The Impact of Obesity On Critical Illnesses
The Impact of Obesity On Critical Illnesses
The Impact of Obesity On Critical Illnesses
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Shock. Author manuscript; available in PMC 2022 November 01.
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Abstract
In the last few decades, obesity became one of the world’s greatest health challenges reaching
a size of global epidemic in virtually all socioeconomic statuses and all age groups. Obesity is
a risk factor for many health problems and as its prevalence gradually increases is becoming a
significant economic and health burden. In this manuscript we describe how normal respiratory
and cardiovascular physiology is altered by obesity. We review past and current literature to
describe how obesity affects outcomes of patients facing critical illnesses and discuss some
controversies related to this topic.
Keywords
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Introduction
Obesity is one of the world’s greatest health challenges, contributing to chronic
diseases, premature mortality, while burdening health services. In 1997 the World Health
Organization (WHO) formally recognized obesity as a global epidemic (1). Once considered
a problem only in high-income countries, obesity is on the rise in low and middle-income
countries. According to the WHO, in 2016 39% of adults aged over 18 years were
overweight and about 13% were obese. In the United States, the prevalence of obesity is
increasing and in 2017–2018 was 42% (2). Based on prevalence data from the National
Health and Nutrition Examination Study (NHANES) some models predict that if current
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trends continue, by 2030, 86% of adults will be overweight and 51% obese (3). In children,
the prevalence of overweight will nearly double by 2030. These same models also predict
that total health-care costs attributable to obesity/overweight would double every decade to
about 900 billion US dollars by 2030, accounting for 16–18% of total US health-care costs
(3). Obesity and overweight may increase risk for other health problems including type 2
diabetes mellitus, heart disease, and cancer (4). Counterintuitively, there is evidence that
Corresponding author: Jennifer Kaplan, Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, 3333
Burnet Avenue, MLC 7006, Cincinnati Ohio, 45229, Telephone number [email protected], +1-513-636-4259.
Ayalon et al. Page 2
overweight and obesity have a protective role in several medical conditions (i.e. the obesity
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paradox) and that being obese may lead to better outcomes and survival advantage.
With the rising incidence of obesity and the increased mortality, morbidity and health
expenditures associated with it, we find it important to understand how obesity may relate to
the development and outcomes of critical care illnesses. In this manuscript we review current
literature related to the effect of obesity in patients with critical illness.
Definition of Obesity
According to the Centers for Disease Control and Prevention (CDC), weight that is higher
than what is considered as a healthy weight for a given height is described as overweight
or obesity. Body mass index (BMI) is used as a screening tool for overweight or obesity
(https://www.cdc.gov/obesity/adult/defining.html). The World Health Organization (WHO)
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serving as an energy store help patients survive periods of stress and low nutrition (11);
2. decreased BMI, as a surrogate of malnutrition, leads to worse outcomes; 3. adipokines
produced by the adipose tissue have cardioprotective role and exert favorable effects on
the cardiovascular system (12); 4. statistical collider stratification bias in which both the
exposure (obesity) and outcome (mortality) are affected by a mutual confounder that falsely
induce an apparent association between the two (13). Whether the obesity paradox is a true
and valid phenomenon, has clinical significance, and is not merely a statistical finding are all
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Physiology in Obesity
Obesity may alter normal physiology making treatment of the critically ill patient more
challenging (table 1).
and airway resistance (16). Clinically, obese patients breathe with a higher respiratory rate
resulting in increased oxygen consumption (17). This increased oxygen consumption has
detrimental implications when obese patients present with respiratory failure or in shock.
The risk of developing obstructive sleep apnea (OSA) increases considerably at a higher
BMI. In patients with severe obesity (BMI >40 kg/m2), the risk of an individual developing
OSA lies between 55% and 90% (18). Obese patients often have a thicker neck, smaller
upper airway caliber, and poor neck mobility. The Mallampati score, used to predict
ease of endotracheal intubation, is often high in obese patients and, particularly, in obese
patients with OSA (19). Thus, patients with obesity are at risk for difficult intubation.
Once intubated, mechanically ventilated patients with obesity are at risk for pulmonary
atelectasis as lower lung volumes and diminished airway calibers predispose to compression
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With time, changes in cardiac morphology (i.e. cardiac remodeling) may ensue. Increased
LV wall thickness and LV hypertrophy (both eccentric and concentric), left atrial
enlargement, right ventricle enlargement and hypertrophy to a variable extent (depending
on the presence of left heart failure and pulmonary hypertension) have all been described
in association with obesity (23, 24). In adolescent patients, obesity was associated with
increased left ventricular concentric hypertrophy which improved after significant weight
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loss (25).
The overall hyperkinetic state is supplanted by evidence of systolic and diastolic myocardial
dysfunction, which may progress to overt clinical heart failure. This cardiomyopathy of
obesity appears to be independent of the adverse cardiac effects of coronary artery disease,
hypertension, and sleep apnea commonly observed in adults with marked obesity. The cause
of this myocardial dysfunction is unclear, but chronic volume overload, insulin resistance,
autonomic changes, and local metabolic derangements have all been implicated as possible
etiologic factors (26).
has a high cost of care (27, 28). The potential negative impact of obesity on the outcome
of septic patients is an area of growing research interest over the past years; however, no
conclusive evidence exists on this issue.
Animal Studies
Several animal models of sepsis are in use including administration of toxins (e.g.
lipopolysaccharide (LPS)), direct injection of bacteria (e.g. intravenous, intraperitoneal)
and host barrier disruption models (e.g. cecal ligation and puncture (CLP)). In contrary
to clinical trials of obesity and sepsis which present conflicting results (see below), most
animal studies demonstrate altered inflammatory response, greater number of complications
and increased mortality among obese animals (29–31). Duburcq et al, induced endotoxic
shock (LPS) in pigs and found that obese pigs developed a more severe hemodynamic
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failure with more pronounced multiple organ dysfunction and proinflammatory response
(32). Obese pigs developed more severe disseminated intravascular coagulation (DIC) with
a more severe procoagulant response than lean pigs, which may explain the more severe
hemodynamic failure and increased rate of multiple organ failure (32). Using the CLP sepsis
model in rats, Vieira et al demonstrated that increase of blood brain barrier permeability
in different brain regions occurs in obese septic rats (33). Using a murine model of CLP
to induce sepsis, we found a higher mortality rate and higher rate of lung and liver injury
among obese mice that corresponded to changes in nuclear factor-κB (NF-κB) (30). Other
studies show contradictory findings and demonstrate protective effect of obesity in sepsis
(34, 35). For animal studies it is important to understand the model of obesity used since
duration of feeding, genetic susceptibility to obesity, administration of fluids or antibiotics
and age of animals may affect outcomes.
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Human studies
The clinical effects of obesity on mortality and morbidity among critically ill patients with
sepsis remain controversial. A growing number of studies suggest a beneficial effect with
obesity. In an observational cohort study analyzing ~1400 adult patients with severe sepsis
found obesity protected against mortality (36). Patients with higher BMIs were associated
with lower 1-year mortality. Wacharasint et al. also reported improved short-term survival
in overweight and obese patients with septic shock despite equal severity of illness upon
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presentation (37). Overweight and obese patients had lower magnitude of inflammatory
response as demonstrated by lower IL-6 levels, received less fluids and needed less
vasopressors compared with normal weight patients (37). Pepper et al, also reported lower
short term mortality in septic patients with higher BMI compared to those with normal BMI
using a large data repository collected from 139 hospitals in the United States and ~55,000
patients (38). In a large multicenter retrospective study Arabi et al found hospital and ICU
mortality were lower in obese and morbid obese adult septic patients than in normal weight
and underweight patients (39). However, after adjustment for baseline characteristics and
sepsis interventions like fluid resuscitation, differences became non-significant statistically
(39). In a subgroup analysis of critically ill children with sepsis enrolled in the Assessment
of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology (AWARE) study we
found underweight status, not overweight or obese, had a higher 28-day mortality (40). No
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association between obesity and sepsis mortality was demonstrated in other studies (41,
42). The reason why obesity confers protection and provides survival advantage in critically
ill septic adult patients is still an unsolved mystery. Furthermore, the gap between sepsis
outcomes in animal versus human studies related to obesity is yet to be explained. For
a detailed review of animal models of critical illness with a focus on obesity readers are
directed to an excellent review by Mittwede et al. (29).
Morbidity
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A large cohort study of severely injured trauma patients demonstrated an increased risk of
multiple organ failure independently associated with obesity (48). In a retrospective analysis
of the 2012 National Trauma Data Bank the prevalence of respiratory and cardiovascular
complications following traumatic injury were 12.6% in obese adults compared to 5.2%
in non-obese adults (52). Bell et al describe a significant increased risk for ARDS,
pulmonary embolism, and unplanned intubation in obese patients compared to non-obese
patients (52). A retrospective, multivariate analysis of the 2014–2015 Pennsylvania Trauma
Outcomes Study (PTOS) demonstrated obese patients compared to non-obese patients had
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higher rates of acute respiratory failure (1.7% vs 1.2%), aspiration pneumonia (1.1% vs
0.4%), and ARDS (0.5% vs 0.2%, respectively) (46). However, there was no difference
in rates of pneumonia or pulmonary embolism (46). In the setting of blunt chest trauma,
obese patients had higher respiratory complications including pneumonia (53). Following
traumatic laparotomy, overweight, severely obese, and morbidly obese patients had a higher
rate of pneumonia compared to normal weight patients (4.9%, 7.1%, and 8.5% vs 3.2%,
respectively) (54). Additionally, obese, severely obese, and morbidly obese patients had
higher rate of pulmonary embolism compared to normal weight patients (2.2%, 2.6%, 3.7%
vs 0.9%). Bell et al also describe a 69% increased risk for cardiac arrest and 83% increase
risk for DVT in obese patients (52). In the multivariate analysis of the 2014–2015 PTOS,
obese patients were more likely to have an arrhythmia and DVT compared to non-obese
patients (2.1% vs 1.6% and 1.4% vs 0.8%) (46).
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There are many possible reasons for the differences in morbidity and mortality between
obese and non-obese trauma patients including prolonged use of mechanical devices, such as
central venous catheters, urinary catheters and ventilators, which increases rate of infectious
complications (44, 55). Another explanation may relate to cytokine response following
trauma in obese patients. Winfield et al utilized the “Inflammation and the Host Response
to Injury” Trauma-Related Database to evaluate the possibility of a differential inflammatory
response between obese and non-obese trauma patients using measurements of leukocyte
genomic expression over time. They found no differences in the initial inflammatory
response to trauma but did find differences in genomic expression over time and suggested
an association between these differences and the development of complications in morbidly
obese patients (56). The same group demonstrated depressed cytokine response (IL-4, IL-6,
IL-10, TNF-α, IL-1β, chemotactic cytokine 3) to severe trauma in obese versus non-obese
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patients and suggested an association between this finding and higher rate of post-injury
infection in the obese group (57). Andruszkow et al also reported an altered post-traumatic
inflammatory response in obese patients but of the opposite spectrum finding increased
levels of IL-6 and C-reactive protein in critically ill obese patients in comparison to non
obese (58).
Trauma causes disruption of micro and macro barriers leading to the release of multiple
danger/damage associated molecular patterns (DAMPs) and pathogen associated molecular
patterns (PAMPs) which in turn activate the innate immune system to induce tissue
repair (59, 60). However, in some cases, production of DAMPs and PAMPs lead to
dysregulated, uncontrolled, and exaggerated activation of the immune system causing
massive inflammation and organ dysfunction rather than providing protection and promoting
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healing. Many cytokines and other inflammatory mediators are involved in this process
(61). Whether DAMPs, PAMPs, cytokine activity and the magnitude of the inflammatory
response to trauma in obese patients is any different in comparison to non-obese patients is
not known and deserves further investigation.
Pediatric Trauma
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Analysis of the 2013–2014 National Trauma Data Bank (NTDB), one of the largest trauma
registry in the world containing data on more than 6,000,000 trauma cases from over 900
trauma centers, demonstrates that children with higher BMI have higher adjusted relative
risks for mortality and certain complications like deep venous thrombosis, pulmonary
embolus, pneumonia and ventilator support (62). Brown et al also described increased rate
of complications (sepsis, wound infection and postoperative fistula) and longer ICU stay in
obese critically ill children with traumatic injuries (63). Consistent with the NTDB findings,
Rana et al. found an increase in DVT and decubitus ulcers in traumatically injured children
with obesity compared to non-obese. The authors also suggested a difference in organ
specific injury pattern among obese patients -higher rate of extremity fractures requiring
operative intervention and lower incidence of intracranial and intraabdominal injuries (64).
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increased risk of mortality after burn injury, delayed resolution of base deficit and a trend
toward greater severity of organ dysfunction compared to non-obese patients (68). In a
multicenter prospective study that enrolled patients aged 0 to 89 years, Jeschke et al. found
no association with obesity and morbidity or mortality in severely burned patients (69).
Stratification of the data by obesity grade showed that in adults, the mild obese group had
the best survival (like that of the normal weight group) and that morbidly obese patients had
a significantly lower survival. The implications are that having nutritional caloric reserve
may offer a survival advantage in this hypermetabolic state.
of respiratory failure include acute respiratory distress syndrome (ARDS), asthma, and
COPD. Obesity alters normal pulmonary mechanics, as previously described, impacting the
management and outcomes of the patient with acute respiratory failure and obesity.
Gong et al reported that BMI was associated with the development of ARDS in 1795
critically ill patients. Among patients with ARDS, increasing BMI was associated with
ICU and hospital increased length of stay but was not associated with ICU mortality
or ventilator-free days (70). Zhi et al. confirmed these findings in a meta-analysis that
obesity was associated with increased risk of ARDS (71). Despite increased risk of ARDS,
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Higher BMI is associated with increased risk of asthma in children and adults (75–77). A
retrospective study found obese children with status asthmaticus have a longer ICU and
hospitalization length of stay compared to non-obese children (78). Okubo found similar
results that obese children had longer length of hospital stay (0.24 days, 95% CI 0.17–0.32
days) and higher odds of using mechanical ventilation (OR 1.59, 95% CI 1.28–1.99) (79).
Obese patients that require mechanical ventilation for respiratory failure have similar
ventilator strategies as non-obese patients with a few modifications. Lung volume does
not increase with body weight therefore tidal volume should be based on ideal body weight
(IBW) rather than actual body weight so as not to administer large tidal volumes. In patients
with ARDS this should be 6–8mL/kg of IBW. To decrease atelectasis, increased in obesity
due to higher abdominal pressure and chest wall mass, a higher PEEP may be needed. In
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patients with ARDS, positioning including proning and reverse Trendelenburg, significantly
improved PaO2/FiO2 ratio in obese patients compared to non-obese patients (80).
and obesity in a cohort of 15,000 critically ill adult patients and found that each 5-kg/m2
increase in BMI was associated with 10% risk of more severe AKI and short and long-term
mortality (83). Soto et al, examined the relationship between obesity, AKI and ARDS
mortality and found obesity to be an independent risk factor for AKI in ARDS adult patients
(84). More than half of the cohort (54%) developed AKI during the first 4 days of admission
with gradual increase in AKI across BMI categories (normal weight 49%, overweight 53%,
obese 59%, p=0.04). Druml et al, used a cohort of 5,232 patients with AKI requiring
renal replacement therapy from 53 Austrian ICUs and also found increased BMI to be an
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Compared to normal BMI (18.5–24.9 kg/m2), risk of first-time infection increased to 31%
for BMI 30–34.9 kg/m2 (95% CI 14–51%), to 87% for BMI 35–39.9 kg/m2 (CI 50–135%),
and 210% for BMI ≥ 40 kg/m2 (CI 117–341%). Similarly, increased risk of mortality from
bloodstream infection increased to 35% for BMI 30–34.9 kg/m2 (95% CI 1–83%), to 144%
for BMI 35–39.9 kg/m2 (CI 55–286%), and 299% for BMI ≥ 40 kg/m2 (CI 93–724%).
BMI is associated with increased risk of nosocomial bloodstream infection in critically ill
adults (44, 90, 91). Bochicchio et al. found obese patients had a significantly higher risk of
mortality compared to normal weight patients. It is possible that this increased risk is in part
due to technical challenges associated with placement of central lines in obese patients in
addition to underlying immune dysregulation associated with obesity. Of note, even though
obese subjects show a higher tendency of acquiring BSI, when BSI leads to sepsis some
evidence suggests that overweight and obese patients have a survival advantage (obesity
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Pneumonia
During the H1N1 epidemic, obese children and adults were more likely to have severe
influenza (92–94). Obese adults with H1N1 were more likely to require ICU admission
(95) and had a longer duration of mechanical ventilation and ICU length of stay (96).
Furthermore, obese patients had higher mortality. While this data provides strong evidence
that obesity is associated with significantly higher morbidity and mortality in the setting
of viral pneumonia, the evidence is less consistent in patients with bacterial pneumonia.
Almirall et al found being underweight was a risk factor for bacterial pneumonia but being
overweight or obese was not a risk factor (97). This contrasts with Baik et al, which
found in women obesity is associated with increased risk for acquiring pneumonia (98).
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Other studies have found obesity to be associated with increased risk for development of
ventilator-associated pneumonia in critically ill patients (86, 87, 97). Despite these findings,
several studies have demonstrated a protective effect against mortality in obese patients with
bacterial pneumonia (99, 100).
Obesity is associated with higher rates of surgical site infections (SSI) in neurosurgical,
thoracic, abdominal, and orthopedic surgeries. A recent retrospective study using 2012–
2017 data from the Dutch national surveillance network PREZIES found increasing risk of
surgical site infection when BMI increased from normal to morbidly obese across nearly
all surgical procedures (101). Procedures included cardiothoracic, abdominal, orthopedic,
obstetrical, and spinal surgeries. The increased risk of SSI was most significant in clean
surgical sites. Winfield et al. also found a significant increase in SSI in clean and clean
contaminated abdominal surgeries in obese patients compared to non-obese patients (102).
Proposed mechanisms for this increased risk include impaired blood supply to adipose tissue
leading to prolonged wound healing and decreased delivery of antibiotics to surgical site,
difference in skin microbiota at surgical sites, and differences in surgical technique in obese
patients leading to larger surgical sites and longer surgical times (103–105).
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independent risk factor for mortality in children admitted to the PICU. They also found over
representation of patients with weights at the extremes in the PICU. The authors suggested
that inclusion of weight centile to currently used severity scores (PIM or PRISM) has the
potential to improve the accuracy of mortality prediction (108).
Prince et al in a single center retrospective study from the UK also found that the PICU
population differs significantly from the general population in weight distribution with
over-representation of weights at the extreme. In addition, a U-shaped association was found
between weight and risk-adjusted mortality with highest mortality rate at the extremes.
Interestingly, lowest risk of death in this study was found among mild to moderately
overweight rather than normal weight children (109). Ross et al did a retrospective analysis
of data collected from the Virtual PICU System database (127,607 patients included) and
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found that being overweight was independently associated with increased PICU mortality
even after controlling for severity of illness, demographic characteristics an comorbidities
(110). Unlike the previously mentioned studies Davis et al in a retrospective single center
study (1817 pediatric critically ill patients) found that being overweight or obese was
neither protective nor a risk factor for mortality. Smaller percentage of overweight and
obese patients required intubation and inotropic support but no difference in duration
of mechanical ventilation was noticed in comparison to normal weight patients (111).
Recently we did a secondary analysis of a prospective multinational observational study
(AWARE study) and found no difference in mortality risk between overweight and obese in
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comparison to normal weight pediatric critically ill patients (40). This finding was noticed in
the general PICU population and in a predefined sepsis subgroup. Underweight rather than
obese patients were found to have increased mortality risk in this study.
In summary, in the pediatric age group underweight rather than obesity plays a key role and
is associated with worse PICU outcomes including death. As described before the obesity
paradox is a finding related to the elderly and not to children, adolescents, and young adults.
and under investigation. According to the CDC, severe obesity (BMI >40 or above) puts
patients at higher risk for complications from COVID-19. Cai et al, in a single center
study from Shenzen, China, collected data from 383 consecutively hospitalized patients with
Covid-19 infection and reported increased adjusted risk to develop severe covid-19 disease
among obese patients (OR-3.4, 95% CI 1.4–2.86, p=0.007). Simonnet et al described 124
COVID-19 patients consecutively admitted to a single center ICU in France and found
an unexpectedly high frequency of obesity among them (47.5% of patients had a BMI
>30 kg/m2). The need for invasive mechanical ventilation (IMV) gradually increased with
BMI, reaching almost 90% in patients with BMI>35 kg/m2 with an odds ratio of 7.4 (1.6–
33.1; p=0.02) for IMV in a multivariate logistic regression analysis (112). Hajifathalian
et al, found patient with obesity to be at increased risk for the composite outcome of
ICU admission or death when compared to normal weight individuals [RR=1.58 (1.2–2.1;
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p=0.002)] in a single center study that included 770 admitted patients with confirmed
COVID-19 infection in the US (New-York) (113). In another study from New-York, Petrilli
et al, used a cohort of 4,103 subjects with laboratory-confirmed Covid-19 disease and
reported a strong association between obesity (BMI>40) and hospitalization risk [OR 6.2,
95% CI (4.2–9.3)] (114). Busetto et al enrolled 92 hospitalized patients with COVID-19
related pneumonia in a single center in Italy and reported over-representation of overweight
and obesity (65%) in their cohort (115). Overweight and obese patients were 10 years
younger (p<0.01), required more assisted respiratory support (p<0.01) and were more likely
to be admitted to the ICU or semi-intensive care unit (p<0.05) compared to normal weight
patients. In a recent correspondence by Kass and colleagues (116) the authors report a
negative correlation between BMI and age in 265 critically ill patients with COVID-19
in the US. The authors conclude that in populations with higher prevalence of obesity,
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COVID-19 affects younger patients. Consistent with this report, in a letter to the editor
Lighter and colleagues report their results from a retrospective analysis of 3,615 SARS
CoV-2 patients who presented to the Emergency Department at a large academic hospital
system in New-York City (117). Patients aged<60 years with BMI between 30–34 and above
35 were 1.8 and 3.6 times more likely to be admitted to critical care, respectively, compared
to patients in the same age category who had BMI<30. The authors concluded that obesity
appears to be a risk factor for hospital admission and need for critical care. Among 393
patients with confirmed COVID-19 admitted to two hospitals in New-York City, 36% were
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obese and of those in need for invasive mechanical ventilation 43% were obese (118).
In summary, a direct association between obesity and a more complicated clinical course in
COVID-19 patients is seen worldwide. Hospitalized Covid-19 obese patients are younger in
age, in need of higher degree of respiratory support, are more likely to be admitted to the
ICU and are at higher risk for mortality in comparison to normal weight Covid-19 patients.
The experience obtained during the influenza A(H1N1) pandemic (2009–2010) about the
disproportionate impact of the virus on obese patients should serve as a warning sign for
those who take care of patients with obesity and COVID-19 (119, 120).
• On the opposite side of the weight spectrum lies underweight status which was
also found by many studies to be a direct modifier of survival among critically ill
patients. Some of these studies also showed over representation of underweight
patients in the ICU in comparison to their prevalence in the general population.
accordingly are necessary for better taking care of obese patients during critical
illness.
References:
1. : Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World
Health Organization Technical Report Series 894:i–xii, 1–253, 2000. [PubMed: 11234459]
2. Hales CM, Carroll MD, Fryar CD and Ogden CL: Prevalence of Obesity and Severe Obesity Among
Adults: United States, 2017–2018. NCHS Data Brief (360):1–8, 2020.
Author Manuscript
3. Wang Y, Beydoun MA, Liang L, Caballero B and Kumanyika SK: Will all Americans become
overweight or obese? estimating the progression and cost of the US obesity epidemic. Obesity
(Silver Spring) 16(10):2323–30, 2008. [PubMed: 18719634]
4. 5853. National Heart LaBI: Clinical guidelines on the identification, evaluation and treatment of
overweight and obesity in adults: the evidence report. Bethesda, MD: National Heart, Lung and
Blood Institute, 1998.
5. Kalantar-Zadeh K, Block G, Humphreys MH and Kopple JD: Reverse epidemiology of
cardiovascular risk factors in maintenance dialysis patients. Kidney Int 63(3):793–808, 2003.
[PubMed: 12631061]
6. Gruberg L, Weissman NJ, Waksman R, Fuchs S, Deible R, Pinnow EE, Ahmed LM, Kent KM,
Pichard AD, Suddath WO, et al. : The impact of obesity on the short-term and long-term outcomes
Author Manuscript
after percutaneous coronary intervention: the obesity paradox? Journal of the American College of
Cardiology 39(4):578–584, 2002. [PubMed: 11849854]
7. Kenchaiah S, Pocock SJ, Wang D, Finn PV, Zornoff LA, Skali H, Pfeffer MA, Yusuf S, Swedberg
K, Michelson EL, et al. : Body mass index and prognosis in patients with chronic heart failure:
insights from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity
(CHARM) program. Circulation 116(6):627–36, 2007. [PubMed: 17638930]
8. Vemmos K, Ntaios G, Spengos K, Savvari P, Vemmou A, Pappa T, Manios E, Georgiopoulos
G and Alevizaki M: Association between obesity and mortality after acute first-ever stroke: the
obesity-stroke paradox. Stroke 42(1):30–6, 2011. [PubMed: 21127299]
9. Landbo C, Prescott E, Lange P, Vestbo J and Almdal TP: Prognostic value of nutritional status
in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160(6):1856–61, 1999.
[PubMed: 10588597]
10. Doehner W, Erdmann E, Cairns R, Clark AL, Dormandy JA, Ferrannini E and Anker SD: Inverse
relation of body weight and weight change with mortality and morbidity in patients with type 2
Author Manuscript
diabetes and cardiovascular co-morbidity: an analysis of the PROactive study population. Int J
Cardiol 162(1):20–6, 2012. [PubMed: 22037349]
11. Casas-Vara A, Santolaria F, Fernandez-Bereciartua A, Gonzalez-Reimers E, Garcia-Ochoa A and
Martinez-Riera A: The obesity paradox in elderly patients with heart failure: analysis of nutritional
status. Nutrition 28(6):616–22, 2012. [PubMed: 22261572]
12. Mattu HS and Randeva HS: Role of adipokines in cardiovascular disease. J Endocrinol
216(1):T17–36, 2013. [PubMed: 23160967]
13. Sperrin M, Candlish J, Badrick E, Renehan A and Buchan I: Collider Bias Is Only a Partial
Explanation for the Obesity Paradox. Epidemiology 27(4):525–30, 2016. [PubMed: 27075676]
14. Bedell GN, Wilson WR and Seebohm PM: Pulmonary function in obese persons. The Journal of
Clinical Investigation 37(7):1049–1060, 1958. [PubMed: 13563634]
15. Barrera F, Reidenberg MM and Winters WL: Pulmonary function in the obese patient. The
American Journal of the Medical Sciences 254(6):785–796, 1967. [PubMed: 6065287]
16. Sahebjami H and Gartside PS: Pulmonary function in obese subjects with a normal FEV1/FVC
ratio. Chest 110(6):1425–1429, 1996. [PubMed: 8989055]
Author Manuscript
17. Murugan AT and Sharma G: Obesity and respiratory diseases. Chronic Respiratory Disease
5(4):233–242, 2008. [PubMed: 19029235]
18. Lettieri CJ, Eliasson AH and Greenburg DL: Persistence of obstructive sleep apnea after surgical
weight loss. Journal of clinical sleep medicine: JCSM: official publication of the American
Academy of Sleep Medicine 4(4):333–338, 2008. [PubMed: 18763424]
19. Zammit C, Liddicoat H, Moonsie I and Makker H: Obesity and respiratory diseases. International
Journal of General Medicine 3:335–343, 2010. [PubMed: 21116339]
20. Magnusson L and Spahn DR: New concepts of atelectasis during general anaesthesia. British
Journal of Anaesthesia 91(1):61–72, 2003. [PubMed: 12821566]
21. Sutton-Tyrrell K, Newman A, Simonsick EM, Havlik R, Pahor M, Lakatta E, Spurgeon H and
Vaitkevicius P: Aortic stiffness is associated with visceral adiposity in older adults enrolled in
the study of health, aging, and body composition. Hypertension 38(3):429–33, 2001. [PubMed:
11566917]
22. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX and Eckel RH: Obesity
Author Manuscript
and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. Arterioscler
Thromb Vasc Biol 26(5):968–76, 2006. [PubMed: 16627822]
23. Warnes CA and Roberts WC: The heart in massive (more than 300 pounds or 136 kilograms)
obesity: analysis of 12 patients studied at necropsy. The American Journal of Cardiology
54(8):1087–1091, 1984. [PubMed: 6496330]
24. Alpert MA, Lambert CR, Panayiotou H, Terry BE, Cohen MV, Massey CV, Hashimi MW and
Mukerji V: Relation of duration of morbid obesity to left ventricular mass, systolic function, and
diastolic filling, and effect of weight loss. The American Journal of Cardiology 76(16):1194–1197,
1995. [PubMed: 7484912]
25. Ippisch HM, Inge TH, Daniels SR, Wang B, Khoury PR, Witt SA, Glascock BJ, Garcia VF and
Kimball TR: Reversibility of cardiac abnormalities in morbidly obese adolescents. J Am Coll
Author Manuscript
43. Christmas AB, Reynolds J, Wilson AK, Franklin GA, Miller FB, Richardson JD and Rodriguez
JL: Morbid obesity impacts mortality in blunt trauma. The American Surgeon 73(11):1122–1125,
Author Manuscript
53. Cone JT, Benjamin ER, Alfson DB, Biswas S and Demetriades D: The effect of body mass
index on outcomes following severe blunt chest trauma. Injury 51(9):2076–2081, 2020. [PubMed:
32646649]
54. Covarrubias J, Grigorian A, Schubl S, Gambhir S, Dolich M, Lekawa M, Nguyen N and Nahmias
J: Obesity associated with increased postoperative pulmonary complications and mortality after
trauma laparotomy. Eur J Trauma Emerg Surg, 2020.
55. Waisbren E, Rosen H, Bader AM, Lipsitz SR, Rogers SO and Eriksson E: Percent body fat and
prediction of surgical site infection. Journal of the American College of Surgeons 210(4):381–389,
2010. [PubMed: 20347729]
56. Winfield RD, Delano MJ, Dixon DJ, Schierding WS, Cendan JC, Lottenberg L, Lopez MC, Baker
HV, Cobb JP, Moldawer LL, et al. : Differences in outcome between obese and nonobese patients
following severe blunt trauma are not consistent with an early inflammatory genomic response.
Crit Care Med 38(1):51–8, 2010. [PubMed: 19661803]
57. Winfield RD, Delano MJ, Cuenca AG, Cendan JC, Lottenberg L, Efron PA, Maier RV, Remick
Author Manuscript
DG, Moldawer LL and Cuschieri J: Obese patients show a depressed cytokine profile following
severe blunt injury. Shock 37(3):253–6, 2012. [PubMed: 22266966]
58. Andruszkow H, Veh J, Mommsen P, Zeckey C, Hildebrand F and Frink M: Impact of the body
mass on complications and outcome in multiple trauma patients: what does the weight weigh?
Mediators Inflamm 2013:345702, 2013. [PubMed: 24023413]
59. Peltz ED, Moore EE, Eckels PC, Damle SS, Tsuruta Y, Johnson JL, Sauaia A, Silliman CC,
Banerjee A and Abraham E: HMGB1 is markedly elevated within 6 hours of mechanical trauma in
humans. Shock 32(1):17–22, 2009. [PubMed: 19533845]
60. Shahbazian LM, Jeevanandam M and Petersen SR: Release of proinflammatory cytokines by
mitogen-stimulated peripheral blood mononuclear cells from critically ill multiple-trauma victims.
Author Manuscript
66. Carpenter AM, Hollett LP, Jeng JC, Wu J, Turner DG and Jordan MH: How long a shadow does
epidemic obesity cast in the burn unit? A dietitian’s analysis of the strengths and weaknesses of
the available data in the National Burn Repository. Journal of Burn Care & Research: Official
Publication of the American Burn Association 29(1):97–101, 2008. [PubMed: 18182904]
67. Ghanem AM, Sen S, Philp B, Dziewulski P and Shelley OP: Body Mass Index (BMI) and
mortality in patients with severe burns: is there a “tilt point” at which obesity influences outcome?
Burns 37(2):208–14, 2011. [PubMed: 21129850]
68. Rae L, Pham TN, Carrougher G, Honari S, Gibran NS, Arnoldo BD, Gamelli RL, Tompkins RG
and Herndon DN: Differences in resuscitation in morbidly obese burn patients may contribute to
high mortality. J Burn Care Res 34(5):507–14, 2013. [PubMed: 23966116]
69. Jeschke MG, Finnerty CC, Emdad F, Rivero HG, Kraft R, Williams FN, Gamelli RL, Gibran
NS, Klein MB, Arnoldo BD, et al. : Mild obesity is protective after severe burn injury. Annals of
Surgery 258(6):1119–1129, 2013. [PubMed: 23877367]
70. Gong MN, Bajwa EK, Thompson BT and Christiani DC: Body mass index is associated with
the development of acute respiratory distress syndrome. Thorax 65(1):44–50, 2010. [PubMed:
Author Manuscript
19770169]
71. Zhi G, Xin W, Ying W, Guohong X and Shuying L: “Obesity Paradox” in Acute Respiratory
Distress Syndrome: Asystematic Review and Meta-Analysis. PLoS One 11(9):e0163677, 2016.
[PubMed: 27684705]
72. Ni YN, Luo J, Yu H, Wang YW, Hu YH, Liu D, Liang BM and Liang ZA: Can body mass index
predict clinical outcomes for patients with acute lung injury/acute respiratory distress syndrome?
A meta-analysis. Crit Care 21(1):36, 2017. [PubMed: 28222804]
73. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, Zhou Q, Matte A, Walter SD,
Lamontagne F, et al. : High-frequency oscillation in early acute respiratory distress syndrome. N
Engl J Med 368(9):795–805, 2013. [PubMed: 23339639]
74. Tlayjeh H, Arabi YM, Ferguson ND, Zhou Q, Lamontagne F, Arroliga A, Danesh V, Dominguez
Cherit G, Jimenez E, Mullaly A, et al. : Body Mass Index and Mortality in Subjects With ARDS:
Post-hoc Analysis of the OSCILLATE Trial. Respir Care 64(9):1042–1048, 2019. [PubMed:
31138733]
Author Manuscript
75. Mamun AA, Lawlor DA, Alati R, O’Callaghan MJ, Williams GM and Najman JM: Increasing
body mass index from age 5 to 14 years predicts asthma among adolescents: evidence from a birth
cohort study. Int J Obes (Lond) 31(4):578–83, 2007. [PubMed: 17384659]
76. Flaherman V and Rutherford GW: A meta-analysis of the effect of high weight on asthma. Arch
Dis Child 91(4):334–9, 2006. [PubMed: 16428358]
77. Beuther DA and Sutherland ER: Overweight, obesity, and incident asthma: a meta-analysis of
prospective epidemiologic studies. Am J Respir Crit Care Med 175(7):661–6, 2007. [PubMed:
17234901]
78. Carroll CL, Bhandari A, Zucker AR and Schramm CM: Childhood obesity increases duration of
therapy during severe asthma exacerbations. Pediatr Crit Care Med 7(6):527–31, 2006. [PubMed:
Author Manuscript
17006390]
79. Okubo Y, Nochioka K, Hataya H, Sakakibara H, Terakawa T and Testa M: Burden of Obesity on
Pediatric Inpatients with Acute Asthma Exacerbation in the United States. J Allergy Clin Immunol
Pract 4(6):1227–1231, 2016. [PubMed: 27372599]
80. De Jong A, Molinari N, Sebbane M, Prades A, Futier E, Jung B, Chanques G and Jaber S:
Feasibility and effectiveness of prone position in morbidly obese patients with ARDS: a case
control clinical study. Chest 143(6):1554–1561, 2013. [PubMed: 23450309]
81. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, Edipidis K, Forni LG,
Gomersall CD, Govil D, et al. : Epidemiology of acute kidney injury in critically ill patients: the
multinational AKI-EPI study. Intensive Care Med 41(8):1411–23, 2015. [PubMed: 26162677]
82. Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL and Investigators A: Epidemiology of Acute
Kidney Injury in Critically Ill Children and Young Adults. N Engl J Med 376(1):11–20, 2017.
[PubMed: 27959707]
83. Danziger J, Chen KP, Lee J, Feng M, Mark RG, Celi LA and Mukamal KJ: Obesity, Acute Kidney
Author Manuscript
Injury, and Mortality in Critical Illness. Crit Care Med 44(2):328–34, 2016. [PubMed: 26496453]
84. Soto GJ, Frank AJ, Christiani DC and Gong MN: Body mass index and acute kidney injury in the
acute respiratory distress syndrome. Crit Care Med 40(9):2601–8, 2012. [PubMed: 22732288]
85. Druml W, Metnitz B, Schaden E, Bauer P and Metnitz PG: Impact of body mass on incidence
and prognosis of acute kidney injury requiring renal replacement therapy. Intensive Care Med
36(7):1221–8, 2010. [PubMed: 20232041]
86. Bercault N, Boulain T, Kuteifan K, Wolf M, Runge I and Fleury JC: Obesity-related excess
mortality rate in an adult intensive care unit: A risk-adjusted matched cohort study. Crit Care Med
32(4):998–1003, 2004. [PubMed: 15071392]
87. Sakr Y, Madl C, Filipescu D, Moreno R, Groeneveld J, Artigas A, Reinhart K and Vincent JL:
Obesity is associated with increased morbidity but not mortality in critically ill patients. Intensive
Care Med 34(11):1999–2009, 2008. [PubMed: 18670756]
88. Falagas ME, Athanasoulia AP, Peppas G and Karageorgopoulos DE: Effect of body mass index on
the outcome of infections: a systematic review. Obes Rev 10(3):280–9, 2009. [PubMed: 19243518]
Author Manuscript
89. Paulsen J, Askim A, Mohus RM, Mehl A, Dewan A, Solligard E, Damas JK and Asvold BO:
Associations of obesity and lifestyle with the risk and mortality of bloodstream infection in a
general population: a 15-year follow-up of 64 027 individuals in the HUNT Study. Int J Epidemiol
46(5):1573–1581, 2017. [PubMed: 28637260]
90. Kaye KS, Marchaim D, Chen TY, Chopra T, Anderson DJ, Choi Y, Sloane R and Schmader KE:
Predictors of nosocomial bloodstream infections in older adults. J Am Geriatr Soc 59(4):622–7,
2011. [PubMed: 21366545]
91. Dossett LA, Dageforde LA, Swenson BR, Metzger R, Bonatti H, Sawyer RG and May AK:
Obesity and site-specific nosocomial infection risk in the intensive care unit. Surg Infect (Larchmt)
10(2):137–42, 2009. [PubMed: 19388836]
92. Athanasiou M, Lytras T, Spala G, Triantafyllou E, Gkolfinopoulou K, Theocharopoulos G, Patrinos
S, Danis K, Detsis M, Tsiodras S, et al. : Fatal cases associated with pandemic influenza A (H1N1)
reported in Greece. PLoS Curr 2:RRN1194, 2010. [PubMed: 21085493]
93. Nguyen-Van-Tam JS, Openshaw PJ, Hashim A, Gadd EM, Lim WS, Semple MG, Read RC,
Taylor BL, Brett SJ, McMenamin J, et al. : Risk factors for hospitalisation and poor outcome
Author Manuscript
with pandemic A/H1N1 influenza: United Kingdom first wave (May-September 2009). Thorax
65(7):645–51, 2010. [PubMed: 20627925]
94. Rothberg MB and Haessler SD: Complications of seasonal and pandemic influenza. Crit Care Med
38(4 Suppl):e91–7, 2010. [PubMed: 19935413]
95. Miller RR 3rd, Markewitz BA, Rolfs RT, Brown SM, Dascomb KK, Grissom CK, Friedrichs MD,
Mayer J, Hirshberg EL, Conklin J, et al. : Clinical findings and demographic factors associated
with ICU admission in Utah due to novel 2009 influenza A(H1N1) infection. Chest 137(4):752–8,
2010. [PubMed: 19933372]
96. Diaz E, Rodriguez A, Martin-Loeches I, Lorente L, Del Mar Martin M, Pozo JC, Montejo JC,
Estella A, Arenzana A, Rello J, et al. : Impact of obesity in patients infected with 2009 influenza
Author Manuscript
mass index on the risk of surgical site infection. Infect Control Hosp Epidemiol 40(9):991–996,
2019. [PubMed: 31232239]
102. Winfield RD, Reese S, Bochicchio K, Mazuski JE and Bochicchio GV: Obesity and the Risk for
Surgical Site Infection in Abdominal Surgery. Am Surg 82(4):331–6, 2016. [PubMed: 27097626]
103. Falagas ME and Kompoti M: Obesity and infection. Lancet Infect Dis 6(7):438–46, 2006.
[PubMed: 16790384]
104. Anaya DA and Dellinger EP: The obese surgical patient: a susceptible host for infection. Surg
Infect (Larchmt) 7(5):473–80, 2006. [PubMed: 17083313]
105. Rood KM, Buhimschi IA, Jurcisek JA, Summerfield TL, Zhao G, Ackerman WE, Wang W,
Rumpf RW, Thung SF, Bakaletz LO, et al. : Skin Microbiota in Obese Women at Risk for
Surgical Site Infection After Cesarean Delivery. Sci Rep 8(1):8756, 2018. [PubMed: 29884793]
106. Simmonds M, Llewellyn A, Owen CG and Woolacott N: Predicting adult obesity from childhood
obesity: a systematic review and meta-analysis. Obesity Reviews: An Official Journal of the
International Association for the Study of Obesity 17(2):95–107, 2016. [PubMed: 26696565]
Author Manuscript
5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ
369:m1966, 2020. [PubMed: 32444366]
Author Manuscript
115. Busetto L, Bettini S, Fabris R, Serra R, Dal Pra C, Maffei P, Rossato M, Fioretto P and Vettor R:
Obesity and COVID-19: An Italian Snapshot. Obesity (Silver Spring), 2020.
116. Kass DA, Duggal P and Cingolani O: Obesity could shift severe COVID-19 disease to younger
ages. Lancet 395(10236):1544–1545, 2020. [PubMed: 32380044]
117. Lighter J, Phillips M, Hochman S, Sterling S, Johnson D, Francois F and Stachel A: Obesity in
Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission. Clin Infect
Dis 71(15):896–897, 2020. [PubMed: 32271368]
118. Goyal P, Choi JJ, Pinheiro LC, Schenck EJ, Chen R, Jabri A, Satlin MJ, Campion TR, Nahid M,
Ringel JB, et al. : Clinical Characteristics of Covid-19 in New York City. New England Journal
of Medicine, 2020.
119. Louie JK, Acosta M, Samuel MC, Schechter R, Vugia DJ, Harriman K, Matyas BT and California
Pandemic Working G: A novel risk factor for a novel virus: obesity and 2009 pandemic influenza
A (H1N1). Clin Infect Dis 52(3):301–12, 2011. [PubMed: 21208911]
120. Morgan OW, Bramley A, Fowlkes A, Freedman DS, Taylor TH, Gargiullo P, Belay B, Jain S, Cox
Author Manuscript
C, Kamimoto L, et al. : Morbid obesity as a risk factor for hospitalization and death due to 2009
pandemic influenza A(H1N1) disease. PloS One 5(3):e9694, 2010. [PubMed: 20300571]
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Figure 1. Obesity in the Critically Ill Patients, Summary and Key points.
A summary of the key points on how obesity impacts critical illness is provided.
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Table 1:
2. Morphological changes
• Increased left ventricular wall thickness
• Increased left atrial size
• Increased right ventricular size and thickness
• Higher incidence of coronary artery stenosis
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