Original Research

Journal of Intensive Care Medicine

1-8
Clinical Outcomes of Weight-Based ª The Author(s) 2018
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Norepinephrine Dosing in Underweight DOI: 10.1177/0885066618768180
journals.sagepub.com/home/jic
and Morbidly Obese Patients:
A Propensity-Matched Analysis

Aditya A. Kotecha, MBBS1,2, Saraschandra Vallabhajosyula, MBBS, FACP2,3,4 ,

Dinesh R. Apala, MBBS2,5 , Erin Frazee, PharmD, MS2,6,
and Vivek N. Iyer, MD, MPH2,4

Abstract
Background: Weight-based dosing strategy for norepinephrine in septic shock patients with extremes of body mass index has
been lesser studied. Methods: This historical study of adult septic shock patients was conducted from January 1, 2010, to
December 31, 2015, at all intensive care units (ICUs) in Mayo Clinic, Rochester. Patients with documented body mass index were
classified into underweight (body mass index <18.5 kg/m2), normal weight (18.5-24.9 kg/m2), and morbidly obese (40 kg/m2)
patients. Patients with repeat ICU admissions, ICU stay <1 day, and body mass index 25 to 39.9 kg/m2 were excluded. The primary
outcome was in-hospital mortality, and secondary outcomes included cumulative norepinephrine exposure acute kidney injury,
cardiac arrhythmias, and 1-year mortality. Two-tailed P < .05 was considered statistically significant. Results: From 2010 to 2015,
2016 patients met inclusion—145, 1406, and 466 patients, respectively, in underweight, normal weight, and morbidly obese
cohorts. Underweight patients used the highest peak dose and absolute exposure was greatest for morbidly obese patients. In-
hospital mortality decreased with increasing log10 body mass index: 41.4% (underweight), 28.4% (normal weight), and 24.7%
(morbidly obese), respectively (P < .001); however, this relationship was not noted at 1 year. Unadjusted log10 norepinephrine
cumulative exposure (mg) was associated with higher in-hospital mortality, acute kidney injury, cardiac arrhythmias, and 1-year
mortality. After adjustment for demographics, body mass index, comorbidity, and illness severity, log10 norepinephrine exposure
was an independent predictor of in-hospital mortality (odds ratio 2.4 [95% confidence interval, 2.0-2.8]; P < .001) and 1-year
mortality (odds ratio 1.7 [95% confidence interval, 1.5-2.0]; P < .001). In a propensity-matched analysis of 1140 patients, log10
norepinephrine was an independent predictor of in-hospital mortality (odds ratio 2.2 [95% confidence interval, 1.8-2.6]; P < .001).
Conclusions: Morbidly obese patients had lower in-hospital mortality but had higher 1-year mortality compared to normal
weight and underweight patients. Cumulative norepinephrine exposure was highest in morbidly obese patients. Total nor-
epinephrine exposure was an independent mortality predictor in septic shock.

Keywords
septic shock, norepinephrine, obesity, underweight, mortality

1
Department of Medicine, Detroit Medical Center/Wayne State University, Detroit, MI, USA
2
Multidisciplinary Epidemiology and Translational Research in Intensive Care (METRIC) Laboratory, Mayo Clinic, Rochester, MN, USA
3
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
4
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA
5
Department of Medicine, Creighton University School of Medicine, Omaha, NE, USA
6
Department of Pharmacy, Mayo Clinic, Rochester, MN, USA

Received October 31, 2017. Received revised March 6, 2018. Accepted March 12, 2018.

Corresponding Author:
Vivek N. Iyer, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Email: iyer.vivek@mayo.edu
2 Journal of Intensive Care Medicine XX(X)

Introduction ICU stay <1 day, BMI 25 to 39.9 kg/m2, and missing height/
weight values were excluded. Patients with BMI <18.5 kg/m2
Septic shock is a major cause of mortality and morbidity in the
(underweight) and 40 kg/m2 (morbidly obese) were compared
intensive care unit (ICU).1,2 A cardinal feature of septic shock
to a control group of patients with BMI 18.5 to 24.9 kg/m2
is cardiovascular dysfunction attributable to decreased periph-
(normal weight). All patients requiring vasoactive medications
eral vascular resistance, changes in microvascular permeabil-
at the Mayo Clinic undergo central venous catheter and arterial
ity, and myocardial dysfunction.3-5 Vasoactive medications,
line placement per institutional protocol. Norepinephrine is
specifically norepinephrine, are the first-line therapy to restore
prescribed in a weight-based dosing using actual body weight
vascular tone and organ perfusion.6 Current guidelines in sepsis
at the Mayo Clinic and is titrated to goal MAP of 65 mm Hg
recommend a mean arterial blood pressure (MAP) of 65 mm Hg
(unless otherwise stated) by the nursing staff.
with potential higher goals for patients with chronic hyperten-
Demographics, comorbidities, and clinical information were
sion.6,7 However, the ideal strategy of achieving target MAP,
automatically abstracted from the electronic health records
optimal dosing of norepinephrine, and role of combining
from the customized iterative electronic data repository—Mul-
vasoactive medications in sepsis has been lesser studied.8
tidisciplinary Epidemiology and Translational Research in
Current strategies for administration of norepinephrine
Intensive Care Laboratory (METRIC) DataMart.15,17 Labora-
include weight-based (mg/kg/min) or nonweight-based
tory, fluid, and urine output data were abstracted at periodic
(mg/min) methods.9,10 Weight-based methods are subject to
intervals from 3 hours before ICU admission to 48 hours after
influence by the body mass index (BMI) of individual patients,
ICU admission. Acute Physiology and Chronic Health Evalua-
specifically in patients outside the normal range. It is unclear
tion III (APACHE-III) scores were recorded every 24 hours to
whether weight-based or nonweight-based dosing of norepi-
assess the severity of illness. Acute kidney injury (AKI) was
nephrine is preferred for optimal medication efficacy and
electronically abstracted by a customized, validated search
safety. This is particularly important in the nearly one-third
algorithm that screens all ICU patients.18 Vasoactive medica-
of ICU patients who are obese, wherein weight-adjusted dosing
tions, ventilator parameters, and hemodynamic data are
approaches may confer much higher absolute drug exposure
recorded into the METRIC DataMart every 15 minutes in real
than comparable strategies in normal weight or underweight
time. Vasopressor start and end times, maximum and total
patients.11 Obesity is associated with alterations in drug meta-
dose, and infusion rates were abstracted. Mortality data were
bolism, distribution, and elimination and can potentially
abstracted from the Mayo Clinic databases, the State of Min-
influence cumulative vasopressor doses.12 The influence of
nesota electronic death certificates, and the Rochester Epide-
BMI on weight-based dosing of norepinephrine has been
miology Project death data system. 19 Three independent
infrequently studied.10,13 We, therefore, sought to evaluate
reviewers (AK, SV, and DRA) reviewed the electronically
the role of norepinephrine dosing on clinical outcomes in
abstracted variables and, when needed, performed manual
extremes of BMI (<18.5 and 40 kg/m 2 ). The primary
chart reviews to ensure accuracy and fidelity of data.
hypothesis was that that greater norepinephrine requirement
The primary outcome was in-hospital mortality, and sec-
in patients with higher BMI was associated with higher mor-
ondary outcomes included total norepinephrine administered
tality, higher incidence of acute kidney injury and cardiac
(in mg), incidence of AKI and cardiac arrhythmias, ICU and
arrhythmias, and greater lengths of stay. The secondary
hospital length of stay, and 1-year mortality in underweight
hypothesis was that in patients with lower BMI, lesser nore-
and morbidly obese patients in comparison to normal weight
pinephrine use was associated with increased need for con-
patients.
comitant vasoactive medications and organ failure.

Material and Methods
This was a retrospective cohort study of clinical data collected
in real time from January 1, 2010, to December 31, 2015,
conducted in all the ICUs at Mayo Clinic, Rochester. The char-
acteristics of these ICU populations have been described pre-
viously.14,15 This study was approved by the Mayo Clinic
institutional review board (#16-005271) as minimal risk to
patients, and all activities were carried out in accordance with
the modified Declaration of Helsinki. Adult (>18 years)
patients diagnosed with septic shock who were prescribed nor-
epinephrine were included in this study. The Sepsis and Septic
Shock criteria were used to define septic shock—sepsis requir-
ing vasopressor use to maintain MAP 65 mm Hg and blood
lactate 2 mmol/L despite fluid resuscitation.16 Patients with-
out Minnesota research authorization, repeat ICU admissions,
Statistical Analysis
Continuous data are presented as median (interquartile range
[IQR]), and categorical data are presented as counts (percen-
tages). Kruskal-Wallis test and 1-way analysis of variance test
were used to evaluate continuous and categorical outcomes.
Given the extreme right skew of the total norepinephrine dose
and BMI distribution, a logarithmic transformation was applied
for the analyses that resulted in a normal distribution of these
variables. Logistic regression models were used for the multi-
variable analysis of in-hospital and 1-year mortality. For the
multivariable modeling, regression analysis with purposeful
selection of statistically and clinically relevant variables was
conducted. Univariable predictors with P < .20 and standar-
dized severity of illness scores were included. Variables with
only <10% missing data were included, and 1 variable for
10-unit outcomes was used to prevent overfitting the model.
Kotecha et al
Figure 1. Study population. Individual percentages are not additive
due to multiplicity of exclusion criteria. Data are represented as
number (percentage).BMI indicates body mass index; ICU, intensive
care unit.
Variables were assessed for collinearity prior to inclusion in the
model, and only independent variables were included. Odds
ratio (OR) with corresponding 95% confidence intervals
(CI) and estimate (Est) with standard error (SE) were used
to report categorical and continuous variables in univariable
analysis. We used a multivariable logistic regression to gen-
erate a propensity score with log10 norepinephrine as the
dependent variable. We then used 1:1 nearest neighbor match-
ing with 0.10 calipers and without replacement to match
patients with similar BMI to those without. Propensity-
matched sample has standardized differences <10% for all
baseline and ICU characteristics of age, male sex, race, prior
heart failure, prior diabetes mellitus type II, prior chronic
obstructive pulmonary disease, and APACHE-III score.
Two-tailed P < .05 was considered statistically significant.
All statistical analyses were performed with JMP version
10.0.1 (SAS Institute, Cary, North Carolina).
Results
During this 5-year period, there were a total of 7516 unique
adult patients admitted to the ICUs at Mayo Clinic, Rochester,
with septic shock. Of these patients, 2016 patients (26.8%) met
our inclusion criteria (Figure 1). Underweight, normal weight,
and morbidly obese cohorts had 145, 1406, and 466 patients,
respectively. The baseline characteristics demonstrated signif-
icant intergroup differences in age, sex, race, and baseline and
admission creatinine. Although the Charlson comorbidity
index and Sequential Organ Failure Assessment scores were
comparable across groups, congestive heart failure and dia-
betes mellitus were more common in morbidly obese patients,
whereas underweight patients more often had a history of
chronic obstructive pulmonary disease. The use of stress dose
steroids was rare in the total cohort (Table 1).
Detailed vasoactive medication data are presented in
Table 2. Underweight patients used the highest peak dose per
kilogram to achieve comparable hemodynamic targets (under-
weight: 0.35 mg/kg/min, normal weight: 0.2 mg/kg/min, and
3
morbidly obese: 0.2 mg/kg/min; P < .001). Total drug exposure
was, however, greatest for morbidly obese patients (under-
weight: 5.4 mg, normal weight: 5.2 mg, and morbidly obese:
9.2 mg; P < .001). Between the 3 cohorts, cumulative fluid
balance was not significantly different at any of the measured
time points (Ps > .05; Figure 2). Median creatinine was signif-
icantly different across the BMI categories at all measured
timepoints (Ps < .001). None of the variables had >10% miss-
ing data in this study.
Clinical Outcomes
In-hospital mortality was inversely related to BMI: 41.4%,
28.4%, and 24.7% for underweight, normal weight, and mor-
bidly obese patients, respectively (P < .001). This relationship
was not noted for 1-year mortality, which was 35.9%, 46.3%,
and 46.6% (P ¼ .006) in the 3 cohorts, respectively.
Secondary outcomes between cohorts are presented in Table 3
and Figure 3. Cardiac arrhythmias occurred in 920 (45.6%)
patients, the most common of which was atrial fibrillation
(66.6%), followed by supraventricular tachycardia (8.6%),
ventricular fibrillation/tachycardia (9.2%), asystole/pulseless
electrical activity (6.2%), and atrioventricular blocks (<1%).
Unadjusted log10 norepinephrine cumulative exposure (mg)
was associated with higher in-hospital mortality (OR 2.8 [95%
CI, 2.4-3.3]; P < .001), AKI (OR 1.8 [95% CI, 1.6-2.1];
P < .001), cardiac arrhythmias (OR 1.5 [95% CI, 3.5-10.5];
P < .001), ICU length of stay (Est 3.0, SE 0.3; P < .001),
hospital length of stay (Est 3.1, SE 0.9; P < .001) and 1-year
mortality (OR 1.8 [95% CI, 1.6-2.1]; P < .001).
Univariable and multivariable predictors of in-hospital and
1-year mortality are presented in Table 4. After adjusting for
age, gender, log10 BMI, comorbidities, severity of illness, car-
diac injury, AKI, cardiac arrhythmia, and use of mechanical
ventilation, log10 norepinephrine exposure was an independent
predictor of in-hospital mortality (OR 2.4 [95% CI, 2.0-2.8];
P < .001) and 1-year mortality (OR 1.7 [95% CI, 1.5-2.0];
P < .001; Table 4). Higher log10 BMI demonstrated a protective
effect for both in-hospital (OR 0.2 [95% CI, 0.1-0.3]; P < .001)
and 1-year mortality (OR 0.3 [95% CI, 0.2-0.6]; P < .001).
Using propensity-matching for age, male sex, race, prior heart
failure, prior diabetes mellitus type II, prior chronic obstructive
pulmonary disease, and APACHE-III score, 570 pairs (1140
patients) were generated. In this cohort of 1140 patients, log10
norepinephrine remained an independent predictor of in-
hospital mortality (OR 2.2 [95% CI, 1.8-2.6]; P < .001).
Discussion
In this large historical cohort study of patients with septic shock
and extremes of BMI, the major findings were as follows: (a)
despite differences in demographic characteristics and baseline
comorbidity, underweight and morbidly obese patients had
similar severity of illness compared to normal weight patients;
(b) morbidly obese patients had significantly higher cumulative
norepinephrine use; (c) total norepinephrine exposure was
4 Journal of Intensive Care Medicine XX(X)

Table 1. Baseline Characteristics of Cohorts.a

Parameter Underweight, n ¼ 145 Normal Weight, n ¼ 1406 Morbidly Obese, n ¼ 466 P

Age (years) 62.4 (50.5-71.7) 65.3 (54.1-76.1) 61.7 (53.2-69.6) <.001

Male sex 63 (43.5) 784 (55.8) 251 (53.9) .02
Caucasian race 130 (89.7) 1241 (88.2) 440 (94.4) .008
Body mass index (kg/m2) 17.4 (16.7-18) 22.8 (21.1-23.9) 42 (42-49.5) <.001
Body surface area (m2) 1.5 (1.4-1.6) 1.7 (1.6-1.9) 2.5 (2.3-2.7) <.001
Charlson comorbidity index 5 (3-8) 5 (3-8) 5 (3-8) .31
Myocardial infarction 12 (8.3) 171 (12.2) 54 (11.6) .35
Heart failure 18 (12.4) 229 (16.3) 120 (25.8) <.001
Chronic obstructive pulmonary disease 40 (27.6) 203 (14.4) 66 (14.2) <.001
Diabetes mellitus, type II 21 (14.5) 257 (18.3) 228 (48.9) <.001
Baseline creatinine (mg/dL) 1.0 (0.7-1.6) 1.0 (0.8-1.5) 1.3 (1-1.9) <.001
Admission APACHE-III score 49 (37.5-67) 55 (42-68) 54 (40-70) .05
Admission SOFA score 9 (7-12) 9 (8-12) 9 (7-12) .41
Admission creatinine (mg/dL) 0.9 (0.6-1.5) 1 (0.8-1.5) 1.4 (1-2.2) <.001
Peak lactate (mmol/L) 3.9 (2.7-5.6) 4.4 (2.9-7.8) 4 (2.-7.6) .02
Peak troponin-T (ng/mL) 0.09 (0.04-0.2) 0.11 (0.04-0.44) 0.1 (0.05-0.36) .43
Hydrocortisone use 0 (0) 9 (0.6) 3 (0.6) .63
Respiratory failure 125 (86.2) 1213 (86.3) 1751 (86.9) .43
Duration of invasive ventilation 2.2 (0.9-5.5) 1.9 (0.7-5.6) 2 (0.7-5.3) .71
Abbreviations: APACHE-III, Acute Physiology and Chronic Health Evaluation III; SOFA, Sequential Organ Failure Assessment.
a
Data are represented as total (percentage) or median (interquartile range).

Table 2. Vasoactive Medications.a

Vasoactive Medication Underweight, n ¼ 145 Normal Weight, n ¼ 1406 Morbidly Obese, n ¼ 466 P

Norepinephrine
Total dose (mg) 5.4 (1.8-11.4) 5.2 (1.4-13.3) 9.1 (3-21.2) <.001
Peak dose (mg/kg/min) 0.35 (0.17-0.64) 0.2 (0.08-0.4) 0.2 (0.08-0.4) <.001
Peak dose (mg/min) 15.4 (7.9-30.4) 11.5 (5-25) 20.6 (8.5-59.1) <.001
Vasopressin
Total patients 80 (55.2) 843 (60) 265 (56.9) .32
Total dose (U) 72.3 (31.6-160.6) 77.8 (41.8-185) 69 (30.6-154.2) .14
Peak dose (U/min) 0.04 (0.04-0.04) 0.04 (0.04-0.04) 0.04 (0.04-0.04) .07
Epinephrine
Total patients 28 (19.3) 437 (31.1) 140 (30.1) .01
Total dose (mg) 7.1 (2-12.8) 8.7 (3-19.6) 10.7 (4.2-24.1) .18
Peak dose (mg/kg/min) 0.1 (0.05-0.2) 0.08 (0.05-0.1) 0.06 (0.05-0.15) .10
Phenylephrine
Total patients 23 (15.9) 220 (15.7) 58 (12.5) .23
Total dose (mg) 13.1 (8.6-36) 9.5 (2.7-29.3) 19.9 (5.1-50.6) .08
Peak dose (mg/kg/min) 1.5 (0.5-2.5) 0.8 (0.4-1.5) 0.6 (0.3-1.5) .05
Dobutamine
Total patients 9 (6.2) 89 (6.3) 27 (5.8) .92
Total dose (mg) 207.5 (39.2-892.3) 204.8 (50.7-660.8) 420.4 (155.4-1620.1) .27
Peak dose (mg/kg/min) 5 (3.8-7.5) 5 (5-10) 5 (5-10) .37
Dopamine
Total patients 14 (9.7) 137 (9.7) 41 (8.8) .83
Total dose (mg) 420.4 (59.7-7518.1) 635.7 (189.2-2512.1) 460.5 (221.7-1781.8) .83
Peak dose (mg/kg/min) 8.8 (5-16.3) 5 (3-7.8) 5 (3-8.5) .01
Milrinone
Total patients 20 (13.8) 257 (18.3) 80 (17.2) .36
Total dose (mg) 0.1 (0.02-0.35) 0.18 (0.04-0.6) 0.15 (0.04-0.49) .42
Peak dose (mg/kg/min) 0.3 (0.25-0.38) 0.3 (0.25-0.5) 0.25 (0.25-0.38) .23
a
Data are represented as total (percentage) or median (interquartile range).
Kotecha et al 5

Figure 2. Median cumulative fluid balance across underweight, nor- Figure 3. Creatinine trends across underweight, normal weight, and
mal weight, and morbidly obese patient cohorts, using one-way anal- morbidly obese patient cohorts, using one-way analysis of variance
ysis of variance (Ps > .05). BMI indicates body mass index. (Ps < .001). BMI indicates body mass index.

authors.22 This can be explained by multiple hypotheses.

a
Table 3. Clinical Outcomes. Firstly, obese patients in sepsis are often underresuscitated and
have higher antibiotic failure due to inadequate dosing, leading
Normal Morbidly
Underweight, Weight, Obese,
to longer and more severe circulatory failure.11,22 Secondly,
Outcome n ¼ 145 n ¼ 1406 n ¼ 466 P obesity is associated with need for higher positive end-
expiratory pressures during mechanical ventilation, further
In-hospital 60 (41.4) 399 (28.4) 115 (24.7) <.001 compromising cardiac output. Obesity is frequently associated
mortality with higher baseline comorbidity such as diabetes, hyperten-
Acute kidney 107 (75.4) 1031 (77.5) 403 (91) <.001
sion, and heart failure, as demonstrated in this study, poten-
injury
Cardiac 53 (36.6) 642 (45.7) 225 (48.3) .05 tially resulting in slower and incomplete resolution of sepsis.23
arrhythmias The patients with normal BMI had lower norepinephrine
ICU length of 4.6 (2.32-7.8) 3.7 (2.1-7.8) 3.8 (2-7.1) .40 requirements in our study, perhaps partially explained by our
stay (days) restriction to only septic shock patients. In a multivariable
Hospital 12 (5.8-25.6) 12.1 (6.9-23.1) 10.1 (6.1-20.7) .03 analysis, the log transformation of BMI was a strong predictor
length of of lesser short- and long-term mortality. Importantly, contrary
stay (days)
to our original hypothesis, patients with higher BMI had lower
1-year 52 (35.9) 651 (46.3) 237 (46.6) .006
mortality mortality despite adjustment of norepinephrine dosing, likely
due to unmeasured confounders from the ICU processes of care
Abbreviation: ICU, intensive care unit. and baseline comorbidity. This can be explained by multiple
a
Data are represented as total (percentage) or median (interquartile range).
hypotheses. Firstly, despite demonstration of the “obesity para-
dox” in other disease states, the higher in-hospital survival in
associated with higher mortality and length of stay, and greater obese sepsis patients is likely a reflection of less severe infec-
incidence of AKI and cardia arrhythmias; (d) total norepinephr- tions and younger age.22 In a multicenter study, Arabi et al
ine exposure was an independent predictor of in-hospital and 1- demonstrated lower hemodynamic disturbances and lower
year mortality after adjusting and propensity-matching for need for vasoactive medications in obese septic patients.22
comorbidities, severity of illness, and use of mechanical venti- Wacharasint et al demonstrated improving survival in obese
lation; and (e) despite higher norepinephrine requirements, patients; however, their study did not distinguish between
morbidly obese patients had reduced in-hospital mortality com- underweight and normal BMI.24 Secondly, acute processes of
pared to other cohorts, but this relationship was not noted for 1- care, such as mechanical ventilation and vasopressor dosing,
year mortality. had greater influence on in-hospital mortality that was partly
The use of a weight-based norepinephrine dosing strategy counteracted by potentially shorter ICU stay in the morbidly
can result in significant cumulative drug exposure, as demon- obese patients. Thirdly, Charlson comorbidity index did not
strated in our study. The role of BMI/weight has been lesser demonstrate any association with in-hospital mortality but was
studied in critical illness and vasopressor dosing.9,10 The BMI a significant contributor to 1-year mortality postulating the role
has a parabolic relationship with mortality in critical illness, for a gradual decline due to a higher comorbidity burden from
with the highest mortality in patients with low (<18.5 kg/m2) obesity in the morbidly obese cohort.
and very high (40 kg/m2) BMI.20,21 Obese patients frequently In septic shock, the maximum effective dose of norepi-
require lower peak doses, but longer duration of vasoactive nephrine remains uncertain, but doses above 1 mg/kg/min have
medications, as demonstrated in our study and by other been associated with >90% mortality. 25 Similar to other
6 Journal of Intensive Care Medicine XX(X)

Table 4. Multivariable Analysis for In-Hospital and 1-Year Mortality.a

In-Hospital Mortality 1-Year Mortality

Univariable Analysis Multivariable Analysisc Univariable Analysis Multivariable Analysisc

Odds Ratio Odds Ratio Odds Ratio Odds Ratio

Parameter (95% CI)b P (95% CI)b P (95% CI)b P (95% CI)b P

Age (in years) 1.1 (1.1-1.1) <.001 1.0 (0.9-1.0) .57 1.1 (1.1-1.1) <.001 1.8 (0.9-3.5) .08
Male sex 1.2 (0.9-1.4) .17 – – 1.0 (0.8-1.2) .96 – –
Log10 body mass index 0.4 (0.2-0.8) .01 0.2 (0.1-0.3) <.001 0.5 (0.3-0.9) .03 0.3 (0.2-0.6) <.001
Charlson comorbidity index 1.1 (1.1-1.1) <.001 1.0 (0.9-1.1) .07 1.2 (1.2-1.3) <.001 1.1 (1.1-1.2) <.001
Prior myocardial infarction 1.1 (0.8-1.4) .70 – – 2.1 (1.6-2.8) <.001 1.4 (1.0-1.9) .09
Prior heart failure 1.1 (0.8-1.4) .63 – – 1.6 (1.3-2.0) <.001 1.1 (0.8-1.5) .51
Prior COPD 1.8 (1.4-2.3) <.001 1.7 (1.3-2.3) <.001 2.3 (1.8-3.0) <.001 1.7 (1.3-2.3) <.001
Prior diabetes mellitus, type II 1.1 (0.9-1.4) .43 – – 1.6 (1.3-2.0) <.001 1.1 (0.8-1.3) .79
APACHE-III 1.1 (1.1-1.1) <.001 1.1 (1.1-1.1) <.001 1.1 (1.1-1.1) <.001 1.1 (1.1-1.1) <.001
Cardiac troponin-T (ng/mL) 1.0 (0.9-1.1) .54 – – 1.0 (0.9-1.1) .69 – –
Acute kidney injury 2.8 (2.1-3.8) <.001 1.8 (1.3-2.5) <.001 2.1 (1.7-2.7) <.001 1.6 (1.2-2.0) <.001
Arrhythmias 1.7 (1.4-2) <.001 1.2 (0.9-1.4) .28 1.7 (1.4-2) <.001 1.1 (0.9-1.4) .34
Invasive mechanical ventilation 1.7 (1.3-2.2) <.001 1.4 (1.0-1.9) .05 0.8 (0.6-1.1) .08 1.4 (1.1-1.8) .03
Log10 norepinephrine (mg) 2.8 (2.4-3.3) <.001 2.4 (2.0-2.8) <.001 1.8 (1.6-2.1) <.001 1.7 (1.5-2.0) <.001

Abbreviations: APACHE-III, Acute Physiology and Chronic Health Evaluation III; CI, confidence interval; COPD, chronic obstructive pulmonary disease.
a
Data are represented as OR (95% CI).
b
Unit OR are represented for continuous variables.
c
Adjusted for age, male sex, log10 body mass index; Charlson comorbidity index, APACHE-III score, peak troponin-T, acute kidney injury, cardiac arrhythmia,
mechanical ventilation, and log10 norepinephrine.

authors, we demonstrated increased mortality with increasing
cumulative norepinephrine requirements.25,26 High norepi-
nephrine exposure could result in incremental mortality or
could alternately reflect a sicker cohort who had an increased
risk of death.8 The definition of catecholamine refractory shock
and high-dose vasopressors is varied in literature and needs
further data to develop an optimal research definition.27 In this
study, higher cumulative norepinephrine exposure was associ-
ated with a greater incidence of adverse events, such as cardiac
arrhythmias and AKI. Our findings corroborate a substudy
from the Vasopressin and Septic Shock trial that noted higher
mortality in patients with serious adverse events while on vaso-
pressors.28 Similar to the Sepsis Occurrence in Acute Ill
Patients trial, the greater incidence of AKI and cardiac arrhyth-
mias in this study could be related to the use of greater epi-
nephrine in patients with normal weight and morbidly obese
patients compared to underweight patients.29 Even though epi-
nephrine did not demonstrate an independent correlation with
outcomes in this population, there is a need for further dedi-
cated studies evaluating cumulative vasopressor dosing in this
population. In obese patients with BMI 30 kg/m2, Vadiei et al
demonstrated higher cumulative norepinephrine dose (12.6 vs
10.5 mg; P ¼ .04) in patients treated using weight-based strat-
egy.10 However, there were no differences in achieving goal
MAP or concomitant use of other vasoactive medications in
their study. Using a composite endpoint of MAP and norepi-
nephrine dosing, Radosevich et al did not demonstrate any
differences in outcomes or cumulative norepinephrine dose
between weight-based and nonweight-based dosing strategies.9
However, this endpoint was restricted to the first 60 minutes of
use, thereby not accounting for the total duration of vasopressor
support. Additionally, in nonweight-based dosing algorithms,
restriction of total administered dose may result in lesser mg/kg
body weight of actual norepinephrine delivered.13
With respect to fluid, electrolytes, and renal function, prior
literature has demonstrated differences in fluid resuscitation of
obese and morbidly obese patients.22 This study, however, did
not show any differences in the cumulative balance between
cohorts from 3 to 48 hours postsepsis onset. In patients with
septic shock, norepinephrine augments renal blood flow and
improves renal function. However, in this study, there was an
increase in AKI with increase in cumulative norepinephrine
dose. This could likely be a result of underresuscitation of mor-
bidly obese patients and significantly higher vasopressor dosing
compared to prior data on AKI.30 Contrary to the original hypoth-
esis, this study was unable to demonstrate significant differences
in need for additional vasopressors in patients with low BMI.
This could potentially be explained by greater fluid resuscitation,
since underweight patients frequently receive >30 mL/kg fluid
resuscitation due to the nonweight-based administration of
fluids.22 Additionally, the incidence of AKI was significantly
lower in patients with BMI <18.5 kg/m2 that could reflect a
bidirectional relationship with vasopressor requirements.31,32
However, in extremes of BMI, creatinine could be influenced
by muscle mass as noted by elevations in baseline creatinine in
the morbidly obese cohort (mean 1.3 [IQR 1.0-1.9] mg/dL). The
baseline creatinine in the underweight population was relatively
similar to the control group in this population.
This study has various limitations. The use of a historical
database is associated with the inherent selection and
Kotecha et al
informational biases. Nearly 48% of our initial population was
excluded as readmissions, so we are unable to comment on the
impact of norepinephrine dosing in these patients. Alternate
endpoints to critical illness, such as functional status, disposi-
tion, and return to work, were not assessed in this study that
could provide a greater understanding of long-term outcomes.
Given the rapidity and nature of ICU interventions, the mea-
sured weight is likely an inaccurate measure of the patients’ dry
weight, which is a significant limitation of using BMI. The
study duration correlated with the evolution of critical care
ultrasonography and changes in health-care delivery at the
Mayo Clinic, which conceivably could have influenced the
study results. Finally, the single region, single institution, and
referral patient population of the Mayo Clinic could impact the
generalizability to other populations.
Conclusions
Using a weight-based dosing strategy, this study demonstrated
greater cumulative norepinephrine exposure in morbidly obese
patients. Higher doses of norepinephrine were associated with
higher in-hospital and 1-year mortality. The use of nonweight-
based regimens, maximum dose thresholds, and alternative
agents to decrease norepinephrine exposure need careful eva-
luation in prospectively designed studies. Despite higher nor-
epinephrine exposure and greater baseline comorbidity,
morbidly obese patients had lower in-hospital mortality. How-
ever, 1-year mortality was higher in morbidly obese patients
compared to normal weight and underweight patients, likely
alluding to the contribution from baseline characteristics neces-
sitating further mechanistic studies in these complex patients.
Authors’ Note
Aditya A. Kotecha, Saraschandra Vallabhajosyula, Erin Frazee, and
Vivek N. Iyer contributed to study design, literature review, data
analysis, and statistical analysis. Data management, data analysis, and
drafting manuscript are done by Aditya A. Kotecha, Saraschandra
Vallabhajosyula, and Dinesh R. Apala. Aditya A. Kotecha, Saraschandra
Vallabhajosyula, Dinesh R. Apala, Erin Frazee, and Vivek N. Iyer
accessed the data. Erin Frazee and Vivek N. Iyer helped in manuscript
revision, intellectual revisions, and mentorship. The poster was
presentation at CHEST 2017, American College of Chest Physicians,
Toronto, ON, October 2017.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for
the research, authorship, and/or publication of this article:
ORCID iD
Saraschandra Vallabhajosyula, MBBS, FACP http://orcid.org/
0000-0002-1631-8238
Dinesh R. Apala, MBBS http://orcid.org/0000-0001-7555-4348
7
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