Tadahiko Shiozaki

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-1β, TNF-α, 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-1β, TNF-α, 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 (r2 = 0.729, P < 0.0001). For the cytokines investigated, only the peak CSF IL-1β concentration correlated significantly and positively with the peak CSF S100B concentration (r2 = 0.397, P < 0.005). Peak CSF concentrations of S100B (1649 ± 415 μg/L, mean ± SEM) and IL-1β (16.5 ± 3.3 pg/mL) in the 6 patients with high ICP were significantly higher than those (233 ± 67 μg/L, 7.6 ± 1.7 pg/mL, respectively) in the 17 patients with low ICP (P < 0.05). The CSF S100B concentration (1231 ± 378 μg/L) in eight patients with an unfavorable outcome was significantly higher than that (267 ± 108 μg/L) in 15 patients with a favorable outcome (P < 0.05). The CSF IL-1β 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-1β may be useful as predictors of outcome in cases of severe TBI.

Cerebrospinal fluid concentrations of anti-inflammatory mediators in early-phase severe traumatic brain injury.

In our previous study of patients with early-phase severe traumatic brain injury (TBI), the anti-inflammatory interleukin (IL)-10 concentration was lower in cerebrospinal fluid (CSF) than in serum, whereas proinflammatory IL-1β and tumor necrosis factor (TNF)-α concentrations were higher in CSF than in serum. To clarify the influence of additional injury on this disproportion between proinflammatory and anti-inflammatory mediators, we compared their CSF and serum concentrations in patients with severe TBI with and without additional injury. All 35 study patients (18 with and 17 without additional injury) had a Glasgow Coma Scale score of 8 or less upon admission. With the exception of additional injury, clinical characteristics did not differ significantly between groups. CSF and serum concentrations of two proinflammatory mediators (IL-1β and TNF-α,) and three anti-inflammatory mediators (IL-1 receptor antagonist [IL-1ra], soluble TNF receptor-I [sTNFr-I], and IL-10) were measured and compared at 6 h after injury. CSF concentrations of proinflammatory mediators were much higher than the corresponding serum concentrations in both patient groups (P < 0.001). In contrast, serum concentrations of anti-inflammatory mediators were much higher than the paired CSF concentrations in patients with additional injury (P < 0.001), but serum concentrations were lower than or equal to the corresponding CSF concentrations in patients without additional injury. CSF concentrations of IL-1β, IL-1ra, sTNFr-I, and IL-10 were significantly higher (P < 0.01 for all) in patients with high intracranial pressure (ICP; n = 11) than in patients with low ICP (n = 24), and were also significantly higher (P < 0.05 for all) in patients with an unfavorable outcome (n = 14) than in patients with a favorable outcome (n = 21). These findings indicate that increased serum concentrations of anti-inflammatory mediators after severe TBI are mainly due to additional extracranial injury. We conclude that anti-inflammatory mediators in CSF may be useful indicators of the severity of brain damage in terms of ICP as well as overall prognosis of patients with severe TBI.

Enhanced expression of heat shock proteins in activated polymorphonuclear leukocytes in patients with sepsis.

BACKGROUND Heat shock proteins (HSPs) in cells, as molecular chaperons, have been reported to regulate cell functions. The objective of this study was to investigate the HSP expression in polymorphonuclear leukocytes (PMNLs) from severe septic patients and the relation between the expression of HSPs and PMNL function. METHODS In blood samples from 21 patients with sepsis and serum C-reactive protein levels more than 10 mg/dL, we used flow cytometry to measure expressions of HSP27, HSP60, HSP70, and HSP90; oxidative activity; and levels of apoptosis in PMNLs during sepsis. In in vitro studies, we used cells from 14 healthy volunteers to examine the relation between the expression of HSP70 and PMNL function. Quercetin (30 microM), a suppressor of HSP, and sodium arsenite (100 microM), an inducer of HSP, were used to regulate the expression of HSP70 in PMNLs, and oxidative activity and apoptosis in these cells were measured. RESULTS In patients with sepsis, the expressions of HSP27, HSP60, HSP70, and HSP90 and oxidative activity in PMNLs were significantly increased. Apoptosis of these PMNLs was markedly inhibited. In the in vitro studies, administration of sodium arsenite enhanced the expression of HSP70, significantly increased oxidative activity, and inhibited apoptosis. Administration of quercetin before sodium arsenite prevented the expression of HSP70, the increase in oxidative activity, and the inhibition of apoptosis. CONCLUSION Sepsis causes the enhanced expression of HSPs in activated PMNLs. In PMNLs with enhanced expression of HSP70, oxidative activity is increased and apoptosis is inhibited. The enhanced expression of HSPs may play a role in regulating PMNL function in patients with sepsis.

Characteristics of infection and leukocyte count in severely head-injured patients treated with mild hypothermia.

OBJECTIVE This study was designed to characterize the infectious complications and kinetics of leukocyte count in severely head-injured patients treated with mild hypothermia. PATIENTS AND METHODS We retrospectively analyzed the incidence and severity of infectious complications as well as daily changes in leukocyte count in 41 severely head-injured patients treated with mild hypothermia (group H). They were retrospectively compared with 25 severely head-injured patients treated with high-dose barbiturates (group B) and to 25 other severely head-injured patients treated with no barbiturates (group N). RESULTS Initial intracranial pressure was significantly higher in group H than in the other groups. No significant differences existed in the incidence of pneumonia or meningitis among the three groups, whereas the incidence of bacteremia was significantly higher in group H than in the other two groups. Pneumonia was significantly more severe in group H than in the other groups. In six patients of group H, pneumonia spread fulminantly to become life threatening. Daily changes in total leukocyte count showed the same pattern, consisting of a peak, a nadir, and a second peak in all groups. Total leukocyte count was, however, significantly lower during the first 2 weeks in group H than in the other two groups. Lymphocyte and neutrophil counts were also lower in group H. CONCLUSION Infectious complications were more severe and leukocyte counts were lower in patients treated with mild hypothermia, who also had the highest initial intracranial pressures, than in patients treated with conventional therapies. Measures against increased susceptibility to infection and leukocyte suppression should be explored.

Prognostic indicators and outcome prediction model for patients with return of spontaneous circulation from cardiopulmonary arrest: The Utstein Osaka Project

OBJECTIVE To determine the most important indicators of prognosis in patients with return of spontaneous circulation (ROSC) following out-of-hospital cardiopulmonary arrest (OHCA) and to develop a best outcome prediction model. DESIGN AND PATIENTS All patients were prospectively recorded based on the Utstein Style in Osaka over a period of 3 years (2005-2007). Criteria for inclusion were a witnessed cardiac arrest, age greater than 17 years, presumed cardiac origin of the arrest, and successful ROSC. Multivariate logistic regression (MLR) analysis was used to develop the best prediction model. The dependent variables were favourable outcome (cerebral-performance category [CPC]: 1-2) and poor outcome (CPC: 3-5) at 1 month after the event. Eight explanatory pre-hospital variables were used concerning patient characteristics and resuscitation. External validation was performed on an independent set of Utstein data in 2007. RESULTS Subjects comprised 285 patients in VF and 577 patients with pulseless electrical activity (PEA)/asystole. The percentage of favourable outcomes was 31.9% (91/285) in VF and 5.7% (33/577) in PEA/asystole. The most important prognostic indicators of favourable outcome found by MLR were age (p=0.10), time from collapse to ROSC (TROSC) (p<0.01), and presence of pre-hospital ROSC (PROSC) (p=0.15) for VF and age (p=0.03), TROSC (p<0.01), PROSC (p<0.01), and conversion to VF (p=0.01) for PEA/asystole. For external validation data, areas under the receiver-operating characteristic curve were 0.867 for VF and 0.873 for PEA/asystole. CONCLUSIONS A model based on four selected indicators showed a high predictive value for favourable outcome in OHCA patients with ROSC.

Effectiveness of the new ‘Mobile AED Map’ to find and retrieve an AED: A randomised controlled trial☆☆☆

BACKGROUND Although early shock with an automated external defibrillator (AED) is one of the several key elements to save out-of-hospital cardiac arrest (OHCA) victims, it is not always easy to find and retrieve a nearby AED in emergency settings. We developed a cell phone web system, the Mobile AED Map, displaying nearby AEDs located anywhere. The simulation trial in the present study aims to compare the time and travel distance required to access an AED and retrieve it with and without the Mobile AED Map. METHODS DESIGN Randomised controlled trial. SETTING Two fields where it was estimated to take 2min (120-170m) to access the nearest AED. Participants were randomly assigned to either the Mobile AED Map group or the control group. We provided each participant in both groups with an OHCA scenario, and measured the time and travel distance to find and retrieve a nearby AED. RESULTS Forty-three volunteers were enrolled and completed the protocol. The time to access and retrieve an AED was not significantly different between the Mobile AED Map group (400±238s) and the control group (407±256s, p=0.92). The travel distance was significantly shorter in the Mobile AED Map group (606m vs. 891m, p=0.019). Trial field conditions affected the results differently. CONCLUSIONS Although the new Mobile AED Map reduced the travel distance to access and retrieve the AED, it failed to shorten the time. Further technological improvements of the system are needed to increase its usefulness in emergency settings (UMIN000002043).

Mild hypothermia reduces expression of heat shock protein 60 in leukocytes from severely head-injured patients

BACKGROUND Infectious complications are among the most serious problems that occur in severely head-injured patients treated with mild hypothermia. The mechanism underlying the susceptibility to infection has not been clarified. Heat shock protein (HSP) 60 has been reported to play an essential role in innate immunity. Thus, we conducted a study to clarify the impact of mild hypothermia on the expression of HSPs in polymorphonuclear leukocytes (PMNLs) in severely head-injured patients. METHODS Between September 1997 and November 1999, 17 severely head-injured patients with a Glasgow Coma Scale score of 8 or less at admission in whom intracranial pressure could be maintained below 20 mm Hg by conventional therapy were randomly assigned to two treatment groups: a mild hypothermia group (HT group, nine patients) and a normothermia group (NT group, eight patients). The HT group was subjected to mild hypothermia (intracranial temperature, 34 degrees C) for 48 hours followed by rewarming at a rate of 1 degrees C per day for 3 days, whereas the NT group was subjected to normothermia (intracranial temperature, 37 degrees C) for 5 days. Blood samples were serially obtained at three time points; days 0 to 1, days 2 to 5, and days 6 to 14 after head injury. We measured the expression of HSP27, HSP60, HSP70, and HSP90 by flow cytometry. RESULTS The two groups were similar with respect to prognostic factors, and there was no difference in clinical outcome. The expression of PMNL HSP60 in the HT group was significantly lower in all three time periods compared with that in the NT group (p < 0.05), whereas expression of the other HSPs did not differ significantly between the groups. The incidence of infectious complications was significantly increased in the HT group over that in the NT group (p < 0.05). In in vitro studies, PMNLs from 10 healthy volunteers were incubated at 37 degrees C, 34 degrees C, or 26 degrees C for 1 hour with sodium arsenite (100 micromol/L), an HSP inducer. The expression of HSP60 at 26 degrees C and 34 degrees C was significantly lower than that at 37 degrees C (p < 0.05), whereas expression of the other HSPs did not differ significantly at 26 degrees C, 34 degrees C, or 37 degrees C. CONCLUSION Mild hypothermia reduces the expression of HSP60 in PMNLs from severely head-injured patients. Thus, mild hypothermia may suppress innate immunity.

Prognostic indicators and outcome prediction model for severe traumatic brain injury

BACKGROUND Although some predictive models for patient outcomes after severe traumatic brain injury have been proposed, a mathematical model with high predictive value has not been established. The purpose of the present study was to analyze the most important indicators of prognosis and to develop the best outcome prediction model. METHODS One hundred eleven consecutive patients with a Glasgow Coma Scale score of <9 were examined and 14 factors were evaluated. Intracranial pressure and cerebral perfusion pressure were recorded at admission to the intensive care unit. The absence of the basal cisterns, presence of extensive subarachnoid hemorrhage, and degree of midline shift were evaluated by means of computed tomography within 24 hours after injury. Multivariate logistic regression analysis was used to identify independent risk factors for a poor prognosis and to develop the best prediction model. RESULTS The best model included the following variables: age (p < 0.01), light reflex (p = 0.01), extensive subarachnoid hemorrhage (p = 0.01), intracranial pressure (p = 0.04), and midline shift (p = 0.12). Positive predictive value of the model was 97.3%, negative predictive value was 87.1%, and overall predictive value was 94.2%. The area under the receiver operating characteristic curve was 0.977, and the p value for the Hosmer-Lemeshow goodness-of-fit was 0.866. CONCLUSIONS Our predictive model based on age, absence of light reflex, presence of extensive subarachnoid hemorrhage, intracranial pressure, and midline shift was shown to have high predictive value and will be useful for decision making, review of treatment, and family counseling in case of traumatic brain injury.

Delayed Hemispheric Neuronal Loss in Severely Head-Injured Patients

Recent experimental studies have revealed that traumatic brain injury as well as ischemic brain injury can cause chronic progressive neuronal damage. In the present study, we demonstrate previously unreported delayed cerebral atrophy on computerized tomography (CT) scans in severely head-injured patients. Seventeen severely head-injured patients who required mild hypothermia to control intracranial hypertension after the failure of conventional therapies were retrospectively analyzed. All 17 patients survived more than 1 year. Delayed neuronal loss (DNL) was observed in only eight of the 17 patients. Eight patients with DNL required longer durations of mild hypothermia to control intracranial hypertension than nine patients without DNL. Six of these eight patients with DNL achieved functional recovery despite progressive atrophic changes demonstrated on CT scans. On CT scans, DNL was characterized by (1) the sudden appearance at several months postinjury of a low-density area in the hemisphere ipsilateral to the injury; (2) the preservation of essential cortical structure although related white matter structures showed severe atrophic changes; and (3) no spread of the low-density area to the contiguous territory of the other main cerebral artery. It is concluded that focal primary injury to underlying brain, if severe enough, can result in delayed hemispheric atrophy.

Granulocyte colony-stimulating factor ameliorates life-threatening infections after combined therapy with barbiturates and mild hypothermia in patients with severe head injuries.

OBJECTIVE The objective of this study was to clarify the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration on infections in patients with severe head injuries after combined therapy with high-dose barbiturates and mild hypothermia. PATIENTS AND METHODS Since 1996, we have administered rhG-CSF to eight patients with severe head injuries for 5 days (group G). Their treatment results were compared with those of 22 patients cared for earlier without rhG-CSF treatment (group N). All patients in both groups met the criteria of total leukocyte count (TLC) less than 5,000/mm3, C-reactive protein (CRP) over 10 mg/dL, and the presence of an infectious complication. Changes in the TLC, CRP, respiratory index, intracranial pressure, and infectious condition were evaluated in both groups. In addition, the nucleated cell count and differentiation from bone marrow aspiration, neutrophil functions, serum concentrations of interleukin-6, and plasma concentration of leukocyte elastase were evaluated in group G. RESULTS In group G, TLC, nucleated cell count, and neutrophil functions significantly increased, whereas CRP, respiratory index, and interleukin-6 decreased reciprocally. There was no deterioration of intracranial pressure and leukocyte elastase. Consequently, seven of the eight patients in group G recovered from life-threatening infections, and none of the eight patients died. However, in group N, CRP and respiratory index remained high and TLC did not increase as much as it did in group G. Infections continued after 5 days in 17 of the 22 patients, 7 of whom died from severe infections during hospitalization. CONCLUSION Administration of rhG-CSF ameliorated life-threatening infections without causing lung injury or increasing brain swelling in patients with severe head injuries who were treated with combined therapy involving high-dose barbiturates and mild hypothermia.