The Association of Premorbid Metformin Exposure With Mortality and Organ Dysfunction in Sepsis: A Systematic Review and Meta-Analysis.
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SUBMITTER: Tan K
PROVIDER: S-EPMC7063877 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
The Association of Premorbid Metformin Exposure With Mortality and Organ Dysfunction in Sepsis: A Systematic Review and Meta-Analysis.
Tan Kaiquan K Simpson Andrew A Huang Stephen S Tang Benjamin B Mclean Anthony A Nalos Marek M
Critical care explorations 20190417 4
To examine the association between premorbid metformin exposure and mortality, hyperlactatemia, and organ dysfunction in sepsis.<h4>Data sources</h4>PubMed and EMBASE (with Medline via Ovid) databases were searched for all studies of premorbid metformin exposure and sepsis published between January 1974 and August 2018.<h4>Study selection</h4>Studies of at least 20 patients with sepsis that reported data on metformin use, mortality, and/or organ dysfunction were independently selected.<h4>Data e ...[more]
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Project description:BackgroundThe effect of premorbid β-blocker exposure on clinical outcomes in patients with sepsis is not well characterized. We aimed to examine the association between premorbid β-blocker exposure and mortality in sepsis.MethodsEMBase, MEDLINE, and Cochrane databases were searched for all studies of premorbid β-blocker and sepsis. The search was last updated on 22 June 2019. Two reviewers independently assessed, selected, and abstracted data from studies reporting chronic β-blocker use prior to sepsis and mortality. Main data extracted were premorbid β-blocker exposure, mortality, study design, and patient data. Two reviewers independently assessed the risk of bias and quality of evidence.ResultsIn total, nine studies comprising 56,414 patients with sepsis including 6576 patients with premorbid exposure to β-blockers were eligible. For the primary outcome of mortality, two retrospective studies reported adjusted odds ratios showing a reduction in mortality with premorbid β-blocker exposure. One study showed that premorbid β-blocker exposure decreases mortality in patients with septic shock. Another study showed that continued β-blockade during sepsis is associated with decreased mortality.ConclusionThis systematic review suggests that β-blocker exposure prior to sepsis is associated with reduced mortality. There was insufficient data to conduct a bona fide meta-analysis. Whether the apparent reduction in mortality may be attributed to the mitigation of catecholamine excess is unclear.Trial registrationPROSPERO, CRD42019130558 registered June 12, 2019.
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Project description:Delayed antimicrobials are associated with poor outcomes in adult sepsis, but data relating antimicrobial timing to mortality and organ dysfunction in pediatric sepsis are limited. We sought to determine the impact of antimicrobial timing on mortality and organ dysfunction in pediatric patients with severe sepsis or septic shock.Retrospective observational study.PICU at an academic medical center.One hundred thirty patients treated for severe sepsis or septic shock.None.We determined if hourly delays from sepsis recognition to initial and first appropriate antimicrobial administration were associated with PICU mortality (primary outcome); ventilator-free, vasoactive-free, and organ failure-free days; and length of stay. Median time from sepsis recognition to initial antimicrobial administration was 140 minutes (interquartile range, 74-277 min) and to first appropriate antimicrobial was 177 minutes (90-550 min). An escalating risk of mortality was observed with each hour delay from sepsis recognition to antimicrobial administration, although this did not achieve significance until 3 hours. For patients with more than 3-hour delay to initial and first appropriate antimicrobials, the odds ratio for PICU mortality was 3.92 (95% CI, 1.27-12.06) and 3.59 (95% CI, 1.09-11.76), respectively. These associations persisted after adjustment for individual confounders and a propensity score analysis. After controlling for severity of illness, the odds ratio for PICU mortality increased to 4.84 (95% CI, 1.45-16.2) and 4.92 (95% CI, 1.30-18.58) for more than 3-hour delay to initial and first appropriate antimicrobials, respectively. Initial antimicrobial administration more than 3 hours was also associated with fewer organ failure-free days (16 [interquartile range, 1-23] vs 20 [interquartile range, 6-26]; p = 0.04).Delayed antimicrobial therapy was an independent risk factor for mortality and prolonged organ dysfunction in pediatric sepsis.
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Project description:IntroductionSepsis is a leading cause of admission to non-cardiological intensive care units (ICUs) and the second leading cause of death among ICU patients. We present the first extensive dataset on the epidemiology of severe sepsis treated in ICUs in Spain.MethodsWe conducted a prospective, observational, multicentre cohort study, carried out over two 3-month periods in 2002. Our aims were to determine the incidence of severe sepsis among adults in ICUs in a specific area in Spain, to determine the early (48 h) ICU and hospital mortality rates, as well as factors associated with the risk of death.ResultsA total of 4,317 patients were admitted and 2,619 patients were eligible for the study; 311 (11.9%) of these presented at least 1 episode of severe sepsis, and 324 (12.4%) episodes of severe sepsis were recorded. The estimated accumulated incidence for the population was 25 cases of severe sepsis attended in ICUs per 100,000 inhabitants per year. The mean logistic organ dysfunction system (LODS) upon admission was 6.3; the mean sepsis-related organ failure assessment (SOFA) score on the first day was 9.6. Two or more organ failures were present at diagnosis in 78.1% of the patients. A microbiological diagnosis of the infection was reached in 209 episodes of sepsis (64.5%) and the most common clinical diagnosis was pneumonia (42.8%). A total of 169 patients (54.3%) died in hospital, 150 (48.2%) of these in the ICU. The mortality in the first 48 h was 14.8%. Factors associated with early death were haematological failure and liver failure at diagnosis, acquisition of the infection prior to ICU admission, and total LODS score on admission. Factors associated with death in the hospital were age, chronic alcohol abuse, increased McCabe score, higher LODS on admission, DeltaSOFA 3-1 (defined as the difference in the total SOFA scores on day 3 and on day 1), and the difference of the area under the curve of the SOFA score throughout the first 15 days.ConclusionsWe found a high incidence of severe sepsis attended in the ICU and high ICU and hospital mortality rates. The high prevalence of multiple organ failure at diagnosis and the high mortality in the first 48 h suggests delays in diagnosis, in initial resuscitation, and/or in initiating appropriate antibiotic treatment.
| S-EPMC2646323 | biostudies-literature
Project description:Near-infrared spectroscopy (NIRS) noninvasively measures peripheral tissue oxygen saturation (StO?). NIRS may be utilized along with a vascular occlusion test, in which limb blood flow is temporarily occluded and released, to quantify a tissue bed's rate of oxygen exchange during ischemia and recovery. The objective of this study was to test the hypothesis that NIRS-derived StO? measures (StO? initial, StO? occlusion and StO? recovery) identify patients who are in shock and at increased risk of organ dysfunction (Sequential Organ Failure Assessment (SOFA) score ? 2 at 24 hours) and dying in the hospital.This prospective, observational study comprised a convenience sample of three cohorts of adult patients (age > 17 years) at three urban university emergency departments: (1) a septic shock cohort (systolic blood pressure < 90 after fluid challenge; the "SHOCK" cohort, n = 58), (2) a sepsis without shock cohort (the "SEPSIS" cohort, n = 60) and emergency department patients without infection (n = 50). We measured the StO? initial, StO? occlusion and StO? recovery slopes for all patients. Outcomes were sepsis syndrome severity, organ dysfunction (SOFA score at 24 hours) and in-hospital mortality.Among the 168 patients enrolled, mean initial StO? was lower in the SHOCK cohort than in the SEPSIS cohort (76% vs 81%), with an impaired occlusion slope (-10.2 and 5.2%/minute vs -13.1 and 4.4%/minute) and an impaired recovery slope (2.4 and 1.6%/second vs 3.9 and 1.7%/second) (P < 0.001 for all). The recovery slope was well-correlated with SOFA score at 24 hours (-0.35; P < 0.001), with a promising area under the curve (AUC) for mortality of 0.81. The occlusion slope correlation with SOFA score at 24 hours was 0.21 (P < 0.02), with a fair mortality AUC of 0.70. The initial StO? was significantly but less strongly correlated with SOFA score at 24 hours (-0.18; P < 0.04), with a poor mortality AUC of 0.56.NIRS measurements for the StO? initial, StO? occlusion and StO? recovery slope were abnormal in patients with septic shock compared to sepsis patients. The recovery slope was most strongly associated with organ dysfunction and mortality. Further validation is warranted.NCT01062685.
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Project description:Obesity is associated with an increased risk for pancreatic cancer, but it is unclear whether it affects mortality. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and mortality from pancreatic cancer.We performed a systematic search through January 2015 and identified studies of the association between premorbid obesity (at least 1 year prior to pancreatic cancer diagnosis) and pancreatic cancer-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence interval (CI), comparing data from obese (body mass index [BMI] ?30 kg/m(2)) and overweight subjects (BMI, 25.0-29.9 kg/m(2)) with those from individuals with a normal BMI (controls) by using random-effects model.We identified 13 studies (including 3 studies that pooled multiple cohorts); 5 studies included only patients with pancreatic cancer, whereas 8 studies evaluated pancreatic cancer-related mortality in cancer-free individuals at inception. In the meta-analysis, we observed increase in pancreatic cancer-related mortality among overweight (aHR, 1.06; 95% CI, 1.02-1.11; I(2) = 0) and obese individuals (aHR, 1.31; 95% CI, 1.20-1.42; I(2) = 43%), compared with controls; the association remained when we analyzed data from only subjects with pancreatic cancer. Each 1 kg/m(2) increase in BMI was associated with 10% increase in mortality (aHR, 1.10; 95% CI, 1.05-1.15) with minimal heterogeneity (I(2) = 0). In the subgroup analysis, obesity was associated with increased mortality in Western populations (11 studies; aHR, 1.32; 95% CI, 1.22-1.42) but not in Asia-Pacific populations (2 studies; aHR, 0.98; 95% CI, 0.76-1.27).In a systematic review and meta-analysis, we associated increasing level of obesity with increased mortality in patients with pancreatic cancer in Western but not Asia-Pacific populations. Strategies to reduce obesity-induced metabolic abnormalities might be developed to treat patients with pancreatic cancer.
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Project description:OBJECTIVES:To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis. DESIGN:Secondary analysis of a prospective, cross-sectional, point prevalence study. SETTING:International, multicenter PICUs. PATIENTS:Pediatric patients with severe sepsis identified on five separate days over a 1-year period. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Of 567 patients from 128 PICUs in 26 countries enrolled, 384 (68%) developed multiple organ dysfunction syndrome within 7 days of severe sepsis recognition. Three hundred twenty-seven had multiple organ dysfunction syndrome on the day of sepsis recognition. Ninety-one of these patients developed progressive multiple organ dysfunction syndrome, whereas an additional 57 patients subsequently developed new multiple organ dysfunction syndrome, yielding a total proportion with severe sepsis-associated new or progressive multiple organ dysfunction syndrome of 26%. Hospital mortality in patients with progressive multiple organ dysfunction syndrome was 51% compared with patients with new multiple organ dysfunction syndrome (28%) and those with single-organ dysfunction without multiple organ dysfunction syndrome (10%) (p < 0.001). Survivors of new or progressive multiple organ dysfunction syndrome also had a higher frequency of moderate to severe disability defined as a Pediatric Overall Performance Category score of greater than or equal to 3 and an increase of greater than or equal to 1 from baseline: 22% versus 29% versus 11% for progressive, new, and no multiple organ dysfunction syndrome, respectively (p < 0.001). CONCLUSIONS:Development of new or progressive multiple organ dysfunction syndrome is common (26%) in severe sepsis and is associated with a higher risk of morbidity and mortality than severe sepsis without new or progressive multiple organ dysfunction syndrome. Our data support the use of new or progressive multiple organ dysfunction syndrome as an important outcome in trials of pediatric severe sepsis although efforts are needed to validate whether reducing new or progressive multiple organ dysfunction syndrome leads to improvements in more definitive morbidity and mortality endpoints.
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Project description:BackgroundSepsis is a heterogeneous syndrome, and the identification of clinical subphenotypes is essential. Although organ dysfunction is a defining element of sepsis, subphenotypes of differential trajectory are not well studied. We sought to identify distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis.MethodsWe created 72-h SOFA score trajectories in patients with sepsis from four diverse intensive care unit (ICU) cohorts. We then used dynamic time warping (DTW) to compute heterogeneous SOFA trajectory similarities and hierarchical agglomerative clustering (HAC) to identify trajectory-based subphenotypes. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership at 6 and 24 h after being admitted to the ICU. The model was tested on three validation cohorts. Sensitivity analyses were performed with alternative clustering methodologies.ResultsA total of 4678, 3665, 12,282, and 4804 unique sepsis patients were included in development and three validation cohorts, respectively. Four subphenotypes were identified in the development cohort: Rapidly Worsening (n = 612, 13.1%), Delayed Worsening (n = 960, 20.5%), Rapidly Improving (n = 1932, 41.3%), and Delayed Improving (n = 1174, 25.1%). Baseline characteristics, including the pattern of organ dysfunction, varied between subphenotypes. Rapidly Worsening was defined by a higher comorbidity burden, acidosis, and visceral organ dysfunction. Rapidly Improving was defined by vasopressor use without acidosis. Outcomes differed across the subphenotypes, Rapidly Worsening had the highest in-hospital mortality (28.3%, P-value < 0.001), despite a lower SOFA (mean: 4.5) at ICU admission compared to Rapidly Improving (mortality:5.5%, mean SOFA: 5.5). An overall prediction accuracy of 0.78 (95% CI, [0.77, 0.8]) was obtained at 6 h after ICU admission, which increased to 0.87 (95% CI, [0.86, 0.88]) at 24 h. Similar subphenotypes were replicated in three validation cohorts. The majority of patients with sepsis have an improving phenotype with a lower mortality risk; however, they make up over 20% of all deaths due to their larger numbers.ConclusionsFour novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Identifying trajectory-based subphenotypes has immediate implications for the powering and predictive enrichment of clinical trials. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets and identify more precise populations and endpoints for clinical trials.
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Project description:Objective: To evaluate serial ferritin levels measured in the initial 72 h of admission as a biomarker for new and progressive multi organ dysfunction syndrome (NPMODS) and mortality (unfavorable outcomes) in critically ill children with sepsis due to tropical infections. Material and Methods: In this prospective observational study from a tertiary care teaching hospital in India, children 3 month to 12 years with a diagnosis of acute febrile illness and any two features suggesting tropical infections [cytopenia (platelet count <1,00,000/cu.mm, total leucocyte count <4,000/cu.mm), hepatomegaly and/or splenomegaly, lymphadenopathy, systemic signs (rash, edema), respiratory distress, and encephalopathy not accounted by localized infection] were eligible for inclusion. Children with known or suspected disorder of iron metabolism were excluded. Primary outcome was to determine the association of serial ferritin levels with mortality and NPMODS. Secondary outcomes included estimation of the prevalence of hyperferritinemia and comparison of risk prediction scores with serial ferritin measurement in predicting unfavorable outcomes. Measurements and Main Results: In the 202 children enrolled, diagnosis could be established in 133 (65.8%) children. Scrub typhus and dengue were the most common infections. Median (IQR) ferritin measured at admission (n = 183) and on day 3 (n = 120) of hospital stay were 798 (378, 3,205) μg/L and 429 (213,680) μg/L, respectively. Majority (n = 180, 89.1%) had MODS at admission defined as per International pediatric sepsis consensus conference. NPMODS occurred in 47 (23.3%) children of whom 37 (18.3%) died. Children with three or less organ dysfunctions had lower mortality. Neither admission ferritin values nor the percentage change over 72 h was different between children with favorable and unfavorable outcomes. Pediatric Risk of Mortality (PRISM-III) and daily Pediatric Logistic Organ Dysfunction score (dPELOD2 score) were significantly different in those with unfavorable outcomes. Admission ferritin levels and percentage change in 72 h had poor discriminatory power for mortality with AUC of 0.53 (0.53, 0.67) and 0.50 (0.50, 0.64), respectively. dPELOD2 had the best discriminatory power for mortality with AUC of 0.89 (0.89, 0.95). Conclusions: Serial ferritin estimation predicted neither organ dysfunction nor mortality in pediatric sepsis with tropical infections. dPELOD-2 and PRISM-III predicted unfavorable outcomes better than ferritin. The current diagnostic criteria for MODS overestimated organ dysfunctions in tropical infections and hence may need modification with further validation in this epidemiological cohort.
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Project description:OBJECTIVE:At least half of patients with systemic lupus erythematosus (SLE) develop organ damage as a consequence of autoimmune disease or long-term therapeutic steroid use. This study synthesised evidence on the association between organ damage and mortality in patients with SLE. DESIGN:Systematic review and meta-analysis. METHODS:Electronic searches were performed in PubMed, Embase, Cochrane Library and Latin American and Caribbean Health Sciences Literature for observational (cohort, case-control and cross-sectional) studies published between January 2000 and February 2017. Included studies reported HRs or ORs on the association between organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score) and mortality. Study quality was assessed using the modified Newcastle-Ottawa assessment. Pooled HRs were obtained using the DerSimonian and Laird random-effects model. Heterogeneity was assessed using the Cochrane Q (Q) and I2 statistics. RESULTS:The search yielded 10 420 articles, from which 21 longitudinal studies were selected. Most studies (85%) were of high quality. For 10 studies evaluating organ damage (SDI) as a continuous variable and reporting HR as a measure of association, a 1-unit increase in SDI was associated with increased mortality; pooled HR was 1.34 (95% CI: 1.24 to 1.44, p<0.001; Q p=0.027, I2=52.1%). Exclusion of one potential outlying study reduced heterogeneity with minimal impact on pooled HR (1.33 (95% CI: 1.25 to 1.42), p<0.001, Q p=0.087, I2=42.0%). The 11 remaining studies, although they could not be aggregated because of their varying patient populations and analyses, consistently demonstrated that greater SDI was associated with increased mortality. CONCLUSIONS:Organ damage in SLE is consistently associated with increased mortality across studies from various countries. Modifying the disease course with effective therapies and steroid-sparing regimens may reduce organ damage, improve outcomes and decrease mortality for patients with SLE.
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Project description:OBJECTIVES:Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis. DESIGN:Prospective observational study SETTING:: Single academic PICU. PATIENTS:One-hundred sixty-seven children with sepsis/septic shock and 19 PICU controls without sepsis, infection, or organ dysfunction. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Mitochondrial respiration and content were measured in peripheral blood mononuclear cells on days 1-2, 3-5, and 8-14 after sepsis recognition or once for controls. Severity and duration of organ dysfunction were determined using the Pediatric Logistic Organ Dysfunction score and organ failure-free days through day 28. Day 1-2 maximal uncoupled respiration (9.7?±?7.7 vs 13.7?±?4.1 pmol O2/s/10 cells; p = 0.02) and spare respiratory capacity (an index of bioenergetic reserve: 6.2?±?4.3 vs 9.6?±?3.1; p = 0.005) were lower in sepsis than controls. Mitochondrial content, measured by mitochondrial DNA/nuclear DNA, was higher in sepsis on day 1-2 than controls (p = 0.04) and increased in sepsis patients who had improving spare respiratory capacity over time (p = 0.005). Mitochondrial respiration and content were not associated with day 1-2 Pediatric Logistic Organ Dysfunction score, but low spare respiratory capacity was associated with higher Pediatric Logistic Organ Dysfunction score on day 3-5. Persistently low spare respiratory capacity was predictive of residual organ dysfunction on day 14 (area under the receiver operating characteristic, 0.72; 95% CI, 0.61-0.84) and trended toward fewer organ failure-free days although day 28 (? coefficient, -0.64; 95% CI, -1.35 to 0.06; p = 0.08). CONCLUSIONS:Mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis despite an increase in mitochondrial content. Over time, a rise in mitochondrial DNA tracked with improved respiration. Although initial mitochondrial alterations in peripheral blood mononuclear cells were unrelated to organ dysfunction, persistently low respiration was associated with slower recovery from organ dysfunction.
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