Effect of an endotoxin-removing column containing immobilized polymyxin B fiber in a patient with septic shock from gram-positive infection

A 67-yr-old patient with septic shock caused by gram-positive infection fell into circulatory collapse. Direct hemoperfusion with an endotoxin-removing column was then carried out for 120 min. As a result, blood pressure and systemic vascular resistance increased significantly during this therapy. Cardiac output changed from hyperdynamic to normodynamic, and plasma endotoxin level decreased. After this treatment, the patient recovered. From this experience, we consider that the endotoxin-removing column may be effective for septic shock patients.     

Release of interleukin-12 in experimental Escherichia coli septic shock in baboons: relation to plasma levels of interleukin-10 and interferon-gamma

Interleukin (IL)-12 is thought to be a key factor for the induction of interferon gamma (IFN-gamma), a cytokine essential for the lethal effects of endotoxin. We report here on the release of the nonfunctional subunit of IL-12, p40, as well as biologically active heterodimeric IL-12, p70, after administration of a lethal (n = 5) or sublethal (n = 8) dose of live Escherichia coli to baboons. Remarkably, on lethal challenge, peak levels of p40 were observed at 3 hours that were about twofold lower than those elicited after sublethal challenge (2,813 +/- 515 pg/mL v 4,972 +/- 732 pg/mL, P < .05). This disparity was also observed, although to a lesser extent, for IL-12 p70 antigen, of which maximum levels of 91 +/- 47 pg/mL and 151 +/- 41 pg/mL were measured 6 hours after a lethal or sublethal dose of E coli, respectively. Circulating p70 antigen correlated with IL-12 biologic activity (r = 0.869; P < .001). When comparing lethal to sublethal conditions, lower peak levels of IL-12 on lethal E coli sharply contrasted with higher levels of other proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, IL-1beta, IL-6, and IL-8 observed in these animals. Lower IL-12 concentrations in the lethal group may have resulted in part from the enhanced production of IL-10, a known inhibitor of IL-12 synthesis in vitro, as peak levels of this cytokine 3 hours postchallenge inversely correlated with peak levels of IL-12, in particular p40 (r = -0.802; P < .01). Contrary to what might be expected if IFN-gamma were solely induced by IL-12, lethally challenged baboons generated threefold more IFN-gamma at 6 hours than those receiving a sublethal dose (P < .05). Moreover, higher levels of IFN-gamma were associated with lower p40/p70 ratios, suggesting that, in agreement with observations in vitro, IFN-gamma may have preferentially upregulated the release of p70 over p40. These data show that IL-12 is released in experimental septic shock in nonhuman primates and suggest that IL-10 and IFN-gamma are involved in the regulation of this release. Furthermore, this study indicates that the systemic release of IL-12 might be essential, but is not likely sufficient, to promote lethal production of IFN-gamma in sepsis.     

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.     

The effects of intravenous antioxidants in patients with septic shock

Oxidative stress is implicated in septic shock. We investigated the effect of intravenous antioxidant therapy on antioxidant status, lipid peroxidation, hemodynamics and nitrite in patients with septic shock. Thirty patients randomly received either antioxidants (n-acetylcysteine 150 mg/kg for 30 min then 20 mg/kg/h plus bolus doses of 1 g ascorbic acid and 400 mg alpha-tocopherol) or 5% dextrose. Basal vitamin C was low and redox-reactive iron was elevated in all patients. In the 16 patients receiving antioxidants, vitamin C increased (p = .0002) but total antioxidant capacity was unaffected. Lipid peroxides were elevated in all patients but did not increase further in the patients receiving antioxidants. Plasma total nitrite also increased (p = .007) in the antioxidant group. Heart rate increased in patients receiving antioxidants at 60 min (p = .018) and 120 min (p = .004). Cardiac index also increased at 60 min (p = .007) and 120 min (p = .05). Systemic vascular resistance index decreased at 120 min in the antioxidant treated patients (p = .003). The effect of antioxidants on hemodynamic variables has not previously been reported. Antioxidant administration may be a useful adjunct to conventional approaches in the management of septic shock.     

Plasma endotoxin and cytokine concentrations in patients with hemorrhagic shock

OBJECTIVES: The roles of cytokines and endotoxin in hemorrhagic shock, particularly the translocation of endotoxin and bacteria during hemorrhagic shock, were investigated. DESIGN: Prospective study. SETTING: Critical care and emergency center of a university hospital. PATIENTS: Twenty-nine patients with hemorrhagic shock and 20 healthy controls. INTERVENTIONS: Serial blood samples were collected from both study and control patients. Standard resuscitation techniques were used. MEASUREMENTS AND MAIN RESULTS: Plasma levels of endotoxin and various cytokines were determined repeatedly during hemorrhagic shock. Endotoxin was measured using an endotoxin-specific assay in addition to a new perchloric acid method for pretreatment of plasma. Cytokines were measured by commercial enzyme-linked immunosorbent assays. Plasma endotoxin concentrations remained within the normal range for 7 days after admission. Although levels of tumor necrosis factor-alpha and several interleukins increased slightly in some patients, these cytokines did not reach the levels seen in septic shock. CONCLUSIONS: Translocation of bacteria or endotoxin from the gastrointestinal tract into the bloodstream has been noted in animal experiments; however, translocation was not detected in our patients with hemorrhagic shock.     

Absence of supply dependence of oxygen consumption in patients with septic shock

We tested whether oxygen consumption (VO2) was dependent on oxygen delivery (QO2) in 10 patients with septic shock when QO2 was changed by the use of the inotropic agent, dobutamine. The mean acute physiology and chronic health evaluation (APACHE) II score of the patients was 27.3 +/- 8.1 with a mean blood pressure on entry of 66.8 +/- 12.4 mm Hg, and all had been volume resuscitated to a pulmonary artery occlusion pressure of greater than 10 mm Hg. We measured VO2 by analysis of respiratory gases (VO2G) while calculating VO2 by the Fick equation (VO2F) at three different O2 deliveries. When the dobutamine infusion rate was increased from 2.5 +/- 4.0 to 12.3 +/- 6.0 micrograms/kg/min, thermodilution cardiac output increased from 7.7 +/- 2.6 to 10.1 +/- 2.7 L/min (P < .01). Accordingly, dobutamine increased QO2 from 13.5 +/- 3.8 to 18.2 +/- 4.3 mL/min per kg (increase of 36.4% +/- 19.7%; P < .01), but VO2G did not increase (3.2 +/- 0.5 to 3.2 +/- 0.6 mL/min per kg). During these same interventions, the VO2F tended to increase (2.9 +/- 0.7 to 3.4 +/- 0.8 mL/min per kg, P < .06), presumably a spurious correlation because of measurement errors shared by the calculation of VO2F and QO2. Neither lactic acidosis nor acute respiratory distress syndrome (ARDS) conferred supply dependence of VO2G, but the presence of ARDS was predictive of death in this cohort. It is concluded that VO2 is independent of QO2 in patients with septic shock and lactic acidosis. These data confirm that maximizing QO2 beyond values achieved by initial fluid and vasoactive drug resuscitation of septic shock does not improve tissue oxygenation as determined by respiratory gas measurement of VO2.     

Increased plasma endothelin-1 concentrations in E. coli septic peritonitis rats with diabetes mellitus

To study the diabetic mellitus (DM) patient's reaction to sepsis, we investigated the survival rate, the bacteremia, plasma endotoxin and plasma endothelin-1 levels in E. coli septic peritonitis rats with or without streptozotocin-induced DM. No significant difference could be detected between the DM and nondiabetic rats in the survival rate, the bacteremia level or the plasma endotoxin level. The DM rat manifested a significant increase compared to the nondiabetic rat in the plasma endothelin-1 level four hours after the outbreak of peritonitis. Endothelin-1 may thus play some role in the E. coli septic peritonitis rat with DM.     

Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock

OBJECTIVES: To obtain systematic information on the extrinsic coagulation pathway, as well as to investigate the time course of the coagulation abnormalities in sepsis. DESIGN: Prospective observational study. SETTING: General intensive care unit. PATIENTS: Nineteen patients with the diagnosis of severe sepsis or septic shock and nine control patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Tissue factor antigen concentration (tissue factor antigen), prothrombin fragment F1+2, thrombin antithrombin III complex, fibrinopeptide A, D-dimer, and antithrombin III concentrations were measured on the day of diagnosis of severe sepsis and septic shock, and on days 1, 2, 3, and 4 after diagnosis. The concentrations of tissue factor antigen, prothrombin fragment F1+2, fibrinopeptide A, and D-dimer were significantly increased in patients with severe sepsis and septic shock compared with control subjects. However, the concentrations of thrombin antithrombin III complex showed no statistical differences between the septic patients and the control subjects. Significantly, low antithrombin III concentrations were observed in the septic patient groups compared with control subjects. With the exception of D-dimer, the concentrations of the hemostatic markers were similar between severe sepsis and septic shock patients. Significant correlations were noted between tissue factor antigen and the disseminated intravascular coagulation score (r2=.236, p< .0001) and the number of dysfunctioning organs (r2=.229, p=.035). CONCLUSIONS: We systematically elucidated coagulation disorders in newly defined sepsis. The extrinsic coagulation pathway is activated in patients with severe sepsis and septic shock. In these patients, enhanced thrombin generation and activation, and fibrin formation were demonstrated when compared with the control subjects. Furthermore, the thrombin generated appears not to be fully neutralized by antithrombin III.     

Increased serum concentrations of interleukin-10 in patients with hepatosplenic candidiasis

Hepatosplenic candidiasis (HSC) becomes clinically overt in cancer patients upon recovery from neutropenia. HSC may be a consequence of a Th1-Th2 imbalance, characterized by increased serum levels of one or more cytokines. Serum levels of two immunosuppressive cytokines, markers of the Th2 pathway, interleukin (IL)-4 and IL-10 were measured by ELISA in 10 patients with HSC (22 samples) and compared with 19 healthy blood donors, 13 patients with cancer but no infection (23 samples), and 11 patients with cancer and various bacterial infections (17 samples). IL-4 was undetectable in all controls and patients. By contrast, levels of IL-10 were increased in HSC patients compared with levels in healthy donors and cancer patients without infection (P < .001) or with bacterial infections (P < .01). These findings indicate that IL-10 but not IL-4 is increased in patients with HSC and suggest that IL-10 plays a role in the pathogenesis of this infection.     

Increased plasma atrial natriuretic peptide and endothelin concentrations after surgery in patients with esophageal and gastric cancer

Endothelin-1 (ET-1) and human atrial natriuretic peptide (hANP) are known as vasoactive substances. In the present study, an attempt was made to evaluate the mode by which these substances are secreted in patients having severe surgical stress. Plasma ET-1 and hANP concentrations were measured in 15 patients with esophageal carcinoma who underwent subtotal esophagectomy via right-thoraco-ventrotomy (EC group) and 10 patients with gastric carcinoma who underwent total gastrectomy via ventrotomy (GC group). The volume of intraoperative hemorrhage was significantly larger and operation time was significantly longer in the EC group than in the GC group. Plasma ET-1 concentration in the EC group increased remarkably on the first operative day (1st POD), whereas that in the GC group did not. Plasma levels of hANP in both the EC and GC groups gradually increased until they peaked on the 2nd POD. The increment of plasma hANP secretion for the EC group was significantly higher than that for the GC group on the day of the operation, suggesting that ET-1 stimulated hANP in the EC group. Plasma hANP levels reached their peak values on the 2nd POD and returned to the preoperation level on the 5th POD, while PCWP did not change significantly after the surgery. Since this discrepancy between the postoperation patterns of PCWP and hANP cannot be explained by changes in the circulating blood volume, hANP secretion may be regulated by certain factors in addition to the left ventricular pressure experienced by patients receiving heavy operation stress, such as those in the EC group.     

The effects of prostacyclin on gastric intramucosal pH in patients with septic shock

OBJECTIVE: To investigate whether infusing prostacyclin (PGI2) in patients with septic shock improves splanchnic oxygenation as assessed by gastric intramucosal pH (pHi). DESIGN: Interventional clinical study. SETTING: Surgical ICU in a university hospital. PATIENTS: 16 consecutive patients with septic shock according to the criteria of the ACCP/SCCM consensus conference all requiring norepinephrine to maintain arterial blood pressure. INTERVENTIONS: All patients received PGI2 (10 ng/kg x min) after no further increase in oxygen delivery could be obtained by volume expansion, red cell transfusion and dobutamine infusion. The results were compared with those before and after conventional resuscitation. The patients received continuous PGI2 infusion for 33-32 days. MEASUREMENTS AND RESULTS: O2 uptake was measured directly in the respiratory gases, pHi was determined by tonometry. Baseline O2 delivery, O2 uptake and pHi were 466 +/- 122 ml/min.m2, 158 +/- 38 ml/min.m2, and 7.29 +/- 0.09, respectively. While O2 uptake remained unchanged, infusing PGI2 increased O2 delivery (from 610 +/- 140 to 682 +/- 155 ml/min.m2, p < 0.01) and pHi (from 7.32 +/- 0.09 to 7.38 +/- 0.08, p < 0.001) beyond the values obtained by conventional resuscitation. While 9 of 11 patients with final pHi > 7.35 survived, all patients with final pHi < 7.35 died (p < 0.01). CONCLUSIONS: Infusing PGI2 in patients with septic shock increases pHi probably by enhancing blood flow to the splanchnic bed and thereby improves splanchnic oxygenation even when conventional resuscitation goals have been achieved.     

Propoxyphene and norpropoxyphene plasma concentrations after oral propoxyphene in cirrhotic patients with and without surgically constructed portacaval shunt

Plasma concentrations of propoxyphene and its major metabolite, norpropoxyphene, were determined over at least 12 hr after oral administration of 130 mg dextropropoxyphene hydrochloride to eight men with hepatic cirrhosis, of whom four had a surgically constructed portacaval shunt, and to seven healthy men. Propoxphene concentrations were appreciably higher and norpropoxyphene concentrations were much lower in the patients than in the normal subjects. The ratio of areas under the plasma concentration-time curve from 0 to 12 hr, norpropoxyphene: propoxyphene, was 0.70 +/- 0.46 (x +/SD) in patients and 3.94 +/ 0.83 in normal subjects. A similar decrease in this ratio was observed previously in otherwise healthy dogs after surgical construction of portacaval shunt when propoxyphene was given orally, but not after intravenous injection of the drug. A woman with portacaval shunt and essentially complete renal failure was also studied; she exhibited the highest propoxyphene peak concentration in this investigation and had no detectable norpropoxyphene in plasma. Most of the patients, unlike the normal subjects, experienced considerable sedation after propoxyphene. These results are probably due to increase systemic availability of orally administered propoxyphene in patients with hepatic cirrhosis and possibly to increased receptor response to the drug by these patients. It is concluded that propoxyphene should be administered cautiously and in reduced doses to patients with hepatic dysfunction.     

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.     

Hypotension during septic shock does not correlate with plasma levels of nitric oxide metabolites in the conscious rat

Hypotension following administration of lipopolysaccharide may be due to excessive production of the potent vasodilator nitric oxide brought about by induction of nitric oxide synthase. The purpose of this study was to determine in conscious, fasted rats what role nitric oxide played in lipopolysaccharide-induced hypotension. When examined by Western immunoblot analysis, inducible nitric oxide synthase immunoreactivity was detected in the aorta at 3 hours and increased over time following administration of intraperitoneal lipopolysaccharide (20 mg/kg). When compared with saline-treated control rats, significant hypotension was observed at 2, 4, and 6 hours following lipopolysaccharide treatment. Blood pressure at 2 hours did not differ significantly from that at 6 hours. Using the Griess reaction to quantify plasma levels of nitrates and nitrites as an index of systemic nitric oxide production, an augmentation in the formation of these nitric oxide metabolites was demonstrated at 4 and 6 hours but not at 2 hours. Subcutaneous administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (5 mg/kg) prevented lipopolysaccharide-induced hypotension, an effect reversed by subcutaneous L-arginine but not D-arginine (350 mg/kg). However, nitric oxide synthase inhibition did not attenuate the ability of lipopolysaccharide to increase plasma nitrate/nitrite levels. These data indicate that lipopolysaccharide-induced production of nitric oxide metabolites does not correlate with lipopolysaccharide-induced hypotension.     

Variations in interleukin-2 and interleukin-6 due to surgical trauma in cancer patients

Inflammatory response after surgical trauma, which is necessary for infection control and tissue repairing, can actually produce some cytokines suppressive of the antitumoral immunity response. In this study the authors evaluate pre- and post-operative IL-2 (antitumor response activator) and IL-6 (lymphocytic response inhibitor and tumor growth factor) levels in 26 cancer patients undergoing resective surgery. Analysis of the results showed a significative IL-6 increase and a tendency to IL-2 decrease in the post-operative period. It is thus confirmed, even on the basis of the cytokines, the meaningful immunosuppressive effect of the surgical trauma on neoplastic growth control.     

An analysis of interleukin-8, interleukin-6 and C-reactive protein serum concentrations to predict fever, gram-negative bacteremia and complicated infection in neutropenic cancer patients

A prospective study was performed to assess the potential value of interleukin (IL)-8, IL-6, and C-reactive protein (CRP) serum levels to predict fever, gram-negative bacteremia and complicated infection in neutropenic patients with cancer. Serum samples were obtained three times a week during 208 neutropenic episodes following cytotoxic chemotherapy. Fever of any cause developed during 104 out of 191 evaluable episodes. Serum levels of neither cytokine nor CRP were predictive of fever within more than 24 h before its onset. Unlike CRP, both IL-6 and IL-8 serum levels were significantly different between microbiologically documented infections and unexplained fevers. The highest values of IL-6 and IL-8 were observed in episodes of gram-negative bacteremia. Using receiver-operating-characteristic curves, the analysis of cytokine levels measured around the onset of fever indicated that IL-8 is potentially useful for predicting gram-negative bacteremia, with a high negative predictive value of > 90% and a moderate positive predictive value of 50% (sensitivity, 70%; specificity, 91%). In patients with persistent fever, predictions of further clinical complications, defined as prolonged fever of more than 7 days' duration, pneumonia, shock and/or death due to infection, were best predicted by IL-6. With an IL-6 cutoff value of 250 pg/ml in samples obtained 8 to 32 h after onset of fever, the positive predictive value was 92%, the negative predictive value 91% (sensitivity, 85%; specificity, 95%). The positive predictive value of IL-6 in samples obtained another 24 h later from patients still febrile remained > 90%, but the negative predictive value dropped to 47%. In any of the analyses, the predictive values of CRP levels were poor and inferior to either cytokine. These findings may have clinical value in identifying subgroups of patients requiring different therapeutic approaches.     

Serum interleukin-6 (IL-6) and interleukin-4 (IL-4) in patients with multiple myeloma (MM)

In this study we determined, in patients with multiple myeloma (MM), serum levels of IL-4 and IL-6 at diagnosis and during the course of the disease, seeking a correlation with disease activity and prognosis. We studied 54 MM patients, 41 of whom responded to chemotherapy whilst 11 were resistant. At diagnosis, IL-6 was increased in 66% of patients (median 35.5 pg/ml) whereas IL-4 was low (median 4 pg/ml) in 75% of patients. In responding patients, IL-4 increased in remission (median 25 pg/ml), whereas IL-6 decreased (median 4 pg/ml). In chemotherapy-resistant patients, IL-6 and IL-4 values remained stable during the course of the disease.