Increased body mass index and adjusted mortality in ICU patients with sepsis or septic shock: a systematic review and meta-analysis

Different from our hypothesis, in studies of adults admitted to the ICU with sepsis, severe sepsis, or septic shock and which adjusted for other baseline variables, patients with overweight or obese BMIs, but not with morbidly obese ones, had reductions in mortality at up to 60 days compared to those with normal BMIs. There are several plausible biologic and physiologic reasons for these mortality reductions with the two former categories. First, increased adipose tissue is associated with increased renin-angiotensin system activity [35]. While this increased activity contributes to the hypertension of overweight and obese patients, it could also have protective hemodynamic effects during sepsis and decreased the need for fluid or vasopressor support, therapies which in excess can adversely impact outcome [36]. Second, increased lipoprotein levels and adipose tissue in patients with increased BMI may bind and inactivate lipopolysaccharide or other harmful bacterial products released during sepsis [37, 38]. Third, excess adipose tissue could provide increased beneficial energy stores during the catabolic septic state [39]. Finally, excess adipose tissue may have beneficial immune functions. For example, adipose tissue has been associated with increased production of both tumor necrosis factor (TNF) and soluble TNF receptor [40, 41]. While increased TNF production might augment protective host defense mechanisms during infection, increased soluble TNF receptor levels could reduce the deleterious effects of excessive TNF production during sepsis. Studies have suggested that obesity suppresses injurious inflammatory mediator release during sepsis and sepsis-associated acute lung injury [42].

Although morbidly obese BMIs were not associated with reductions in mortality, they, perhaps surprisingly, were also not associated with mortality increases. However, there were few studies and considerably fewer patients with morbidly obese BMIs investigated, and this may have limited our ability to demonstrate a potential survival benefit with this category. Also, as discussed further below, there may be a diminishing benefit as BMI levels exceed the overweight and obese categories.

It is possible that methodology in studies may have contributed to an apparent but not real reduction in mortality in septic patients with overweight and obese BMIs. First, mortality may not have been adjusted for baseline variables favoring improved outcomes in overweight and obese patients. While septic patients with increased BMI may have infections (e.g., skin and soft tissue) more responsive to treatment than those with normal BMIs, only two studies adjusted for the site and type of underlying infection [16, 17]. Only one study adjusted for interventions patients received at admission [15]. However, time to antibiotic therapy may have differed across BMI categories and impacted outcomes. Also, administration of non-weight-based therapies such as fluids or vasopressors (e.g., norepinephrine) may have benefited patients with increased BMIs. In two studies analyzed here, when weight was accounted for, septic patients with increased BMI received less overall fluid than normal weight patients and this may have protected organ function [16, 17]. Second, selection bias may have altered the results. Concerns about airway protection and hypoventilation in patients with increased BMI may have prompted intubation with mechanical ventilation and ICU admission in patients with more easily treated infection [43, 44]. Inability to administer adequate care for obese patients on general wards may have also caused ICU admission of obese patients with less severe infection [17]. Third, missing data may have influenced the results. The study with the largest number of septic patients did not provide adjusted mortality rates for those with underweight or overweight BMIs, even after our attempts to obtain this information from investigators. Finally, inaccurate height and weight estimates are common in the ICU setting and may have caused assignment of patients to incorrect BMI categories [45–47]. Weight first measured in the ICU following aggressive emergency room fluid resuscitation may have resulted in patients with normal BMIs at baseline being categorized as overweight or obese at the time of study entry [17]. Notably, only one study appeared to clearly define both how and when height and weight measurements were calculated [16], and no study explicitly reported the reliability of the BMI calculations made.

There are several potential limitations to this study. The most important one has to do with the design and selection of patients included in the studies analyzed. Four of the six studies were retrospective ones, with three of these studies having 87 % of the patients available to examine the influence of BMI on mortality in sepsis. The largest study, a retrospective one, only included 33 % of patients from the population available for analysis due to missing BMI data [17]. This study reported that included patients were significantly different from excluded patients, having fewer comorbid conditions but higher hospital mortality rates (Table 3) [17]. The second-largest study did not report the proportion of patients with sepsis that did not have a recorded BMI [33]. Those with unrecorded BMIs may have had fulminant sepsis and died prior to BMI measurement. This study also examined critical care patients admitted in 84 different countries over a 2-week period during the year. Clinical practice in intensive care units may have differed across centers and countries, while severity of illness and outcomes may have differed with seasonal variation [33]. The third-largest study was a retrospective analysis of a randomized controlled study of vasopressin therapy that included only 15 % of patients screened for enrollment (Table 3) [16]. However these three retrospective studies together contributed 90 % and 89 % respectively to the weight of the analyses suggesting that overweight or obese BMIs reduced adjusted mortality.

Other potential limitations include the following. First, the studies we examined which adjusted for comorbid illnesses that have been associated with increased BMI (e.g., diabetes, coronary artery disease) may have decreased or negated the potential detrimental effects of overweight or obese BMIs [48, 49]. Second, BMI does not differentiate changes in adipose versus muscle tissue. As people age, decreased BMI related to loss of muscle tissue (sarcopenia) [50–52] may be associated with a worsened outcome from sepsis. However, while BMI is not a perfect measure of adiposity [53], routine use of other measures of adiposity such as waist circumference, calipers or computed tomography, are not routinely performed in the ICU. Studies in our review likely utilized BMI as a measure of adiposity, due to its ease of use and measurement. Third, the studies included in this meta-analysis did not describe the types of nutritional support patients were receiving (e.g., low-calorie, high-protein therapy, conventional therapy, or nothing). Differences in nutritional support may have influenced outcome [54]. Finally, all the studies included in this analysis used sepsis definitions that predate the new sepsis-3 guideline nomenclature [55]. Five of the six studies used definitions of severe sepsis and septic shock by Bone et al. [25], and one study used a definition of sepsis by Vincent et al. [26]. As previously noted though, correlations can be drawn between this prior sepsis nomenclature and that of the new sepsis-3 guideline [55].

Despite its potential limitations, this study contributes in several ways to the current literature regarding the influence of increased BMI on outcomes in critically ill patients. With regard to sepsis specifically, a previous systematic review by Trivedi et al. [12] examined outcomes for obese and non-obese BMIs in adults and children admitted with sepsis to both ICU and non-ICU settings but did not incorporate a meta-analysis. Our systematic review has focused only on adult patients requiring ICU admission and has included a meta-analysis. In contrast to the prior review, the present one has also analyzed patients with morbidly obese BMIs and, in employing adjusted outcomes, has highlighted variables future analyses may need to consider (Table 2). Notably, our study and this prior one are in agreement regarding the need for more rigorous investigation into the potential impact of obesity on outcomes in septic patients.

With regard to the potential relationship between increased BMI and outcomes in critically ill patients in general, the present analysis adds to others suggesting that there may be an association between overweight and obese BMIs and unexpected increases in survival [56–58]. This possible relationship has been referred to as the obesity survival paradox since the documented adverse effects of obesity on chronic disease and long-term mortality would reasonably be expected to also worsen and not improve outcomes during acute illness of whatever nature [55]. However, the actual existence and basis for this apparent paradox are debated [8, 59, 60]. More in keeping with expectations, in critically ill populations as in the septic ones analyzed here, patients with underweight or morbidly obese BMIs have demonstrated either no increased survival or worsened survival [61–63]. This has lead to the proposal that the relationship between BMI and outcome during acute disease is U-shaped, with worsened outcomes only apparent at the extremes of increased or decreased BMIs [8, 60, 64]. Whether such a relationship clearly holds for patients with sepsis requires further investigation in well-designed studies that adequately adjust for other confounding conditions and variables.