Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study

Introduction

Cross-talk between the coagulation system and inflammatory reactions during sepsis causes organ damage followed by multiple organ dysfunction syndrome or even death. Therefore, anticoagulant therapies have been expected to be beneficial in the treatment of severe sepsis. Recombinant human soluble thrombomodulin (rhTM) binds to thrombin to inactivate coagulation, and the thrombin-rhTM complex activates protein C to produce activated protein C. The purpose of this study was to examine the efficacy of rhTM for treating patients with sepsis-induced disseminated intravascular coagulation (DIC).

Methods

This study comprised 65 patients with sepsis-induced DIC who required ventilatory management. All patients fulfilled the criteria of severe sepsis and the International Society on Thrombosis and Haemostasis criteria for overt DIC. The initial 45 patients were treated without rhTM (control group), and the following 20 consecutive patients were treated with rhTM (0.06 mg/kg/day) for six days (rhTM group). The primary outcome measure was 28-day mortality. Stepwise multivariate Cox regression analysis was used to assess which independent variables were associated with mortality. Comparisons of Sequential Organ Failure Assessment (SOFA) score on sequential days between the two groups were analyzed by repeated measures analysis of variance.

Results

Cox regression analysis showed 28-day mortality to be significantly lower in the rhTM group than in the control group (adjusted hazard ratio, 0.303; 95% confidence interval, 0.106 to 0.871; P = 0.027). SOFA score in the rhTM group decreased significantly in comparison with that in the control group (P = 0.028). In the post hoc test, SOFA score decreased rapidly in the rhTM group compared with that in the control group on day 1 (P < 0.05).

Conclusions

We found that rhTM administration may improve organ dysfunction in patients with sepsis-induced DIC. Further clinical investigations are necessary to evaluate the effect of rhTM on the pathophysiology of sepsis-induced DIC.     

Ionized calcium level predicts in-hospital mortality of severe sepsis patients: A retrospective cross-sectional study

Objective: To evaluate the effect of serum ionized calcium levels on the prognosis of severe sepsis patients. Methods: This retrospective cross-sectional study included sepsis patients who were hospitalized in an intensive care unit between January 2011 and December 2014. The demographic and baseline data of the patients who died and survived were compared. The cutoff value of ionized calcium for in-hospital mortality was determined by the receiver operating characteristics curve (ROC). In-hospital mortalities and the survival rates were compared between patients with different ionized calcium levels. Besides, the risk factor of in-hospital mortality was determined. Results: This study included 145 patients with 113 patients who died in the hospital. The patients who died had significantly lower ionized calcium levels (U=2.25, P=0.034). A cut-off value of 0.93 mmol/L of ionized calcium was determined by the ROC curve. The patients with ionized calcium>0.93 mmol/L showed a significantly lower morality (χ2=9.90, P=0.002) and higher survival rate than with ≤0.93 mmol/L (log rank=6.20, P=0.010). Multivariate Cox regression revealed that ionized calcium ≤0.93 mmol/L was a risk factor of in-hospital mortality. Conclusions: Ionized calcium level≤0.93 mmol/L was an independent predictor of in-hospital mortality of severe sepsis.     

Recombinant human thrombopoietin improves platelet counts and reduces platelet transfusion possibility among patients with severe sepsis and thrombocytopenia: A prospective study

Introduction

Thrombocytopenia is prevalent in patients with severe sepsis, and it is associated with mortalities. Effectively adjunctive treatment might be needed to reverse low platelet counts (PCs). With a growing understanding of thrombocytopenia, recombinant human thrombopoietin (rhTPO) is considered a promising beneficial drug. The present study was dedicated to evaluate the efficiency of rhTPO in improving PCs in patients with severe sepsis.

Materials and Methods

We performed a prospective study in patients with severe sepsis between March 2012 and February 2013. All enrolled patients were divided into rhTPO group and control group, depending on whether rhTPO was prescribed or not. Platelet counts and other parameters were measured initially and in the following 15 days.

Results

Totally, 72 patients (38 in the rhTPO group and 34 in the control group) were included. All enrolled parameters exhibited no significant differences between groups at the baseline. Platelet counts showed a significant increase over time in both groups. Faster improvement of PCs in the rhTPO group was observed with a significant difference. Less platelet transfusion occurred in patients who received rhTPO in our study, as well. No drug-related adverse event during the rhTPO therapy was recorded.

Conclusion

The use of rhTPO in combination with conventional medical therapies could significantly improve the PCs in patients with severe sepsis and thrombocytopenia and effectively reduce the platelet transfusion possibility.     

Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis

Purpose

Evidence of efficacy and safety of, and especially mortality related to, recombinant human thrombomodulin (rhTM) treatment for sepsis-induced disseminated intravascular coagulation (DIC) is limited. We hypothesized that patients with sepsis-induced DIC receiving treatment with rhTM would have improved mortality compared with those with similar acuity who did not.

Methods

This retrospective cohort study conducted in three tertiary referral hospitals in Japan between January 2006 and June 2011 included all patients with sepsis-induced DIC who required ventilator management. Primary endpoint was in-hospital mortality, with duration of intensive care unit treatment, changes in DIC scores and rate of bleeding complications as secondary endpoints. Regression technique was used to develop a propensity model adjusted for baseline imbalances between groups.

Results

Eligible were 162 patients with sepsis-induced DIC; 68 patients received rhTM and 94 did not. Patients receiving rhTM had higher severity of illness according to baseline characteristics. After adjusting for these imbalances by stratified propensity score analysis, treatment with rhTM was significantly associated with reduced in-hospital mortality (adjusted hazard ratio, 0.45; 95 % confidential interval, 0.26–0.77; p = 0.013). An association between rhTM treatment and higher numbers of intensive care unit-free days, ventilator-free days, and vasopressor-free days were observed. DIC scores were significantly decreased in the rhTM group compared with the control group in the early period after rhTM treatment, whereas the incidence of bleeding-related adverse events did not differ between the two groups.

Conclusions

Therapy with rhTM may be associated with reduced in-hospital mortality in adult mechanically ventilated patients with sepsis-induced DIC.     

Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis

Introduction

CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis.

Methods

This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint.

Results

Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03).

Conclusions

In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target.     

Initial venous lactate levels as a predictor of mortality in severe sepsis: a single-center retrospective cohort study

<正>Sepsis is the most common cause of death among critically ill patients.^[1] Accordingly, most patients with sepsis are diagnosed and initially treated in the emergency department (ED).^[2] Moreover, some studies have shown that early resuscitation is an important determinant of sepsis survival.^[2,3]Elevated serum lactate levels, which have been observed even during hemodynamic stability, have been considered an important marker of impaired tissue perfusion...     

他汀类药物对中国老年脓毒症患者住院期间病死率的影响

目的探讨他汀类药物对中国老年脓毒症患者住院病死率的影响。 方法对212例2009年3月至2012年3月在浙江大学医学院附属第一医院老年科住院的老年脓毒症患者进行研究。以出院为观察终点,将患者分为死亡组和存活组。采用多因素Logistic回归模型分析,以确定应用他汀类药物是否为住院期间病死率的的独立影响因素。 结果存活组使用他汀类药物的患者比例高于死亡组[13.9%（5/36）vs. 34.7%（61/176）,χ² = 6.014,P = 0.014],调整后的比值比（OR）有统计学意义（OR：0.17;95%CI：0.04 ~ 0.85;P = 0.03）。 结论他汀类药物的使用可能可以降低中国老年脓毒症患者住院期间的病死率。     

Recombinant human activated protein C for use in severe sepsis

OBJECTIVE: To review the efficacy and safety of drotrecogin alfa (recombinant human activated protein C) in the treatment of sepsis. DATA SOURCES: Literature was identified through a MEDLINE search (1966-January 2002), the product manufacturer, and the Food and Drug Administration. STUDY SELECTION/DATA EXTRACTION: All relevant information identified from the data sources was evaluated. DATA SYNTHESIS: Drotrecogin alfa reduces coagulation and inflammation in septic patients. A large placebo-controlled clinical trial (n = 1690) of drotrecogin alfa in severely septic patients demonstrated a reduction in mortality (24.7% vs. 30.8%; p = 0.005), with increased bleeding risks (24.9% vs. 17.7%; p <0.001). Patients with more severe sepsis appeared to gain the most benefit. The complete clinical and economic impact of this agent requires further analysis. CONCLUSIONS: Drotrecogin alfa offers a significant advance in the treatment of severe sepsis. Judicious use in appropriate patients is necessary to control cost and maximize clinical benefits.     

The influence of volume and intensive care unit organization on hospital mortality in patients admitted with severe sepsis: a retrospective multicentre cohort study

Introduction  

The aim of the study was to assess the influence of annual volume and factors related to intensive care unit (ICU) organization on in-hospital mortality among patients admitted to the ICU with severe sepsis.     

Dynamic evolution of coagulopathy in the first day of severe sepsis: relationship with mortality and organ failure

OBJECTIVE: To determine whether changes in coagulation biomarkers during the first day of severe sepsis correlate with progression from single to multiple organ failure and subsequent death. DESIGN: Analysis of secondary endpoints in a prospective, randomized, placebo-controlled, multinational clinical trial (PROWESS). SETTING: The study involved 164 medical centers. PATIENTS: A total of 840 patients who met criteria for severe sepsis and were randomized to receive placebo plus supportive care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Coagulation biomarkers, prothrombin time, antithrombin activity, and D-dimer and protein C levels were measured, and Sequential Organ Failure Assessment was performed daily. Multiple logistic regression analysis identified baseline antithrombin activity <54% and changes in prothrombin time, D-dimer, and antithrombin activity during the first calendar day after the onset of the first sepsis-induced organ dysfunction (i.e., the first day of severe sepsis, day 1) as predictive of 28-day mortality (p < or = .01). A composite coagulopathy score was determined using points for predetermined levels of change from baseline to day 1. The composite coagulopathy score correlated with progression from single to multiple organ failure (p = .0007), time to resolution of organ failure (p = .0004), and 28-day mortality (p < .0001). Combining the composite coagulopathy score with the Acute Physiology and Chronic Health Evaluation (APACHE) II score improved ability to identify patients who would progress to multiple organ failure (area under receiver operating characteristic curve 0.61 APACHE II vs. 0.65 APACHE II + composite coagulopathy score) and who would die (area under receiver operating characteristic curve 0.69 APACHE II vs. 0.74 APACHE II + composite coagulopathy score). CONCLUSIONS: Continuation or worsening of coagulopathy during the first day of severe sepsis was associated with increased development of new organ failure and 28-day mortality. These results further suggest that coagulation abnormalities contribute to organ failure and death.     

Antithrombin III in patients with severe sepsis: a pharmacokinetic study

Objectives: To evaluate the safety, pharmacokinetics, and the practicability of two different antithrombin III (AT III) high-dose regimens in patients with severe sepsis.¶Design: Prospective, open, randomized, 2 parallel groups, multinational clinical trial.¶Setting: Eleven academic medical center intensive care units (ICU) in Austria, Belgium, Denmark, Germany, Norway and Sweden.¶Patients: Thirty-three patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III.¶Interventions: Patients received an intravenous loading dose of 6,000 IU AT III followed by either intermittent bolus infusions of 1,000 IU AT III every 4 h or a continuous infusion of 250 IU AT III/h for 4 days, resulting in a total dose for both dosage regimens of 30,000 IU AT III.¶Measurements: All patients were evaluated for safety and all but one for pharmacokinetics.¶Results and conclusions: The administration of AT III was safe and well tolerated. The overall 28-day all-cause mortality was 30 % (43 % intermittent bolus infusions; 21 % continuous infusion). The mean probability of dying according to the SAPS II was 48 %. The difference in mortality between both groups was within the range of chance. AT III plasma levels were elevated from low baseline levels to above 120 % soon after onset of AT III therapy and remained at these levels for the treatment phase of 4 days. Functional and immunologic levels of AT III corresponded very well. With an overall median volume of distribution of 4.5 l (range: 2.4–6.5 l), AT III only moderately extended beyond plasma. The overall median elimination half-life was 18.6 h (range: 5.1–37.4). Overall, median response was 1.75 % per IU/kg (range: 1.14–2.8).¶The variability of elimination parameters was quite noteworthy (CV = 41–59 %), whereas distribution-related parameters showed a moderate variability (CV = 24 %). In spite of this variability, both high-dose IV regimens reliably provided AT III levels above 120 % for all but one patient. An increased mortality was observed for patients with a distribution volume exceeding 4.5 l (or a response < 1.7 % per IU/kg). AT III distribution volumes above 4.5 l might indicate a capillary leak phenomenon. The continuous infusion regimen was slightly preferred by the investigators with regard to practicability.     

Troponin-I as a prognosticator of mortality in severe sepsis patients

Purpose

The purpose of this retrospective study was to evaluate cardiac troponin-I (cTnI) as a 28-day mortality prognosticator and predictor for a drotrecogin alfa (activated) (DrotAA) survival benefit in recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis patients.

Methods

Cardiac troponin-I was measured using the Access AccuTnI Troponin I assay (Beckman Coulter, Fullerton, CA). There were 598 patients (305 DrotAA, 293 placebo) with baseline cTnI data (cTnI negative [<0.06 ng/mL], n = 147; cTnI positive [≥0.06 ng/mL], n = 451).

Results

Cardiac troponin-I–positive patients were older (mean age, 61 vs 56 years; P = .002), were sicker (mean Acute Physiology and Chronic Health Evaluation II, 26.1 vs 22.3; P < .001), had lower baseline protein C levels (mean level, 49% vs 56%; P = .017), and had higher 28-day mortality (32% vs 14%, P < .0001) than cTnI-negative patients. Elevated cTnI was an independent prognosticator of mortality (odds ratio, 2.020; 95% confidence interval, 1.153-3.541) after adjusting for other significant variables. Breslow-Day interaction test between cTnI levels and treatment was not significant (P = .65).

Conclusion

This is the largest severe sepsis study reporting an association between elevated cTnI and higher mortality. Cardiac troponin-I elevation was not predictive of a survival benefit with DrotAA treatment.     

Apheresis in patients with sepsis: A multicenter retrospective study

Background and objectivesTo consider the effectiveness of apheresis, which is a supportive treatment method, in sepsis.Materials and methodsA hundred and eleven adults with sepsis or septic shock were included in this retrospective study. The demographic characteristics of the patients, the focus and source of infection causing sepsis or septic shock, characteristics of the pathogen, Acute Physiological and Chronic Health Assessment (APACHE) II score, routine laboratory values, which apheresis method was used, the characteristics of the replacement fluids used during the apheresis procedure, the number of apheresis procedures, complications related to the apheresis procedure, the follow-up time after the procedure, and mortality were recorded. The primary outcome was 28-day mortality.ResultsSixty-nine (62.2 %) of the patients were male. The mean age of the patients was 47.7 ± 18.6 years. The most common source of sepsis was hospital-acquired (79.3 %), the most common pathogen causing sepsis was gram-negative bacteria (41.4 %), and the most common infection site was the respiratory tract (58.7 %). The median APACHE II score was 19 (13−24). 92 (82.9 %) of the patients had septic shock. Theropeutic plasma exchange (TPE) was performed in 11.7 % of the patients and immunoabsorbtion IA in 88.3 %. The median number of sessions was 3 (3−5). No procedure-related fatal complication was observed in the study. While 28-day mortality was 61.3 % in all patients, when the mortality according to the apheresis procedures was examined, it was 11.3 % and 88.2 % in the patients who underwent TPE and IA, respectively. The most common cause of mortality was multiorgan failure.ConclusionsApheresis in sepsis can be considered as a salvage treatment. The indication for apheresis in sepsis is still at the level of patient-based individualized decision in line with the studies done so far, including our study. However, there is a need for a multicenter randomized controlled study with a large number of patients in order to give positive or negative recommendations about its effectiveness.