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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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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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Sepsis-related anemia in a pediatric intensive care unit: transfusion-associated outcomes
Elshinawy M, Kamal M, Nazir H, Khater D, Hassan R, Elkinany H, Wali Y
Transfusion. 2020;60 Suppl 1:S4-s9
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Editor's Choice
Abstract
BACKGROUND Pediatric patients with sepsis in intensive care units are at high risk of developing anemia, which might have adverse effects on their prognosis. This study aimed to evaluate the impact of red blood cell (RBC) transfusion on the outcomes of patients admitted to a pediatric intensive care unit (PICU) with sepsis. METHODS We conducted a prospective randomized clinical trial, enrolling 67 children, aged 2 to 144 months who were admitted to a PICU with a new episode of sepsis from November 2017 to April 2018. Patients were allocated randomly to two groups: Group 1, liberal transfusion strategy group, including 33 patients who had initial hemoglobin (Hb) between 7 or greater and less than 10 g/dL and received an RBC top-up transfusion to 12 g/dL; and Group 2, restrictive strategy group, including 34 patients who had the same Hb range and did not receive RBCs. Patients with Hb less than 7 or greater than 10 g/dL were excluded. RESULTS Of 33 patients who received liberal transfusions, 31 (93.94%) required ventilation, and 29 (87.88%) had multiorgan dysfunction. They had a significantly lengthier hospital stay and a higher incidence of acute respiratory distress syndrome and acute lung injury. Moreover, mortality was significantly higher in the liberal transfusion group (42.4% vs. 17.6%). CONCLUSIONS Compared to the restrictive transfusion strategy, liberal transfusion might be associated with a worse outcome. However, the possible role of other known and unknown confounding factors and minor protocol violations should be taken into consideration. We recommend minimizing factors worsening anemia in PICU patients to reduce the need for transfusion.
PICO Summary
Population
Children admitted to a pediatric intensive care unit (PICU) with new episode of sepsis (n= 67).
Intervention
Liberal transfusion strategy group, (Group 1) received an red blood cell (RBC) top-up transfusion to 12 g/dL (n=33).
Comparison
Restrictive strategy group, (Group 2) did not receive RBCs. (n= 34).
Outcome
Of 33 patients who received liberal transfusions, 31 (93.94%) required ventilation, and 29 (87.88%) had multiorgan dysfunction. They had a significantly lengthier hospital stay and a higher incidence of acute respiratory distress syndrome and acute lung injury. Moreover, mortality was significantly higher in the liberal transfusion group (42.4% vs. 17.6%).
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Outcome of Early Hemostatic Intervention in Children With Sepsis and Nonovert Disseminated Intravascular Coagulation Admitted to PICU: A Randomized Controlled Trial
El-Nawawy AA, Elshinawy MI, Khater DM, Moustafa AA, Hassanein NM, Wali YA, Nazir HF
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2020
Abstract
Critically ill children with sepsis may develop catastrophic thrombotic and hemorrhagic syndrome of disseminated intravascular coagulopathy as a final common pathway. OBJECTIVES Evaluation of the outcome of early hemostatic management of disseminated intravascular coagulopathy in patients with severe sepsis/septic shock admitted to PICU, before the development of clinically overt disseminated intravascular coagulopathy. DESIGN Prospective interventional, open label randomized controlled clinical trial. SETTING PICU at Alexandria University Children's Hospital. PATIENTS The study included 80 patients with proven severe sepsis/septic shock in nonovert disseminated intravascular coagulopathy stage. They were randomly assigned into two groups (group 1 and group 2). INTERVENTIONS Specific intervention was applied for group 1 (plasma transfusion, low-dose unfractionated heparin, and tranexamic acid). MEASUREMENTS All patients had assessment of Pediatric Index of Mortality 2 score, Pediatric Logistic Organ Dysfunction score, inotropic score, routine laboratory, and hemostatic tests including fibrin degradation products and D-dimers. Disseminated intravascular coagulopathy risk assessment scores were calculated on daily basis. RESULTS Mortality rate was significantly higher in group 2. Progression to overt disseminated intravascular coagulopathy was significantly more common among group 2 patients than group 1 (45% and 10%, respectively) (p < 0.0001). Disseminated intravascular coagulopathyRisk Assessment Scores were significantly higher on the second and fifth days among group 2 patients. The initial specific hemostatic intervention was the only significant predictor of survival and prevention of progression to overt disseminated intravascular coagulopathy. CONCLUSIONS Our results suggest that early use of a combination of fresh frozen plasma transfusion, low-dose heparin, and tranexamic acid in children with severe sepsis/septic shock in the "window of opportunity" before the development of overt disseminated intravascular coagulopathy stage was associated with better outcome for survival and prevention of progression to overt disseminated intravascular coagulopathy, with no increase in bleeding risk. Larger multicenter studies are needed to further prove this practice.
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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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Heterogenous treatment effects of transfusion thresholds by patient age: post-hoc analysis of the TRISS trial
Jonsson AB, Granholm A, Rygard SL, Holst LB, Moller MH, Perner A
Acta anaesthesiologica Scandinavica. 2019
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Editor's Choice
Abstract
BACKGROUND Use of a lower haemoglobin (Hb) threshold to guide red blood cell (RBC) transfusion is now generally recommended in critically ill patients, but uncertainty remains regarding the optimal HB-threshold for RBC transfusion in patients of different ages. METHODS We conducted a post-hoc analysis of 998 patients with septic shock and anaemia randomised to RBC transfusion at a Hb-threshold of 7 g/dl [4.3 mmol/l] vs. 9 g/dl [5.6 mmol/l] in the Transfusion Requirements in Septic Shock (TRISS) trial. We assessed if there were heterogeneous effects between the allocated Hb-threshold and patient age categorised and on the continuous scale. The primary outcome was 1-year mortality; the secondary outcome was 90-day mortality. Both outcomes were analysed using logistic regression models and in sensitivity analyses with additional adjusting for site of enrolment, presence of haematological malignancy and the Sequential Organ Failure Assessment (SOFA) score. The secondary analyses were Kaplan-Meier curves with corresponding log-rank tests. RESULTS We found no heterogeneity between patient age and the allocated Hb-thresholds for RBC transfusion for 1-year mortality or 90-day mortality in the primary analyses. The sensitivity analyses suggested heterogeneity between age groups regarding 90-day mortality, however, this was not consistent for 1-year mortality or when assessing age on the continuous scale. CONCLUSION In this post-hoc study of ICU patients with septic shock, we found no reliable heterogeneous effects of transfusion at a Hb-threshold of 7 vs. 9 g/dl according to patient age on mortality. However, due to low power, this study should only be considered as hypothesis-generating.
PICO Summary
Population
Patients with septic shock and anaemia, (n=998) who had not previously been transfused in the intensive care unit (ICU).
Intervention
Lower threshold group: RBC transfusion at a lower Hb-threshold of 7 g/dl [4.3 mmol/l], (n=502).
Comparison
Higher threshold group: RBC transfusion at a higher Hb-threshold of 9 g/dl [5.6 mmol/l], (n=496).
Outcome
No heterogeneity between patient age and the allocated Hb-thresholds for RBC transfusion for 1-year mortality or 90-day mortality in the primary analyses. The sensitivity analyses suggested heterogeneity between age groups regarding 90-day mortality, however, this was not consistent for 1-year mortality or when assessing age on the continuous scale.
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Effects of anemia and blood transfusion on clot formation and platelet function in patients with septic shock: a substudy of the randomized TRISS trial
Russell L, Holst LB, Lange T, Liang X, Ostrowski SR, Perner A
Transfusion. 2018;58((12):):2807-2818.
Abstract
BACKGROUND The effects of anemia and red blood cell (RBC) transfusion on markers of clot formation and platelet function in patients with septic shock are unknown. We assessed these effects in a randomized transfusion trial of patients with septic shock. STUDY DESIGN AND METHODS We performed a prospective substudy of the Transfusion Requirements in Septic Shock (TRISS) trial, randomly assigning patients in the intensive care unit with septic shock and hemoglobin concentration of 9.0 g/dL or less to transfusion with one unit of RBCs at a hemoglobin level of 9.0 g/dL or a level of 7.0 g/dL. We assessed thromboelastography (TEG), multiple electrode aggregometry (MEA), platelet count, and international normalized ratio (INR) immediately before and after the first blood transfusion and again 3 hours after. The effects of hemoglobin level were analyzed using multiple linear regression and the association between markers of hemostasis and subsequent bleeding by Cox regression models. RESULTS We included 58 patients in this substudy. We observed no differences in whole blood clot formation, platelet count or function, or INR between patients with hemoglobin levels of 7.0 and 9.0 g/dL, and we found no effect of RBC transfusion on these markers. Platelet function, assessed by MEA, but not whole blood clot formation, was associated with subsequent bleeding. CONCLUSIONS In patients with septic shock, the level of anemia and the transfusion of RBCs did not appear to influence clot formation or platelet function. Low platelet function, as evaluated by MEA, was associated with increased risk of subsequent bleeding.