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1.
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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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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4.
[The role of recombinant human thrombopoietin in critically ill patients with sepsis-associated thrombocytopenia: a clinical study]
Dong, F., Ma, N., Chang, S., Yang, H., Gao, M., Liu, Q., Sun, X., Liang, M., Sun, R.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020;32(12):1445-1449
Abstract
OBJECTIVE To investigate the effect of recombinant human thrombogenin (rhTPO) on sepsis-associated thrombocytopenia. METHODS A prospective randomized controlled study was conducted. One hundred patients with sepsis-associated thrombocytopenia admitted to the department of critical care medicine of the First Affiliated Hospital of Zhengzhou University from August 2019 to October 2020 were enrolled. The enrolled patients were divided into rhTPO-using group (TPO group) and routine group (control group) by random number table method, with 50 cases in each group. Both groups were treated according to the guideline of Sepsis-3. In addition, TPO group received rhTPO 15 000 U, once daily for 7 days. Geneal information and acute physiology and chronic health evaluation II (APACHE II) were recorded. The levels of platelet count (PLT), blood coagulation function [prothrombin time (PT) and prothrombin activity (PTA)], myocardial enzyme indexes [troponin (Tn) and creatine kinase (CK)], liver and kidney function [aspartate aminotransferase (AST), total bilirubin (TBil) and creatinine (Cr)] and inflammatory biomarkers [procalcitonin (PCT) and C-reactive protein (CRP)] were recorded before treatment and 1, 3, 5 and 7 days after treatment. The infusion volume of blood components, duration of mechanical ventilation, length of stay in ICU, total length of hospitalization, total cost of hospitalization and 28-day outcome were recorded. According to whether the PLT was lower than 50×10(9)/L, the patients in TPO group were divided into the TPO A group (PLT ≥ 50×10(9)/L, 16 cases) and TPO B group (PLT < 50×10(9)/L, 34 cases), and the absolute value of PLT increase, duration of mechanical ventilation, length of stay in ICU, total length of hospitalization, total cost of hospitalization and 28-day outcome of the two groups were compared. RESULTS (1) In TPO and control groups, there were no statistically significant differences in gender, age, proportion of patients with primary infection site, APACHEII score, PLT, coagulation function, myocardial enzymes, liver and kidney function and inflammation indexes before treatment (all P > 0.05). (2) The PLT levels of the TPO group were significantly higher than those of the control group on the 5th and 7th day after treatment (×10(9)/L: day 5, 63.94±44.01 vs. 49.85±29.26, day 7, 125.85±112.31 vs. 76.81±50.87, both P < 0.05), and there were no statistically significant differences in PT, PTA, Tn, CK, AST, TBil, Cr, PCT or CRP before and on the 1, 3, 5, 7 days after treatment between TPO and control groups (all P > 0.05). (3) The amount of platelet transfusion in the TPO group was lower than that in the control group [treatment amount: 0 (0, 0) vs 0 (0, 2.00), P = 0.001]. (4) There were no statistically significant differences in mechanical ventilation time, length of stay in ICU, total length of hospitalization, total cost of hospitalization or 28-day outcome between TPO and control groups (all P > 0.05). The mechanical ventilation time, ICU stay time and total hospitalization time of TPO A group were longer than those in TPO B group, but the differences were not statistically significant [mechanical ventilation time (hours): 131.00 (0, 311.00) vs. 50.00 (0, 192.00), ICU stay time (days): 14.44±8.57 vs. 11.73±9.24, total hospitalization time (days): 15.00 (6.00, 23.50) vs. 18.00 (8.00, 31.00), all P > 0.05]. The absolute value of PLT increase in TPO A group was higher than that of TPO B group, but the difference was not statistically significant [×10(9)/L: 65.00 (16.50, 131.50) vs. 36.00 (18.00, 130.00), P > 0.05]. CONCLUSIONS RhTPO can significantly increase the PLT of patients with sepsis-related thrombocytopenia, thereby reduce the amount of platelet transfusion, but it cannot shorten the length of ICU stay time and total hospitalization time, and it cannot reduce 28-day mortality.
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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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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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Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial
Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S
American journal of respiratory and critical care medicine. 2019
Abstract
RATIONALE Recent retrospective evidence suggests the efficacy of early norepinephrine administration during resuscitation; however, prospective data to support this assertion are scarce. OBJECTIVES To conduct a Phase II trial evaluating the hypothesis that early low-dose norepinephrine in adults sepsis with hypotension increases shock control by six hours compared with standard care. METHODS This single-center, randomized, double-blind, placebo-controlled clinical trial was conducted at Siriraj Hospital, Bangkok, Thailand. The study enrolled 310 adults diagnosed with sepsis with hypotension. The patients were randomly divided into two groups: early norepinephrine (n=155) and standard treatment (n=155). The primary outcome was shock control rate (defined as achievement of mean arterial blood pressure >65mmHg, with urine flow >0.5mL/kg/h for 2 consecutive hours, or decreased serum lactate >10% from baseline) by 6 hours after diagnosis. MEASUREMENTS AND MAIN RESULTS The patients in both groups were well matched in background characteristics and disease severity. Median time from emergency room arrival to norepinephrine administration was significantly shorter in early norepinephrine group (93 vs.192min;P<0.001). Shock control rate by 6 hours was significantly higher in early norepinephrine group (118/155[76.1%] vs.75/155[48.4%];P<0.001). 28 day mortality was not different between groups: 24/155(15.5%) in the early norepinephrine group versus 34/155(21.9%) in the standard treatment group (P=0.15). The early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (22/155[14.4%] vs. 43/155[27.7%]; P=0.004) and new-onset arrhythmia (17/155[11%] vs. 31/155[20%]; P=0.03). CONCLUSIONS Early norepinephrine was significantly associated with increased shock control by 6 hours. Further studies are needed before this approach is introduced in clinical resuscitation practice. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01945983.
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Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial
Macdonald SPJ, Keijzers G, Taylor DM, Kinnear F, Arendts G, Fatovich DM, Bellomo R, McCutcheon D, Fraser JF, Ascencio-Lane JC, et al
Intensive Care Medicine. 2018;44((12):):2070-2078.
Abstract
PURPOSE To determine if a regimen of restricted fluids and early vasopressor compared to usual care is feasible for initial resuscitation of hypotension due to suspected sepsis. METHODS A prospective, randomised, open-label, clinical trial of a restricted fluid resuscitation regimen in the first 6 h among patients in the emergency department (ED) with suspected sepsis and a systolic blood pressure under 100 mmHg, after minimum 1000 ml of IV fluid. Primary outcome was total fluid administered within 6 h post randomisation. RESULTS There were 99 participants (50 restricted volume and 49 usual care) in the intention-to-treat analysis. Median volume from presentation to 6 h in the restricted volume group was 2387 ml [first to third quartile (Q1-Q3) 1750-2750 ml]; 30 ml/kg (Q1-Q3 32-39 ml/kg) vs. 3000 ml (Q1-Q3 2250-3900 ml); 43 ml/kg (Q1-Q3 35-50 ml/kg) in the usual care group (p < 0.001). Median duration of vasopressor support was 21 h (Q1-Q3 9-42 h) vs. 33 h (Q1-Q3 15-50 h), (p = 0.13) in the restricted volume and usual care groups, respectively. At 90-days, 4 of 48 (8%) in the restricted volume group and 3 of 47 (6%) in the usual care group had died. Protocol deviations occurred in 6/50 (12%) in restricted group and 11/49 (22%) in the usual care group, and serious adverse events in four cases (8%) in each group. CONCLUSIONS A regimen of restricted fluids and early vasopressor in ED patients with suspected sepsis and hypotension appears feasible. Illness severity was moderate and mortality rates low. A future trial is necessary with recruitment of high-risk patients to determine effects on clinical outcomes in this setting.
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Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicentre, randomised, double-blinded trial
Liu ZM, Chen J, Kou Q, Lin Q, Huang X, Tang Z, Kang Y, Li K, Zhou L, Song Q, et al
Intensive Care Medicine. 2018;44((11):):1816-1825
Abstract
PURPOSE Recent clinical data suggest that terlipressin, a vasopressin analogue, may be more beneficial in septic shock patients than catecholamines. However, terlipressin's effect on mortality is unknown. We set out to ascertain the efficacy and safety of continuous terlipressin infusion compared with norepinephrine (NE) in patients with septic shock. METHODS In this multicentre, randomised, double-blinded trial, patients with septic shock recruited from 21 intensive care units in 11 provinces of China were randomised (1:1) to receive either terlipressin (20-160 microg/h with maximum infusion rate of 4 mg/day) or NE (4-30 microg/min) before open-label vasopressors. The primary endpoint was mortality 28 days after the start of infusion. Primary efficacy endpoint analysis and safety analysis were performed on the data from a modified intention-to-treat population. RESULTS Between 1 January 2013 and 28 February 2016, 617 patients were randomised (312 to the terlipressin group, 305 to the NE group). The modified intention-to-treat population comprised 526 (85.3%) patients (260 in the terlipressin group and 266 in the NE group). There was no significant difference in 28-day mortality rate between the terlipressin group (40%) and the NE group (38%) (odds ratio 0.93 [95% CI 0.55-1.56]; p = 0.80). Change in SOFA score on day 7 was similar between the two groups: - 7 (IQR - 11 to 3) in the terlipressin group and - 6 (IQR - 10 to 5) in the NE group. There was no difference between the groups in the number of days alive and free of vasopressors. Overall, serious adverse events were more common in the terlipressin group than in the NE group (30% vs 12%; p < 0.001). CONCLUSIONS In this multicentre, randomised, double-blinded trial, we observed no difference in mortality between terlipressin and NE infusion in patients with septic shock. Patients in the terlipressin group had a higher number of serious adverse events. TRIAL REGISTRATION This trial is registered at ClinicalTrials.gov: ID NCT01697410.
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Vasopressin in septic shock; assessment of sepsis biomarkers: a randomized, controlled trial
Barzegar E, Nouri M, Mousavi S, Ahmadi A, Mojtahedzadeh M
Indian Journal of Critical Care Medicine : Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine. 2017;21((9)):578-584.
Abstract
BACKGROUND AND AIMS Vasopressin (VP) in sepsis apart from vasoconstrictive effect may have some immunomodulatory effects. The aim of this study was to evaluate the effect of VP on different aspect of sepsis by measuring of sepsis biomarkers. MATERIALS AND METHODS In this trial, a total number of 42 septic shock patients were included. The first group received norepinephrine (NE) infusion to reach the target mean arterial pressure (MAP) of ≥ 65 mm Hg and the second group received arginine vasopressin (AVP) infusion in addition to NE. Serum lactate, C-reactive protein (CRP), interleukin-6 (IL-6), IL-10, pentraxin 3 (PTX3), angiopoietin 1 and 2 (Ang 1 and 2) levels were assessed. RESULTS Level of IL-6 and IL-10 decreased, but there was no significant difference between the two groups after 48 h. CRP and PTX3 levels were not also significantly different between groups. Although Angs were not statistically different, there was a trend toward higher Ang-1 in and lower Ang 2 in AVP group after 24 and 48 h. In addition, lactate level did not differ between NE and AVP groups. There was no interaction between VP and hydrocortisone use on IL-6, IL-10, and PTX3, but a significant statistical interaction on Ang 1 and Ang 2 were observed. CONCLUSIONS Although analysis of sepsis biomarkers showed no significant difference between two groups, no immunomodulatory effect for VP alone, subgroup analysis of hydrocortisone used in this study showed that the combination of glucocorticoids and AVP had a significant effect on Angs level which eventually causes less endothelial permeability and higher MAP in this group of patients.