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This trial comparing treatment strategies that emphasized the use of vasopressors or intravenous fluids for early treatment of sepsis-induced hypotension showed no difference in 90-day mortality before discharge home.

Patients with vasodilatory shock were randomly assigned to angiotensin II or placebo. At 3 hours, more patients in the angiotensin II group than in the placebo group had an increase in mean arterial pressure of at least 10 mm Hg or to at least 75 mm Hg.

In a phase 3 randomized trial, 199 patients with type 1 hepatorenal syndrome were assigned to receive the vasoconstrictor terlipressin plus albumin and 101 to receive placebo plus albumin. Renal function was better with terlipressin than with placebo; however, mortality was not lower, and terlipressin was associated with adverse events, including respiratory failure.

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 with sepsis with hypotension increases shock control by 6 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 ≥65 mm Hg, with urine flow ≥0.5 ml/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 the early norepinephrine group (93 vs. 192 min; P < 0.001). Shock control rate by 6 hours was significantly higher in the early norepinephrine group (118/155 [76.1%] vs. 75/155 [48.4%]; P < 0.001). The 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 registered with www.clinicaltrials.gov (NCT01945983) (CENSER trial).

Vasopressors and fluids are the cornerstones for the treatment of shock. The current international guidelines on shock recommend norepinephrine as the first-line vasopressor and vasopressin as the second-line vasopressor. In clinical practice, due to drug availability, local practice variations, special settings, and ongoing research, several alternative vasoconstrictors and adjuncts are used in the absence of precise equivalent doses. Norepinephrine equivalence (NEE) is frequently used in clinical trials to overcome this heterogeneity and describe vasopressor support in a standardized manner. NEE quantifies the total amount of vasopressors, considering the potency of each such agent, which typically includes catecholamines, derivatives, and vasopressin. Intensive care studies use NEE as an eligibility criterion and also an outcome measure. On the other hand, NEE has several pitfalls which clinicians should know, important the lack of conversion of novel vasopressors such as angiotensin II and also adjuncts such as methylene blue, including a lack of high-quality data to support the equation and validate its predictive performance in all types of critical care practice. This review describes the history of NEE and suggests an updated formula incorporating novel vasopressors and adjuncts.

In this comparative-effectiveness trial, there was no significant difference in the overall survival rate between patients with shock who were treated with dopamine and those who were treated with norepinephrine. However, dopamine was associated with more cardiac arrhythmias and with a higher mortality rate among patients with cardiogenic shock. This comparative-effectiveness trial found no significant difference in overall survival in patients with shock treated with dopamine or with norepinephrine. However, dopamine was associated with more cardiac arrhythmias and a higher mortality rate in those with cardiogenic shock. Circulatory shock is a life-threatening condition that is associated with high mortality. 1 , 2 The administration of fluids, which is the first-line therapeutic strategy, is often insufficient to stabilize the patient's condition, and adrenergic agents are frequently required to correct hypotension. Among these agents, dopamine and norepinephrine are used most frequently. 3 Both of these agents influence alpha-adrenergic and beta-adrenergic receptors, but to different degrees. Alpha-adrenergic effects increase vascular tone but may decrease cardiac output and regional blood flow, especially in cutaneous, splanchnic, and renal beds. Beta-adrenergic effects help to maintain blood flow through inotropic and chronotropic effects and to increase splanchnic . . .

The main mechanism of hypotension in septic shock is persistent vasodilation secondary to vascular hyporeactivity despite high endogenous catecholamine levels and despite endogenous activation of the renin-angiotensin-aldosterone system. The classic stepwise approach involves initiation of norepinephrine, up-titration of the dosage to achieve a specified mean arterial pressure and moving to a second-line vasopressor if the patient remains refractory to norepinephrine. This approach often leads to prolonged states of hypoperfusion and high dose catecholamine exposure and is associated with poor clinical outcomes. Given the multifactorial basis of vasodilation in septic shock there is a strong physiological rationale for the early introduction of a multimodal vasopressor strategy that would provide a more physiologically guided approach. This study will compare the effects of a classic stepwise vs. an early balanced multimodal vasopressor strategy in septic shock. This is a single blind randomized Phase II study. Patients with septic shock will be randomly assigned to control (classic stepwise vasopressor administration, n = 40) versus interventional (balanced multimodal vasopressor administration, n = 40) groups. The study employs a superiority trial design. Patients in the control group will be started on norepinephrine followed by vasopressin. Additional vasoactive drugs will be added as per the clinical team's decision. In the interventional group, patients will simultaneously receive norepinephrine, angiotensin II and vasopressin at equipotent starting doses. We hypothesize that balanced multimodal vasopressor administration will result in a significant decrease in renin levels compared to the conventional stepwise strategy. Several secondary and exploratory outcome measures will be investigated. Univariate statistical tests with generalized linear modeling will be used to test for significant differences between the groups. The goal of this randomized controlled trial is to test the clinical efficacy of an early multimodal vasopressor strategy in septic shock. It aims to provide new insights and contribute to improved management of vasodilatory states. ClinicalTrials.gov NCT06155812.

Background Critically ill patients with shock receiving vasopressor or inotrope therapy in ICU are often exposed to relative hypotension, which is quantified as percentage blood pressure deficit relative to usual pre-illness blood pressure. Whether minimising such blood pressure deficit, by adjusting blood pressure targets according to patients’ pre-illness blood pressure (individualised blood pressure target strategy), can improve clinical outcomes remains unclear. Therefore, we are conducting a multicenter randomised controlled trial, the REACT SHOCK RCT, comparing individualised blood pressure targets to standard care among critically ill patients with shock. Methods The REACT SHOCK RCT is an international, multicenter, parallel-group, randomised, standard-care controlled, clinical superiority trial that will be conducted in up to 35 ICUs in Australia, Ireland, Singapore, UK and USA. In total, 1260 patients, receiving vasopressor therapy for non-haemorrhagic shock in ICU, will be randomly assigned to individualised mean arterial blood pressure (MAP) targets (determined as an average of 2–5 recent pre-illness blood pressure readings within last 3 years, with a MAP target range of 55 to 95 mmHg) or standard care (default MAP target of 65 mmHg) in a 1:1 ratio. The REACT SHOCK RCT is anticipated to complete recruitment by 2028. The primary endpoint is all-cause 14-day mortality. Secondary endpoints are major adverse kidney events by day 14, all-cause 90-day mortality, survival time to 14 days and 90 days, and renal replacement therapy free days by day 28. Discussion The REACT SHOCK RCT is the first international multicenter randomised clinical trial designed to ascertain whether an individualised blood pressure target strategy is superior to standard care for critically ill patients with shock. This trial will generate evidence that may influence current recommendations for MAP targets during management of shock in ICU. The pre-specified protocol summary and statistical analysis plan are presented here. Trial registration Prospectively registered on Australian and New Zealand Clinical Trials Registry (ANZCTRN 12623000044628); ClinicalTrials.gov ID NCT05850962 dated 29th April 2023.

INTRODUCTION:This trial was to shorten the duration of both vasoconstrictors and prophylactic antibiotics to only 2 days in the therapy of acute gastroesophageal variceal hemorrhage.METHODS:After successful endoscopic hemostasis of gastroesophageal variceal hemorrhage, eligible patients were randomized to receive terlipressin infusion 1 mg per 6 hours and ceftriaxone 1 g daily for 5 days (group A) or a similar regimen for 2 days (group B). Primary end points were very early rebleeding at 5 days, and secondary end points included 48-hour hemostasis, 42-day rebleeding, and hospitalization days.RESULTS:Group A comprised 48 patients, and group B comprised 52 patients. Both groups were comparable in the severity of liver disease. Forty-eight-hour initial hemostasis was 95.8% in group A and 100% in group B (P = 0.13). Very early rebleeding between 3 and 5 days occurred in 1 patient (2.1%) in group A and 2 patients (3.8%) in group B (P = 0.60). The difference was 1.8% and the 95% confidence interval was −1.31% to 2.08%, which demonstrated noninferiority. Forty-two-day rebleeding occurred in 5 patients (10.4%) in group A and 4 patients (7.7%) in group B (P = 0.63). The median hospitalization days were 8.5 ± 3.8 days in group A vs 5.6 ± 2.6 days in group B (P < 0.001).DISCUSSION:After successful endoscopic hemostasis of acute variceal bleeding, combination of 2-day terlipressin infusion and ceftriaxone therapy was not inferior to the 5-day regimen in terms of very early rebleeding, with the advantage of shortening hospitalization stay.

Background Septic shock is associated with decreased vasopressor responsiveness. Experimental data suggest that central alpha2-agonists like dexmedetomidine (DEX) increase vasopressor responsiveness and reduce catecholamine requirements in septic shock. However, DEX may also cause hypotension and bradycardia. Thus, it remains unclear whether DEX is hemodynamically safe or helpful in this setting. Methods In this post hoc subgroup analysis of the Sedation Practice in Intensive Care Evaluation (SPICE III) trial, an international randomized trial comparing early sedation with dexmedetomidine to usual care in critically patients receiving mechanical ventilation, we studied patients with septic shock admitted to two tertiary ICUs in Australia and Switzerland. The primary outcome was vasopressor requirements in the first 48 h after randomization, expressed as noradrenaline equivalent dose (NEq [μg/kg/min] = noradrenaline + adrenaline + vasopressin/0.4). Results Between November 2013 and February 2018, 417 patients were recruited into the SPICE III trial at both sites. Eighty-three patients with septic shock were included in this subgroup analysis. Of these, 44 (53%) received DEX and 39 (47%) usual care. Vasopressor requirements in the first 48 h were similar between the two groups. Median NEq dose was 0.03 [0.01, 0.07] μg/kg/min in the DEX group and 0.04 [0.01, 0.16] μg/kg/min in the usual care group ( p  = 0.17). However, patients in the DEX group had a lower NEq/MAP ratio, indicating lower vasopressor requirements to maintain the target MAP. Moreover, on adjusted multivariable analysis, higher dexmedetomidine dose was associated with a lower NEq/MAP ratio. Conclusions In critically ill patients with septic shock, patients in the DEX group received similar vasopressor doses in the first 48 h compared to the usual care group. On multivariable adjusted analysis, dexmedetomidine appeared to be associated with lower vasopressor requirements to maintain the target MAP. Trial registration The SPICE III trial was registered at ClinicalTrials.gov ( NCT01728558 ).