Low-dose corticosteroid therapy for cardiogenic shock in adults (COCCA): study protocol for a randomized controlled trial

Background Cardiogenic shock (CS) is a life-threatening condition characterized by circulatory insufficiency caused by an acute dysfunction of the heart pump. The pathophysiological approach to CS has recently been enriched by the tissue consequences of low flow, including inflammation, endothelial dysfunction, and alteration of the hypothalamic-pituitary-adrenal axis. The aim of the present trial is to evaluate the impact of early low-dose corticosteroid therapy on shock reversal in adults with CS. Method/design This is a multicentered randomized, double-blind, placebo-controlled trial with two parallel arms in adult patients with CS recruited from medical, cardiac, and polyvalent intensive care units (ICU) in France. Patients will be randomly allocated into the treatment or control group (1:1 ratio), and we will recruit 380 patients (190 per group). For the treatment group, hydrocortisone (50 mg intravenous bolus every 6 h) and fludrocortisone (50 μg once a day enterally) will be administered for 7 days or until discharge from the ICU. The primary endpoint is catecholamine-free days at day 7. Secondary endpoints include morbidity and all-cause mortality at 28 and 90 days post-randomization. Pre-defined subgroups analyses are planned, including: postcardiotomy, myocardial infarction, etomidate use, vasopressor use, and adrenal profiles according the short corticotropin stimulation test. Each patient will be followed for 90 days. All analyses will be conducted on an intention-to-treat basis. Discussion This trial will provide valuable evidence about the effectiveness of low dose of corticosteroid therapy for CS. If effective, this therapy might improve outcome and become a therapeutic adjunct for patients with CS. Trial registration ClinicalTrials.gov, NCT03773822. Registered on 12 December 2018

Continuous Renal Replacement Therapy Using Membranes with Increased Adsorption Capacity in Patients with Septic Shock after Neurosurgical Interventions

Introduction. The combination of primary brain injury with cytokine storm and hemodynamic disturbance in septic shock leads to secondary brain damage and growing neurological deficit. Blood purification procedures can be considered as an additional option in the treatment of septic shock in this group of patients.Subjects and Methods. The study included 11 patients after neurosurgical interventions with septic shock and acute kidney injury who underwent continuous renal replacement therapy (CRRT) using membranes with increased adsorption capacity.Results. During CRRT there was a significant regression in severity of multiorgan dysfunction according to SOFA score, a decrease in the requirement for vasopressor support with norepinephrine, and a decrease in lactate blood level. In addition, after the end of the procedure, there was a significant decrease in procalcitonin blood level. Septic shock reversal was observed in 8/11 patients (72.7%). In 3/11 patients, neurological deficits regressed during the procedure.Conclusions. The results indicate the possibility of using CRRT with membranes with increased adsorption capacity in patients after neurosurgical interventions with septic shock. Changes in neurological status can be considered as an additional parameter for the effectiveness of therapy for septic shock in patients with primary brain injury.

Observational case series: six neurosurgical patients with septic shock demonstrating clinical improvement after a combination of standard care and blood purification

Background For patients with primary brain injury, septic shock is especially dangerous due to the possibility of secondary cerebral damage. The key factor of sepsis-associated brain injury is inflammatory mediators, pathogen and damage-associated molecular patterns (PAMPs, DAMPs) release. Theoretically, blood purification may be beneficial for patients with primary brain injury due to its possibility for fast removal of inflammatory mediators. Case presentation We report on six post-neurosurgery septic shock patients treated with combined blood purification (CBP), which included CRRT with high adsorption capacity membrane in combination with CytoSorb adsorber. Clinical improvement in the course of CBP was registered in all patients. Three patients had a stable clinical improvement; the other three patients had only a transient improvement due to underlying neurological and cardiac deficits aggravation. We observed septic shock reversal in four patients. The key observations of the case series are a significant decrease in MOF severity (measured by SOFA score) and in catecholamine need (not statistically significant). By the end of CBP we observed a significant decrease in blood lactate, PCT and IL-6 levels. Two patients demonstrated level of consciousness increase in the setting of CBP therapy measured by GCS and FOUR score. Conclusion This case series demonstrates that CBP therapy may have a role for septic shock patients with primary brain injury.

Report On Complete Endpoints and Predictors of Response to Plasma Exchange – Results From a Randomized Controlled Trial in Septic Shock Patients

Background: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy.Methods: In the original RCT patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here we report all clinical and biological endpoints of this study. Subgroup analysis of NE reduction and 28-day mortality was performed to investigate characteristics that could be associated with clinical response.Results: Early hemodynamic stabilization was preserved in the TPE group for 24 hours and was accompanied by a reduction of lactate suggestive for shock reversal. A reduction of injurious mediators (such as PCT, vWF:Ag, Angpt-2, sTie-2) and a repletion of exhausted protective factors (such as AT-III, Protein C, ADAMTS-13) could be observed in the TPE but not in the SOC group. Significant NE reduction (> 50% from baseline) upon TPE occurred more often in patients with 1) a pulmonary focus of infection, 2) profound respiratory failure (pO2/FiO2<150 mmHg), 3) critical hemodynamic instability (NE > 0.6 μg/kg/min and lactate >0.4 mmol/l) as well as 4) substantial degree of organ failure (SOFA Score > 16) at randomization. Patients with a pulmonary focus of infection had a 28-day mortality of 15% in the TPE group while it was 42% in the SOC group. Conclusions: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. It is We identified potential response predictors (lung focus, PF ratio < 150, higher SOFA score etc.) that might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration: Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994), https://clinicaltrials.gov/ct2/show/NCT04231994?term=NCT04231994&draw=2&rank=1

The order of vasopressor discontinuation and incidence of hypotension: a retrospective cohort analysis

The optimal order of vasopressor discontinuation during shock resolution remains unclear. We evaluated the incidence of hypotension in patients receiving concomitant vasopressin (VP) and norepinephrine (NE) based on the order of their discontinuation. In this retrospective cohort study, consecutive patients receiving concomitant VP and NE infusions for shock admitted to intensive care units were evaluated. The primary outcome was hypotension incidence following discontinuation of VP or NE (VP1 and NE1 groups, respectively). Secondary outcomes included the incidence of acute kidney injury (AKI) and arrhythmias. Subgroup analysis was conducted by examining outcomes based on the type of shock. Of the 2,035 included patients, 952 (46.8%) were VP1 and 1,083 (53.2%) were NE1. VP1 had a higher incidence of hypotension than NE1 (42.1% vs. 14.2%; P < 0.001), longer time to shock reversal (median: 2.5 vs. 2.2 days; P = .009), higher hospital [29% (278/952) vs. 24% (258/1083); P = .006], and 28-day mortality [37% (348/952) vs. 29% (317/1,083); P < 0.001] when compared with the NE1 group. There were no differences in ICU mortality, ICU and hospital length of stay, new-onset arrhythmia, or AKI incidence between the two groups. In subgroup analyses based on different types of shock, similar outcomes were observed. After adjustments, hypotension in the following 24 h and 28-day mortality were significantly higher in VP1 (Odds ratios (OR) 4.08(3.28, 5.07); p-value < .001 and 1.27(1.04, 1.55); p-value < .001, respectively). Besides, in a multivariable model, the need for renal replacement therapy (OR 1.68 (1.34, 2.12); p-value < .001) was significantly higher in VP1. Among patients with shock who received concomitant VP and NE, the VP1 group was associated with a higher incidence of hypotension in comparison with NE1. Future studies need to validate our findings and their impact on clinical outcomes.

A combined application of extracorporal detoxification techniques in children at the acute stage of severe concomitant traumtic brain injury

Introduction. In modern literature, there is a limited information on the techniques of extracorporeal detoxification in children with severe concomitant injuries. Moreover, in fact there are no data on their application in children with severe concomitant traumatic brain injuries. It has defined the relevance of this research.Purpose. To improve outcomes of treatment in children with severe concomitant traumatic brain injuries who have manifestations of toxic-resorptive syndrome (TRS), septic complications, acute renal failure of mixed genesis using a combined application of extracorporeal detoxification techniques.Material and methods. The article describes authors’ experience in a combined application of extracorporeal detoxification techniques, including continuous veno-venous hemodiafiltration (CVVHDF) and membrane plasma separation (MPS) in ICU patients with severe concomitant traumatic brain injuries complicated by toxic-resorptive syndrome, sepsis and septic shock.Results. The combined application of extracorporeal detoxification techniques promoted the regression of toxic-resorptive syndrome, shock reversal, stabilization of hemodynamic parameters, parameters of internal homeostasis as well as the regression of multiple organ failure.Conclusion. Early extracorporeal detoxification improves clinical course at the acute stage of trauma. The authors underline that the key requirement for safety in extracorporeal detoxification in patients with severe concomitant traumatic brain injury is the invasive monitoring of intracranial pressure.

Therapeutic application of recombinant human ADAMTS-13 improves shock reversal and coagulation status in a trauma hemorrhage and transfusion rat model

Introduction In hemorrhaging trauma patients, the endothelium is activated, resulting in excessive endothelial synthesis of von Willebrand Factor (vWF), which may enhance micro-thrombi formation, resulting in obstruction of the microcirculation and endothelial injury, aggravating bleeding, as well as contributing to organ failure. Under normal conditions, vWF is cleaved by the metalloprotease ADAMTS-13. After trauma, ADAMTS-13 levels are reduced. Objectives To assess whether recombinant human ADAMTS-13 inhibits endothelial injury and organ failure in a rat trauma-transfusion model. Methods Blood products were prepared from syngeneic rat blood according to blood bank standards. Polytrauma was induced in rats by crush injury to the intestines and liver and by fracture of the femur. The rats were hemorrhaged until a mean arterial pressure (MAP) of 40 mmHg was reached. Rats were randomized to receive transfusion of RBCs, FFPs, and platelets in a 1:1:1 ratio to achieve a MAP of 70 mmHg, with or without the addition of ADAMTS-13 (50 μg/kg). Blood samples were assessed for biochemistry and rotational thromboelastometry (ROTEM). Syndecan-1 and VE-cadherin levels were measured as a reflection of endothelial integrity. The amount of leakage of dextran-FITC from the vascular system to the parenchyma in lungs was quantified. To assess inflammation, IL-6 and IL-8 levels were determined. Organ damage was assessed by histopathology. Results All rats were severely shocked, with no significant differences in shock parameters between groups. Rats treated with ADAMTS-13 showed signs of a more effective shock reversal (higher blood pressure, lower lactate levels) compared to controls. Also, ROTEM parameters of clot formation in rats receiving ADAMTS-13 improved compared to controls, which was mainly platelet-dependent. Syndecan-1 levels relative to baseline trended to be lower in ADAMTS-13 treated rats compared to controls (107 vs 149%, p = 0.08). ADAMTS-13 reduced albuminuria (1.7 vs 4.4 g/L, p < 0.01) and organ-specific inflammation (pulmonary IL-6 243 vs 369 pg/mL, p = 0.08; splenic IL-6 253 vs 307, p = 0.03) compared to controls, but did not improve histopathological scores. Conclusions The use of ADAMTS-13 in a rat trauma-transfusion model improves parameters of shock, platelet-driven coagulation, endothelial damage, and organ inflammation. These results suggest that ADAMTS-13 is important in mediating outcome of trauma. Whether ADAMTS-13 can be used as a therapeutic adjunct to treat bleeding trauma patients remains to be determined.

Non-catecholamine vasopressors in the treatment of adult patients with septic shock—evidence from meta-analysis and trial sequential analysis of randomized clinical trials

Background Norepinephrine (NE) has currently been the first-choice vasopressor in treating septic shock despite generally insufficient for patients with refractory septic shock. The aim of this update meta-analysis was to assess the safety and efficacy of a combination of non-catecholamine vasopressors (vasopressin/pituitrin/terlipressin/selepressin/angiotensin II) and NE versus NE in managing adult septic shock patients. Methods We conducted this study of literatures published from the inception to April 30, 2020, using PubMed, Embase, and the Cochrane Library databases without language restriction. Randomized controlled trials comparing NE with non-catecholamine vasopressors among adult septic shock patients were included in this meta-analysis. Pooled effects of relative risk (RR) or standard mean difference (SMD) and corresponding 95% confidence interval (CI) were calculated using a random-effects model. Results Twenty-three studies covering 4380 participants were finally enrolled. The combined analysis of non-catecholamine vasopressors resulted in a nonsignificant reduction in 90-day/ICU/hospital mortality except for a decreased in 28-day mortality (n = 4217; RR, 0.92; 95% CI 0.86–0.99; P = 0.02). This favorable result was subsequently verified by the subgroup analyses of low risk of bias studies (RR = 0.91, 95% CI = 0.84 to 0.98; P = 0.02) and catecholamine-resistant refractory shock patients group (RR, 0.84; 95% CI = 0.70–1.00; P = 0.048). The pooled analysis of non-catecholamine vasopressors showed a 14% higher success rate of shock reversal at 6 h, a 29% decreased risk of continuous renal replacement therapy, but a 51% increased risk of hyponatremia and a 2.43 times higher risk of digital ischemia. Besides, the pooled data showed that non-catecholamine vasopressors decreased heart rate (HR) (SMD, − 0.43; 95% CI − 0.66 – − 0.19; P < 0.001), serum creatinine (− 0.15; 95% CI − 0.29 – − 0.01; P = 0.04), and the length of mechanical ventilation (MV) (− 0.19; 95% CI − 0.31 – − 0.07; P < 0.01, but there was no significant difference in other parameters. Conclusions Current pooled results suggest that the addition of NE to non-catecholamine vasopressors was associated with a marginally significant reduction in 28-day mortality. Moreover, they were able to shorten the length of MV, improved renal function, decreased HR, and increased the 6-h shock reversal success rate at the expense of increased the risk of hyponatremia and digital ischemia.