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PURPOSE: Disease heterogeneity in coronavirus disease 2019 (COVID-19) may render the current one-size-fits-all treatment approach suboptimal. We aimed to identify and immunologically characterize clinical phenotypes among critically ill COVID-19 patients, and to assess heterogeneity of corticosteroid treatment effect. METHODS: We applied consensus k-means clustering on 21 clinical parameters obtained within 24 h after admission to the intensive care unit (ICU) from 13,279 COVID-19 patients admitted to 82 Dutch ICUs from February 2020 to February 2022. Derived phenotypes were reproduced in 6225 COVID-19 ICU patients from Spain (February 2020 to December 2021). Longitudinal immunological characterization was performed in three COVID-19 ICU cohorts from the Netherlands and Germany, and associations between corticosteroid treatment and survival were assessed across phenotypes. RESULTS: We derived three phenotypes: COVIDICU1 (43% of patients) consisted of younger patients with the lowest Acute Physiology And Chronic Health Evaluation (APACHE) scores, highest body mass index (BMI), lowest PaO2/FiO2 ratio, and a 90-day in-hospital mortality rate of 18%. COVIDICU2 patients (37%) had the lowest BMI, were older and had higher APACHE scores and mortality rate (24%) than COVIDICU1. Patients with COVIDICU3 (20%) were the eldest with the most comorbidities, the highest APACHE scores, acute kidney injury and metabolic dysregulations, and the highest mortality rate (47%). These patients also displayed the most pronounced inflammatory response. Corticosteroid therapy started at day 5 [2-9] after ICU admission and administered for 5 [3-7] days was associated with an increased risk for 90-day mortality in patients with the COVIDICU1 and COVIDICU2 phenotypes (hazard ratio [HR] 1.59 [1.09-2.31], p = 0.015 and HR 1.79 [1.42-2.26], p < 0.001, respectively), but not in patients with the COVIDICU3 phenotype (HR 1.08 [0.76-1.54], p = 0.654). CONCLUSION: Our multinational study identified three distinct clinical COVID-19 phenotypes, each exhibiting marked differences in demographic, clinical, and immunological features, and in the response to late and short-term corticosteroid treatment.
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BACKGROUND: Acute limb ischemia (ALI) is a morbid and deadly diagnosis. However, existing epidemiologic studies describing ALI predate the introduction of the Affordable Care Act in 2010 and direct oral anticoagulants in 2011. Thus, we synergized the National Inpatient Sample (NIS) and United States Census to define contemporary trends in the incidence, treatment, and outcomes of ALI in the US. METHODS: We included emergent admissions of adults with primary diagnosis of lower extremity ALI in survey-weighted NIS data (2005-2020). Mann-Kendal trend test evaluated ALI incidence (primary outcome), anticoagulation usage, insurance coverage, revascularization type, and in-hospital amputation/death. Multivariable logistic regression quantified covariate associations with in-hospital amputation/death. RESULTS: Of the 582,322,862 estimated hospitalizations in the NIS, 227,440 met the inclusion criteria (mean age 68.80 years, 49.94% women, 76.66% White). ALI incidence peaked in 2006 (7.16/100,000 person-years) but has declined since 2015 to 4.16/100,000 person-years in 2020 (ptrend = 0.008). Endovascular revascularization, anticoagulation, and Medicaid coverage increased, while self-pay insurance decreased (ptrend < 0.05). Amputation rates significantly decreased from 8.04 to 6.54% (ptrend = 0.01) while death rate remained at 5.59% (ptrend = 0.16) over the study period. Prehospitalization anticoagulation was associated with decreased amputation (adjusted odds ratio [aOR] = 0.74 (95% confidence interval [CI] 0.65-0.84)) and death (aOR = 0.50 (95% CI 0.43-0.57)). When controlling for covariates, women had a higher risk of death (aOR = 1.17 (95% CI 1.07-1.27), P < 0.0001), while Black patients had a higher risk of amputation (aOR = 1.24 (95% CI 1.10-1.41), P < 0.0001). CONCLUSIONS: Our US population based epidemiological study demonstrates that ALI incidence and in-hospital amputation rates are decreasing, while mortality remains unchanged. We further highlight the ongoing need for ALI investigation specifically as it relates to access to care, antithrombotic therapy use, treatment strategy, and strategies to combat gender and racial disparities.
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Importance: Frailty is associated with adverse outcomes after even minor physiologic stressors. The validated Risk Analysis Index (RAI) quantifies frailty; however, existing methods limit application to in-person interview (clinical RAI) and quality improvement datasets (administrative RAI). Objective: To expand the utility of the RAI utility to available International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) administrative data, using the National Inpatient Sample (NIS). Design, Setting, and Participants: RAI parameters were systematically adapted to ICD-10-CM codes (RAI-ICD) and were derived (NIS 2019) and validated (NIS 2020). The primary analysis included survey-weighed discharge data among adults undergoing major surgical procedures. Additional external validation occurred by including all operative and nonoperative hospitalizations in the NIS (2020) and in a multihospital health care system (UPMC, 2021-2022). Data analysis was conducted from January to May 2023. Exposures: RAI parameters and in-hospital mortality. Main Outcomes and Measures: The association of RAI parameters with in-hospital mortality was calculated and weighted using logistic regression, generating an integerized RAI-ICD score. After initial validation, thresholds defining categories of frailty were selected by a full complement of test statistics. Rates of elective admission, length of stay, hospital charges, and in-hospital mortality were compared across frailty categories. C statistics estimated model discrimination. Results: RAI-ICD parameters were weighted in the 9â¯548â¯206 patients who were hospitalized (mean [SE] age, 55.4 (0.1) years; 3â¯742â¯330 male [weighted percentage, 39.2%] and 5â¯804â¯431 female [weighted percentage, 60.8%]), modeling in-hospital mortality (2.1%; 95% CI, 2.1%-2.2%) with excellent derivation discrimination (C statistic, 0.810; 95% CI, 0.808-0.813). The 11 RAI-ICD parameters were adapted to 323 ICD-10-CM codes. The operative validation population of 8â¯113â¯950 patients (mean [SE] age, 54.4 (0.1) years; 3â¯148â¯273 male [weighted percentage, 38.8%] and 4â¯965â¯737 female [weighted percentage, 61.2%]; in-hospital mortality, 2.5% [95% CI, 2.4%-2.5%]) mirrored the derivation population. In validation, the weighted and integerized RAI-ICD yielded good to excellent discrimination in the NIS operative sample (C statistic, 0.784; 95% CI, 0.782-0.786), NIS operative and nonoperative sample (C statistic, 0.778; 95% CI, 0.777-0.779), and the UPMC operative and nonoperative sample (C statistic, 0.860; 95% CI, 0.857-0.862). Thresholds defining robust (RAI-ICD <27), normal (RAI-ICD, 27-35), frail (RAI-ICD, 36-45), and very frail (RAI-ICD >45) strata of frailty maximized precision (F1 = 0.33) and sensitivity and specificity (Matthews correlation coefficient = 0.26). Adverse outcomes increased with increasing frailty. Conclusion and Relevance: In this cohort study of hospitalized adults, the RAI-ICD was rigorously adapted, derived, and validated. These findings suggest that the RAI-ICD can extend the quantification of frailty to inpatient adult ICD-10-CM-coded patient care datasets.
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Fragilidade , Mortalidade Hospitalar , Classificação Internacional de Doenças , Humanos , Masculino , Feminino , Idoso , Fragilidade/diagnóstico , Medição de Risco/métodos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Estados Unidos/epidemiologia , Avaliação Geriátrica/métodos , Avaliação Geriátrica/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Idoso Fragilizado/estatística & dados numéricosRESUMO
This cohort study characterizes heterogeneity in cardiac function prior to sepsis and describes associations with hospitalization outcomes and mortality.
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Sepse , Disfunção Ventricular , Humanos , Coração/diagnóstico por imagem , Coração/fisiopatologia , Prognóstico , Sepse/epidemiologia , Sepse/mortalidade , Sepse/terapia , Avaliação de Resultados em Cuidados de Saúde , Estados Unidos/epidemiologia , Hospitalização , Ecocardiografia , Função Ventricular , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Disfunção Ventricular/epidemiologia , Disfunção Ventricular/mortalidade , Disfunção Ventricular/terapia , ComorbidadeRESUMO
OBJECTIVE: Endovascular aortic repair (EVAR) is a less invasive method than the more physiologically stressful open surgical repair (OSR) for patients with anatomically appropriate abdominal aortic aneurysms (AAAs). Early postoperative outcomes are associated with both patients; physiologic reserve and the physiologic stresses of the surgical intervention. Among frail patients with reduced physiologic reserve, the stress of an aortic rupture in combination with the stress of an operative repair are less well tolerated, raising the risk of complications and mortality. This study aims to evaluate the difference in association between frailty and outcomes among patients undergoing minimally invasive EVAR and the physiologically more stressful OSR for ruptured AAAs (rAAAs). METHODS: Our retrospective cohort study included adults undergoing rAAA repair in the Vascular Quality Initiative from 2010 to 2022. The validated Risk Analysis Index (RAI) (robust, ≤20; normal, 21-29; frail, 30-39; very frail, ≥40) quantified frailty. The association between the primary outcome of 1-year mortality and frailty status as well as repair type were compared using multivariable Cox models generating adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Interaction terms evaluated the association's moderation. RESULTS: We identified 5806 patients (age, 72 ± 9 years; 77% male; EVAR, 65%; robust, 6%; normal, 48%; frail, 36%; very, frail 10%) with a 53% observed 1-year mortality rate following rAAA repair. OSR (aHR, 1.43; 95% CI, 1.19-1.73) was associated with increased 1-year mortality when compared with EVAR. Increasing frailty status (frail aHR, 1.26; 95% CI, 1.00-1.59; very frail aHR, 1.64; 95% CI, 1.26-2.13) was associated with increased 1-year mortality, which was moderated by repair type (P-interaction < .05). OSR was associated with increased 1-year mortality in normal (aHR, 1.49; 95% CI, 1.20-1.87) and frail (aHR, 1.51; 95% CI, 1.20-1.89), but not among robust (aHR, 0.88; 95% CI, 0.59-1.32) and very frail (aHR, 1.29; 95% CI, 0.97-1.72) patients. CONCLUSIONS: Frailty and OSR were associated with increased adjusted risk of 1-year mortality following rAAA repair. Among normal and frail patients, OSR was associated with an increased adjusted risk of 1-year mortality when compared with EVAR. However, there was no difference between OSR and EVAR among robust patients who can well tolerate the stress of OSR and among very frail patients who are unable to withstand the surgical stress from rAAA regardless of repair type.
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Aneurisma da Aorta Abdominal , Ruptura Aórtica , Implante de Prótese Vascular , Procedimentos Endovasculares , Idoso Fragilizado , Fragilidade , Humanos , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/mortalidade , Aneurisma da Aorta Abdominal/complicações , Masculino , Idoso , Fragilidade/complicações , Fragilidade/mortalidade , Fragilidade/diagnóstico , Estudos Retrospectivos , Feminino , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Ruptura Aórtica/cirurgia , Ruptura Aórtica/mortalidade , Ruptura Aórtica/fisiopatologia , Fatores de Risco , Medição de Risco , Idoso de 80 Anos ou mais , Resultado do Tratamento , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Fatores de Tempo , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/etiologia , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Bases de Dados FactuaisRESUMO
BACKGROUND: Sepsis is the most common cause of acute kidney injury (AKI) in critically ill patients. Four phenotypes (α, ß, γ, δ) for sepsis, which have different outcomes and responses to treatment, were described using routine clinical data in the electronic health record. RESEARCH QUESTION: Do the frequencies of AKI, acute kidney disease (AKD), chronic kidney disease (CKD), and AKI on CKD differ by sepsis phenotype? STUDY DESIGN AND METHODS: This was a secondary analysis of a randomized clinical trial of early resuscitation, including patients with septic shock at 31 sites. After excluding patients with end-stage kidney disease and missing data, we determined frequencies of the following clinical outcomes: AKI (defined within 24 h as Kidney Disease: Improving Global Outcomes stages 2 or 3 or stage 1 with tissue inhibitor of metalloproteinases-2 × insulin-like growth factor binding protein 7 value of > 2.0), CKD, and AKD (persistence of AKI at any stage on day 7 after enrollment) across four phenotypes. We performed multivariable logistic regression to assess the risk-adjusted association between development of AKI and AKD and phenotype. RESULTS: Among 1,090 eligible patients, 543 patients (50%) had AKI. Across phenotypes, the frequencies of AKI varied, being highest in the δ and ß phenotypes (78% and 71%, respectively) and the lowest in the α phenotype (26%; P < .001). AKD occurred most often in the δ phenotype (41%) and least often in the α phenotype (8%; P < .001). The highest frequencies of CKD and of AKI on CKD were found in the ß phenotype (53% and 38% respectively; P < .001 for both). In the multivariable logistic regression models (α phenotype as reference), δ phenotype showed the strongest association with AKI (OR, 12.33; 95% CI, 7.81-19.47; P < .001) and AKD (OR, 9.18; 95% CI, 5.44-15.51; P < .001). INTERPRETATION: The rates of AKI and AKD differed across clinical sepsis phenotypes and are more common among patients with phenotypes ß and δ. Phenotype ß showed a higher level of underlying CKD that predisposed patients to new AKI. The α and γ phenotypes showed lower frequencies of AKI and less progression to AKD.
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Sepsis is a heterogeneous syndrome and phenotypes have been proposed using clinical data. Less is known about the contribution of protein biomarkers to clinical sepsis phenotypes and their importance for treatment effects in randomized trials of resuscitation. The objective is to use both clinical and biomarker data in the Protocol-Based Care for Early Septic Shock (ProCESS) randomized trial to determine sepsis phenotypes and to test for heterogeneity of treatment effect by phenotype comparing usual care to protocolized early, goal-directed therapy(EGDT). In this secondary analysis of a subset of patients with biomarker sampling in the ProCESS trial (n = 543), we identified sepsis phenotypes prior to randomization using latent class analysis of 20 clinical and biomarker variables. Logistic regression was used to test for interaction between phenotype and treatment arm for 60-day inpatient mortality. Among 543 patients with severe sepsis or septic shock in the ProCESS trial, a 2-class model best fit the data (p = 0.01). Phenotype 1 (n = 66, 12%) had increased IL-6, ICAM, and total bilirubin and decreased platelets compared to phenotype 2 (n = 477, 88%, p < 0.01 for all). Phenotype 1 had greater 60-day inpatient mortality compared to Phenotype 2 (41% vs 16%; p < 0.01). Treatment with EGDT was associated with worse 60-day inpatient mortality compared to usual care (58% vs. 23%) in Phenotype 1 only (p-value for interaction = 0.05). The 60-day inpatient mortality was similar comparing EGDT to usual care in Phenotype 2 (16% vs. 17%). We identified 2 sepsis phenotypes using latent class analysis of clinical and protein biomarker data at randomization in the ProCESS trial. Phenotype 1 had increased inflammation, organ dysfunction and worse clinical outcomes compared to phenotype 2. Response to EGDT versus usual care differed by phenotype.
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Sepse , Choque Séptico , Humanos , Biomarcadores , Protocolos Clínicos , Fenótipo , Sepse/diagnóstico , Sepse/terapia , Choque Séptico/diagnóstico , Choque Séptico/terapiaRESUMO
BACKGROUND: To understand delirium heterogeneity, prior work relied on psychomotor symptoms or risk factors to identify subtypes. Data-driven approaches have used machine learning to identify biologically plausible, treatment-responsive subtypes of other acute illnesses but have not been used to examine delirium. METHODS: We conducted a secondary analysis of a large, multicenter prospective cohort study involving adults in medical or surgical ICUs with respiratory failure or shock who experienced delirium per the Confusion Assessment Method for the ICU. We used data collected before delirium diagnosis in an unsupervised latent class model to identify delirium subtypes and then compared demographics, clinical characteristics, and outcomes between subtypes in the final model. FINDINGS: The 731 patients who developed delirium during critical illness had a median age of 63 [IQR, 54-72] years, a median Sequential Organ Failure Assessment score of 8.0 [6.0-11.0] and 613 [83.4%] were mechanically ventilated at delirium identification. A four-class model best fit the data with 50% of patients in subtype (ST) 1, 18% in subtype 2, 17% in subtype 3, and 14% in subtype 4. Subtype 2-which had more shock and kidney impairment-had the highest mortality (33% [ST2] vs. 17% [ST1], 25% [ST3], and 17% [ST4], p = 0.003). Subtype 4-which received more benzodiazepines and opioids-had the longest duration of delirium (6 days [ST4] vs. 3 [ST1], 4 [ST2], and 3 days [ST3], p < 0.001) and coma (4 days [ST4] vs. 2 [ST1], 1 [ST2], and 2 days [ST3], p < 0.001). Each of the four data-derived delirium subtypes was observed within previously identified psychomotor and risk factor-based delirium subtypes. Clinically significant cognitive impairment affected all subtypes at follow-up, but its severity did not differ by subtype (3-month, p = 0.26; 12-month, p = 0.80). INTERPRETATION: The four data-derived delirium subtypes identified in this study should now be validated in independent cohorts, examined for differential treatment effects in trials, and inform mechanistic work evaluating treatment targets. FUNDING: National Institutes of Health (T32HL007820, R01AG027472).
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Disfunção Cognitiva , Delírio , Adulto , Humanos , Pessoa de Meia-Idade , Idoso , Delírio/diagnóstico , Delírio/etiologia , Estudos Prospectivos , Estado Terminal , Proteína 1 Semelhante a Receptor de Interleucina-1 , Disfunção Cognitiva/complicaçõesRESUMO
BACKGROUND: Acute limb ischemia (ALI) carries a 15% to 20% risk of combined death or amputation at 30 days and 50% to 60% at 1 year. Percutaneous mechanical thrombectomy (PT) is an emerging minimally invasive alternative to open thrombectomy (OT). However, ALI thrombectomy cases are omitted from most quality databases, limiting comparisons of limb and survival outcomes between PT and OT. Therefore, our aim was to compare in-hospital outcomes between PT and OT using the National Inpatient Sample. METHODS: We analyzed survey-weighted National Inpatient Sample data (2015-2020) to include emergent admissions of aged adults (50+ years) with a primary diagnosis of lower extremity ALI undergoing index procedures within 2 days of hospitalization. We excluded hospitalizations with concurrent trauma or dissection diagnoses and index procedures using catheter-directed thrombolysis. Our primary outcome was composite in-hospital major amputation or death. Secondary outcomes included in-hospital major amputation, death, in-hospital reintervention (including angioplasty/stent, thrombolysis, PT, OT, or bypass), and extended length of stay (eLOS; defined as LOS >75th percentile). Adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs) were generated by multivariable logistic regression, adjusting for demographics, frailty (Risk Analysis Index), secondary diagnoses including atrial fibrillation and peripheral artery disease, hospital characteristics, and index procedure data including the anatomic thrombectomy level and fasciotomy. A priori subgroup analyses were performed using interaction terms. RESULTS: We included 23,795 survey-weighted ALI hospitalizations (mean age: 72.2 years, 50.4% female, 79.2% White, and 22.3% frail), with 7335 (30.8%) undergoing PT. Hospitalization characteristics for PT vs OT differed by atrial fibrillation (28.7% vs 36.5%, P < .0001), frequency of intervention at the femoropopliteal level (86.2% vs 88.8%, P = .009), and fasciotomy (4.8% vs 6.9%, P = .006). In total, 2530 (10.6%) underwent major amputation or died. Unadjusted (10.1% vs 10.9%, P = .43) and adjusted (aOR = 0.96 [95% CI, 0.77-1.20], P = .74) risk did not differ between the groups. PT was associated with increased odds of reintervention (aOR = 2.10 [95% CI, 1.72-2.56], P < .0001) when compared with OT, but this was not seen in the tibial subgroup (aOR = 1.31 [95% CI, 0.86-2.01], P = .21, Pinteraction < .0001). Further, 79.1% of PT hospitalizations undergoing reintervention were salvaged with endovascular therapy. Lastly, PT was associated with significantly decreased odds of eLOS (aOR = 0.80 [95% CI, 0.69-0.94], P = .005). CONCLUSIONS: PT was associated with comparable in-hospital limb salvage and mortality rates compared with OT. Despite an increased risk of reintervention, most PT reinterventions avoided open surgery, and PT was associated with a decreased risk of eLOS. Thus, PT may be an appropriate alternative to OT in appropriately selected patients.
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Arteriopatias Oclusivas , Fibrilação Atrial , Procedimentos Endovasculares , Doença Arterial Periférica , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Extremidade Inferior/irrigação sanguínea , Procedimentos Endovasculares/efeitos adversos , Fatores de Risco , Resultado do Tratamento , Trombectomia/efeitos adversos , Isquemia/diagnóstico por imagem , Isquemia/cirurgia , Arteriopatias Oclusivas/cirurgia , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/terapia , Salvamento de Membro , Estudos RetrospectivosRESUMO
PURPOSE: The heterogeneity in sepsis is held responsible, in part, for the lack of precision treatment. Many attempts to identify subtypes of sepsis patients identify those with shared underlying biology or outcomes. To date, though, there has been limited effort to determine overlap across these previously identified subtypes. We aimed to determine the concordance of critically ill patients with sepsis classified by four previously described subtype strategies. METHODS: This secondary analysis of a multicenter prospective observational study included 522 critically ill patients with sepsis assigned to four previously established subtype strategies, primarily based on: (i) clinical data in the electronic health record (α, ß, γ, and δ), (ii) biomarker data (hyper- and hypoinflammatory), and (iii-iv) transcriptomic data (Mars1-Mars4 and SRS1-SRS2). Concordance was studied between different subtype labels, clinical characteristics, biological host response aberrations, as well as combinations of subtypes by sepsis ensembles. RESULTS: All four subtype labels could be adjudicated in this cohort, with the distribution of the clinical subtype varying most from the original cohort. The most common subtypes in each of the four strategies were γ (61%), which is higher compared to the original classification, hypoinflammatory (60%), Mars2 (35%), and SRS2 (54%). There was no clear relationship between any of the subtyping approaches (Cramer's V = 0.086-0.456). Mars2 and SRS1 were most alike in terms of host response biomarkers (p = 0.079-0.424), while other subtype strategies showed no clear relationship. Patients enriched for multiple subtypes revealed that characteristics and outcomes differ dependent on the combination of subtypes made. CONCLUSION: Among critically ill patients with sepsis, subtype strategies using clinical, biomarker, and transcriptomic data do not identify comparable patient populations and are likely to reflect disparate clinical characteristics and underlying biology.
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Estado Terminal , Sepse , Humanos , Biomarcadores , Perfilação da Expressão Gênica , Sepse/genética , Estudos ProspectivosRESUMO
BACKGROUND: Sepsis is common, deadly, and heterogenous. Prior analyses of patients with sepsis and septic shock in New York State showed a risk-adjusted association between more rapid antibiotic administration and bundled care completion, but not an intravenous fluid bolus, with reduced in-hospital mortality. However, it is unknown if clinically identifiable sepsis subtypes modify these associations. METHODS: Secondary analysis of patients with sepsis and septic shock enrolled in the New York State Department of Health cohort from January 1, 2015 to December 31, 2016. Patients were classified as clinical sepsis subtypes (α, ß, γ, δ-types) using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Exposure variables included time to 3-h sepsis bundle completion, antibiotic administration, and intravenous fluid bolus completion. Then logistic regression models evaluated the interaction between exposures, clinical sepsis subtypes, and in-hospital mortality. RESULTS: 55,169 hospitalizations from 155 hospitals were included (34% α, 30% ß, 19% γ, 17% δ). The α-subtype had the lowest (N = 1,905, 10%) and δ-subtype had the highest (N = 3,776, 41%) in-hospital mortality. Each hour to completion of the 3-h bundle (aOR, 1.04 [95%CI, 1.02-1.05]) and antibiotic initiation (aOR, 1.03 [95%CI, 1.02-1.04]) was associated with increased risk-adjusted in-hospital mortality. The association differed across subtypes (p-interactions < 0.05). For example, the outcome association for the time to completion of the 3-h bundle was greater in the δ-subtype (aOR, 1.07 [95%CI, 1.05-1.10]) compared to α-subtype (aOR, 1.02 [95%CI, 0.99-1.04]). Time to intravenous fluid bolus completion was not associated with risk-adjusted in-hospital mortality (aOR, 0.99 [95%CI, 0.97-1.01]) and did not differ among subtypes (p-interaction = 0.41). CONCLUSION: Timely completion of a 3-h sepsis bundle and antibiotic initiation was associated with reduced risk-adjusted in-hospital mortality, an association modified by clinically identifiable sepsis subtype.
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Doenças Transmissíveis , Sepse , Choque Séptico , Humanos , Choque Séptico/tratamento farmacológico , Tempo para o Tratamento , Sepse/tratamento farmacológico , Antibacterianos/uso terapêuticoAssuntos
Serviços Médicos de Emergência , Proteína HMGB1 , Sepse , Humanos , Sepse/diagnóstico , Sepse/terapiaRESUMO
BACKGROUND: Sepsis is a common and deadly syndrome, accounting for more than 11 million deaths annually. To mature a deeper understanding of the host and pathogen mechanisms contributing to poor outcomes in sepsis, and thereby possibly inform new therapeutic targets, sophisticated, and expensive biorepositories are typically required. We propose that remnant biospecimens are an alternative for mechanistic sepsis research, although the viability and scientific value of such remnants are unknown. METHODS AND RESULTS: The Remnant Biospecimen Investigation in Sepsis study is a prospective cohort study of 225 adults (age ≥ 18 yr) presenting to the emergency department with community sepsis, defined as sepsis-3 criteria within 6 hours of arrival. The primary objective was to determine the scientific value of a remnant biospecimen repository in sepsis linked to clinical phenotyping in the electronic health record. We will study candidate multiomic readouts of sepsis biology, governed by a conceptual model, and determine the precision, accuracy, integrity, and comparability of proteins, small molecules, lipids, and pathogen sequencing in remnant biospecimens compared with paired biospecimens obtained according to research protocols. Paired biospecimens will include plasma from sodium-heparin, EDTA, sodium fluoride, and citrate tubes. CONCLUSIONS: The study has received approval from the University of Pittsburgh Human Research Protection Office (Study 21120013). Recruitment began on October 25, 2022, with planned release of primary results anticipated in 2024. Results will be made available to the public, the funders, critical care societies, laboratory medicine scientists, and other researchers.
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Importance: Intravenous fluid administration is recommended to improve outcomes for patients with septic shock. However, there are few data on fluid administration for patients with preexisting heart failure with reduced ejection fraction (HFrEF). Objective: To evaluate the association between preexisting HFrEF, guideline-recommended intravenous fluid resuscitation, and mortality among patients with community-acquired sepsis and septic shock. Design, Setting, and Participants: A cohort study was conducted of adult patients hospitalized in an integrated health care system from January 1, 2013, to December 31, 2015, with community-acquired sepsis and preexisting assessment of cardiac function. Follow-up occurred through July 1, 2016. Data analyses were performed from November 1, 2020, to August 8, 2022. Exposures: Preexisting heart failure with reduced ejection fraction (≤40%) measured by transthoracic echocardiogram within 1 year prior to hospitalization for sepsis. Main Outcomes and Measures: Multivariable models were adjusted for patient factors and sepsis severity and clustered at the hospital level to generate adjusted odds ratios (aORs) and 95% CIs. The primary outcome was the administration of 30 mL/kg of intravenous fluid within 6 hours of sepsis onset. Secondary outcomes included in-hospital mortality, intensive care unit admission, rate of invasive mechanical ventilation, and administration of vasoactive medications. Results: Of 5278 patients with sepsis (2673 men [51%]; median age, 70 years [IQR, 60-81 years]; 4349 White patients [82%]; median Sequential Organ Failure Assessment score, 4 [IQR, 3-5]), 884 (17%) had preexisting HFrEF, and 2291 (43%) met criteria for septic shock. Patients with septic shock and HFrEF were less likely to receive guideline-recommended intravenous fluid than those with septic shock without HFrEF (96 of 380 [25%] vs 699 of 1911 [37%]; P < .001), but in-hospital mortality was similar (47 of 380 [12%] vs 244 of 1911 [13%]; P = .83). In multivariable models, HFrEF was associated with a decreased risk-adjusted odds of receiving 30 mL/kg of intravenous fluid within the first 6 hours of sepsis onset (aOR, 0.63; 95% CI, 0.47-0.85; P = .002). The risk-adjusted mortality was not significantly different among patients with HFrEF (aOR, 0.92; 95% CI, 0.69-1.24; P = .59) compared with those without, and there was no interaction with intravenous fluid volume (aOR, 1.00; 95% CI, 0.98-1.03; P = .72). Conclusions and Relevance: The results of this cohort study of patients with community-acquired septic shock suggest that preexisting HFrEF was common and was associated with reduced odds of receiving guideline-recommended intravenous fluids.
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Insuficiência Cardíaca , Sepse , Choque Séptico , Idoso , Estudos de Coortes , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Sepse/complicações , Sepse/terapia , Choque Séptico/complicações , Choque Séptico/terapia , Volume SistólicoAssuntos
MicroRNAs , Sepse , Estudos de Coortes , Humanos , Hipóxia/genética , MicroRNAs/genética , Sepse/genéticaRESUMO
In a real-world implementation of a machine-learning (ML)-based sepsis early warning system (EWS), Adams et al.1,2 found that timely provider response to an alert was associated with improved mortality, highlighting the potential utility of these systems in patient care.
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Sepse , Humanos , Aprendizado de Máquina , Assistência ao Paciente , Sepse/diagnósticoRESUMO
BACKGROUND: A greater understanding of disease heterogeneity may facilitate precision medicine for coronavirus disease 2019 (COVID-19). Previous work identified four distinct clinical phenotypes associated with outcome and treatment responses in non-COVID-19 sepsis patients, but it is unknown if and how these phenotypes are recapitulated in COVID-19 sepsis patients. METHODS: We applied the four non-COVID-19 sepsis phenotypes to a total of 52,274 critically ill patients, comprising two cohorts of COVID-19 sepsis patients (admitted before and after the introduction of dexamethasone as standard treatment) and three non-COVID-19 sepsis cohorts (non-COVID-19 viral pneumonia sepsis, bacterial pneumonia sepsis, and bacterial sepsis of non-pulmonary origin). Differences in proportions of phenotypes and their associated mortality were determined across these cohorts. RESULTS: Phenotype distribution was highly similar between COVID-19 and non-COVID-19 viral pneumonia sepsis cohorts, whereas the proportion of patients with the δ-phenotype was greater in both bacterial sepsis cohorts compared to the viral sepsis cohorts. The introduction of dexamethasone treatment was associated with an increased proportion of patients with the δ-phenotype (6% vs. 11% in the pre- and post-dexamethasone COVID-19 cohorts, respectively, p < 0.001). Across the cohorts, the α-phenotype was associated with the most favorable outcome, while the δ-phenotype was associated with the highest mortality. Survival of the δ-phenotype was markedly higher following the introduction of dexamethasone (60% vs 41%, p < 0.001), whereas no relevant differences in survival were observed for the other phenotypes among COVID-19 patients. CONCLUSIONS: Classification of critically ill COVID-19 patients into clinical phenotypes may aid prognostication, prediction of treatment efficacy, and facilitation of personalized medicine.
Assuntos
COVID-19 , Doenças Transmissíveis , Pneumonia , Sepse , Estado Terminal/epidemiologia , Estado Terminal/terapia , Dexametasona/uso terapêutico , Humanos , Fenótipo , SARS-CoV-2RESUMO
Importance: The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant. Objective: To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab. Design, Setting, and Participants: This study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria. Exposure: For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy. Main Outcomes and Measures: For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned -1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound. Results: A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence. Conclusions and Relevance: In this propensity score-matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant. Trial Registration: ClinicalTrials.gov Identifier: NCT04790786.
Assuntos
Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes , Teorema de Bayes , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Importance: Rapid source control is recommended to improve patient outcomes in sepsis. Yet there are few data to guide how rapidly source control is required. Objective: To determine the association between time to source control and patient outcomes in community-acquired sepsis. Design, Setting, and Particpants: Multihospital integrated health care system cohort study of hospitalized adults (January 1, 2013, to December 31, 2017) with community-acquired sepsis as defined by Sepsis-3 who underwent source control procedures. Follow-up continued through January 1, 2019, and data analyses were completed March 17, 2022. Exposures: Early (<6 hours) compared with late (6-36 hours) source control as well as each hour of source control delay (1-36 hours) from sepsis onset. Main Outcomes and Measures: Multivariable models were clustered at the level of hospital with adjustment for patient factors, sepsis severity, resource availability, and the physiologic stress of procedures generating adjusted odds ratios (aOR) and 95% CI. Results: Of 4962 patients with sepsis (mean [SD] age, 62 [16] years; 52% male; 85% White; mean [SD] Sequential Organ Failure Assessment score, 3.8 [2.5]), source control occurred at a median (IQR) of 15.4 hours (5.5-21.7) after sepsis onset, with 1315 patients (27%) undergoing source control within 6 hours. The crude 90-day mortality was similar for early and late source control (n = 177 [14%] vs n = 529 [15%]; P = .35). In multivariable models, early source control was associated with decreased risk-adjusted odds of 90-day mortality (aOR, 0.71; 95% CI, 0.63-0.80). This association was greater among gastrointestinal and abdominal (aOR, 0.56; 95% CI, 0.43-0.80) and soft tissue interventions (aOR, 0.72; 95% CI, 0.55-0.95) compared with orthopedic and cranial interventions (aOR, 1.33; 95% CI, 0.96-1.83; P < .001 for interaction). Conclusions and Relevance: Source control within 6 hours of community-acquired sepsis onset was associated with a reduced risk-adjusted odds of 90-day mortality. Prioritizing the rapid identification of septic foci and initiation of source control interventions can reduce the number of avoidable deaths among patients with sepsis.
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Sepse , Adulto , Estudos de Coortes , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab. METHODS: A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound. FINDINGS: Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab. INTERPRETATION: Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb. FUNDING AND REGISTRATION: This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.