The Impact of Obesity on Critical Illnesses

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.

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 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 overweight and obesity have a protective role in several medical conditions (i.e. the obesity 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) defines overweight and obesity as abnormal or excessive (respectively) fat accumulation that presents a risk to health and suggests BMI as a screening tool (https://www.who.int/health-topics/obesity#tab=tab_1). In adults BMI above 25 kg/m² falls within the overweight range and above 30 kg/m² within the obesity range. Obesity is further classified into 3 categories: Class 1: BMI of 30–35 kg/m², class 2: BMI of 35–40 kg/m² and class 3: BMI of 40 kg/m² or higher (extreme or severe obesity). In children and teens, BMI is also used as a screening tool for overweight and obesity, but there is a lack of consistency between the WHO (Z-scores), CDC (BMI percentiles) and International Obesity Task Force definitions. Obesity is often perceived as a multifactorial disorder characterized by a longstanding positive energy balance causing an excess of body fats (subcutaneous and visceral) and deranged metabolism. The complexity of how obesity affects critical illness is summarized in Figure 1. Throughout the manuscript the terms underweight, overweight and obese/obesity refer to distinct weight categories.

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.

Reverse Epidemiology and the Obesity Paradox

Reverse epidemiology also known as “risk factor paradox” is a term used to describe a phenomenon in which conventional risk factors for increased mortality in the general population, are also found to be associated with mortality in other specific populations but in the opposite direction. The obesity paradox is a specific case of reverse epidemiology. In this case overweight and obesity appear to confer survival advantage in comparison to normal weight. The obesity paradox was observed in patients with several medical conditions including end stage renal failure requiring dialysis, coronary heart disease, chronic heart failure, stroke, chronic obstructive pulmonary disease, diabetes mellitus and other conditions (5–10). There are several proposed explanations for the obesity paradox: 1. body fat 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 questions subjected to ongoing research with no conclusive answers so far.

Physiology in Obesity

Obesity may alter normal physiology making treatment of the critically ill patient more challenging (table 1).

Table 1:

Altered Physiology in Obesity

Effects of Obesity on Respiratory physiology:

1. Restrictive lung physiology:

• Reduced expiratory reserve volume

• Reduced functional residual capacity

• Reduced vital capacity

• Reduced total lung capacity

• Reduced expiratory flow rates

2. Higher respiratory rate

3. Higher incidence of obstructive sleep apnea and hypoventilation syndrome

4. Smaller upper airway caliber and increased airway resistance

5. In the mechanically ventilated obese patients:

• Higher incidence of difficult intubation

• Higher incidence of pulmonary atelectasis

Effects of Obesity on Cardiovascular physiology and morphology:

1. Physiological changes

• Increased total body volume

• Increased cardiac output (hyperdynamic circulation)

• Increased right side preload

• Higher intracardiac filling pressures

• Increased left and right ventricular afterloads

• Higher incidence of pulmonary hypertension

• Higher incidence of systemic hypertension

• Systolic and diastolic myocardial dysfunction (cardiomyopathy)

2. Morphological changes

• Increased left ventricular wall thickness

• Increased left atrial size

• Increased right ventricular size and thickness

• Higher incidence of coronary artery stenosis

Effects of obesity on respiratory physiology

BMI is associated with decreased lung volume, which are reflected by a restrictive ventilatory pattern on spirometry. This includes reduced expiratory reserve volume (ERV) and functional residual capacity (FRC) (14, 15). Obese, nonsmoking individuals may also have reduced vital capacity (VC), total lung capacity (TLC), and forced expiratory flow rates at low lung volumes associated with increased residual volume (RV), RV/TLC ratio, 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 atelectasis. Further, mechanical ventilation distorts normal diaphragmatic movement, which is aggravated by the increased abdominal pressure present with central adiposity (20).

Effects of obesity on cardiovascular physiology

Obesity produces a variety of hemodynamic changes that predispose to alterations in cardiac physiology and morphology and eventually lead to heart failure. The high metabolic demand induced by excess body weight, produces an increase in total body volume, plasma volume and cardiac output (hyperdynamic circulation) which in turn increases venous return (preload) to the right and left ventricles and results in higher intracardiac filling pressures. In addition, left ventricular afterload is elevated due to increased peripheral resistance and artery stiffness (21). Right ventricular afterload may also be elevated for various reasons like pulmonary hypertension (OSA, obesity hypoventilation syndrome or recurrent pulmonary thromboembolism) and abnormal left ventricular function (22).

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 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).

Obesity and Sepsis

Sepsis is the leading cause of morbidity and mortality in intensive care units worldwide and 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 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.

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 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 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).

Obesity and Trauma

Mortality

Obesity impacts traumatic injury outcomes in pediatric and adult patients. In a large study of patients with blunt trauma the incidence, mortality and morbidity in morbidly obese adult patients (BMI 40 kg/m² or greater) was significantly higher than lean patients (43). Bochicchio et al reported a 7.1-fold increase in mortality related to obesity in 1,167 trauma patients admitted to the ICU (44). Other studies support higher mortality rates in adult trauma patients with overweight and obesity compared to non-obese patients (45, 46). Recently, a meta-analysis of 31 studies was performed to determine the impact of BMI and obesity on injury and mortality from motor vehicle accidents and found a positive relationship between obesity and mortality (47). Despite evidence overweight and obesity is associated with higher mortality, there are studies with no difference in mortality between non-obese trauma patients and obese trauma patients (48–50). Furthermore, being overweight, but not obese, may be protective against mortality from injuries from motor vehicle accidents (51).

Morbidity

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 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).

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 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 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

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).

Obesity and Burns

Severe burns are characterized by physiological responses that result in a hypermetabolic and hypercatabolic states. Whether obesity has a beneficial or deleterious impact on the overall outcome of severely burned patients is not clear and till now clinical trials yielded conflicting results. In a large study conducted by Ray et al in 14,602 burn patients, obesity was found to be an independent predictor of adverse events (wound infection, urinary tract infection, deep vein thrombosis) (65). However, obesity was also associated with decreased mortality. In contrast, Carpenter et al used a National Burn Repository (n = 101,450) to report 2.6 times increase in mortality among burn patients described as obese (66). Ghanem et al described BMI>35 kg/m² as a tilt point at which burn patients with obesity is associated with higher than predicted mortality compared to burn patients without obesity (67). In a retrospective observational multicenter study, morbidly obese patients had a significantly 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.

Obesity and Respiratory Failure

Respiratory failure is the 3^rd leading cause of death in the United States. Common causes 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, obese patients have similar or improved mortality from ARDS. In a meta-analysis it was demonstrated that compared to normal weight patients with ARDS, patients with obesity and morbid obesity had lower mortality (72). High Frequency Oscillation in Early Acute Respiratory Distress Syndrome (OSCILLATE) is a large, multicenter randomized control trial in which adults with moderate to severe ARDS were randomized to high frequency oscillatory ventilation or conventional mechanical ventilation, employing low tidal volume mechanical ventilation(73). The primary outcome was in-hospital mortality. The study was terminated early due to the high mortality in patients randomized to high frequency oscillatory ventilation, with a 12% higher mortality compared to the conventional mechanical ventilation group. A post-hoc analysis of the OSCILLATE trial showed no mortality difference between the conventional mechanical ventilation arm and high frequency oscillator ventilation arm across BMI strata (74).

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 patients with ARDS, positioning including proning and reverse Trendelenburg, significantly improved PaO2/FiO2 ratio in obese patients compared to non-obese patients (80).

Obesity and Renal failure

Acute Kidney Injury

The prevalence of acute renal injury (AKI) in patients admitted to the ICU worldwide is high, exceeding 50% in adults and 25% in children. Increasing KDIGO (Kidney Disease: Improving Global Outcomes) AKI severity in both populations is a known risk factor for mortality and worse outcomes (81, 82). Growing evidence suggests that obesity is a risk factor for AKI in critically ill patients and hence a risk factor for mortality and worse outcomes. Danziger et al, in a single center study evaluated the association between AKI 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 independent risk factor for developing AKI (85).

Obesity and Infections

Obesity is an independent risk factor for nosocomial infections in critically ill patients (86, 87). A systematic review of 11 studies found increased body mass index is associated with worse outcomes from bacterial infections in hospitalized patients, including a higher mortality, longer duration of mechanical ventilation, and longer ICU-days and length of hospitalization (88).

Blood Stream Infection (BSI)

In a prospective cohort study of 64,027 participants, increased body mass index was associated with increased risk of first-time BSI and blood BSI related mortality (89). 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 paradox, see above).

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). 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).

Surgical Site Infection

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).

Obesity and Critical Illnesses in Children

According to the WHO, over 340 million children and adolescents aged 5–19 years were overweight or obese in 2016. Since 1975 the prevalence of obesity in this age group has risen dramatically from just 1% to over 7% in 2016 (https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight). Obese children are five times more likely to become obese as adults compared to nonobese children (106) and hence are more likely to acquire diseases like diabetes, coronary heart disease and a range of cancers (107). Whether childhood obesity effects outcomes of children admitted to the intensive care unit for critical illnesses is a matter of debate.

Numa et al in a retrospective single center study found weights at the extreme to be an 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 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 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.

Obesity and COVID-19

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 was first reported in China in December 2019 and has since evolved into a global pandemic. Many aspects of this new and challenging disease are still obscure 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; 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, 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 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).

Conclusions and Future Directions

• The duration of obesity is a seldom mentioned concept in current published literature that may be a major modifier and confounder of short-term outcomes and disease course following critical illnesses and may also explain why results among the pediatric (short duration of obesity) and adult (longer duration of obesity) age groups are somewhat different. We suggest that future research studies consider this concept.

• 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.

• Knowing the physiological alternations, special medical considerations and nursing challenges related to severe obesity and allocating special resources accordingly are necessary for better taking care of obese patients during critical illness.