The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder and health-related quality of life in survivors

OBJECTIVES: The exposure to intense physical and psychological stress during intensive care can result in posttraumatic stress disorder (PTSD) in survivors. Cortisol is a biological stress mediator that can have a protective effect during severe stress. The administration of stress doses of hydrocortisone during treatment in the intensive care unit could theoretically result in a lower incidence of PTSD. We tested this hypothesis in survivors of septic shock. DESIGN: A retrospective case-controlled analysis. SETTING: A 20-bed multidisciplinary intensive care unit of a tertiary-care university hospital. PATIENTS: We identified 27 patients who received standard therapy for septic shock. These patients served as controls and were compared with an equal number of patients who received hydrocortisone in addition to standard treatment. These patients were selected from our database with regard to age (+/-4 yrs), gender, and cause of septic shock to be as similar as possible with control patients. INTERVENTIONS: Patients from the hydrocortisone group had received stress doses of hydrocortisone (100 mg bolus, followed by 0.18 mg/kg/hr) in addition to standard treatment. Patients from the control group received standard protocol-driven treatment only. PTSD was diagnosed with the Posttraumatic Stress Syndrome-10 inventory, a self-report scale for diagnosis of PTSD. Health-related quality of life was measured using the Medical Outcomes Study Short-Form Survey (Medical Outcomes Trust, Boston, MA), which consists of 36 questions. MEASUREMENTS AND MAIN RESULTS: Patients who received hydrocortisone during septic shock had a significantly lower incidence of PTSD than patients who received standard treatment only (5 of 27 vs. 16 of 27; p = .01) and had significantly higher scores on the mental health index of the Medical Outcomes Study Short-Form health-related quality-of-life questionnaire (68 vs. 44 points; p = .009). CONCLUSIONS: Data from this study support the hypothesis that the administration of stress doses of hydrocortisone in doses equivalent to the maximal endocrine secretion rate during septic shock reduces the incidence of PTSD and improves emotional well-being in survivors. This hypothesis should be tested in a prospective randomized trial.     

Influences of hydrocortisone therapy on arginine vasopressin plasma levels in septic shock

Concomitant hydrocortisone and arginine vasopressin therapy increases arginine vasopressin plasma levels and may improve survival in septic shock. The objective of this post hoc analysis of a prospective study was to determine whether hydrocortisone therapy increases arginine vasopressin plasma levels in patients with septic shock. Forty-five patients were included into the study, of whom 23 (51.1%) received a hydrocortisone infusion because of escalating vasopressor dosages. Median arginine vasopressin plasma levels did not differ between patients treated with and without hydrocortisone therapy [4.2 (2.2-6.2) vs. 4.3 (2.7-6.1) pmol/L] both in a bivariate (p = 0.43, Mann-Whitney U-test) and a logistic regression model adjusted for differences in disease severity (p = 0.38). No association was further detected between hydrocortisone therapy and arginine vasopressin plasma levels in an adjusted linear regression model [β-coefficient, -0.57 (-1.86-0.73), p = 0.39]. We conclude that increased arginine vasopressin plasma levels during concomitant arginine vasopressin and hydrocortisone therapy in septic shock result from reduced arginine vasopressin clearance and not increased arginine vasopressin secretion or interaction of hydrocortisone with the arginine vasopressin assay.     

Stress doses of hydrocortisone in septic shock: beneficial effects on opsonization-dependent neutrophil functions

Objective To assess the effects of stress doses of hydrocortisone (HC) on clinical parameters and neutrophil functions in patients with septic shock. Design Prospective, double-blind, randomized, placebo-controlled study. Setting Intensive care units of a university hospital. Patients and participants 30 adult patients with septic shock. Interventions Patients were allocated to receive either HC (intravenous bolus of 100 mg preceding a continuous infusion 10 mg/h, n = 15) or placebo (n = 15), respectively. The effects of HC were assessed at baseline and after 24 h. Measurements and results As compared with placebo-treated patients, administration of HC significantly decreased norepinephrine requirements (from 1.5 to 0.8 mg/h; p < 0.001), interleukin-6 serum concentrations (from 388.8 to 88.8 pg/ml; p < 0.02), and the spontaneous release of hydrogen peroxide (H₂O₂) by neutrophils (−33.0%; p < 0.05). Additionally, HC treatment preserved the autologous plasma-induced amplification of phagocytosis of zymosan particles [factor of opsonin-induced amplification of phagocytosis of unopsonized particles: 1.80 for placebo vs. 1.75 for HC at baseline (not significant between groups) and 0.50 for placebo vs. 1.75 for HC after 24 h of treatment (p < 0.05)]. These effects were paralleled by respective changes in the phagocytosis-associated H₂O₂ production. Conclusions In patients with septic shock stress doses of HC exert beneficial effects in terms of improvements in hemodynamics, decrease in pro-inflammatory mediators, and oxidative stress without the compromise of opsonization-dependent phagocytic neutrophil functions; thus, HC treatment does not aggravate non-specific immunosuppression but instead improves innate immunity in the early stage of septic shock.     

Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock

OBJECTIVES: To investigate the effect of low-dose hydrocortisone on time to shock reversal, the cytokine profile, and its relation to adrenal function in patients with early septic shock. DESIGN: Prospective, randomized, double-blind, single-center study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Forty-one consecutive patients with early hyperdynamic septic shock. INTERVENTIONS: After inclusion and a short adrenocorticotropic hormone test, all patients were randomized to receive either low-dose hydrocortisone (50-mg bolus followed by a continuous infusion of 0.18 mg/kg body of weight/hr) or matching placebo. After shock reversal, the dose was reduced to 0.06 mg/kg/hr and afterward slowly tapered. Severity of illness was estimated using Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score. MEASUREMENTS AND MAIN RESULTS: Time to cessation of vasopressor support (primary end point) was significantly shorter in hydrocortisone-treated patients compared with placebo (53 hrs vs. 120 hrs, p < .02). This effect was more profound in patients with impaired adrenal reserve. Irrespective of endogenous steroid production, cytokine production was reduced in the treatment group with lower plasma levels of interleukin-6 and a diminished ex vivo lipopolysaccharide-stimulated interleukin-1 and interleukin-6 production. Interleukin-10 levels were unaltered. Adverse events were not more frequent in the treatment group. CONCLUSIONS: Treatment with low-dose hydrocortisone accelerates shock reversal in early hyperdynamic septic shock. This was accompanied by reduced production of proinflammatory cytokines, suggesting both hemodynamic and immunomodulatory effects of steroid treatment. Hemodynamic improvement seemed to be related to endogenous cortisol levels, whereas immune effects appeared to be independent of adrenal reserve.     

Effect of hydrocortisone on phenylephrine--mean arterial pressure dose-response relationship in septic shock

BACKGROUND: Septic shock is characterized by decreased responsiveness to catecholamines. Because endogenous steroids are known to play a role in the modulation of vasomotor tone, the purpose of our study was to investigate the phenylephrine-mean arterial pressure dose-response relationship in patients with septic shock and the effect of a physiological dose of hydrocortisone on it. METHODS: Twelve patients meeting usual criteria for septic shock and 12 age-matched control subjects were investigated before and 1 hour after receiving 50 mg intravenous hydrocortisone. Sixteen incremental doses of phenylephrine (microg/kg/min) were infused, and the effects on mean arterial pressure (mm Hg) were recorded. A sigmoid model, E = E0 + [Emax x Dgamma/(ED50gamma + Dgamma)], was fitted to individual data. In this model, E is the predicted effect and D is the dose of phenylephrine infused. E0 represents the basal value of effect (ie, the value of mean arterial pressure without drug), Emax is the maximum theoretical effect, ED50 is the dose of phenylephrine for which an effect of 50% of Emax is observed, and gamma is the Hill coefficient which accounts for the sigmoidicity of the curve. RESULTS: As compared with in control subjects, in patients, E0 was decreased before (58 +/- 8 versus 73 +/- 7 mm Hg) and after (64 +/- 12 versus 82 +/- 10 mm Hg) administration of hydrocortisone (P = .0001 for group), Emax was reduced before (39 +/- 17 versus 84 +/- 18 mm Hg) and after (77 +/- 26 versus 106 +/- 21 mm Hg) administration of hydrocortisone (P = .0001 for group), ED50 was not modified, and gamma was increased before (3.5 +/- 1.8 versus 1.3 +/- 0.3) and after (1.9 +/- 1.1 versus 1.3 +/- 0.3) administration of hydrocortisone (P = .0010 for group). Hydrocortisone similarly increased E0 in both groups (P = .0003 for sequence, P = .2883 for interaction), increased more Emax in patients than in control subjects (P < .0001 for sequence; P = .0280 for interaction), did not change ED50, and decreased y in patients but not in control subjects (P = .0025 for sequence, P = .0025 for interaction). CONCLUSIONS: In patients with septic shock, the Emax of phenylephrine is decreased, whereas its ED50 is not modified, both before and after administration of hydrocortisone. A physiological dose of hydrocortisone tends to normalize the relationship.     

小剂量氢化可的松在脓毒性休克治疗中的应用

目的 探讨小剂量氢化可的松对脓毒性休克患者炎性反应的疗效.方法 将脓毒性休克患者80例均予常规治疗.40例只行常规治疗(对照组);另40例加用小剂量氢化可的松治疗(氢可组).治疗后4、12、24、48 h、7 d采用ELISA法测定血浆TNF-α, IL-1β, IL-6和IL-10含量;治疗前及后24、48 h、7 d行急性生理功能和慢性健康状况(APACHEⅡ)评分,并检测降钙素原(PCT)以及皮质醇浓度,记录28 d病死率.结果 治疗前两组患者外周血上述指标水平差异无统计学意义.治疗前后比较, TNF-α、IL-1β和IL-6明显下降(P<0.05),IL-10差异无统计学意义;治疗24、48 h、7 d后APACHEⅡ评分下降(P<0.05)与对照组相比,在各时间点TNF-α,IL-1β,IL-6下降差异有统计学意义(P<0.05);APACHEⅡ评分降低(P<0.05),PCT下降(P<0.05),28 d病死率下降.但血皮质醇浓度与28 d生存率无明显相关性.结论 小剂量氢化可的松能减轻脓毒性休克患者的炎症反应,改善预后.     

Serum levels of neural protein S-100B in phenylketonuria

BACKGROUND: Serum neural protein S-100B concentration is considered as a marker of CNS lesions. Phenylketonuria (PKU) is a metabolic disorder characterized by high phenylalanine (Phe) levels in blood and foci of myelin absence in the CNS of untreated patients. AIM: To evaluate S-100B blood levels in PKU patients. METHODS: Twenty-five (N = 25) PKU patients of comparable age, who were diagnosed by neonatal screening and "followed up" in our Inborn Error of Metabolism Department, were divided into two groups: group A (N = 13) with almost normal Phe levels and group B (N = 12) "off diet" with high Phe concentrations. Their MRI examinations were normal 12-14 months before the beginning of the study. Twenty-three (N = 23) healthy children were the controls. Serum S-100B levels, measured with an immunoluminometric assay, were greatly elevated in the group B (0.48 +/- 0.6 microg/l) as compared to those of group A (0.16 +/- 0.4 microg/l, P < 0.001) and controls (0.10 +/- 0.02, P < 0.001). Positive correlation was found between S-100B and Phe blood concentration (r = 0.46, P < 0.01). Foci of myelin absence in MRIs were observed in 1/13 of group A and in 10/12 of group B at the end of this study. CONCLUSIONS: (a) Serum S-100B protein level, for the first time evaluated in PKU, was positively correlated with Phe blood level in PKU patients. (b) S-100B blood estimation could be a useful peripheral marker of CNS lesions in patients with demyelinated disease such as PKU.     

多巴胺对感染性休克患者IL-8、CRP水平的影响

目的探究多巴胺治疗感染性休克患者的临床效果。方法将50例感染性休克患者以单双号编号法随机分为试验组(25例,常规治疗+多巴胺)和对照组(25例,常规治疗)。比较两组的治疗效果。结果试验组的治疗总有效率高于对照组(P<0.05)。治疗后,两组WBC、APACHEⅡ评分、RR、HR、动脉血乳酸、PCT、TNF-α、CRP、IL-8、IL-6水平均低于治疗前,SBP高于治疗前,且试验组优于对照组(P<0.05)。试验组并发症总发生率低于对照组(P<0.05)。结论多巴胺治疗感染性休克患者的效果显著,能降低炎性因子水平以及并发症发生率,改善患者的血压、RR、HR、动脉血乳酸等指标水平。     

Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study.

OBJECTIVE: To investigate the effects of stress doses of hydrocortisone on the duration of vasopressor therapy in human septic shock. DESIGN: Prospective, randomized, double-blind, single-center study. SETTING: Twenty-bed multidisciplinary intensive care unit in a 1400-bed university hospital. PATIENTS: Forty consecutive patients who met the ACCP/SCCM criteria for septic shock. An additional criterion for inclusion in the study was vasopressor support and high-output circulatory failure with a cardiac index of >4 L/min/m2 after fluid resuscitation (pulmonary capillary wedge pressure: 12-15 mm Hg) and without the use of positive inotropes such as dobutamine or dopexamine. The primary study end point was the time to cessation of vasopressor support (norepinephrine or epinephrine in any dose, dopamine > or = 6 microg/kg/min). Secondary study end points were the evolution of hemodynamics and the multiple organ dysfunction syndrome (MODS). 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. MODS was described by the Sepsis-related Organ Failure Assessment score. INTERVENTIONS: All eligible patients were prospectively randomized to receive either stress doses of hydrocortisone or placebo. Hydrocortisone was started with a loading dose of 100 mg given within 30 mins and followed by a continuous infusion of 0.18 mg/ kg/hr. When septic shock had been reversed, the dose of hydrocortisone was reduced to 0.08 mg/kg/hr. This dose was kept constant for 6 days. As soon as the underlying infection had been treated successfully or sodium serum concentrations had increased to >155 mmol/L, the hydrocortisone infusion was tapered in steps of 24 mg/day. Physiologic saline solution was the placebo. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and oxygen-derived variables were measured at previously defined time points over a study period of 5 days. Relevant clinical and laboratory measurements were registered for a study period of 14 days to assess the evolution of organ dysfunction. Baseline data at recruitment did not differ between the two groups. Shock reversal was achieved in 18 of the 20 patients treated with hydrocortisone vs. 16 of the 20 patients treated with placebo. Hydrocortisone significantly reduced the time to cessation of vasopressor support. The median time of vasopressor support was 2 days (1st and 3rd Quartiles, 1 and 6 days) in the hydrocortisone-treated group and 7 days (1st and 3rd Quartiles, 3 and 19 days) in the placebo group (p = .005 Breslow test). There was a trend to earlier resolution of the organ dysfunction syndrome in the hydrocortisone group. CONCLUSIONS: Infusion of stress doses of hydrocortisone reduced the time to cessation of vasopressor therapy in human septic shock. This was associated with a trend to earlier resolution of sepsis-induced organ dysfunctions. Overall shock reversal and mortality were not significantly different between the groups in this low-sized single-center study.     

Gluco- and mineralocorticoid biological effects of a 7-day treatment with low doses of hydrocortisone and fludrocortisone in septic shock

Purpose

The benefits of low-dose steroids in septic shock remain controversial. We investigated if these low doses were able to induce their expected hormonal effects by analyzing the biological modifications observed during the study, which first demonstrated the survival benefit of low-dose steroids.

Methods

This was a multicenter, placebo-controlled, randomized, double-blind study in which 299 septic shock patients received a 7-day treatment with a combination of hydrocortisone (50?mg intravenously four times daily) and fludrocortisone (50?μg orally once daily) or matching placebos. Gluco- and mineralocorticoid biological effects observed during the 7?days of treatment were compared between groups.

Results

Steroids significantly decreased eosinophil counts from day?2 to day?7. Steroids significantly increased plasma glucose from day?2 (compared with placebos: +0.8?mmol/l) to day?7 (+1.8?mmol/l) and cholesterol from day?3 (+0.54?mmol/l) to day?7 (+0.39?mmol/l). Steroids significantly increased plasma sodium from day?3 (+2?mmol/l) to day?7 (+5?mmol/l) and significantly decreased plasma potassium on day?7 (?0.2?mmol/l). Steroids significantly decreased urinary sodium/potassium ratio from day?2 (?47?%) to day?7 (?57?%) and sodium fractional excretion from day?3 (?25?%) to day?7 (?66?%). Steroids significantly increased urine output on day?4 and 5 and osmolar clearance from day?4 to day?7, and decreased free-water clearance from day?4 to day?7, this effect being significant on day?4 and 6.

Conclusions

In septic shock, low-dose steroids induced both gluco- and mineralocorticoid biological effects and seemed to improve renal function. Most of these effects appeared after 2–3?days of treatment and lasted at least until the end of treatment.     

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.     

Impact of bolus application of low-dose hydrocortisone on glycemic control in septic shock patients

Objective To determine whether glycemic control is less feasible when hydrocortisone is given as a bolus compared with continuous application in septic shock patients. Design Observational prospective pilot study. Setting Fourteen-bed surgical university hospital ICU. Patients Sixteen consecutive patients with septic shock receiving a continuous infusion of 200 mg hydrocortisone/day and an infusion regime of insulin keeping blood glucose below 150 mg/dl. Intervention Blood glucose and insulin infusion were adjusted to steady state before intervention. At baseline, the continuous hydrocortisone infusion was replaced with a single bolus of 50 mg hydrocortisone. During a subsequent 6-h period, blood glucose was monitored hourly and insulin infusion was kept constant. Afterwards, hydrocortisone application and adjustment of blood glucose was resumed according to standard treatment. Results Mean blood glucose in steady state at baseline immediately prior to intervention was 128 mg/dl (range 114–141 mg/dl; 95% confidence interval). After bolus injection of hydrocortisone, blood glucose increased significantly within 6 h with peak levels of 154 mg/dl (range 132–178 mg/dl; p < 0.01). Blood glucose returned to baseline with restoration of continuous hydrocortisone infusion. There were marked inter-individual variations with peak glucose values up to 254 mg/dl, but no significant difference in intra-individual glucose variability before and after bolus injection of hydrocortisone. Conclusions Bolus injections of hydrocortisone may induce significant increases of blood glucose in patients with septic shock. The individual response is highly variable and we speculate that repetitive boluses would induce marked undulation of blood glucose. In terms of glycemic-control strategies, a continuous infusion of hydrocortisone seems to be preferable.     

血清、脑脊液中S-100B、NSE水平与缺血性脑卒中的研究

目的探讨血清、脑脊液中S-100B、神经元特异性烯醇化酶(NSE)与缺血性脑卒中的关系。方法将无特定病原体(SPF)级48只SD大鼠随机编号分为8组,每组6只,手术后8 h做行为学评价。按照不同时间段,术后8 h、12 h、1 d、3 d、5 d、7 d、21 d腹腔取血及抽取脑脊液,检测S-100B蛋白及NSE水平;进行2,3,5-氯化三苯基四氮唑(TTC)大脑染色及行为学功能评价并分析其相关性。结果SD大鼠血清及脑脊液中S-100B及NSE在不同时间段呈趋势性变化;脑脊液中S-100B、NSE水平增高时间均早于血清中S-100B、NSE水平增高时间;脑损伤后12 h,脑脊液中NSE水平即可达到峰值,血清中S-100B、NSE水平增加,3 d后达到峰值,7 d后S-100B、NSE水平与对照组比较,差异无统计学意义(P>0.05);血清和脑脊液中S-100B、NSE水平与梗死面积、神经功能评分均呈正相关(P<0.05)。结论脑脊液及血清中S-100B及NSE均能反应脑损伤程度,作为缺血性脑卒中的生物学指标,可进一步为临床患者提供血液及脑脊液标本采集的时间窗口。     

Effect of mode of hydrocortisone administration on glycemic control in patients with septic shock: a prospective randomized trial

Introduction  

Low-dose hydrocortisone treatment is widely accepted therapy for the treatment of vasopressor-dependent septic shock. The question of whether corticosteroids should be given to septic shock patients by continuous or by bolus infusion is still unanswered. Hydrocortisone induces hyperglycemia and it is possible that continuous hydrocortisone infusion would reduce the fluctuations in blood glucose levels and that tight blood glucose control could be better achieved with this approach.     

C1-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2

C1-inhibitor (C1-INH) is the major plasma inhibitor of the complement and contact systems. Activation of either system has been shown to occur in patients with septic shock and is associated with a poor outcome. Functional levels of C1-INH tend to be normal in septic patients although paradoxically this inhibitor is an acute phase protein. Moreover, levels of proteolytically inactivated C1-INH are increased in sepsis pointing to an increased turn-over. These observations suggest a relative deficiency of biologically active C1-INH in sepsis. Complement and contact activation have also been shown to occur in the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2), which syndrome may be regarded as a human model for septic shock. The similarity between VLS and sepsis encompasses more than complement and contact activation since a number of other inflammatory mediators considered to play a role in the pathogenesis of septic shock, are also involved in the development of VLS. The role and the mechanisms of complement and contact activation in sepsis and in the VLS are reviewed in this paper. Initial results of intervention therapy with high doses of C1-INH in these syndromes are also reported. It is concluded that high doses of C1-INH can be safely administered to patients with septic shock or with VLS and may attenuate complement and contact activation in these conditions. Double-blind controlled studies are needed to definitely prove these effects and to establish whether this treatment is able to reduce mortality and morbidity of these syndromes.     

Role of neutrophil elastase in development of pulmonary vascular injury and septic shock in rats

Prostacyclin prevents pulmonary vascular injury and shock by inhibiting increases in lung tissue levels of TNF in rats administered endotoxin. We previously reported that NO derived from eNOS increases endothelial production of prostacyclin. Because neutrophil elastase has been shown to decrease endothelial production of prostacyclin by inhibiting NOS activity, we examined whether neutrophil elastase inhibitors reduce pulmonary vascular injury and hypotension by inhibiting the decrease in pulmonary endothelial production of prostacyclin in rats administered endotoxin. Animals were pretreated with sivelestat or L-658,758, neutrophil elastase inhibitors, before endotoxin administration. Lung tissue levels of 6-keto-prostaglandin F1alpha were markedly increased after endotoxin administration, followed by a rapid decrease to baseline levels. Sivelestat and L-658,758 inhibited these decreases as well as inhibiting increases in lung tissue levels of TNF and lung wet-to-dry weight ratios in animals administered endotoxin. These inhibitors also reduced hypotension and inhibited increases in lung tissue levels of mRNA of the inducible form of NOS in animals administered endotoxin. The effects of neutrophil elastase inhibitors were completely reversed by pretreatment with nitro-L-arginine methyl ester, an inhibitor of NOS, or indomethacin, a nonspecific cyclooxygenase inhibitor. These observations suggested that neutrophil elastase might decrease the pulmonary endothelial production of prostacyclin by inhibiting endothelial NO production, thereby contributing to the development of pulmonary vascular injury and shock through increases in lung tissue levels of TNF in rats administered endotoxin.     

C1-inhibitor substitution therapy in septic shock and in the vascular leak syndrome induced by high doses of interleukin-2

C1-inhibitor (C1-INH) is the major plasma inhibitor of the complement and contact systems. Activation of either system has been shown to occur in patients with septic shock and is associated with a poor outcome. Functional levels of C1-INH tend to be normal in septic patients although paradoxically this inhibitor is an acute phase protein. Moreover, levels of proteolytically inactivated C1-INH are increased in sepsis pointing to an increased turn-over. These observations suggest a relative deficiency of biologically active C1-INH in sepsis. Complement and contact activation have also been shown to occur in the vascular leak syndrome (VLS) induced by immunotherapy with the cytokine interleukin-2 (IL-2), which syndrome may be regarded as a human model for septic shock. The similarity between VLS and sepsis encompasses more than complement and contact activation since a number of other inflammatory mediators considered to play a role in the pathogenesis of septic shock, are also involved in the development of VLS. The role and the mechanisms of complement and contact activation in sepsis and in the VLS are reviewed in this paper. Initial results of intervention therapy with high doses of C1-INH in these syndromes are also reported. It is concluded that high doses of C1-INH can be safely administered to patients with septic shock or with VLS and may attenuate complement and contact activation in these conditions. Double-blind controlled studies are needed to definitely prove these effects and to establish whether this treatment is able to reduce mortality and morbidity of these syndromes.     

Influence of pentoxifylline on cytokine levels and inflammatory parameters in septic shock

Objective To evaluate the influence of pentoxifylline (PTX), a phosphodiesterase inhibitor, on cytokines and inflammatory proteins in patients suffering from septic shock.Design Prospective study comparing a therapy group to a matched control group.Setting Medical intensive care unit at a university hospital.Patients Twenty four patients fulfilling the criteria of septic shock were included in this study. Twelve patients received PTX (therapy group) and 12 patients matched for diagnosis, age and gender served as the control group.Interventions Pentoxifylline at 1 mg/kg per hour over 24 h in the therapy group.Measurements ad results Cytokine levels [tumor necrosis factor- (TNF)], soluble TNF receptor [TNF-R], and interleukin-6 [IL-6] and inflammatory proteins [C-reactive protein, -1-antitrypsin (AAT), fibronectin, and haptoglobin], as well as hemodynamic parameters and the APACHE III score were evaluated before initiation of therapy and 24 h later. After 24 h, TNF levels were significantly lower in the therapy group (p=0.013), while IL-6 levels were significantly higher in the therapy group (p=0.030). Within the 24 h TNF declined significantly in the therapy group (p=0.006), while IL-6 showed a significant increase (p=0.043). AAT and the APACHE III score tended to differ significantly after 24 h between the groups [AAT levels higher in the therapy group (p=0.05), APACHE III score lower (p=0.05)]. In the therapy group, the systemic vascular resistance index was significantly higher after 24 h (p=0.0026) whereas the cardiac index declined (p=0.035).Conclusions PTX does influence TNF levels in septic shock patients. Nevertheless, inhibiting a single mediator in severe septic shock cannot stop the inflammatory overreaction.     

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.     

低剂量氢化可的松对感染性休克患者外周血胸腺依赖性淋巴细胞凋亡的影响

目的 探讨低剂量氢化可的松治疗感染性休克时对外周血胸腺依赖性淋巴细胞(T淋巴细胞)凋亡的影响.方法 前瞻性地将南京市第一医院ICU 2006年1月至2009年1月收治的57例感染性休克患者,按照随机(随机数字法)对照的原则分为氢化可的松治疗组和对照组,同时选取20例健康志愿者及18例脓毒血症患者进行对比,采取人选的健康志愿者和患者发病的0 h,24 h,48 h,72h,168 h的外周血,用Annexin V法和流式细胞仪,动态测定T淋巴细胞亚群的凋亡情况.组间两两比较时采用LSD-t检验法.结果 在初始状态下,感染性休克患者的外周血T淋巴细胞CD4+亚群的凋亡为(11.01±4.52)%,健康对照组为(4.41±1.45)%,脓毒血症患者为(7.87±3.82)%;感染性休克患者的外周血T淋巴细胞CD4+亚群的凋亡多于健康对照组(P<0.05)及脓毒血症患者(P<0.05);而初始状态下感染性休克患者外周血T淋巴细胞CD8+亚群的凋亡为(11.33±19.62)%,健康对照组(9.62±8.32)%,脓毒血症患者(13.09±15.84)%,三组比较差异无统计学意义(P>0.05).感染性休克对照组患者24 h,48 h,72 h外周血CD4+亚群的凋亡分别为(13.51±6.85)%,(19.39±6.63)%,(15.33±6.21)%,治疗组24 h,48h,72 h外周血CD4+亚群的凋亡分别为(17.4±7.21)%,(22.61±5.64)%,(25.73±6.91)%,治疗组的CD4+亚群的凋亡比例明显多于对照组(P<0.05);感染性休克对照组患者24 h,48 h,72 h外周血CD8+亚群的凋亡分别为(11.49±11.73)%,(12.74±10.39)%,(13.28±16.6)%,治疗组24 h,48h,72 h外周血CD8+亚群的凋亡分别为(9.49±8.9)%,(15.32±18.17)%,(13.68±16.84)%,两组比较差异无统计学意义(P>0.05);发病168 h后,感染性休克对照组和治疗组外周血CD4+亚群的凋亡分别为(5.64±4.58)%vs.(6.79±6.80)%,两组比较差异无统计学意义(P>0.05),发病168 h感染性休克对照组和治疗组外周血CD8+亚群的凋亡分别为(12.72±19.69)%vs.(13.88±13.28)%,两组比较差异也无统计学意义(P>0.05).结论 采用氢化可的松治疗感染性休克时,CD4+淋巴细胞凋亡明显增多,而CD8+亚群不受影响.