Increased adrenomedullin in cerebrospinal fluid after traumatic brain injury in infants and children.

Adrenomedullin is a recently discovered 52-amino acid peptide that is a potent vasodilator and is produced in the brain in experimental models of cerebral ischemia. Infusion of adrenomedullin increases regional cerebral blood flow and reduces infarct volume after vascular occlusion in rats, and thus may represent an endogenous neuroprotectant. Disturbances in cerebral blood flow (CBF), including hypoperfusion and hyperemia, frequently occur after severe traumatic brain injury (TBI) in infants and children. We hypothesized that cerebrospinal fluid (CSF) adrenomedullin concentration would be increased after severe TBI in infants and children, and that increases in adrenomedullin would be associated with alterations in CBF. We also investigated whether posttraumatic CSF adrenomedullin concentration was associated with relevant clinical variables (CBF, age, Glasgow Coma Scale [GCS] score, mechanism of injury, and outcome). Total adrenomedullin concentration was measured using a radioimmunometric assay. Sixty-six samples of ventricular CSF from 21 pediatric patients were collected during the first 10 days after severe TBI (GCS score < 8). Control CSF was obtained from children (n = 10) undergoing lumbar puncture without TBI or meningitis. Patients received standard neurointensive care, including CSF drainage. CBF was measured using Xenon computed tomography (CT) in 11 of 21 patients. Adrenomedullin concentration was markedly increased in CSF of infants and children after severe TBI vs control (median 4.5 versus 1.0 fmol/mL, p < 0.05). Sixty-two of 66 CSF samples (93.9%) from head-injured infants and children had a total adrenomedullin concentration that was greater than the median value for controls. Increases in CSF adrenomedullin were most commonly observed early after TBI. CBF was positively correlated with CSF adrenomedullin concentration (p < 0.001), but this relationship was not significant when controlling for the effect of time. CSF adrenomedullin was not significantly associated with other selected clinical variables. We conclude adrenomedullin is markedly increased in the CSF of infants and children early after severe TBI. We speculate that adrenomedullin participates in the regulation of CBF after severe TBI.

Adenovirus-mediated transfer and expression of beta-gal in injured hippocampus after traumatic brain injury in mice.

In models of focal cerebral ischemia, adenoviral gene transfer is often attenuated or delayed versus naive. After controlled cortical impact (CCI)-induced traumatic brain injury in mice, CA1 and CA3 hippocampus exhibit delayed neuronal death by 3 days, with subsequent near complete loss of hippocampus by 21 days. We hypothesized that adenoviral-mediated expression of the reporter gene beta-Galactosidase (beta-Gal) in hippocampus would be attenuated after CCI in mice. C57BL6 mice (n = 16) were subjected to either CCI to left parietal cortex or sham (burr hole). Adenovirus carrying the beta-Gal gene (AdlacZ; 1 x 10(9) plaque-forming units [pfu]/mL) was then injected into left dorsal hippocampus. At 24 or 72 h, beta-Gal expression was quantified (mU/mg protein). Separate mice (n = 10) were used to study beta-Gal spatial distribution in brain sections. Beta-Gal expression in left hippocampus was similar in shams at 24 h (48.4 +/- 4.1) versus 72 h (68.8 +/- 8.8, not significant). CCI did not reduce beta-Gal expression in left hippocampus (68.8 +/- 8.8 versus 88.1 +/- 7.0 at 72 h, sham versus CCI, not significant). In contrast, CCI reduced beta-Gal expression in right (contralateral) hippocampus versus sham (p < 0.05 at both 24 and 72 h). Beta-Gal was seen in many cell types in ipsilateral hippocampus, including CA3 neurons. Despite eventual loss of ipsilateral hippocampus, adenovirus-mediated gene transfer was surprisingly robust early after CCI providing an opportunity to test novel genes targeting delayed hippocampal neuronal death.

Increased adenosine in cerebrospinal fluid after severe traumatic brain injury in infants and children: association with severity of injury and excitotoxicity.

OBJECTIVES: To measure adenosine concentration in the cerebrospinal fluid of infants and children after severe traumatic brain injury and to evaluate the contribution of patient age, Glasgow Coma Scale score, mechanism of injury, Glasgow Outcome Score, and time after injury to cerebrospinal fluid adenosine concentrations. To evaluate the relationship between cerebrospinal fluid adenosine and glutamate concentrations in this population. DESIGN: Prospective survey. SETTING: Pediatric intensive care unit in a university-based children's hospital. PATIENTS: Twenty-seven critically ill infants and children who had severe traumatic brain injury (Glasgow Coma Scale < 8), who required placement of an intraventricular catheter and drainage of cerebrospinal fluid as part of their neurointensive care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients ranged in age from 2 months to 14 yrs. Cerebrospinal fluid samples (n = 304) were collected from 27 patients during the first 7 days after traumatic brain injury. Control cerebrospinal fluid samples were obtained from lumbar puncture on 21 infants and children without traumatic brain injury or meningitis. Adenosine concentration was measured by using high-pressure liquid chromatography. Adenosine concentration was increased markedly in cerebrospinal fluid of children after traumatic brain injury vs. controls (p < .001). The increase in cerebrospinal fluid adenosine was independently associated with Glasgow Coma Scale < or = 4 vs. > 4 and time after injury (both p < .005). Cerebrospinal fluid adenosine concentration was not independently associated with either age (< or = 4 vs. > 4 yrs), mechanism of injury (abuse vs. other), or Glasgow Outcome Score (good/moderately disabled vs. severely disabled, vegetative, or dead). Of the 27 patients studied, 18 had cerebrospinal fluid glutamate concentration previously quantified by high-pressure liquid chromatography. There was a strong association between increases in cerebrospinal fluid adenosine and glutamate concentrations (p < .005) after injury. CONCLUSIONS: Cerebrospinal fluid adenosine concentration is increased in a time- and severity-dependent manner in infants and children after severe head injury. The association between cerebrospinal fluid adenosine and glutamate concentrations may reflect an endogenous attempt at neuroprotection against excitotoxicity after severe traumatic brain injury.

Increased adrenomedullin in cerebrospinal fluid after traumatic brain injury in children: a preliminary report.

Adrenomedullin is a recently discovered 52-amino-acid peptide that is a potent vasodilator. Infusion of adrenomedullin increases regional cerebral blood flow and reduces infarct volume after vascular occlusion in rats. Adrenomedullin may represent an endogenous neuroprotectant since it is increased after focal brain ischemia. Cerebral hypoperfusion is present after traumatic brain injury (TBI) in children. We hypothesized that adrenomedullin levels would be increased in children with severe TBI. Total adrenomedullin concentrations were measured using a radioimmunometric assay. Thirty-six samples of ventricular cerebrospinal fluid (CSF) from 10 pediatric patients were collected during the first 10 days after severe TBI (GCS < 8). Control CSF was obtained from 5 children undergoing lumbar puncture, who had normal CSF parameters and no evidence of central nervous system infection. Patients underwent standard neuro-intensive care, including cerebrospinal fluid drainage. Data were analyzed using a univariate regression model. Adrenomedullin concentration was markedly elevated in CSF of children following TBI versus control (mean level 10.65 vs 1.51 fmol/ml, p = 0.006). All 36 case samples had an adrenomedullin concentration above the median value for the controls (1.52 fmol/ml). We conclude adrenomedullin is elevated in the CSF of children following severe TBI. We speculate that it participates in the endogenous response to cerebral hypoperfusion after TBI.