85(9):1298-1303.
Aim
Advances in cardiopulmonary resuscitation (CPR) have focused on the generation and maintenance of adequate myocardial blood flow to optimize the return of spontaneous circulation and survival. Much of the morbidity associated with cardiac arrest survivors can be attributed to global brain hypoxic ischemic injury. The objective of this study was to compare cerebral physiological variables using a hemodynamic directed resuscitation strategy versus an absolute depth-guided approach in a porcine model of ventricular fibrillation (VF) cardiac arrest.
Methods
Intracranial pressure and brain tissue oxygen tension probes were placed in the frontal cortex prior to induction of VF in 21 female 3month old swine. After 7 minutes of VF, animalswere randomized to receive one of three resuscitation strategies: 1) Hemodynamic Directed Care (CPP-20): chest compressions (CCs) with depth titrated to a target systolic blood pressure of 100 mmHg and titration of vasopressors to maintain coronary perfusion pressure (CPP)> 20 mmHg; 2) Depth 33mm(D33): target CC depth of 33mm with standard American Heart Association (AHA) epinephrine dosing; or 3) Depth 51mm(D51): target CC depth of 51mm with standard AHA epinephrine dosing.
Results
Cerebral perfusion pressures (CerePP)were significantly higher in the CPP-20 group compared to both D33 (p<0.01) and D51 (P=0.046), and higher in survivors compared to non-survivors irrespective of treatment group (P<0.01).Brain tissue oxygen tension was also higher in the CPP-20 group compared to both D33 (P<0.01) and D51 (P=0.013), and higher in survivors compared to non-survivors irrespective of treatment group (P<0.01).Subjects with a CPP > 20 mm Hg were 2.7 times more likely to have a CerePP > 30 mm Hg (P< 0.001).
Conclusions
Hemodynamic directed resuscitation strategy targeting coronary perfusion pressure > 20 mmHg following VF arrest was associated with higher cerebral perfusion pressures and brain tissue oxygen tensions during CPR.
doi:10.1016/j.resuscitation.2014.05.040
PMCID: PMC4138228  PMID: 24945902
cardiac arrest; cardiopulmonary resuscitation; coronary perfusion pressure; cerebral perfusion pressure; intracranial pressure; brain tissue oxygen tension; ventricular fibrillation; swine
5.  Hemodynamic Directed CPR Improves Short-term Survival from Ventricular Fibrillation Cardiac Arrest 
Critical care medicine  2013;41(12):10.1097/CCM.0b013e318298ad6b.
Objectives
During cardiopulmonary resuscitation (CPR), adequate coronary perfusion pressure (CPP) is essential for establishing return of spontaneous circulation. Current American Heart Association (AHA) guidelines recommend standardized interval administration of epinephrine for patients in cardiac arrest. The objective of this study was to compare short-term survival using a hemodynamic directed resuscitation strategy versus chest compression depth directed CPR in a porcine model of cardiac arrest.
Design
Randomized interventional study
Setting
Preclinical animal laboratory
Subjects
Twenty four female 3-month old swine
Interventions / Measurements
After 7 minutes of ventricular fibrillation, pigs were randomized to receive one of three resuscitation strategies: 1) Hemodynamic Directed Care (CPP-20): chest compressions (CCs) with depth titrated to a target systolic blood pressure of 100 mmHg and titration of vasopressors to maintain CPP > 20 mmHg; 2) Depth 33mm(D33): target CC depth of 33mm with standard AHA epinephrine dosing; or 3) Depth 51mm(D51): target CC depth of 51mm with standard AHA epinephrine dosing. All animals received manual CPR guided by audiovisual feedback for 10 minutes before first shock.
Main Results
45-minute survival was higher in the CPP-20 group (8/8) compared to D33 (1/8) or D51 (3/8) groups; p=0.002. Coronary perfusion pressures were higher in the CPP-20 group compared to D33 (p=0.004) and D51 (p=0.006), and in survivors compared to non-survivors (p<0.01). Total epinephrine dosing and defibrillation attempts were not different.
Conclusions
Hemodynamic directed resuscitation targeting CPPs > 20 mmHg during 10 minutes of CPR for VF cardiac arrest improves short-term survival, when compared to resuscitation with depth of compressions guided to 33mm or 51mm and standard AHA vasopressor dosing.
doi:10.1097/CCM.0b013e318298ad6b
PMCID: PMC3812371  PMID: 23887237
cardiac arrest; cardiopulmonary resuscitation; coronary perfusion pressure; ventricular fibrillation; swine
6.  Authors’ Reply 
doi:10.1097/PCC.0000000000000334
PMCID: PMC4339286  PMID: 25647138
hyponatremia; externalized ventricular drain; children; seizures; dysnatremia; pediatrics; mortality
7.  The Anesthetic Effects on Vasopressor Modulation of Cerebral Blood Flow in an Immature Swine Model 
Anesthesia and analgesia  2013;116(4):838-844.
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 (15) four-week-old piglets were given one of 2 anesthetic protocols: total IV anesthesia (TIVA) (midazolam 1 mg/kg/hr and fentanyl 100 mcg/kg/hr, N=8) or ISO (isoflurane 1.5–2% and fentanyl 100 mcg/kg/hr, 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 two groups (ISO 38±10 vs. TIVA 35±26 ml/100gm/min) despite lower baseline cerebral perfusion pressure in the ISO group, 45±11 vs. 71±11 mmHg (p< 0.0005). Piglets in ISO group displayed increases in ICP with PE and NE (11±4 vs. 16±4 mmHg and 11±8 vs. 18±5 mmHg; p< 0.05), but in the TIVA group only exposure to PE resulted in increases in ICP when comparing maximal dose values to baseline data (11±4 vs. 15±5 mmHg; p < 0.05). Normalized CBF displayed statistically significant increases with regards to 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 to 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.
doi:10.1213/ANE.0b013e3182860fe7
PMCID: PMC3606687  PMID: 23460561
8.  Patient-centric Blood Pressure–targeted Cardiopulmonary Resuscitation Improves Survival from Cardiac Arrest 
Rationale: Although current resuscitation guidelines are rescuer focused, the opportunity exists to develop patient-centered resuscitation strategies that optimize the hemodynamic response of the individual in the hopes to improve survival.
Objectives: To determine if titrating cardiopulmonary resuscitation (CPR) to blood pressure would improve 24-hour survival compared with traditional CPR in a porcine model of asphyxia-associated ventricular fibrillation (VF).
Methods: After 7 minutes of asphyxia, followed by VF, 20 female 3-month-old swine randomly received either blood pressure–targeted care consisting of titration of compression depth to a systolic blood pressure of 100 mm Hg and vasopressors to a coronary perfusion pressure greater than 20 mm Hg (BP care); or optimal American Heart Association Guideline care consisting of depth of 51 mm with standard advanced cardiac life support epinephrine dosing (Guideline care). All animals received manual CPR for 10 minutes before first shock. Primary outcome was 24-hour survival.
Measurements and Main Results: The 24-hour survival was higher in the BP care group (8 of 10) compared with Guideline care (0 of 10); P = 0.001. Coronary perfusion pressure was higher in the BP care group (point estimate +8.5 mm Hg; 95% confidence interval, 3.9–13.0 mm Hg; P < 0.01); however, depth was higher in Guideline care (point estimate +9.3 mm; 95% confidence interval, 6.0–12.5 mm; P < 0.01). Number of vasopressor doses before first shock was higher in the BP care group versus Guideline care (median, 3 [range, 0–3] vs. 2 [range, 2–2]; P = 0.003).
Conclusions: Blood pressure–targeted CPR improves 24-hour survival compared with optimal American Heart Association care in a porcine model of asphyxia-associated VF cardiac arrest.
doi:10.1164/rccm.201407-1343OC
PMCID: PMC4315818  PMID: 25321490
asphyxia; heart arrest; vascular access devices
9.  Greater fluctuations in serum sodium levels are associated with increased mortality in children with externalized ventriculostomy drains in a pediatric intensive care unit 
Objective
Dysnatremia is common in critically ill children due to disruption of hormonal homeostasis. Children with brain injury are at risk for SIADH, cerebral salt wasting and sodium losses due to externalized ventricular drain (EVD) placement. We hypothesized that among pediatric intensive care unit (PICU) patients managed with an EVD, hyponatremia is common, hyponatremia is associated with seizures and in-hospital mortality, and greater sodium fluctuations are associated with in-hospital mortality.
Design
Retrospective observational study
Setting
Tertiary care PICU
Patients
All pediatric patients treated in the PICU with an EVD from January 2005 to December 2009. Patients were identified by searching the physician order entry database for EVD orders. Hyponatremia was defined as the minimum sodium during patients’ EVD time and was categorized as mild (131-134 meq/L) or moderate-severe (≤130 meq/L). Magnitude of sodium fluctuation was defined as the difference between a patient’s highest and lowest sodium during the time in which an EVD was in use (up to 14 days). Seizure was defined as a clinically evident convulsion during EVD presence. A priori confounders were age, history of epilepsy, and EVD indication. Multivariable regression was performed to test the association between sodium derangements and outcomes.
Interventions
None.
Measurements and Main Results
Three hundred eighty patients were eligible. One hundred nine (29%) had mild hyponatremia, and 30 (8%) moderate-severe hyponatremia. Twenty eight (7%) patients had a seizure while hospitalized. Eighteen patients died (5%) prior to discharge. Survivors had a median daily sodium fluctuation of 1 [0, 5] vs non-survivors 9 [6, 11], (p< 0.001) and a median sodium fluctuation of 5 meq/L [interquartile range 2, 8] vs non-survivors 15 meq/L [9, 24] (p<0.001) during EVD management. After controlling for a priori covariates and potential confounders, hyponatremia was not associated with an increased odds of seizures or in-hospital mortality. However, greater fluctuations in daily sodium (OR 1.38, 95% CI (1.06, 1.8)) and greater fluctuations in sodium during EVD management were associated with increased odds of in-hospital mortality (OR 1.59, 95% CI (1.2, 2.11)).
Conclusion
Hyponatremia was common in PICU patients treated with EVDs but not associated with seizures or in-hospital mortality. Greater sodium fluctuations during EVD management were independently associated with increased odds of in-hospital mortality.
doi:10.1097/PCC.0000000000000223
PMCID: PMC4221432  PMID: 25137551
hyponatremia; externalized ventricular drain; children; seizures; dysnatremia; pediatrics; mortality
10.  Advanced Neuromonitoring and Imaging in Pediatric Traumatic Brain Injury 
While the cornerstone of monitoring following severe pediatric traumatic brain injury is serial neurologic examinations, vital signs, and intracranial pressure monitoring, additional techniques may provide useful insight into early detection of evolving brain injury. This paper provides an overview of recent advances in neuromonitoring, neuroimaging, and biomarker analysis of pediatric patients following traumatic brain injury.
doi:10.1155/2012/361310
PMCID: PMC3363371  PMID: 22675618
11.  Improved Behavior, Motor, and Cognition Assessments in Neonatal Piglets 
Journal of Neurotrauma  2013;30(20):1770-1779.
Abstract
The alterations of animal behavior after traumatic brain injury (TBI) can be subtle, and their quantitative characterization can present significant methodological challenges. Meeting these challenges is a critical need, because quantitative measures are required in studies that compare the efficacy of different clinical interventions. We developed a battery of assessments to quantify behavioral, motor, and cognitive changes in neonatal piglets with good sensitivity and specificity to the detection of persistent deficits that correlate with axonal injury severity after a rapid non-impact head rotation with a diffuse pattern of axonal injury. The battery of measures developed included open field behaviors of sniffing and moving a toy, locomotion measures of Lempel-Ziv complexity and the probability of remaining in the current location, and a novel metric for evaluating motor performance. Our composite porcine disability score was able to detect brain injury with a sensitivity of 100% and specificity of 85.7% at day +4 post-injury for n=8 injured and n=7 sham piglets and significantly correlated with the percent axonal injury in these animals (day +4: ρ=0.76, p=0.0011). A significant improvement over our previous assessments, this new porcine disability score has potential use in a wide variety of porcine disease and injury models.
doi:10.1089/neu.2013.2913
PMCID: PMC3796335  PMID: 23758416
cognition; neurobehavioral assessment; pediatric brain injury; porcine; traumatic brain injury
12.  Hemodynamic–directed cardiopulmonary resuscitation during in–hospital cardiac arrest* 
Resuscitation  2014;85(8):983-986.
Cardiopulmonary resuscitation (CPR) guidelines assume that cardiac arrest victims can be treated with a uniform chest compression (CC) depth and a standardized interval administration of vasopressor drugs. This non-personalized approach does not incorporate a patient’s individualized response into ongoing resuscitative efforts. In previously reported porcine models of hypoxic and normoxic ventricular fibrillation (VF), a hemodynamic-directed resuscitation improved short-term survival compared to current practice guidelines. Skilled in-hospital rescuers should be trained to tailor resuscitation efforts to the individual patient’s physiology. Such a strategy would be a major paradigm shift in the treatment of in-hospital cardiac arrest victims.
doi:10.1016/j.resuscitation.2014.04.015
PMCID: PMC4087068  PMID: 24783998
Arterial blood pressure; Cardiac arrest; Cardiopulmonary resuscitation
13.  Improved Oxygenation 24 Hours After Transition to Airway Pressure Release Ventilation or High-Frequency Oscillatory Ventilation Accurately Discriminates Survival in Immunocompromised Pediatric Patients With Acute Respiratory Distress Syndrome* 
Objectives
Children with an immunocompromised condition and requiring invasive mechanical ventilation have high risk of death. Such patients are commonly transitioned to rescue modes of non-conventional ventilation, including airway pressure release ventilation and high-frequency oscillatory ventilation, for acute respiratory distress syndrome refractory to conventional ventilation. Our aim was to describe our experience with airway pressure release ventilation and high-frequency oscillatory ventilation in children with an immunocompromised condition and acute respiratory distress syndrome refractory to conventional ventilation and to identify factors associated with survival.
Design
Retrospective cohort study.
Setting
Tertiary care, university-affiliated PICU.
Patients
Sixty pediatric patients with an immunocompromised condition and acute respiratory distress syndrome refractory to conventional ventilation transitioned to either airway pressure release ventilation or high-frequency oscillatory ventilation.
Interventions
None.
Measurements and Main Results
Demographic data, ventilator settings, arterial blood gases, oxygenation index, and Pao2/Fio2 were recorded before transition to either mode of nonconventional ventilation and at predetermined intervals after transition for up to 5 days. Mortality in the entire cohort was 63% and did not differ between patients transitioned to airway pressure release ventilation and high-frequency oscillatory ventilation. For both airway pressure release ventilation and high-frequency oscillatory ventilation, improvements in oxygenation index and Pao2/Fio2 at 24 hours expressed as a fraction of pretransition values (oxygenation index24/oxygenation indexpre and Pao2/Fio224/Pao2/FIO2pre) reliably discriminated nonsurvivors from survivors, with receiver operating characteristic areas under the curves between 0.89 and 0.95 (p for all curves < 0.001). Sensitivity-specificity analysis suggested that less than 15% reduction in oxygenation index (90% sensitive, 75% specific) or less than 90% increase in Pao2/Fio2 (80% sensitive, 94% specific) 24 hours after transition to airway pressure release ventilation were the optimal cutoffs to identify nonsurvivors. The comparable values 24 hours after transition to high-frequency oscillatory ventilation were less than 5% reduction in oxygenation index (100% sensitive, 83% specific) or less than 80% increase in Pao2/Fio2 (91% sensitive, 89% specific) to identify nonsurvivors.
Conclusions
In this single-center retrospective study of pediatric patients with an immunocompromised condition and acute respiratory distress syndrome failing conventional ventilation transitioned to either airway pressure release ventilation or high-frequency oscillatory ventilation, improved oxygenation at 24 hours expressed as Pao2/Fio224/Pao2/Fio2pre or oxygenation index24/oxygenation indexpre reliably discriminates nonsurvivors from survivors. These findings should be prospectively verified.
doi:10.1097/PCC.0000000000000069
PMCID: PMC4114308  PMID: 24413319
acute lung injury; acute respiratory distress syndrome; airway pressure release ventilation; high-frequency oscillatory ventilation; mechanical ventilation; pediatric
14.  High Frequency Oscillation and Airway Pressure Release Ventilation in Pediatric Respiratory Failure 
Pediatric pulmonology  2013;49(7):707-715.
Summary
Background
Airway pressure release ventilation (APRV) and high frequency oscillatory ventilation (HFOV) are frequently used in acute lung injury (ALI) refractory to conventional ventilation. Our aim was to describe our experience with APRV and HFOV in refractory pediatric ALI, and to identify factors associated with survival.
Methods
We analyzed 104 patients with hypoxemia refractory to conventional ventilation transitioned to either APRV or HFOV. Demographics, oxygenation index (OI), and PaO2/FiO2 (PF ratio) were recorded before transition to either mode of nonconventional ventilation (NCV) and for every 12 hr after transition.
Results
Relative to APRV, patients on HFOV were younger and had more significant lung disease evidenced by higher OI (28.5 [18.6, 36.2] vs. 21.0 [15.5, 30.0], P = 0.008), lower PF ratios (73 [59,94] vs. 99 [76,131], P = 0.002), and more frequent use of inhaled nitric oxide. In univariate analysis, HFOV was associated with more frequent neuromuscular blockade. Forty-one of 104 patients died on NCV (39.4%). Survivors demonstrated improvement in OI 24 hr after transition to NCV, whereas non-survivors did not (12.9 [8.9, 20.9] vs. 28.1 [17.6, 37.1], P < 0.001). After controlling for immunocompromised status, number of vasopressors, and OI before transition, mode of NCV was not associated with mortality.
Conclusions
In a heterogeneous PICU population with hypoxemia refractory to conventional ventilation transitioned to NCV, improvement in oxygenation at 24 hr was associated with survival. Immunocompromised status, number of vasopressor infusions, and the OI before transition to NCV were independently associated with survival.
doi:10.1002/ppul.22853
PMCID: PMC4092114  PMID: 23853049
mechanical ventilation; high frequency oscillatory ventilation; airway pressure release ventilation; acute respiratory distress syndrome; acute lung injury; pediatric
15.  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.
doi:10.1097/PCC.0b013e3182917b83
PMCID: PMC4082326  PMID: 23842589
abusive head trauma; electroencephalographic monitoring; electroencephalography; seizure; traumatic brain injury
16.  Hemodynamic Directed CPR Improves Short-term Survival from Asphyxia-Associated Cardiac Arrest 
Resuscitation  2012;84(5):696-701.
Aim
Adequate coronary perfusion pressure (CPP) during cardiopulmonary resuscitation (CPR) is essential for establishing return of spontaneous circulation. The objective of this study was to compare short-term survival using a hemodynamic directed resuscitation strategy versus an absolute depth-guided approach in a porcine model of asphyxia-associated cardiac arrest. We hypothesized that a hemodynamic directed approach would improve short-term survival compared to depth-guided care.
Methods
After 7 minutes of asphyxia, followed by induction of ventricular fibrillation, 19 female 3-month old swine (31 ± 0.4 kg) were randomized to receive one of three resuscitation strategies: 1) Hemodynamic Directed Care (CPP-20): chest compressions (CCs) with depth titrated to a target systolic blood pressure of 100 mmHg and titration of vasopressors to maintain CPP > 20 mmHg; 2) Depth 33mm (D33): target CC depth of 33mm with standard American Heart Association (AHA) epinephrine dosing; or 3) Depth 51mm (D51): target CC depth of 51mm with standard AHA epinephrine dosing. All animals received manual CPR guided by audiovisual feedback for 10 minutes before first shock.
Results
45-minute survival was higher in the CPP-20 group (6/6) compared to D33 (1/7) or D51 (1/6) groups; p=0.002. Coronary perfusion pressures were higher in the CPP-20 group compared to D33 (p=0.011) and D51 (p=0.04), and in survivors compared to non-survivors (p<0.01). Total number of vasopressor doses administered and defibrillation attempts were not different.
Conclusions
Hemodynamic directed care targeting CPPs > 20 mmHg improves short-term survival in an intensive care unit porcine model of asphyxia-associated cardiac arrest.
doi:10.1016/j.resuscitation.2012.10.023
PMCID: PMC3612383  PMID: 23142199
Asphyxia; cardiac arrest; cardiopulmonary resuscitation; coronary perfusion pressure; hypoxia
17.  Behavioral Deficits and Axonal Injury Persistence after Rotational Head Injury Are Direction Dependent 
Journal of Neurotrauma  2013;30(7):538-545.
Abstract
Pigs continue to grow in importance as a tool in neuroscience. However, behavioral tests that have been validated in the rodent model do not translate well to pigs because of their very different responses to behavioral stimuli. We refined metrics for assessing porcine open field behavior to detect a wide spectrum of clinically relevant behaviors in the piglet post-traumatic brain injury (TBI). Female neonatal piglets underwent a rapid non-impact head rotation in the sagittal plane (n=8 evaluable) or were instrumented shams (n=7 evaluable). Open field testing was conducted 1 day prior to injury (day −1) in order to establish an individual baseline for analysis, and at days +1 and +4 after injury. Animals were then killed on day +6 after injury for neuropathological assessment of axonal injury. Injured piglets were less interested in interacting with environmental stimuli and had a lower activity level than did shams. These data were compared with previously published data for axial rotational injuries in neonatal piglets. Acute behavioral outcomes post-TBI showed a dependence on the rotational plane of the brain injury, with animals with sagittal injuries demonstrating a greater level of inactivity and less random usage of the open field space than those with axial injuries. The persistence of axonal injury is also dependent on the rotational plane, with sagittal rotations causing more prolonged injuries than axial rotations. These results are consistent with animal studies, finite element models, and studies of concussions in football, which have all demonstrated differences in injury severity depending upon the direction of head impact rotation.
doi:10.1089/neu.2012.2594
PMCID: PMC3636580  PMID: 23216054
behavioral assessments; cognitive function; pediatric brain injury; TBI
18.  Electrographic Status Epilepticus is Associated with Mortality and Worse Short-Term Outcome in Critically Ill Children 
Critical care medicine  2013;41(1):210-218.
Objectives
Electrographic seizures (ES) and electrographic status epilepticus (ESE) are common in critically ill children. We aimed to determine whether ES and ESE are associated with higher mortality or worse short-term neurologic outcome.
Design
Prospective observational study.
Setting
Pediatric intensive care unit of a tertiary children’s hospital.
Patients
Non-neonatal children admitted to a pediatric intensive care unit (PICU) with acute encephalopathy underwent continuous electroencephalographic (cEEG) monitoring. EEGs were scored as (1) no seizures, (2) ES, or (3) ESE. Covariates included age, acute neurologic disorder category, prior neurodevelopmental status, sex, and EEG background category. Outcomes were mortality and worsening of Pediatric Cerebral Performance Category (PCPC) from pre-admission to PICU discharge. Chi-squared analysis, Fisher’s exact test, and multivariable logistic regression were used to evaluate the associations between ES or ESE and mortality or short-term neurologic outcome, using odds ratios (OR) and 95% confidence intervals (95%CI).
Interventions
None
Main Results
Two hundred children underwent cEEG. Eighty-four (42%) had seizures which were categorized as ES in 41 (20.5%) and ESE in 43 (21.5%). Thirty-six subjects (18%) died and 88 subjects (44%) had PCPC worsening. In multivariable analysis ESE was associated with an increased risk of mortality (OR 5.1; 95%CI 1.4, 18, p=0.01) and PCPC worsening (OR 17.3; 95%CI 3.7, 80, p<0.001) while ES was not associated with an increased risk of mortality (OR 1.3; 95%CI 0.3, 5.1; p=0.74) or PCPC worsening (OR 1.2; 95%CI 0.4, 3.9; p=0.77).
Conclusions
ESE, but not ES, is associated with mortality and worse short-term neurologic outcome in critically ill children with acute encephalopathy.
doi:10.1097/CCM.0b013e3182668035
PMCID: PMC3531581  PMID: 23164815
EEG Monitoring; Seizure; Status Epilepticus; Pediatric; Outcome; Non-Convulsive Seizure
19.  Early Cerebral Perfusion Pressure Augmentation with Phenylephrine after Traumatic Brain Injury may be Neuroprotective in a Pediatric Swine Model 
Critical Care Medicine  2012;40(8):2400-2406.
Objective
Cerebral perfusion pressure (CPP) less than 40 mm Hg following pediatric traumatic brain injury (TBI) has been associated with increased mortality independent of age, and current guidelines recommend maintaining CPP between 40–60 mm Hg. Although adult TBI studies have observed an increased risk of complications associated with targeting a CPP > 70, we hypothesize that targeting a CPP of 70 mm Hg with the use of phenylephrine early after injury in the immature brain will be neuroprotective.
Design
Animals were randomly assigned to injury with CPP = 70 mm Hg (CPP70) or CPP = 40 mm Hg (CPP40). Diffuse TBI was produced by a single rapid rotation of the head in the axial plane. Cerebral microdialysis, brain tissue oxygen, intracranial pressure, and cerebral blood flow (CBF) were measured 30 min – 6 h post-injury. One hour after injury, CPP was manipulated with the vasoconstrictor phenylephrine. Animals were euthanized 6 h post-TBI, brains fixed, and stained to assess regions of cell injury and axonal dysfunction.
Setting
University center.
Subject
21 four week-old female swine.
Measurements and Main Results
Augmentation of CPP to 70 mm Hg resulted in no change in axonal dysfunction, but significantly smaller cell injury volumes at 6 hours post injury compared to CPP40 (1.1% vs. 7.4%, p < 0.05). Microdialysis lactate/pyruvate ratios were improved at CPP70 compared to CPP40. CBF was higher in the CPP70 group but did not reach statistical significance. Phenylephrine was well tolerated and there were no observed increases in serum lactate or intracranial pressure in either group.
Conclusions
Targeting a CPP of 70 mm Hg resulted in a greater reduction in metabolic crisis and cell injury volumes compared to a CPP of 40 mm Hg in an immature swine model. Early aggressive CPP augmentation to a CPP of 70 mm Hg in pediatric TBI before severe intracranial hypertension has the potential to be neuroprotective, and further investigations are needed.
doi:10.1097/CCM.0b013e31825333e6
PMCID: PMC3400930  PMID: 22809910
pediatric head injury; cerebral perfusion pressure; phenylephrine; neuroprotection; swine; cerebral blood flow
20.  Neurocritical Care Monitoring Correlates with Neuropathology in a Swine Model of Pediatric Traumatic Brain Injury 
Neurosurgery  2011;69(5):1139-1147.
BACKGROUND
Small animal models have been used in traumatic brain injury (TBI) research to investigate the basic mechanisms and pathology of TBI. Unfortunately, successful TBI investigations in small animal models have not resulted in marked improvements in clinical outcomes of TBI patients.
OBJECTIVE
To develop a clinically relevant immature large animal model of pediatric neurocritical care following TBI.
METHODS
Eleven 4 week old piglets were randomized to either rapid axial head rotation without impact (N=6) or instrumented sham (N=5). All animals had an intracranial pressure monitor, brain tissue oxygen (PbtO2) probe, and cerebral microdialysis probe placed in the frontal lobe and data collected for 6 h following injury.
RESULTS
Injured animals had sustained elevations in intracranial pressure and lactate-pyruvate ratio (LPR), and decreased PbtO2 compared to sham. PbtO2 and LPR from separate frontal lobes had strong linear correlation in both sham and injured animals. Neuropathologic examination demonstrated significant axonal injury and infarct volumes in injured animals compared to sham at 6 hours post-injury. Averaged over time, PbtO2 in both injured and sham animals had a strong inverse correlation with total injury volume. Average LPR had a strong correlation with total injury volume.
CONCLUSION
LPR and PbtO2 can be utilized as serial non-terminal secondary markers in our injury model for neuropathology, and as evaluation metrics for novel interventions and therapeutics in the acute post-injury period. This translational model bridges a vital gap in knowledge between TBI studies in small animal models and clinical trials in the pediatric TBI population.
doi:10.1227/NEU.0b013e3182284aa1
PMCID: PMC3188667  PMID: 21670716
neurocritical care monitoring; pediatric head injury; swine; TBI model
21.  Physiological and histopathological responses following closed rotational head injury depend on direction of head motion 
Experimental neurology  2010;227(1):79-88.
Rotational inertial forces are thought to be the underlying mechanism for most severe brain injuries. However, little is known about the effect of head rotation direction on injury outcomes, particularly in the pediatric population. Neonatal piglets were subjected to a single non-impact head rotation in the horizontal, coronal, or sagittal direction, and physiological and histopathological responses were observed. Sagittal rotation produced the longest duration of unconsciousness, highest incidence of apnea, and largest intracranial pressure increase, while coronal rotation produced little change, and horizontal rotation produced intermediate and variable derangements. Significant cerebral blood flow reductions were observed following sagittal but not coronal or horizontal injury compared to sham. Subarachnoid hemorrhage, ischemia, and brainstem pathology were observed in the sagittal and horizontal groups but not in a single coronal animal. Significant axonal injury occurred following both horizontal and sagittal rotations. For both groups, the distribution of injury was greater in the frontal and parietotemporal lobes than in the occipital lobes, frequently occurred in the absence of ischemia, and did not correlate with regional cerebral blood flow reductions. We postulate that these direction-dependent differences in injury outcomes are due to differences in tissue mechanical loading produced during head rotation.
doi:10.1016/j.expneurol.2010.09.015
PMCID: PMC3021173  PMID: 20875409
animal models; brain ischemia; brain trauma; cerebral blood flow; neuropathology; subarachnoid hemorrhage
22.  Diffuse optical monitoring of hemodynamic changes in piglet brain with closed head injury 
Journal of biomedical optics  2009;14(3):034015.
We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R = 0.89, p < 0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.
doi:10.1117/1.3146814
PMCID: PMC3169814  PMID: 19566308
diffuse correlation spectroscopy (DCS); diffuse reflectance spectroscopy (DRS); cerebral hemodynamics; cerebral blood flow; traumatic brain injury; near—infrared spectroscopy (NIRS)
23.  Sedation and Analgesia in Children with Developmental Disabilities and Neurologic Disorders 
Sedation and analgesia performed by the pediatrician and pediatric subspecialists are becoming increasingly common for diagnostic and therapeutic purposes in children with developmental disabilities and neurologic disorders (autism, epilepsy, stroke, obstructive hydrocephalus, traumatic brain injury, intracranial hemorrhage, and hypoxic-ischemic encephalopathy). The overall objectives of this paper are (1) to provide an overview on recent studies that highlight the increased risk for respiratory complications following sedation and analgesia in children with developmental disabilities and neurologic disorders, (2) to provide a better understanding of sedatives and analgesic medications which are commonly used in children with developmental disabilities and neurologic disorders on the central nervous system.
doi:10.1155/2010/189142
PMCID: PMC2913544  PMID: 20706547
24.  Repeated Traumatic Brain Injury Affects Composite Cognitive Function in Piglets 
Journal of Neurotrauma  2009;26(7):1111-1121.
Abstract
Cumulative effects of repetitive mild head injury in the pediatric population are unknown. We have developed a cognitive composite dysfunction score that correlates white matter injury severity in neonatal piglets with neurobehavioral assessments of executive function, memory, learning, and problem solving. Anesthetized 3- to 5-day-old piglets were subjected to single (n = 7), double one day apart (n = 7), and double one week apart (n = 7) moderate (190 rad/s) rapid non-impact axial rotations of the head and compared to instrumented shams (n = 7). Animals experiencing two head rotations one day apart had a significantly higher mortality rate (43%) compared to the other groups and had higher failures rates in visual-based problem solving compared to instrumented shams. White matter injury, assessed by β-APP staining, was significantly higher in the double one week apart group compared to that with single injury and sham. Worsening performance on cognitive composite score correlated well with increasing severity of white matter axonal injury. In our immature large animal model of TBI, two head rotations produced poorer outcome as assessed by neuropathology and neurobehavioral functional outcomes compared to that with single rotations. More importantly, we have observed an increase in injury severity and mortality when the head rotations occur 24 h apart compared to 7 days apart. These observations have important clinical translation to infants subjected to repeated inflicted head trauma.
doi:10.1089/neu.2008.0845
PMCID: PMC2848948  PMID: 19275468
axonal injury; neurobehavioral assessment; pediatric brain injury; traumatic brain injury
25.  Neurobehavioral Functional Deficits Following Closed Head Injury in the Neonatal Pig 
Experimental neurology  2006;204(1):234-243.
Neurobehavioral deficits in higher cortical systems have not been described previously in a large animal model of diffuse brain injury. Anesthetized 3–5 day old piglets were subjected to either mild (142 rad/sec) or moderate (188 rad/sec) rapid non-impact axial rotations of the head. Multiple domains of cortical function were evaluated 5 times during the 12 day post-injury period using tests of neurobehavioral function devised for piglets. There were no observed differences in neurobehavioral outcomes between mild injury pigs (N = 8) and instrumented shams (N = 4). Moderately injured piglets (N = 7) had significantly lower interest in exploring their environment and had higher failure rates in visual-based problem solving compared to instrumented shams (N = 5) on Day 1 and 4 after injury. Neurobehavioral functional deficits correlated with neuropathologic damage in the neonatal pigs after inertial head injury. Injured axons detected by immunohistochemistry (β-APP) were absent in mild injury and sham piglets, but were observed in moderately injured piglet brains. In summary, we have developed a quantitative battery of neurobehavioral functional assessments for large animals that correlate with neuropathologic axonal damage and may have wide applications in the fields of cardiac resuscitation, stroke, and hypoxic-ischemic brain injury.
doi:10.1016/j.expneurol.2006.10.010
PMCID: PMC1892165  PMID: 17174304
head injury; neurobehavioral assessment; axonal injury

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