Endotoxin adsorption therapy for septic shock using polymyxin B-immobilized fibers (PMX): evaluation by high-sensitivity endotoxin assay and measurement of the cytokine production capacity

Because of its low sensitivity, the conventional measurement method for endotoxin (ET) is not the most appropriate for monitoring the effect of ET adsorption therapy. Thus, the efficacy of ET adsorption therapy was investigated using a newly developed high-sensitivity ET assay method. The changes in the cytokine production capacity of whole blood were also examined. We treated 24 peritonitis patients who had developed postoperative septic shock with ET adsorption therapy using a column of polymyxin B-immobilized fibers (PMX) and their serum ET levels were measured using the high-sensitivity ET assay based on the kinetic turbidimetric Limulus assay. In addition, the changes in the tumor necrosis factor-(TNF-alpha) production capacity of whole blood following lipopolysaccharide (LPS) stimulation and clinical outcome in the study patients were also examined. The 28-day mortality rate was 12%. PMX-direct hemoperfusion (PMX-DHP) was associated with elevation of the mean arterial pressure and urine output, reduction in the mean dose requirement of vasopressor agents, and recovery from the shock state in all the patients. The PaO2/FIO2 ratio also showed significant improvement. Using the high-sensitivity ET assay, ET was detected in the blood of 20 out of the 24 patients (80%) before the PMX-DHP, and a significant reduction in the ET level was noted after the PMX-DHP. The TNF-alpha production capacity of whole blood, which was found to be lower in the septic shock patients than in healthy subjects, was significantly increased after PMX-DHP. Elimination of ET by PMX-DHP in septic shock patients was confirmed by the high-sensitivity ET assay. PMX-DHP is thus considered to be a useful adjuvant therapeutic technique in the treatment of septic shock. Also, PMX-DHP might alleviate the immunosuppression associated with severe sepsis.     

Removal of 2-arachidonylglycerol by direct hemoperfusion therapy with polymyxin B immobilized fibers benefits patients with septic shock

Arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are endocannabinoids involved in septic shock, and 8-epi prostaglandin F2alpha (F2-isoprostane) is a biomarker of oxidative stress in biological systems. Because the antibiotic polymyxin B absorbs endocannabinoids as well as endotoxins, direct hemoperfusion therapy with polymyxin B-immobilized fibers (PMX-DHP) decreases serum levels of endocannabinoids. To investigate the features of sepsis and determine the proper use of PMX-DHP, we measured the changes in levels of endocannabinoids and F2-isoprostane in patients with septic shock. Twenty-six patients with septic shock, including those with septic shock induced by peritonitis, underwent laparotomy for drainage. Endocannabinoids absorption with PMX-DHP was examined in two groups of patients: patients whose mean arterial blood pressure (mABP) had increased more than 20 mm Hg (responder group; N = 13); and patients iwhose mABP did not increase or had increased no more than 20 mm Hg (non-responder group; N = 13). Levels of AEA did not change after PMX-DHP in either the non-responder or responder groups, whereas levels of 2-AG decreased significantly after PMX-DHP in the responder group, but not in the non-responder group. F2-isoprostane gradually increased after PMX-DHP treatment; on the other hand, levels of F2-isoprostane remained constant in the responder group. Patients with septic shock are under considerable oxidative stress, and 2-AG plays an important role in the cardiovascular status of these patients. The removal of 2-AG by PMX-DHP benefits patients with septic shock by stabilizing cardiovascular status and decreasing long-term oxidative stress.     

Effect over time of endotoxin adsorption therapy in sepsis

Despite the use of potent antibiotics and intensive supportive care, the mortality among patients with sepsis and Gram-negative bacteremia remains high. In recent years, endotoxin adsorption therapy (PMX-DHP, polymyxin-direct hemoperfusion) has been widely used in Japan to remove endotoxin, a causative agent of sepsis. In septic patients whose clinical condition may change at any moment, the decision of when to perform blood purification in addition to conventional intensive care is a critical factor in the therapeutic strategy and prognosis. In the present study, we investigated the effect over time of PMX-DHP in sepsis. The subjects were 16 patients with systemic inflammatory response syndrome (SIRS) who required surgical treatment including a surgical operation and drainage. The following six parameters were compared between the first and second PMX-DHP: mean blood pressure and time-restricted urine at four time points - at baseline and at 6, 24 and 72 h after PMX-DHP; and white blood cell count, platelet count, base excess and Septic Severity Score (SSS) at 24 and 72 h after PMX-DHP. Mean blood pressure improved over time up to 24 h after both the first and second PMX-DHP. Time-restricted urine volume improved only at 6 h after the first PMX-DHP. White blood cell count improved over time up to 24 h after both the first and second PMX-DHP. The SSS improved at all time points studied except for 3 days after the second PMX-DHP. We conclude that PMX-DHP is expected to have important implications in terms of (i) correction of clinical conditions (by severity assessment); (ii) improvement of hemodynamics; (iii) possible anti-inflammatory effect; and (iv) possible improvement of oxygen metabolism in tissues.     

Polymyxin B-immobilized fiber hemoperfusion after emergency surgery in patients with chronic renal failure

The purpose of this study was to evaluate the effect of direct hemoperfusion using a Polymyxin B (PMX) immobilized fiber column in septic patients with chronic renal failure after emergency surgery. Twenty-four renal failure patients, including 19 dialysis patients, with sepsis or septic shock were treated with direct hemoperfusion after emergency surgery. The 24 consecutive patients included nine with necrotic enterocolitis, six with colonic perforation due to diverticulitis, three with ruptured suture after colectomy, one with duodenal perforation, four with blood access infection, and one with an infected abdominal aortic aneurysm. The acute physiology and chronic health evaluation II score ranged from 13 to 26 (19 +/- 3). After completion of the first and the second hemoperfusion, mean blood pressure was significantly elevated from 69 +/- 12 mm Hg to 89 +/- 15 mm Hg and from 78 +/- 14 mm Hg to 95 +/- 13 mm Hg, respectively (P < 0.01). In addition, the catecholamine dosage needed to maintain the circulation could be decreased markedly after the treatment. The blood concentration of endotoxin in patients with Gram-negative sepsis, before and after the treatment, significantly decreased from 36 +/- 19 pg/mL to 19 +/- 19 pg/mL (P < 0.05). PMX was effective in patients with Gram-positive sepsis as well as Gram-negative sepsis. The 28-day mortality rate in patients who had emergency abdominal surgery was 10% (2/20), whereas that in patients with dialysis access infection was 50% (2/4). There was a significant difference in the Sequential Organ Failure Assessment (SOFA) score of all patients before and after treatment using PMX (9.2 +/- 3.3 vs. 7.5 +/- 3.5, P < 0.05). Furthermore, the SOFA score of survivors decreased significantly after PMX treatment (8.4 +/- 3.5 vs. 6.7 +/- 2.6, P < 0.01). Our results suggest that the early application of PMX may prevent multiple organ failure and improve survival in patients with chronic renal failure and sepsis/septic shock after emergency abdominal surgery, regardless of the type of pathogenic bacteria involved.     

Endotoxin adsorption therapy using polymyxin B-immobilized fiber as a treatment for septic shock-associated severe acute cholangitis

The application of endotoxin adsorption therapy for severe acute cholangitis is controversial. We present a survival case of septic shock and multiple organ failure due to severe acute cholangitis. The patient was treated by endotoxin adsorption therapy using polymyxin B-immobilized fiber because he continued to remain in shock even after successful endoscopic nasobiliary drainage. The patient was an 84-year-old male diagnosed with acute cholangitis and acute pancreatitis who was transferred to our department because of shock and severe dyspnea. The patient had already developed acute respiratory failure, acute renal failure, and disseminated intravascular coagulation. We performed endoscopic nasobiliary drainage immediately, but the patient continued to remain in shock and plasma endotoxin level was markedly elevated at 133.6 pg/mL. Therefore, we performed direct hemoperfusion with polymyxin B-immobilized fiber. On starting the hemoperfusion, blood pressure and urine volume increased, and the plasma endotoxin level reduced considerably. On the basis of our experience in this case, we think that direct hemoperfusion with polymyxin B-immobilized fiber may be a useful modality in the management of severe acute cholangitis.     

Hemoadsorption in Critical Care

Abstract: This paper concerns the results of endotoxin hemoadsorption therapy using a PMX column in patients with perforative peritonitis complicated by multiple organ failure. The subjects were 31 patients aged 68 ± 12 years. When systolic arterial pressure decreased to less than 90 mm Hg, endotoxin hemoadsorption was initiated and continued for 2 h. At the completion of endotoxin hemoadsorption, systolic arterial pressure, diastolic arterial pressure, and mean arterial pressure were significantly increased. Platelet count decreased to less than 50,000/mm³ in 30% of patients. As for cytokines and vascular endothelial cell function markers, interleukin‐6 and plasminogen activator inhibitor‐1 significantly decreased. These results suggest favorable effects of endotoxin hemoadsorption on the hemodynamic and pathophysiological conditions in patients with septic shock although attention should be given to the decrease in platelet count.     

Endotoxemia in human septic shock

To evaluate the incidence, pattern and clinical importance of endotoxemia in septic shock, frequent, serial endotoxin determinations were made prospectively in patients with shock. Detectable endotoxin occurred in 43 of 100 patients with septic shock, but in only one of ten patients with shock due to nonseptic causes. During septic shock, endotoxemia frequently occurred in the absence of Gram-negative bacteremia. Using a logistic regression model, multiple organ failure occurred 10.3 times more frequently and depression of left ventricular ejection fraction (less than or equal to 45 percent) 4.8 times more frequently in endotoxemic patients. In patients with positive blood cultures, endotoxemia was associated with a high mortality. We conclude that endotoxemia occurs frequently in septic shock and is associated with severe manifestations of this syndrome, including cardiac depression and multiple organ failure. This study suggests that endotoxin is an important mediator of septic shock and supports efforts to develop anti-endotoxin therapies for treating patients with this disease.     

Extracorporeal Endotoxin Removal by Polymyxin B Immobilized Fiber Cartridge: Designing and Antiendotoxin Efficacy in the Clinical Application

Abstract: We have developed an extracorporeal hemoad-sorption cartridge, the PMX cartridge, to eliminate endotoxin from peripheral blood circulation. As an adsorbent, a polymyxin B covalently immobilized fiber (PMX-F) was developed. After the optimization of the condition of immobilization, fixed polymyxin B maintained its ability to adsorb endotoxin and its bactericidal activity. PMX-F could detoxify many kinds of endotoxin in vitro. Fixed polymyxin B was estimated to interact with the lipid A portion of endotoxin. Utilization of fibrous adsorbents enabled us to design the PMX cartridge with a large surface area and low blood pressure drop in the blood flow compartment and to apply it safely to the direct hemoperfusion procedure. In Japan, the PMX cartridge is now being clinically applied as one of the therapeutical interventions for sepsis, septic shock, and septic multiple organ failure. In multicenter clinical studies, the blood endotoxin level has been significantly decreased. Accompanied with elimination of endotoxin, hemodynamic abnormalities such as low blood pressure and low systemic vascular resistance were significantly improved. In more recent multicenter studies, the average number of failed organs; severity of illness score, such as Goris score; and vasopressor dosage were significantly decreased. The PMX cartridge is expected to be effective in the intervention for the treatment of septic shock. Endotoxin may be one of the therapeutical targets for the treatment of sepsis.     

Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock.

Plasma endotoxin and lipopolysaccharide-binding protein (LBP) levels were measured in a group of 253 patients at the onset of severe sepsis and/or septic shock. Endotoxin levels were significantly greater than control levels (n=33; mean +/- SD, 5.1+/-7.3 pg/mL) in 78.3% of patients. Median endotoxin levels in patients with sepsis were 300 pg/mL (25%-75% interquartile range, 110-726 pg/mL). LBP levels were elevated in 97% of patients compared with normal control values of 4.1+/-1.65 microgram/mL. Median LBP levels in patients with sepsis were 31.2 microgram/mL (interquartile range, 22.5-47.7 microgram/mL). Median endotoxin levels at study entry were more highly elevated (515 vs. 230 pg/mL; P<.01), and LBP levels were less highly elevated (28.0 vs. 33.2 microgram/mL; P<.05) in nonsurvivors than survivors over the 28-day study period. No correlation was found between endotoxin and LBP levels. The quantitative level of both endotoxin and LBP may have prognostic significance in patients with severe sepsis.     

Extracorporeal endotoxin removal for the treatment of sepsis: endotoxin adsorption cartridge (Toraymyxin)

Toray Industries Inc. has developed an endotoxin removal cartridge (Toraymyxin) composed of a polymyxin B immobilized, fibrous adsorbent. Toraymyxin has been listed as a blood purification medical device for endotoxin removal to be reimbursed by the Japanese national health insurance since 1994. Toraymyxin can be applied to patients with endotoxemia or suspected gram-negative infection, which fulfilll the conditions of Systemic Inflammatory Response Syndrome (SIRS) and have septic shock demanding vasopressor infusion. Since 1994, over 30,000 patients have received this treatment. The safety of this device has been confirmed and improvement of hemodynamic dysfunction has been shown to be a major benefit. Infection resulting from an acute abdominal condition requiring surgery has been shown to be one of the good indications for Toraymyxin. Further studies are now ongoing to establish Toraymyxin treatment as one of the options to treat sepsis and septic shock patients and to clarify the mechanisms involved in this therapy.     

Continuous Hemodiafiltration with Polymyxin‐B Immobilized Fiber Is Effective in Patients with Sepsis Syndrome and Acute Renal Failure

Abstract: The aim of this study was first, to evaluate the effects of continuous hemodiafiltration (CHDF) alone or combined with CHDF and polymyxin‐B immobilized fiber (PMX) on survival rates of patients with sepsis and acute renal failure, and second, to evaluate the changes in plasma levels of inflammatory cytokines before and after treatment with CHDF and PMX and CHDF alone in these patients. Forty‐eight patients with septic shock and acute renal failure were enrolled in this study. The survival rate of all patients at 28 days was 25% for those with CHDF and 75% for those with PMX and CHDF treatment. Combination treatment produced a significant reduction of plasma levels of endotoxin and interleukin‐6 compared to the basal values and to the treatment with CHDF alone. From these data, it is suggested that the combined therapy with PMX and CHDF is effective in improvement of survival rate of patients with septic shock and acute renal failure.     

Case of acute respiratory distress syndrome treated with direct hemoperfusion using a polymyxin B immobilized fiber colum]

During a 54-year-old woman's visit to a hot-spring resort, she suffered a fever and became dizzy and unable to speak clearly. She was admitted to our hospital due to serious pneumonia and respiratory failure type I. She was treated with antibiotics, but her condition became worse and developed into acute respiratory distress syndrome (ARDS). She was intubated and received artificial ventilation. Her blood pressure gradually decreased and she suffered septic shock probably due to endotoxin with gram negative coccus infection. Subsequently, she was treated with a direct hemoperfusion using a polymyxin B immobilized fiber column (PMX-DHP), which resulted in an improvement of oxygenation. However, her pneumonia led to the development of septic shock with gram negative coccus infection, and PMX-DHP treatment was resumed. After PMX-DHP re-treatment, she recovered gradually in intensive care including prone positioning ventilation.     

Effectiveness of polymyxin B-direct hemoperfusion (PMX-DHP) therapy using a polymyxin B-immobilized fiber column in patients with post-esophagectomy sepsis

Background

Post-esophagectomy complications have an extremely poor prognosis. Recently, polymyxin B-direct hemoperfusion (PMX-DHP) therapy using a polymyxin B-immobilized fiber column was reported to be beneficial in gram-negative and/or gram-positive bacterial sepsis. The present retrospective study investigated the effectiveness and safety of PMX-DHP therapy in severe sepsis or septic shock after esophagectomy.

Methods

Fifteen severe sepsis or septic shock patients were included. Seven (four, pneumonia; two, anastomotic leakage; and one, reconstructed colon necrosis) patients received 2–5 h of PMX-DHP therapy (PMX-DHP therapy group), whereas 8 (three, pneumonia; three, anastomotic leakage; and two, gastric tube necrosis) received conventional therapy (control group).

Results

Length of stay in the intensive care unit (ICU) was significantly shorter in the PMX-DHP therapy group than in the conventional therapy group (P = 0.040). In the comparison of pre- and post-PMX-DHP therapy groups, the total Sequential Organ Failure Assessment (SOFA) score, respiratory system score, and P/F ratio improved (P = 0.0027, P = 0.025, and P = 0.0087, respectively) in the post-PMX-DHP therapy group. In the comparison of conventional and PMX-DHP therapy groups, the variations in the total SOFA score, respiratory system score, and P/F ratio improved (P = 0.019, P = 0.0063, and P = 0.0015, respectively) in the PMX-DHP therapy group. Moreover, the respiratory system score was lower (P = 0.0062) in the PMX-DHP therapy group at the time of discharge from the ICU. No adverse effects were observed during the course of PMX-DHP therapy.

Conclusions

PMX-DHP therapy was safe and effective in improving respiratory and general conditions of patients with severe sepsis and septic shock after esophagectomy and decreased the length of stay in the ICU.     

Effects of PMX-DHP treatment for patients with directly induced acute respiratory distress syndrome

Endotoxin-removal direct hemoperfusion column containing polymyxin B immobilized fibers (PMX-DHP) is an effective procedure for the treatment of sepsis-induced acute respiratory distress syndrome (ARDS). We investigated retrospectively the effects and appropriate timing of PMX-DHP induction for directly induced ARDS in 38 patients. PMX-DHP was carried out twice for two hours. Blood pressure, heart rate (HR) and PaO(2)/FIO(2) (PF) ratio, leukocytes, platelets, endotoxin, inflammatory cytokines and clusters of differentiated peripheral neutrophils and monocytes were measured before and after PMX-DHP. Acute Physiology and Chronic Health Evaluation (APACHE) II scores, Sequential Organ Failure Assessment (SOFA) scores and lung injury scores (LIS) were determined at the time of starting PMX-DHP. The underlying causes of ARDS were pneumonia in 29 patients and aspiration pneumonia in 9 patients. The patients were divided into Survivors (n = 21) and Nonsurvivors (n = 17). Mortality was 45% at 30 days after PMX-DHP. The APACHE II and SOFA scores and the LIS were not significantly different between the two groups. The time from the onset of ARDS to the start of PMX-DHP was significantly delayed between the two groups. PMX-DHP significantly improved the PF ratio, HR and systolic blood pressure in the Survivors compared to the Nonsurvivors. The function of active monocytes in the peripheral blood was significantly suppressed after PMX-DHP. This early induction of PMX-DHP is indicated for directly induced ARDS. In the Nonsurvivors, this delay could have led to undesirable responses to oxygenation and circulation after PMX-DHP.     

Granulocyte colony-stimulating factor (G-CSF) serum levels in surgical intensive care patients

Summary The granulocyte colony-stimulating factor (G-CSF) regulates neutrophil differentiation and function. Serum levels of G-CSF increase during acute infectious processes. The levels of G-CSF were measured in 59 surgical intensive care unit (ICU) patients. In general, G-CSF was only elevated during the first 2 days after admission to the ICU. Higher G-CSF levels were more frequently observed in patients without infectious complications and in patients who survived. Later on, G-CSF levels were below 100 pg/ml in almost all patients studied. The highest G-CSF level (20,000 pg/ml) was observed in one patient with septic shock 36 h after leukopenia. The patient recovered from septic shock and multiple organ failure and was discharged. It is proposed that surgical ICU patients with low or undetectable G-CSF serum levels may benefit from exogenous G-CSF substitution protocols.     

Therapeutic strategy of emergency surgery for colon cancer in 71 patients over 70 years of age in Japan

BACKGROUND/AIMS: The prognosis for colon cancer is poorest in cases of emergency situation in the elderly not only in Japan, but worldwide. The aim was to design a therapeutic approach used for colon cancer in the elderly. METHODOLOGY: Seventy-one patients, who were all older than 70 years, with colon carcinoma in an emergency situation were examined. Lethality, surgical procedure, risk of comorbidity, multiple organ system failure and the effect of endotoxin absorption were examined. RESULTS: Any increase in comorbidity was associated with a higher clinical lethality in the lungs, heart, kidney, and diabetes. The highest postoperative mortality rate was recorded in patients who underwent primary resection after perforation, while the lowest postoperative mortality rate was recorded in patients who underwent primary resection after obstruction. Postoperative failure of the lungs and heart and renal failure were associated with a significantly higher mortality rate. Twenty-five septic patients received an endotoxin adsorption due to blood filtration and 8 patients survived. Of the eight survivors, the endotoxin concentration was significantly decreased by an endotoxin absorption. CONCLUSIONS: In cases of ileus, the resection may be performed positively. In cases of perforation, we may safely say now that stoma and resection is to be recommended. Endotoxin absorption due to blood filtration may be an effective additional therapy for post-operative septic shock.     

Serum TNF-related and weak inducer of apoptosis levels in septic shock patients

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds. In sepsis, this feature is fundamentally altered. We have previously reported elevated levels of angiopoietin-2 in patients with septic shock, and have investigated tumor necrosis factor (TNF)-related and weak inducer of apoptosis (TWEAK), which mediates both angiogenesis and inflammation, in those patients. Enzyme-linked immunoassay was used to measure serum TWEAK levels in 20 patients with septic shock, all of whom were treated by direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX), and in 20 non-septic controls. The TWEAK levels were higher in patients with septic shock (192.8 ± 230.5 pg/mL) than in controls (84.1 ± 28.7 pg/mL, P = 0.043). Between 11 survivors and 10 non-survivors, there was no significant difference in the serum TWEAK levels before the DHP-PMX therapy. During DHP-PMX therapy, however, the serum TWEAK levels were significantly increased in non-survivors (142.2 ± 88.1 pg/mL to 399.0 ± 307.1 pg/mL, P = 0.022). There was a significant correlation between the serum TWEAK levels and white blood cell counts (r = 0.393, P < 0.001), platelet counts (r = 0.418, P < 0.001), or serum CRP levels (r = 0.259, P = 0.029), but there was no correlation between the serum TWEAK levels and blood pressure. The serum TWEAK levels were also correlated with the ratio of angiopoietin-2 to -1 (r = 0.464, P < 0.001). TWEAK may be a suitable marker of disease severity and mortality in septic patients, and TWEAK levels may be associated with vascular permeability via angiopoietin balance.     

Endotoxin, TNF-alpha, interleukin-6 and parameters of the cellular immune system in patients with intraabdominal sepsis.

The correlation of endotoxin (ET), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and cellular immune parameters with multiple organ failure and lethal outcome in intraabdominal infections was studied in a group of 18 patients with peritonitis, abscess or pancreatitis. Of these patients, 7 developed respiratory failure and 5 died due to multiple septic organ failure. The peak levels of ET (2.7 +/- 1.3 ng/ml) in the course of the disease were followed by moderate increases of TNF-alpha (mean 147 +/- 41 pg/ml) and IL-6 (170 +/- 61 pg/ml) within 2 days. Analysis of the parameters for the last 12 days prior to death or discharge showed, that the patient group with lethal outcome was characterized by significant lower mean plasma levels of TNF-alpha (less than 75 pg/ml versus greater than 160 pg/ml) and IL-6 (less than 130 pg/ml versus greater than 270 pg/ml), as well as high rates of unstimulated thymidine uptake into peripheral mononuclear blood cells (greater than 44000 cpm/8 x 10(6) PMBC/18 h versus less than 24000 cmp), T-lymphocyte depression (CD3; approximately greater than 40% reduction) with lower T-helper/inducer subset cell numbers (mean CD:CD8 ratio 1.0 +/- 0.55 versus 1.8 +/- 0.2) and lower lectin (PHA) stimulation values (1.9 +/- 1.4 versus 4.1 +/- 1.0). These data demonstrate an anergic immune status with low mediator levels and depressed T-lymphocyte function in patients with poor prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients

Septic shock and multiple organ failure may be associated with coagulation activation, disseminated fibrin formation, and consumption of coagulation inhibitors such as antithrombin III. We have evaluated prospectively coagulation measurements in patients with severe chemotherapy-induced neutropenia. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective coagulation testing before and during evolving sepsis or septic shock. Sixty-two patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and 13 additional patients to septic shock as defined according to standard diagnostic criteria. At the onset of fever, factor (F) VIIa activity, FVII antigen and antithrombin III (AT III) activity decreased from normal baseline levels and were significantly lower in the group of patients who progressed to septic shock compared with those that developed severe sepsis (medians: 0.3 v 1.4 ng/mL, 21 v 86 U/dL and 45% v 95%; P < .001). The decrease of these measurements in septic shock was accompanied by an increase in prothrombin fragment 1+2 (median: 3.6 v 1.4 nmol/L; P = .05), a marker of thrombin generation. These differences were sustained throughout the septic episode (P < .0001). FVIIa and AT III levels of < 0.8 ng/mL and < 70%, respectively, at onset of fever predicted a lethal outcome with a sensitivity of 100% and 85%, and a specificity of 75% and 85%, respectively. In contrast, FXIIa-alpha antigen levels were not different between groups at onset of fever but increased modestly during the course of septic shock (P = .001). Thus, septic shock in neutropenic patients is associated with increased thrombin generation. Furthermore, both FVIIa and AT III measurements are sensitive markers of an unfavorable prognosis.     

丙酮酸乙酯对脓毒症休克犬抗氧化及器官保护作用研究

目的:研究丙酮酸乙酯(EP)对脓毒症休克犬的抗氧化及器官保护作用。方法:健康雄性杂种犬20只,内毒素(LPS)静脉注射复制犬脓毒症休克模型,随机分为对照组(n=8)和EP治疗组(n=12)。对照组只接受林格氏液复苏,EP治疗组另外给予EP首剂0.05g/kg,然后0.05g/(kg.h)持续泵入。脓毒症休克模型建立前及建立后0、8、12、24h取血测定氧化应激指标丙二醛(MDA)、超氧化物歧化酶(SOD)活力、总抗氧化能力(T-AOC)、一氧化氮(NO)水平、谷胱苷肽过氧化物酶(GSH-PX)活性;测定血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、尿素氮(BUN)、肌酐(Cr)、二胺氧化酶(DAO)水平、D-乳酸含量。结果:治疗后两组血清MDA、NO水平均显著上升(P<0.05);SOD活力、T-AOC、GSH-PX活性均明显下降(P<0.05),8h后对照组与EP组比较,有明显差异(P<0.05)。治疗后两组血清ALT、AST、BUN、Cr、DAO、D-乳酸水平均升高(P<0.05),12h后对照组与EP组比较有明显差异(P<0.05)。结论:丙酮酸乙酯能改善脓毒症休克犬的氧化应激状态,对多种脏器功能具有保护作用。