Richard Mink

Hyperbaric Oxygen After Global Cerebral Ischemia in Rabbits Reduces Brain Vascular Permeability and Blood Flow

BACKGROUND AND PURPOSE Hyperbaric oxygen (HBO) has been advocated as a therapy to improve neurological recovery after ischemia, since HBO may improve tissue oxygen delivery. We examined the effect of HBO treatment after global cerebral ischemia on early brain injury. METHODS Rabbits were subjected to 10 minutes of global cerebral ischemia by cerebrospinal fluid compression. After 30 minutes of reperfusion, rabbits either were subjected to HBO for 125 minutes and then breathed 100% O2 at ambient pressure for 90 minutes or breathed 100% O2 for 215 minutes. At the end of reperfusion and 90 minutes after exposure, brain vascular permeability and cerebral blood flow were measured. Somatosensory evoked potentials were monitored throughout the experiment. RESULTS HBO treatment reduced (P < .05) brain vascular permeability by 16% in gray matter and by 20% in white matter. Cerebral blood flow was lower (P < .05) in the HBO group (40.9 +/- 1.9 mL/min per 100 g, mean +/- SEM) compared with controls (50.8 +/- 2.0 mL/min per 100 g). Somatosensory evoked potential recovery was similar in the two groups (P > .05). CONCLUSIONS HBO administered after global cerebral ischemia promoted blood-brain barrier integrity. HBO treatment also reduced cerebral blood flow; this effect was not associated with a reduction in evoked potential recovery. Since neurological outcome after global cerebral ischemia is generally poor and treatment options are limited, HBO should be further investigated as a potential therapy.

Pediatric traumatic brain injury: not just little adults.

Purpose of reviewThis review will update the reader on the most significant recent findings with regards to both the clinical research and basic science of pediatric traumatic brain injury. Recent findingsThe developing brain is not simply a smaller version of the mature brain. Studies have uncovered important distinctions of the younger brain after traumatic brain injury, including an increased propensity for apoptosis, age-dependent parameters for cerebral blood flow and metabolism, development-specific biomarkers, increased likelihood of early posttraumatic seizures, differential sensitivity to commonly used neuroactive medications and altered neuroplasticity during recovery from injury. Specifically, there is strong preclinical evidence for increased neuronal apoptosis in the developing brain being triggered by anesthetics and anticonvulsants, making it paramount that future studies more clearly delineate preferred agents and specific indications for use, incorporating long-term functional outcomes as well as short-term benefits. In addition, the young brain may actually benefit from therapeutic interventions that have been less effective following adult traumatic brain injury, such as decompressive craniectomy and hypothermia. SummaryAn increasing body of evidence demonstrates the importance of establishing age-dependent guidelines for physiological monitoring, pharmacological intervention, management of intracranial pressure and facilitating recovery of function.

Hyperbaric oxygen after global cerebral ischemia in rabbits does not promote brain lipid peroxidation.

OBJECTIVE To determine whether hyperbaric oxygen administered immediately after global cerebral ischemia increases free radical generation and lipid peroxidation in the brain or alters neurophysiologic recovery. DESIGN Prospective, randomized, controlled trial. SETTING Animal research laboratory. SUBJECTS Adult male New Zealand white rabbits. INTERVENTIONS Anesthetized rabbits were subjected to 10 mins of global cerebral ischemia by infusing a mock cerebrospinal fluid into the subarachnoid space and increasing intracranial pressure equal to mean arterial pressure. Immediately upon reperfusion, one group of rabbits (n = 9) was treated with hyperbaric oxygen at 2.8 atmospheres absolute for 75 mins while the control group (n = 9) breathed room air for an equivalent period of time. At the end of the reperfusion period, oxyradical brain damage was determined by measuring brain levels of oxidized and total glutathione and free malondialdehyde. Neurophysiologic brain injury was assessed with cortical somatosensory evoked potentials. MEASUREMENTS AND MAIN RESULTS Both oxidized glutathione and the ratio of oxidized glutathione to reduced glutathione (total minus oxidized) were higher (p < .05) in the hyperbaric oxygen group, indicating that hyperbaric oxygen increased free radical generation. Nonetheless, brain malondialdehyde content, an index of lipid peroxidation, was similar (p > .05) in the two groups. Cortical somatosensory evoked potential recovery at the end of reperfusion was 50% higher (p < .05) in the hyperbaric oxygen-treated animals compared with controls. CONCLUSIONS Treatment with hyperbaric oxygen after ischemia increased the amount of oxygen free radicals in the brain. However, this increase in free radical generation was not associated with an increase in lipid peroxidation or a reduction in neurophysiologic recovery when measured after 75 mins of recirculation. These results suggest that hyperbaric oxygen administered immediately after global ischemia does not promote early brain injury.

Acute care clinical indicators associated with discharge outcomes in children with severe traumatic brain injury.

Objective:The effect of the 2003 severe pediatric traumatic brain injury (TBI) guidelines on outcomes has not been examined. We aimed to develop a set of acute care guideline–influenced clinical indicators of adherence and tested the relationship between these indicators during the first 72 hours after hospital admission and discharge outcomes. Design:Retrospective multicenter cohort study. Setting:Five regional pediatric trauma centers affiliated with academic medical centers. Patients:Children under 18 years with severe traumatic brain injury (admission Glasgow Coma Scale score ⩽ 8, International Classification of Diseases, 9th Edition, diagnosis codes of 800.0–801.9, 803.0–804.9, 850.0–854.1, 959.01, 950.1–950.3, 995.55, maximum head abbreviated Injury Severity Score ≥ 3) who received tracheal intubation for at least 48 hours in the ICU between 2007 and 2011 were examined. Interventions:None. Measurements and Main Results:Total percent adherence to the clinical indicators across all treatment locations (prehospital, emergency department, operating room, and ICU) during the first 72 hours after admission to study center were determined. Main outcomes were discharge survival and Glasgow Outcome Scale score. Total adherence rate across all locations and all centers ranged from 68% to 78%. Clinical indicators of adherence were associated with survival (adjusted hazard ratios, 0.94; 95% CI, 0.91–0.96). Three indicators were associated with survival: absence of prehospital hypoxia (adjusted hazard ratios, 0.20; 95% CI, 0.08–0.46), early ICU start of nutrition (adjusted hazard ratios, 0.06; 95% CI, 0.01–0.26), and ICU PaCO2 more than 30 mm Hg in the absence of radiographic or clinical signs of cerebral herniation (adjusted hazard ratios, 0.22; 95% CI, 0.06–0.8). Clinical indicators of adherence were associated with favorable Glasgow Outcome Scale among survivors (adjusted hazard ratios, 0.99; 95% CI, 0.98–0.99). Three indicators were associated with favorable discharge Glasgow Outcome Scale: all operating room cerebral perfusion pressure more than 40 mm Hg (adjusted relative risk, 0.61; 95% CI, 0.58–0.64), all ICU cerebral perfusion pressure more than 40 mm Hg (adjusted relative risk, 0.73; 95% CI, 0.63–0.84), and no surgery (any type; adjusted relative risk, 0.68; 95% CI, 0.53– 0.86). Conclusions:Acute care clinical indicators of adherence to the Pediatric Guidelines were associated with significantly higher discharge survival and improved discharge Glasgow Outcome Scale. Some indicators were protective, regardless of treatment location, suggesting the need for an interdisciplinary approach to the care of children with severe traumatic brain injury.

Metabolic Levels in the Corpus Callosum and Their Structural and Behavioral Correlates after Moderate to Severe Pediatric TBI

Diffuse axonal injury (DAI) secondary to traumatic brain injury (TBI) contributes to long-term functional morbidity. The corpus callosum (CC) is particularly vulnerable to this type of injury. Magnetic resonance spectroscopy (MRS) was used to characterize the metabolic status of two CC regions of interest (ROIs) (anterior and posterior), and their structural (diffusion tensor imaging; DTI) and neurobehavioral (neurocognitive functioning, bimanual coordination, and interhemispheric transfer time [IHTT]) correlates. Two groups of moderate/severe TBI patients (ages 12-18 years) were studied: post-acute (5 months post-injury; n = 10), and chronic (14.7 months post-injury; n = 8), in addition to 10 age-matched healthy controls. Creatine (energy metabolism) did not differ between groups across both ROIs and time points. In the TBI group, choline (membrane degeneration/inflammation) was elevated for both ROIs at the post-acute but not chronic period. N-acetyl aspartate (NAA) (neuronal/axonal integrity) was reduced initially for both ROIs, with partial normalization at the chronic time point. Posterior, not anterior, NAA was positively correlated with DTI fractional anisotropy (FA) (r = 0.88), and most domains of neurocognition (r range 0.22-0.65), and negatively correlated with IHTT (r = -0.89). Inverse corerlations were noted between creatine and posterior FA (r = -0.76), neurocognition (r range -0.22 to -0.71), and IHTT (r = 0.76). Multimodal studies at distinct time points in specific brain structures are necessary to delineate the course of the degenerative and reparative processes following TBI, which allows for preliminary hypotheses about the nature and course of the neural mechanisms of subsequent functional morbidity. This will help guide the future development of targeted therapeutic agents.

Low-dose inhaled nitric oxide improves the oxygenation and ventilation of infants and children with acute, hypoxemic respiratory failure.

OBJECTIVE To describe the effects of inhaled nitric oxide on oxygenation and ventilation in patients with acute, hypoxic respiratory failure and to characterize those who respond to low doses with a significant improvement in PaO2. DESIGN Prospective dose response trial of inhaled nitric oxide. Patients who demonstrated a > or =15% improvement in PaO2 were randomized to receive conventional mechanical ventilation with or without prolonged inhaled nitric oxide. SETTING Pediatric intensive care unit of a tertiary care childrens hospital serving as a regional referral center for respiratory failure. PATIENTS Pediatric patients with an acute parenchymal lung disease requiring mechanical ventilation, an F(IO2) of > or =0.5, a positive end-expiratory pressure of > or =7 cm H2O, and whose PaO2/FIO2 ratio was < or =160. INTERVENTIONS PaO2, PaCO2, pH, heart rate, blood pressure, and methemoglobin were recorded at baseline and after inhaling 1, 5, 10, and 20 ppm of nitric oxide. Peak expiratory flow rate and mean airway resistance were measured while subjects received 0 and 20 ppm of inhaled nitric oxide. Patients were followed up until extubation or death. MEASUREMENTS AND MAIN RESULTS Twenty-six patients (median age, 2.6 yrs [range, 1 mo-18.2 yrs]) were enrolled in the study. PaO2 increased (p< .001) and Pa(CO2) fell (p< .0001) from baseline with the administration of inhaled nitric oxide. There was no statistical difference among 1, 5, 10, and 20 ppm with regard to effects on oxygenation. Sixteen patients (62%) responded to inhaled nitric oxide with a > or =15% improvement in PaO2; 14 of these responses occurred at a dose of 1 or 5 ppm. Response to inhaled nitric oxide was not associated with age, length of intubation, presence of primary lung disease, chest radiograph, or illness severity. Among patients weighing < or =20 kg, responders showed a greater fall in mean airway resistance (p < .05) than nonresponders. Mortality was not influenced by prolonged inhaled nitric oxide when analyzed by intention to treat. Patients receiving prolonged inhaled nitric oxide at doses of < or =20 ppm maintained methemoglobin levels of <3.0% and circuit concentrations of NO2 of <1 ppm. CONCLUSIONS Inhaled nitric oxide at doses of < or =5 ppm improves the oxygenation and (to a lesser extent) ventilation of most children with acute, hypoxic respiratory failure. The unpredictable response of patients necessitates individualized dosing of inhaled nitric oxide, starting at concentrations of < or =1 ppm. Inhaled nitric oxide at < or =20 ppm may exert a small salutary effect on bronchial tone. The benefits of prolonged inhaled nitric oxide remain unknown.

White matter disruption in moderate/severe pediatric traumatic brain injury: Advanced tract-based analyses

Traumatic brain injury (TBI) is the leading cause of death and disability in children and can lead to a wide range of impairments. Brain imaging methods such as DTI (diffusion tensor imaging) are uniquely sensitive to the white matter (WM) damage that is common in TBI. However, higher-level analyses using tractography are complicated by the damage and decreased FA (fractional anisotropy) characteristic of TBI, which can result in premature tract endings. We used the newly developed autoMATE (automated multi-atlas tract extraction) method to identify differences in WM integrity. 63 pediatric patients aged 8–19 years with moderate/severe TBI were examined with cross sectional scanning at one or two time points after injury: a post-acute assessment 1–5 months post-injury and a chronic assessment 13–19 months post-injury. A battery of cognitive function tests was performed in the same time periods. 56 children were examined in the first phase, 28 TBI patients and 28 healthy controls. In the second phase 34 children were studied, 17 TBI patients and 17 controls (27 participants completed both post-acute and chronic phases). We did not find any significant group differences in the post-acute phase. Chronically, we found extensive group differences, mainly for mean and radial diffusivity (MD and RD). In the chronic phase, we found higher MD and RD across a wide range of WM. Additionally, we found correlations between these WM integrity measures and cognitive deficits. This suggests a distributed pattern of WM disruption that continues over the first year following a TBI in children.

Bacterial Endosymbiosis Is Widely Present among Zygomycetes but Does Not Contribute to the Pathogenesis of Mucormycosis

Environmental isolates of the fungus Rhizopus have been shown to harbor a bacterial endosymbiont (Burkholderia) that produces rhixozin, a plant mycotoxin. We sought to define the role of rhizoxin production by endosymbionts in the pathogenesis of mucormycosis. Endosymbiotic bacteria were identified by polymerase chain reaction in 15 (54%) of 28 clinical isolates of Zygomycetes, with 33% of the bacterial strains showing 87% identity to Burkholderia 16S rDNA. The presence of rhizoxin in myclial extracts from fungi harboring bacteria was confirmed by high-performance liquid chromatography analysis. However, fungal strains with or without endosymbionts did not differ in their ability to cause endothelial cell injury in vitro, nor did antibiotic-mediated eradication of endosymbionts and rhizoxin production decrease the virulence of fungal strains in mice or flies. In summary, although bacterial endosymbiosis is widely detected in clinical isolates of Zygomycetes, including Rhizopus oryzae strains, we found no evidence that bacterial endosymbionts and rhizoxin contribute to the pathogenesis of mucormycosis in the models studied.

National Variability in Intracranial Pressure Monitoring and Craniotomy for Children With Moderate to Severe Traumatic Brain Injury

BACKGROUND Traumatic brain injury (TBI) is a significant cause of mortality and disability in children. Intracranial pressure monitoring (ICPM) and craniotomy/craniectomy (CRANI) may affect outcomes. Sources of variability in the use of these interventions remain incompletely understood. OBJECTIVE To analyze sources of variability in the use of ICPM and CRANI. METHODS Retrospective cross-sectional study of patients with moderate/severe pediatric TBI with the use of data submitted to the American College of Surgeons National Trauma Databank. RESULTS We analyzed data from 7140 children at 156 US hospitals during 7 continuous years. Of the children, 27.4% had ICPM, whereas 11.7% had a CRANI. Infants had lower rates of ICPM and CRANI than older children. A lower rate of ICPM was observed among children hospitalized at combined pediatric/adult trauma centers than among children treated at adult-only trauma centers (relative risk = 0.80; 95% confidence interval 0.66-0.97). For ICPM and CRANI, 18.5% and 11.6%, respectively, of residual model variance was explained by between-hospital variation in care delivery, but almost no correlation was observed between within-hospital tendency toward performing these procedures. CONCLUSION Infants received less ICPM than older children, and children hospitalized at pediatric trauma centers received less ICPM than children at adult-only trauma centers. In addition, significant between-hospital variability existed in the delivery of ICPM and CRANI to children with moderate-severe TBI.

Elevation of brain natriuretic peptide levels in children with septic shock.

Objectives: 1) To compare brain natriuretic peptide levels in pediatric patients with septic shock with both children admitted to the pediatric intensive care unit without infection and with healthy subjects; and 2) to evaluate the correlation between brain natriuretic peptide with severity of illness and with myocardial dysfunction in children with septic shock. Design: Prospective, observational study. Setting: Childrens Hospital pediatric intensive care unit. Patients: Children from age 2 wks to 18 yrs. Thirteen children with septic shock requiring inotropic support, 12 healthy controls, and five critically ill patients without infection or heart disease were evaluated. Interventions: For patients with septic shock, brain natriuretic peptide was measured within 6 hrs of admission and throughout the pediatric intensive care unit course. Echocardiograms were performed within 12 hrs of admission and then repeated if the patient continued to require inotropic support. For controls, one measurement was performed. Measurements and Main Results: Children with septic shock had an elevated (p < 0.0001) brain natriuretic peptide on admission (median 115 pg/mL [range 26–2960]) when compared with healthy (9 pg/mL [5–30]) and pediatric intensive care unit controls (10 pg/mL [5–30]). In patients with septic shock, brain natriuretic peptide at 12 hrs correlated directly with Pediatric Risk of Mortality III score (rs = .80, p = 0.002) and inversely with fractional shortening (rs = −.66, p = 0.014). In children with cold shock, brain natriuretic peptide at 12 hrs (718 pg/mL) [63–1530] was higher (p = 0.007) than in those with warm shock (208 pg/mL [20–366]). There was no pattern (p > 0.05) observed for brain natriuretic peptide over time. Conclusions: Brain natriuretic peptide measured early after admission is increased in children with septic shock, especially in those with cold shock. In addition, the level at 12 hrs correlates with both severity of illness and myocardial dysfunction. Brain natriuretic peptide may be useful in assessing myocardial dysfunction from septic shock, particularly in identifying children with cold shock. Further studies are warranted to determine whether this measurement will be helpful in guiding therapy in pediatric septic shock.