Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock.

Stress doses of hydrocortisone are known to have immunomodulatory effects in patients with hyperdynamic septic shock. The prognosis correlates with the presence and severity of septic encephalopathy. However, neurological evaluation is influenced by the use of analgesia sedation during artificial ventilation. The objective of this study was to demonstrate the effect of stress doses of hydrocortisone during the initial phase of human septic shock on the serum values of the neurospecific protein S-100B in comparison to the inflammation markers interleukin (IL)-8 in serum and polymorphonuclear (PMN) elastase in plasma. A total of 24 consecutive patients, who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock, were enrolled in this prospective, randomized, double-blind, single-center trial. The severity of illness at recruitment was graded using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems. Multi-organ dysfunction syndrome was described by the Sepsis-related Organ Failure Assessment (SOFA) score. All patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started in 12 patients with a loading dose of 100 mg and followed by a continuous infusion of 0.18 mg/kg/h for 6 days. Median S-100B serum levels of the hydrocortisone group decreased from 0.32 ng/mL at study entry to 0.07 ng/mL 6 days later without significant differences compared to the placebo group. Initial IL-8 serum levels were significantly higher in the hydrocortisone group up to 12 h after study entry, and significantly decreased from 715 to 17 pg/mL at the end of the observation period. Median PMN elastase plasma levels were not affected by hydrocortisone infusion. Patients with initial S-100B serum levels > 0.50 ng/mL revealed significantly higher SOFA scores up to 30 h, IL-8 serum levels up to 12 h, and PMN elastase plasma levels up to 36 h after study entry than those patients with < or = 0.50 ng/mL. These effects were independent of the amount of fluid correction for hemodilution. Starting S-100B, IL-8 and PMN elastase values of the hydrocortisone group were within the ranges already known in patients with out-of-hospital cardiac arrest or severe traumatic brain injury. Stress doses of hydrocortisone resulted in a significant reduction in IL-8 serum, but not in S-100B serum and PMN elastase plasma concentrations in patients with hyperdynamic septic shock. For the first time, a similar extent of S-100B increase in serum of septic patients at the time of diagnosis was shown as reported for cardiac arrest or severe traumatic brain injury.     

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.     

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.     

S-100beta protein-serum levels in healthy children and its association with outcome in pediatric traumatic brain injury

OBJECTIVE: To describe normal serum levels of S-100beta in healthy children and determine whether serum S-100beta levels after traumatic brain injury are associated with outcome. DESIGN: Prospective cohort study. SETTING: Urban, tertiary care, children's teaching hospital. PATIENTS: A total of 136 healthy children and 27 children with traumatic brain injury. METHODS: Serum S-100beta levels were measured in 136 healthy children. A total of 27 children with traumatic brain injury had S-100beta levels collected within 12 hrs of injury. Other indices of severity of injury measured were admission Glasgow Coma Scale score, and Pediatric Risk of Mortality score at 24 hrs (PRISM 24). Outcome was measured by the Pediatric Cerebral Performance Category (PCPC) score at hospital discharge and 6 months postinjury or at death. MEASUREMENTS AND MAIN RESULTS: S-100beta levels in healthy children had a mean of 0.3 microg/L (90% confidence interval, 0.03-1.47) and inversely correlated with age, (r = -.32, p <.001). In children with traumatic brain injury, 6-month postinjury outcome inversely correlated with Glasgow Coma Scale score (r = -.47, p =.01) and correlated with PRISM 24 score (r =.83, p <.001) and S-100beta levels (r =.75, p <.001). Six months postinjury, comparing good outcome (PCPC < or = 3, n = 20) vs. poor outcome (PCPC > or = 4, n = 7), median admission Glasgow Coma Scale scores were 8 (range, 3-15) and 3 (range, 3-7, p =.01), median PRISM 24 scores were 7 (range, 0-19) and 30 (range, 18-35, p <.001), and median S-100beta levels were 0.85 microg/L (range, 0.08-4.8 microg/L) and 3.6 microg/L (range, 1.4-20 microg/L, p <.001), respectively. A serum S-100beta level of > or =2.0 microg/L is associated with poor outcome, with a sensitivity of 86% and a specificity of 95%. The area under the receiver operating curve for S-100beta was 0.94 (+/-0.05). CONCLUSIONS: Serum S-100beta levels in healthy children have a moderate inverse correlation with age. After traumatic brain injury in children, the acute assessment of serum S-100beta levels seems to be associated with outcome.     

Dose-dependent neuroprotection by 17beta-estradiol after cardiac arrest and cardiopulmonary resuscitation

OBJECTIVE: Despite recent advances in the treatment of cardiac arrest, neurologic outcome remains poor. 17beta-Estradiol (E2) has been widely shown to reduce damage after experimental brain injury. The present study determined whether E2 also improves neuronal survival after experimental cardiac arrest and cardiopulmonary resuscitation and if any protection is dose-dependent. DESIGN: A randomized trial. SETTING: A research laboratory. SUBJECTS: Male C57Bl/6 mice weighing 20-25 g. INTERVENTIONS: Mice were randomized into one of six groups, receiving treatment with 0.5, 2.5, 12.5, 25, or 50 mug of E2 or vehicle 1.5 mins after return of spontaneous circulation. Ten minutes after induction of cardiac arrest (by KCl injection), cardiopulmonary resuscitation was initiated (with chest compressions, intravenous epinephrine, and ventilation with 100% O2). Additional animals of each E2-treated group were used for plasma estradiol-level analysis. Brains were removed for quantification of injury in the hippocampus and caudoputamen on day 3. MEASUREMENTS AND MAIN RESULTS: The E2 0.5 group had physiologic estrogen levels 60 min after injection (mean +/- se, 28 +/- 5 pg/mL), whereas the E2 50 group still showed supraphysiologic levels 360 min after administration (245 +/- 32 pg/mL). Hippocampal damage was not altered with E2 treatment. Only posttreatment with the lowest E2 dose (E2 0.5) resulted in attenuated neuronal injury in the rostral and caudal caudoputamen (34 +/- 11% and 27 +/- 11%), in comparison with vehicle (68 +/- 5, p < .05; 63 +/- 4%, p < .001). Higher E2 doses did not affect brain injury. CONCLUSIONS: We conclude that E2 has a critical dosing effect on neuronal survival, physiologic levels of E2 are neuroprotective after cardiac arrest/cardiopulmonary resuscitation, and acute exposure is sufficient for brain resuscitation.     

Serum levels of the brain-derived proteins S-100 and NSE predict long-term outcome after cardiac arrest

Background and purpose: patients with cardiac arrest have a high mortality and the long-term outcome is doubtful. The prognosis is mainly dependent on clinical parameters. S-100 and neurone specific enolase (NSE) are established biochemical markers of central nervous system (CNS) injury. The purpose of this study was to validate the use of serum determinations of S-100 and NSE with neurological investigations in regard to brain damage and long-term outcome after cardiac arrest. Methods: neurological examinations were performed on 66 patients after cardiac arrest. Serum levels of S-100 and NSE were determined during the first 3 days of post arrest, using commercial luminescent immunoassays (LIAs). The main outcome variable was the Glasgow Outcome Scale (GOS), while secondary variables were the activity of daily living (ADL) index and mini mental state examination (MMSE). Outcome was determined at 1 year. Results: the serum levels of S-100 and NSE were increased during the first 3 days after the arrest and were related to coma depth, time of anoxia and abnormal brain stem reflexes. High levels predicted a poor outcome, according to the GOS (death, vegetative state and severe disability). The prognostic value of the brain damage markers was comparable with that of traditional clinical parameters. None of the secondary outcome variables (ADL and MMSE) was strongly associated with S-100 or NSE. Discussion: the serum levels of S-100 and NSE increased after cardiac arrest due to the anoxic brain damage. The determination of S-100 and NSE can be used as an adjunct to predict long-term outcome after cardiac arrest.     

Early cellular brain damage and systemic inflammatory response after cardiopulmonary resuscitation or isolated severe head trauma: a comparative pilot study on common pathomechanisms

Severe neurological deficits are common characteristics of patients surviving cardiopulmonary resuscitation (CPR) or isolated severe head trauma (SHT). For comparative evaluation of underlying pathomechanisms, 22 patients with out-of-hospital cardiac arrest and successful CPR as well as 10 patients with SHT were included in our prospective study. Circulating S-100B was determined as an indicator of cellular brain damage. Interleukin-8 (IL-8), soluble E-selectin (sE-selectin) and polymorphonuclear (PMN-) elastase were measured as markers of systemic inflammation following whole body ischaemia and reperfusion injury. Venous blood samples were drawn on scene (median time 11.0 min after starting basic life support) and in the intensive care unit (median time 12.5 h thereafter) in CPR patients and at admission to hospital (median time 43.8 min after trauma) and approx. 12 h later in SHT patients. Biochemical parameters in these samples were compared with specimens taken from 20 healthy volunteers. Initial median S-100B levels of the CPR and SHT patients were both significantly increased compared with the controls. Twelve hours later, significant falls in S-100B revealed no differences between the two patient groups, but did not reach control values. Median IL-8 and sE-selectin levels entry to the study were elevated in both patient groups compared with controls and showed further rises within the following 12 h. Finally, increased initial median levels of PMN-elastase revealed significant differences between the patient groups and between patients and controls. Twelve hours later, median PMN-elastase values were equally elevated in the CPR and SHT subjects. Our preliminary data suggest similar pathomechanisms occurring after both CPR and SHT. Both clinical entities seem to be associated with early transient cellular brain damage as shown by prolonged rapidly increasing and subsequent fall in S-100B serum levels. In contrast, the prolonged elevation of circulating IL-8, sE-selectin and PMN-elastase may indicate a very similar systemic inflammatory response by endothelial cells and neutrophils initiated by ischaemia and reperfusion injury in both conditions. Further studies should be carried out to determine the cause and the prognostic value of these biochemical parameters in relation to long-term neurological outcome.     

Interleukin-10 and its role in clinical immunoparalysis following pediatric cardiac surgery

OBJECTIVE: A systemic insult is associated with subsequent hyporesponsiveness to endotoxin (as measured by ex vivo tumor necrosis factor [TNF]-alpha production) and an increased risk of late nosocomial infection in some patients. When combined with low monocyte surface major histocompatibility complex class II expression, this state of altered host defense is now commonly referred to as immunoparalysis. This study was undertaken to delineate the relationship between observed levels of the anti-inflammatory cytokine interleukin-10, common genetic polymorphisms that influence these levels, and the occurrence and severity of endotoxin hyporesponsiveness in children following elective cardiac surgery requiring cardiopulmonary bypass. DESIGN: A prospective observational clinical study. SETTING: A tertiary pediatric cardiac center. PATIENTS: Thirty-six infants and children <2 yrs of age undergoing elective cardiac surgery requiring cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We investigated the production of TNF-alpha, interleukin-6, interleukin-8, interleukin-1 receptor antagonist, and interleukin-10 in whole blood in response to lipopolysaccharide (Neisseria meningitides 10 ng/mL) in samples drawn before, during, and up to 48 hrs after surgery. Patients were genotyped for the -1082, -819, and -592 interleukin-10 promoter polymorphisms. Whole blood cytokine response to lipopolysaccharide was reduced postoperatively to 100 pg/mL) over the first 48 hrs were more likely to have an uncomplicated short stay (odds ratio 4.7, 95% confidence interval 1-22). CONCLUSIONS: Immediately following cardiac surgery, many children become relatively refractory to lipopolysaccharide stimulation. This immunoparalysis appears to be related in part to high circulating levels of interleukin-10 and places these patients at increased risk of postoperative complications. Interleukin-10 genotype may be a risk factor for immunoparalysis.     

Serum S-100B as an indicator of early postoperative deterioration after meningioma surgery

BACKGROUND: S-100B protein is an established serum marker of primary and secondary brain damage in head injury and stroke. Despite major progress in neurophysiologic monitoring, there are still difficulties in the early identification and quantification of evolving edema or trauma after craniotomy for tumor. In this study we aimed to correlate serum S-100B values with early postoperative neurologic course as well as late outcome in meningioma surgery. METHODS: We enrolled 50 consecutive patients who underwent meningioma resection. Serum S-100B was measured preoperatively and postcraniotomy for 7 consecutive days. Twenty-five patients (50%) developed immediate postoperative neurologic deterioration, and 15 (30%) had unfavorable 6-month outcomes. We used the Mann-Whitney U-test to assess the association of S-100B with all variables of interest. We used multiple logistic regression to search for the most significant predictor of postoperative deterioration. RESULTS: Increased S-100B was highly correlated with larger tumors, intraoperative difficulties, postcraniotomy acute deterioration, and long-term poor outcome. In addition, multiple logistic regression showed that age, sex, site, preoperative edema, history of meningioma resection, extent of resection, and histologic type did not correlate with postoperative increases in S-100B. Furthermore, patients with postoperative S-100B values >0.4 microg/L had increased risk of deterioration (relative risk = 9.0; 95% confidence interval, 2.4-34; P <0.0001) and of poor ultimate outcome (relative risk = 11; 95% confidence interval, 1.6-77; P = 0.002). CONCLUSIONS: After meningioma excision, postcraniotomy increases in serum S-100B appear to be an early indicator of short-term postoperative neurologic deterioration and of a poor longer-term outcome.     

Early elevation of S-100B protein in blood after cardiac surgery is not a predictor of ischemic cerebral injury

BACKGROUND: We hypothesized that early changes in S-100B levels after cardiac surgery are nonspecific and mostly reflect damage to tissues outside the brain rather than ischemic brain damage. METHODS: We measured serum levels of S-100B at several times perioperatively in 21 patients undergoing cardiac surgery. In addition, we measured levels of neuron specific enolase (NSE), glial fibrillary acidic protein (GFAP), creatine kinase (CK), the cardiac isoenzyme of CK (CK-MB), and myoglobin (MB) in these patients. RESULTS: Early increases in serum S-100B concentration were significantly (p<0.01) correlated with increases in markers of tissue injury outside the brain: S-100B/CK: r(2)=0.69; S-100B/CK-MB: r(2)=0.64; S-100B/myoglobin: r(2)=0.60; S-100B/NSE: r(2)=0.51; CK/NSE: r(2)=0.60; CK-MB/NSE: r(2)=0.59; and myoglobin/NSE: r(2)=0.54. CONCLUSIONS: Our findings indicate that increases in S-100B in the early phase after cardiac surgery are not due to release of S-100B from brain alone but also from tissue outside the brain.     

Induced hypothermia in critical care medicine: a review

BACKGROUND: Clinical trials of induced hypothermia have suggested that this treatment may be beneficial in selected patients with neurologic injury. OBJECTIVES: To review the topic of induced hypothermia as a treatment of patients with neurologic and other disorders. DESIGN: Review article. INTERVENTIONS: None. MAIN RESULTS: Improved outcome was demonstrated in two prospective, randomized, controlled trials in which induced hypothermia (33 degrees C for 12-24 hrs) was used in patients with anoxic brain injury following resuscitation from prehospital cardiac arrest. In addition, prospective, randomized, controlled trials have been conducted in patients with severe head injury, with variable results. There also have been preliminary clinical studies of induced hypothermia in patients with severe stroke, newborn hypoxic-ischemic encephalopathy, neurologic infection, and hepatic encephalopathy, with promising results. Finally, animal models have suggested that hypothermia that is induced rapidly following traumatic cardiac arrest provides significant neurologic protection and improved survival. CONCLUSIONS: Induced hypothermia has a role in selected patients in the intensive care unit. Critical care physicians should be familiar with the physiologic effects, current indications, techniques, and complications of induced hyperthermia.     

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.     

Immediate S-100B and neuron-specific enolase plasma measurements for rapid evaluation of primary brain damage in alcohol-intoxicated,minor head-injured patients

The neuroproteins S-100B and neuron-specific enolase (NSE) released into the circulation are suggested to be reliable markers for primary brain damage. However, safe identification of relevant post-traumatic complications after minor head injury (MHI) is often hampered by acute intoxication of the patients. The objective of this study was to determine the diagnostic validity of immediate plasma measurements of S-100B and NSE in comparison with neurological examinations and cerebral computed tomography (CCT) findings in alcohol-intoxicated MHI patients. One hundered thrity-nine MHI individuals were enrolled in this prospective study during Munich's Oktoberfest 2000. Plasma levels of S-100B and NSE as well as serum alcohol and glucose values were determined by fully automated assays immediately after admission. The results were compared with Glasgow Coma Scale score, a brief neurological examination, and the CCT findings. Without being influenced by alcohol, median S-100B levels of the CCT+ group were significantly increased compared with those of the CCT- group (P < 0.001). NSE, alcohol, and glucose levels showed no significant group differences. As calculated by the ROC analysis, a cutoff value of 0.21 ng/mL with an area under the curve of 0.864 clearly differentiates between CCT+ and CCT- patients at a sensitivity of 100%, a specificity of 50.0%, and a positive likelihood ratio of 2.0. Although acute alcohol intoxication did not confound plasma measurements of S-100B and NSE, only S-100B levels below the cutoff level of 0.21 ng/mL seem to indicate absence of primary brain damage. Thus, in addition to routine neurological examinations, S-100B measurements immediately after admission might help to reduce CCT scans in alcohol-intoxicated patients early after MHI.     

No interplay between the pathways mediating coagulation and inflammation in tissue factor-induced disseminated intravascular coagulation in rats

OBJECTIVE: Previous reports have suggested an interplay between the pathways mediating coagulation and inflammation in endotoxemia and sepsis. The present study was designed to examine whether cross-signaling between the pathways mediating coagulation and inflammation occurs, as suggested by the pattern of cytokine production observed following tissue-factor (TF)-induced disseminated intravascular coagulation (DIC). DESIGN: Prospective, comparative, experimental study. SETTING: Laboratory at a university hospital. SUBJECTS: Male Wistar rats, aged 6-7 wks, and weighing 160-170 g. INTERVENTIONS: Male Wistar rats were administered TF (3.75 units/kg every 4 hrs), TF, and tranexamic acid (TA; 50 mg/kg every 4.5 hrs) or lipopolysaccharide (30 mg/kg every 4 hrs) via the tail vein, and blood was sampled at 0, 4, 8 and 12 hrs. MEASUREMENTS AND MAIN RESULTS: Subsequent alterations in thrombin-antithrombin complex and fibrinogen levels, as well as platelet counts, indicated that the severity of both types of experimental DIC (TF-induced and lipopolysaccharide-induced) was similar with respect to hemostatic activation and development of consumption coagulopathy. In lipopolysaccharide-induced DIC, a sharp increase in plasma tumor necrosis factor levels was observed at 4 hrs, after which a sharp decline was noted. Plasma levels of interleukin-6 were markedly increased at 4 hrs, after which a sustained elevation was observed for the duration of the experimental period (tumor necrosis factor, 1270 +/- 280, 180 +/- 40, and 120 +/- 30 pg/mL at 4, 8 and 12 hrs, respectively; interleukin-6, 5810 +/- 1320, 4850 +/- 730, and 5230 +/- 1280 pg/mL at 4, 8 and 12 hrs, respectively). On the other hand, tumor necrosis factor and interleukin-6 were not detected following TF-induced DIC (0 +/- 0 at 4, 8, and 12 hrs for both tumor necrosis factor and interleukin-6). In the TF+TA group, significant increases in tumor necrosis factor and interleukin-6 were observed, compared with the TF group. CONCLUSIONS: There is no overt interplay between the pathways mediating coagulation and inflammation in TF-induced DIC, as observed in lipopolysaccharide-induced DIC.     

Release of neuron-specific enolase and S100 after implantation of cardioverters/defibrillators

OBJECTIVE: Repeated induction of ventricular fibrillation with ensuing alterations in electroencephalogram and jugular venous oxygen saturation is common practice during insertion of transvenous implantable cardioverters/defibrillators. We investigated whether these functional changes are also associated with cerebral injury. DESIGN: Prospective study. SETTING: University hospital. PATIENTS: We studied 45 patients undergoing implantable cardioverter/defibrillator insertion. Eleven patients with cardiac pacemaker implantation, which was performed in the same manner yet without the necessity to induce ventricular fibrillation, served as controls. MEASUREMENTS AND MAIN RESULTS: Serum neuron-specific enolase and S100 were determined before, immediately postoperatively, and 2 hrs postoperatively. In a randomly composed subgroup, neuron-specific enolase was also determined 6 and 24 hrs after surgery. Implantable cardioverter/defibrillator patients only showed an increase of both markers postoperatively. Median neuron-specific enolase values climbed from a preoperative 9.9 to 12.3 and 14.4 microg/L at 2 and 24 hrs after surgery, respectively. This increase was associated with the number of shocks and the cumulative time in circulatory arrest. The highest median S100 level (0.075 microg/L) was reached 2 hrs after the procedure. Neuron-specific enolase and S100 were extremely elevated (13.7 and 0.970 microg/L, respectively) in one patient after an extended episode of ventricular fibrillation. Plasma hemoglobin levels were in the normal range in implantable cardioverter/defibrillator patients throughout the observation period. CONCLUSIONS: Apparently, even brief successive periods of global cerebral ischemia cause neuronal damage without obvious severe neurologic deficits. However, they may be related to subtle postoperative neurologic or cognitive dysfunctions that a number of implantable cardioverter/defibrillator patients exhibit after implantation.     

Plasma interferon-gamma and interleukin-10 concentrations in systemic meningococcal disease compared with severe systemic Gram-positive septic shock

OBJECTIVE: To analyze plasma interferon-gamma and interleukin-10 concentrations in patients with systemic meningococcal disease and patients with severe Gram-positive septic shock caused by Streptococcus pneumoniae or Staphylococcus aureus. To study the in vitro cytokine (interferon-gamma and interleukin-10) responses in a whole blood model boosted with heat-killed Neisseria meningitidis, S. pneumoniae, and S. aureus before and after treatment with recombinant interleukin-10 or recombinant interferon-gamma. DESIGN: Experimental study. SETTING: Laboratory. SUBJECTS: Plasma samples were collected from patients with systemic meningococcal disease (n = 66) and patients with severe Gram-positive septic shock caused by S. pneumoniae (n = 4) or S. aureus (n = 3). INTERVENTIONS: Whole blood was boosted with heat-killed N. meningitidis, S. pneumoniae, and S. aureus (1 x 106 colony forming units/mL), and plasmas were analyzed for interleukin-10 or interferon-gamma at 0, 5, 12, and 24 hrs. Furthermore, recombinant interleukin-10 or recombinant interferon-gamma was added before bacteria, and the effect on the secretion of interferon-gamma and interleukin-10, respectively, was analyzed after 24 hrs. MEASUREMENTS AND MAIN RESULTS: The median concentration of interferon-gamma was 15 pg/mL and of interleukin-10 was 10,269 pg/mL in patients with meningococcal septic shock (n = 24) compared with median interferon-gamma concentration of 3400 pg/mL and interleukin-10 concentration of 465 pg/mL in patients with severe Gram-positive shock (p =.001). Increased interferon-gamma concentrations were associated with case fatality (p =.011). In a whole blood model we demonstrated that 1 x 106 colony forming units/mL of N. meningitidis induced more interleukin-10 but less interferon-gamma than S. pneumoniae. S. aureus induced minimal secretion of both cytokines. Recombinant interleukin-10 efficiently down-regulated the secretion of interferon-gamma, and vice versa, as shown in a whole blood model. CONCLUSION: We speculate whether high concentrations of interleukin-10 contribute to the low concentrations of interferon-gamma in fulminant meningococcal septicemia. In addition, it appears as if interferon-gamma plays a minor role in the pathophysiology of meningococcal septic shock.     

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.     

Mild hypothermia during prolonged cardiopulmonary cerebral resuscitation increases conscious survival in dogs

OBJECTIVE: Therapeutic hypothermia during cardiac arrest and after restoration of spontaneous circulation enables intact survival after prolonged cardiopulmonary cerebral resuscitation (CPCR). The effect of cooling during CPCR is not known. We hypothesized that mild to moderate hypothermia during CPCR would increase the rate of neurologically intact survival after prolonged cardiac arrest in dogs. DESIGN: Randomized, controlled study using a clinically relevant cardiac arrest outcome model in dogs. SETTING: University research laboratory. SUBJECTS: Twenty-seven custom-bred hunting dogs (19-29 kg; three were excluded from outcome evaluation). INTERVENTIONS: Dogs were subjected to cardiac arrest no-flow of 3 mins, followed by 7 mins of basic life support and 10 mins of simulated unsuccessful advanced life support attempts. Another 20 mins of advanced life support continued with four treatments: In control group 1 (n = 7), CPCR was with normothermia; in group 2 (n = 6, 1 of 7 excluded), with moderate hypothermia via venovenous extracorporeal shunt cooling to tympanic temperature 27 degrees C; in group 3 (n = 6, 2 of 8 excluded), the same as group 2 but with mild hypothermia, that is, tympanic temperature 34 degrees C; and in group 4 (n = 5), with normothermic venovenous shunt. After 40 mins of ventricular fibrillation, reperfusion was with cardiopulmonary bypass for 4 hrs, including defibrillation to achieve spontaneous circulation. All dogs were maintained at mild hypothermia (tympanic temperature 34 degrees C) to 12 hrs. Intensive care was to 96 hrs. MEASUREMENTS AND MAIN RESULTS: Overall performance categories and neurologic deficit scores were assessed from 24 to 96 hrs. Regional and total brain histologic damage scores and extracerebral organ damage were assessed at 96 hrs.In normothermic groups 1 and 4, all 12 dogs achieved spontaneous circulation but remained comatose and (except one) died within 58 hrs with multiple organ failure. In hypothermia groups 2 and 3, all 12 dogs survived to 96 hrs without gross extracerebral organ damage (p < .0001). In group 2, all but one dog achieved overall performance category 1 (normal); four of six dogs had no neurologic deficit and normal brain histology. In group 3, all dogs achieved good functional outcome with normal or near-normal brain histology. Myocardial damage scores were worse in the normothermic groups compared with both hypothermic groups (p < .01). CONCLUSION: Mild or moderate hypothermia during prolonged CPCR in dogs preserves viability of extracerebral organs and improves outcome.