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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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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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Methylene blue versus vasopressin analog for refractory septic shock in the preterm neonate: A randomized controlled trial
Ismail R, Awad H, Allam R, Youssef O, Ibrahim M, Shehata B
Journal of neonatal-perinatal medicine. 2021
Abstract
BACKGROUND Refractory septic shock in neonates is still associated with high mortality, necessitating an alternative therapy, despite all currently available treatments. This study aims to assess the vasopressor effect of methylene blue (MB) in comparison to terlipressin (TP) as adjuvant therapy for refractory septic shock in the preterm neonate. METHODS A double-blinded randomized controlled trial was conducted in the Neonatal Intensive Care Units at Ain Shams University, Egypt. Thirty preterm neonates with refractory septic shock were randomized to receive either MB or TP as an adjuvant to conventional therapy. Both MB and TP were administered as an intravenous loading dose followed by continuous intravenous infusion. The hemodynamic variables, functional echocardiographic variables, and oxidant stress marker were assessed over a 24 h period together with the side effects of MB. RESULTS MB causes significant improvement in mean arterial blood pressure with a significant decrease of the norepinephrine requirements (1.15±0.21μm/kg/min at baseline vs. 0.55±0.15μm/kg/min at 24 h). MB infusion causes an increase of the pulmonary pressure (44.73±8.53 mmHg at baseline vs. 47.27±7.91 mmHg after 24 h) without affecting the cardiac output. Serum malonaldehyde decreased from 5.45±1.30 nmol/mL at baseline to 4.40±0.90 nmol/mL at 24 h in the MB group. CONCLUSION Administration of MB to preterm infants with refractory septic shock showed rapid increases in systemic vascular resistance and arterial blood pressure with minimal side effects.
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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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5.
[Effect of terlipressin on prognosis of adult septic shock patients: a Meta-analysis]
Li W, Pan P, Wang Y, Du X, Yu X
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020;32(2):134-139
Abstract
OBJECTIVE To investigate the effect of terlipressin on prognosis of adult septic shock patients. METHODS All randomized controlled clinical trials (RCT) of terlipressin in the treatment of adult septic shock patients from January 1980 to December 2019 were retrieved from CNKI, Wanfang, SinoMed, PubMed, Embase, Springer Link, Cochrane Library, Google Scholar, and etc. Patients in the treatment group received terlipressin while patients in the control group received norepinephrine or other vasopressors. Main outcome indicator was mortality. Secondary outcome indicators included the incidence of severe adverse events, limb peripheral ischemic events and renal complications. Literature screening, data extraction and quality evaluation were conducted by two researchers respectively. Meta-analysis was performed with RevMan 5.3 software. Funnel plot was used to analyze the publication bias. RESULTS A total of 507 related literatures were retrieved. According to the inclusion and exclusion criteria, 8 RCT studies were finally included, with a total of 811 patients. One study was considered to have a lower risk of bias, 6 studies had uncertain risk of bias, and 1 study had a higher risk of bias. The Meta-analysis showed that terlipressin did not significantly improve the mortality of septic shock patients compared with the control group [odds ratio (OR) = 0.89, 95% confidence interval (95%CI) was 0.67-1.19, P = 0.45]; increased the incidence of severe adverse events (OR = 2.98, 95%CI was 1.99-4.45, P < 0.000 01); there was a tendency to increase the incidence of limb peripheral ischemic events, but without statistical difference (OR = 10.81, 95%CI was 0.88-133.19, P = 0.06); and reduced the incidence of renal complications (OR = 0.30, 95%CI was 0.09-0.96, P = 0.04). Funnel plot analysis indicated that there might be publication bias in a study on case fatality and incidence of serious adverse events in the included literature. No significant publication bias was found in studies on the incidence of limb peripheral ischemic events and the incidence of kidney-related complications. CONCLUSIONS The available evidence suggests that terlipressin could not significantly improve mortality in adult's septic shock patients, but it may reduce the incidence of renal complications. A tendency to increase the incidence of limb peripheral ischemic events in the terlipressin-treated group needs to be emphasized.
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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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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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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.
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Effects of the discontinuation sequence of norepinephrine and vasopressin on hypotension incidence in patients with septic shock: A meta-analysis
Duclos G, Baumstarck K, Dunser M, Zieleskiewicz L, Leone M
Heart & lung : the journal of critical care. 2019
Abstract
BACKGROUND Although the order of vasopressor initiation in patients with septic shock is established, limited information is available on the order of vasopressor discontinuation. METHODS We performed a meta-analysis of nine studies involving 1245 patients in whom norepinephrine (n=787) or vasopressin (n=458) was withdrawn first to compare the risk of hypotension. RESULTS The risk of hypotension increased in patients whom vasopressin was withdrawn first (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.3-8.9; p=0.01). A sensitivity analysis indicated that this effect was observed in four studies with a high risk of bias (OR, 5.4; 95%CI, 1.3-23.5; p=0.02) and was not observed in five studies with a low risk of bias (OR, 2.4; 95%CI, 0.6-8.4; p=0.18). CONCLUSION Our results suggest that the risk of hypotension is higher in patients with septic shock in whom vasopressin is withdrawn before norepinephrine.
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Effects of norepinephrine and vasopressin discontinuation order in the recovery phase of septic shock: a systematic review and individual patient data meta-analysis
Hammond DA, Sacha GL, Bissell BD, Musallam N, Altshuler D, Flannery AH, Lam SW, Bauer SR
Pharmacotherapy. 2019
Abstract
OBJECTIVE The impact of vasopressin and norepinephrine discontinuation order in the recovery phase of septic shock remains controversial. This systematic review and patient-level meta-analysis was performed to determine the impact of vasopressin and norepinephrine discontinuation order on clinically significant outcomes in the recovery phase of septic shock. METHODS Cumulative Index to Nursing and Allied Health Literature, Embase, PubMed, and Clinicaltrials. gov were searched from inception through November 2018 for studies comparing outcomes after the discontinuation of vasopressin or norepinephrine in septic shock. Individual patient-level data were obtained from included studies and combined using a 2-stage meta-analysis. RESULTS Six studies of low or moderate risk of bias with 957 patients were included. Clinically significant hypotension occurred more frequently when vasopressin was discontinued first compared to norepinephrine (60.7% vs. 43.3%, respectively). First discontinuation of norepinephrine compared to vasopressin had lower pooled odds of developing clinically significant hypotension (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.07-0.68, I(2) 87%). No differences were detected in short-term mortality (OR 1.12, 95% CI 0.67-1.86, I(2) 45%), intensive care unit length of stay (mean difference 0.15 day, 95% CI -1.58 to 1.88, I(2) 21%), or hospital length of stay (mean difference 1.65 days, 95% CI -0.47 to 3.76, I(2) 0%). CONCLUSIONS Discontinuation of norepinephrine prior to vasopressin during the recovery phase of septic shock resulted in less clinically significant hypotension but no difference in mortality or lengths of stay. Larger, prospective studies evaluating the impact of relative vasopressin deficiency and norepinephrine and vasopressin discontinuation order and timing on patient-centered outcomes are needed. This article is protected by copyright. All rights reserved.