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1.
Effects of combination therapy of antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis
Totoki, T., Makino, Y., Yamakawa, K., Koami, H., Wada, T., Ito, T., Iba, T.
Thrombosis journal. 2024;22(1):10
Abstract
BACKGROUND Disseminated intravascular coagulation (DIC) syndrome is a highly lethal condition characterized by the complication of multiple organ damage. Although the effects of combined antithrombin (AT) and recombinant thrombomodulin (rTM) on DIC syndrome have previously been examined, the results are inconsistent and inconclusive. Therefore, we conducted a systematic review on the combined administration of AT and rTM for the treatment of septic DIC to investigate the superiority of the combination therapy over either AT or rTM monotherapy using a random-effects analysis model. METHOD We searched electronic databases, including Medline, Cochrane Central Register of Controlled Trials, Scopus, and Igaku-Chuo Zasshi (ICHU-SHI) Japanese Central Review of Medicine Web from inception to January 2022. Studies assessing the efficacy of combined AT and rTM were included. The primary outcome was all-cause mortality, and the secondary outcome was occurrence of serious bleeding complications compared to monotherapy. We presented the pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI) depending on reporting results in each primary study. RESULTS We analyzed seven enrolled clinical trials, all of which were observational studies. Combination therapy had a non-significant favorable association with lower 28-day mortality compared to monotherapy (HR 0.67 [0.43-1.05], OR 0.73 [0.45-1.18]). The I(2) values were 60% and 72%, respectively, suggesting high heterogeneity. As a secondary outcome, bleeding complications were similar between the two groups (pooled OR 1.11 [0.55-2.23], I(2) value 55%). CONCLUSIONS Although the findings in this analysis could not confirm a statistically significant effect of AT and rTM combination therapy for septic DIC, it showed a promising effect in terms of improving mortality. The incidence of bleeding was low and clinically feasible. Further research is warranted to draw more conclusive results. TRIAL REGISTRATION This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID 000049820).
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2.
A Network Meta-Analysis of Two Doses of Recombinant Human Thrombopoietin for Treating Sepsis-Related Thrombocytopenia
Chen, D., Hou, Y., Wei, C., Cai, X.
International Journal of Clinical Practice. 2022;2022:2124019
Abstract
Previous studies suggest that sepsis remains a common critical illness with a global incidence of 31.5 million. The aim of this study was to evaluate the comparative therapeutic value of recombinant human thrombopoietin (rhTPO) in treating sepsis patients with thrombocytopenia. We conducted a comprehensive electronic search of PubMed, EMBASE, the Cochrane Library, and CNKI from its inception through December 31, 2021. Thirteen randomized controlled trials (RCTs) involving 963 patients were included. Network meta-analyses showed that rhTPO 300 U/kg/day and rhTPO 15000 U/day significantly increased the platelet (PLT) levels on the 7(th) day and decreased the requirement of transfusion of red blood cells (RBCs), plasma, and PLT compared with IVIG and NAT. SUCRA showed that rhTPO 300 U/kg/day ranked first in terms of 28-day mortality (85.5%) and transfusion, including RBC (88.7%), plasma (89.6%), and PLT (95.2%), while rhTPO 15000 U/day ranked first for the length of the intensive care unit (ICU) stay (95.9%) and PLT level at day 7 (91.6%). rhTPO 300 U/kg/day may be the optimal dose to reduce 28-day mortality and transfusion requirements. However, rhTPO 15000 U/day may be the optimal dose for shortening the ICU stay and increasing the PLT level on the 7th day. However, additional studies to further validate our findings are needed.
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3.
Addition of terlipressin to norepinephrine in septic shock and effect of renal perfusion: a pilot study
Wang, J., Shi, M., Huang, L., Li, Q., Meng, S., Xu, J., Xue, M., Xie, J., Liu, S., Huang, Y.
Renal Failure. 2022;44(1):1207-1215
Abstract
PURPOSE Terlipressin improves renal function in patients with septic shock. However, the mechanism remains unclear. Here, we aimed to evaluate the effects of terlipressin on renal perfusion in patients with septic shock. MATERIALS AND METHODS This pilot study enrolled patients with septic shock in the intensive care unit of the tertiary hospital from September 2019 to May 2020. We randomly assigned patients to terlipressin and usual care groups using a 1:1 ratio. Terlipressin was intravenously pumped at a rate of 1.3 μg/kg/hour for 24 h. We monitored renal perfusion using renal contrast-enhanced ultrasound (CEUS). The primary outcome was peak sonographic signal intensity (a renal perfusion parameter monitored by CEUS) at 24 h after enrollment. RESULTS 22 patients were enrolled in this study with 10 in the terlipressin group and 12 in the usual care group. The baseline characteristics of patients between the two groups were comparable. The peak sonographic signal intensity at 24 h after enrollment in the terlipressin group (60.5 ± 8.6 dB) was significantly higher than that in the usual care group (52.4 ± 7.0 dB; mean difference, 7.1 dB; 95% CI, 0.4-13.9; adjusted p = .04). Patients in the terlipressin group had a lower time to peak, heart rates, norepinephrine dose, and a higher stroke volume at 24 h after enrollment. No significant difference in the urine output within 24 h and incidence of acute kidney injury within 28 days was found between the two groups. CONCLUSIONS Terlipressin improves renal perfusion, increases stroke volume, and decreases norepinephrine dose and heart rates in patients with septic shock.
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4.
The effect of early vasopressin use on patients with septic shock: A systematic review and meta-analysis
Huang H, Wu C, Shen Q, Xu H, Fang Y, Mao W
The American journal of emergency medicine. 2021;48:203-208
Abstract
BACKGROUND The effect of early vasopressin initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early start of vasopressin support within 6 h after the diagnosis on clinical outcomes in septic shock patients. METHODS We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of February 2021. We included studies involving adult patients (> 16 years)with septic shock. All authors reported our primary outcome of short-term mortality and in the experimental group patients in the studies receiving vasopressin infusion within 6 h after diagnosis of septic shock and in the control group patients in the studies receiving no vasopressin infusion or vasopressin infusion 6 h after diagnosis of septic shock, clearly comparing with clinically relevant secondary outcomes(use of renal replacement therapy(RRT),new onset arrhythmias, ICU length of stay and length of hospitalization). Results were expressed as odds ratio (OR) and mean difference (MD) with accompanying 95% confidence interval (CI). RESULTS Five studies including 788 patients were included. The primary outcome of this meta-analysis showed that short-term mortality between the two groups was no difference (odds ratio [OR] = 1.09; 95% CI, 0.8 to 1.48; P = 0.6; χ2 = 0.83; I2 = 0%). Secondary outcomes demonstrated that the use of RRT was less in the experimental group than that of the control group (OR = 0.63; 95% CI, 0.44 to 0.88; P = 0.007; χ2 = 3.15; I2 = 36%).The new onset arrhythmias between the two groups was no statistically significant difference (OR = 0.59; 95% CI, 0.31 to 1.1; P = 0.10; χ2 = 4.7; I2 = 36%). There was no statistically significant difference in the ICU length of stay(mean difference = 0.16; 95% CI, - 0.91 to 1.22; P = 0.77; χ2 = 6.08; I2 = 34%) and length of hospitalization (mean difference = -2.41; 95% CI, -6.61 to 1.78; P = 0.26; χ2 = 8.57; I2 = 53%) between the two groups. CONCLUSIONS Early initiation of vasopressin in patients within 6 h of septic shock onset was not associated with decreased short-term mortality, new onset arrhythmias, shorter ICU length of stay and length of hospitalization, but can reduce the use of RRT. Further large-scale RCTs are still needed to evaluate the benefit of starting vasopressin in the early phase of septic shock.
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5.
Assessing the Course of Organ Dysfunction Using Joint Longitudinal and Time-to-Event Modeling in the Vasopressin and Septic Shock Trial
Harhay MO, Gasparini A, Walkey AJ, Weissman GE, Crowther MJ, Ratcliffe SJ, Russell JA
Crit Care Explor. 2020;2(4):e0104
Abstract
Non-mortality septic shock outcomes (e.g., Sequential Organ Failure Assessment score) are important clinical endpoints in pivotal sepsis trials. However, comparisons of observed longitudinal non-mortality outcomes between study groups can be biased if death is unequal between study groups or is associated with an intervention (i.e., informative censoring). We compared the effects of vasopressin versus norepinephrine on the Sequential Organ Failure Assessment score in the Vasopressin and Septic Shock Trial to illustrate the use of joint modeling to help minimize potential bias from informative censoring. Design: Secondary analysis of the Vasopressin and Septic Shock Trial data. Setting: Twenty-seven ICUs in Canada, Australia, and United States. Subjects: Seven hundred sixty-three participants with septic shock who received blinded vasopressin (n = 389) or norepinephrine infusions (n = 374). Measurements and Main Results: Sequential Organ Failure Assessment scores were calculated daily until discharge, death, or day 28 after randomization. Mortality was numerically higher in the norepinephrine arm (28 d mortality of 39% vs 35%; p = 0.25), and there was a positive association between higher Sequential Organ Failure Assessment scores and patient mortality, characteristics that suggest a potential for bias from informative censoring of Sequential Organ Failure Assessment scores by death. The best-fitting joint longitudinal (i.e., linear mixed-effects model) and survival (i.e., Cox proportional hazards model for the time-to-death) model showed that norepinephrine was associated with a more rapid improvement in the total Sequential Organ Failure Assessment score through day 4, and then the daily Sequential Organ Failure Assessment scores converged and overlapped for the remainder of the study period. Conclusions: Short-term reversal of organ dysfunction occurred more rapidly with norepinephrine compared with vasopressin, although differences between study arms did not persist after day 4. Joint models are an accessible methodology that could be used in critical care trials to assess the effects of interventions on the longitudinal progression of key outcomes (e.g., organ dysfunction, biomarkers, or quality of life) that may be informatively truncated by death or other censoring events.
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6.
Efficacy and Safety of Recombinant Human Thrombopoietin on Sepsis Patients With Thrombocytopenia: A Systematic Review and Meta-Analysis
Zhang J, Lu Z, Xiao W, Hua T, Zheng Y, Yang M
Front Pharmacol. 2020;11:940
Abstract
BACKGROUND The efficacy and safety of the administration of recombinant human thrombopoietin (rhTPO) in sepsis patients with thrombocytopenia were still inconclusive. OBJECTIVES To investigate whether rhTPO is a benefit for sepsis patients with thrombocytopenia. METHODS PubMed, Cochrane library, Embase, China National Knowledge Infrastructure, and Wanfang Database were electronically searched to the randomized controlled trials (RCTs) from inception to March 4, 2020. The primary outcome was the level of platelet (PLT) on the 7(th) day of treatment, and secondary outcomes were 28-d mortality, the level of coagulation indicators, hepatic and renal function indicators, blood transfusion, and length of intensive care unit (ICU) stay. RESULTS Ten RCTs involving 681 patients were included. For compared with conventional antibiotic therapy, rhTPO could significantly increase platelet counts (PCs) [standardized mean difference (SMD), 2.61; 95% confidence interval (CI), 1.28-3.94; P < 0.001], decreased 28-d mortality [relative risk (RR), 0.66; 95%CI, 0.46-0.97; P=0.03], transfusion volume of blood products and length of ICU stay. Additionally, for compared with conventional antibiotic therapy combined with intravenous immunoglobulin, the pooled results shown that rhTPO also associated with an improvement of PCs on 7(th) of treatment (SMD, 0.86; 95%CI, 0.54-1.17; P < 0.001), and a reduced transfusion volume of blood products. However, there were no differences in 28-d mortality and the length of ICU stay. CONCLUSIONS Current evidence shown that rhTPO could increase PCs on 7(th) day of treatment and reduce the transfusion volume of blood products in sepsis-related thrombocytopenia during hospitalization. The conclusions are needed to be verified indeed by more multicenter RCTs due to the limitation of the included studies.
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7.
Clinical Efficiency of Vasopressin or Its Analogs in Comparison With Catecholamines Alone on Patients With Septic Shock: A Systematic Review and Meta-Analysis
Yao RQ, Xia DM, Wang LX, Wu GS, Zhu YB, Zhao HQ, Liu Q, Xia ZF, Ren C, Yao YM
Front Pharmacol. 2020;11:563
Abstract
Background: Vasopressin is an efficient remedy for septic shock patients as its great capacity in promoting hemodynamic stabilization. The aim of current systematic review and meta-analysis is to compare the clinical efficiency of vasopressin or its analogs with sole catecholamines on patients with septic shock. Methods: A systematic search of Cochrane Library, EMBASE, and PubMed online databases was performed up to 30 Oct 2019 to identify randomized controlled trials comparing use of vasopressin or its analogs (e.g., terlipressin, selepressin) with administration of catecholamines alone. Results: We included 23 RCTs with 4,225 patients in the current study. Compared with solely use of catecholamines, administration of vasopressin or its analogs was not associated with reduced 28-day or 30-day mortality among patients with septic shock [RR=0.94 (95% CI, 0.87-1.01), P=0.08, I(2) = 0%]. The result of primary endpoint remained unchanged after conducting sensitivity analysis. Despite a significantly higher risk of digital ischemia in patients receiving vasopressin or its analogs [RR=2.65 (95% CI, 1.26-5.56), P < 0.01, I(2) = 48%], there was no statistical significance in the pooled estimate for other secondary outcomes, including total adverse events, arrhythmia, acute myocardial infarction (AMI) and cardiac arrest, acute mesenteric ischemia, ICU/hospital length of stay, and mechanical ventilation (MV) duration. Conclusions: The administration of vasopressin or its analogs was not associated with reduced 28-day or 30-day mortality among patients with septic shock, while an increased incidence of digital ischemia should be noted in patients receiving agonists for vasopressin receptors.
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8.
Terlipressin for the treatment of septic shock in adults: a systematic review and meta-analysis
Huang L, Zhang S, Chang W, Xia F, Liu S, Yang Y, Qiu H
BMC anesthesiology. 2020;20(1):58
Abstract
BACKGROUND Catecholamines are the first-line vasopressors used in patients with septic shock. However, the search for novel drug candidates is still of great importance due to the development of adrenergic hyposensitivity accompanied by a decrease in catecholamine activity. Terlipressin (TP) is a synthetic vasopressin analogue used in the management of patients with septic shock. In the current study, we aimed to compare the effects of TP and catecholamine infusion in treating septic shock patients. METHODS A systematic review and meta-analysis was conducted by searching articles published in PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials between inception and July 2018. We only selected randomized controlled trials evaluating the use of TP and catecholamine in adult patients with septic shock. The primary outcome was overall mortality. The secondary outcomes were the ICU length of stay, haemodynamic changes, tissue perfusion, renal function, and adverse events. RESULTS A total of 9 studies with 850 participants were included in the analysis. Overall, no significant difference in mortality was observed between the TP and catecholamine groups (risk ratio(RR), 0.85 (0.70 to 1.03); P = 0.09). In patients < 60 years old, the mortality rate was lower in the TP group than in the catecholamine group (RR, 0.66 (0.50 to 0.86); P = 0.002). There was no significant difference in the ICU length of stay (mean difference, MD), - 0.28 days; 95% confidence interval (CI), - 1.25 to 0.69; P = 0.58). Additionally, TP improved renal function. The creatinine level was decreased in patients who received TP therapy compared to catecholamine-treated participants (standard mean difference, SMD), - 0.65; 95% CI, - 1.09 to - 0.22; P = 0.003). No significant difference was found regarding the total adverse events (Odds Ratio(OR), 1.48(0.51 to 4.24); P = 0.47), whereas peripheral ischaemia was more common in the TP group (OR, 8.65(1.48 to 50.59); P = 0.02). CONCLUSION The use of TP was associated with reduced mortality in septic shock patients less than 60 years old. TP may also improve renal function and cause more peripheral ischaemia. PROSPERO registry: CRD42016035872.
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The effect of recombinant human thrombopoietin (rhTPO) on sepsis patients with acute severe thrombocytopenia: a study protocol for a multicentre randomised controlled trial (RESCUE trial)
Zhou, Z., Feng, T., Xie, Y., Huang, P., Xie, H., Tian, R., Qian, B., Wang, R.
BMC infectious diseases. 2019;19(1):780
Abstract
BACKGROUND Sepsis is still a common critical disease with high morbidity and mortality in intensive care unit. Despite published guidelines for sepsis, development of antibiotic therapy and advanced organ support technologies, the mortality of sepsis patients is still 25% or more. It is necessary to distinguish the subtypes of sepsis, and the targeted therapy for the patients need to be explored. Platelets have various biological functions in hemostasis and thrombosis, host defense, inflammatory/immune responses and tissue repair/regeneration. Moreover, severe thrombocytopenia or sustained thrombocytopenia was closely associated with multiply organ dysfunction and higher mortality in sepsis patients. The clinical therapies for thrombocytopenia are platelet transfusion and platelet-elevating drugs. However, platelet transfusion has many defects in clinical practice in sepsis patients, and the impact of platelet-elevating drugs for sepsis patients is still unclear. RESCUE trial is aim to explore the effect of a platelet-elevating drug, recombinant human thrombopoietin (rhTPO), as an effective rescue therapy on sepsis patients with acute severe thrombocytopenia. METHODS It is a randomized, open-label, multi-center, controlled trial in 5 tertiary academic hospitals including medical, surgical or general ICUs. In this study, a total of 200 sepsis patients with severe thrombocytopenia will be randomly assigned in a 1:1 ratio to the control and rhTPO group. The patients will be followed up to 28 days after randomization. All patients in two groups receive the same treatment based on the guideline of Surviving Sepsis Campaign. Primary outcome is 28-day mortality. Secondary outcomes are the changes of PCs, blood transfusion, biomarkers of infection and organ function, days free from advanced organ support, drug-related adverse events, the length of ICU and hospital stay. DISCUSSION RESCUE trial is the first randomized controlled trial to explore the impact of rhTPO for severe thrombocytopenia in sepsis patients diagnosed by sepsis-3.0 standard. Furthermore, RESCUE trial results will be of significant clinical value on the targeted therapy and add clinical evidence that rhTPO is an effective rescue therapy for these sepsis patients. TRIAL REGISTRATION ClinicalTrials.gov : NCT02707497. Registered Date: March 3rd, 2016. Protocol Version 3. Protocol Date: January 25th, 2019.
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10.
Vasopressin Versus Norepinephrine for the Management of Septic Shock in Cancer Patients: The VANCS II Randomized Clinical Trial
Hajjar LA, Zambolim C, Belletti A, de Almeida JP, Gordon AC, Oliveira G, Park CHL, Fukushima JT, Rizk SI, Szeles TF, et al
Critical care medicine. 2019
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Abstract
OBJECTIVES Previous trials suggest that vasopressin may improve outcomes in patients with vasodilatory shock. The aim of this study was to evaluate whether vasopressin could be superior to norepinephrine to improve outcomes in cancer patients with septic shock. DESIGN Single-center, randomized, double-blind clinical trial, and meta-analysis of randomized trials. SETTING ICU of a tertiary care hospital. PATIENTS Two-hundred fifty patients 18 years old or older with cancer and septic shock. INTERVENTIONS Patients were assigned to either vasopressin or norepinephrine as first-line vasopressor therapy. An updated meta-analysis was also conducted including randomized trials published until October 2018. MEASUREMENTS AND MAIN RESULTS The primary outcome was all-cause mortality at 28 days after randomization. Prespecified secondary outcomes included 90-days all-cause mortality rate; number of days alive and free of advanced organ support at day 28; and Sequential Organ Failure Assessment score 24 hours and 96 hours after randomization. We also measure the prevalence of adverse effects in 28 days. A total of 250 patients were randomized. The primary outcome was observed in 71 patients (56.8%) in the vasopressin group and 66 patients (52.8%) in the norepinephrine group (p = 0.52). There were no significant differences in 90-day mortality (90 patients [72.0%] and 94 patients [75.2%], respectively; p = 0.56), number of days alive and free of advanced organ support, adverse events, or Sequential Organ Failure Assessment score. CONCLUSIONS In cancer patients with septic shock, vasopressin as first-line vasopressor therapy was not superior to norepinephrine in reducing 28-day mortality rate.