Pediatric critical care medicine: planning for our research future.

Objective: To introduce to the pediatric critical care medicine community a new program in pediatric critical care medicine at the National Institutes of Health.

Data Source: Summary of literature review and conference proceedings.

Data Synthesis: At the National Institute of Child Health and Human Development (NICHD), a new program in pediatric critical care and rehabilitation research has been established in the National Center for Medical Rehabilitation Research.

Caspase-8 expression and proteolysis in human brain after severe head injury.

Programmed cell death involves a complex and interrelated cascade of cysteine proteases termed caspases that are synthesized as inactive zymogens, which are proteolytically processed to active enzymes. Caspase-8 is an initiator caspase that becomes activated when Fas death receptor-Fas ligand (FasL) coupling on the cell surface leads to coalescence of a "death complex" perpetuating the programmed cell death cascade. In this study, brain tissue samples removed from adult patients during the surgical management of severe intracranial hypertension after traumatic brain injury (TBI; n=17) were compared with postmortem control brain tissue samples (n=6).

Moderate hypothermia may be detrimental after traumatic brain injury in fentanyl-anesthetized rats.

Objectives: To determine whether transient, moderate hypothermia is beneficial after traumatic brain injury in fentanyl-anesthetized rats.

Design: Prospective, randomized study.

Setting: University-based animal research facility.

A dual role for poly-ADP-ribosylation in spatial memory acquisition after traumatic brain injury in mice involving NAD+ depletion and ribosylation of 14-3-3gamma.

Poly(ADP-ribose) polymerase-1 (PARP-1) is a homeostatic enzyme that paradoxically contributes to disturbances in spatial memory acquisition after traumatic brain injury (TBI) in transgenic mice, thought to be related to depletion of its substrate nicotinamide adenine dinucleotide (NAD+). In this study, systemic administration of the PARP-1 inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) after TBI preserved brain NAD+ levels and dose-dependently reduced poly-ADP-ribosylation 24 h after injury. While moderate-dose INH2BP improved spatial memory acquisition after TBI; strikingly, both injured- and sham-mice receiving high-dose INH2BP were unable to learn in the Morris-water maze.

Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress.

Poly(ADP-ribosylation), primarily via poly(ADP-ribose) polymerase-1 (PARP-1), is a pluripotent cellular process important for maintenance of genomic integrity and RNA transcription in cells. However, during conditions of oxidative stress and energy depletion, poly(ADP-ribosylation) paradoxically contributes to mitochondrial failure and cell death. Although it has been presumed that poly(ADP-ribosylation) within the nucleus mediates this pathologic process, PARP-1 and other poly(ADP-ribosyltransferases) are also localized within mitochondria.

Induced hyperthermia exacerbates neurologic neuronal histologic damage after asphyxial cardiac arrest in rats.

Background: Temperature is an important modulator of the evolution of ischemic brain injury--with hypothermia lessening and hyperthermia exacerbating damage. We recently reported that children resuscitated from predominantly asphyxial arrest often develop an initial spontaneous hypothermia followed by delayed hyperthermia. The initial hypothermia observed in these children was frequently treated with warming lights which, despite careful monitoring, often resulted in overshoot hyperthermia.

Alterations in inducible 72-kDa heat shock protein and the chaperone cofactor BAG-1 in human brain after head injury.

The stress response in injured brain is well characterized after experimental ischemic and traumatic brain injury (TBI); however, the induction and regulation of the stress response in humans after TBI remains largely undefined. Accordingly, we examined injured brain tissue from adult patients (n = 8) that underwent emergent surgical decompression after TBI, for alterations in the inducible 72-kDa heat shock protein (Hsp70), the constitutive 73-kDa heat shock protein (Hsc70), and isoforms of the chaperone cofactor BAG-1. Control samples (n = 6) were obtained postmortem from patients dying of causes unrelated to CNS trauma.

Mild hypothermia during hemorrhagic shock in rats improves survival without significant effects on inflammatory responses.

Objective: To explore the hypothesis that the survival benefit of mild, therapeutic hypothermia during hemorrhagic shock is associated with inhibition of lipid peroxidation and the acute inflammatory response.

Design: Prospective and randomized.

Setting: Animal research facility.

Promising strategies to minimize secondary brain injury after head trauma.

Objective: To review novel therapeutic approaches in the treatment of severe traumatic brain injury.

Design: Eighty-three studies were reviewed specific to the treatment of traumatic brain injury, in either experimental models or in patients.

Conclusion: Four therapeutic strategies appear to be the most promising approaches currently in clinical trials for severe traumatic brain injury: a) the novel pharmacologic agent dexanabinol; b) hypertonic saline; c) mild hypothermia; and d) decompressive craniectomy.

Changes in expression of amyloid precursor protein and interleukin-1beta after experimental traumatic brain injury in rats.

There is increasing evidence linking neurodegenerative mechanisms in Alzheimer's disease (AD) and traumatic brain injury (TBI), including increased production of amyloid precursor protein (APP), and amyloid-beta (Abeta) peptide. In vitro data indicate that expression of APP may be regulated in part by the inflammatory cytokine IL-1beta. To further investigate the mechanisms involved, we measured APP and IL-1beta protein levels and examined immunohistochemical localization of APP in brain tissue from rats subjected to controlled cortical impact (CCI) injury.

Increased S-nitrosothiols and S-nitrosoalbumin in cerebrospinal fluid after severe traumatic brain injury in infants and children: indirect association with intracranial pressure.

Nitric oxide (NO) is implicated in both secondary damage and recovery after traumatic brain injury (TBI). Transfer of NO groups to cysteine sulfhydryls on proteins produces S-nitrosothiols (RSNO). S-nitrosothiols may be neuroprotective after TBI by nitrosylation of N-methyl-D-aspartate receptor and caspases.

Serum S100B concentrations are increased after closed head injury in children: a preliminary study.

Traumatic brain injury (TBI) is a leading cause of death and disability in children. The current gold standards for diagnosis of TBI after closed head injury (CHI) have limitations, particularly in cases of inflicted injury. S100B is a protein that is specific to astrocytes.

Effect of hyperventilation on extracellular concentrations of glutamate, lactate, pyruvate, and local cerebral blood flow in patients with severe traumatic brain injury.

Objective: To determine the potential adverse effects of brief periods of hyperventilation commonly used for acute neurologic deterioration.

Design: Prospective clinical trial.

Setting: University medical school.

Cerebral blood flow at one year after controlled cortical impact in rats: assessment by magnetic resonance imaging.

Progressive tissue loss and delayed cognitive deficits are seen in rats during the initial year after experimental traumatic brain injury (TBI). As much as 10% of parenchymal volume is lost even in the contralateral hemisphere by 1 year after controlled cortical impact (CCI) in rats. Progressive declines in cerebral blood flow (CBF) are also associated with advanced age and neurodegenerative diseases.

Systemic hypothermia, but not regional gut hypothermia, improves survival from prolonged hemorrhagic shock in rats.

Background: Extracorporeal blood perfusion of the gut or enterectomy can improve survival during hemorrhagic shock (HS), suggesting that the gut may be of primary importance in resuscitation. We hypothesized that cooling the gut alone could improve survival in a rat HS model and avoid potential deleterious effects of systemic hypothermia.

Methods: Thirty-two Sprague-Dawley rats were anesthetized with halothane.

Critical mechanisms of secondary damage after inflicted head injury in infants and children.

A number of critical mechanisms are involved in the pathophysiology of inflicted head injury. Excitotoxicity, oxidative stress, inflammation, programmed cell death, and mediators of blood flow and metabolism all contribute to secondary injury after abusive head trauma. These mechanisms are reviewed and the implications for clinical practice discussed.

Administration of adenosine receptor agonists or antagonists after controlled cortical impact in mice: effects on function and histopathology.

Adenosine is an endogenous neuroprotectant via anti-excitotoxic effects at A(1) receptors, and blood flow promoting and anti-inflammatory effects at A(2a) receptors. Previous studies showed improved motor function after fluid percussion injury (FPI) in rats treated with the broad-spectrum adenosine receptor agonist 2-chloroadenosine (2-CA). We studied the effects of 2-CA, a specific A(1) agonist (2-chloro-N(6)-cyclopentyladenosine, CCPA), and a specific A(1) antagonist (8-cyclopentyl-1,3-dipropylxanthine, DPCPX) on motor task and Morris water maze (MWM) performance, and histopathology (contusion volume, hippocampal cell counts) after controlled cortical impact (CCI) in mice.

Conventional and functional proteomics using large format two-dimensional gel electrophoresis 24 hours after controlled cortical impact in postnatal day 17 rats.

Conventional and functional proteomics have significant potential to expand our understanding of traumatic brain injury (TBI) but have not yet been used. The purpose of the present study was to examine global hippocampal protein changes in postnatal day (PND) 17 immature rats 24 h after moderate controlled cortical impact (CCI). Silver nitrate stains or protein kinase B (PKB) phosphoprotein substrate antibodies were used to evaluate high abundance or PKB pathway signal transduction proteins representing conventional and functional proteomic approaches, respectively.

Intranuclear localization of apoptosis-inducing factor (AIF) and large scale DNA fragmentation after traumatic brain injury in rats and in neuronal cultures exposed to peroxynitrite.

Programmed cell death occurs after ischemic, excitotoxic, and traumatic brain injury (TBI). Recently, a caspase-independent pathway involving intranuclear translocation of mitochondrial apoptosis-inducing factor (AIF) has been reported in vitro; but whether this occurs after acute brain injury was unknown. To address this question adult rats were sacrificed at various times after TBI.

Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury.

Increases in brain interstitial excitatory amino acid (EAA(I)) concentrations after ischemia are ameliorated by use-dependent Na+ channel antagonists and by supplementing interstitial glucose, but the regulation of EAA(I) after traumatic brain injury (TBI) is unknown. We studied the regulation of EAA(I) after TBI using the controlled cortical impact model in rats. To monitor changes in EAA(I), microdialysis probes were placed in the cortex adjacent to the contusion and in the ipsilateral hippocampus.

Regulation of interstitial excitatory amino acid concentrations after cortical contusion injury.

Increases in brain interstitial excitatory amino acid (EAA(I)) concentrations after ischemia are ameliorated by use-dependent Na+ channel antagonists and by supplementing interstitial glucose, but the regulation of EAA(I) after traumatic brain injury (TBI) is unknown. We studied the regulation of EAA(I) after TBI using the controlled cortical impact model in rats. To monitor changes in EAA(I), microdialysis probes were placed in the cortex adjacent to the contusion and in the ipsilateral hippocampus.

Clinical trials in head injury.

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate significant long-term disabilities.

Acute systemic administration of interleukin-10 suppresses the beneficial effects of moderate hypothermia following traumatic brain injury in rats.

Traumatic injury to the central nervous system initiates inflammatory processes such as the synthesis of proinflammatory mediators that contribute to secondary tissue damage. Hence, administration of anti-inflammatory cytokines, such as interleukin-10 (IL-10) may be neuroprotective. Moderate hypothermia (30-32 degrees C) also decreases the pro-inflammatory response to traumatic brain injury (TBI).

Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children.

Studies in experimental traumatic brain injury (TBI) support a key role for oxidative stress. The degree of oxidative injury in clinical TBI, however, remains to be defined. We assessed antioxidant defenses and oxidative stress in pediatric TBI by applying a comprehensive battery of assays to cerebrospinal fluid samples.