ORIGINAL RESEARCH

The Epidemiology of Extremity Threat and Amputation after

Vasopressor-Dependent Sepsis
Katherine M. Reitz1,2,3, Jason Kennedy2,4, Caroline Rieser1, Callie Hlavin1, Hayley B. Gershengorn5,6,
Matthew D. Neal1,4, Nicole Bensen2,4, Kelsey Linstrum2,4, Hallie C. Prescott7, Matthew R. Rosengart1,4,
Victor Talisa2,8, Daniel E. Hall1,9,10,11, Edith Tzeng1,3,9, Hannah Wunsch12,13, Sachin Yende2,4,10,
Derek C. Angus2,4, and Christopher W. Seymour2,4
1
Department of Surgery, 4Department of Critical Care Medicine, and 8Department of Biostatistics, University of Pittsburgh, Pittsburgh,
Pennsylvania; 2Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, and 3Division of Vascular Surgery,
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 5Division of Pulmonary, Critical Care, and Sleep Medicine, Miller
School of Medicine, University of Miami, Miami, Florida; 6Division of Critical Care Medicine, Albert Einstein College of Medicine, Bronx,
New York; 7Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan; 9Veterans Affairs Pittsburgh
Healthcare System, and 11Center for Health Equity Research and Promotion, Veterans Affairs, Pittsburgh, Pennsylvania; 10Wolff Center,
University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 12Department of Critical Care Medicine, Sunnybrook Health Science
Centre, Toronto, Ontario, Canada; and 13Department of Anesthesia and Interdepartmental Division of Critical Care Medicine, University
of Toronto, Toronto, Ontario, Canada

ORCID IDs: 0000-0002-9397-321X (K.M.R.); 0000-0002-7360-2489 (H.B.G.); 0000-0002-6596-8034 (S.Y.).

Abstract years; male, 6,548 [54%]; sequential organ failure assessment

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 6 standard deviation age, 64 6 16
[SOFA], 10 6 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 6 4 vs.
10 6 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: sepsis; vasopressor; symmetric peripheral gangrene;
amputation; peripheral ischemia

(Received in original form May 7, 2021; accepted in final form October 12, 2021)
Supported in part by the National Heart, Lung, and Blood Institute (5T32HL0098036) and National Institute on Aging (L30AG064730) (K.M.R.);
the National Cancer Institute (T32CA113263) (C.R.); and grants for the National Institute of General Medical Sciences (R35GM119519 and
1R35GM119526-01) (M.D.N., D.C.A., and C.W.S.). These funding sources had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit for
publication. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data;
preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Ann Am Thorac Soc Vol 19, No 4, pp 625–632, Apr 2022
Copyright © 2022 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.202105-547OC
Internet address: www:atsjournals:org

Reitz, Kennedy, Rieser, et al.: Extremity Threat and Amputation after Sepsis 625
 ORIGINAL RESEARCH

Sepsis is a life-threatening event in which the
body’s response to an infection results in
injury to its own tissues and organs (1).
Sepsis occurs in nearly 50 million people per
year (2), and although deadly, more than
four in five patients survive (3, 4). A
particularly devastating and well-publicized
complication among these survivors is the
loss of extremities (5).
Extremity ischemia after sepsis,
historically termed symmetric peripheral
gangrene, was described over 100 years ago
(6). It has been attributed to a variety of
causes, including preexisting peripheral
vascular disease (7), vasopressor use (8–17),
various pathogens (18–21), and
disseminated intravascular coagulation
(22–24). Although amputation after sepsis is
an impactful outcome for patients, the
incidence of a threatened extremity with or
without amputation after sepsis is not well
described.
In an integrated health system using
electronic health record (EHR) data, we
quantified the incidence of and risk factors
for the surgical evaluation for a threatened
extremity with or without amputation in
patients with vasopressor-dependent sepsis.
A subset of summarized data maybe
shared upon request to the corresponding
author.
Methods
The project was approved with a waiver of
informed consent and Health Insurance
Portability and Accountability Act
authorization by the University of Pittsburgh
Human Research Protection Office (Study
20040001).
Study Design
We performed a retrospective cohort study
among hospitalized adults (age >18 yr) who
met International Consensus Criteria for
Sepsis-3 (1) and received vasopressors from
January 1, 2013, to December 31, 2017, at 14
community and academic University of
Pittsburgh Medical Center hospitals in
western Pennsylvania. Hospital EHR data
(CERNER Co.) was linked with a unique
patient identifier to outpatient records before
and after the incident sepsis encounter (EPIC
Systems Co.). All reporting is consistent with
the Strengthening the Reporting of
Observational Studies statement (25).
Data
We studied inpatient EHR encounter data
including baseline demographics, admitting
hospital, and known factors affecting
peripheral blood supply and/or coagulation
(i.e., diabetes, cancer, congestive heart
failure [CHF], peripheral vascular disease
[PVD], and cardiovascular disease [CVD])
(12, 26, 27) and the Charlson Comorbidity
Index were identified using the
International Classification of Diseases,
Clinical Modification, of the 9th and 10th
revision codes (Table E1) (28). We
quantified patient status in the 48 hours
before to 24 hours after sepsis onset
using vital signs, laboratory results, and
evidence of end organ dysfunction
measured by the sequential organ failure
assessment (SOFA) score (29). In the 2
days before and 90 days after sepsis onset,
we quantified the magnitude of vasopressor
exposure each day by the number of
vasopressors used and norepinephrine
equivalents (14). We captured intensive
care unit (ICU), hospital length of stay,
and outpatient data including smoking
status at the most recent clinic visit before
incident sepsis. Among all reviewed
hospitalizations, the missingness of EHR
abstracted variables was measured. Current
Procedural Terminology and intraoperative
reports were captured independent of
inpatient status to capture those completed
electively, after discharge from the index
hospitalization. Mortality was determined
using both inpatient discharge disposition
and monthly updated Social Security Death
Index linked to the outpatient EHR
(30–32).
Definition of Vasopressor-
dependent Sepsis
We defined vasopressor-dependent sepsis as
evidence of International Consensus Criteria
for Sepsis-3 in the EHR at any point during
the hospital encounter (1), including 1)
evidence of suspected infection, and 2)
presence of organ dysfunction. A suspected
infection was identified as the administration
of either oral or parenteral antibiotics and
acquisition of a body fluid culture specimen.
Organ dysfunction was defined as at least 2
SOFA points within the 48 hours before to
24 hours after the suspected infection (29).
Only the first episode of sepsis was included.
Vasopressor-dependent sepsis was defined as
the receipt of intravenous epinephrine,
norepinephrine, phenylephrine, vasopressin,
or dopamine for at least 1 hour in the 48
hours before to 24 hours after sepsis
onset (1).
Outcomes
The primary outcome was a threatened
extremity (i.e., limb and/or digit) with or
without surgical amputation in the 90 days
after vasopressor-dependent sepsis
onset. The EHR was reviewed for
documented surgical evaluation within 90
days of sepsis onset, including 1) consult
notes by orthopedic, vascular, or plastic
surgery; or 2) surgical amputation(s),
independent of surgical specialty. We used a
broad definition of extremity threat, which
includes evidence of acute onset ischemia
with or without large vessel occlusion or
iatrogenic external tissue trauma (i.e.,
pressure ulcers). This definition explicitly
excludes primarily infected extremities (e.g.,
diabetic foot wound, antecedent traumatic
injury, pressure wounds, etc.) which were the
source of sepsis. Two independent reviewers
(K.M.R. and C.R.) evaluated patient
admission, consult, progress, and operative
notes; laboratory results; imaging, vascular
laboratory, and pathology reports; and
discharge and/or death summaries to
determine the presence of threatened
extremities in all patients with surgical

Author Contributions: Study concept and design: K.M.R., J.K., H.B.G., H.C.P., H.W., D.C.A., and C.W.S. Acquisition of data: K.M.R., J.K., C.R.,
C.H., N.B., K.L., D.E.H., and C.W.S. Interpretation of data: all authors. Drafting of the manuscript: K.M.R. Critical revision of the manuscript for
important intellectual content: all authors. Study supervision: K.M.R., D.C.A., and C.W.S. K.M.R. and C.W.S. take full responsibility for the
integrity of the data and the accuracy of the data analysis.
Correspondence and requests for reprints should be addressed to Katherine M. Reitz, M.D., M.Sc., Division of Vascular Surgery, University of
Pittsburgh School of Medicine, 200 Lothrop Street, F677 Presbyterian Hospital, Pittsburgh, PA 15213. E-mail: reitzkm2@upmc.edu.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.

626 AnnalsATS Volume 19 Number 4 | April 2022

 ORIGINAL RESEARCH
evaluations. Interrater agreement was
measured with a kappa statistic. The
independent reviewers discussed categorical
disagreements. If a consensus could not be
reached, a third reviewer (C.W.S.)
determined the categorization.
Surgical amputations were identified
using standard procedural descriptions in the
EHR on mandated and time-stamped
intraoperative reports and/or by Current
Procedural Terminology code (Table E2).
Surgical amputations were categorized by
anatomic location, surgical specialty, the
number of amputations if multiple, and
autoamputations (i.e., spontaneous
separation of nonviable tissue) occurred.
The secondary outcomes were ICU and
hospital length of stay, ICU mortality,
hospital disposition, and 90-day as well as
365-day mortality. Outcomes were measured
through January 1, 2019.
Statistical Analysis
We estimated the proportion of patients with
extremity threat and calculated the incidence
risk (events in the 90 days after sepsis onset,
per 1,000 patients) with binomial exact 95%
confidence intervals (CI) of threat with or
without amputation in those with
vasopressor-dependent sepsis. To
understand the range of extremity threat, we
stratified the observed risks among those
with or without amputation by 1) admitting
hospital; 2) patient age; 3) individual baseline
risk factors known to affect cardiovascular
health and coagulation (i.e., diabetes, cancer,
smoking, CHF, PVD, or CVD); and 4) the
total sum of baseline risk factors; 5) among
those who survived to a nonhospice hospital
discharge.
We evaluated the clinical course of
patients with vasopressor-dependent sepsis,
stratified by degree of extremity threat, using
estimated length of stay (both ICU and
hospital), hospital discharge disposition, and
mortality in-hospital and within 90 and 365
days.
To display the relationship between
vasopressor exposure and extremity threat,
we present the proportion of patients
exposed to any and each individual
vasopressor from 2 days before to 14 days
after sepsis onset. We used heatmaps of daily
cardiovascular SOFA points from 2 days
prior to 28 days after sepsis onset to illustrate
the variation in the cumulative of
cardiovascular dysfunction (i.e., hypotension
[mean arterial blood pressure less than 70
mm Hg]) and vasopressor support (i.e.,
Reitz, Kennedy, Rieser, et al.: Extremity Threat and Amputation after Sepsis
multiple vasopressors and escalating
dosages), as well as the competing risk of
mortality (29).
Data were presented as mean (6
standard deviation) or median (interquartile
range [IQR]), as appropriate. For
comparisons, we used t tests, analysis of
variance, and Kruskal-Wallis tests for
continuous data and chi-square or Fischer
exact tests for categorical data. The
association between extremity threat with or
without amputation and comorbid
conditions, sepsis severity at onset, and daily
sepsis treatments were assessed with an
exploratory Cox proportional hazards model
censoring at 90 days and for the competing
risk of mortality, with a robust variance
estimator (33). Analyses were performed by
March 20, 2021, with Stata 15.0 (StataCorp)
and R 4.0 (the R Foundation), with a
significance threshold of P , 0.05 in two-
sided tests (34).
Sensitivity Analysis
We performed sensitivity analyses evaluating
the robustness of the risk of extremity threat.
First, we determined risks after excluding
specific groups of patients with known risks
for amputation prior to sepsis onset: 1) CHF;
2) PVD; 3) diabetes; 4) CHF or PVD; or 5)
PVD or diabetes (12, 27). Second, we
determined the risks using five alternative
definitions of vasopressor-dependent sepsis
to explore the risk of extremity threat across
varying degrees of critical illness: 1) 3 or
more maximal SOFA score points; 2) 4 or
more maximal SOFA score points; 3) no
more than 2 consecutive calendar days of
vasopressors for more than 1 hour; 4) serum
lactate in the 48 hours before and 24 hours
after sepsis onset; and 5) serum lactate more
than 2.0 mmol/L during the 48 hours before
to 24 hours after sepsis onset (septic shock by
Sepsis-3 [1, 35]). Third, we determined the
risks among patients with or without
bacteremia at sepsis onset. Finally, in
additional multivariable models, we
accounted for hospital-specific variability in
the adjusted risk of extremity threat by 1)
clustering by hospital to estimate variance
using robust sandwich estimators; and 2)
using treating hospital as a random effect.
Results
Among 1,107,255 adult patients hospitalized,
237,764 (21%) were treated for a suspected
infection, 168,103 had sepsis (15%), and
12,060 (1%) were vasopressor dependent
(Figure 1). Among those, the mean age was
64 6 16 years, 54% (n = 6,548) were male,
and the mean SOFA score was 10 6 4.
Among the 8,221 (68%) patients who
survived to discharge, a majority (60%) were
not discharged to home. Death occurred in
4,806 patients (40%) by 90 days and in 5,747
patients (48%) at 1 year.
Risk of Extremity Threat with or
without Amputation
Among 12,060 patients with vasopressor-
dependent sepsis, 1,506 (12%) patients had a
surgical evaluation. We excluded 1,275 for
evaluations unrelated to extremity threat or if
the threatened extremity was the source of
sepsis. The remaining 231 (2%) patients were
deemed to have a threatened extremity. In
the 90 days after sepsis onset, 26 underwent
amputation, a risk of 2.2 patients (95% CI,
1.4–3.2) per 1,000, and 205 had threat but no
amputation, a risk of 17.0 (95% CI,
14.8–19.5) per 1,000 (Figure 1). Interrater
agreement for extremity threat generated a
Cohen’s kappa of 0.6 with less than 1%
(n = 12) requiring third-party review.
A total of 26 patients underwent one or
more amputation, 7 (27%) had more than
one surgical amputation, and 1 (4%) had a
documented toe autoamputation. Among
amputated patients, a total of 37 surgical
amputations occurred, most of which were
below- or above-knee amputations (n = 21
[56%]) and nearly all occurred in the lower
extremities (n = 35 [95%]) (Figure E1). More
than 90% of extremity amputations for threat
were performed by vascular, orthopedic, or
plastic surgery (Table E3).
Compared with patients with no
extremity threat, patients with threat had a
higher SOFA score (mean, 11 6 4 vs. 10 6 4;
P , 0.001), international normalized ratio
(median, 1.7 [IQR, 1.3–2.7] vs. 1.5 [IQR,
1.2–2.0]; P , 0.001), serum lactate (median,
4.6 mmol/L [IQR, 2.4–8.7] vs. 3.1 [IQR
1.7–6.0]; P , 0.001); lower fibrinogen
(median, 226 mg/dL [IQR, 150–374] vs. 276
[IQR, 176–425]; P = 0.039); and more
bacteremia (n = 37 [37%] vs. n = 2,087 [26%];
P , 0.001) at sepsis onset. Among patients
with threat, those who underwent
amputations had a lower platelet count than
those who did not (P = 0.003) (Table 1).
The risks of extremity threat after
vasopressor-dependent sepsis varied by
hospital (range with amputation, from 1.1 to
4.4 per 1,000; range without amputation,
from 3.2 to 25.3 per 1,000) and by age (range
627

1,506 Surgical evaluation
231 Extremity threat
26 Extremity threat with
amputation
Figure 1. Cohort accrual.
with amputation, from 0.5 to 5.0 per 1,000;
range without amputation, from 9.8 to 25.5
per 1,000) (Figure E2). The risks of extremity
threat with (7.3 [95% CI, 2.0–18.8] per 1,000)
or without amputation (35.1 [95% CI,
21.2–54.2] per 1,000) were higher among
those with baseline PVD (Figure 2). Finally,
the risk of extremity threat among those
discharged alive was 2.6 (95% CI, 1.6–3.9)
per 1,000 with and 15.1 (95% CI, 12.6–18.0)
per 1,000 without amputation. In an
exploratory Cox proportional hazard model,
norepinephrine equivalents, SOFA score at
sepsis onset, and comorbid conditions,
including CHF and PVD, were associated
with the risk of extremity threat with or
without amputation (Figure 3, Figures E3
and E4, and Table E5).
Timing of Surgical Evaluations and
Outcomes among Patients with
Extremity Threat
The time to surgical evaluations for threat
after sepsis was not significantly different
among those with or without amputations
(median days, 2 [IQR, 0–8] vs. 2 [IQR, 0–7];
P = 0.600), and the median time to
amputation was 16 days (IQR, 6–40) (Figure
E5). For those who underwent amputations,
the ICU length of stay was shorter (median,
8 days [IQR, 6–24] vs. 10 [IQR, 5–18];
P , 0.001) than those without. The risk of
ICU mortality was not observed to be
628
1,107,255 Hospitalized adult
patients
237,764 Suspected infection
168,103 Sepsis
12,060 Vasopressor-dependent
sepsis
10,554 No surgical evaluation
1,275 Sepsis without extremity threat
1,106 Evaluation not for extremity
threat
169 Extremity cause of sepsis
205 Extremity threat without
11,829 No extremity threat
amputation
significantly different (n = 4 [15%] vs. n = 64
[31%]; P = 0.095) among those with or
without amputation. However, the hospital
length of stay was longer (median, 19 days
[IQR, 12–32] vs. 16 [IQR, 9–29]; P , 0.001)
and there was a lower risk of in-hospital
mortality (n = 5 [19%] vs. n = 82 [40%];
P = 0.039) among those with amputations
when compared with those without. No
significant differences were detected in the
risk of discharge home (n = 3/21 [14%] vs.
n = 27/123 [22%]; P = 0.816) among
survivors with or without amputation. There
were no statistical differences found in the
90-day (n = 11/26 [42%] vs. n = 97/205
[47%]; P = 0.630) or 365-day (n = 18/26
[69%] vs. n = 118/205 [58%]; P = 0.255)
mortality among those with or without
amputations (Table E6).
Vasopressor Use
From the 2 days before until 28 days
after sepsis onset, the total days of
vasopressor exposure (median days, 5 [IQR,
3–8] vs. 3 [IQR, 2–4]; P , 0.001) (Figure 4),
total number of vasopressors per day of
exposure (median vasopressors, 1.4 [IQR,
1.0–2.0] vs. 1.0 [IQR, 1.0–1.6]; P , 0.001),
and daily total cardiovascular SOFA score
(median cardiovascular SOFA, 19 [IQR,
12–31] versus 11 [IQR, 6–19]; P = 0.001)
(Figure E6) were greater among those with
extremity threat, compared with those
AnnalsATS Volume 19 Number 4 | April 2022
ORIGINAL RESEARCH
without. There were no differences found in
these parameters compared with those with
or without amputation (P , 0.05 for all).
Sensitivity Analysis
After excluding patients with baseline risk
factors for amputation (i.e., CHF or PVD),
the risk of extremity threat with amputation
was 2.1 (95% CI, 1.1–3.4) and without
amputation was 14.8 (95% CI, 12.3–17.5) per
1,000 patients (Table E7). Changes in the risk
of amputation were not observed using
alternative definitions of vasopressor-
dependent sepsis, ranging from 2.1 to 2.4 per
1,000 patients. Restricting the cohort to
patients with 2 or more days of vasopressor
exposure or Sepsis-3 septic shock, the risks of
threat without amputation were 23.6 (95%
CI, 19.1–28.8) and 21.4 (95% CI, 18.2–25.0)
per 1,000. Among those with bacteremia at
sepsis onset, the risks of threat with
amputation were higher, 5.1 (95% CI,
2.5–9.1) per 1,000 patients (Table E7). Model
estimates accounting for hospital variability
demonstrate similar estimates as the primary
model (Table E8).
Discussion
Among patients with vasopressor-dependent
sepsis, extremity threat with surgical
amputation occurred in 2 per 1,000 patients,
 ORIGINAL RESEARCH

Table 1. Baseline characteristics of patients with vasopressor-dependent sepsis

Extremity Threat Extremity Threat with

No Extremity Threat without Amputation Amputation
Characteristic (n = 11,829) (n = 205) (n = 26) P*

Age, mean (6 SD), yr 65 (616) 61 (618) 58 (618) 0.006

Sex, n (%)
Male 6,420 (54.3) 113 (55.1) 15 (57.7) 0.914
Race/ethnicity, n (%) 0.151
Black 9,668 (81.7) 159 (77.6) 20 (76.9)
White 1,021 (8.7) 21 (10.2) 5 (19.3)
Other† 1,140 (9.6) 25 (12.2) 1 (3.8)
Tobacco use, n (%) 0.354
Never 2,318 (19.6) 40 (19.5) 6 (23.1)
Quit 1,817 (15.4) 24 (11.7) 4 (15.4)
Current 1,438 (12.2) 33 (16.1) 4 (15.4)
Unknown 6,256 (52.8) 108 (52.7) 12 (46.1)
Charlson Comorbidity Index, median (IQR)‡ 1.0 (0.0–3.0) 1.0 (0.0–3.0) 1.5 (0.0–3.0) 0.377
Baseline comorbidities, n (%)
Diabetes 4,667 (39.5) 85 (41.5) 12 (46.2) 0.663
Cancer 744 (15.3) 9 (11.1) 1 (6.2) 0.353
Congestive heart failure 2,895 (24.5) 68 (33.2) 8 (30.8) 0.013
Peripheral vascular disease 519 (4.4) 19 (9.3) 4 (15.4) ,0.001
Cardiovascular disease 1,149 (9.7) 25 (12.2) 2 (7.7) 0.464
Measures of organ dysfunction at sepsis onset§
Maximum SOFA scorejj, mean (6 SD) 9.7 (63.7) 11.0 (64.0) 11.6 (63.9) ,0.001
Norepinephrine equivalents¶, median 0.7 (0.1–3.0) 1.0 (0.3–4.2) 1.8 (0.3–4.35) ,0.001
(IQR) m g/kg/min
Vital signs at sepsis
onset**§, mean (6 SD)
Temperature ( C) 37.8 (61.1) 37.8 (61.1) 38.0 (61.0) 0.417
Oxygen saturation (%) 92.9 (66.3) 92.6 (66.7) 89.0 (612.5) 0.006
Heart rate (beats per minute) 122 (68) 124 (628) 132 (627) 0.068
Systolic blood pressure (mm Hg) 97 (626) 97 (627) 93 (621) 0.721
Glasgow coma scale 10 (65) 9 (64) 10 (65) 0.026
Microbiology at sepsis onset – n (%)
Blood cultures collected†† 5,820 (49) 101 (49) 15 (58) 0.688
Positive blood cultures 2,087 (26) 53 (35) 11 (55) ,0.001
Laboratory values at sepsis
onset**– median (IQR)
Fibrinogen (mg/dL) 276 (176–425) 231 (150–412) 208 (159–250) 0.106
Platelet count (109/L) 170 (116–234) 168 (117–234) 101 (70–179) 0.006
International normalized ratio 1.5 (1.2–2.0) 1.7 (1.3–2.5) 2.0 (1.4–3.3) ,0.001
Serum lactate (mmol/L) 3.1 (1.7–6.0) 4.6 (2.5–8.7) 4.6 (1.8–8.9) ,0.001
Definition of abbreviations: IQR = interquartile range; SD = standard deviation; SOFA = sequential organ failure assessment.
*Kruskal-Wallis, analysis of variance, or chi-square P value as appropriate comparing across all three cohorts. Tests of significance are
completed across all three groups.
†
Other race corresponds to Chinese, Filipino, Hawaiian, American Indian/Alaskan, Asian, Hawaiian/other Pacific Islander, Middle Eastern, Native
American, not specified, or Pacific Islander.
‡
Charlson is a method of categorizing comorbidities of patients based on the International Classification of Diseases diagnosis codes found in
administrative data, ranging from 0 to 24.
§
Corresponds to minimum or maximum value, as appropriate, within the 48 hours before to 24 hours after sepsis onset.
jj
SOFA score corresponds to the severity of organ dysfunction, reflecting six organ systems each with a score range of 0 to 4 points
(cardiovascular, hepatic, hematologic, respiratory, neurological, and renal), with a total score range of 0 to 24 points.
¶
Total days of vasopressor exposure includes the 48 hours before to 24 hours after sepsis onset.
**Missingness of variables can be found within Table E4.
††
Blood cultures collected within 48 hours before to 24 hours after sepsis onset.

most commonly in the lower extremities.
Extremity threat with no amputation
occurred in 17 per 1,000 patients. In the
United States, these data correspond to an
estimated 1,000 surgical amputations
annually after vasopressor-dependent
sepsis (36).
Extremity threat and surgical
amputation are important complications of
sepsis. Common manifestations may include
symmetric peripheral gangrene or purpura
fulminans (6, 12), but there is no consensus
definition or clinical criteria. Three
randomized controlled trials evaluated the
effectiveness of vasopressors on 28-day
mortality among nearly 3,000 patients with
septic shock and included peripheral
ischemia, ranging from cold skin to frank
tissue loss from ischemia, as exploratory
outcomes (13, 16, 17). The range of ischemia
was from 9.5 to 24.2 per 1,000 patients. A

Reitz, Kennedy, Rieser, et al.: Extremity Threat and Amputation after Sepsis 629
 ORIGINAL RESEARCH

All patients Threat with

amputation
Baseline risk factors
Diabetes Threat without
amputation
Cancer

Smoking a

Heart failure

PVD

CVD

Sum of risk factors

0 Factors

1– 2 Factors

!2 Factors

0 10 20 30 40 50
No. threatened extremities, per 1,000
with vasopressor-dependent sepsis

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.

recent meta-analysis of observational studies
concluded that nearly 66 per 1,000 patients
with septic shock had concurrent extremity
ischemia (37). These disparate findings
indicate a paucity of evidence to accurately
estimate a generalizable, and internally valid
incidence risk (37). We extended this prior
work by studying nearly 250,000 patients
with a suspected infection and over 12,000
with vasopressor-dependent sepsis in 14
community and academic hospitals. We
generated a unified definition of extremity
threat, used clinical adjudication of events in
the EHR to identify extremity threat with or
without amputation, and excluded sepsis
resulting from an extremity source or those
that occurred before sepsis onset.
There are many potential mechanisms
for a threat to extremities after sepsis. A
dysregulated immune response to infection
results in a broad range of physiologic
changes (35). First, activation of coagulation
pathways and endothelial dysfunction leads
microcirculatory thrombosis or disseminated
intravascular coagulation in as many as 60%
of patients with shock (38, 39). Second, a loss
of vascular tone and intravascular volume
can lead to circulatory failure and
hypotension. Vasoactive medications
required to support perfusion to vital organs,
however, can worsen peripheral ischemia.
Third, the microbial source of sepsis,
through endotoxin release or direct tissue
infiltration, may directly cause damage to
peripheral tissues (21, 40). These processes
could be exacerbated among patients with
preexisting risk factors. Patients with PVD or
CHF comorbidities may have blood flow-
limiting atherosclerotic disease and even
ventricular dysfunction (41). When
challenged with sepsis and hypotension,
these derangements in peripheral blood
supply may contribute to the higher risks of
extremity threat and amputation seen in this
study.

Norepinephrine
equivalents
Age, years
Male
Race (White)
Black
Other
SOFA, sepsis onset
7–8
9–11
12+
Comorbid conditions
CHF
PVD
CVD
Diabetes
1 2 3 4 5
Hazard Ratio

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.

630 AnnalsATS Volume 19 Number 4 | April 2022

 ORIGINAL RESEARCH

100 Any Vasopressor 100 Norepinephrine 100 Epinephrine

Patients on Any Vasopressor (%)

Patients on Norepinephrine (%)

Patients on Epinephrine (%)

80 No extremity threat 80 80
Threat with amputation
Threat without amputation
60 60 60

40 40 40

20 20 20

0 0 0
0 7 14 0 7 14 0 7 14
Days from Sepsis Onset Days from Sepsis Onset Days from Sepsis Onset

100 Vasopressin 100 Phenylephrine 100 Dopamine

Patients on Phenylephrine (%)
Patients on Vasopressin (%)

80 80 80

Patients on Dopamine (%)

60 60 60

40 40 40

20 20 20

0 0 0
0 7 14 0 7 14 0 7 14
Days from Sepsis Onset Days from Sepsis Onset Days from Sepsis Onset

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.

An immortal time bias and a clinician’s
view that the patient must survive to benefit
from and therefore be considered for both
surgical consultation and amputation may
impact these results. Such effects are
demonstrated by the shorter ICU length of
stay and equivalent ICU mortality among
those with threat who underwent
amputation when compared with those
without amputation. The clinical significance
of threatened extremities to long-term
outcomes is difficult to discern. In this
cohort, one in three patients did not survive
to hospital discharge after sepsis onset, and
survival at discharge was more common
among those with when compared with
those without amputation.
Limitations
This study has limitations. First, patients
identified retrospectively in the EHR with
sepsis and extremity threat may be
misclassified for many reasons, such as 1) no
surgical consultation completed or reported,
2) surgical consultation by an excluded
subspecialty, or 3) autoamputation in those
without a surgical amputation. These
misclassifications would lead to an
underestimate of risks of extremity threat in
this study. We sought to minimize
misclassification by using clinical
adjudication, enrichment for specialties most
likely to evaluate extremity threat in our
healthcare system, and specialty-independent
identification of amputations. Second, the
reported differences in baseline factors and
sepsis treatments were exploratory.
Missingness exists and likely reflects
differences in practice patterns of
measurement. Multivariable models were
limited to variables with less than 1%
missingness; however, the associations with
extremity threat with or without amputation
must be interpreted with caution. Third, we
restricted our analysis to patients with sepsis
who were administered vasoactive
medications, quantified as norepinephrine
equivalents and not individual vasopressors,
independent of resuscitation fluid volumes.
The risks of extremity threat and amputation
may be different among less acute sepsis
patients and critical illness among patients
without sepsis. Finally, we studied patients in
high-resource settings, and these risks may
not be generalizable to sepsis in low- or
middle-income countries.
Conclusion
The evaluation of a threatened extremity
resulting in surgical amputation occurred in
2 per 1,000 patients with vasopressor-
dependent sepsis. 䊏
Author disclosures are available with the
text of this article at www.atsjournals.org.
Acknowledgment: The authors thank the staff
at UPMC Clinical Analytics, the UPMC Wolff
Center, and Biostatistics and Data
Management Core at the CRISMA Center in the
Department of Critical Care Medicine at the
University of Pittsburgh for curating and
managing the data.

Reitz, Kennedy, Rieser, et al.: Extremity Threat and Amputation after Sepsis 631

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AnnalsATS Volume 19 Number 4 | April 2022