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IntroductionRefractory septic shock (RSS) is characterized by high vasopressor requirements, as a consequence of vasopressor resistance, which may be caused or enhanced by sympathetic hyperactivation. Experimental models and clinical trials show a reduction in vasopressor requirements and improved microcirculation compared to conventional sedation. Dexmedetomidine did not reduce mortality in clinical trials, but few septic shock patients were enrolled. This pilot trial aims to evaluate vasopressor re-sensitization with dexmedetomidine and assess the effect size, in order to design a larger trial.MethodsThis is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, comparing dexmedetomidine versus placebo in RSS patients with norepinephrine dose ≥0.5μg/kg/min. The primary outcome is blood pressure response to phenylephrine challenge, 6 hours after completion of a first challenge, after study treatment initiation. Secondary outcomes include feasibility and safety outcomes (bradycardia), mortality, vasopressor requirements, heart rate variability, plasma and urine catecholamines levels. The sample size is estimated at 32 patients to show a 20% improvement in blood pressure response to phenylephrine. Randomization (1:1) will be stratified by center, sedation type and presence of liver cirrhosis. Blood pressure and ECG will be continuously recorded for the first 24 h, enabling high-quality data collection for the primary and secondary endpoints. The study was approved by the ethics committee “Sud-Est VI” (2019-000726-22) and patients will be included after informed consent.DiscussionThe present study will be the first randomized trial to specifically address the hemodynamic effects of dexmedetomidine in patients with septic shock. We implement a high-quality process for data acquisition and recording in the first 24 h, ensuring maximal quality for the evaluation of both efficacy and safety outcomes, as well as transparency of results. The results of the study will be used to elaborate a full-scale randomized controlled trial with mortality as primary outcome in RSS patients.Trial registrationRegistered with ClinicalTrials.gov (NCT03953677). Registered 16 May 2019, https://clinicaltrials.gov/ct2/show/NCT03953677.

BackgroundThe benefits of extracorporeal membrane oxygenation in patients with refractory septic shock remain controversial. Current guidelines on the management of refractory septic shock recommend the consideration of extracorporeal membrane oxygenation as a salvage therapy. The difference between adults and children with septic refractory shock treated with extracorporeal membrane oxygenation has not been previously analyzed. We aimed to review peer-reviewed publications on the role of extracorporeal membrane oxygenation in adults and children with refractory septic shock.MethodsStudies reporting on mortality in both adults and children with refractory septic shock supported with extracorporeal membrane oxygenation published in PubMed, Cochrane Library, and Embase databases were included in the meta-analysis. Study eligibility was independently assessed by two authors, and disagreements were resolved by a third author. The outcome measure was survival at discharge. Subgroup analysis included the adult and pediatric groups.ResultsOf the 293 articles screened, 14 original articles were identified for systematic review and meta-analysis. The cumulative estimate of survival (14 studies, 535 patients) in the cohort was 39% (95% confidence interval [CI]: 27–51%). During the subgroup analysis, the cumulative estimate of survival at discharge in the adult group (6 studies, 276 patients) in the cohort was 18% (95% CI: 10–27%), and that in the pediatric group (8 studies, 259 patients) was 53% (95% CI: 47–59%).ConclusionsThe survival rate of adults with refractory septic shock requiring extracorporeal membrane oxygenation was 18%, and children with refractory septic shock requiring extracorporeal membrane oxygenation had a higher survival rate (53%) than adults.

Abstract Background Currently, the appropriate method of management of patients with refractory septic shock remains unclear. This study aimed to evaluate the factors associated with response to epinephrine in norepinephrine-refractory septic shock. Methods A retrospective single-center observational study was performed using data from adult patients (≥ 18 years old) admitted to our emergency and medical intensive care unit (ICU) from January 2014 to December 2017 who had received epinephrine to treat norepinephrine-refractory septic shock. The response was considered positive if there was increase in mean arterial pressure of 10 mmHg or decrease in arterial lactate level 3 h after epinephrine administration. Results Forty-one patients were included: 24 responders (59%) and 17 non-responders (41%). Responders showed higher rate of survival from shock (92% vs. 18%; P

Background: Vasoplegia is vascular hyporesponsiveness to vasopressors and is an important phenomenon in children with refractory septic shock. This study aimed to develop an objective formula correlated with vasoplegia and evaluate the predictive power for mortality in children with refractory septic shock. Materials and Methods: We retrospectively analyzed children with refractory septic shock admitted to a pediatric intensive care unit (PICU) and monitored their hemodynamics via a pulse index continuous cardiac output (PiCCO) system. Serial hemodynamic data including cardiac index (CI), systemic vascular resistant index (SVRI) and vasoactive-inotropic score (VIS) were recorded during the first 72 hours after PICU admission. We defined vascular reactivity index (VRI) as SVRI/VIS and analyzed the effect of VRI in predicting mortality in children with refractory septic shock. Results: Thirty-three children with refractory septic shock were enrolled. The SVRI was lower in the mortality group compared to the survival group (P < .05). The average area under the receiver operating characteristic curve of VRI within the first 72 hours was 0.8 and the serial values of VRI were significantly lower in the mortality group during the period from 0 to 48 hours (P < .05). However, there were no significant differences in serial CI values between the survival and mortality groups. Conclusions: Vasoactive-inotropic score may potentially be used to quantify the severity of vasoplegia based on the clinical response of vessels after resuscitation with vasopressors. Lower VRI levels may indicate a higher risk of mortality in children with septic shock. [ABSTRACT FROM AUTHOR]

Abstract Despite timely intervention, there exists a small subgroup of patients with septic shock who develop progressive multi-organ failure. Seemingly refractory to conventional therapy, they exhibit a very high mortality. Such patients are often poorly represented in large clinical trials. Consequently, good evidence for effective treatment strategies is lacking. In this article, we describe a pragmatic, multi-faceted approach to managing patients with refractory septic shock based on our experience of toxin-mediated sepsis in a specialist referral centre. Many components of this strategy are inexpensive and widely accessible, and so may offer an opportunity to improve outcomes in these critically ill patients.

Abstract Background In this article, we present a clinical case of refractory septic shock resulting from intestinal perforation treated with high doses of vasopressin and hydrocortisone during emergency surgery. The use of such high doses of vasopressin for this type of shock is not described in the literature. Case presentation A 49-year-old white woman with grade III obesity, Crohn’s disease, and an intestinal perforation presented with refractory septic shock. Initially, a low dose of vasopressin was used. Then, the dosage was increased to 0.4 U/minute; in the literature, this is defined as “salvage therapy.” This therapy consists of an initial load followed by a continuous infusion of hydrocortisone. Conclusions The significant increase in her cardiac index and stroke volume index resulted in an improvement in peripheral resistance, gas exchange, and urine output and a decrease in her heart rate, interleukin-6 level, and tumor necrosis factor-α level. The administration of high doses of vasopressin and corticosteroids was demonstrated to be safe for the immune system, to reduce the systemic inflammatory response, and to have direct cardiovascular effects. Further studies are required to examine the use of vasopressin as an initial vasopressor as well as its use in high dosages and in combination with corticosteroids.

Background: In this article, we present a clinical case of refractory septic shock resulting from intestinal perforation treated with high doses of vasopressin and hydrocortisone during emergency surgery. The use of such high doses of vasopressin for this type of shock is not described in the literature.Case Presentation: A 49-year-old white woman with grade III obesity, Crohn's disease, and an intestinal perforation presented with refractory septic shock. Initially, a low dose of vasopressin was used. Then, the dosage was increased to 0.4 U/minute; in the literature, this is defined as "salvage therapy." This therapy consists of an initial load followed by a continuous infusion of hydrocortisone.Conclusions: The significant increase in her cardiac index and stroke volume index resulted in an improvement in peripheral resistance, gas exchange, and urine output and a decrease in her heart rate, interleukin-6 level, and tumor necrosis factor-α level. The administration of high doses of vasopressin and corticosteroids was demonstrated to be safe for the immune system, to reduce the systemic inflammatory response, and to have direct cardiovascular effects. Further studies are required to examine the use of vasopressin as an initial vasopressor as well as its use in high dosages and in combination with corticosteroids. [ABSTRACT FROM AUTHOR]

Sepsis is the most common cause of death in medical intensive care units (ICU). If sepsis progresses to refractory septic shock, mortality may reach 90-100% despite optimum current therapy. Extracorporeal cytokine adsorption in addition to regular therapy was studied prospectively in refractory septic shock patients on a medical ICU. Refractory shock was defined as increasing vasopressor dose required to maintain mean arterial blood pressure above 65 mmHg or increasing lactate levels despite protocol-guided shock therapy for 6 h. We analysed noradrenaline requirements after 6 and 12 h (primary endpoint), lactate clearance after 6 and 12 h, SOFA-scores in the first days and achievement of shock reversal (i.e., normalization of lactate concentrations and sustained discontinuation of vasopressors; secondary endpoints). Twenty consecutive patients with refractory septic shock were included; CytoSorb treatment was started after 7.8 ± 3.7 h of shock therapy. Following the initiation of adsorption therapy, noradrenaline dose could be significantly reduced after 6 (−0.4 µg/kg/min; p = 0.03) and 12 h (−0.6 µg/kg/min; p = 0.001). Lactate clearance improved significantly. SOFA-scores on day 0, 1 and 2 remained unchanged. Shock reversal was achieved in 13 (65%) patients; 28-day survival was 45%. In severe septic shock unresponsive to standard treatment, haemodynamic stabilization was achieved using cytokine adsorption therapy, resulting in shock reversal in two-thirds of these patients. The study was registered in the German Register for Clinical Trials (DRKS) No. 00005149. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to compare terlipressin versus adrenaline in refractory septic shock. Patients and methods In this interventional prospective randomized study, 80 patients between 18 and 60 years of age who presented with refractory septic shock were enrolled. The patients were divided randomly into two groups of 40 patients each. Group A patients were treated with adrenaline and group T patients were treated with terlipressin. The goals of the therapy were to achieve and maintain for 6 h all of the following: (i) mean blood pressure greater than 65 mmHg; (ii) systemic vascular resistance index greater than 1300 dynes s/cm5/m2; (iii) cardiac index (CI) greater than 4.0 l/min/m2; and (iv) oxygen delivery index greater than 550 ml/min/m2. The patients were classified into responders and nonresponders to the drugs used. Results The number of responders was significantly higher in the terlipressin group. There were 23 (58.97%) responders in the T group and 13 (35.13%) responders in the A group. The terlipressin group showed a significant increase in mean blood pressure from 49.9 ± 14.82 to 77.79 ± 20 mmHg and a significant increase in systemic vascular resistance index from 898 ± 292 to 1420 ± 537 dynes s/cm5/m2; urine output and creatinine clearance also showed an increase. Group T patients showed a significant decrease in heart rate and norepinephrine infusion. As regards cardiac index and oxygen delivery index, they showed minimal decrease at the end of the study, but their levels were still above our target levels. Conclusion Terlipressin therapy is better than adrenaline in improving the hemodynamic variables and kidney functions in refractory septic-shock patients. [ABSTRACT FROM AUTHOR]

Introduction: Refractory septic shock (RSS) is characterized by high vasopressor requirements, as a consequence of vasopressor resistance, which may be caused or enhanced by sympathetic hyperactivation. Experimental models and clinical trials show a reduction in vasopressor requirements and improved microcirculation compared to conventional sedation. Dexmedetomidine did not reduce mortality in clinical trials, but few septic shock patients were enrolled. This pilot trial aims to evaluate vasopressor re-sensitization with dexmedetomidine and assess the effect size, in order to design a larger trial., Methods: This is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, comparing dexmedetomidine versus placebo in RSS patients with norepinephrine dose ≥0.5μg/kg/min. The primary outcome is blood pressure response to phenylephrine challenge, 6 hours after completion of a first challenge, after study treatment initiation. Secondary outcomes include feasibility and safety outcomes (bradycardia), mortality, vasopressor requirements, heart rate variability, plasma and urine catecholamines levels. The sample size is estimated at 32 patients to show a 20% improvement in blood pressure response to phenylephrine. Randomization (1:1) will be stratified by center, sedation type and presence of liver cirrhosis. Blood pressure and ECG will be continuously recorded for the first 24 h, enabling high-quality data collection for the primary and secondary endpoints. The study was approved by the ethics committee "Sud-Est VI" (2019-000726-22) and patients will be included after informed consent., Discussion: The present study will be the first randomized trial to specifically address the hemodynamic effects of dexmedetomidine in patients with septic shock. We implement a high-quality process for data acquisition and recording in the first 24 h, ensuring maximal quality for the evaluation of both efficacy and safety outcomes, as well as transparency of results. The results of the study will be used to elaborate a full-scale randomized controlled trial with mortality as primary outcome in RSS patients., Trial Registration: Registered with ClinicalTrials.gov (NCT03953677). Registered 16 May 2019, https://clinicaltrials.gov/ct2/show/NCT03953677., Competing Interests: The pharmaceutical company ORION Pharma, manufacturer of DEXDOR®, agreed to provide the necessary amount of drug to conduct the study. ORION Pharma did not provide financial support, or any other form of support. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dargent, Bourredjem, Argaud, Levy, Fournel, Cransac, Badie, Quintin and Quenot.)

Mortality in the setting of septic shock varies between 20% and 100%. Refractory septic shock leads to early circulatory failure and carries the worst prognosis. The pathophysiology is poorly understood despite studies of the microcirculatory defects and the immuno-paralysis. The acute circulatory distress is treated with volume expansion, administration of vasopressors (usually noradrenaline: NA), and inotropes. Ventilation and anti-infectious strategy shall not be discussed here. When circulation is considered, the literature is segregated between interventions directed to the systemic circulation vs. interventions directed to the micro-circulation. Our thesis is that, after stabilization of the acute cardioventilatory distress, the prolonged sympathetic hyperactivity is detrimental in the setting of septic shock. Our hypothesis is that the sympathetic hyperactivity observed in septic shock being normalized towards baseline activity will improve the microcirculation by recoupling the capillaries and the systemic circulation. Therefore, counterintuitively, antihypertensive agents such as beta-blockers or alpha-2 adrenergic agonists (clonidine, dexmedetomidine) are useful. They would reduce the noradrenaline requirements. Adjuncts (vitamins, steroids, NO donors/inhibitors, etc.) proposed to normalize the sepsis-evoked vasodilation are not reviewed. This itemized approach (systemic vs. microcirculation) requires physiological and epidemiological studies to look for reduced mortality. [ABSTRACT FROM AUTHOR]

Background: Vasoplegia is vascular hyporesponsiveness to vasopressors and is an important phenomenon in children with refractory septic shock. This study aimed to develop an objective formula correlated with vasoplegia and evaluate the predictive power for mortality in children with refractory septic shock., Materials and Methods: We retrospectively analyzed children with refractory septic shock admitted to a pediatric intensive care unit (PICU) and monitored their hemodynamics via a pulse index continuous cardiac output (PiCCO) system. Serial hemodynamic data including cardiac index (CI), systemic vascular resistant index (SVRI) and vasoactive-inotropic score (VIS) were recorded during the first 72 hours after PICU admission. We defined vascular reactivity index (VRI) as SVRI/VIS and analyzed the effect of VRI in predicting mortality in children with refractory septic shock., Results: Thirty-three children with refractory septic shock were enrolled. The SVRI was lower in the mortality group compared to the survival group ( P < .05). The average area under the receiver operating characteristic curve of VRI within the first 72 hours was 0.8 and the serial values of VRI were significantly lower in the mortality group during the period from 0 to 48 hours ( P < .05). However, there were no significant differences in serial CI values between the survival and mortality groups., Conclusions: Vasoactive-inotropic score may potentially be used to quantify the severity of vasoplegia based on the clinical response of vessels after resuscitation with vasopressors. Lower VRI levels may indicate a higher risk of mortality in children with septic shock.

Background: Refractory septic shock is a serious disorder with high mortality. There is currently limited evidence to support the use of extracorporeal membrane oxygenation (ECMO) in adult septic shock. We describe the outcome of patients with refractory septic shock in our hospital and try to identify prognostic factors., Methods: We studied a total of 23 (14 males and 9 females) refractory septic shock patients treated with venoarterial (VA) ECMO in our hospital. Clinical parameters of survival and death groups, laboratory parameters before and after ECMO placement were analyzed., Results: Eight patients were successfully weaned off ECMO and five patients were discharged. The sepsis-related organ failure assessment (SOFA) score and shock-to-ECMO interval before ECMO placement in the survival group were significantly lower than those in the death group (12.0 vs. 15.0, P=0.007; 23.5 vs. 42.2 h, P=0.037). The number of cases who had the normal range of ScvO 2 % between the survival group and the death group at 12 h (4 vs. 4, P=0.033), 18 h (5 vs. 7, P=0.016) and 24 h (5 vs. 9, P=0.043) during ECMO was significantly different. In univariate logistic regression analysis, the case of patients with normal central venous oxygen saturation (ScvO 2 ) % at 12 h during ECMO [odds ratio (OR) 14.0, 95% confidence interval (CI): 1.200-163.367, P=0.035] was significantly associated with risk of the prognosis of patients., Conclusions: In adult refractory septic shock patients, ScvO 2 % at 12 h during ECMO may be a risk factor for patient prognosis., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Objective: To analyze the association of the clinical inflammatory indices with the severity of urinary sepsis., Methods: We reviewed the clinical data of 70 patients with urinary sepsis treated in our hospital between January, 2013 and April, 2018. All the patients were diagnosed in line with the Guidelines for Diagnosis and Treatment of Urological Diseases in China (2014 edition), including 22 patients with sepsis, 12 with hypotension and severe sepsis, 17 with septic shock, and 19 with critical septic shock. White blood cell count (WBC), neutrophil percentage (N%), platelets (PLT), fibrinogen (FIB), Ddimer, interleukin-6 (IL-6), procalcitonin (PCT) and C-reactive protein (CRP) were examined in all the cases and compared among the 4 groups. The correlations of these inflammatory markers with the severity of sepsis were analyzed using logistic regression analysis., Results: The 4 groups of patients showed significant differences in N%, PLT, D-dimer, and PCT ( P &lt; 0.05) but not in CRP ( P &gt;0.05). Kruskal-Wallis Pairwise comparisons showed that the N% and PCT in patients with sepsis differed significantly from those in the other 3 groups; platelets in patients with sepsis differed significantly from those in patients with septic shock and critical septic shock; D-dimer differed significantly between patients with sepsis and those with septic shock. Among the 4 groups, the median levels of PLT decreased and PCT and N% increased with the worsening of sepsis. Logistic regression analysis indicated that PCT ( r =0.186, P =0.000), N% ( r =0.047, P =0.035) and PLT ( r =-0.012, P =0.003) were significantly correlated with the severity of sepsis in these patients., Conclusions: PCT, PLT and N% are all significantly correlated with the severity of sepsis, and their combined detection can be informative for assessing the severity of sepsis to facilitate clinical decisions on treatment.