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Hyperoxia toxicity in septic shock patients according to the Sepsis-3 criteria: a post hoc analysis of the HYPER2S trial.

ABSTRACT: BACKGROUND:Criteria for the Sepsis-3 definition of septic shock include vasopressor treatment to maintain a mean arterial pressure?>?65 mmHg and a lactate concentration?>?2 mmol/L. The impact of hyperoxia in patients with septic shock using these criteria is unknown. METHODS:A post hoc analysis was performed of the HYPER2S trial assessing hyperoxia versus normoxia in septic patients requiring vasopressor therapy, in whom a plasma lactate value was available at study inclusion. Mortality was compared between patients fulfilling the Sepsis-3 septic shock criteria and patients requiring vasopressors for hypotension only (i.e., with lactate???2 mmol/L). RESULTS:Of the 434 patients enrolled, 397 had available data for lactate at inclusion. 230 had lactate?>?2 mmol/L and 167???2 mmol/L. Among patients with lactate?>?2 mmol/L, 108 and 122 were "hyperoxia"- and "normoxia"-treated, respectively. Patients with lactate?>?2 mmol/L had significantly less COPD more cirrhosis and required surgery more frequently. They also had higher illness severity (SOFA 10.6?±?2.8 vs. 9.5?±?2.5, p?=?0.0001), required more renal replacement therapy (RRT), and received vasopressor and mechanical ventilation for longer time. Mortality rate at day 28 was higher in the "hyperoxia"-treated patients with lactate?>?2 mmol/L as compared to "normoxia"-treated patients (57.4% vs. 44.3%, p = 0.054), despite similar RRT requirements as well as vasopressor and mechanical ventilation-free days. A multivariate analysis showed an independent association between hyperoxia and mortality at day 28 and 90. In patients with lactate???2 mmol/L, hyperoxia had no effect on mortality nor on other outcomes. CONCLUSIONS:Our results suggest that hyperoxia may be associated with a higher mortality rate in patients with septic shock using the Sepsis-3 criteria, but not in patients with hypotension alone.

SUBMITTER: Demiselle J

PROVIDER: S-EPMC6141409 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Hyperoxia toxicity in septic shock patients according to the Sepsis-3 criteria: a post hoc analysis of the HYPER2S trial.

Demiselle Julien J Wepler Martin M Hartmann Clair C Radermacher Peter P Schortgen Frédérique F Meziani Ferhat F Singer Mervyn M Seegers Valérie V Asfar Pierre P

Annals of intensive care 20180917 1

<h4>Background</h4>Criteria for the Sepsis-3 definition of septic shock include vasopressor treatment to maintain a mean arterial pressure > 65 mmHg and a lactate concentration > 2 mmol/L. The impact of hyperoxia in patients with septic shock using these criteria is unknown.<h4>Methods</h4>A post hoc analysis was performed of the HYPER2S trial assessing hyperoxia versus normoxia in septic patients requiring vasopressor therapy, in whom a plasma lactate value was available at study inclusion. Mor ...[more]

PMID: 30225670

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Project description:ImportanceThe Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach.ObjectiveTo derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings.Design, setting, and participantsMulticenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set.ExposureStacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock.Main outcomes and measuresThe primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity.ResultsAmong the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings.Conclusions and relevanceThe novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

Project description:ImportanceThe Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.ObjectiveTo evaluate the validity of clinical criteria to identify patients with suspected infection who are at risk of sepsis.Design, settings, and populationAmong 1.3 million electronic health record encounters from January 1, 2010, to December 31, 2012, at 12 hospitals in southwestern Pennsylvania, we identified those with suspected infection in whom to compare criteria. Confirmatory analyses were performed in 4 data sets of 706,399 out-of-hospital and hospital encounters at 165 US and non-US hospitals ranging from January 1, 2008, until December 31, 2013.ExposuresSequential [Sepsis-related] Organ Failure Assessment (SOFA) score, systemic inflammatory response syndrome (SIRS) criteria, Logistic Organ Dysfunction System (LODS) score, and a new model derived using multivariable logistic regression in a split sample, the quick Sequential [Sepsis-related] Organ Failure Assessment (qSOFA) score (range, 0-3 points, with 1 point each for systolic hypotension [≤100 mm Hg], tachypnea [≥22/min], or altered mentation).Main outcomes and measuresFor construct validity, pairwise agreement was assessed. For predictive validity, the discrimination for outcomes (primary: in-hospital mortality; secondary: in-hospital mortality or intensive care unit [ICU] length of stay ≥3 days) more common in sepsis than uncomplicated infection was determined. Results were expressed as the fold change in outcome over deciles of baseline risk of death and area under the receiver operating characteristic curve (AUROC).ResultsIn the primary cohort, 148,907 encounters had suspected infection (n = 74,453 derivation; n = 74,454 validation), of whom 6347 (4%) died. Among ICU encounters in the validation cohort (n = 7932 with suspected infection, of whom 1289 [16%] died), the predictive validity for in-hospital mortality was lower for SIRS (AUROC = 0.64; 95% CI, 0.62-0.66) and qSOFA (AUROC = 0.66; 95% CI, 0.64-0.68) vs SOFA (AUROC = 0.74; 95% CI, 0.73-0.76; P < .001 for both) or LODS (AUROC = 0.75; 95% CI, 0.73-0.76; P < .001 for both). Among non-ICU encounters in the validation cohort (n = 66 522 with suspected infection, of whom 1886 [3%] died), qSOFA had predictive validity (AUROC = 0.81; 95% CI, 0.80-0.82) that was greater than SOFA (AUROC = 0.79; 95% CI, 0.78-0.80; P < .001) and SIRS (AUROC = 0.76; 95% CI, 0.75-0.77; P < .001). Relative to qSOFA scores lower than 2, encounters with qSOFA scores of 2 or higher had a 3- to 14-fold increase in hospital mortality across baseline risk deciles. Findings were similar in external data sets and for the secondary outcome.Conclusions and relevanceAmong ICU encounters with suspected infection, the predictive validity for in-hospital mortality of SOFA was not significantly different than the more complex LODS but was statistically greater than SIRS and qSOFA, supporting its use in clinical criteria for sepsis. Among encounters with suspected infection outside of the ICU, the predictive validity for in-hospital mortality of qSOFA was statistically greater than SOFA and SIRS, supporting its use as a prompt to consider possible sepsis.

Project description:PurposeThe EUPHRATES trial examined the impact of polymyxin B hemoperfusion (PMX) on mortality in patients with septic shock and endotoxemia, defined as EAA ≥ 0.60. No difference was found in 28-day all-cause mortality. However, the trial showed that in some patients with septic shock the burden of endotoxin activity was extreme (EAA ≥ 0.9). In a post hoc analysis, we evaluated the impact of PMX use in patients with septic shock and endotoxin activity measured between 0.6-0.89.MethodsPost-hoc analysis of the EUPHRATES trial for the 194 patients with EAA ≥ 0.6-0.89 who completed two treatments (PMX or sham). The primary end point was mortality at 28 days adjusted for APACHE II score and baseline mean arterial pressure (MAP). Additional end points included changes in MAP, cumulative vasopressor index (CVI), median EAA reduction, ventilator-free days (VFD), dialysis-free days (DFD) and hospital length of stay. Subpopulations analyzed were site and type of infection and those with norepinephrine dose > 0.1 mcg/kg/min at baseline.ResultsAt 28 days, 23 patients of 88 (26.1%) in the PMX group died versus 39 of 106 (36.8%) in the sham group [risk difference 10.7%, OR 0.52, 95% CI (0.27, 0.99), P = 0.047]. When unadjusted for baseline variables, P = 0.11. The 28-day survival time in the PMX group was longer than for the sham group [HR 0.56 (95% CI 0.33, 0.95) P = 0.03]. PMX treatment compared with sham showed greater change in MAP [median (IQR) 8 mmHg (- 0.5, 19.5) vs. 4 mmHg (- 4.0, 11) P = 0.04] and VFD [median (IQR) 20 days (0.5, 23.5) vs. 6 days (0, 20), P = 0.004]. There were no significant differences in other end points. There was a significant difference in mortality in PMX-treated patients with no bacterial growth on culture [PMX, 6/30 (20%) vs. sham, 13/31 (41.9%), P = 0.005]. The median EAA change in the population was - 12.9% (range: increase 49.2%-reduction 86.3%). The mortality in the above median EAA change group was PMX: 6/38 (15.7%) vs. sham 15/49 (30.6%), P = 0.08.ConclusionsThese hypothesis-generating results, based on an exploratory post hoc analysis of the EUPHRATES trial, suggest measurable responses in patients with septic shock and an EAA ≥ 0.6 to 0.89 on changes in mean arterial pressure, ventilator-free days and mortality.Trial registrationClinicaltrials.gov Identifier: NCT01046669. Funding Spectral Medical Incorporated.

Project description:PurposeAdrecizumab, a non-neutralizing antibody of adrenomedullin (ADM) was recently investigated regarding its potential to restore endothelial barrier function in septic shock patients with high plasma ADM levels. Circulating dipeptidyl peptidase 3 (cDPP3), a protease involved in the degradation of several cardiovascular mediators, represents another biological pathway strongly associated with outcome in septic shock, although unrelated to ADM. Therefore, the prognosis of patients with elevated cDPP3 may not be influenced by Adrecizumab. Also, time until initiation of treatment may influence efficacy.ObjectiveTo evaluate effects of cDPP3-based enrichment on treatment efficacy of Adrecizumab.Materials and methodsPost-hoc analysis of AdrenOSS-2, a phase-II, double-blind, randomized, placebo-controlled biomarker-guided trial of Adrecizumab.ResultsCompared to the total study cohort [HR for 28-day mortality of 0.84 (95% CI 0.53;1.31), p = 0.439], therapeutic benefit of Adrecizumab tended to be more pronounced in the subgroup of 249 patients with low cDPP3 (<50 ng/mL); [HR of 0.61 (95% CI 0.34;1.08), p = 0.085]. Median duration to study drug infusion was 8.5 h. In the subgroup of 129 patients with cDPP3 <50 ng/mL and an early start of treatment (<8.5 h after septic shock diagnosis) HR for 28-day mortality vs. placebo was 0.49 (95% CI 0.21-1.18), p = 0.105. In multivariate interaction analyses corrected for baseline disease severity, both cDPP3, as well as the cDPP3 * treatment interaction term were associated with a reduced HR for 28-day mortality in the Adrecizumab treated group; p = 0.015 for cDPP3 in univariate analysis, p = 0.025 for the interaction term between cDPP3 and treatment group. In contrast, treatment timing was not significantly associated with 28-day mortality in multivariate interaction analyses.DiscussionIn septic shock patients with high ADM levels, a further post-hoc enrichment strategy based on cDPP3 may indicate (with all the caveats to be considered for post-hoc subgroup analyses) that therapeutic efficacy is most pronounced in patients with lower cDPP3 levels.

Project description:IntroductionIt is unclear to which level mean arterial blood pressure (MAP) should be increased during septic shock in order to improve outcome. In this study we investigated the association between MAP values of 70 mmHg or higher, vasopressor load, 28-day mortality and disease-related events in septic shock.MethodsThis is a post hoc analysis of data of the control group of a multicenter trial and includes 290 septic shock patients in whom a mean MAP > or = 70 mmHg could be maintained during shock. Demographic and clinical data, MAP, vasopressor requirements during the shock period, disease-related events and 28-day mortality were documented. Logistic regression models adjusted for the geographic region of the study center, age, presence of chronic arterial hypertension, simplified acute physiology score (SAPS) II and the mean vasopressor load during the shock period was calculated to investigate the association between MAP or MAP quartiles > or = 70 mmHg and mortality or the frequency and occurrence of disease-related events.ResultsThere was no association between MAP or MAP quartiles and mortality or the occurrence of disease-related events. These associations were not influenced by age or pre-existent arterial hypertension (all P > 0.05). The mean vasopressor load was associated with mortality (relative risk (RR), 1.83; confidence interval (CI) 95%, 1.4-2.38; P < 0.001), the number of disease-related events (P < 0.001) and the occurrence of acute circulatory failure (RR, 1.64; CI 95%, 1.28-2.11; P < 0.001), metabolic acidosis (RR, 1.79; CI 95%, 1.38-2.32; P < 0.001), renal failure (RR, 1.49; CI 95%, 1.17-1.89; P = 0.001) and thrombocytopenia (RR, 1.33; CI 95%, 1.06-1.68; P = 0.01).ConclusionsMAP levels of 70 mmHg or higher do not appear to be associated with improved survival in septic shock. Elevating MAP >70 mmHg by augmenting vasopressor dosages may increase mortality. Future trials are needed to identify the lowest acceptable MAP level to ensure tissue perfusion and avoid unnecessary high catecholamine infusions.

Project description:Sepsis is commonly associated with acute kidney injury (AKI), particularly in those requiring dialysis (AKI-D). To date, Sepsis-3 criteria have not been applied to AKI-D patients. We investigated sepsis prevalence defined by Sepsis-3 criteria and evaluated the outcomes of septic-associated AKI-D among critically ill patients. Using the data collected from a prospective multi-center observational study, we applied the Sepsis-3 criteria to critically ill AKI-D patients treated in intensive care units (ICUs) in 30 hospitals between September 2014 and December 2015. We described the prevalence, outcomes, and characteristics of sepsis as defined by the screening Sepsis-3 criteria among AKI-D patients, and compared the outcomes of AKI-D patients with or without sepsis using the Sepsis-3 criteria. A total of 1078 patients (median 70 years; 673 (62.4%) men) with AKI-D were analyzed. The main etiology of AKI was sepsis (71.43%) and the most frequent indication for acute dialysis was oliguria (64.4%). A total of 577 (53.3% of 1078 patients) met the Sepsis-3 criteria, and 206 among the 577 patients (19.1%) had septic shock. Having sepsis and septic shock were independently associated with 90-day mortality among these ICU AKI-D patients (hazard ratio (HR) 1.23 (p = 0.027) and 1.39 (p = 0.004), respectively). Taking mortality as a competing risk factor, AKI-D patients with septic shock had a significantly reduced chance of weaning from dialysis at 90 days than those without sepsis (HR 0.65, p = 0.026). The combination of the Sepsis-3 criteria with the AKI risk score led to better performance in forecasting 90-day mortality. Sepsis affects more than 50% of ICU AKI patients requiring dialysis, and one-fifth of these patients had septic shock. In AKI-D patients, coexistent with or induced by sepsis (as screened by the Sepsis-3 criteria), there is a significantly higher mortality and reduced chance of recovering sufficient renal function, when compared to those without sepsis.

Project description:BackgroundData assessing outcomes of patients with solid tumors demonstrating septic shock using the Third International Consensus Definitions for Sepsis and Septic Shock are scarce.Research questionWhat are the independent predictors of 28-day mortality in critically ill adults with solid tumors and septic shock?Study design and methodsCohort of solid tumor patients admitted to the ICU with septic shock. Demographic and clinical characteristics were gathered from the electronic health records. We developed a reduced multivariate logistics regression model to identify independent predictors of 28-day mortality and used Kaplan-Meier plots to assess survival.ResultsA total of 271 patients were included. The median age was 62 years (range, 19-94 years); 57.2% were men and 53.5% were White. The most common underlying malignancies were lung (19.2%), breast (7.7%), pancreatic (7.7%), and colorectal (7.4%) cancers. Most patients (84.5%) harbored metastatic disease. Twenty-eight days after ICU admission, 188 patients (69.4%) had died. Nonsurvivors showed a higher rate of advanced cancer, longer hospital stays before ICU admission, and higher Sequential Organ Failure Assessment scores at admission and throughout the ICU stay (P < .001 for all). The multivariate analysis identified metastatic disease (OR, 3.17; 95% CI, 1.43-7.03), respiratory failure (OR, 2.34; 95% CI, 1.15-4.74), elevated lactate levels (OR, 3.19; 95% CI, 1.90-5.36), and Eastern Cooperative Oncology Group performance scores of 3 or 4 (OR, 2.72; 95% CI, 1.33-5.57) as independent predictors of 28-day mortality. Only 38 patients (14%) were discharged home without medical assistance.InterpretationThe 28-day mortality rate of patients with solid tumors and septic shock was considerably high. Factors associated with worse survival included advanced oncologic disease, poor performance status, high lactate level, and concomitant acute respiratory failure. Early goals-of-care discussions should be considered for frail patients with septic shock and advanced metastatic disease without denying access to the appropriate level of care.

Project description:ObjectiveTo identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock.DesignA consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations.MethodsEach committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science.ResultsThe Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction?ConclusionsWhile the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.

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Hyperoxia toxicity in septic shock patients according to the Sepsis-3 criteria: a post hoc analysis of the HYPER2S trial.

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Hyperoxia toxicity in septic shock patients according to the Sepsis-3 criteria: a post hoc analysis of the HYPER2S trial.

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