Comorbidities, Weight-Based Initial Fluid Resuscitation, and Mortality in Patients With Sepsis.

Importance: Guidelines suggest administering at least 30 mL/kg of initial fluid to patients with sepsis-induced hypoperfusion. However, there is uncertainty regarding the benefits of fluid resuscitation in patients with severe cardiac or kidney comorbidities or intermediate elevation of lactate level (18.0-36.0 mg/dL). Objective: To evaluate the association of 30 mL/kg or more of fluid administered within 6 hours of hospital arrival with 30-day mortality across key target populations with community-onset sepsis. Design, Setting, and Participants: This cohort study included adults hospitalized for community-onset sepsis in 67 hospitals in the Michigan Hospital Medicine Safety Consortium (discharge dates from December 2021 to January 2025) who had an indication for fluid resuscitation (ie, hypotension or lactate level of 18.0 mg/dL or greater) within 3 hours of hospital arrival. Data were analyzed from November 26, 2024, to November 16, 2025. Exposure: Receipt of at least 30 mL/kg vs less than 30 mL/kg fluid in the first 6 hours after hospital arrival. Fluid volume included all crystalloid fluid and blood products. Main Outcomes and Measures: Association between administration of 30 mL/kg or more of fluid within 6 hours of hospital arrival and 30-day mortality using weighted regression models adjusted for patient characteristics. Target populations were defined by (1) fluid indication: hypoperfusion (hypotension or lactate level >36.0 mg/dL) vs intermediate lactate elevation (18.0-36.0 mg/dL) and (2) presence of severe comorbidities that might increase risk of fluid overload (left ventricular ejection fraction <40%, severe-to-critical aortic stenosis, or end-stage kidney disease). Secondary analyses used adjusted logistic regression models with restricted cubic spline terms to evaluate associations of fluid volume administered with mortality. Results: Among 43 321 patients hospitalized for community-onset sepsis, 25 481 (58.8%) had an indication for fluid resuscitation and were included in the study (median age, 71 years [IQR, 61-80 years]; 50.5% male; 37.0% with body mass index >30.0, calculated as weight in kilograms divided by height in meters squared). A total of 12 943 (50.8%) had hypoperfusion without severe comorbidities; 1741 (6.8%), hypoperfusion with severe comorbidities; 9974 (39.1%), intermediate lactate elevation without severe comorbidities; and 823 (3.2%), intermediate lactate elevation with severe comorbidities. Administration of 30 mL/kg or more of fluid vs less than 30 mL/kg was associated with lower adjusted 30-day mortality rates in patients with hypoperfusion without severe comorbidities (26.0% [95% CI, 24.9%-27.2%] vs 30.4% [95% CI, 28.8%-32.0%]; adjusted absolute difference [diff], -4.4 percentage points [pp] [95% CI, -6.1 to -2.7 pp]) and intermediate lactate elevation without severe comorbidities (12.0% [95% CI, 10.6%-13.5%] vs 13.9% [95% CI, 12.9%-14.8%]; diff, -1.8 pp [95% CI, -3.6 to -0.1 pp]). For patients with hypoperfusion and severe cardiac or kidney comorbidities, the association between 30-day adjusted mortality and receiving 30 mL/kg or more of fluid vs less than 30 mL/kg was not statistically significant (34.7% [95% CI, 30.8%-38.6%] vs 38.8% [95% CI, 35.8%-41.8%]; diff, -4.1 pp [95% CI, -9.0 to 0.8 pp]), although spline models indicated decreasing mortality with fluid resuscitation of 30 mL/kg or more of fluid. Conclusions and Relevance: In this cohort study of patients with community-onset sepsis, initial administration of 30 mL/kg or more of fluid was associated with lower 30-day mortality among patients who had either hypoperfusion or intermediate lactate elevation without severe cardiac or kidney comorbidities. The findings suggest that broader application of at least 30 mL/kg of initial fluid resuscitation for sepsis in patients with hypoperfusion and cardiac or kidney comorbidities or intermediate lactate elevation may reduce sepsis-related mortality.