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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).

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 . . .

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 ).

Whether the route of early feeding affects outcomes of patients with severe critical illnesses is controversial. We hypothesised that outcomes were better with early first-line enteral nutrition than with early first-line parenteral nutrition. In this randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2 trial) done at 44 French intensive-care units (ICUs), adults (18 years or older) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned (1:1) to either parenteral nutrition or enteral nutrition, both targeting normocaloric goals (20–25 kcal/kg per day), within 24 h after intubation. Randomisation was stratified by centre using permutation blocks of variable sizes. Given that route of nutrition cannot be masked, blinding of the physicians and nurses was not feasible. Patients receiving parenteral nutrition could be switched to enteral nutrition after at least 72 h in the event of shock resolution (no vasopressor support for 24 consecutive hours and arterial lactate <2 mmol/L). The primary endpoint was mortality on day 28 after randomisation in the intention-to-treat-population. This study is registered with ClinicalTrials.gov, number NCT01802099. After the second interim analysis, the independent Data Safety and Monitoring Board deemed that completing patient enrolment was unlikely to significantly change the results of the trial and recommended stopping patient recruitment. Between March 22, 2013, and June 30, 2015, 2410 patients were enrolled and randomly assigned; 1202 to the enteral group and 1208 to the parenteral group. By day 28, 443 (37%) of 1202 patients in the enteral group and 422 (35%) of 1208 patients in the parenteral group had died (absolute difference estimate 2·0%; [95% CI −1·9 to 5·8]; p=0·33). Cumulative incidence of patients with ICU-acquired infections did not differ between the enteral group (173 [14%]) and the parenteral group (194 [16%]; hazard ratio [HR] 0·89 [95% CI 0·72–1·09]; p=0·25). Compared with the parenteral group, the enteral group had higher cumulative incidences of patients with vomiting (406 [34%] vs 246 [20%]; HR 1·89 [1·62–2·20]; p<0·0001), diarrhoea (432 [36%] vs 393 [33%]; 1·20 [1·05–1·37]; p=0·009), bowel ischaemia (19 [2%] vs five [<1%]; 3·84 [1·43–10·3]; p=0·007), and acute colonic pseudo-obstruction (11 [1%] vs three [<1%]; 3·7 [1·03–13·2; p=0·04). In critically ill adults with shock, early isocaloric enteral nutrition did not reduce mortality or the risk of secondary infections but was associated with a greater risk of digestive complications compared with early isocaloric parenteral nutrition. La Roche-sur-Yon Departmental Hospital and French Ministry of Health.

The management of sepsis has substantially improved over the past 15 years. In this study, early, goal-directed therapy, which focuses on the initial resuscitation efforts, was compared with usual care for the management of severe sepsis in the United Kingdom. The incidence of severe sepsis and septic shock in adults is estimated to range from 56 to 91 per 100,000 population per year. 1 Affected patients have high rates of death, complications, and resource utilization. 2 – 5 Since 2002, the Surviving Sepsis Campaign (SSC) has promoted best practice, including early recognition, source control, appropriate and timely antibiotic administration, and resuscitation with intravenous fluids and vasoactive drugs. 6 – 8 Resuscitation guidance is largely based on a 2001 single-center, proof-of-concept study by Rivers et al., which indicated that protocolized delivery of 6 hours of early, goal-directed therapy (EGDT) to patients presenting to the emergency department . . .

Vasoplegia is a ubiquitous phenomenon in all advanced shock states, including septic, cardiogenic, hemorrhagic, and anaphylactic shock. Its pathophysiology is complex, involving various mechanisms in vascular smooth muscle cells such as G protein-coupled receptor desensitization (adrenoceptors, vasopressin 1 receptors, angiotensin type 1 receptors), alteration of second messenger pathways, critical illness-related corticosteroid insufficiency, and increased production of nitric oxide. This review, based on a critical appraisal of the literature, discusses the main current treatments and future approaches. Our improved understanding of these mechanisms is progressively changing our therapeutic approach to vasoplegia from a standardized to a personalized multimodal treatment with the prescription of several vasopressors. While norepinephrine is confirmed as first line therapy for the treatment of vasoplegia, the latest Surviving Sepsis Campaign guidelines also consider that the best therapeutic management of vascular hyporesponsiveness to vasopressors could be a combination of multiple vasopressors, including norepinephrine and early prescription of vasopressin. This new approach is seemingly justified by the need to limit adrenoceptor desensitization as well as sympathetic overactivation given its subsequent deleterious impacts on hemodynamics and inflammation. Finally, based on new pathophysiological data, two potential drugs, selepressin and angiotensin II, are currently being evaluated.

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.