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Relationship Between Alternative Resuscitation Strategies, Host Response and Injury Biomarkers, and Outcome in Septic Shock: Analysis of the Protocol-Based Care for Early Septic Shock Study.

ABSTRACT: The Protocol-based Care for Early Septic Shock trial found no differences across alternative resuscitation strategies in all-cause mortality. A separate aim was to determine whether differences in resuscitation strategies affected trajectories of biomarkers of key pathways associated with downstream clinical outcomes of sepsis and whether there were differences in survival across treatment arms for patients with different baseline biomarker profiles.Secondary analysis of a large randomized clinical trial.Thirty-one U.S. hospitals.Six hundred twenty-eight patients with septic shock.Two resuscitation protocols versus usual care.We measured a panel of biomarkers representing four pathophysiologic domains: "inflammation" (tumor necrosis factor, interleukin-6, and -10); "coagulation" (D-dimers, thrombin-antithrombin complex); "oxidative stress" (urine isoprostane); and "tissue hypoxia" (lactate) at 0, 6, 24, and 72 hours after treatment. We analyzed whether alternative resuscitation strategies affected biomarker trajectories over 72 hours and whether effects on 90-day hospital mortality varied by baseline (time 0) biomarker profiles-both using regression models with interaction terms for treatment arms. For all baseline biomarkers, higher concentrations were associated with increased risk of death by 90 days. However, there was no significant effect of treatment assignment on subsequent biomarker trajectories. We did find evidence for heterogeneity of treatment effect of protocol-based care on mortality for patients with different baseline [interleukin-6] and [interleukin-6] × [interleukin-10] profiles, whereas patients with the lowest quartiles fared better with protocol-based care (odds ratios, 0.32 [0.13-075]; p = 0.01 and 0.32 [0.14-0.73]; p = 0.01, respectively).In patients with septic shock, alterations in inflammation, coagulation, oxidative stress, and tissue hypoxia are common and associated with adverse outcomes but are not influenced by protocol-based resuscitation compared with usual care. However, contrary to expectation, protocol-based resuscitation appeared to be superior in patients with lower concentrations of inflammatory biomarkers. The mechanisms responsible for this effect are unclear.

SUBMITTER: Kellum JA

PROVIDER: S-EPMC5448291 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Relationship Between Alternative Resuscitation Strategies, Host Response and Injury Biomarkers, and Outcome in Septic Shock: Analysis of the Protocol-Based Care for Early Septic Shock Study.

Kellum John A JA Pike Francis F Yealy Donald M DM Huang David T DT Shapiro Nathan I NI Angus Derek C DC

Critical care medicine 20170301 3

<h4>Objectives</h4>The Protocol-based Care for Early Septic Shock trial found no differences across alternative resuscitation strategies in all-cause mortality. A separate aim was to determine whether differences in resuscitation strategies affected trajectories of biomarkers of key pathways associated with downstream clinical outcomes of sepsis and whether there were differences in survival across treatment arms for patients with different baseline biomarker profiles.<h4>Design</h4>Secondary an ...[more]

PMID: 28079606

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Project description:BackgroundWe hypothesized that the cardiovascular responses to Surviving Sepsis Guidelines (SSG)-defined resuscitation are predictable based on the cardiovascular state.MethodsFifty-five septic patients treated by SSG were studied before and after volume expansion (VE), and if needed norepinephrine (NE) and dobutamine. We measured mean arterial pressure (MAP), cardiac index (CI), and right atrial pressure (Pra) and calculated pulse pressure and stroke volume variation (PPV and SVV), dynamic arterial elastance (Eadyn), arterial elastance (Ea) and left ventricular (LV) end-systolic elastance (Ees), Ees/Ea (VAC), LV ejection efficiency (LVeff), mean systemic pressure analogue (Pmsa), venous return pressure gradient (Pvr), and cardiac performance (Eh), using standard formulae.ResultsAll patients were hypotensive (MAP 56.8 ± 3.1 mmHg) and tachycardic (113.1 ± 7.5 beat min-1), with increased lactate levels (lactate = 5.0 ± 4.2 mmol L-1) with a worsened VAC. CI was variable but > 2 L min-1 M-2 in 74%. Twenty-eight-day mortality was 48% and associated with admission lactate, blood urea nitrogen (BUN), and creatinine levels but not cardiovascular state. In all patients, both MAP and CI improved following VE, as well as cardiac contractility (Ees). Fluid administration improved Pra, Pmsa, and Pvr in all patients, whereas both HR and Ea decreased after VE, thus normalizing VAC. CI increases were proportional to baseline PPV and SVV. CI increases proportionally decreased PPV and SVV. VE increased MAP > 65 mmHg in 35/55 patients. MAP responders had higher PPV, SVV, and Eadyn than non-responders. NE was given to 20/55 patients in septic shock, but increased MAP > 65 mmHg in only 12. NE increased Ea, Eadyn, Pra, Pmsa, and VAC while decreasing HR, PPV, SVV, and LVeff. MAP responders had higher pre-NE Ees and lower VAC. Dobutamine was given to 6/8 patients who remained hypotensive following NE. It increased Ees, MAP, CI, and LVeff, while decreasing HR, Pra, and VAC. At all times and all steps of the protocol, CI changes were proportional to Pvr changes independent of treatment.ConclusionsThe cardiovascular response to SSG-based resuscitation is highly heterogeneous but predictable from pre-treatment measures of cardiovascular state.

Project description:Septic shock is the leading cause of cardiovascular failure in the intensive care unit (ICU). Cardiac output is a primary component of global oxygen delivery to organs and a sensitive parameter of cardiovascular failure. Any mismatch between oxygen delivery and rapidly varying metabolic demand may result in tissue dysoxia, hence organ dysfunction. Since the intricate alterations of both vascular and cardiac function may rapidly and widely change over time, cardiac output should be measured repeatedly to characterize the type of shock, select the appropriate therapeutic intervention, and evaluate patient's response to therapy. Among the numerous techniques commercially available for measuring cardiac output, transpulmonary thermodilution (TPT) provides a continuous monitoring with external calibration capability, whereas critical care echocardiography (CCE) offers serial hemodynamic assessments. CCE allows early identification of potential sources of inaccuracy of TPT, including right ventricular failure, severe tricuspid or left-sided regurgitations, intracardiac shunt, very low flow states, or dynamic left ventricular outflow tract obstruction. In addition, CCE has the unique advantage of depicting the distinct components generating left ventricular stroke volume (large cavity size vs. preserved contractility), providing information on left ventricular diastolic properties and filling pressures, and assessing pulmonary artery pressure. Since inotropes may have deleterious effects if misused, their initiation should be based on the documentation of a cardiac dysfunction at the origin of the low flow state by CCE. Experts widely advocate using CCE as a first-line modality to initially evaluate the hemodynamic profile associated with shock, as opposed to more invasive techniques. Repeated assessments of both the efficacy (amplitude of the positive response) and tolerance (absence of side-effect) of therapeutic interventions are required to best guide patient management. Overall, TPT allowing continuous tracking of cardiac output variations and CCE appear complementary rather than mutually exclusive in patients with septic shock who require advanced hemodynamic monitoring.

Project description:IntroductionRecent evidence suggests that early, aggressive resuscitation in patients with septic shock reduces mortality. The objective of this survey was to characterize reported resuscitation practices of Canadian physicians caring for adult critically ill patients with early septic shock.MethodsA scenario-based self-administered national survey was sent out to Canadian critical care physicians. One hypothetical scenario was developed to obtain information on several aspects of resuscitation in early septic shock, including monitoring and resuscitation end-points, fluid administration, red blood cell transfusion triggers, and use of inotropes. The sampling frame was physician members of Canadian national and provincial critical care societies.ResultsThe survey response rate was 232 out of 355 (65.3%). Medicine was the most common primary specialty (60.0%), most respondents had practiced for 6 to 10 years (30.0%), and 82.0% were male. The following monitoring devices/parameters were reported as used/measured 'often' or 'always' by at least 89% of respondents: oxygen saturation (100%), Foley catheters (100%), arterial blood pressure lines (96.6%), telemetry (94.3%), and central venous pressure (89.2%). Continuous monitoring of central venous oxygen saturation was employed 'often' or 'always' by 9.8% of respondents. The two most commonly cited resuscitation end-points were urine output (96.5%) and blood pressure (91.8%). Over half of respondents used normal saline (84.5%), Ringers lactate (52.2%), and pentastarch (51.3%) 'often' or 'always' for early fluid resuscitation. In contrast, 5% and 25% albumin solutions were cited as used 'often' or 'always' by 3.9% and 1.3% of respondents, respectively. Compared with internists, surgeons and anesthesiologists (odds ratio (95% confidence interval): 9.8 (2.9 to 32.7) and 3.8 (1.7 to 8.7), respectively) reported greater use of Ringers lactate. In the setting of a low central venous oxygen saturation, 52.5% of respondents reported use of inotropic support 'often' or 'always'. Only 7.6% of physicians stated they would use a red blood cell transfusion trigger of 100 g/l to optimize oxygen delivery further.ConclusionOur survey results suggest that there is substantial practice variation in the resuscitation of adult patients with early septic shock. More randomized trials are needed to determine the optimal approach.

Project description:BackgroundSepsis and septic shock are life-threatening diseases with high mortality rate in intensive care unit (ICU). Acute kidney injury (AKI) is a common complication of sepsis, and its occurrence is a poor prognostic sign to septic patients. We analyzed co-differentially expressed genes (co-DEGs) to explore relationships between septic shock and AKI and reveal potential biomarkers and therapeutic targets of septic-shock-associated AKI (SSAKI).MethodsTwo gene expression datasets (GSE30718 and GSE57065) were downloaded from the Gene Expression Omnibus (GEO). The GSE57065 dataset included 28 septic shock patients and 25 healthy volunteers and blood samples were collected within 0.5, 24 and 48 h after shock. Specimens of GSE30718 were collected from 26 patients with AKI and 11 control patents. AKI-DEGs and septic-shock-DEGs were identified using the two datasets. Subsequently, Gene Ontology (GO) functional analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed to elucidate molecular mechanisms of DEGs. We also evaluated co-DEGs and corresponding predicted miRNAs involved in septic shock and AKI.ResultsWe identified 62 DEGs in AKI specimens and 888, 870, and 717 DEGs in septic shock blood samples within 0.5, 24 and 48 h, respectively. The hub genes of EGF and OLFM4 may be involved in AKI and QPCT, CKAP4, PRKCQ, PLAC8, PRC1, BCL9L, ATP11B, KLHL2, LDLRAP1, NDUFAF1, IFIT2, CSF1R, HGF, NRN1, GZMB, and STAT4 may be associated with septic shock. Besides, co-DEGs of VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 coupled with corresponding predicted miRNAs, especially miR-29b-3p, miR-152-3p, and miR-223-3p may be regarded as promising targets for the diagnosis and treatment of SSAKI in the future.ConclusionsSeptic shock and AKI are related and VMP1, SLPI, PTX3, TIMP1, OLFM4, LCN2, and S100A9 genes are significantly associated with novel biomarkers involved in the occurrence and development of SSAKI.

Project description:BackgroundThe decision of when to stop septic shock resuscitation is a critical but yet a relatively unexplored aspect of care. This is especially relevant since the risks of over-resuscitation with fluid overload or inotropes have been highlighted in recent years. A recent guideline has proposed normalization of central venous oxygen saturation and/or lactate as therapeutic end-points, assuming that these variables are equivalent or interchangeable. However, since the physiological determinants of both are totally different, it is legitimate to challenge the rationale of this proposal. We designed this study to gain more insights into the most appropriate resuscitation goal from a dynamic point of view. Our objective was to compare the normalization rates of these and other potential perfusion-related targets in a cohort of septic shock survivors.MethodsWe designed a prospective, observational clinical study. One hundred and four septic shock patients with hyperlactatemia were included and followed until hospital discharge. The 84 hospital-survivors were kept for final analysis. A multimodal perfusion assessment was performed at baseline, 2, 6, and 24 h of ICU treatment.ResultsSome variables such as central venous oxygen saturation, central venous-arterial pCO2 gradient, and capillary refill time were already normal in more than 70% of survivors at 6 h. Lactate presented a much slower normalization rate decreasing significantly at 6 h compared to that of baseline (4.0 [3.0 to 4.9] vs. 2.7 [2.2 to 3.9] mmol/L; p?<?0.01) but with only 52% of patients achieving normality at 24 h. Sublingual microcirculatory variables exhibited the slowest recovery rate with persistent derangements still present in almost 80% of patients at 24 h.ConclusionsPerfusion-related variables exhibit very different normalization rates in septic shock survivors, most of them exhibiting a biphasic response with an initial rapid improvement, followed by a much slower trend thereafter. This fact should be taken into account to determine the most appropriate criteria to stop resuscitation opportunely and avoid the risk of over-resuscitation.

Dataset Information

Relationship Between Alternative Resuscitation Strategies, Host Response and Injury Biomarkers, and Outcome in Septic Shock: Analysis of the Protocol-Based Care for Early Septic Shock Study.

Publications

Relationship Between Alternative Resuscitation Strategies, Host Response and Injury Biomarkers, and Outcome in Septic Shock: Analysis of the Protocol-Based Care for Early Septic Shock Study.

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