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Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial.

ABSTRACT: OBJECTIVES:Sepsis, the acute organ dysfunction caused by a dysregulated host response to infection, poses a serious public health burden. Current management includes early detection, initiation of antibiotics and fluids, and source control as necessary. Although observational data suggest that delays of even a few hours in the initiation of antibiotics or IV fluids is associated with survival, these findings are controversial. There are no randomized data in humans, and prior animal studies studied time from experimental manipulation, not from the onset of clinical features of sepsis. Using a recently developed murine cecal ligation and puncture model that precisely monitors physiologic deterioration, we hypothesize that incremental hourly delays in the first dose of antibiotics, in the first bolus of fluid resuscitation, or a combination of the two at a clinically relevant point of physiologic deterioration during polymicrobial sepsis will shorten survival. DESIGN:Randomized laboratory animal experimental trial. SETTING:University basic science laboratory. SUBJECTS:Male C57BL/6J, female C57BL/6J, aged (40-50?wk old) male C57BL/6J, and BALB/C mice. INTERVENTIONS:Mice (n = 200) underwent biotelemetry-enhanced cecal ligation and puncture and were randomized after meeting validated criteria for acute physiologic deterioration. Treatment groups consisted of a single dose of imipenem/cilastatin, a single bolus of 30?mL/kg fluid resuscitation, or a combination of the two. Mice were allocated to receive treatment at the time of meeting deterioration criteria, after a 2-hour delay or after a 4-hour delay. MEASUREMENTS AND MAIN RESULTS:Hourly delays in the initiation of antibiotic therapy led to progressively shortened survival in our model (p < 0.001). The addition of fluid resuscitation was unable to rescue animals, which received treatment 4 hours after meeting enrollment criteria. Systemic inflammation was increased, and host physiology was increasingly deranged with hourly delays to antibiotics. CONCLUSIONS:We conclude that antibiotic therapy is highly time sensitive, and efforts should be made to deliver this critical therapy as early as possible in sepsis, perhaps extending into the first point of medical contact outside the hospital.

SUBMITTER: Lewis AJ

PROVIDER: S-EPMC5899032 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial.

Lewis Anthony J AJ Griepentrog John E JE Zhang Xianghong X Angus Derek C DC Seymour Christopher W CW Rosengart Matthew R MR

Critical care medicine 20180501 5

<h4>Objectives</h4>Sepsis, the acute organ dysfunction caused by a dysregulated host response to infection, poses a serious public health burden. Current management includes early detection, initiation of antibiotics and fluids, and source control as necessary. Although observational data suggest that delays of even a few hours in the initiation of antibiotics or IV fluids is associated with survival, these findings are controversial. There are no randomized data in humans, and prior animal stud ...[more]

PMID: 29369056

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Project description:BACKGROUND:Clinical and biologic phenotypes of sepsis are proposed in human studies, yet it is unknown whether prognostic or drug response phenotypes are present in animal models of sepsis. Using a biotelemetry-enhanced, murine cecal ligation and puncture (CLP) model, we determined phenotypes of polymicrobial sepsis prior to physiologic deterioration, and the association between phenotypes and outcome in a randomized trial of prompt or delayed antibiotics and fluids. METHODS:We performed a secondary analysis of male C57BL/6J mice in two observational cohorts and two randomized, laboratory animal experimental trials. In cohort 1, mice (n?=?118) underwent biotelemetry-enhanced CLP, and we applied latent class mixed models to determine optimal number of phenotypes using clinical data collected between injury and physiologic deterioration. In cohort 2 (N?=?73 mice), inflammatory cytokines measured at 24?h after deterioration were explored by phenotype. In a subset of 46 mice enrolled in two trials from cohort 1, we tested the association of phenotypes with the response to immediate (0?h) vs. delayed (2 to 4?h) antibiotics or fluids initiated after physiologic deterioration. RESULTS:Latent class mixture modeling derived a two-class model in cohort 1. Class 2 (N?=?97) demonstrated a shorter time to deterioration (mean SD 7.3 (0.9) vs. 9.7 (3.2) h, p?<?0.001) and lower heart rate at 7?h after injury (mean (SD) 564 (55) vs. 626 (35) beats per minute, p?<?0.001). Overall mortality was similar between phenotypes (p?=?0.75). In cohort 2 used for biomarker measurement, class 2 mice had greater plasma concentrations of IL6 and IL10 at 24?h after CLP (p?=?0.05). In pilot randomized trials, the effects of sepsis treatment (immediate vs. delayed antibiotics) differed by phenotype (p?=?0.03), with immediate treatment associated with greater survival in class 2 mice only. Similar differential treatment effect by class was observed in the trial of immediate vs. delayed fluids (p?=?0.02). CONCLUSIONS:We identified two sepsis phenotypes in a murine cecal ligation and puncture model, one of which is characterized by faster deterioration and more severe inflammation. Response to treatment in a randomized trial of immediate versus delayed antibiotics and fluids differed on the basis of phenotype.

Project description:BACKGROUND:Due to the rise in incidence, the long term effect of sepsis are becoming more evident. There is increasing evidence that sepsis may result in an impaired health related quality of life. The aim of this study was to investigate whether health related quality of life is impaired in sepsis survivors and which clinical parameters are associated with the affected health related quality of life. METHODS:We analyzed 880 Short Form 36 (SF-36) questionnaires that were sent to sepsis survivors who participated in the Prehospital Antibiotics Against Sepsis (PHANTASi) trial. These questionnaires were sent by email, 28 days after discharge. Data entry and statistical analyses were performed in SPSS. The data from the general Dutch population, was obtained from the Netherlands Cancer Institute (NKI-AVL) and served as a control group. Subsequently, 567 sepsis survivors were matched to 567 controls. Non-parametric Wilcoxon signed-rank test was performed to compare these two groups. Within the group, we sought to explain the diminished health related quality of life by factor analysis. RESULTS:We found that sepsis survivors have a worse health related quality of life compared to the general Dutch population. This negative effect was more evident for the physical component than the mental component of health related quality of life. We found that health related quality of life was significantly altered by advancing age and female sex. We also found that the total length of stay (in the hospital) and (previous) comorbidity negatively affect the physical component of health related quality of life. CONCLUSION:In our study we found that health related quality of life in sepsis survivors, 28 days after discharge, is severely diminished in comparison with the general Dutch population. The physical domain is severely affected, whereas the mental domain is less influenced. The length of stay, comorbidity, advancing age and female sex all have a negative effect on the Physical Component Scale of the health related quality of life.

Project description:INTRODUCTION:Observational evidence suggests physiological benefits and lower mortality with lower chloride solutions; however, 0.9% saline remains the most widely used fluid worldwide. Given uncertainty regarding the association of lower chloride on mortality, it is unlikely that practice will change without direct randomised clinical trial (RCT) evidence. This pilot RCT will investigate the feasibility of a large-scale trial directly comparing low chloride with high chloride fluids in patients with septic shock. METHODS AND ANALYSIS:This is a randomised, concealed, blinded parallel-group multicentre pilot trial. We will include adult critically ill patients with septic shock, defined as ongoing hypotension despite 1 L of fluid, or a serum lactate >4?mmol/L, who are within 6?hours of hospital presentation or rapid response team activation. We will exclude patients if they have an aetiology of shock other than sepsis, if they have acute burn injury, elevated intracranial pressure, intent to withdraw life support or previous enrolment in this or a competing trial. Following informed consent, patients will be randomised to a low chloride fluid strategy or a high chloride fluid strategy for the duration of their ICU stay or until 30 days postrandomisation. Clinicians, patients, families and research staff will be blinded. The primary outcome for this trial will be feasibility, assessed by consent rate, recruitment success and protocol adherence. Patient-important clinical outcomes include mortality, receipt of renal replacement therapy, intensive care unit and hospital lengths of stay and surrogate outcomes of incidence of acidosis, hyperkalaemia and acute kidney injury. ETHICS AND DISSEMINATION:This pilot trial will test the feasibility of conducting the main trial, which will examine the effect of high versus low chloride fluids in patients with septic shock on patient-important outcomes. TRIAL REGISTRATION NUMBER:NCT02748382, registered 8 April 2016. PROTOCOL DATE:1 July 2016.

Project description:Background/aimsDespite evidence that preferential use of balanced/buffered fluids may improve outcomes compared with chloride-rich 0.9% saline, saline remains the most commonly used fluid for children with septic shock. We aim to determine if resuscitation with balanced/buffered fluids as part of usual care will improve outcomes, in part through reduced kidney injury and without an increase in adverse effects, compared to 0.9% saline for children with septic shock.MethodsThe Pragmatic Pediatric Trial of Balanced versus Normal Saline Fluid in Sepsis (PRoMPT BOLUS) study is an international, open-label pragmatic interventional trial being conducted at > 40 sites in the USA, Canada, and Australia/New Zealand starting on August 25, 2020, and continuing for 5 years. Children > 6 months to < 18 years treated for suspected septic shock with abnormal perfusion in an emergency department will be randomized to receive either balanced/buffered crystalloids (intervention) or 0.9% saline (control) for initial resuscitation and maintenance fluids for up to 48 h. Eligible patients are enrolled and randomized using serially numbered, opaque envelopes concurrent with clinical care. Given the life-threatening nature of septic shock and narrow therapeutic window to start fluid resuscitation, patients may be enrolled under "exception from informed consent" in the USA or "deferred consent" in Canada and Australia/New Zealand. Other than fluid type, all decisions about timing, volume, and rate of fluid administration remain at the discretion of the treating clinicians. For pragmatic reasons, clinicians will not be blinded to study fluid type. Anticipated enrollment is 8800 patients. The primary outcome will be major adverse kidney events within 30 days (MAKE30), a composite of death, renal replacement therapy, and persistent kidney dysfunction. Additional effectiveness, safety, and biologic outcomes will also be analyzed.DiscussionPRoMPT BOLUS will provide high-quality evidence for the comparative effectiveness of buffered/balanced crystalloids versus 0.9% saline for the initial fluid management of children with suspected septic shock in emergency settings.Trial registrationPRoMPT BOLUS was first registered at ClinicalTrials.gov ( NCT04102371 ) on September 25, 2019. Enrollment started on August 25, 2020.

Project description:BackgroundResuscitation with crystalloid fluid is a cornerstone of pediatric septic shock treatment. However, the optimal type of crystalloid fluid is unknown. We aimed to determine the feasibility of conducting a pragmatic randomized trial to compare balanced (lactated Ringer's [LR]) with 0.9% normal saline (NS) fluid resuscitation in children with suspected septic shock.MethodsOpen-label pragmatic randomized controlled trial at a single academic children's hospital from January to August 2018. Eligible patients were >6 months to <18 years old who were treated in the emergency department for suspected septic shock, operationalized as blood culture, parenteral antibiotics, and fluid resuscitation for abnormal perfusion. Screening, enrollment, and randomization were carried out by the clinical team as part of routine care. Patients were randomized to receive either LR or NS for up to 48 hours following randomization. Other than fluid type, all treatment decisions were at the clinical team's discretion. Feasibility outcomes included proportion of eligible patients enrolled, acceptability of enrollment via the U.S. federal exception from informed consent (EFIC) regulations, and adherence to randomized study fluid administration.ResultsOf 59 eligible patients, 50 (85%) were enrolled and randomized. Twenty-four were randomized to LR and 26 to NS. Only one (2%) of 44 patients enrolled using EFIC withdrew before study completion. Total median (interquartile range [IQR]) crystalloid fluid volume received during the intervention window was 107 (60 to 155) mL/kg and 98 (63 to 128) mL/kg in the LR and NS arms, respectively (p = 0.50). Patients randomized to LR received a median (IQR) of only 20% (13 to 32) of all study fluid as NS compared to 99% (64% to 100%) of study fluid as NS in the NS arm (absolute difference = 79%, 95% CI = 48% to 85%).ConclusionsA pragmatic study design proved feasible to study comparative effectiveness of LR versus NS fluid resuscitation for pediatric septic shock.

Project description:ObjectivesHospitalization is potentially detrimental to nursing home patients and resource demanding for the specialist health care. This study assessed if a brief training program in administrating intravenous fluids and antibiotics in nursing homes could reduce hospital transfers and ensure high quality care locally.DesignA pragmatic and modified cluster randomized stepped-wedge trial with randomization on nursing home level.Participants330 cases in 296 nursing home residents from 30 nursing homes were included. Cases were patients provided intravenous antibiotics or intravenous fluids, in nursing home or hospital. Primary outcome was localization of treatment, secondary outcomes were number of days treated, days of hospitalization among admitted patients, type of antibiotics used and 30-day mortality.InterventionThe nursing homes sequentially received a one-day educational program for the health workers including theory and practical training in intravenous treatment of dehydration and infection, run by two skilled nurses. After completing the training program, the nursing homes had competence to provide intravenous treatment locally.ResultsThe intervention had a highly significant effect on treatment in nursing homes (OR 8.35, 2.08 to 33.6; P<0.01, or RR 2.23, 1.48 to 2.56). The number treated in nursing homes was stable over time; the number treated in hospital gradually decreased (chi square for trend P< 0.001). Among patients receiving intravenous antibiotics in the nursing homes, 50 (46%) died within 30 days, compared to 30 (36%) treated in the hospital (P = 0.19). Among patients receiving intravenous fluids locally, 21 (19%) died within 30 days, compared to 2 (8%) in the hospital group (P = 0.34). Mortality was associated with reduced consciousness and elevated c-reactive protein.ConclusionsA brief educational program delivered to nursing home personnel was feasible and effective in reducing acute hospital admissions from nursing homes for treatment of dehydration and infections.

Dataset Information

Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial.

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Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial.

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