The Epidemiology of Extremity Threat and Amputation after Vasopressor-Dependent Sepsis

Abstract

Rationale: Extremity threat and amputation after sepsis is a well-publicized and devastating event. However, there is a paucity of data about the epidemiology of extremity threat after sepsis onset. Objectives: To estimate the incidence of extremity threat with or without surgical amputation in community sepsis. Methods: Retrospective cohort study of adults with Sepsis-3 hospitalized at 14 academic and community sites from 2013 to 2017. Vasopressor-dependent sepsis was identified by administration of epinephrine, norepinephrine, phenylephrine, vasopressin, or dopamine for more than 1 hour during the 48 hours before to 24 hours after sepsis onset. Outcomes included the incidence of extremity threat, defined as acute onset ischemia, with or without amputation, in the 90 days after sepsis onset. The association between extremity threat, demographics, comorbid conditions, and time-varying sepsis treatments was evaluated using a Cox proportional hazards model. Results: Among 24,365 adults with sepsis, 12,060 (54%) were vasopressor dependent (mean ± standard deviation age, 64 ± 16 years; male, 6,548 [54%]; sequential organ failure assessment [SOFA], 10 ± 4). Of these, 231 (2%) patients had a threatened extremity with 26 undergoing 37 amputations, a risk of 2.2 (95% confidence interval [CI], 1.4-3.2) per 1,000, and 205 not undergoing amputation, a risk of 17.0 (95% CI, 14.8-19.5) per 1,000. Most amputations occurred in lower extremities (95%), a median (interquartile range) of 16 (6-40) days after sepsis onset. Compared with patients with no extremity threat, patients with threat had a higher SOFA score (11 ± 4 vs. 10 ± 4; P < 0.001), serum lactate (4.6 mmol/L [2.4-8.7] vs. 3.1 [1.7-6.0]; P < 0.001), and more bacteremia (n = 37 [37%] vs. n = 2,087 [26%]; P < 0.001) at sepsis onset. Peripheral vascular disease, congestive heart failure, SOFA score, and norepinephrine equivalents were significantly associated with extremity threat. Conclusions: The evaluation of a threatened extremity resulting in surgical amputation occurred in 2 per 1,000 patients with vasopressor-dependent sepsis.

Keywords: amputation; peripheral ischemia; sepsis; symmetric peripheral gangrene; vasopressor.

Figure 1.

Cohort accrual.

Figure 2.

Risk of extremity threat with or without amputation in 90 days after vasopressor-dependent sepsis (n = 12,060). Risk of extremity threat with (red) and without (orange) amputation in the 90 days after sepsis onset. The vertical dashed lines indicate the overall risk of patients with threat or without amputation. All error bars are 95% confidence intervals. ^aMissingness for smoking status was common among patients with (n = 10 [38%]) and without (n = 104 [51%]) amputation (Table E4). CVD = cardiovascular disease; PVD = peripheral vascular disease.

Figure 3.

Adjusted risk of extremity threat with or without amputation. Forest plot depicting the hazard ratio (dot) contribution to the risk of extremity threat with or without amputation. All error bars demonstrate 95% confidence intervals. Associated Schoenfeld residuals, cumulative hazard graphs stratified by subgroups, and full model are available in the online supplement (Figures E6 and E7 and Table E5). CHF = congestive heart failure; CVD = cardiovascular disease; PVD = peripheral vascular disease; SOFA = sequential organ failure assessment.

Figure 4.

Vasopressor exposure. Corresponds to the proportion of alive patients who received any and each individual vasopressor daily, from the 2 days before to the 14 days after sepsis onset. Green corresponds to patients without extremity threat, red to with threat with amputation, and orange to with threat without amputation in the 90 days after sepsis onset.