Journal of Critical Care 30 (2015) 518–524

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Journal of Critical Care

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Sepsis/Infection

Impact of obesity on sepsis mortality: A systematic review☆

Vrinda Trivedi, MD, Chirag Bavishi, MD, MPH, Raymonde Jean, MD ⁎
Mount Sinai St Luke's Roosevelt Hospital, New York, NY

a r t i c l e i n f o a b s t r a c t

Keywords: Purpose: Sepsis and severe sepsis are the most common cause of death among critically ill patients admitted in
Obesity medical intensive care units. As more than one-third of the adult population of the United States is obese; we un-
BMI dertook a systematic review of the association between obesity and mortality among patients admitted with sep-
Sepsis
sis, severe sepsis, or septic shock.
Mortality
Materials and methods: A systematic review was conducted to identify pertinent studies using a comprehensive
Systematic review
search strategy. Studies reporting mortality in obese patients admitted with sepsis were identified.
Results: Our initial search identified 183 studies of which 7 studies met our inclusion criteria. Three studies re-
ported no significant association between obesity and mortality, 1 study observed increased mortality among
obese patients, whereas 3 studies found lower mortality among obese patients.
Conclusion: Our review of the current clinical evidence of association of obesity with sepsis mortality revealed
mixed results. Clinicians are faced with a number of challenges while managing obese patients with sepsis and
should be mindful of the impact of obesity on antibiotics administration, fluid resuscitation, and ventilator man-
agement. Further studies are needed to elicit the impact of obesity on mortality in patients with sepsis.
© 2014 Elsevier Inc. All rights reserved.

1. Purpose sepsis is not well studied. Hence, we undertook a systematic review to

Sepsis and severe sepsis are the most common cause of death among
critically ill patients admitted in medical intensive care units (ICUs) [1].
As per the Centers for Disease Control and Prevention National
Center for Health statistics report, septicemia was the 11th leading
cause of death in the United States in 2010 [2]. Between 2003 and
2007, the number of patients hospitalized for severe sepsis increased
by 71%, at an annual rate of 17.8% per year [3]. In addition to high mor-
tality and morbidity, severe sepsis is associated with increased health
care expenditures. In 2007, the health care costs for patients admitted
for severe sepsis exceeded $24 billion, an increase of 57% since 2003 [3].
Obesity is one of the major public health problems. Current esti-
mates suggest that 69% of adults in United States are either overweight
or obese with approximately 35% obese [4]. Furthermore, overweight
and obesity are major contributors to chronic diseases. Obesity has
been shown to be associated with an increased all-cause mortality [5],
myocardial infarction [6], diabetes mellitus [7], and hypertension [7].
The high prevalence of obesity in the general population has led to a
higher number of obese patients being hospitalized in ICUs. Although
prognostic effect of obesity has been extensively studied in critically ill
patients [8,9], the impact of obesity on the outcomes of patients with
☆ Conflict(s) of interest/disclosures (s): None of the authors has any financial or other
relations that could lead to a conflict of interest.
⁎ Corresponding author. Division of Pulmonary and Critical Care Medicine, Mount
Sinai St Luke's-Roosevelt Hospital, 1000 Tenth Ave, New York, NY 10019, USA.
E-mail address: RJean@chpnet.org (R. Jean).
study the association between obesity and mortality among patients ad-
mitted with sepsis, severe sepsis, or septic shock.
2. Materials and methods
2.1. Search strategy
A comprehensive literature search of all the pertinent studies pub-
lished until May 2014 was undertaken in PubMed, Scopus, and Ovid
Medline databases. A literature search was undertaken using the key
words (“obese,” “obesity,” “overweight,” “morbidly obese,” “morbid
obesity,” “BMI,” or “body mass index”) and (“sepsis,” “severe sepsis,”
“septic shock” “bacteremia,” or “septicemia”) and (“mortality” or “out-
comes”). In addition, a manual search of the full text for the relevant re-
view articles and original studies was performed to identify additional
studies (Figure 1).
2.2. Selection criteria
For initial review, studies were considered as eligible if they referred
to any aspect of sepsis and obesity. We then restricted our search to
studies reporting specific data on mortality outcomes among obese pa-
tients admitted with sepsis. Studies selected defined obesity using ei-
ther prespecified body mass index (BMI) categories or the World
Health Organization obesity classification: underweight, BMI less than
18.5; normal weight, BMI 18.5 to 24.9; overweight, BMI 25 to 29.9; obe-
sity, BMI 30 to 39.9; and morbid obesity, BMI greater than or equal to 40.

http://dx.doi.org/10.1016/j.jcrc.2014.12.007
0883-9441/© 2014 Elsevier Inc. All rights reserved.
 V. Trivedi et al. / Journal of Critical Care 30 (2015) 518–524
We excluded reviews, letters, correspondence, editorials, and nonhu-
man studies; however, the reference lists of these articles were searched
to identify other potential studies.
2.3. Study selection and data abstraction
Two physician reviewers (VT and CB) independently reviewed and
selected studies based on the inclusion criteria. Disagreement in study
selection or data extraction was resolved with consensus. Study data
were abstracted independently by each reviewer using a standardized
data collection form. The following data were collected from each
study: author information, year of publication, study location, type of
study, categories of BMI studied, outcomes, effect size, confounding var-
iables adjusted in the analysis, and other salient features.
2.4. Data analysis
Given significant methodological and statistical differences be-
tween studies, combining the data using meta-analytic techniques
was deemed inappropriate. Therefore, we used qualitative analysis
and prepared a systematic review of all the available studies that
evaluated the association between obesity and mortality among
sepsis patients.
3. Results
Our initial search identified 183 studies of which 7 studies met our
inclusion criteria [10-16] (Table 1). Six studies were retrospective,
whereas 1 was a prospective cohort study [15]. All studies used World
Health Organization cut-offs to define obesity categories. Out of the 7 ar-
ticles, 3 studied hospital/inpatient mortality [11,12,14]; 2 studied 28-
day mortality [13,16]; 1 studied 30-day mortality [15]; and 1 studied
in-hospital, 90-day, and 1-year mortality [10]. Six studies reported re-
sults by obese categories (overweight/obese vs nonobese/normal
BMI), whereas 1 study reported results using BMI as a continuous vari-
able [13]. The results were heterogeneous. Three studies reported no
Records identified through database
searching and after removing duplicates
(n = 409)
Records screened
(n =409)
Full-text articles assessed
for eligibility
(n = 23)
Studies included in
qualitative synthesis
(n = 7)
Figure 1. Flow diagram of literature search and study selection.
519
significant association between obesity and mortality [12,14,16], 1
study observed increased mortality [15] among obese patients, whereas
3 studies found lower mortality among obese patients [10,11,13].
Prescott et al [10] studied 1404 Medicare beneficiaries (adults N65
years) hospitalized for severe sepsis and reported in-hospital, 90-day,
and 1-year mortality. Multivariate logistic regression models showed
that overweight, obese, and severely obese patients had a statistically
significant association with lower in-hospital, 90-day and 1-year mor-
tality. The results were persistent, when stratified by age (patients
b70 and N70 years). The risk of developing functional limitations after
an episode of sepsis was similar in obese and normal weight individuals.
Interestingly, obese patients that survived hospitalization for sepsis re-
quired higher annual Medicare spending after being discharged from
the hospital, but this apparent increase was attributed to greater surviv-
al and not increased utilization. Similar results were demonstrated by
Wurzinger et al [11] who investigated ICU mortality in their single-
center study of 301 septic shock patients. Patients with a BMI more
than 50 were excluded from the study population. As compared with
normal weight patients, overweight and obese patients were associated
with lower mortality in multivariable analysis. High BMI was indepen-
dently associated with lower risk of acute delirium and ICU readmission
but with a higher rate of ICU-acquired urinary tract infections. In anoth-
er single-center study, Kuperman et al [12] studied 792 patients admit-
ted with sepsis. Patients with BMI more than 50 were excluded from the
study. Unadjusted analysis revealed that survivors had a higher BMI, but
after adjusting for comorbidities in the multivariate regression model,
the association of decreased mortality with higher BMI was no longer
statistically significant. Wacharasint et al [13] published post hoc analy-
sis of Vasopressin and Septic Shock trial to investigate if overweight and
obese patients had a lower 28-day mortality as compared with patients
with a BMI less than 25. They found that for every 1-U increase in BMI,
mortality decreased by 2%. Results remained similar on reanalysis after
excluding the underweight group, and obese patients had the lowest
mortality followed by overweight and normal BMI patients. Obese and
overweight patients had a lower rate of pneumonia and fungal infec-
tions and received less weight adjusted intravenous fluids and pressors
Records excluded based on titles
and abstracts
(n = 386)
Full-text articles excluded:
Reviews (5)
No mortality outcomes (7)
Not sepsis patients (4)
 520
Table 1
Characteristics of studies evaluating the association between obesity and mortality in sepsis patients

First author, Study type BMI categories Sample size Outcome Result BMI as Result BMI as Variables adjusted for Comments
year, country studied and patient continuous categorical
profile variable OR variable OR
(95% CI) (95% CI)a

Arabi et al [14], Nested Underweight: b18.5, 2882 In-hospital NR Obese Age, sex, All patients were
normal: 18.5-24.9, mortality admitted
2013 multicenter overweight: patients with Unadjusted: mechanical to the ICU.
cohort 25.0-29.9, obese: septic shock ventilation, Largest study
study conducted APACHE II score, evaluating
in 28 centers chronic obesity and
comorbidities outcomes
nosocomial in septic
infection, shock patients
bacteremia,
Canada, USA, 30.0-39.9, 0.80 (0.66-0.97) infections,
Saudi Arabia very obese: N40 creatinine
clearance,
Adjusted: country,

V. Trivedi et al. / Journal of Critical Care 30 (2015) 518–524

inappropriate/
0.80 (0.62-1.02) combination/delayed
antimicrobial therapy,
vasopressor doses,
the use of a pulmonary
artery catheter, activated
Very obese protein C and
low-dose steroids
Unadjusted:
0.61 (0.44-0.85)
Adjusted:
0.69 (0.45-1.04)
Gaulton et al [16], Retrospective Obese: BMI ≥30 1779 patients with 28-day NR Obese Sex, 66% patients
cohort study, nonobese: presumed sepsis mortality Unadjusted: admitting hospital, were
single center ≥18.5-30. admitted to
2014 1.21 ICU location, the ICU.
(0.95-1.54) BMI b18.5 were
USA Adjusted: vasopressor excluded
1.11 (0.85-1.41)
Huttunen et al [15], Prospective cohort Obese: 149 patients 30-day mortality NR Obese Age, sex, 32% patients were
2007 study, single center BMI N30 with bacteremia Unadjusted: smoking, alcohol abuse, admitted to the ICU.
S aureus, S pneumonia, Only prospective
β-hemolytic streptococcus and cohort study evaluating
Finland nonobese: BMI b30 9.8 (2.3-41.3) E coli bacteremia obesity and outcomes
Adjusted: in patients
6.4 (1.2-34.4) with bacteremia
Kuperman et al Retrospective cohort Underweight: b18.5, 792 patients In-hospital Unadjusted: Morbid obesity Age, No data
[12], 2013 study, single center normal: 18.5-24.9, with sepsis mortality unadjusted: race, sex, length provided on the
of stay, diabetes, level of care.
neutropenia, Patients with
cancer, liver disease, BMI N50 were
cardiovascular excluded.
disease,
COPD, liver disease,
USA overweight: 0.97 (0.94-1.0) 0.7 (0.12-4.2) immunosuppression,
25.0-29.9, modified
APACHE II
 obese: 30.0-39.9, Adjusted:
morbidly obese:
40.0-49.9 0.90 (0.76-1.06)
Prescott et al [10] Retrospetive cohort Normal: 18.5-24.9, 1404 patients In-hospital, Adjusted: Adjusted Age, sex 49% patients were
2014 study, multicenter overweight: 25-29.9, with severe sepsis 90-day, hospital mortality: hospital admitted to the ICU.
obese: 30-34.9, and 1-year 0.96 (0.93-0.99) mortality: Multicenter study of
USA severely obese: ≥35 mortality 90-day mortality: obese Medicare beneficiaries.
0.95 (0.93-0.98) 0.64 (0.40-1.01) Patients with BMI b18.5
1-year mortality: severely obese: were excluded.
0.96 (0.93-0.99) 0.54 (0.31-0.95)
90-day mortality
obese: marital status,
0.53 (0.35-0.79) race, wealth,
severely obese: acute organ
0.43 (0.25-0.74) dysfunction, ICU
1-year use, mechanical
mortality ventilation use, diabetes,
obese: baseline cognitive
0.59 (0.39-0.88) status, functional
severely obese: limitations
0.46 (0.26-0.80)

V. Trivedi et al. / Journal of Critical Care 30 (2015) 518–524

Wacharasint et al [13], Retrospective Normal: BMI b25 730 patients 28-day Adjusted: NR APACHE II, sex, All patients were
2013 cohort Overweight: with mortality 0.98 (0.97-0.99) lung infection, diabetes, admitted
study BMI 25-30 septic shock fungal infection to the ICU.
Canada (from VASST trial) Obese: BMI N30 Excluding underweight
patients yielded
similar results
Wurzinger et al [11], Retrospective Underweight: b18.5; 301 ICU mortality Unadjusted: Obese Admission year, All patients
cohort study normal: 18.5-24.9; age, sex, were admitted
overweight: 25-29.9; heart disease, to the ICU.
obese and morbidly chronic renal
obese: ≥30 insufficiency,
2010 patients with 0.91 (0.86- 0.98) Adjusted: premorbidities,
origin of sepsis,
Austria septic shock Adjusted: 0.28 (0.08-0.93) SAPS II
0.93 (0.86-1.01)

OR indicates
odds ratio; CI, confidence
interval; NR, not reported; APACHE, Acute Physiology and Chronic Health Evaluation; S aureus, Staphylococcus aureus;
S pneumoniae, Streptococcus pneumoniae; E coli, Escherichia coli; COPD, chronic obstructive pulmonary disease; VASST, Vasopressin and Septic Shock trial; SAPS, Simplified Acute
Physiology Score.
a
As compared with normal BMI.

521
522 V. Trivedi et al. / Journal of Critical Care 30 (2015) 518–524
as compared with patients with a BMI less than 25. In a large multicen-
ter nested cohort study, Arabi et al [14] investigated the association be-
tween obesity and in-hospital mortality in 2882 septic shock patients.
Results revealed that, although obese and very obese patients had a
lower mortality in comparison with patients with normal BMI, the asso-
ciation became insignificant after adjusting for baseline characteristics
and sepsis interventions. In another large cohort study by Gaulton
et al [16], multivariable-adjusted analysis showed that 28-day mortality
was not significantly higher among obese sepsis patients as compared
with sepsis patients with BMI less than 30. However, severely obese pa-
tients had higher mortality than normal BMI group patients. Huttunen
et al [15] prospectively studied the association between BMI and 30-
day mortality rate in 149 patients with bacteremia. Patients enrolled in-
cluded those with positive blood cultures, and the severity of illness
ranged from milder symptoms and signs to those who developed septic
shock and required an ICU stay. In multivariate analysis, obese patients
were associated with both increased 30-day mortality and an increased
ICU mortality.
4. Discussion
Clinical studies evaluating the impact of obesity on mortality in crit-
ically ill sepsis patients have yielded conflicting results. Obesity is
thought to be a state of chronic inflammation, as it is associated with
increased oxidative stress. Cytokines secreted from adipocytes such as
interleukins (IL-1, IL-3, IL-6, and IL-8), tumor necrosis factor α, and
transforming growth factor β have been found to correlate with increas-
ing BMI and waist-to-hip ratio [17,18]. Hence, it is speculated that,
when obese individuals develop sepsis, the systemic inflammatory
response may be different as compared with those with a normal BMI.
4.1. Experimental models and animal studies
Several studies have utilized nonhuman models to examine sepsis in
obese states. Vachharajani et al using cecal ligation and puncture-
induced sepsis model showed that cerebral microvasculature in obese
septic mice is more prone to pronounced inflammatory responses and
endothelial dysfunction as compared with their lean counterparts
[19]. In another study, Singer et al [20] studied ob/ob (leptin deficient)
and db/db (leptin resistant) mice and found that both mutant models
produced augmented inflammatory and thrombogenic responses dur-
ing sepsis. These findings suggest that inflammatory responses are
heightened in obese mice during sepsis when compared with their
lean counterparts.
4.2. Role of adipokines
Leptin and adiponectin are cytokines synthesized in adipose cells
and stored in adipose tissue. Adiponectin is an antiinflammatory and
insulin-sensitizing cytokine that is deficient in obese individuals [21].
Adiponectin levels have been proven to be depressed in critically ill in-
cluding septic as well as morbidly obese patients and are associated
with insulin-resistant and inflammatory response in these populations
[22]. Adiponectin deficiency has been shown to intensify sepsis-
related microvascular dysfunction and endothelial activation in murine
models [23,24]. However, other clinical studies have not established the
same association. Koch et al [25] found that low adiponectin levels in
critically ill patients had a significantly better outcome. Walkey et al
[26] demonstrated that high serum adiponectin levels correlated with
increased 28-day mortality in patients requiring mechanical ventilation.
Leptin levels are elevated in obese patients [27], and it has been
studied for its role as a regulator of cell-mediated immunity, endothelial
activation, and cytokine production in the setting of acute systemic in-
flammation [28]. Although the exact pathophysiologic role of leptin in
sepsis is not well understood, leptin levels have been shown to be
elevated 3-fold in critically ill patients with sepsis in correlation with
levels of tumor necrosis factor α and IL-6 [29,30].
4.3. Obesity and Infection
Obesity has been associated with increased risk of nosocomial infec-
tion [31], surgical site infections [32,33], Clostridium difficile infection
[34], urinary tract infection [35], and increased future sepsis events
[36]. Obesity has significant effects on respiratory function. Obese pa-
tients have been shown to have lower tidal volumes, increased respira-
tory rate, impaired gas exchange, increase in airway resistance, and
decrease in respiratory system compliance [37]. However, associations
of obesity with respiratory infections have been conflicting. Studies
post-H1N1 pandemic showed increased risk of influenza-related ad-
verse outcomes such as pneumonia, hospitalization, critical illness, ICU
admission, and death in obese and morbidly obese patients [38,39]. In-
terestingly, obesity has been found have a protective effect on mortality
associated with community-acquired pneumonia [40,41]. The reasons
for such paradoxical results are unknown and require further studies.
4.4. Challenges in management of critically ill septic obese patients
4.4.1. Antibiotic dosing
Early administration of broad spectrum antibiotics within 1 hour of
recognition of severe sepsis and septic shock is a component of early
goal-directed therapy and a class I recommendation of the “Surviving
Sepsis Campaign [42].” Obesity has been implicated as a risk factor for
antibiotic treatment failure [43]. A multitude of physiologic changes af-
fecting the distribution, metabolism, and clearance of antibiotics can
occur in obese patients and may be responsible for lower serum concen-
trations [44]. Antibiotics can be classified as hydrophilic (β lactams and
aminoglycosides) or lipophilic (fluoroquinolones, macrolides, and tige-
cycline) based on their affinity for adipose tissue [45]. Lipophilic agents
are affected more by the presence of obesity, as they achieve a higher
volume of distribution due to binding to adipose tissue [46]. Kidney vol-
ume has shown to correlate with lean body mass, and obesity has been
shown to increase glomerular filtration rate, which can potentially alter
clearance of antibiotics [47]. Alterations in volume of distribution and
clearance can also impact pharmacodynamics parameters [48]. Vanco-
mycin, aminoglycosides, and β lactams are most extensively studied in
obese population. For example, data suggest that initial dosing of vanco-
mycin should be based on total body weight, and adjustments should be
made by following drug levels [49]. Hall et al [50] have shown that
obese patients are more likely to receive lower-than-recommended
doses of vancomycin, potentially causing subtherapeutic levels and
worse outcomes. In morbidly obese patients undergoing elective surgi-
cal procedures, higher doses of prophylactic cefepime and cefazolin
were required to maintain an adequate time above minimum inhibitory
concentration levels [51]. Another study involving the use of
tobramycin or gentamicin in morbidly obese patients showed that
only 71% of patients attained therapeutic drug concentrations [52]. Fail-
ure to recognize obesity-related pharmacokinetic and pharmacody-
namic alterations could result in underdosing and treatment failures.
Further studies are needed to guide clinicians in making antibiotic dos-
age adjustments based on body indices.
4.4.2. Fluid resuscitation
In an observational study investigating fluid resuscitation in patients
with burn injuries, it was found that obese patients had received sub-
stantially lower volume of fluids based on actual body weight in com-
parison with their normal weight counterparts. Expectedly, volume of
fluid received by the morbidly obese group was significantly higher as
compared with all other groups, when based on ideal body weight.
[53] Similarly, in a study involving trauma patients, the volume of crys-
talloid and colloid resuscitation in obese patients was lower than in the
nonobese. Subsequently, the obese group had a higher mortality despite
 V. Trivedi et al. / Journal of Critical Care 30 (2015) 518–524
similar severity due to persistent hypovolemia [54]. Arabi et al [14] spe-
cifically investigated sepsis interventions and outcomes in obese pa-
tients and found that the obese and morbidly obese group received
notably lower volumes of crystalloid and colloid fluids in the initial
resuscitation phase. Future research needs to be directed toward better
defining adequate fluid resuscitation and establishing methods to assess
volume requirements in the obese, taking into account disparity in BMI
and lean weight in these patients.
4.4.3. Mechanical ventilation
Obesity impairs gas exchange, increases alveolar-to-arterial gradi-
ent, increases upper and lower airway resistance, decreases compliance
of the chest wall and lung tissue, and increases the risk for atelectasis.
Functional residual capacity and expiratory reserve volume are reduced
in obese subjects as compared to their normal weight counterparts.
Vital capacity and total lung capacity can also be decreased in morbidly
obese patients [55,56]. Respiratory failure secondary to organ dysfunc-
tion is seen in severe sepsis and septic shock and often manifests as
acute respiratory distress syndrome (ARDS). Gong et al [57] showed
that patients with increasing BMI were at an increased risk for develop-
ing ARDS and had a longer length of stay but not higher mortality. Other
studies have demonstrated similar results, wherein obesity did not have
statistically significant association with mortality in patients with ARDS
[58,59]. However, patients who are obese and develop ARDS offer a
unique challenge to the clinician with regards to ventilation manage-
ment. Strategies to optimize pulmonary mechanics in such patients in-
clude positioning in reverse Trendelenburg at a 45° angle, positioning in
the prone in patients with severe hypoxemia, inhaled nitric oxide, low
tidal volume ventilation based on ideal body weight, optimal positive
end-expiratory pressure titration, and alveolar recruitment maneuvers
such as the intermittent application of high airway pressures for a few
seconds [60].
4.4.4. Nursing care and other challenges
There are several challenges to the management of obese patients in
the critical care setting. The obese patient may require increased time
and resources with regards to hygiene, repositioning, and transferring
in and out of bed [61]. The risk of developing decubitus ulcer increases
with increasing BMI [62]. In addition, portable radiologic films provide
poorer quality images due to increased scatter, and bedside ultrasonog-
raphy is limited due to difficulty in obtaining appropriate positioning as
well as poor penetration [63].
5. Limitations
There are several important limitations to our analysis. First, clinical
evidence examining the association of BMI with outcomes in sepsis is
scarce and has not been adequately analyzed in studies involving criti-
cally ill patients. Moreover, very obese patients with a BMI greater
than or equal to 35 are underrepresented in most studies. The sample
sizes are often limited due to missing height and weight data, and inac-
curacies can develop if weight is checked after fluid resuscitation. All
studies used BMI cut-offs to define obesity. Studies using anthropomet-
ric indices other than BMI to define obesity could help us better under-
stand the relationship of obesity with sepsis. Finally, most of the studies
identified were retrospective cohort studies. To limit confounding ef-
fect, wherever available, we have reported the adjusted risk estimates.
However, there may be residual confounding from other unmeasured
factors.
6. Conclusions
Our review of the current clinical evidence of association of obesity
with sepsis mortality revealed mixed results. Three studies reported
no significant association between obesity and mortality, 1 study ob-
served increased mortality among obese patients with bacteremia,
523
whereas 3 studies found decreased mortality among obese patients. Cli-
nicians are faced with a number of challenges while managing obese pa-
tients with sepsis and should be mindful of the impact of obesity on
antibiotics administration, fluid resuscitation, and ventilator manage-
ment. The currently available experimental and clinical evidence is not
conclusive and indicates that there are differences in biology, treatment
interventions, and epidemiology in obese and nonobese patients with
sepsis. Future research should be directed toward studying larger
cohorts and toward developing an individualized approach to guide
the clinician in treatment interventions that influence outcomes of pa-
tients with sepsis.
References
[1] Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemi-
ology of severe sepsis in the United States: analysis of incidence, outcome, and asso-
ciated costs of care. Crit Care Med 2001;29(7):1303–10.
[2] Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep 2013;
61(4):1–117.
[3] Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitaliza-
tions, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit
Care Med 2012;40(3):754–61.
[4] Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity
in the United States, 2011-2012. JAMA 2014;311(8):806–14.
[5] Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with
overweight and obesity using standard body mass index categories: a systematic
review and meta-analysis. JAMA 2013;309(1):71–82.
[6] Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, et al. Obesity
and the risk of myocardial infarction in 27,000 participants from 52 countries: a
case-control study. Lancet 2005;366(9497):1640–9.
[7] Savva SC, Lamnisos D, Kafatos AG. Predicting cardiometabolic risk: waist-to-height
ratio or BMI. A meta-analysis. Diabetes Metab Syndr Obes 2013;6:403–19.
[8] Oliveros H, Villamor E. Obesity and mortality in critically ill adults: a systematic re-
view and meta-analysis. Obesity 2008;16(3):515–21.
[9] Akinnusi ME, Pineda LA, El Solh AA. Effect of obesity on intensive care morbidity and
mortality: a meta-analysis. Crit Care Med 2008;36(1):151–8.
[10] Prescott HC, Chang VW, O'Brien Jr JM, Langa KM, Iwashyna T. Obesity and 1-year
outcomes in older Americans with severe sepsis. Crit Care Med 2014;42(8):
1766–74.
[11] Wurzinger B, Dunser MW, Wohlmuth C, Deutinger MC, Ulmer H, Torgersen C, et al.
The association between body-mass index and patient outcome in septic shock: a
retrospective cohort study. Wien Klin Wochenschr 2010;122(1–2):31–6.
[12] Kuperman EF, Showalter JW, Lehman EB, Leib AE, Kraschnewski JL. The impact of
obesity on sepsis mortality: a retrospective review. BMC Infect Dis 2013;13(1):377.
[13] Wacharasint P, Boyd JH, Russell JA, Walley KR. One size does not fit all in severe
infection: obesity alters outcome, susceptibility, treatment, and inflammatory
response. Crit Care 2013;17(3):R122.
[14] Arabi YM, Dara SI, Tamim HM, Rishu AH, Bouchama A, Khedr MK, et al. Clinical char-
acteristics, sepsis interventions and outcomes in the obese patients with septic
shock: an international multicenter cohort study. Crit Care 2013;17(2):R72.
[15] Huttunen R, Laine J, Lumio J, Vuento R, Syrjanen J. Obesity and smoking are factors as-
sociated with poor prognosis in patients with bacteraemia. BMC Infect Dis 2007;7:13.
[16] Gaulton TG, Weiner MG, Morales KH, Gaieski DF, Mehta J, Lautenbach E. The effect of
obesity on clinical outcomes in presumed sepsis: a retrospective cohort study. Intern
Emerg Med 2014;9(2):213–21.
[17] Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, et al. The chronic
inflammatory hypothesis for the morbidity associated with morbid obesity: implica-
tions and effects of weight loss. Obes Surg 2004;14(5):589–600.
[18] Vachharajani V, Vital S. Obesity and sepsis. J Intensive Care Med 2006;21(5):287–95.
[19] Vachharajani V, Russell JM, Scott KL, Conrad S, Stokes KY, Tallam L, et al. Obesity ex-
acerbates sepsis-induced inflammation and microvascular dysfunction in mouse
brain. Microcirculation 2005;12(2):183–94.
[20] Singer G, Stokes KY, Terao S, Granger DN. Sepsis-induced intestinal microvascular
and inflammatory responses in obese mice. Shock 2009;31(3):275–9.
[21] Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical de-
crease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res
Commun 1999;257(1):79–83.
[22] Venkatesh B, Hickman I, Nisbet J, Cohen J, Prins J. Changes in serum adiponectin con-
centrations in critical illness: a preliminary investigation. Crit Care 2009;13(4):R105.
[23] Vachharajani V, Cunningham C, Yoza B, Carson Jr J, Vachharajani TJ, McCall C.
Adiponectin-deficiency exaggerates sepsis-induced microvascular dysfunction in
the mouse brain. Obesity 2012;20(3):498–504.
[24] Teoh H, Quan A, Bang KW, Wang G, Lovren F, Vu V, et al. Adiponectin deficiency
promotes endothelial activation and profoundly exacerbates sepsis-related mortali-
ty. Am J Physiol Endocrinol Metab 2008;295(3):E658–64.
[25] Koch A, Sanson E, Voigt S, Helm A, Trautwein C, Tacke F. Serum adiponectin upon ad-
mission to the intensive care unit may predict mortality in critically ill patients. J Crit
Care 2011;26(2):166–74.
[26] Walkey AJ, Rice TW, Konter J, Ouchi N, Shibata R, Walsh K, et al. Plasma adiponectin
and mortality in critically ill subjects with acute respiratory failure. Crit Care Med
2010;38(12):2329–34.
[27] Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000;62:413–37.
524 V. Trivedi et al. / Journal of Critical Care 30 (2015) 518–524
[28] Behnes M, Brueckmann M, Lang S, Putensen C, Saur J, Borggrefe M, et al. Alterations
of leptin in the course of inflammation and severe sepsis. BMC Infect Dis 2012;12:
217.
[29] Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P, et al. Plasma
leptin levels are increased in survivors of acute sepsis: associated loss of diurnal
rhythm, in cortisol and leptin secretion. J Clin Endocrinol Metab 1998;83(1):280–3.
[30] Yousef AA, Amr YM, Suliman GA. The diagnostic value of serum leptin monitoring
and its correlation with tumor necrosis factor-alpha in critically ill patients: a pro-
spective observational study. Crit Care 2010;14(2):R33.
[31] Dossett LA, Dageforde LA, Swenson BR, Metzger R, Bonatti H, Sawyer RG, et al. Obe-
sity and site-specific nosocomial infection risk in the intensive care unit. Surg Infect
2009;10(2):137–42.
[32] Hourigan JS. Impact of obesity on surgical site infection in colon and rectal surgery.
Clin Colon Rectal Surg 2011;24(4):283–90.
[33] Yuan K, Chen HL. Obesity and surgical site infections risk in orthopedics: a meta-
analysis. Int J Surg 2013;11(5):383–8.
[34] Bishara J, Farah R, Mograbi J, Khalaila W, Abu-Elheja O, Mahamid M, et al. Obesity as
a risk factor for Clostridium difficile infection. Clin Infect Dis 2013;57(4):489–93.
[35] Semins MJ, Shore AD, Makary MA, Weiner J, Matlaga BR. The impact of obesity on
urinary tract infection risk. Urology 2012;79(2):266–9.
[36] Wang HE, Griffin R, Judd S, Shapiro NI, Safford MM. Obesity and risk of sepsis: a
population-based cohort study. Obesity 2013;21(12):E762–9.
[37] Littleton SW. Impact of obesity on respiratory function. Respirology 2012;17(1):43–9.
[38] Fezeu L, Julia C, Henegar A, Bitu J, Hu FB, Grobbee DE, et al. Obesity is associated with
higher risk of intensive care unit admission and death in influenza A (H1N1)
patients: a systematic review and meta-analysis. Obes Rev 2011;12(8):653–9.
[39] Morgan OW, Bramley A, Fowlkes A, Freedman DS, Taylor TH, Gargiullo P, et al. Mor-
bid obesity as a risk factor for hospitalization and death due to 2009 pandemic influ-
enza A (H1N1) disease. PLoS One 2010;5(3):e9694.
[40] Inoue Y, Koizumi A, Wada Y, Iso H, Watanabe Y, Date C, et al. Risk and protective fac-
tors related to mortality from pneumonia among middle-aged and elderly commu-
nity residents: the JACC study. J Epidemiol 2007;17(6):194–202.
[41] Corrales-Medina VF, Valayam J, Serpa JA, Rueda AM, Musher DM. The obesity para-
dox in community-acquired bacterial pneumonia. Int J Infect Dis 2011;15(1):e54–7.
[42] Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving
sepsis campaign: international guidelines for management of severe sepsis and
septic shock: 2012. Crit Care Med 2013;41(2):580–637.
[43] Longo C, Bartlett G, Macgibbon B, Mayo N, Rosenberg E, Nadeau L, et al. The effect of
obesity on antibiotic treatment failure: a historical cohort study. Pharmacoepidemiol
Drug Saf 2013;22(9):970–6.
[44] Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients.
Pharmacotherapy 2007;27(8):1081–91.
[45] Falagas ME, Karageorgopoulos DE. Adjustment of dosing of antimicrobial agents for
body weight in adults. Lancet 2010;375(9710):248–51.
[46] Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci
1999;88(1):1–7.
[47] Nawaratne S, Brien JE, Seeman E, Fabiny R, Zalcberg J, Cosolo W, et al. Relationships
among liver and kidney volumes, lean body mass and drug clearance. Br J Clin
Pharmacol 1998;46(5):447–52.
[48] Janson B, Thursky K. Dosing of antibiotics in obesity. Curr Opin Infect Dis 2012;
25(6):634–49.
[49] Blouin RA, Bauer LA, Miller DD, Record KE, Griffen Jr WO. Vancomycin pharmacoki-
netics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982;
21(4):575–80.
[50] Hall II RG, Payne KD, Bain AM, Rahman AP, Nguyen ST, Eaton SA, et al. Multicenter eval-
uation of vancomycin dosing: emphasis on obesity. Am J Med 2008;121(6):515–8.
[51] Rich BS, Keel R, Ho VP, Turbendian H, Afaneh CI, Dakin GF, et al. Cefepime dosing in
the morbidly obese patient population. Obes Surg 2012;22(3):465–71.
[52] Ross AL, Tharp JL, Hobbs GR, McKnight R, Cumpston A. Evaluation of extended inter-
val dosing aminoglycosides in the morbidly obese population. Adv Pharm Sci 2013;
2013:194389.
[53] Rae L, Pham TN, Carrougher G, Honari S, Gibran NS, Arnoldo BD, et al. Differences in
resuscitation in morbidly obese burn patients may contribute to high mortality. J
Burn Care Res 2013;34(5):507–14.
[54] Nelson J, Billeter AT, Seifert B, Neuhaus V, Trentz O, Hofer CK, et al. Obese trauma pa-
tients are at increased risk of early hypovolemic shock: a retrospective cohort anal-
ysis of 1,084 severely injured patients. Crit Care 2012;16(3):R77.
[55] McCallister JW, Adkins EJ, O'Brien Jr JM. Obesity and acute lung injury. Clin Chest
Med 2009;30(3):495–508 [viii].
[56] Bahammam AS, Al-Jawder SE. Managing acute respiratory decompensation in the
morbidly obese. Respirology 2012;17(5):759–71.
[57] Gong MN, Bajwa EK, Thompson BT, Christiani DC. Body mass index is associated with
the development of acute respiratory distress syndrome. Thorax 2010;65(1):44–50.
[58] O'Brien Jr JM, Welsh CH, Fish RH, Ancukiewicz M, Kramer AM, National Heart L, et al.
Excess body weight is not independently associated with outcome in mechanically
ventilated patients with acute lung injury. Ann Intern Med 2004;140(5):338–45.
[59] Morris AE, Stapleton RD, Rubenfeld GD, Hudson LD, Caldwell E, Steinberg KP. The as-
sociation between body mass index and clinical outcomes in acute lung injury. Chest
2007;131(2):342–8.
[60] Hibbert K, Rice M, Malhotra A. Obesity and ARDS. Chest 2012;142(3):785–90.
[61] Muir M, Heese GA, McLean D, Bodnar S, Rock BL. Handling of the bariatric patient in
critical care: a case study of lessons learned. Crit Care Nurs Clin North Am 2007;
19(2):223–40.
[62] Newell MA, Bard MR, Goettler CE, Toschlog EA, Schenarts PJ, Sagraves SG, et al. Body
mass index and outcomes in critically injured blunt trauma patients: weighing the
impact. J Am Coll Surg 2007;204(5):1056–61 [discussion 62–4].
[63] Olson M, Pohl C. Bedside and radiologic procedures in the critically ill obese patient.
Crit Care Clin 2010;26(4):665–8.