Lower vs Higher Fluid Volumes in Adult Patients With Sepsis: An Updated Systematic Review With Meta-Analysis and Trial Sequential Analysis.

BACKGROUND: IV fluids are recommended for adults with sepsis. However, the optimal strategy for IV fluid management in sepsis is unknown, and clinical equipoise exists. RESEARCH QUESTION: Do lower vs higher fluid volumes improve patient-important outcomes in adult patients with sepsis? STUDY DESIGN AND METHODS: We updated a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials assessing lower vs higher IV fluid volumes in adult patients with sepsis. The coprimary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. We followed the recommendations from the Cochrane Handbook and used the Grading of Recommendations Assessment, Development and Evaluation approach. Primary conclusions were based on trials with low risk of bias if available. RESULTS: We included 13 trials (N = 4,006) with four trials (n = 3,385) added to this update. The meta-analysis of all-cause mortality in eight trials with low risk of bias showed a relative risk of 0.99 (97% CI, 0.89-1.10; moderate certainty evidence). Six trials with predefined definitions of serious adverse events showed a relative risk of 0.95 (97% CI, 0.83-1.07; low certainty evidence). Health-related quality of life was not reported. INTERPRETATION: Among adult patients with sepsis, lower IV fluid volumes probably result in little to no difference in all-cause mortality compared with higher IV fluid volumes, but the interpretation is limited by imprecision in the estimate, which does not exclude potential benefit or harm. Similarly, the evidence suggests lower IV fluid volumes result in little to no difference in serious adverse events. No trials reported on health-related quality of life. TRIAL REGISTRATION: PROSPERO; No.: CRD42022312572; URL: https://www.crd.york.ac.uk/prospero/.

Bacteremia Prediction With Prognostic Scores and a Causal Probabilistic Network - A Cohort Study of Emergency Department Patients.

BACKGROUND: Physicians tend to overestimate patients' pretest probability of having bacteremia. The low yield of blood cultures and contaminants is associated with significant financial cost, as well as increased length of stay and unnecessary antibiotic treatment. OBJECTIVE: This study examined the abilities of the National Early Warning Score (NEWS), the Quick Sequential Organ Failure Assessment (qSOFA), the Modified Sequential Organ Failure Assessment (mSOFA), and two versions of the causal probabilistic network, SepsisFinder™ (SF) to predict bacteremia in adult emergency department (ED) patients. METHODS: This cohort study included adult ED patients from a large urban, academic tertiary hospital, with blood cultures obtained within 24 h of admission between 2016 and 2017. The outcome measure was true bacteremia. NEWS, qSOFA, mSOFA, and the two versions of SF score were calculated for all patients based on the first available full set of vital signs within 2 h and laboratory values within 6 h after drawing the blood cultures. Area under the receiver operating characteristic curve (AUROC) was calculated for each scoring system. RESULTS: The study included 3106 ED patients, of which 199 (6.4%) patients had true bacteremia. The AUROCs for prediction of bacteremia were: NEWS = 0.65, qSOFA = 0.60, SF I = 0.65, mSOFA = 0.71, and SF II = 0.80. CONCLUSIONS: Scoring systems using only vital signs, NEWS, and SF I showed moderate abilities in predicting bacteremia, whereas qSOFA performed poorly. Scoring systems using both vital signs and laboratory values, mSOFA and especially SF II, showed good abilities in predicting bacteremia.

Intraoperative respiratory and hemodynamic strategies for reducing nausea, vomiting, and pain after surgery: Systematic review and meta-analysis.

BACKGROUND: Despite improved medical treatment strategies, postoperative pain, nausea, and vomiting remain major challenges. This systematic review investigated the relationship between perioperative respiratory and hemodynamic interventions and postoperative pain, nausea, and vomiting. METHODS: PubMed and Embase were searched on March 8, 2021 for randomized clinical trials investigating the effect of perioperative respiratory or hemodynamic interventions in adults undergoing non-cardiac surgery. Investigators reviewed trials for relevance, extracted data, and assessed risk of bias. Meta-analyses were performed when feasible. GRADE was used to assess the certainty of the evidence. RESULTS: This review included 65 original trials; of these 48% had pain, nausea, and/or vomiting as the primary focus. No reduction of postoperative pain was found in meta-analyses when comparing recruitment maneuvers with no recruitment, high (80%) to low (30%) fraction of oxygen, low (5-7 ml/kg) to high (9-12 ml/kg) tidal volume, or goal-directed hemodynamic therapy to standard care. In the meta-analysis comparing recruitment maneuvers with no recruitment maneuvers, patients undergoing laparoscopic gynecological surgery had less shoulder pain 24 h postoperatively (mean difference in the numeric rating scale from 0 to 10: -1.1, 95% CI: -1.7, -0.5). In meta-analyses, comparing high to low fraction of inspired oxygen and goal-directed hemodynamic therapy to standard care in patients undergoing abdominal surgery, the risk of postoperative nausea and vomiting was reduced (odds ratio: 0.45, 95% CI: 0.24, 0.87 and 0.48, 95% CI: 0.27, 0.85). The certainty in the evidence was mostly very low to low. The results should be considered exploratory given the lack of prespecified hypotheses and corresponding risk of Type 1 errors. CONCLUSION: There is limited evidence regarding the impact of intraoperative respiratory and hemodynamic interventions on postoperative pain or nausea and vomiting. More definitive trials are needed to guide clinical care within this area.

Fraction of inspired oxygen during general anesthesia for non-cardiac surgery: Systematic review and meta-analysis.

BACKGROUND: Controversy exists regarding the effects of a high versus a low intraoperative fraction of inspired oxygen (FiO2 ) in adults undergoing general anesthesia. This systematic review and meta-analysis investigated the effect of a high versus a low FiO2 on postoperative outcomes. METHODS: PubMed and Embase were searched on March 22, 2022 for randomized clinical trials investigating the effect of different FiO2 levels in adults undergoing general anesthesia for non-cardiac surgery. Two investigators independently reviewed studies for relevance, extracted data, and assessed risk of bias. Meta-analyses were performed for relevant outcomes, and potential effect measure modification was assessed in subgroup analyses and meta-regression. The evidence certainty was evaluated using GRADE. RESULTS: This review included 25 original trials investigating the effect of a high (mostly 80%) versus a low (mostly 30%) FiO2 . Risk of bias was intermediate for all trials. A high FiO2 did not result in a significant reduction in surgical site infections (OR: 0.91, 95% CI 0.81-1.02 [p = .10]). No effect was found for all other included outcomes, including mortality (OR = 1.27, 95% CI: 0.90-1.79 [p = .18]) and hospital length of stay (mean difference = 0.03 days, 95% CI -0.25 to 0.30 [p = .84). Results from subgroup analyses and meta-regression did not identify any clear effect modifiers across outcomes. The certainty of evidence (GRADE) was rated as low for most outcomes. CONCLUSIONS: In adults undergoing general anesthesia for non-cardiac surgery, a high FiO2 did not improve outcomes including surgical site infections, length of stay, or mortality. However, the certainty of the evidence was assessed as low.

Restrictive fluids versus standard care in adults with sepsis in the emergency department (REFACED): A multicenter, randomized feasibility trial.

BACKGROUND: Fluid treatment in sepsis is a challenge and clinical equipoise exists regarding intravenous (IV) volumes. We aimed to determine whether a 24-h protocol restricting IV fluid was feasible in adult patients with sepsis without shock presenting to the emergency department (ED). METHODS: The REFACED Sepsis trial is an investigator-initiated, multicenter, randomized, open-label, feasibility trial, assigning sepsis patients without shock to 24 h of restrictive, crystal IV fluid administration or standard care. In the IV fluid restriction group fluid boluses were only permitted if predefined criteria for hypoperfusion occurred. Standard care was at the discretion of the treating team. The primary outcome was total IV crystalloid fluid volumes at 24 h after randomization. Secondary outcomes included total fluid volumes, feasibility measures, and patient-centered outcomes. RESULTS: We included 123 patients (restrictive 61 patients and standard care 62 patients) in the primary analysis. A total of 32% (95% confidence interval [CI] 28%-37%) of eligible patients meeting all inclusion criteria and no exclusion criteria were included. At 24 h, the mean (±SD) IV crystalloid fluid volumes were 562 (±1076) ml versus 1370 (±1438) ml in the restrictive versus standard care group (mean difference -801 ml, 95% CI -1257 to -345 ml, p = 0.001). Protocol violations occurred in 21 (34%) patients in the fluid-restrictive group. There were no differences between groups in adverse events, use of mechanical ventilation or vasopressors, acute kidney failure, length of stay, or mortality. CONCLUSIONS: A protocol restricting IV crystalloid fluids in ED patients with sepsis reduced 24-h fluid volumes compared to standard care. A future trial powered toward patient-centered outcomes appears feasible.

Ventilation Strategies During General Anesthesia for Noncardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: The optimal ventilation strategy during general anesthesia is unclear. This systematic review investigated the relationship between ventilation targets or strategies (eg, positive end-expiratory pressure [PEEP], tidal volume, and recruitment maneuvers) and postoperative outcomes. METHODS: PubMed and Embase were searched on March 8, 2021, for randomized trials investigating the effect of different respiratory targets or strategies on adults undergoing noncardiac surgery. Two investigators reviewed trials for relevance, extracted data, and assessed risk of bias. Meta-analyses were performed for relevant outcomes, and several subgroup analyses were conducted. The certainty of evidence was evaluated using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: This review included 63 trials with 65 comparisons. Risk of bias was intermediate for all trials. In the meta-analyses, lung-protective ventilation (ie, low tidal volume with PEEP) reduced the risk of combined pulmonary complications (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.28-0.49; 9 trials; 1106 patients), atelectasis (OR, 0.39; 95% CI, 0.25-0.60; 8 trials; 895 patients), and need for postoperative mechanical ventilation (OR, 0.36; 95% CI, 0.13-1.00; 5 trials; 636 patients). Recruitment maneuvers reduced the risk of atelectasis (OR, 0.44; 95% CI, 0.21-0.92; 5 trials; 328 patients). We found no clear effect of tidal volume, higher versus lower PEEP, or recruitment maneuvers on postoperative pulmonary complications when evaluated individually. For all comparisons across targets, no effect was found on mortality or hospital length of stay. No effect measure modifiers were found in subgroup analyses. The certainty of evidence was rated as very low, low, or moderate depending on the intervention and outcome. CONCLUSIONS: Although lung-protective ventilation results in a decrease in pulmonary complications, randomized clinical trials provide only limited evidence to guide specific ventilation strategies during general anesthesia for adults undergoing noncardiac surgery.

Goal-directed haemodynamic therapy during general anaesthesia for noncardiac surgery: a systematic review and meta-analysis.

BACKGROUND: During general anaesthesia for noncardiac surgery, there remain knowledge gaps regarding the effect of goal-directed haemodynamic therapy on patient-centred outcomes. METHODS: Included clinical trials investigated goal-directed haemodynamic therapy during general anaesthesia in adults undergoing noncardiac surgery and reported at least one patient-centred postoperative outcome. PubMed and Embase were searched for relevant articles on March 8, 2021. Two investigators performed abstract screening, full-text review, data extraction, and bias assessment. The primary outcomes were mortality and hospital length of stay, whereas 15 postoperative complications were included based on availability. From a main pool of comparable trials, meta-analyses were performed on trials with homogenous outcome definitions. Certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). RESULTS: The main pool consisted of 76 trials with intermediate risk of bias for most outcomes. Overall, goal-directed haemodynamic therapy might reduce mortality (odds ratio=0.84; 95% confidence interval [CI], 0.64 to 1.09) and shorten length of stay (mean difference=-0.72 days; 95% CI, -1.10 to -0.35) but with low certainty in the evidence. For both outcomes, larger effects favouring goal-directed haemodynamic therapy were seen in abdominal surgery, very high-risk surgery, and using targets based on preload variation by the respiratory cycle. However, formal tests for subgroup differences were not statistically significant. Goal-directed haemodynamic therapy decreased risk of several postoperative outcomes, but only infectious outcomes and anastomotic leakage reached moderate certainty of evidence. CONCLUSIONS: Goal-directed haemodynamic therapy during general anaesthesia might decrease mortality, hospital length of stay, and several postoperative complications. Only infectious postoperative complications and anastomotic leakage reached moderate certainty in the evidence.

Twenty-four-hour fluid administration in emergency department patients with suspected infection: A multicenter, prospective, observational study.

BACKGROUND: To describe 24-hour fluid administration in emergency department (ED) patients with suspected infection. METHODS: A prospective, multicenter, observational study conducted in three Danish hospitals, January 20 to March 2, 2020. We included consecutive adult ED patients with suspected infection (drawing of blood culture and/or intravenous antibiotic administration within 6 hours of admission). Oral and intravenous fluids were registered for 24 hours. PRIMARY OUTCOME: 24-hour total fluid volume. We used linear regression to investigate patient and disease characteristics' effect on 24-hour fluids and to estimate the proportion of the variance in fluid administration explained by potential predictors. RESULTS: 734 patients had 24-hour fluids available: 387 patients had simple infection, 339 sepsis, eight septic shock. Mean total 24-hour fluid volumes were 3656 mL (standard deviation [SD]:1675), 3762 mL (SD: 1839), and 6080 mL (SD: 3978) for the groups, respectively. Fluid volumes varied markedly. Increasing age (mean difference [MD]: 60-79 years: -470 mL [95% CI: -789, -150], +80 years; -974 mL [95% CI: -1307, -640]), do-not-resuscitate orders (MD: -466 mL [95% CI: -797, -135]), and preexisting atrial fibrillation (MD: -367 mL [95% CI: -661, -72) were associated with less fluid. Systolic blood pressure < 100 mmHg (MD: 1182 mL [95% CI: 820, 1543]), mean arterial pressure < 65 mmHg (MD: 1317 mL [95% CI: 770, 1864]), lactate ≥ 2 mmol/L (MD: 655 mL [95% CI: 306, 1005]), heart rate > 120 min (MD: 566 [95% CI: 169, 962]), low (MD: 1963 mL [95% CI: 813, 3112]) and high temperature (MD: 489 mL [95% CI: 234, 742]), SOFA score > 5 (MD: 1005 mL [95% CI: 501, 510]), and new-onset atrial fibrillation (MD: 498 mL [95% CI: 30, 965]) were associated with more fluid. Clinical variables explained 37% of fluid variation among patients. CONCLUSIONS: Patients with simple infection and sepsis received equal fluid volumes. Fluid volumes varied markedly, a variation that was partly explained by clinical characteristics.

Including oxygen supplement in the early warning score: a prediction study comparing TOKS, modified TOKS and NEWS in a cohort of emergency patients.

BACKGROUND: Early warning scores (EWS) are widely used in emergency departments and on general wards to detect critical illness and deterioration. TOKS ("Tidlig Opsporing af Kritisk Sygdom") is an early warning score used in Central Denmark Region to monitor hospitalized patients. The objective of this study is to investigate whether inclusion of supplement in the TOKS algorithm (modified TOKS; mTOKS), would improve the ability to predict 7-day mortality. Secondarily, we compare the discriminatory ability between TOKS, mTOKS and the National Early Warning Score (NEWS). METHODS: This is a prediction study including a cohort of adult patients who attended an emergency department in Central Denmark Region during a 3-month period in 2015. The discriminatory ability of TOKS, mTOKS and NEWS was evaluated by calculating the area under the receiver operating characteristics- curve (AUROC) with 7-day mortality as outcome. mTOKS was defined by adding 2 points for oxygen supplement to the normal TOKS score. RESULTS: 18.853 patients were included. AUROC for TOKS: 0,78 (95%-CI: 0,76-0,81). AUROC for mTOKS: 0,81 (95 %-CI: 0,78-0,83). AUROC for NEWS: 0,83 (95%-CI: 0,80-0,85). The predictive ability of all three early warning scores are statistically significantly different from each other (p-value < 0,01). CONCLUSION: The discriminatory ability of TOKS improved statistically by including oxygen supplement. All models showed moderate to good discriminatory ability.

The 7-day mortality associated with an early warning score varies between age groups in a cohort of adult Danish emergency department patients.

INTRODUCTION: Early warning scores are designed for monitoring hospitalized patients and enable a timely response to deviating vital signs. The aim of this study was to examine whether 7-day mortality, associated with an initial early warning score, differs between age groups. Our hypothesis was that elderly patients are at greater risk of dying compared to a younger patient with a similar early warning score. METHODS: This observational cohort study included adult emergency department patients from five hospitals in Denmark over three consecutive months in 2015. Logistic regression was used to examine the relationship between patients' initial early warning scores category (0, 1-2, 3-4, 5-6, 7+) and 7-day mortality in different age groups (16-59 years, 60-79 years, 80+ years). Mortality rates in each early warning scores category are compared between the youngest patients (16-59 years, reference group) and the two older age groups (60-79 years and 80+ years). RESULTS: A total of 19 123 emergency patients were included. The senior age groups (60-79 years and 80+ years) both displayed significantly higher 7-day mortality, in all early warning score categories, when compared to the youngest patients (16-59 years). The mortality difference between the youngest (16-59 years) and oldest age group (80+ years) remained significant in all early warning scores categories after adjusting for comorbidity. CONCLUSION: Our findings show that the oldest emergency department patients (80+ years) have a higher 7-day mortality compared to young patients (16-59 years) with a similar initial early warning score.

Number of organ dysfunctions predicts mortality in emergency department patients with suspected infection: a multicenter validation study.

OBJECTIVES: The aim of this study was to validate the association between number of organ dysfunctions and mortality in emergency department (ED) patients with suspected infection. METHODS: This study was conducted at two medical care center EDs. The internal validation set was a prospective cohort study conducted in Boston, USA. The external validation set was a retrospective case-control study conducted in Aarhus, Denmark. The study included adult patients (>18 years) with clinically suspected infection. Laboratory results and clinical data were used to assess organ dysfunctions. Inhospital mortality was the outcome measure. Multivariate logistic regression was used to determine the independent mortality odds for number and types of organ dysfunctions. RESULTS: We enrolled 4952 (internal) and 483 (external) patients. The mortality rate significantly increased with increasing number of organ dysfunctions: internal validation: 0 organ dysfunctions: 0.5% mortality, 1: 3.6%, 2: 9.5%, 3: 17%, and 4 or more: 37%; external validation: 2.2, 6.7, 17, 41, and 57% mortality (both P<0.001 for trend). Age-adjusted and comorbidity-adjusted number of organ dysfunctions remained an independent predictor. The effect of specific types of organ dysfunction on mortality was most pronounced for hematologic [odds ratio (OR) 3.3 (95% confidence interval (CI) 2.0-5.4)], metabolic [OR 3.3 (95% CI 2.4-4.6); internal validation], and cardiovascular dysfunctions [OR 14 (95% CI 3.7-50); external validation]. CONCLUSION: The number of organ dysfunctions predicts sepsis mortality.

Prediction of bacteremia in the emergency department: an external validation of a clinical decision rule.

OBJECTIVE: The objective of this study was to validate a previously published clinical decision rule for predicting a positive blood culture in emergency department (ED) patients with suspected infection on the basis of major and minor criteria and a total score (Shapiro et al., J Emerg Med, 2008; 35:255-264). METHODS: This is a retrospective matched cohort study of adult ED patients with blood cultures obtained from 1 January 2011 through to 31 December 2011. ED patients with blood culture-confirmed bacteremia were matched 1 : 3 with patients with negative cultures. The outcome was 'true bacteremia'. Data on clinical history, comorbid illnesses, physical observations, and laboratory tests were used to evaluate the application of the clinical decision rule. We report the sensitivity, specificity, and area under the curve. RESULTS: Among 1526 patients, 105 (6.9%) patients were classified with true bacteremia. The sensitivity of the prediction rule was 94% (95% confidence interval, 88-98%) and the specificity was 48% (95% confidence interval, 42-53%). The area under the receiver-operating characteristics curve was 0.83. CONCLUSION: The clinical decision rule performed well in our ED setting and is likely to be a useful supplement to clinical judgment.

Predictors of intensive care unit transfer or death in emergency department patients with suspected infection.

OBJECTIVES: The aim of this study was to identify predictors of ICU transfer or death within 48 h obtainable within 4 h of admission in emergency department (ED) patients with suspected infection. PATIENTS AND METHODS: This was a nested case-control study based on a prospective cohort of adult patients admitted to the ED at Aarhus University Hospital, in 2011, who had a blood culture drawn upon admission. Cases met the composite endpoint of ICU transfer or death within 4-48 h of admission. We identified up to three controls for each case, matched by age and admission month. We collected data on possible predictors from medical records. Univariate and multivariate logistic regressions were performed to identify predictors. RESULTS: A total of 1578 patients had a blood culture drawn in the ED. Among these, 61 (4%) patients were transferred to an ICU and 15 (1%) patients died within 4-48 h of admission. We could obtain complete data on 59 cases, which were matched to 165 controls. Significant predictors of ICU transfer or death within 4-48 h included temperature as a continuous variable, and neurologic (altered mental status), respiratory, and cardiovascular dysfunction. CONCLUSION: Readily available clinical and laboratory variables at arrival in the ED can support identification of late deterioration leading to ICU transfer or death within 48 h of admission.