Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock

OBJECTIVE: We investigated whether serum levels of neuron-specific enolase (NSE) and S-100beta protein could be used to evaluate cerebral injury and to predict outcome in severe sepsis and severe septic shock. DESIGN: Prospective study. SETTING: University hospital. PATIENTS AND MEASUREMENTS: In 170 consecutively enrolled patients with severe sepsis and septic shock, serum S-100beta and NSE were measured daily during four consecutive days after intensive care unit admission. Admission Glasgow Coma Scale before sedation and daily Sequential Organ Failure Assessment scores were recorded in all patients. Acute encephalopathy was defined as either a state of agitation, confusion, irritability, and convulsions (type A) or characterized by somnolence, stupor, and coma (type B) and persistently observed during 72 hrs after withdrawing sedation. When clinically indicated, contrast computed tomography or magnetic resonance imaging were performed to evaluate brain injury. MAIN RESULTS: S-100beta and NSE increased in, respectively, 72 (42%) and 90 (53%) patients. High biomarker levels were associated with the maximum Sequential Organ Failure Assessment scores (p = .001), and the highest values were found in patients who died early, within 4 days of inclusion (p = .005). Low consciousness encephalopathy type B was more frequently observed in patients with elevated S-100beta (p = .004). S-100beta levels of >or=4 microg/L were associated with severe brain ischemia or hemorrhage, and values of <2 microg/L were found in patients with diffuse cerebral embolic infarction lesions. High S-100beta levels were associated with higher intensive care unit mortality (p = .04) and represented the strongest independent predictor of intensive care unit survival, whereas NSE and the Glasgow Coma Scale failed to predict fatal outcome. CONCLUSIONS: S-100beta and NSE are frequently increased and associated with brain injury in patients with severe sepsis and septic shock. S-100beta levels more closely reflected severe encephalopathy and type of brain lesions than NSE and the Glasgow Coma Scale.     

Predictors of outcome in severely head-injured children

OBJECTIVE: Determine variables in the acute care period associated with survival and pediatric intensive care unit (PICU) length of stay (LOS) for children with severe traumatic brain injury. DESIGN: Retrospective cohort. SETTING: Level 1 pediatric trauma center. PATIENTS: Children (0-17 yrs) admitted 1991 to 1995 with nonpenetrating traumatic brain injury and admission Glasgow Coma Scale score of or=14. Predictors of outcome were abstracted, including Pediatric Trauma Score, Glasgow Coma Scale score, Pediatric Risk of Mortality, physiologic variables, computed tomography evidence of brain injury, and neuroresuscitative medications. The fatality rate was 24%. Age and gender were similar between groups (p >or= .1). Survival was independently predicted by 6-hr Glasgow Coma Scale score (odds ratio [OR] 4.6; 95% confidence interval [CI] 2.06-11.9; p < .001) and maximum systolic blood pressure (OR 1.05; 95% CI 1.01-1.09; p < .02). Odds of survival increased 19-fold when maximum systolic blood pressure was >or=135 mm Hg (OR 18.8; 95% CI 2.0-178.0; p < .01). By discharge, 67% of patients had an age-appropriate Glasgow Coma Scale score. Median hospital costs were 8,798 dollars for survivors: only mannitol use independently predicted high cost (odds ratio 4.9; 95% CI 1.2-19.1; p < .01). For survivors, median PICU LOS was 2 days, although 25% had LOS >6 days. Six-hour Glasgow Coma Scale score (OR 0.62; 95% CI 0.48-0.80; p < .001) and mannitol (OR 7.9; 95% CI 2.3-27.3; p < .001) were each independently associated with a prolonged LOS among survivors. CONCLUSIONS: Patients with higher 6-hr Glasgow Coma Scale scores were more likely to survive. Adjusting for severity of injury, survival was associated with maximum systolic blood pressure >or=135 mm Hg, suggesting that supranormal blood pressures are associated with improved outcome. Mannitol administration was associated with prolonged LOS, yet conferred no survival advantage. We suggest reevaluation of blood pressure targets and mannitol use in children with severe traumatic brain injury.     

The early fall in levels of S-100 beta in traumatic brain injury.

Protein S-100 beta has been suggested as a prognostic marker in traumatic brain injury. However, little is known of its behaviour in the immediate post-injury period. With Ethics Committee approval, we recruited 30 patients with a history of head injury presenting to our Accident and Emergency Department. Blood was taken on arrival and at four hours post-injury. Serum S-100 beta was estimated using an immunoluminometric assay. Levels of S-100 beta were seen to fall rapidly with time. Half-time was distributed non-parametrically with a median of 198 minutes. Using the Mann-Whitney U test we found a statistically significant difference between non-desirable (Glasgow Outcome Score 1-3) and desirable (Glasgow Outcome Score 4-5) outcome on admission (p = 0.0155) but not at four hours (p = 0.1336). Levels of S-100 beta fell rapidly after its release following traumatic brain injury. Time after injury is therefore critical in assessing the significance of levels of S-100 beta, and sampling should be as early as possible to gain maximum information. If S-100 beta is to be assessed as a monitor of ongoing brain injury in the intensive therapy unit sampling must be frequent (e.g. every 4 hours) to be able to detect rises in serum levels before they have decayed to baseline.     

Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury

S100B protein (S100B) has been described as a marker of brain injury. Various cytokines also increase in the cerebrospinal fluid (CSF) of patients with severe traumatic brain injury (TBI). Thus, we investigated early changes in the concentrations of CSF S100B and various cytokines after TBI and evaluated the relations of both S100B and cytokines to intracranial pressure (ICP) and prognosis. Twenty-three patients with severe TBI and a Glasgow Coma Scale score of 8 or less on admission were included in this study. CSF and serum samples were obtained on admission and at 6, 12, 24, 48, 72, and 96 h after injury. CSF concentrations of S100B and CSF and serum concentrations of five cytokines (IL-1beta, TNF-alpha, IL-6, IL-8, and IL-10) were measured and compared. The CSF S100B concentration was increased for 6 h after injury and decreased thereafter. The CSF concentrations of IL-6 and IL-8 peaked within 6 h after injury; other cytokines (IL-1beta, TNF-alpha, and IL-10) were elevated for 24 h after injury and gradually decreased thereafter. Peak CSF S100B concentrations correlated significantly with ICP determined at the time CSF samples were taken (r = 0.729, P < 0.0001). For the cytokines investigated, only the peak CSF IL-1beta concentration correlated significantly and positively with the peak CSF S100B concentration (r = 0.397, P < 0.005). Peak CSF concentrations of S100B (1649 +/- 415 microg/L, mean +/- SEM) and IL-1beta (16.5 +/- 3.3 pg/mL) in the 6 patients with high ICP were significantly higher than those (233 +/- 67 microg/L, 7.6 +/- 1.7 pg/mL, respectively) in the 17 patients with low ICP (P < 0.05). The CSF S100B concentration (1231 +/- 378 microg/L) in eight patients with an unfavorable outcome was significantly higher than that (267 +/- 108 microg/L) in 15 patients with a favorable outcome (P < 0.05). The CSF IL-1beta concentration (14.8 +/- 3.4 pg/mL) in eight patients with an unfavorable outcome tended to be higher than that (7.3 +/- 1.5 pg/mL) in 15 patients with a favorable outcome (P = 0.057). CSF concentrations of S100B and cytokines peak within 24 h after severe TBI and decrease gradually thereafter. CSF S100B and IL-1beta may be useful as predictors of outcome in cases of severe TBI.     

重型颅脑损伤患者血浆S-100B蛋白测定的临床意义

目的　探讨血浆 S 10 0 B蛋白作为一种生物学指标在重型颅脑损伤诊断及预后判断中的应用价值。方法　重型颅脑损伤患者 6 6例 ,伤后早期 (2～ 6 h)抽取血浆标本 ,并从伤后 2 4 h起连续 3～ 7d检测血浆 S 10 0 B蛋白含量 ,将其结果与患者伤后 6个月格拉斯哥预后评分 (GOS)进行比较。结果　 6 6例患者中死亡 2 5例 ,致残 2 2例 ,良好 19例。死亡组 S 10 0 B平均 2 .6 0 μg/ L,明显高于存活组 (0 .5 5 μg/ L,P<0 .0 0 1) ;死亡组中有 14例 S 10 0 B峰值超过 2 .0 0 μg/ L,而存活组中只有 4例峰值超过 2 .0 0 μg/ L(P<0 .0 0 5 )。结论　血浆 S 10 0 B蛋白在重型颅脑损伤的诊断及预后判断中具有可靠的应用价值。     

Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study

OBJECTIVE: To determine the prevalence, time course, clinical characteristics, and effect of adrenal insufficiency (AI) after traumatic brain injury (TBI). DESIGN: Prospective intensive care unit-based cohort study. SETTING: Three level 1 trauma centers. PATIENTS: A total of 80 patients with moderate or severe TBI (Glasgow Coma Scale score, 3-13) and 41 trauma patients without TBI (Injury Severity Score, >15) enrolled between June 2002 and November 2003. MEASUREMENTS: Serum cortisol and adrenocorticotropic hormone levels were drawn twice daily for up to 9 days postinjury; AI was defined as two consecutive cortisols of < or =15 microg/dL (25th percentile for extracranial trauma patients) or one cortisol of < 5 microg/dL. Principal outcome measures included: injury characteristics, hemodynamic data, usage of vasopressors, metabolic suppressive agents (high-dose pentobarbital and propofol), etomidate, and AI status. MAIN RESULTS: AI occurred in 42 TBI patients (53%). Adrenocorticotropic hormone levels were lower at the time of AI (median, 18.9 vs. 36.1 pg/mL; p = .0001). Compared with patients without AI, those with AI were younger (p = .01), had higher injury severity (p = .02), had a higher frequency of early ischemic insults (hypotension, hypoxia, severe anemia) (p = .02), and were more likely to have received etomidate (p = .049). Over the acute postinjury period, patients with AI had lower trough mean arterial pressure (p = .001) and greater vasopressor use (p = .047). Mean arterial pressure was lower in the 8 hrs preceding a low (< or =15 microg/dL) cortisol level (p = .003). There was an inverse relationship between cortisol levels and vasopressor use (p = .0005) and between cortisol levels within 24 hrs of injury and etomidate use (p = .002). Use of high-dose propofol and pentobarbital was strongly associated with lower cortisol levels (p < .0001). CONCLUSIONS: Approximately 50% of patients with moderate or severe TBI have at least transient AI. Younger age, greater injury severity, early ischemic insults, and the use of etomidate and metabolic suppressive agents are associated with AI. Because lower cortisol levels were associated with lower blood pressure and higher vasopressor use, consideration should be given to monitoring cortisol levels in intubated TBI patients, particularly those receiving high-dose pentobarbital or propofol. A randomized trial of stress-dose hydrocortisone in TBI patients with AI is underway.     

Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis

OBJECTIVE: To determine whether nonconvulsive electrographic post-traumatic seizures result in increases in intracranial pressure and microdialysis lactate/pyruvate ratio. DESIGN: Prospective monitoring with retrospective data analysis. SETTING: Single center academic neurologic intensive care unit. PATIENTS: Twenty moderate to severe traumatic brain injury patients (Glasgow Coma Score 3-13). MEASUREMENTS AND MAIN RESULTS: Continuous electroencephalography and cerebral microdialysis were performed for 7 days after injury. Ten patients had seizures and were compared with a matched cohort of traumatic brain injury patients without seizures. The seizures were repetitive and constituted status epilepticus in seven of ten patients. Using a within-subject design, post-traumatic seizures resulted in episodic increases in intracranial pressure (22.4 +/- 7 vs. 12.8 +/- 4.3 mm Hg; p < .001) and an episodic increase in lactate/pyruvate ratio (49.4 +/- 16 vs. 23.8 +/- 7.6; p < .001) in the seizure group. Using a between-subjects comparison, the seizure group demonstrated a higher mean intracranial pressure (17.6 +/- 6.5 vs. 12.2 +/- 4.2 mm Hg; p < .001), a higher mean lactate/pyruvate ratio (38.6 +/- 18 vs. 27 +/- 9; p < .001) compared with nonseizure patients. The intracranial pressure and lactate/pyruvate ratio remained elevated beyond postinjury hour 100 in the seizure group but not the nonseizure group (p < .02). CONCLUSION: Post-traumatic seizures result in episodic as well as long-lasting increases in intracranial pressure and microdialysis lactate/pyruvate ratio. These data suggest that post-traumatic seizures represent a therapeutic target for patients with traumatic brain injury.     

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.     

Gender associations with cerebrospinal fluid glutamate and lactate/pyruvate levels after severe traumatic brain injury

OBJECTIVE: Female sex hormones appear to be neuroprotective after traumatic brain injury by attenuating multiple mechanisms of secondary insult, including excitotoxicity and ischemia. The purpose of this study was to evaluate associations between gender and cerebrospinal fluid glutamate and lactate/pyruvate production and the role of hypothermia with gender in attenuating these markers. DESIGN: Prospectively collected data were analyzed for adult patients with severe traumatic brain injury. Gender comparisons for cerebrospinal fluid glutamate and lactate/pyruvate production were determined using ventricular samples obtained over the first 48 hrs postinjury. SETTING: University-based level I trauma center. PATIENTS: There were 123 patients, male n = 93 and female n = 30 (n = 686 cerebrospinal fluid samples), with severe traumatic brain injury (Glasgow Coma Scale score < or =8). INTERVENTIONS: A portion of these patients were part of a randomized controlled trial evaluating the effect of (48 hrs) therapeutic hypothermia after severe traumatic brain injury. The remainder received hypothermia (24 hrs) if they met clinical care criteria. Patients were cooled to 32-33 degrees C (within approximately 8 hrs) for either 24 or 48 hrs and then were rewarmed or remained normothermic. MEASUREMENTS AND MAIN RESULTS: Regression analyses using generalized estimating equations for repeated measures showed significant increases in cerebrospinal fluid glutamate production for males compared with females (p = .0023) and a significant interaction between glutamate concentration, gender, and time (p = .0035) by 24 hrs postinjury. Females had lower lactate/pyruvate ratios than males (p = .0006), and there was a significant interaction between lactate/pyruvate, gender, and time (p = .0045) throughout the first 48 hrs postinjury. Hypothermia attenuated glutamate levels, particularly for males, over the time course studied. CONCLUSIONS: These data suggest significant gender differences with glutamate and lactate/pyruvate production after severe traumatic brain injury. Gender- and hormone-mediated differences in central nervous system pathophysiology should be considered with clinical trials in traumatic brain injury.     

Role of serum S100B as a predictive marker of fatal outcome following isolated severe head injury or multitrauma in males.

BACKGROUND: Severe traumatic brain injury (TBI) is associated with a 30%-70% mortality rate. S100B has been proposed as a biomarker for indicating outcome after TBI. Nevertheless, controversy has arisen concerning the predictive value of S100B for severe TBI in the context of multitrauma. Therefore, our aim was to determine whether S100B serum levels correlate with primary outcome following isolated severe TBI or multitrauma in males. METHODS: Twenty-three consecutive male patients (age 18-65 years), victims of severe TBI [Glasgow Coma Scale (GCS) 3-8] (10 isolated TBI and 13 multitrauma with TBI) and a control group consisting of eight healthy volunteers were enrolled in this prospective study. Clinical outcome variables of severe TBI comprised: survival, time to intensive care unit (ICU) discharge, and neurological assessment [Glasgow Outcome Scale (GOS) at ICU discharge]. Venous blood samples were taken at admission in the ICU (study entry), 24 h later, and 7 days later. Serum S100B concentration was measured by an immunoluminometric assay. RESULTS: At study entry (mean time 10.9 h after injury), mean S100B concentrations were significantly increased in the patient with TBI (1.448 microg/L) compared with the control group (0.037 microg/L) and patients with fatal outcome had higher mean S100B (2.10 microg/L) concentrations when compared with survivors (0.85 microg/L). In fact, there was a significant correlation between higher initial S100B concentrations and fatal outcome (Spearman's =0.485, p=0.019). However, there was no correlation between higher S100B concentrations and the presence of multitrauma. The specificity of S100B in predicting mortality according to the cut-off of 0.79 microg/L was 73% at study entry. Conclusions: Increased serum S100B levels constitute a valid predictor of unfavourable outcome in severe TBI, regardless of the presence of associated multitrauma.     

Renal elimination of protein S-100beta in pigs with acute encephalopathy

BACKGROUND: Protein S-100beta is an established biochemical marker for cerebral injury in serum. For the further interpretation and possible use of S-100beta serum measurements in acute hepatic encephalopathy, renal elimination of S-100beta was measured in pigs with elevated S-100beta levels due to hepatic encephalopathy. METHODS: Eighteen female Norwegian Landrace pigs were randomly allocated to either hepatic devascularization (n=13) or sham operation (n=5). Repeated samples from the common carotid artery, right renal vein, and urine were simultaneously drawn for S-100beta analysis, using the Sangtec100 Liamat immunoassay. RESULTS: In hepatic devascularized pigs, arterial serum levels of S-100beta increased from 0.96+/-0.04 microg/L (mean +/- SEM) at t = 0h to 1.74+/-0.11 microg/L (mean +/- SEM) at t = 5 h. Urinary excretion increased simultaneously from 8.48+/-3.66 ng/h (mean +/- SEM) to 20.4+/-9.54 ng/h (mean +/- SEM), while renal arterial-venous fluxes for both kidneys increased from 1022+/-404 ng/h (mean +/- SEM) to 2444+/-590 ng/h (mean +/- SEM). CONCLUSIONS: Increased arterial S-100beta levels in pigs with acute hepatic encephalopathy are not a result of decreased renal elimination. The large difference between the renal arterial venous S-100beta concentrations and the urinary excretion of S-100beta indicate that renal metabolism is the major route of elimination.     

Severe traumatic brain injury in pediatric patients: treatment and outcome using an intracranial pressure targeted therapy—the Lund concept

Objective This study evaluated the outcome of treatment according to the Lund concept in children with severe traumatic brain injury and investigated whether the preset goals of the protocol were achieved.Design and setting A two-center retrospective study in neurointensive care units at university hospitals.Patients Forty-one children with severe traumatic brain injury from blunt trauma and arriving at hospital within 24 h after injury. Median age was 8.8 years (range 3 months–14.2 years), Glasgow Coma Scale 7 (3–8), and Injury Severity Score 25 (16–75). All children had pathological findings on initial computed tomography. All developed intracranial hypertension, and survivors required intensive care longer than 72 h.Interventions Treatment according to the principles of the Lund concept.Measurements and results Neurosurgery was required in 46% of the children. Survival rate was 93% and favorable outcome (Glasgow Outcome Score 4 or 5) was 80% at long-term follow-up (median 12 months postinjury, range 2.5–26). The preset physiological and biochemical goals were achieved in over 90% of observations.Conclusions Treating pediatric patients with severe traumatic brain injury, according to the Lund concept, results in a favorable outcome when the protocol is followed.     

Serum S-100B and interleukin-8 as predictive markers for comparative neurologic outcome analysis of patients after cardiac arrest and severe traumatic brain injury

OBJECTIVE: To compare S-100B and interleukin-8 serum values on scene/at admission and 12 hrs later with respect to neurologic long-term outcome 12 months after cardiac arrest and return of spontaneous circulation, as well as after severe traumatic brain injury. DESIGN: Prospective comparative cohort study. SETTING: On scene; intensive care units of a university hospital. PATIENTS: Twenty patients with out-of-hospital cardiac arrest. Twenty patients with severe traumatic brain injury. INTERVENTIONS: Therapy was adjusted to the standards of modern prehospital and intensive care management by physicians who were not involved in the study. MEASUREMENTS AND MAIN RESULTS: First median S-100B values of the cardiac arrest group (4.42 ng/mL) mounted as high as those of the traumatic brain injury group (4.11 ng/mL). Within 12 hrs, S-100B levels significantly decreased to 0.75 ng/mL in cardiac arrest patients and to 0.68 ng/mL in traumatic brain injury patients but remained significantly elevated compared with the controls (0.04 ng/mL). Interleukin-8 levels of the cardiac arrest patients on scene (30.33 pg/mL) were clearly elevated above normal (12.60 pg/mL) and increased significantly to 101.40 pg/mL after 12 hrs. They showed no significant difference compared with those of the traumatic brain injury patients (78.75 pg/mL and 96.00 pg/mL, respectively). Multivariate Cox regression analysis in cardiac arrest patients identified only the S-100B level measured 12 hrs after study entry as an independent predictor for unfavorable neurologic outcome according to the Glasgow Outcome Scale score. In contrast, S-100B as well as interleukin-8 levels quantified 12 hrs after admission significantly predicted an unfavorable neurologic course in the traumatic brain injury group. CONCLUSIONS: Significantly elevated S-100B and interleukin-8 serum levels 12 hrs after cardiac arrest suggest that primary brain damage and systemic inflammatory response are comparably serious with that of traumatic brain injury. In both collectives, increased S-100B values measured 12 hrs after insult correlated well with an unfavorable neurologic outcome after 12 months.     

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.     

Children show decreased dynamic balance after mild traumatic brain injury

OBJECTIVE: To compare the balance skills of children after mild traumatic brain injury (TBI) with that of noninjured children matched for age, sex, and premorbid level of physical activity. DESIGN: Cohort study. SETTING: Pediatric trauma center. PARTICIPANTS: Thirty-eight children aged 7 to 16 years (mean, 12.2+/-2.8 y) were recruited in each group. Children with mild TBI had a mean Glasgow Coma Scale score of 14.8 and were considered normal on a neurologic assessment at hospital discharge. Noninjured children were friends of those with mild TBI. INTERVENTION: Assessments of balance were conducted at 1, 4, and 12 weeks after mild TBI and at corresponding time intervals for the controls. MAIN OUTCOME MEASURES: The balance subtest of the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP), the Pediatric Clinical Test of Sensory Interaction for Balance (P-CTSIB), and the Postural Stress Test (PST) were used. RESULTS: Over the time interval of the study, analyses of variance revealed that children with mild TBI performed significantly worse than the noninjured group on the BOTMP balance subtest (P<.001) and on the PST (P=.031), as well as on the eyes-closed conditions in the P-CTSIB tandem position (P=.05). CONCLUSIONS: Children with a mild TBI still showed balance deficits at 12 weeks postinjury. These deficits should be taken into consideration when planning a return to physical activities, particularly to those that require subtle balance skills.     

Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury

OBJECTIVE: To determine interleukin (IL)-8 concentrations in ventricular cerebrospinal fluid from children with severe traumatic brain injury (TBI). DESIGN: Prospective study. SETTING: University children's hospital. PATIENTS: Twenty-seven children hospitalized with severe TBI (Glasgow Coma Scale score < or =8), seven children with cerebrospinal fluid culture-positive bacterial meningitis, and twenty-four age-equivalent controls. INTERVENTIONS: Placement of an intraventricular catheter and continuous drainage of cerebrospinal fluid. MEASUREMENTS AND MAIN RESULTS: Median [range] cerebrospinal fluid IL-8 concentration in children with TBI (0-12 hrs) (4,452.5 [0-20,000] pg/mL) was markedly greater than that in controls (14.5 [0-250]) (p < .0001) and equivalent to concentrations in children with meningitis (5,300 [1,510-22,000] pg/mL) (p = .33). Cerebrospinal fluid IL-8 remained increased in children with severe TBI for up to 108 hrs after injury. Univariate logistic regression analysis demonstrated an association between cerebrospinal fluid IL-8 and child abuse (p = .07) and mortality (p = .01). Multivariate analysis demonstrated a strong, independent association between cerebrospinal fluid IL-8 and mortality (p = .01). CONCLUSIONS: The data are consistent with an acute inflammatory component of TBI in children and suggest an association between cerebrospinal fluid IL-8 and outcome after TBI. IL-8 may represent a potential target for anti-inflammatory therapy.     

Heart rate variability after acute traumatic brain injury in children

OBJECTIVE: To evaluate heart rate variability (HRV) by power spectral analysis of heart rate and its relationship to intracranial pressure (ICP), cerebral perfusion pressure (CPP), and outcomes in children with acute traumatic head injury. DESIGN: Prospective, case series. SETTING: Pediatric intensive care unit in a level II trauma center/children's hospital. SUBJECTS: Fifteen critically ill children with documented acute traumatic brain injury and four control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The normalized total power from 0.04 to 0.15 Hz was used to quantify low-frequency HRV and from 0.15 to 0.40 Hz to quantify high-frequency HRV. The ratio of low- to high-frequency (LF/HF) power was used as a measure of sympathetic modulation of heart rate. The power spectral data from the 5-min samples were averaged over each hour of data collection, and an hourly LF/HF ratio was obtained based on a 60-min electrocardiogram collection (twelve 5-min segments). The daily mean LF/HF ratio was calculated from the hourly LF/HF measurements. We found no linear correlation between the LF/HF ratio and either ICP or CPP (p = NS). There was a significant decrease in the LF/HF ratio when the intracranial pressure was >30 mm Hg (p < .001) or the cerebral perfusion pressure was <40 mm Hg (p < .001). Children with a Glasgow Coma Scale score of 3-4 had a lower LF/HF ratio compared with those who had a Glasgow Coma Scale score of 5-8 (p < .005). Patients who progressed to brain death had a markedly lower LF/HF ratio (p < .001), with a significant decrease after the first 4 hrs of hospitalization. Patients with more favorable outcomes had significantly higher LF/HF ratios. CONCLUSIONS: Our findings suggest that an ICP of >30 mm Hg or a CPP of <40 mm Hg may be associated with marked autonomic dysfunction and poor outcome. We speculate that HRV power spectral analysis may be a useful adjunct in determining the severity of neurologic insult and the prognosis for recovery in children. The LF/HF ratio may be helpful not only in identifying those patients who will progress to brain death but also in predicting which patients will have favorable outcomes.     

A comparison of two different assays for determining S-100B in serum and urine

BACKGROUND: Brain injury after head trauma can be detected by S-100B measurements in serum. Recent preliminary studies indicate that urinary levels of S-100B are also increased after head injury, a finding that is of possible clinical value. The aims of the present study are two-fold: to compare serum measurements of two assays, the Liaison Sangtec 100 system and the Elecsys S100 test, and to investigate to what extent they can detect and measure S-100B in urine. METHODS: A total of 191 serum and 174 urine samples from 107 patients (children aged between 1 and 18 years following head trauma) were measured with both assays. The results were compared using correlation analysis and Bland-Altman difference plots. RESULTS: Serum values of the Sangtec system ranged from 0.02 to 2.28 microg/L, and from 0.005 to 2.13 microg/L for the Elecsys test. Comparisons showed a clear correlation (correlation coefficient 0.80) but not an agreement between the methods. The Sangtec system could only detect S-100B in 20 out of 174 urine samples (range 0.02-0.06 microg/L), whereas the Elecsys test could detect S-100B in 171 samples (range 0.005-0.14 microg/L). No clear relation was observed between the two methods in urine analysis (correlation coefficient 0.60). CONCLUSION: The Sangtec and Elecsys assays are not interchangeable methods when analyzing S-100B in serum or urine samples after head injury.     

Hypothalamic-pituitary-adrenal axis dysfunction in critically ill patients with traumatic brain injury: incidence, pathophysiology, and relationship to vasopressor dependence and peripheral interleukin-6 levels

OBJECTIVE: To investigate hypothalamic-pituitary-adrenal axis function in patients requiring mechanical ventilation for traumatic brain injury and to assess the relation of hypothalamic-pituitary-adrenal axis abnormalities with vasopressor dependence and peripheral cytokine levels. DESIGN: Prospective study. SETTING: General intensive care unit in a university teaching hospital. PATIENTS: Forty patients (33 men and 7 women) with moderate to severe traumatic brain injury (mean age, 37 +/- 16 yrs) were studied the day after termination of mechanical ventilation (7-60 days after trauma). INTERVENTIONS: First, a morning blood sample was obtained to measure baseline cortisol, corticotropin, interleukin-6, and tumor necrosis factor alpha. Subsequently, 1 microg of synthetic corticotropin was injected intravenously, and 30 mins later, a second blood sample was drawn to determine stimulated plasma cortisol. Based on data derived from healthy volunteers, patients having stimulated cortisol levels <18 microg/dL were defined as nonresponders to the low-dose stimulation test. Thirty-one patients underwent also a human corticotropin releasing hormone test. MEASUREMENTS AND MAIN RESULTS: In traumatic brain injury patients, mean baseline and low-dose stimulation test-stimulated cortisol levels were 17.2 +/- 5.4 microg/dL and 24.0 +/- 6.6 microg/dL, respectively. The median increment in cortisol was 5.9 microg/dL. Basal corticotropin levels ranged from 3.9 to 118.5 pg/mL. Six of the 40 patients (15%) failed the low-dose stimulation test. The human corticotropin releasing hormone test (performed in 26 responders and five nonresponders) revealed diminished cortisol release only in the low-dose stimulation test nonresponder patients. Corticotropin responses to corticotropin releasing hormone were consistent with both primary (three patients) and/or secondary (two patients) adrenal dysfunction. In retrospect, nonresponders to the low-dose stimulation test more frequently required vasopressors (6/6 [100%] vs. 16/34 [47%]; p =.02) and for a longer time interval (median, 0 vs. 293 hrs; p =.006) compared with responders. Furthermore, nonresponders had higher interleukin-6 levels compared with responders (56.03 vs. 28.04 pg/mL; p =.01), whereas tumor necrosis factor alpha concentrations were similar in the two groups (2.42 vs. 1.55 pg/mL; p =.53). CONCLUSIONS: Adrenal cortisol secretion after dynamic stimulation is deficient in a subset of critically ill patients with moderate to severe head injury. This disorder is associated with prior vasopressor dependency and higher interleukin-6 levels.     

Elevation of serum cerebral injury markers correlates with serum choline decline after coronary artery bypass grafting surgery.

The aims of this study were to determine circulating choline status and its relationship to circulating levels of S-100beta protein and neuron-specific enolase, biochemical markers of cerebral injury and cognitive decline, after coronary artery bypass grafting (CABG) surgery. Preoperatively, patients scheduled for off-pump or on-pump CABG surgery had serum concentrations of 12.0+/-0.2 and 11.7+/-0.4 micromol/L free choline and 2640+/-65 and 2675+/-115 micromol/L phospholipid-bound choline, respectively. Serum free and bound choline levels decreased by 22-37% or 34-47% and 16-36% or 31-38% at 48 h after off-pump or on-pump surgery, respectively. Serum S-100beta and neuron-specific enolase increased from preoperative values of 0.083+/-0.009 and 6.3+/-0.2 microg/L to 0.405+/-0.022 and 11.4+/-0.8 microg/L, respectively, at 0 h postoperatively and remained elevated for 48 h after off-pump surgery. Serum free and bound choline concentrations were inversely correlated with the concentrations of S-100beta (r=-0.798; p<0.001 and r=-0.734; p<0.001) and neuron-specific enolase (r=-0.840; p<0.001 and r=-0.728; p<0.001). In conclusion, CABG surgery induces a decline in serum free and phospholipid-bound choline concentrations. The decreased serum choline concentrations were inversely correlated with the elevated levels of circulating cerebral injury markers. Thus, a decline in circulating choline may be involved in postoperative cognitive decline.