Circulating methemoglobin and nitrite/nitrate concentrations as indicators of nitric oxide overproduction in critically ill children with septic shock

OBJECTIVES: To examine the relationship between circulating methemoglobin and nitrite/nitrate concentrations and to compare these markers of nitric oxide overproduction with clinical variables in children diagnosed with septic shock. DESIGN: Prospective, controlled, clinical study. SETTING: Pediatric intensive care unit and outpatient clinic in a children's hospital. PATIENTS: Twenty-two children diagnosed with septic shock and ten age-matched healthy control patients. INTERVENTIONS: Patients diagnosed with septic shock had blood specimens taken on study entry and every 6 hrs for 72 hrs for methemoglobin and nitrite/nitrate determinations. Single blood specimens were obtained from controls. MEASUREMENTS AND MAIN RESULTS: Circulating methemoglobin and nitrite/nitrate concentrations were significantly higher in children diagnosed with septic shock in comparison with healthy control children (p = .01 and .05, respectively). Peak nitrite/nitrate concentrations correlated with serum creatinine (r2 = .19; p = .04) and were inversely correlated with arterial pH (r2 = .28; p = .01) and urine output (r2 = .21; p = .03) when analyzed by log-linear regression. There were no significant relationships between methemoglobin and nitrite/nitrate or between methemoglobin and any other clinical variable. CONCLUSIONS: Circulating methemoglobin and nitrite/nitrate concentrations are increased in children diagnosed with septic shock. Plasma nitrite/nitrate values correlate with selected clinical variables in these children. Circulating methemoglobin measurements are not superior to plasma nitrite/nitrate concentrations as an indicator of endogenous overproduction of nitric oxide in children diagnosed with septic shock. A need remains to develop markers of endogenous nitric oxide activity that have greater accuracy and reliability.     

Influence of angiotensin-converting enzyme inhibitor enalaprilat on endothelial-derived substances in the critically ill

OBJECTIVE: To assess the effects of the angiotensin-converting enzyme inhibitor enalaprilat on endothelial cells in septic patients. DESIGN: Prospective, randomized, placebo-controlled, blinded study. SETTING: Clinical investigation on a surgical intensive care unit of a university hospital. PATIENTS: Forty surgical septic patients (noncardiac/nonneurosurgical patients). INTERVENTIONS: After inclusion in the study and after baseline data were obtained, either 0.25 mg/hr (enalaprilat group, n = 20) or saline solution as placebo (control group, n = 20) was continuously given and continued throughout the following 5 days. MEASUREMENTS AND MAIN RESULTS: Extensive hemodynamic monitoring was carried out in all patients. Plasma concentrations of endothelin-1, angiotensin II, soluble thrombomodulin, and soluble adhesion molecules (endothelial leukocyte adhesion molecule-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and granule membrane protein-140) were measured from arterial blood samples. All measurements were carried out before the start of the infusion ("baseline" values) and daily during the following 5 days. All endothelial-derived substances (thrombomodulin, endothelin-1, and all soluble adhesion molecules) were similarly increased beyond normal in both group. Endothelin-1 increased only in the untreated control patients (from 6.9 +/- 0.7 to 14.3 +/- 1.4 mg/mL). Soluble thrombomodulin increased in the untreated control patients (from 58 +/- 9 to 79 +/- 14 ng/mL [p < .05]), but significantly decreased in the enalaprilat-treated patients. Soluble adhesion molecules increased in the untreated control group (endothelial leukocyte adhesion molecule from 92 +/- 14 to 192 +/- 29 ng/mL; intercellular adhesion molecule-1 from 480 +/- 110 to 850 +/- 119 ng/ mL) and returned almost to normal values in the enalaprilat patients. The survival rate did not differ significantly between the two groups. Control patients developed severe sepsis and septic shock more often than the enalaprilat-treated group. CONCLUSIONS: The complex pathogenesis of endothelial function abnormalities in sepsis may offer a large number of pharmacologic interventions. Administration of the angiotensin-converting enzyme inhibitor enalaprilat resulted in a reduced release of soluble endothelial-derived substances into the circulating blood, which may indicate an improved endothelial function. The specific actions of enalaprilat on the endothelium have to be elucidated in further studies.     

Changes in plasma erythropoietin and interleukin-6 concentrations in patients with septic shock after hemoperfusion with polymyxin B-immobilized fiber

OBJECTIVE: To find out whether polymyxin B-immobilized fiber (PMX-F) treatment affects the clinical parameters and plasma concentrations of erythropoietin (EPO) and interleukin (IL)-6. DESIGN: A prospective case series study. SETTING: Intensive care unit of the Department of Internal Medicine, Misato Junshin Hospital, Saitama, and Koto Hospital, Tokyo, Japan. PATIENTS: 17 consecutive patients (10 men, 7 women; mean age 54.6 years) with clinically defined septic shock and 20 healthy volunteers (12 men, 8 women; mean age 52.2 years). MAIN RESULTS: Of the 17 patients with septic shock, 9 (53 %) survived. The systolic blood pressure increased significantly from 78+/-6 to 106+/-8 mm Hg 2 h after PMX-F treatment in patients with septic shock. Plasma endotoxin levels decreased significantly after treatment, from 40+/-6 to 12+/-4 pg/ml. The pretreatment plasma concentrations of EPO and IL-6 were significantly higher in the 8 nonsurviving patients with septic shock (EPO: 400+/-36 mlU/ml; IL-6: 6260+/-1180 pg/ml) than in the 9 surviving patients (EPO: 120+/-22 mlU/ml; IL-6: 680+/-138 pg/ml) and the 20 control subjects (EPO, 12+/-6 mlU/ml; IL-6, 8+/-2 pg/ml). Plasma concentrations of EPO and IL-6 in patients with septic shock decreased significantly after PMX-F treatment (EPO, nonsurviving: 320+/-28 mlU/ml, p < 0.05; survivors: 26+/-8 mlU/ ml, p < 0.001; IL-6, nonsurviving: 3860+/-840 pg/ml, p < 0.01; survivors: 84+/-20 pg/ml, p < 0.001). CONCLUSIONS: Plasma concentrations of EPO and IL-6 may be prognostic indicators in patients with septic shock: PMX-F treatment may be effective in reducing the plasma concentrations of EPO and IL-6 in patients with septic shock.     

American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions of the systemic inflammatory response syndrome and allied disorders in relation to critically injured patients

OBJECTIVES: To determine the frequency of the proposed definitions for the systemic inflammatory response syndrome (SIRS), sepsis and septic shock, and to further define severe SIRS and sterile shock as determined at 24 hrs of admission to an intensive care unit (ICU) in critically ill trauma patients without head injury, and their relationships to mechanism of injury, Acute Physiology and Chronic Health Evaluation (APACHE) II score, risk of death, Injury Severity Score (ISS), number of organ failures, and mortality rate. DESIGN: Prospective, inception cohort analysis. SETTING: Sixteen-bed surgical ICU in a teaching hospital. PATIENTS: Four hundred fifty critically injured patients without associated head trauma. Penetrating trauma accounted for 70% (gunshot 202; stab 113) and nonpenetrating trauma for 30% (motor vehicle collision 103; blunt 32) of admissions. Three hundred ninety-four (88%) patients underwent surgical procedures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Infective and noninfective insults were distinguished by the need for therapeutic or prophylactic antibiotics, respectively, based on an established antibiotic policy. Three hundred ninety-five (87.8%) patients fulfilled a definition of the SIRS criteria. The frequency of the definitive categories was SIRS 21.8%, sepsis 14.4%, severe SIRS 8.4%, severe sepsis 13.6%, sterile shock 9.3%, and septic shock 20.2%. Patients with penetrating trauma had a significantly higher frequency of sepsis, severe sepsis, and septic shock (p < .01). The APACHE II score, risk of death, and number of organ failures increased significantly in both infective and noninfective groups with increasing severity of the inflammatory response. Sterile shock was associated with a significantly higher APACHE II score (p < .02), risk of death (p < .01), and number of organ failures (p = .03) compared with septic shock. Only sterile shock was associated with a significantly higher ISS (p < .01). Organ system failure was significantly (p < .001) higher in nonsurvivors compared with survivors in all categories. The only significant (p < .001) difference in mortality rate was found between patients in shock and all other categories. CONCLUSIONS: The current definitions of SIRS, sepsis, and related disorders in critically injured patients without head trauma show a significant association with physiologic deterioration and increasing organ dysfunction. The only significant association with mortality, however, is the presence of shock. The definitions require refinement, with the possible inclusion of more objective gradations of organ system failure, if they are to be used for stratifying severity of illness in seriously injured patients.     

Expression of beta 2-integrins and L-selectin on polymorphonuclear leukocytes in septic patients

Adhesion molecules on polymorphonuclear leukocytes (PMNL) play an important role in nonspecific defense mechanisms directed at invading microorganisms. When local infection, however, cannot be controlled, a systemic inflammatory response syndrome (SIRS) ensues which may progress to septic shock and multiple organ failure, these being major determinants of the patient's outcome. In the present study, the expression of beta 2-integrins and L-selectin on blood PMNL was measured on subsequent days in patients with sepsis (n = 17) and in healthy volunteers (n = 15). beta 2-Integrins and L-selectin molecules were detected by flow cytometry, using the monoclonal antibodies IB4 (anti-CD18) and Dreg200 (anti-CD62L), respectively. Adhesion molecules were determined at baseline immediately after blood collection and also 45 min after incubation of cells in vitro at body temperature to allow for spontaneous regulation. In addition, PMNL were activated by receptor-dependent and receptor-independent stimuli to characterize stimulus-specific adhesion molecule expression. In parallel with the measurement of adhesion molecules, severity of sepsis was assessed by the Elebute score. The results demonstrate significant differences in the basal, spontaneous and stimulus-induced expression of adhesion molecules between healthy volunteers, survivors (n = 11) and nonsurvivors (n = 6). Moreover, when survivors and nonsurvivors with severe sepsis (Elebute score > 12) were compared, basal expressions of both beta 2-integrins and L-selectin were significantly lower in patients who did not survive. Thus, measurement of adhesion molecules on circulating PMNL may be useful to identify septic patients at high risk for lethal outcome.     

Differential diagnosis of facial nerve palsy

Endothelial cell dysfunction is likely to be important in the pathophysiology of ischaemic heart disease and increased levels of endothelial cell markers soluble E-selectin and soluble thrombomodulin may reflect this damage. To determine whether increased levels of these markers were predictive of disease progression, we obtained plasma from 54 patients who had survived a myocardial infarction. Soluble E-selectin and soluble thrombomodulin were measured by ELISA. After 49 months, 24 patients had suffered an additional cardiovascular event such as a second myocardial infarction or requirement for arterial surgery. Soluble E-selectin was 60+/-30 ng/mL in patients who suffered an end-point and was 54+/-23 ng/mL in those without an end-point (p=0.43). Soluble thrombomodulin was 65+/-24 ng/mL in patients who suffered an end-point and was 49+/-19 ng/mL in patients who were free of an end-point (p=0.009). The major risk factors for atherosclerosis (hypercholesterolaemia, hypertension, smoking) or peak creatinine kinase levels were unable to predict the development of an end-point. Using life tables, soluble thrombomodulin had a significant effect on survival free of an end-point (p=0.011). We conclude that the measurement of soluble E-selectin is of limited value in epidemiological studies, and that raised soluble thrombomodulin is a new marker for the progression of atherosclerosis in patients with ischaemic heart disease.     

Epidemiology of sepsis and multiple organ dysfunction syndrome in children

STUDY OBJECTIVES: To determine the cumulated incidence and the density of incidence of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS) in critically ill children; to distinguish patients with primary from those with secondary MODS. DESIGN: Prospective cohort study. SETTING: Pediatric ICU of a university hospital. PATIENTS: One thousand fifty-eight consecutive hospital admissions. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: SIRS occurred in 82% (n=869) of hospital admissions, 23% (n=245) had sepsis, 4% (n=46) had severe sepsis, 2% (n=25) had septic shock; 16% (n=168) had primary MODS and 2% (n=23) had secondary MODS; 6% (n=68) of the study population died. The pediatric risk of mortality (PRISM) scores on the first day of admission to pediatric ICU were as follows: 3.9 +/- 3.6 (no SIRS), 7.0 +/- 7.0 (SIRS), 9.5 +/- 8.3 (sepsis), 8.8 +/- 7.8 (severe sepsis), 21.8 +/- 15.8 (septic shock); differences among groups (p=0.0001), all orthogonal comparisons, were significant (p<0.05), except for patients with severe sepsis. The observed mortality for the whole study population was also different according to the underlying diagnostic category (p=0.0001; p<0.05 for patients with SIRS and those with septic shock, compared with all groups). Among, patients with MODS, the difference in mortality between groups did not reach significance (p=0.057). Children with secondary MODS had a longer duration of organ dysfunction (p<0.0001), a longer stay in pediatric ICU after MODS diagnosis (p<0.0001), and a higher risk of mortality (odds ratio, 6.5 [2.7 to 15.9], p<0.0001) than patients with primary MODS. CONCLUSIONS: SIRS and sepsis occur frequently in critically ill children. The presence of SIRS, sepsis, or septic shock is associated with a distinct risk of mortality among critically ill children admitted to the pediatric ICU; more data are needed concerning children with MODS. Secondary MODS is much less common than primary MODS, but it is associated with an increased morbidity and mortality; we speculate that distinct pathophysiologic mechanisms are involved in these two conditions.     

Histamine release in sepsis: a prospective, controlled, clinical study

OBJECTIVE: To determine if histamine release occurs in clinical sepsis. DESIGN: Prospective, controlled, clinical study. SETTING: Interdisciplinary intensive care unit and trauma ward. PATIENTS: Sepsis was confirmed in 20 patients (test group) by the criteria of the Veterans Administration Systemic Sepsis Cooperative Study Group (1987) and was verified by positive blood culture. In addition, patients were scored by the Elebute and Stoner Sepsis Score (1983), as modified by Dionigi et al (1985). A concomitant control group consisted of 20 postoperative patients with non-life-threatening trauma to the extremities and without signs of local or systemic infection. INTERVENTIONS: Observational study. Blood samples were collected for determination of plasma histamine concentrations in both groups at the time of study entry and on five succeeding days. MEASUREMENTS AND MAIN RESULTS: The patients were well matched, and the groups were not significantly different for all criteria known to influence histamine release. Comparison of the median values of each group on days 1 through 5 demonstrated significantly higher plasma histamine values in the test group on days 1 through 4, but these values were no longer significantly higher on day 5. While none of the nonseptic control patients achieved a plasma histamine concentration of > 1 ng/mL (the concentration of which was considered to be the pathologic cutoff point representing histamine release), these values (i.e., > 1 ng/ mL) were found in nine of 20 test group patients. In the test group, nonsurvivors (n = 9) had significantly higher plasma histamine concentrations than survivors (n = 11) throughout the whole study and eight of nine nonsurvivors showed a plasma histamine concentration of > 1 ng/mL. Correlation of plasma histamine concentrations on day 1 to sepsis severity (initial Sepsis Score) showed that all but one patient with a combined low Sepsis Score (< 20 points) and histamine concentration of < 1 ng/mL survived, while all patients with a Sepsis Score of > 20 points and histamine release (plasma histamine concentration of > 1 ng/mL) died. CONCLUSION: Increased histamine concentrations were shown to be causally associated (contributory determinant) with sepsis.     

Cellular injury score for multiple organ failure severity scoring system

BACKGROUND: Cellular Injury Score (CIS) is an index of cellular injury, being calculated from three parameters of intracellular metabolism: arterial ketone body ratio, osmolality gap, and blood lactate. METHODS: The usefulness of CIS as a severity scoring system for patients with multiple organ failure was prospectively evaluated in 157 consecutive patients with MOF (58 survivors, 99 nonsurvivors). RESULTS: CISs in nonsurvivors were significantly higher compared with those in survivors throughout the clinical courses. CIS was significantly correlated with the number of failing organs and mortality rate. The optimal cutoff point of CIS from receiver operating characteristics curve analysis was 4 for the maximal value during the clinical course. The changes in CIS well reflected the severity of injury in survivors and nonsurvivors who died within 2 weeks. CONCLUSION: CIS could be a useful index for mortality risk prediction and is potentially applicable as a severity scoring system for individual patients with MOF.     

Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine

OBJECTIVE: To evaluate the use of the Sequential Organ Failure Assessment (SOFA) score in assessing the incidence and severity of organ dysfunction in critically ill patients. DESIGN: Prospective, multicenter study. SETTING: Forty intensive care units (ICUs) in 16 countries. PATIENTS: Patients admitted to the ICU in May 1995 (n = 1,449), excluding patients who underwent uncomplicated elective surgery with an ICU length of stay <48 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main outcome measures included incidence of dysfunction/failure of different organs and the relationship of this dysfunction with outcome. In this cohort of patients, the median length of ICU stay was 5 days, and the ICU mortality rate was 22%. Multiple organ dysfunction and high SOFA scores for any individual organ were associated with increased mortality. The presence of infection on admission (28.7% of patients) was associated with higher SOFA scores for each organ. The evaluation of a subgroup of 544 patients who stayed in the ICU for at least 1 wk showed that survivors and nonsurvivors followed a different course. This subgroup had greater respiratory, cardiovascular, and neurologic scores than the other patients. In this subgroup, the total SOFA score increased in 44% of the nonsurvivors but in only 20% of the survivors (p < .001). Conversely, the total SOFA score decreased in 33% of the survivors compared with 21% of the nonsurvivors (p < .001). CONCLUSIONS: The SOFA score is a simple, but effective method to describe organ dysfunction/failure in critically ill patients. Regular, repeated scoring enables patient condition and disease development to be monitored and better understood. The SOFA score may enable comparison between patients that would benefit clinical trials.     

N-acetyl-L-cysteine depresses cardiac performance in patients with septic shock

OBJECTIVE: To investigate the effects of adjunctive therapy with parenteral N-acetyl-L-cysteine in patients with newly diagnosed septic shock. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Multidisciplinary intensive care unit at a university teaching hospital. PATIENTS: Twenty patients (N-acetyl-L-cysteine group [n = 10], placebo group [n = 10]), 15 male and five female, of mean age 64 +/- 15 (SD) yrs and Acute Physiology and Chronic health Evaluation (APACHE) II score 33 +/- 6, with septic shock within 24 hrs of diagnosis. INTERVENTIONS: After a 2-hr stabilization period (time-zero minus 2 hrs to time-zero), patients received either N-acetyl-L-cysteine in 5% dextrose (150 mg/kg in 100 mL over 15 mins, followed by 50 mg/kg in 250 mL over 4 hrs, and then 100 mg/kg/24 hrs in 500 mL for 44 hrs; N-acetyl-L-cysteine group) or the equivalent volume of 5% dextrose (placebo group). MEASUREMENTS AND MAIN RESULTS: Hemodynamic and oxygen transport indices were measured at time-zero minus 2 hrs and time-zero, and at multiple time points thereafter until completion of the trial infusion (time-zero plus 48 hrs). A daily Organ Failure Score was recorded for 14 days. Treatment group demographics and hemodynamic variables did not differ significantly between the two groups at time-zero. Mean (SD), pooled mean arterial pressure (MAP), and cardiac index were 75 +/- 15 mm Hg and 3.9 +/- 1.2 L/min/m2, respectively. Over the next 48 hrs, in the N-acetyl-L-cysteine group, there was a progressive decrease, relative to both time-zero and the placebo group, in MAP, cardiac index, and left ventricular stroke work index (p < .01, repeated-measures analysis of variance). Percentage reductions in these values relative to the placebo group at 48 hrs were 23%, 18%, and 43%, respectively Oxygen transport indices, arterial blood gas analyses, Pao2/Fio2 ratio, and shunt did not differ over time between the groups. There was no difference in either daily Organ Failure Score over time (p > .01, repeated-measures analysis of variance) or hospital mortality rate (90% N-acetyl-L-cysteine group, 50% placebo group) (p > .1, logistic regression) between the two groups. CONCLUSION: Adjunctive therapy with N-acetyl-L-cysteine in newly diagnosed septic shock was associated with a depression in cardiovascular performance, as indicated by progressive reductions in cardiac index, left ventricular stroke work index, and MAP.     

Insulin resistance and hypertension in non-obese Africans in Tanzania

OBJECTIVE: This study was done to evaluate the differences in base deficit (BD) clearance, pH normalization, and the occurrence of complications between survivors and nonsurvivors after trauma. DESIGN: Concurrent data entry with retrospective review. METHODS: Trauma patients meeting registry criteria from July 1990 through August 1995 with arterial blood gases performed within 1 hour of admission and admission BD < or = -6 were included. Data was grouped by BD category (moderate, -6 to -9; severe, < or = -10). Group means +/- SEM were compared with a two-tailed t test. MEASUREMENTS and MAIN RESULTS: Six hundred seventy-four patients met entry criteria. Survivors in both the moderate and severe BD groups had improved their BD within 4 hours and normalized their BD by 16 hours. Nonsurvivors did not improve their BD category until 8 hours (for the severe group) and 16 hours (for the moderate group) and did not normalize BD before 24 hours. The BD differences between survivors and nonsurvivors were significant at each time interval, whereas pH differences were significant at 2 hours in the moderate group and at 2, 16, and 24 hours in the severe group. Patients who failed to improve their BD > -6 had an increased frequency of adult respiratory distress syndrome, multiple organ failure, and mortality. CONCLUSION: Base deficit reveals differences in metabolic acidosis between survivors and nonsurvivors not shown by pH determinations and is clearly a better marker of acidosis clearance after shock.     

Endothelial selectins in acute mountain sickness and high-altitude pulmonary edema

STUDY OBJECTIVES: Mechanical or inflammatory injury to pulmonary endothelial cells may cause impaired pulmonary gas exchange in acute mountain sickness (AMS) and noncardiogenic pulmonary edema in high-altitude pulmonary edema (HAPE). This study was designed to determine whether markers of endothelial cell activation or injury, plasma E- and P-selectin, were increased after ascent to high altitude, in AMS or in HAPE. DESIGN: We collected clinical data and plasma specimens in control subjects at sea level and after ascent to 4,200 m, and in climbers with AMS or HAPE at 4,200 m. Data analysis was performed using standard nonparametric statistical methods, and results reported as mean+/-SD. SETTING: National Park Service medical camp at 4,200 m on Mt. McKinley (Denali), Alaska. PATIENTS: Blood samples and clinical data were collected from 17 healthy climbers at sea level and again after ascent to 4,200 m, and from a different group of 13 climbers with AMS and 8 climbers with HAPE at 4,200 m. Climbers with AMS were divided into normoxic (n=7) and hypoxemic (n=6) groups. MEASUREMENTS AND RESULTS: Using an enzyme immunoassay technique, plasma E-selectin concentrations were found to be increased in the 17 control subjects after ascent to 4,200 m (17.2+/-8.2 ng/mL) as compared to sea level (12.9+/-8.2 ng/mL) (p=0.001). Plasma E-selectin concentrations were also increased in subjects with hypoxemic AMS (30.6+/-13.4 ng/mL) and HAPE (23.3+/-9.1 ng/mL) compared to control subjects at sea level (p=0.009). Increased plasma E-selectin concentration significantly correlated with hypoxemia (p=0.006). Plasma P-selectin concentrations were unchanged after ascent to 4,200 m and in subjects with AMS and HAPE. CONCLUSION: Because E-selectin is produced only by endothelial cells, increased plasma E-selectin after ascent to high altitude and in hypoxemic climbers with AMS and HAPE provides evidence that endothelial cell activation or injury is a component of hypoxic altitude illness.     

Cytokine patterns in patients after major vascular surgery, hemorrhagic shock, and severe blunt trauma. Relation with subsequent adult respiratory distress syndrome and multiple organ failure

OBJECTIVE: This study investigates the course of serum cytokine levels in patients with multiple trauma, patients with a ruptured abdominal aortic aneurysm (AAA), and patients undergoing elective AAA repair and the relationship of these cytokines to the development of adult respiratory distress syndrome (ARDS) and multiple organ failure (MOF). SUMMARY BACKGROUND DATA: Severe tissue trauma, hemorrhagic shock, and ischemia-reperfusion injury are pathophysiologic mechanisms that may result in an excessive uncontrolled activation of inflammatory cells and mediators. This inflammatory response is thought to play a key role in the development of (remote) cell and organ dysfunction, which is the basis of ARDS and MOF. METHODS: The study concerns 28 patients with multiple trauma, 20 patients admitted in shock because of a ruptured AAA, and 18 patients undergoing elective AAA repair. Arterial blood was serially sampled from admission (or at the start of elective operation) to day 13 in the intensive care unit, and the serum concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6 were determined. RESULTS: Twenty-two patients died, 15 within 48 hours and 7 after several weeks, as a result of ARDS/MOF. At hospital admission and after 6 hours, these nonsurvivors had significantly higher plasma TNF-alpha and IL-1 beta levels than did the survivors. At the same measuring points, TNF-alpha and IL-1 beta were significantly more elevated in patients with ruptured AAA than in traumatized patients. However, IL-6 was significantly higher in the traumatized patients. In 10 patients, ARDS/MOF developed, and 41 had an uncomplicated course in this respect. Those with ARDS/MOF exhibited significantly different cytokine patterns in the early postinjury phase. TNF-alpha and IL-1 beta levels were higher mainly on the first day of admission; IL-6 concentrations were significantly elevated in patients with ARDS/MOF from the second day onward. The latter cytokine showed a good correlation with the daily MOF score during the whole 2-week observation period. CONCLUSIONS: In the early postinjury phase, higher concentrations of these cytokines are associated, not only with an increased mortality rate, but also with an increased risk for subsequent ARDS and MOF. These data therefore support the concept that these syndromes are caused by an overwhelming autodestructive inflammatory response.     

Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome. The Sepsis Intervention Group

OBJECTIVE: To assess the value of measuring circulating concentrations of mediators (endotoxin, tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta [IL-1 beta], and interleukin-6[IL-6]) and their endogenous antagonists (antiendotoxin core antibody [EndoCAb], interleukin-1 receptor antagonist [IL-1ra], and soluble TNF receptors [sTNF-R]) in predicting mortality and organ failure in sepsis syndrome. DESIGN: Cohort study with a follow-up period of 30 days. SETTING: Intensive therapy units of five tertiary referral centers in Scotland. SUBJECTS: A total of 146 intensive therapy unit patients with sepsis syndrome underwent repeated sampling during a 10-day period following admission to an intensive therapy unit. MAIN OUTCOME MEASURES: Circulating concentrations of mediators and antagonists were compared in survivors and nonsurvivors. RESULTS: Median Acute Physiology and Chronic Health Evaluation II score was 23 (range, 8 to 40). Mortality at 30 days was 49%. On entry to the study, circulating endotoxin was detected in 66% of patients, TNF-alpha in 14%, and IL-1 beta in 29%. Levels did not predict mortality or organ failure. Patients with IL-6 concentrations in excess of 3000 pg/mL had an increased mortality rate (64% vs 40%, P = .02). The incidence of IgG EndoCAb depletion on entry to the study was 26% in nonsurvivors and 10% in survivors (P = .02). Initial concentrations of both type I and type II sTNF-R were significantly higher in nonsurvivors (P < .01). Initial circulating IL-1ra concentrations were not of value in predicting mortality. Cytokine antagonists were present in concentrations 30- to 100,000-fold greater than their corresponding cytokine. CONCLUSION: The observed high circulating levels of the cytokine antagonists IL-1ra and sTNF-R and the relatively small proportion of patients developing EndoCAb depletion may contribute to the limitations of therapies that aim to augment natural defenses against endotoxin or the proinflammatory cytokines.     

Elevated concentrations of circulating adhesion molecules and their association with microvascular complications in insulin-dependent diabetes mellitus

To better understand potential associations of circulating adhesion molecules (cAMs) with diabetic microangiopathy, circulating serum concentrations of intercellular adhesion molecule-1 (cICAM-1), vascular cell adhesion molecule-1 (cVCAM-1), and endothelial leukocyte adhesion molecule-1 (cELAM-1) were determined in patients with insulin-dependent diabetes mellitus (IDDM) (n = 70) presenting with varying degree of metabolic control and status of diabetic late complications, and were compared with age-matched healthy subjects (n = 70) in a cross-sectional study. Concentrations of cICAM-1 and cVCAM-1 were elevated in IDDM vs. age-matched controls (cICAM-1: 276 +/- 71 vs. 212 +/- 57 ng/mL; P < 0.0001; cVCAM-1: 781 +/- 245 vs. 615 +/- 151 ng/mL; P < 0.0001), whereas cELAM-1 did not differ between the groups (cELAM-1: 50 +/- 25 vs. 46 +/- 23 ng/mL, P = 0.31). The levels of cVCAM-1 were more markedly elevated in IDDM patients with diabetic retinopathy (n = 32) than in those without (n = 38) (cVCAM-1: 848 +/- 281 vs. 724 +/- 197 ng/mL, P < 0.05), as well as in patients with micro- or macroalbuminuria (n = 10) vs. those without (n = 60) (cVCAM-1: 947 +/- 256 ng/mL vs. 753 +/- 234 ng/mL, P < 0.05), whereas no difference in cICAM-1 and cELAM-1 was apparent regarding the clinical status of diabetic microangiopathy. No correlations were found between hemoglobin A1e and cAMs in the individual subgroups of patients and healthy subjects. Interestingly, however, low density lipoprotein cholesterol correlated with cVCAM-1 (r = 0.38, P = 0.03) in IDDM patients with diabetic microangiopathy (n = 33), but not in healthy controls or patients without microangiopathy (n = 37). Analyzing the pooled data of diabetic patients and healthy subjects (n = 140), concentrations of cICAM-1 were markedly related to cVCAM-1 (r = 0.45, P < 0.0001) and cELAM-1 (r = 0.31, P < 0.0002), whereas cVCAM-1 was related less to cELAM-1 (r = 0.19, P = 0.03), respectively. We conclude that, irrespective of actual metabolic control, serum concentrations of cICAM-1 and cVCAM-1 but not cELAM-1 are elevated in patients with IDDM, reflecting ongoing endothelial cell stimulation and leukocyte activation. More specifically, more marked elevation of cVCAM-1 may even hint at clinically manifest diabetic microangiopathy.     

Does N-acetyl-L-cysteine influence cytokine response during early human septic shock?

STUDY OBJECTIVE: To assess the effects of adjunctive treatment with N-acetyl-L-cysteine (NAC) on hemodynamics, oxygen transport variables, and plasma levels of cytokines in patients with septic shock. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: A 24-bed medicosurgical ICU in a university hospital. PATIENTS: Twenty-two patients included within 4 h of diagnosis of septic shock. INTERVENTIONS: Patients were randomly allocated to receive either NAC (150 mg/kg bolus, followed by a continuous infusion of 50 mg/kg over 4 h; n= 12) or placebo (n=10) in addition to standard therapy. MEASUREMENTS: Plasma concentrations of tumor necrosis factor-alpha (TNF), interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor-alpha receptor-p55 (sTNFR-p55) were measured by sensitive immunoassays at 0, 2, 4, 6 and 24 h. Pulmonary artery catheter-derived hemodynamics, blood gases, hemoglobin, and arterial lactate were measured at baseline, after infusion (4 h), and at 24 h. RESULTS: NAC improved oxygenation (PaO2/FIO2 ratio, 214+/-97 vs 123+/-86; p<0.05) and static lung compliance (44+/-11 vs 31+/-6 L/cm H2O; p<0.05) at 24 h. NAC had no significant effects on plasma TNF, IL-6, or IL-10 levels, but acutely decreased IL-8 and sTNFR-p55 levels. The administration of NAC had no significant effect on systemic and pulmonary hemodynamics, oxygen delivery, and oxygen consumption. Mortality was similar in both groups (control, 40%; NAC, 42%) but survivors who received NAC had shorter ventilator requirement (7+/-2 days vs 20+/-7 days; p<0.05) and were discharged earlier from the ICU (13+/-2 days vs 32+/-9 days; p<0.05). CONCLUSION: In this small cohort of patients with early septic shock, short-term IV infusion of NAC was well-tolerated, improved respiratory function, and shortened ICU stay in survivors. The attenuated production of IL-8, a potential mediator of septic lung injury, may have contributed to the lung-protective effects of NAC.     

Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock

OBJECTIVE: The aim of this study was to investigate the acute effects of methylene blue (MB), an inhibitor of the L-arginine nitric oxide pathway, in patients with septic shock. DESIGN: A prospective, open, single-dose study. SETTING: The medical ICU of a university hospital. PATIENTS: Six patients with severe septic shock. INTERVENTIONS: Complete hemodynamic values were recorded before and 20 min after the infusion of intravenous MB (3 mg kg(-1)). Arterial pressure was then monitored during the next 24 h or until death. MEASUREMENTS AND RESULTS: Methylene blue increased the mean arterial pressure from 69.7 +/- 4.5 to 83.7 +/- 5.1 mmHg (p = 0.028) and the mean pulmonary artery pressure, from 34.3 +/- 7.2 to 38.7 +/- 8.0 mmHg (p = 0.023). Systemic vascular resistance index was increased from 703.1 +/- 120.6 to 903.7 +/- 152.2 dyne.s.cm(-5).m(-2) (p = 0.028) and pulmonary vascular resistance index, from 254.6 +/- 96.9 to 342.2 +/- 118.9 dyne.s.cm(-5) .m(-2) (p = 0.027). The PaO2/FIO2 decreased from 229.2 +/- 54.4 to 162.2 +/- 44.1 mmHg (p = 0.028), without significant modification of intrapulmonary shunting. Heart rate, cardiac index, right atrial pressure, DO2, VO2, oxygen extraction and arterial lactate were essentially unchanged. Sequential measurements of arterial pressure demonstrated a return to baseline level in 2-3 h. All but one patients died, three in shock and two in multiple organ failure. CONCLUSIONS: MB induces systemic and pulmonary vasoconstriction in patients with septic shock, without significant decrease in cardiac index. The worsening of arterial oxygenation following MB injection may limit its use in patients with the adult respiratory distress syndrome. Larger studies are required to determine whether MB improves the outcome of patients with septic shock.     

Effect of plasma and LPS on respiratory burst of neutrophils in septic patients

OBJECTIVE: To compare the respiratory burst of neutrophils in sepsis and control patients using lipopolysaccharide (LPS), autologous plasma, and a combination of the two. DESIGN: Prospective, consecutive case study. SETTING: A 16-bed intensive care unit (ICU) in a university teaching hospital. INTERVENTIONS: None. PATIENTS: Plasma was obtained from 23 healthy patients scheduled for minor surgery immediately prior to induction of anesthesia (controls) and from 23 ICU patients within 24 h of diagnosis of sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: Respiratory burst was determined by lucigenin chemiluminescence expressed as mean +/- SEM of peak values of relative light units per neutrophil. There were no significant differences between neutrophils of septic patients and controls for the stimuli saline, phorbol myristate acetate, formyl-methionyl-leucyl-phenylalanine, and LPS alone. Septic patients showed a lower respiratory burst than controls (p < 0.05) under the following stimuli: plasma alone (5911 +/- 803 vs 15,397 +/- 3038) and LPS and plasma combined (13,857 +/- 1537 vs 23,026 +/- 2640). However, when stimulated with plasma after priming with LPS, septic patients elicited a higher value than control subjects (11,373 +/- 1758 vs 5987 +/- 1234, p < 0.05). CONCLUSIONS: (1) Some components of the plasma of septic patients may have a profound effect on neutrophil response; (2) plasma as a respiratory burst stimulus differentiates between sepsis and non-sepsis samples better than other common stimuli; (3) precautions must be taken when using plasma together with LPS because of the different response depending on whether LPS-priming precedes the plasma stimulus or both are introduced simultaneously and whether septic or nonseptic plasma is used.