Evidence for free radical mechanisms of brain injury resulting from ischemia/reperfusion-induced events.

Free radicals have been implicated in the injury that occurs to brain tissue in response to ischemia and reperfusion insults. Confirmatory in vivo studies have been limited by the difficulty in measuring free radicals in brain tissue. This review discusses potential mechanisms for free radical production in brain tissue and the evidence supporting the therapeutic efficacy of free radical scavengers. Free radicals may be produced during ischemia/reperfusion as a result of multiple mechanisms involving normal regulatory systems of intra-/extracellular metabolism. For example, metabolism of free fatty acids by the cyclo-oxygenase pathway and adenine nucleotides by xanthine oxidase has been proposed to produce free radical adducts during reperfusion. Therapeutic strategies aimed at decreasing brain injury from free radical production include administration of free radical scavengers at the time of reperfusion. Pharmacologic interventions for protection from free radical injury in brain are hindered because of limited access to the site of free production.

Increased hematocrit and decreased transfusion requirements in children given erythropoietin before undergoing craniofacial surgery.

OBJECT: This study was undertaken to determine the efficacy of preoperative erythropoietin administration in infants scheduled for craniofacial surgery and, in so doing, to minimize problems associated with blood transfusions. METHODS: Families were offered the option of having their children receive erythropoietin injections before undergoing craniofacial surgery. The children whose families accepted this option received daily iron and 300 U/kg erythropoietin three times per week for 3 weeks preoperatively. Weekly complete blood counts with reticulocyte counts were measured and transfusion requirements were noted. Blood transfusions were administered depending on the clinical condition of the child. A case-matched control population was also evaluated to compare initial hematocrit levels and transfusion requirements. Thirty patients in the erythropoietin treatment group and 30 control patients were evaluated. The dose of erythropoietin administered was shown to increase hematocrit levels from 35.4 +/- 0.9% to 43.3 +/- 0.9% during the course of therapy. The resulting hematocrit levels in patients treated with erythropoietin at the time of surgery were higher compared with baseline hematocrit levels obtained in control patients at the time of surgery (34.2 +/- 0.5%). Transfusion requirements also differed: all control patients received transfusions, whereas 64% (19 of 30) of erythropoietin-treated patients received transfusions. CONCLUSIONS: The authors conclude that treatment with erythropoietin in otherwise healthy young children will increase hematocrit levels and modify transfusion requirements. Erythropoietin therapy for elective surgery in children of this age must be individualized according to the clinical situation, family and physician beliefs, and cost effectiveness, as evaluated at the individual center.

Pediatric airway issues.

Airway management in the pediatric patient requires an understanding and knowledge of the differences and characteristics unique to the child and infant. New and exciting techniques are currently being explored and developed for management of the pediatric airway. Technology in the area of imaging has allowed clinicians to better visualize the airway and aberrations of it. Presently, there are many different modes and routes of ventilation and oxygenation that are being applied to the pediatric patient for different disease states. Work continues to probe for methods and ways that will allow us to take care of infants and children better and to provide the safest and most effective means of delivering that care. No doubt, there will be more advances and exciting ideas to come that lead to better management of the pediatric airway.

Airway pressure release ventilation in pediatrics.

OBJECTIVES: The purpose of this study was to determine the effectiveness of airway pressure release ventilation in children. DESIGN: Prospective, randomized, crossover clinical trial. SETTING: This study was conducted in our 33-bed pediatric intensive care unit at The Children's Hospital of Philadelphia. PATIENTS: Patients requiring mechanical ventilatory support and weighing >8 kg were considered for enrollment. Patients were excluded if they required mechanical ventilatory support for >7 days or required >.50 Fio(2) for >7 days before enrollment. Patients with documented obstructive airway disease and congenital or acquired heart disease were excluded as well. INTERVENTIONS: Each patient received both volume-controlled synchronized intermittent mechanical ventilation (SIMV) and airway pressure release ventilation (APRV) via the Drager Evita ventilator (Drager, Lubeck, Germany). Measurements were obtained after the patient was stabilized on each ventilation mode. Stabilization was defined as oxygenation, ventilation, hemodynamic variables, and patient comfort within the acceptable range for each patient as determined by the bedside physician. After measurements were obtained on the initial mode of ventilation, the subjects crossed over to the alternative study mode. Stabilization was again achieved, and measurements were repeated. After completion of the second study measurements, patients were placed on the ventilation modality preferred by the bedside clinician and were followed through weaning and extubation. Measurements: Vital signs, airway pressures, minute ventilation, Spo(2), and E(T)CO(2) were recorded at enrollment and at each study condition. MAIN RESULTS: APRV provided similar ventilation, oxygenation, mean airway pressure, hemodynamics, and patient comfort as SIMV. Inspiratory airway pressures were lower with APRV when compared with SIMV. CONCLUSIONS: Using APRV in children with mild to moderate lung disease resulted in comparable levels of ventilation and oxygenation at significantly lower inspiratory peak and plateau pressures. Based on these findings, we plan to evaluate APRV in children with significant lung disease.

Obstructive sleep apnea, control of ventilation, and anesthesia in children.

Pathologic disturbances in breathing in children become clinically apparent in the syndrome of obstructive sleep apnea. The surgical approach to this syndrome is often removal of hypertrophied tonsils and adenoids. The preoperative, operative, and postoperative concerns with special attention to the role of anesthesia are reviewed.

Purple glove syndrome.

Purple glove syndrome (PGS) often begins with discoloration and progresses to a petechial rash with induration or evidence of infiltration. The etiology of PGS is unknown, although various theories center around i.v. extravasation. We report a case of PGS in a child's foot associated with administration of Dilantin (phenytoin).

Recurrent seizures in a neonate after lidocaine administration.

OBJECTIVE: We report recurrent seizures in a neonate after intravenous lidocaine administration at the recommended dose for intubation and supplementation of general anesthesia. STUDY DESIGN: Further evaluation of this case included determination of serum lidocaine level, serum electrolyte levels, and arterial blood gas values; cerebral spinal fluid analysis; an electroencephalogram; head ultrasonography; brain stem auditory evoked response testing; and a complete developmental evaluation. Previously published literature discussing lidocaine toxicity and pharmacokinetics is reviewed. RESULTS: The lidocaine level in the patient was 0.3 mg/L 2 hours after the last dose was administered. Results of the remaining studies were within normal limits, and the patient had no additional seizures several months after birth. CONCLUSION: We caution that lidocaine administration to newborn infants at previously accepted doses may result in life-threatening side effects, including prolonged seizures.

Permissive hypercapnia with high-frequency oscillatory ventilation and one-lung isolation for intraoperative management of lung resection in a patient with multiple bronchopleural fistulae.

We report the use of high-frequency oscillatory ventilation in the operating room during repair of multiple bronchopleural fistulae in a 9-year-old boy. In addition, we used principles of permissive hypercapnia to further minimize barotrauma. There were no cardiovascular consequences due to either the high-frequency ventilation or the permissive hypercapnia. Our goals in employing this strategy were to minimize barotrauma, minimize gas flow through the fistulae, and optimize the surgical results.

Electroencephalographic monitoring during hypothermia after pediatric cardiac arrest.

BACKGROUND: Hypoxic ischemic brain injury secondary to pediatric cardiac arrest (CA) may result in acute symptomatic seizures. A high proportion of seizures may be nonconvulsive, so accurate diagnosis requires continuous EEG monitoring. We aimed to determine the safety and feasibility of long-term EEG monitoring, to describe electroencephalographic background and seizure characteristics, and to identify background features predictive of seizures in children undergoing therapeutic hypothermia (TH) after CA. METHODS: Nineteen children underwent TH after CA. Continuous EEG monitoring was performed during hypothermia (24 hours), rewarming (12-24 hours), and then an additional 24 hours of normothermia. The tolerability of these prolonged studies and the EEG background classification and seizure characteristics were described in a standardized manner. RESULTS: No complications of EEG monitoring were reported or observed. Electrographic seizures occurred in 47% (9/19), and 32% (6/19) developed status epilepticus. Seizures were nonconvulsive in 67% (6/9) and electrographically generalized in 78% (7/9). Seizures commenced during the late hypothermic or rewarming periods (8/9). Factors predictive of electrographic seizures were burst suppression or excessively discontinuous EEG background patterns, interictal epileptiform discharges, or an absence of the expected pharmacologically induced beta activity. Background features evolved over time. Patients with slowing and attenuation tended to improve, whereas those with burst suppression tended to worsen. CONCLUSIONS: EEG monitoring in children undergoing therapeutic hypothermia after cardiac arrest is safe and feasible. Electrographic seizures and status epilepticus are common in this setting but are often not detectable by clinical observation alone. The EEG background often evolves over time, with milder abnormalities improving and more severe abnormalities worsening.

Head injury in children.

Head injuries in children are frequently preventable. These injuries are usually the result of bicycle or motor vehicle accidents, abuse, or gun shot wounds. Maintenance of airway, breathing, and circulation immediately after the initial event may protect against ongoing cerebral damage. Despite these best efforts, brain injury often worsens after the initial insult (so called secondary brain injury). The pathophysiology of head injury has been more clearly delineated as a result of clinical and basic science research. It is still impossible to accurately predict, at the time of presentation, who will have a good and who will have a bad outcome. The focus of initial treatment is based on a sound understanding of cerebral pathophysiology, which is reviewed in this article. Maintenance of adequate cerebral blood flow and metabolism can be monitored by intracranial pressure monitors, jugular bulb catheter data, as well as noninvasive blood flow measurements. In the future, more specific pharmacologic agents will be available to prevent the sequence of events leading to secondary brain injury. A multidisciplinary approach to the treatment of the patients throughout their hospital and posthospital course is described. The hope is that early intervention and aggressive treatment will lead to improved outcome for children suffering head injury.

Anesthetic modulation of cerebral hemodynamic and evoked responses to transient middle cerebral artery occlusion in cats.

We measured cerebral blood flow and somatosensory evoked potentials during transient focal cerebral ischemia in cats to compare the effects of four commonly used anesthetic regimens: ketamine/fentanyl/N2O (fentanyl), pentobarbital, ketamine/alpha-chloralose (alpha-chloralose), and ketamine/halothane/N2O (halothane). Six cats in each group were subjected to 60 minutes of left middle cerebral artery occlusion followed by 120 minutes of reperfusion. Although the amplitude of the initial somatosensory evoked potential wave complex was highest in the alpha-chloralose group (58.6 +/- 16.5 microV) and smallest in the halothane group (27.5 +/- 5.7 microV), amplitude fell by 75% in all groups upon occlusion. Baseline cerebral blood flow varied substantially between groups (e.g., in the right intersylvian gyrus: fentanyl, 96 +/- 12; pentobarbital, 30 +/- 5; alpha-chloralose, 24 +/- 3; and halothane, 76 +/- 11 ml/min/100 g). Occlusion decreased cerebral blood flow to subcortical (e.g., left caudate) structures in all groups (fentanyl, 29 +/- 11%; pentobabital, 45 +/- 12%; alpha-chloralose, 27 +/- 13%; and halothane, 18 +/- 5% of baseline). Postischemic hyperemia occurred in the cortical regions of cats anesthetized with pentobarbital or alpha-chloralose that had reduced cerebral blood flows during occlusion but not in cats anesthetized with fentanyl (cerebral blood flow during occlusion not different from that of cats anesthetized with pentobarbital or alpha-chloralose) or halothane. After 120 minutes of reperfusion, cerebral blood flow had returned to baseline values in all groups. Recovery of cerebral blood flow and somatosensory evoked potential amplitude at that time did not differ among groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related cerebrovascular response to global ischemia in pigs.

We tested the hypothesis that 1- to 2-wk-old pigs (piglet) have improved recovery of cerebral blood flow (CBF), cerebral oxygen consumption (CMRO2), and somatosensory-evoked potentials (SEP) compared with 6- to 8-mo-old pigs (pig) after transient global cerebral ischemia. All animals were anesthetized with pentobarbital sodium. After tracheostomy ventilation was adjusted to maintain normoxia (arterial oxygen pressure, 100-150 mmHg) and normocarbia (arterial carbon dioxide pressure, 35-40 mmHg). Arterial blood gases, blood pressure, and hemoglobin concentration remained within physiological limits throughout the experiment. Cerebral ischemia was produced by sequentially tightening ligatures around the inferior vena cava and ascending aorta. During ischemia the electroencephalogram and SEP became isoelectric within 40 and 120 s, respectively. At 10 min of reperfusion hyperemia occurred in most brain regions (e.g., whole brain: piglet, 270 +/- 45%; pig, 316 +/- 48%). In pigs delayed hypoperfusion occurred in all regions except white matter. In contrast, piglets only had delayed hyperperfusion to the brain stem and caudate nucleus. Throughout reperfusion CMRO2 was decreased in pigs (3.3 +/- 0.4 to 1.9 +/- 0.2 ml.min-1.100 g-1) but was not different from control (2.7 +/- 0.3 ml.min-1.100 g-1) in piglets. By the end of reperfusion SEP amplitude was closer to control in piglets than pigs (55 +/- 9 vs. 32 +/- 4% of control). We conclude that 1- to 2-wk-old piglets have quicker return of CBF, CMRO2, and SEP to control values after global ischemia, which mechanistically may explain previous reports of improved neurological recovery in young animals after transient ischemia.

Age-related differences in recovery of blood flow and metabolism after cerebral ischemia in swine.

We tested two hypotheses: 1) that cerebral blood flow, oxygen consumption, and evoked potentials recover to preischemic values at 120 minutes of reperfusion more completely in 1-2-week-old piglets than in 6-10-month-old pigs after complete ischemia; and 2) that recovery of cerebral blood flow, oxygen consumption, and electrical function in piglets and pigs at 120 minutes of reperfusion is better after incomplete than after complete ischemia. During 30 minutes of ischemia produced by intracranial pressure elevation, cerebral blood flow determined by the microspheres technique was decreased to 0-1 ml/min/100 g with complete ischemia, to 1-10 ml/min/100 g with severe incomplete ischemia, or to 10-20 ml/min/100 g with moderate incomplete ischemia. During reperfusion after complete ischemia, both piglets and pigs demonstrated hyperemia but delayed hypoperfusion occurred in more brain regions in pigs, oxygen consumption returned to preischemic values in piglets but not in pigs (70 +/- 10% of preischemic values), and evoked potentials recovered better in piglets than in pigs (24 +/- 4% and 9 +/- 4% of preischemic values, respectively). Both piglets and pigs had fewer brain areas with hyperemia and hypoperfusion and improved oxygen consumption and electrical function during recovery from incomplete than from complete ischemia. We speculate that piglets tolerate complete ischemia better than pigs because of decreased reperfusion injury and that both groups recover better from incomplete than complete ischemia because of improved substrate supply during ischemia.

Comparison of cerebral blood flow by radionuclide cerebral angiography and by microspheres in cats.

BACKGROUND: Radionuclide cerebral angiography is commonly used as an adjunct to the diagnosis of brain death. Despite its acceptance as a diagnostic tool, it is not clear whether the absence of cerebral blood flow by radionuclide cerebral angiography denotes a complete lack of cerebral blood flow. METHODS: To compare cerebral blood flow estimated by radionuclide cerebral angiography with cerebral blood flow measured by the radiolabeled microsphere technique, we systematically varied cerebral perfusion pressure (mean arterial BP minus intracranial pressure) in anesthetized cats by infusing artificial cerebral spinal fluid into the lateral ventricle to increase intracranial pressure. We measured cerebral blood flow with both techniques as cerebral perfusion pressure was decreased from its baseline of 111 +/- 10 mm Hg to 20, 10, 5, 0, and less than 0 mm Hg, causing a stepwise decrease in cerebral blood flow. RESULTS: We found a correlation by regression analysis (r2 = .47, p less than .05) between radionuclide cerebral angiography and microsphere measurements of cerebral blood flow, when both blood flow measurements were expressed as a percentage of baseline values. However, if 20% of baseline flow was assigned as a cut-off point for critically low cerebral blood flow (based on human studies), radionuclide cerebral angiography was only 33% sensitive to detect critically reduced cerebral blood flow and had a positive predictive accuracy (of low-flow interpretation) of only 60%. Radionuclide cerebral angiography was unable to demonstrate a complete lack of cerebral blood flow, even in two instances when cerebral blood flow by microspheres was less than 0.1% of baseline. CONCLUSIONS: We conclude that the ability of radionuclide cerebral angiography to quantify low cerebral blood flow is poor, and that this technique may not identify severely reduced cerebral blood flow.

Pulmonary edema associated with child abuse: case reports and review of the literature.

Pulmonary edema has been an unreported finding in the evaluation of abused children. We describe 2 cases of pulmonary edema in abused infants, 1 after confessed suffocation and the other after inflicted head injury. A review of the literature regarding postobstructive and neurogenic pulmonary edema suggests useful inferences for the forensic evaluation of maltreated children who present with this finding.

Early hyperthermia after traumatic brain injury in children: risk factors, influence on length of stay, and effect on short-term neurologic status.

OBJECTIVES: a) To determine the risk factors for early hyperthermia after traumatic brain injury in children; b) to identify the contribution of early hyperthermia to neurologic status at pediatric intensive care unit (PICU) discharge and to PICU length of stay in head-injured children. STUDY DESIGN: Observational cohort study. SETTING: PICU at a tertiary care, university medical center. PATIENTS: Children (n = 117) admitted to a PICU from July 1995 to May 1997 with traumatic brain injury. These children had a median age of 5.4 yrs (3 wks to 15.2 yrs old), and 33.4% were girls. MEASUREMENTS AND MAIN RESULTS: Early hyperthermia (temperature >38.5 degrees C within the first 24 hrs of admission) occurred in 29.9% of patients admitted to the PICU with traumatic brain injury. Risk factors predicting early hyperthermia included Glasgow Coma Scale score in the emergency department < or =8, pediatric trauma score < or =8, cerebral edema or diffuse axonal injury on initial head computed tomography scan, admission blood glucose >150 mg/dL (8.2 mmol/L), admission white cell count >14,300 cells/mm3 (14.3 x 10(9) cells/L), and systolic hypotension. The presence of early hyperthermia significantly increased the risk for Glasgow Coma Scale score <13 at PICU discharge (odds ratio [OR] 9.7, 95% confidence interval [CI] 2.8, 24.4) and PICU stay > or =3 days (OR 13.8, CI 5.1, 37.5). When we used multiple logistic regression models including injury severity and hypotension, early hyperthermia remained an independent predictor of lower Glasgow Coma Scale score at PICU discharge (OR 4.7, CI 1.4, 15.6) and longer PICU length of stay (OR 8.5, CI 2.8, 25.6). CONCLUSIONS: Early hyperthermia is independently associated with a measure of early neurologic status and resource utilization in children with traumatic brain injury serious enough to require PICU admission. These results support the prevention of hyperthermia in the management of traumatic brain injury in children. Further research is required to understand the mechanisms of this response and to identify appropriate preventive or therapeutic interventions.

Age-related differences in acute physiologic response to focal traumatic brain injury in piglets.

INTRODUCTION: The goal of the present study was to determine whether age-related differences in the acute physiologic response to scaled cortical impact injury contribute to differences in vulnerability to traumatic brain injury (TBI). METHODS: Heart rate (HR), mean arterial pressure (MAP), brain temperature (BrT) and cerebral blood flow (CBF) were measured in 22 piglets (7 of age 5 days, 8 of age 1 month, 7 of age 4 months) at baseline and for 3 h following scaled cortical impact injury. RESULTS: There were no age-dependent variations from baseline in HR, MAP or BrT following injury. CBF increased in the 5-day-old animals following injury while CBF in the 1- and 4-month-old animals decreased following injury (p = 0.0049). CONCLUSION: CBF was shown to have a significant age-dependent response to TBI with the youngest animals exhibiting increased CBF following injury.