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Impact of obesity on sepsis mortality: A systematic review
Journal of Critical Care 30 (2015) 518–524
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Sepsis/Infection
Impact of obesity on sepsis mortality: A systematic review☆ Vrinda Trivedi, MD, Chirag Bavishi, MD, MPH, Raymonde Jean, MD ⁎ Mount Sinai St Luke's Roosevelt Hospital, New York, NY
a r t i c l e
i n f o
Keywords: Obesity BMI Sepsis Mortality Systematic review
a b s t r a c t Purpose: Sepsis and severe sepsis are the most common cause of death among critically ill patients admitted in medical intensive care units. As more than one-third of the adult population of the United States is obese; we undertook a systematic review of the association between obesity and mortality among patients admitted with sepsis, severe sepsis, or septic shock. Materials and methods: A systematic review was conducted to identify pertinent studies using a comprehensive search strategy. Studies reporting mortality in obese patients admitted with sepsis were identified. Results: Our initial search identified 183 studies of which 7 studies met our inclusion criteria. Three studies reported no significant association between obesity and mortality, 1 study observed increased mortality among obese patients, whereas 3 studies found lower mortality among obese patients. Conclusion: Our review of the current clinical evidence of association of obesity with sepsis mortality revealed mixed results. Clinicians are faced with a number of challenges while managing obese patients with sepsis and should be mindful of the impact of obesity on antibiotics administration, fluid resuscitation, and ventilator management. Further studies are needed to elicit the impact of obesity on mortality in patients with sepsis. © 2014 Elsevier Inc. All rights reserved.
1. Purpose Sepsis and severe sepsis are the most common cause of death among critically ill patients admitted in medical intensive care units (ICUs) [1]. As per the Centers for Disease Control and Prevention National Center for Health statistics report, septicemia was the 11th leading cause of death in the United States in 2010 [2]. Between 2003 and 2007, the number of patients hospitalized for severe sepsis increased by 71%, at an annual rate of 17.8% per year [3]. In addition to high mortality and morbidity, severe sepsis is associated with increased health care expenditures. In 2007, the health care costs for patients admitted for severe sepsis exceeded $24 billion, an increase of 57% since 2003 [3]. Obesity is one of the major public health problems. Current estimates suggest that 69% of adults in United States are either overweight or obese with approximately 35% obese [4]. Furthermore, overweight and obesity are major contributors to chronic diseases. Obesity has been shown to be associated with an increased all-cause mortality [5], myocardial infarction [6], diabetes mellitus [7], and hypertension [7]. The high prevalence of obesity in the general population has led to a higher number of obese patients being hospitalized in ICUs. Although prognostic effect of obesity has been extensively studied in critically ill patients [8,9], the impact of obesity on the outcomes of patients with
☆ Conflict(s) of interest/disclosures (s): None of the authors has any financial or other relations that could lead to a conflict of interest. ⁎ Corresponding author. Division of Pulmonary and Critical Care Medicine, Mount Sinai St Luke's-Roosevelt Hospital, 1000 Tenth Ave, New York, NY 10019, USA. E-mail address: [email protected] (R. Jean). http://dx.doi.org/10.1016/j.jcrc.2014.12.007 0883-9441/© 2014 Elsevier Inc. All rights reserved.
sepsis is not well studied. Hence, we undertook a systematic review to study the association between obesity and mortality among patients admitted with sepsis, severe sepsis, or septic shock. 2. Materials and methods 2.1. Search strategy A comprehensive literature search of all the pertinent studies published until May 2014 was undertaken in PubMed, Scopus, and Ovid Medline databases. A literature search was undertaken using the key words (“obese,” “obesity,” “overweight,” “morbidly obese,” “morbid obesity,” “BMI,” or “body mass index”) and (“sepsis,” “severe sepsis,” “septic shock” “bacteremia,” or “septicemia”) and (“mortality” or “outcomes”). In addition, a manual search of the full text for the relevant review articles and original studies was performed to identify additional studies (Figure 1). 2.2. Selection criteria For initial review, studies were considered as eligible if they referred to any aspect of sepsis and obesity. We then restricted our search to studies reporting specific data on mortality outcomes among obese patients admitted with sepsis. Studies selected defined obesity using either prespecified body mass index (BMI) categories or the World Health Organization obesity classification: underweight, BMI less than 18.5; normal weight, BMI 18.5 to 24.9; overweight, BMI 25 to 29.9; obesity, BMI 30 to 39.9; and morbid obesity, BMI greater than or equal to 40.
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We excluded reviews, letters, correspondence, editorials, and nonhuman studies; however, the reference lists of these articles were searched to identify other potential studies. 2.3. Study selection and data abstraction Two physician reviewers (VT and CB) independently reviewed and selected studies based on the inclusion criteria. Disagreement in study selection or data extraction was resolved with consensus. Study data were abstracted independently by each reviewer using a standardized data collection form. The following data were collected from each study: author information, year of publication, study location, type of study, categories of BMI studied, outcomes, effect size, confounding variables adjusted in the analysis, and other salient features. 2.4. Data analysis Given significant methodological and statistical differences between studies, combining the data using meta-analytic techniques was deemed inappropriate. Therefore, we used qualitative analysis and prepared a systematic review of all the available studies that evaluated the association between obesity and mortality among sepsis patients. 3. Results Our initial search identified 183 studies of which 7 studies met our inclusion criteria [10-16] (Table 1). Six studies were retrospective, whereas 1 was a prospective cohort study [15]. All studies used World Health Organization cut-offs to define obesity categories. Out of the 7 articles, 3 studied hospital/inpatient mortality [11,12,14]; 2 studied 28day mortality [13,16]; 1 studied 30-day mortality [15]; and 1 studied in-hospital, 90-day, and 1-year mortality [10]. Six studies reported results by obese categories (overweight/obese vs nonobese/normal BMI), whereas 1 study reported results using BMI as a continuous variable [13]. The results were heterogeneous. Three studies reported no
significant association between obesity and mortality [12,14,16], 1 study observed increased mortality [15] among obese patients, whereas 3 studies found lower mortality among obese patients [10,11,13]. Prescott et al [10] studied 1404 Medicare beneficiaries (adults N65 years) hospitalized for severe sepsis and reported in-hospital, 90-day, and 1-year mortality. Multivariate logistic regression models showed that overweight, obese, and severely obese patients had a statistically significant association with lower in-hospital, 90-day and 1-year mortality. The results were persistent, when stratified by age (patients b70 and N70 years). The risk of developing functional limitations after an episode of sepsis was similar in obese and normal weight individuals. Interestingly, obese patients that survived hospitalization for sepsis required higher annual Medicare spending after being discharged from the hospital, but this apparent increase was attributed to greater survival and not increased utilization. Similar results were demonstrated by Wurzinger et al [11] who investigated ICU mortality in their singlecenter study of 301 septic shock patients. Patients with a BMI more than 50 were excluded from the study population. As compared with normal weight patients, overweight and obese patients were associated with lower mortality in multivariable analysis. High BMI was independently associated with lower risk of acute delirium and ICU readmission but with a higher rate of ICU-acquired urinary tract infections. In another single-center study, Kuperman et al [12] studied 792 patients admitted with sepsis. Patients with BMI more than 50 were excluded from the study. Unadjusted analysis revealed that survivors had a higher BMI, but after adjusting for comorbidities in the multivariate regression model, the association of decreased mortality with higher BMI was no longer statistically significant. Wacharasint et al [13] published post hoc analysis of Vasopressin and Septic Shock trial to investigate if overweight and obese patients had a lower 28-day mortality as compared with patients with a BMI less than 25. They found that for every 1-U increase in BMI, mortality decreased by 2%. Results remained similar on reanalysis after excluding the underweight group, and obese patients had the lowest mortality followed by overweight and normal BMI patients. Obese and overweight patients had a lower rate of pneumonia and fungal infections and received less weight adjusted intravenous fluids and pressors
Records identified through database searching and after removing duplicates (n = 409)
Records screened (n =409)
Full-text articles assessed for eligibility (n = 23)
519
Records excluded based on titles and abstracts (n = 386)
Full-text articles excluded: Reviews (5) No mortality outcomes (7) Not sepsis patients (4)
Studies included in qualitative synthesis (n = 7) Figure 1. Flow diagram of literature search and study selection.
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Table 1 Characteristics of studies evaluating the association between obesity and mortality in sepsis patients Study type
BMI categories studied
Sample size and patient profile
Outcome
Result BMI as continuous variable OR (95% CI)
Result BMI as categorical variable OR (95% CI)a
Variables adjusted for
Comments
Arabi et al [14],
Nested
2882
In-hospital mortality
NR
Obese
Age, sex,
2013
multicenter cohort study conducted in 28 centers
Underweight: b18.5, normal: 18.5-24.9, overweight: 25.0-29.9, obese:
Unadjusted:
mechanical ventilation, APACHE II score, chronic comorbidities nosocomial infection, bacteremia, infections, creatinine clearance, country, inappropriate/ combination/delayed antimicrobial therapy, vasopressor doses, the use of a pulmonary artery catheter, activated protein C and low-dose steroids
All patients were admitted to the ICU. Largest study evaluating obesity and outcomes in septic shock patients
Canada, USA, Saudi Arabia
patients with septic shock
30.0-39.9, very obese: N40
0.80 (0.66-0.97)
Adjusted: 0.80 (0.62-1.02)
Very obese
Gaulton et al [16],
Retrospective cohort study, single center
Obese: BMI ≥30 nonobese: ≥18.5-30.
1779 patients with presumed sepsis
28-day mortality
NR
2014 USA Huttunen et al [15], 2007
Prospective cohort study, single center
USA
149 patients with bacteremia
30-day mortality
NR
nonobese: BMI b30
Finland
Kuperman et al [12], 2013
Obese: BMI N30
Retrospective cohort study, single center
Underweight: b18.5, normal: 18.5-24.9,
overweight: 25.0-29.9,
792 patients with sepsis
In-hospital mortality
Unadjusted:
0.97 (0.94-1.0)
Unadjusted: 0.61 (0.44-0.85) Adjusted: 0.69 (0.45-1.04) Obese Unadjusted: 1.21 (0.95-1.54) Adjusted: 1.11 (0.85-1.41) Obese Unadjusted:
9.8 (2.3-41.3) Adjusted: 6.4 (1.2-34.4) Morbid obesity unadjusted:
0.7 (0.12-4.2)
Sex, admitting hospital, ICU location, vasopressor Age, sex, smoking, alcohol abuse, S aureus, S pneumonia, β-hemolytic streptococcus and E coli bacteremia
Age, race, sex, length of stay, diabetes, neutropenia, cancer, liver disease, cardiovascular disease, COPD, liver disease, immunosuppression, modified APACHE II
66% patients were admitted to the ICU. BMI b18.5 were excluded 32% patients were admitted to the ICU. Only prospective cohort study evaluating obesity and outcomes in patients with bacteremia No data provided on the level of care. Patients with BMI N50 were excluded.
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First author, year, country
Prescott et al [10] 2014
Retrospetive cohort study, multicenter
USA
Canada
Wurzinger et al [11],
Adjusted:
1404 patients with severe sepsis
In-hospital, 90-day, and 1-year mortality
0.90 (0.76-1.06) Adjusted: hospital mortality: 0.96 (0.93-0.99) 90-day mortality: 0.95 (0.93-0.98) 1-year mortality: 0.96 (0.93-0.99)
Adjusted hospital mortality: obese 0.64 (0.40-1.01) severely obese: 0.54 (0.31-0.95) 90-day mortality obese: 0.53 (0.35-0.79) severely obese: 0.43 (0.25-0.74) 1-year mortality obese: 0.59 (0.39-0.88) severely obese: 0.46 (0.26-0.80) NR
Age, sex
Admission year, age, sex, heart disease, chronic renal insufficiency, premorbidities, origin of sepsis, SAPS II
Retrospective cohort study (from VASST trial)
Normal: BMI b25 Overweight: BMI 25-30 Obese: BMI N30
730 patients with septic shock
28-day mortality
Adjusted: 0.98 (0.97-0.99)
Retrospective cohort study
Underweight: b18.5; normal: 18.5-24.9; overweight: 25-29.9; obese and morbidly obese: ≥30
301
ICU mortality
Unadjusted:
Obese
2010
patients with
0.91 (0.86- 0.98)
Adjusted:
Austria
septic shock
Adjusted: 0.93 (0.86-1.01)
0.28 (0.08-0.93)
OR indicates odds ratio; CI, confidence interval; NR, not reported; APACHE, Acute Physiology and Chronic Health Evaluation; S aureus, Staphylococcus aureus; S pneumoniae, Streptococcus pneumoniae; E coli, Escherichia coli; COPD, chronic obstructive pulmonary disease; VASST, Vasopressin and Septic Shock trial; SAPS, Simplified Acute Physiology Score. a As compared with normal BMI.
49% patients were admitted to the ICU. Multicenter study of Medicare beneficiaries. Patients with BMI b18.5 were excluded.
marital status, race, wealth, acute organ dysfunction, ICU use, mechanical ventilation use, diabetes, baseline cognitive status, functional limitations APACHE II, sex, lung infection, diabetes, fungal infection
All patients were admitted to the ICU. Excluding underweight patients yielded similar results All patients were admitted to the ICU.
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Wacharasint et al [13], 2013
obese: 30.0-39.9, morbidly obese: 40.0-49.9 Normal: 18.5-24.9, overweight: 25-29.9, obese: 30-34.9, severely obese: ≥35
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as compared with patients with a BMI less than 25. In a large multicenter nested cohort study, Arabi et al [14] investigated the association between obesity and in-hospital mortality in 2882 septic shock patients. Results revealed that, although obese and very obese patients had a lower mortality in comparison with patients with normal BMI, the association became insignificant after adjusting for baseline characteristics and sepsis interventions. In another large cohort study by Gaulton et al [16], multivariable-adjusted analysis showed that 28-day mortality was not significantly higher among obese sepsis patients as compared with sepsis patients with BMI less than 30. However, severely obese patients had higher mortality than normal BMI group patients. Huttunen et al [15] prospectively studied the association between BMI and 30day mortality rate in 149 patients with bacteremia. Patients enrolled included those with positive blood cultures, and the severity of illness ranged from milder symptoms and signs to those who developed septic shock and required an ICU stay. In multivariate analysis, obese patients were associated with both increased 30-day mortality and an increased ICU mortality. 4. Discussion Clinical studies evaluating the impact of obesity on mortality in critically ill sepsis patients have yielded conflicting results. Obesity is thought to be a state of chronic inflammation, as it is associated with increased oxidative stress. Cytokines secreted from adipocytes such as interleukins (IL-1, IL-3, IL-6, and IL-8), tumor necrosis factor α, and transforming growth factor β have been found to correlate with increasing BMI and waist-to-hip ratio [17,18]. Hence, it is speculated that, when obese individuals develop sepsis, the systemic inflammatory response may be different as compared with those with a normal BMI. 4.1. Experimental models and animal studies Several studies have utilized nonhuman models to examine sepsis in obese states. Vachharajani et al using cecal ligation and punctureinduced sepsis model showed that cerebral microvasculature in obese septic mice is more prone to pronounced inflammatory responses and endothelial dysfunction as compared with their lean counterparts [19]. In another study, Singer et al [20] studied ob/ob (leptin deficient) and db/db (leptin resistant) mice and found that both mutant models produced augmented inflammatory and thrombogenic responses during sepsis. These findings suggest that inflammatory responses are heightened in obese mice during sepsis when compared with their lean counterparts. 4.2. Role of adipokines Leptin and adiponectin are cytokines synthesized in adipose cells and stored in adipose tissue. Adiponectin is an antiinflammatory and insulin-sensitizing cytokine that is deficient in obese individuals [21]. Adiponectin levels have been proven to be depressed in critically ill including septic as well as morbidly obese patients and are associated with insulin-resistant and inflammatory response in these populations [22]. Adiponectin deficiency has been shown to intensify sepsisrelated microvascular dysfunction and endothelial activation in murine models [23,24]. However, other clinical studies have not established the same association. Koch et al [25] found that low adiponectin levels in critically ill patients had a significantly better outcome. Walkey et al [26] demonstrated that high serum adiponectin levels correlated with increased 28-day mortality in patients requiring mechanical ventilation. Leptin levels are elevated in obese patients [27], and it has been studied for its role as a regulator of cell-mediated immunity, endothelial activation, and cytokine production in the setting of acute systemic inflammation [28]. Although the exact pathophysiologic role of leptin in sepsis is not well understood, leptin levels have been shown to be
elevated 3-fold in critically ill patients with sepsis in correlation with levels of tumor necrosis factor α and IL-6 [29,30]. 4.3. Obesity and Infection Obesity has been associated with increased risk of nosocomial infection [31], surgical site infections [32,33], Clostridium difficile infection [34], urinary tract infection [35], and increased future sepsis events [36]. Obesity has significant effects on respiratory function. Obese patients have been shown to have lower tidal volumes, increased respiratory rate, impaired gas exchange, increase in airway resistance, and decrease in respiratory system compliance [37]. However, associations of obesity with respiratory infections have been conflicting. Studies post-H1N1 pandemic showed increased risk of influenza-related adverse outcomes such as pneumonia, hospitalization, critical illness, ICU admission, and death in obese and morbidly obese patients [38,39]. Interestingly, obesity has been found have a protective effect on mortality associated with community-acquired pneumonia [40,41]. The reasons for such paradoxical results are unknown and require further studies. 4.4. Challenges in management of critically ill septic obese patients 4.4.1. Antibiotic dosing Early administration of broad spectrum antibiotics within 1 hour of recognition of severe sepsis and septic shock is a component of early goal-directed therapy and a class I recommendation of the “Surviving Sepsis Campaign [42].” Obesity has been implicated as a risk factor for antibiotic treatment failure [43]. A multitude of physiologic changes affecting the distribution, metabolism, and clearance of antibiotics can occur in obese patients and may be responsible for lower serum concentrations [44]. Antibiotics can be classified as hydrophilic (β lactams and aminoglycosides) or lipophilic (fluoroquinolones, macrolides, and tigecycline) based on their affinity for adipose tissue [45]. Lipophilic agents are affected more by the presence of obesity, as they achieve a higher volume of distribution due to binding to adipose tissue [46]. Kidney volume has shown to correlate with lean body mass, and obesity has been shown to increase glomerular filtration rate, which can potentially alter clearance of antibiotics [47]. Alterations in volume of distribution and clearance can also impact pharmacodynamics parameters [48]. Vancomycin, aminoglycosides, and β lactams are most extensively studied in obese population. For example, data suggest that initial dosing of vancomycin should be based on total body weight, and adjustments should be made by following drug levels [49]. Hall et al [50] have shown that obese patients are more likely to receive lower-than-recommended doses of vancomycin, potentially causing subtherapeutic levels and worse outcomes. In morbidly obese patients undergoing elective surgical procedures, higher doses of prophylactic cefepime and cefazolin were required to maintain an adequate time above minimum inhibitory concentration levels [51]. Another study involving the use of tobramycin or gentamicin in morbidly obese patients showed that only 71% of patients attained therapeutic drug concentrations [52]. Failure to recognize obesity-related pharmacokinetic and pharmacodynamic alterations could result in underdosing and treatment failures. Further studies are needed to guide clinicians in making antibiotic dosage adjustments based on body indices. 4.4.2. Fluid resuscitation In an observational study investigating fluid resuscitation in patients with burn injuries, it was found that obese patients had received substantially lower volume of fluids based on actual body weight in comparison with their normal weight counterparts. Expectedly, volume of fluid received by the morbidly obese group was significantly higher as compared with all other groups, when based on ideal body weight. [53] Similarly, in a study involving trauma patients, the volume of crystalloid and colloid resuscitation in obese patients was lower than in the nonobese. Subsequently, the obese group had a higher mortality despite
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similar severity due to persistent hypovolemia [54]. Arabi et al [14] specifically investigated sepsis interventions and outcomes in obese patients and found that the obese and morbidly obese group received notably lower volumes of crystalloid and colloid fluids in the initial resuscitation phase. Future research needs to be directed toward better defining adequate fluid resuscitation and establishing methods to assess volume requirements in the obese, taking into account disparity in BMI and lean weight in these patients. 4.4.3. Mechanical ventilation Obesity impairs gas exchange, increases alveolar-to-arterial gradient, increases upper and lower airway resistance, decreases compliance of the chest wall and lung tissue, and increases the risk for atelectasis. Functional residual capacity and expiratory reserve volume are reduced in obese subjects as compared to their normal weight counterparts. Vital capacity and total lung capacity can also be decreased in morbidly obese patients [55,56]. Respiratory failure secondary to organ dysfunction is seen in severe sepsis and septic shock and often manifests as acute respiratory distress syndrome (ARDS). Gong et al [57] showed that patients with increasing BMI were at an increased risk for developing ARDS and had a longer length of stay but not higher mortality. Other studies have demonstrated similar results, wherein obesity did not have statistically significant association with mortality in patients with ARDS [58,59]. However, patients who are obese and develop ARDS offer a unique challenge to the clinician with regards to ventilation management. Strategies to optimize pulmonary mechanics in such patients include positioning in reverse Trendelenburg at a 45° angle, positioning in the prone in patients with severe hypoxemia, inhaled nitric oxide, low tidal volume ventilation based on ideal body weight, optimal positive end-expiratory pressure titration, and alveolar recruitment maneuvers such as the intermittent application of high airway pressures for a few seconds [60]. 4.4.4. Nursing care and other challenges There are several challenges to the management of obese patients in the critical care setting. The obese patient may require increased time and resources with regards to hygiene, repositioning, and transferring in and out of bed [61]. The risk of developing decubitus ulcer increases with increasing BMI [62]. In addition, portable radiologic films provide poorer quality images due to increased scatter, and bedside ultrasonography is limited due to difficulty in obtaining appropriate positioning as well as poor penetration [63]. 5. Limitations There are several important limitations to our analysis. First, clinical evidence examining the association of BMI with outcomes in sepsis is scarce and has not been adequately analyzed in studies involving critically ill patients. Moreover, very obese patients with a BMI greater than or equal to 35 are underrepresented in most studies. The sample sizes are often limited due to missing height and weight data, and inaccuracies can develop if weight is checked after fluid resuscitation. All studies used BMI cut-offs to define obesity. Studies using anthropometric indices other than BMI to define obesity could help us better understand the relationship of obesity with sepsis. Finally, most of the studies identified were retrospective cohort studies. To limit confounding effect, wherever available, we have reported the adjusted risk estimates. However, there may be residual confounding from other unmeasured factors. 6. Conclusions Our review of the current clinical evidence of association of obesity with sepsis mortality revealed mixed results. Three studies reported no significant association between obesity and mortality, 1 study observed increased mortality among obese patients with bacteremia,
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whereas 3 studies found decreased mortality among obese patients. Clinicians are faced with a number of challenges while managing obese patients with sepsis and should be mindful of the impact of obesity on antibiotics administration, fluid resuscitation, and ventilator management. The currently available experimental and clinical evidence is not conclusive and indicates that there are differences in biology, treatment interventions, and epidemiology in obese and nonobese patients with sepsis. Future research should be directed toward studying larger cohorts and toward developing an individualized approach to guide the clinician in treatment interventions that influence outcomes of patients with sepsis. References [1] Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29(7):1303–10. [2] Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep 2013; 61(4):1–117. [3] Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med 2012;40(3):754–61. [4] Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014;311(8):806–14. [5] Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013;309(1):71–82. [6] Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005;366(9497):1640–9. [7] Savva SC, Lamnisos D, Kafatos AG. Predicting cardiometabolic risk: waist-to-height ratio or BMI. A meta-analysis. Diabetes Metab Syndr Obes 2013;6:403–19. [8] Oliveros H, Villamor E. Obesity and mortality in critically ill adults: a systematic review and meta-analysis. Obesity 2008;16(3):515–21. [9] Akinnusi ME, Pineda LA, El Solh AA. Effect of obesity on intensive care morbidity and mortality: a meta-analysis. Crit Care Med 2008;36(1):151–8. [10] Prescott HC, Chang VW, O'Brien Jr JM, Langa KM, Iwashyna T. Obesity and 1-year outcomes in older Americans with severe sepsis. Crit Care Med 2014;42(8): 1766–74. [11] Wurzinger B, Dunser MW, Wohlmuth C, Deutinger MC, Ulmer H, Torgersen C, et al. The association between body-mass index and patient outcome in septic shock: a retrospective cohort study. Wien Klin Wochenschr 2010;122(1–2):31–6. [12] Kuperman EF, Showalter JW, Lehman EB, Leib AE, Kraschnewski JL. The impact of obesity on sepsis mortality: a retrospective review. BMC Infect Dis 2013;13(1):377. [13] Wacharasint P, Boyd JH, Russell JA, Walley KR. One size does not fit all in severe infection: obesity alters outcome, susceptibility, treatment, and inflammatory response. Crit Care 2013;17(3):R122. [14] Arabi YM, Dara SI, Tamim HM, Rishu AH, Bouchama A, Khedr MK, et al. Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study. Crit Care 2013;17(2):R72. [15] Huttunen R, Laine J, Lumio J, Vuento R, Syrjanen J. Obesity and smoking are factors associated with poor prognosis in patients with bacteraemia. BMC Infect Dis 2007;7:13. [16] Gaulton TG, Weiner MG, Morales KH, Gaieski DF, Mehta J, Lautenbach E. The effect of obesity on clinical outcomes in presumed sepsis: a retrospective cohort study. Intern Emerg Med 2014;9(2):213–21. [17] Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, et al. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg 2004;14(5):589–600. [18] Vachharajani V, Vital S. Obesity and sepsis. J Intensive Care Med 2006;21(5):287–95. [19] Vachharajani V, Russell JM, Scott KL, Conrad S, Stokes KY, Tallam L, et al. Obesity exacerbates sepsis-induced inflammation and microvascular dysfunction in mouse brain. Microcirculation 2005;12(2):183–94. [20] Singer G, Stokes KY, Terao S, Granger DN. Sepsis-induced intestinal microvascular and inflammatory responses in obese mice. Shock 2009;31(3):275–9. [21] Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257(1):79–83. [22] Venkatesh B, Hickman I, Nisbet J, Cohen J, Prins J. Changes in serum adiponectin concentrations in critical illness: a preliminary investigation. Crit Care 2009;13(4):R105. [23] Vachharajani V, Cunningham C, Yoza B, Carson Jr J, Vachharajani TJ, McCall C. Adiponectin-deficiency exaggerates sepsis-induced microvascular dysfunction in the mouse brain. Obesity 2012;20(3):498–504. [24] Teoh H, Quan A, Bang KW, Wang G, Lovren F, Vu V, et al. Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality. Am J Physiol Endocrinol Metab 2008;295(3):E658–64. [25] Koch A, Sanson E, Voigt S, Helm A, Trautwein C, Tacke F. Serum adiponectin upon admission to the intensive care unit may predict mortality in critically ill patients. J Crit Care 2011;26(2):166–74. [26] Walkey AJ, Rice TW, Konter J, Ouchi N, Shibata R, Walsh K, et al. Plasma adiponectin and mortality in critically ill subjects with acute respiratory failure. Crit Care Med 2010;38(12):2329–34. [27] Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000;62:413–37.
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[28] Behnes M, Brueckmann M, Lang S, Putensen C, Saur J, Borggrefe M, et al. Alterations of leptin in the course of inflammation and severe sepsis. BMC Infect Dis 2012;12: 217. [29] Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P, et al. Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion. J Clin Endocrinol Metab 1998;83(1):280–3. [30] Yousef AA, Amr YM, Suliman GA. The diagnostic value of serum leptin monitoring and its correlation with tumor necrosis factor-alpha in critically ill patients: a prospective observational study. Crit Care 2010;14(2):R33. [31] Dossett LA, Dageforde LA, Swenson BR, Metzger R, Bonatti H, Sawyer RG, et al. Obesity and site-specific nosocomial infection risk in the intensive care unit. Surg Infect 2009;10(2):137–42. [32] Hourigan JS. Impact of obesity on surgical site infection in colon and rectal surgery. Clin Colon Rectal Surg 2011;24(4):283–90. [33] Yuan K, Chen HL. Obesity and surgical site infections risk in orthopedics: a metaanalysis. Int J Surg 2013;11(5):383–8. [34] Bishara J, Farah R, Mograbi J, Khalaila W, Abu-Elheja O, Mahamid M, et al. Obesity as a risk factor for Clostridium difficile infection. Clin Infect Dis 2013;57(4):489–93. [35] Semins MJ, Shore AD, Makary MA, Weiner J, Matlaga BR. The impact of obesity on urinary tract infection risk. Urology 2012;79(2):266–9. [36] Wang HE, Griffin R, Judd S, Shapiro NI, Safford MM. Obesity and risk of sepsis: a population-based cohort study. Obesity 2013;21(12):E762–9. [37] Littleton SW. Impact of obesity on respiratory function. Respirology 2012;17(1):43–9. [38] Fezeu L, Julia C, Henegar A, Bitu J, Hu FB, Grobbee DE, et al. Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis. Obes Rev 2011;12(8):653–9. [39] Morgan OW, Bramley A, Fowlkes A, Freedman DS, Taylor TH, Gargiullo P, et al. Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A (H1N1) disease. PLoS One 2010;5(3):e9694. [40] Inoue Y, Koizumi A, Wada Y, Iso H, Watanabe Y, Date C, et al. Risk and protective factors related to mortality from pneumonia among middle-aged and elderly community residents: the JACC study. J Epidemiol 2007;17(6):194–202. [41] Corrales-Medina VF, Valayam J, Serpa JA, Rueda AM, Musher DM. The obesity paradox in community-acquired bacterial pneumonia. Int J Infect Dis 2011;15(1):e54–7. [42] Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41(2):580–637. [43] Longo C, Bartlett G, Macgibbon B, Mayo N, Rosenberg E, Nadeau L, et al. The effect of obesity on antibiotic treatment failure: a historical cohort study. Pharmacoepidemiol Drug Saf 2013;22(9):970–6. [44] Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy 2007;27(8):1081–91. [45] Falagas ME, Karageorgopoulos DE. Adjustment of dosing of antimicrobial agents for body weight in adults. Lancet 2010;375(9710):248–51.
[46] Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999;88(1):1–7. [47] Nawaratne S, Brien JE, Seeman E, Fabiny R, Zalcberg J, Cosolo W, et al. Relationships among liver and kidney volumes, lean body mass and drug clearance. Br J Clin Pharmacol 1998;46(5):447–52. [48] Janson B, Thursky K. Dosing of antibiotics in obesity. Curr Opin Infect Dis 2012; 25(6):634–49. [49] Blouin RA, Bauer LA, Miller DD, Record KE, Griffen Jr WO. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982; 21(4):575–80. [50] Hall II RG, Payne KD, Bain AM, Rahman AP, Nguyen ST, Eaton SA, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med 2008;121(6):515–8. [51] Rich BS, Keel R, Ho VP, Turbendian H, Afaneh CI, Dakin GF, et al. Cefepime dosing in the morbidly obese patient population. Obes Surg 2012;22(3):465–71. [52] Ross AL, Tharp JL, Hobbs GR, McKnight R, Cumpston A. Evaluation of extended interval dosing aminoglycosides in the morbidly obese population. Adv Pharm Sci 2013; 2013:194389. [53] Rae L, Pham TN, Carrougher G, Honari S, Gibran NS, Arnoldo BD, et al. Differences in resuscitation in morbidly obese burn patients may contribute to high mortality. J Burn Care Res 2013;34(5):507–14. [54] Nelson J, Billeter AT, Seifert B, Neuhaus V, Trentz O, Hofer CK, et al. Obese trauma patients are at increased risk of early hypovolemic shock: a retrospective cohort analysis of 1,084 severely injured patients. Crit Care 2012;16(3):R77. [55] McCallister JW, Adkins EJ, O'Brien Jr JM. Obesity and acute lung injury. Clin Chest Med 2009;30(3):495–508 [viii]. [56] Bahammam AS, Al-Jawder SE. Managing acute respiratory decompensation in the morbidly obese. Respirology 2012;17(5):759–71. [57] Gong MN, Bajwa EK, Thompson BT, Christiani DC. Body mass index is associated with the development of acute respiratory distress syndrome. Thorax 2010;65(1):44–50. [58] O'Brien Jr JM, Welsh CH, Fish RH, Ancukiewicz M, Kramer AM, National Heart L, et al. Excess body weight is not independently associated with outcome in mechanically ventilated patients with acute lung injury. Ann Intern Med 2004;140(5):338–45. [59] Morris AE, Stapleton RD, Rubenfeld GD, Hudson LD, Caldwell E, Steinberg KP. The association between body mass index and clinical outcomes in acute lung injury. Chest 2007;131(2):342–8. [60] Hibbert K, Rice M, Malhotra A. Obesity and ARDS. Chest 2012;142(3):785–90. [61] Muir M, Heese GA, McLean D, Bodnar S, Rock BL. Handling of the bariatric patient in critical care: a case study of lessons learned. Crit Care Nurs Clin North Am 2007; 19(2):223–40. [62] Newell MA, Bard MR, Goettler CE, Toschlog EA, Schenarts PJ, Sagraves SG, et al. Body mass index and outcomes in critically injured blunt trauma patients: weighing the impact. J Am Coll Surg 2007;204(5):1056–61 [discussion 62–4]. [63] Olson M, Pohl C. Bedside and radiologic procedures in the critically ill obese patient. Crit Care Clin 2010;26(4):665–8.
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Sepsis/Infection
Impact of obesity on sepsis mortality: A systematic review☆ Vrinda Trivedi, MD, Chirag Bavishi, MD, MPH, Raymonde Jean, MD ⁎ Mount Sinai St Luke's Roosevelt Hospital, New York, NY
a r t i c l e
i n f o
Keywords: Obesity BMI Sepsis Mortality Systematic review
a b s t r a c t Purpose: Sepsis and severe sepsis are the most common cause of death among critically ill patients admitted in medical intensive care units. As more than one-third of the adult population of the United States is obese; we undertook a systematic review of the association between obesity and mortality among patients admitted with sepsis, severe sepsis, or septic shock. Materials and methods: A systematic review was conducted to identify pertinent studies using a comprehensive search strategy. Studies reporting mortality in obese patients admitted with sepsis were identified. Results: Our initial search identified 183 studies of which 7 studies met our inclusion criteria. Three studies reported no significant association between obesity and mortality, 1 study observed increased mortality among obese patients, whereas 3 studies found lower mortality among obese patients. Conclusion: Our review of the current clinical evidence of association of obesity with sepsis mortality revealed mixed results. Clinicians are faced with a number of challenges while managing obese patients with sepsis and should be mindful of the impact of obesity on antibiotics administration, fluid resuscitation, and ventilator management. Further studies are needed to elicit the impact of obesity on mortality in patients with sepsis. © 2014 Elsevier Inc. All rights reserved.
1. Purpose Sepsis and severe sepsis are the most common cause of death among critically ill patients admitted in medical intensive care units (ICUs) [1]. As per the Centers for Disease Control and Prevention National Center for Health statistics report, septicemia was the 11th leading cause of death in the United States in 2010 [2]. Between 2003 and 2007, the number of patients hospitalized for severe sepsis increased by 71%, at an annual rate of 17.8% per year [3]. In addition to high mortality and morbidity, severe sepsis is associated with increased health care expenditures. In 2007, the health care costs for patients admitted for severe sepsis exceeded $24 billion, an increase of 57% since 2003 [3]. Obesity is one of the major public health problems. Current estimates suggest that 69% of adults in United States are either overweight or obese with approximately 35% obese [4]. Furthermore, overweight and obesity are major contributors to chronic diseases. Obesity has been shown to be associated with an increased all-cause mortality [5], myocardial infarction [6], diabetes mellitus [7], and hypertension [7]. The high prevalence of obesity in the general population has led to a higher number of obese patients being hospitalized in ICUs. Although prognostic effect of obesity has been extensively studied in critically ill patients [8,9], the impact of obesity on the outcomes of patients with
☆ Conflict(s) of interest/disclosures (s): None of the authors has any financial or other relations that could lead to a conflict of interest. ⁎ Corresponding author. Division of Pulmonary and Critical Care Medicine, Mount Sinai St Luke's-Roosevelt Hospital, 1000 Tenth Ave, New York, NY 10019, USA. E-mail address: [email protected] (R. Jean). http://dx.doi.org/10.1016/j.jcrc.2014.12.007 0883-9441/© 2014 Elsevier Inc. All rights reserved.
sepsis is not well studied. Hence, we undertook a systematic review to study the association between obesity and mortality among patients admitted with sepsis, severe sepsis, or septic shock. 2. Materials and methods 2.1. Search strategy A comprehensive literature search of all the pertinent studies published until May 2014 was undertaken in PubMed, Scopus, and Ovid Medline databases. A literature search was undertaken using the key words (“obese,” “obesity,” “overweight,” “morbidly obese,” “morbid obesity,” “BMI,” or “body mass index”) and (“sepsis,” “severe sepsis,” “septic shock” “bacteremia,” or “septicemia”) and (“mortality” or “outcomes”). In addition, a manual search of the full text for the relevant review articles and original studies was performed to identify additional studies (Figure 1). 2.2. Selection criteria For initial review, studies were considered as eligible if they referred to any aspect of sepsis and obesity. We then restricted our search to studies reporting specific data on mortality outcomes among obese patients admitted with sepsis. Studies selected defined obesity using either prespecified body mass index (BMI) categories or the World Health Organization obesity classification: underweight, BMI less than 18.5; normal weight, BMI 18.5 to 24.9; overweight, BMI 25 to 29.9; obesity, BMI 30 to 39.9; and morbid obesity, BMI greater than or equal to 40.
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We excluded reviews, letters, correspondence, editorials, and nonhuman studies; however, the reference lists of these articles were searched to identify other potential studies. 2.3. Study selection and data abstraction Two physician reviewers (VT and CB) independently reviewed and selected studies based on the inclusion criteria. Disagreement in study selection or data extraction was resolved with consensus. Study data were abstracted independently by each reviewer using a standardized data collection form. The following data were collected from each study: author information, year of publication, study location, type of study, categories of BMI studied, outcomes, effect size, confounding variables adjusted in the analysis, and other salient features. 2.4. Data analysis Given significant methodological and statistical differences between studies, combining the data using meta-analytic techniques was deemed inappropriate. Therefore, we used qualitative analysis and prepared a systematic review of all the available studies that evaluated the association between obesity and mortality among sepsis patients. 3. Results Our initial search identified 183 studies of which 7 studies met our inclusion criteria [10-16] (Table 1). Six studies were retrospective, whereas 1 was a prospective cohort study [15]. All studies used World Health Organization cut-offs to define obesity categories. Out of the 7 articles, 3 studied hospital/inpatient mortality [11,12,14]; 2 studied 28day mortality [13,16]; 1 studied 30-day mortality [15]; and 1 studied in-hospital, 90-day, and 1-year mortality [10]. Six studies reported results by obese categories (overweight/obese vs nonobese/normal BMI), whereas 1 study reported results using BMI as a continuous variable [13]. The results were heterogeneous. Three studies reported no
significant association between obesity and mortality [12,14,16], 1 study observed increased mortality [15] among obese patients, whereas 3 studies found lower mortality among obese patients [10,11,13]. Prescott et al [10] studied 1404 Medicare beneficiaries (adults N65 years) hospitalized for severe sepsis and reported in-hospital, 90-day, and 1-year mortality. Multivariate logistic regression models showed that overweight, obese, and severely obese patients had a statistically significant association with lower in-hospital, 90-day and 1-year mortality. The results were persistent, when stratified by age (patients b70 and N70 years). The risk of developing functional limitations after an episode of sepsis was similar in obese and normal weight individuals. Interestingly, obese patients that survived hospitalization for sepsis required higher annual Medicare spending after being discharged from the hospital, but this apparent increase was attributed to greater survival and not increased utilization. Similar results were demonstrated by Wurzinger et al [11] who investigated ICU mortality in their singlecenter study of 301 septic shock patients. Patients with a BMI more than 50 were excluded from the study population. As compared with normal weight patients, overweight and obese patients were associated with lower mortality in multivariable analysis. High BMI was independently associated with lower risk of acute delirium and ICU readmission but with a higher rate of ICU-acquired urinary tract infections. In another single-center study, Kuperman et al [12] studied 792 patients admitted with sepsis. Patients with BMI more than 50 were excluded from the study. Unadjusted analysis revealed that survivors had a higher BMI, but after adjusting for comorbidities in the multivariate regression model, the association of decreased mortality with higher BMI was no longer statistically significant. Wacharasint et al [13] published post hoc analysis of Vasopressin and Septic Shock trial to investigate if overweight and obese patients had a lower 28-day mortality as compared with patients with a BMI less than 25. They found that for every 1-U increase in BMI, mortality decreased by 2%. Results remained similar on reanalysis after excluding the underweight group, and obese patients had the lowest mortality followed by overweight and normal BMI patients. Obese and overweight patients had a lower rate of pneumonia and fungal infections and received less weight adjusted intravenous fluids and pressors
Records identified through database searching and after removing duplicates (n = 409)
Records screened (n =409)
Full-text articles assessed for eligibility (n = 23)
519
Records excluded based on titles and abstracts (n = 386)
Full-text articles excluded: Reviews (5) No mortality outcomes (7) Not sepsis patients (4)
Studies included in qualitative synthesis (n = 7) Figure 1. Flow diagram of literature search and study selection.
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Table 1 Characteristics of studies evaluating the association between obesity and mortality in sepsis patients Study type
BMI categories studied
Sample size and patient profile
Outcome
Result BMI as continuous variable OR (95% CI)
Result BMI as categorical variable OR (95% CI)a
Variables adjusted for
Comments
Arabi et al [14],
Nested
2882
In-hospital mortality
NR
Obese
Age, sex,
2013
multicenter cohort study conducted in 28 centers
Underweight: b18.5, normal: 18.5-24.9, overweight: 25.0-29.9, obese:
Unadjusted:
mechanical ventilation, APACHE II score, chronic comorbidities nosocomial infection, bacteremia, infections, creatinine clearance, country, inappropriate/ combination/delayed antimicrobial therapy, vasopressor doses, the use of a pulmonary artery catheter, activated protein C and low-dose steroids
All patients were admitted to the ICU. Largest study evaluating obesity and outcomes in septic shock patients
Canada, USA, Saudi Arabia
patients with septic shock
30.0-39.9, very obese: N40
0.80 (0.66-0.97)
Adjusted: 0.80 (0.62-1.02)
Very obese
Gaulton et al [16],
Retrospective cohort study, single center
Obese: BMI ≥30 nonobese: ≥18.5-30.
1779 patients with presumed sepsis
28-day mortality
NR
2014 USA Huttunen et al [15], 2007
Prospective cohort study, single center
USA
149 patients with bacteremia
30-day mortality
NR
nonobese: BMI b30
Finland
Kuperman et al [12], 2013
Obese: BMI N30
Retrospective cohort study, single center
Underweight: b18.5, normal: 18.5-24.9,
overweight: 25.0-29.9,
792 patients with sepsis
In-hospital mortality
Unadjusted:
0.97 (0.94-1.0)
Unadjusted: 0.61 (0.44-0.85) Adjusted: 0.69 (0.45-1.04) Obese Unadjusted: 1.21 (0.95-1.54) Adjusted: 1.11 (0.85-1.41) Obese Unadjusted:
9.8 (2.3-41.3) Adjusted: 6.4 (1.2-34.4) Morbid obesity unadjusted:
0.7 (0.12-4.2)
Sex, admitting hospital, ICU location, vasopressor Age, sex, smoking, alcohol abuse, S aureus, S pneumonia, β-hemolytic streptococcus and E coli bacteremia
Age, race, sex, length of stay, diabetes, neutropenia, cancer, liver disease, cardiovascular disease, COPD, liver disease, immunosuppression, modified APACHE II
66% patients were admitted to the ICU. BMI b18.5 were excluded 32% patients were admitted to the ICU. Only prospective cohort study evaluating obesity and outcomes in patients with bacteremia No data provided on the level of care. Patients with BMI N50 were excluded.
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First author, year, country
Prescott et al [10] 2014
Retrospetive cohort study, multicenter
USA
Canada
Wurzinger et al [11],
Adjusted:
1404 patients with severe sepsis
In-hospital, 90-day, and 1-year mortality
0.90 (0.76-1.06) Adjusted: hospital mortality: 0.96 (0.93-0.99) 90-day mortality: 0.95 (0.93-0.98) 1-year mortality: 0.96 (0.93-0.99)
Adjusted hospital mortality: obese 0.64 (0.40-1.01) severely obese: 0.54 (0.31-0.95) 90-day mortality obese: 0.53 (0.35-0.79) severely obese: 0.43 (0.25-0.74) 1-year mortality obese: 0.59 (0.39-0.88) severely obese: 0.46 (0.26-0.80) NR
Age, sex
Admission year, age, sex, heart disease, chronic renal insufficiency, premorbidities, origin of sepsis, SAPS II
Retrospective cohort study (from VASST trial)
Normal: BMI b25 Overweight: BMI 25-30 Obese: BMI N30
730 patients with septic shock
28-day mortality
Adjusted: 0.98 (0.97-0.99)
Retrospective cohort study
Underweight: b18.5; normal: 18.5-24.9; overweight: 25-29.9; obese and morbidly obese: ≥30
301
ICU mortality
Unadjusted:
Obese
2010
patients with
0.91 (0.86- 0.98)
Adjusted:
Austria
septic shock
Adjusted: 0.93 (0.86-1.01)
0.28 (0.08-0.93)
OR indicates odds ratio; CI, confidence interval; NR, not reported; APACHE, Acute Physiology and Chronic Health Evaluation; S aureus, Staphylococcus aureus; S pneumoniae, Streptococcus pneumoniae; E coli, Escherichia coli; COPD, chronic obstructive pulmonary disease; VASST, Vasopressin and Septic Shock trial; SAPS, Simplified Acute Physiology Score. a As compared with normal BMI.
49% patients were admitted to the ICU. Multicenter study of Medicare beneficiaries. Patients with BMI b18.5 were excluded.
marital status, race, wealth, acute organ dysfunction, ICU use, mechanical ventilation use, diabetes, baseline cognitive status, functional limitations APACHE II, sex, lung infection, diabetes, fungal infection
All patients were admitted to the ICU. Excluding underweight patients yielded similar results All patients were admitted to the ICU.
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Wacharasint et al [13], 2013
obese: 30.0-39.9, morbidly obese: 40.0-49.9 Normal: 18.5-24.9, overweight: 25-29.9, obese: 30-34.9, severely obese: ≥35
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as compared with patients with a BMI less than 25. In a large multicenter nested cohort study, Arabi et al [14] investigated the association between obesity and in-hospital mortality in 2882 septic shock patients. Results revealed that, although obese and very obese patients had a lower mortality in comparison with patients with normal BMI, the association became insignificant after adjusting for baseline characteristics and sepsis interventions. In another large cohort study by Gaulton et al [16], multivariable-adjusted analysis showed that 28-day mortality was not significantly higher among obese sepsis patients as compared with sepsis patients with BMI less than 30. However, severely obese patients had higher mortality than normal BMI group patients. Huttunen et al [15] prospectively studied the association between BMI and 30day mortality rate in 149 patients with bacteremia. Patients enrolled included those with positive blood cultures, and the severity of illness ranged from milder symptoms and signs to those who developed septic shock and required an ICU stay. In multivariate analysis, obese patients were associated with both increased 30-day mortality and an increased ICU mortality. 4. Discussion Clinical studies evaluating the impact of obesity on mortality in critically ill sepsis patients have yielded conflicting results. Obesity is thought to be a state of chronic inflammation, as it is associated with increased oxidative stress. Cytokines secreted from adipocytes such as interleukins (IL-1, IL-3, IL-6, and IL-8), tumor necrosis factor α, and transforming growth factor β have been found to correlate with increasing BMI and waist-to-hip ratio [17,18]. Hence, it is speculated that, when obese individuals develop sepsis, the systemic inflammatory response may be different as compared with those with a normal BMI. 4.1. Experimental models and animal studies Several studies have utilized nonhuman models to examine sepsis in obese states. Vachharajani et al using cecal ligation and punctureinduced sepsis model showed that cerebral microvasculature in obese septic mice is more prone to pronounced inflammatory responses and endothelial dysfunction as compared with their lean counterparts [19]. In another study, Singer et al [20] studied ob/ob (leptin deficient) and db/db (leptin resistant) mice and found that both mutant models produced augmented inflammatory and thrombogenic responses during sepsis. These findings suggest that inflammatory responses are heightened in obese mice during sepsis when compared with their lean counterparts. 4.2. Role of adipokines Leptin and adiponectin are cytokines synthesized in adipose cells and stored in adipose tissue. Adiponectin is an antiinflammatory and insulin-sensitizing cytokine that is deficient in obese individuals [21]. Adiponectin levels have been proven to be depressed in critically ill including septic as well as morbidly obese patients and are associated with insulin-resistant and inflammatory response in these populations [22]. Adiponectin deficiency has been shown to intensify sepsisrelated microvascular dysfunction and endothelial activation in murine models [23,24]. However, other clinical studies have not established the same association. Koch et al [25] found that low adiponectin levels in critically ill patients had a significantly better outcome. Walkey et al [26] demonstrated that high serum adiponectin levels correlated with increased 28-day mortality in patients requiring mechanical ventilation. Leptin levels are elevated in obese patients [27], and it has been studied for its role as a regulator of cell-mediated immunity, endothelial activation, and cytokine production in the setting of acute systemic inflammation [28]. Although the exact pathophysiologic role of leptin in sepsis is not well understood, leptin levels have been shown to be
elevated 3-fold in critically ill patients with sepsis in correlation with levels of tumor necrosis factor α and IL-6 [29,30]. 4.3. Obesity and Infection Obesity has been associated with increased risk of nosocomial infection [31], surgical site infections [32,33], Clostridium difficile infection [34], urinary tract infection [35], and increased future sepsis events [36]. Obesity has significant effects on respiratory function. Obese patients have been shown to have lower tidal volumes, increased respiratory rate, impaired gas exchange, increase in airway resistance, and decrease in respiratory system compliance [37]. However, associations of obesity with respiratory infections have been conflicting. Studies post-H1N1 pandemic showed increased risk of influenza-related adverse outcomes such as pneumonia, hospitalization, critical illness, ICU admission, and death in obese and morbidly obese patients [38,39]. Interestingly, obesity has been found have a protective effect on mortality associated with community-acquired pneumonia [40,41]. The reasons for such paradoxical results are unknown and require further studies. 4.4. Challenges in management of critically ill septic obese patients 4.4.1. Antibiotic dosing Early administration of broad spectrum antibiotics within 1 hour of recognition of severe sepsis and septic shock is a component of early goal-directed therapy and a class I recommendation of the “Surviving Sepsis Campaign [42].” Obesity has been implicated as a risk factor for antibiotic treatment failure [43]. A multitude of physiologic changes affecting the distribution, metabolism, and clearance of antibiotics can occur in obese patients and may be responsible for lower serum concentrations [44]. Antibiotics can be classified as hydrophilic (β lactams and aminoglycosides) or lipophilic (fluoroquinolones, macrolides, and tigecycline) based on their affinity for adipose tissue [45]. Lipophilic agents are affected more by the presence of obesity, as they achieve a higher volume of distribution due to binding to adipose tissue [46]. Kidney volume has shown to correlate with lean body mass, and obesity has been shown to increase glomerular filtration rate, which can potentially alter clearance of antibiotics [47]. Alterations in volume of distribution and clearance can also impact pharmacodynamics parameters [48]. Vancomycin, aminoglycosides, and β lactams are most extensively studied in obese population. For example, data suggest that initial dosing of vancomycin should be based on total body weight, and adjustments should be made by following drug levels [49]. Hall et al [50] have shown that obese patients are more likely to receive lower-than-recommended doses of vancomycin, potentially causing subtherapeutic levels and worse outcomes. In morbidly obese patients undergoing elective surgical procedures, higher doses of prophylactic cefepime and cefazolin were required to maintain an adequate time above minimum inhibitory concentration levels [51]. Another study involving the use of tobramycin or gentamicin in morbidly obese patients showed that only 71% of patients attained therapeutic drug concentrations [52]. Failure to recognize obesity-related pharmacokinetic and pharmacodynamic alterations could result in underdosing and treatment failures. Further studies are needed to guide clinicians in making antibiotic dosage adjustments based on body indices. 4.4.2. Fluid resuscitation In an observational study investigating fluid resuscitation in patients with burn injuries, it was found that obese patients had received substantially lower volume of fluids based on actual body weight in comparison with their normal weight counterparts. Expectedly, volume of fluid received by the morbidly obese group was significantly higher as compared with all other groups, when based on ideal body weight. [53] Similarly, in a study involving trauma patients, the volume of crystalloid and colloid resuscitation in obese patients was lower than in the nonobese. Subsequently, the obese group had a higher mortality despite
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similar severity due to persistent hypovolemia [54]. Arabi et al [14] specifically investigated sepsis interventions and outcomes in obese patients and found that the obese and morbidly obese group received notably lower volumes of crystalloid and colloid fluids in the initial resuscitation phase. Future research needs to be directed toward better defining adequate fluid resuscitation and establishing methods to assess volume requirements in the obese, taking into account disparity in BMI and lean weight in these patients. 4.4.3. Mechanical ventilation Obesity impairs gas exchange, increases alveolar-to-arterial gradient, increases upper and lower airway resistance, decreases compliance of the chest wall and lung tissue, and increases the risk for atelectasis. Functional residual capacity and expiratory reserve volume are reduced in obese subjects as compared to their normal weight counterparts. Vital capacity and total lung capacity can also be decreased in morbidly obese patients [55,56]. Respiratory failure secondary to organ dysfunction is seen in severe sepsis and septic shock and often manifests as acute respiratory distress syndrome (ARDS). Gong et al [57] showed that patients with increasing BMI were at an increased risk for developing ARDS and had a longer length of stay but not higher mortality. Other studies have demonstrated similar results, wherein obesity did not have statistically significant association with mortality in patients with ARDS [58,59]. However, patients who are obese and develop ARDS offer a unique challenge to the clinician with regards to ventilation management. Strategies to optimize pulmonary mechanics in such patients include positioning in reverse Trendelenburg at a 45° angle, positioning in the prone in patients with severe hypoxemia, inhaled nitric oxide, low tidal volume ventilation based on ideal body weight, optimal positive end-expiratory pressure titration, and alveolar recruitment maneuvers such as the intermittent application of high airway pressures for a few seconds [60]. 4.4.4. Nursing care and other challenges There are several challenges to the management of obese patients in the critical care setting. The obese patient may require increased time and resources with regards to hygiene, repositioning, and transferring in and out of bed [61]. The risk of developing decubitus ulcer increases with increasing BMI [62]. In addition, portable radiologic films provide poorer quality images due to increased scatter, and bedside ultrasonography is limited due to difficulty in obtaining appropriate positioning as well as poor penetration [63]. 5. Limitations There are several important limitations to our analysis. First, clinical evidence examining the association of BMI with outcomes in sepsis is scarce and has not been adequately analyzed in studies involving critically ill patients. Moreover, very obese patients with a BMI greater than or equal to 35 are underrepresented in most studies. The sample sizes are often limited due to missing height and weight data, and inaccuracies can develop if weight is checked after fluid resuscitation. All studies used BMI cut-offs to define obesity. Studies using anthropometric indices other than BMI to define obesity could help us better understand the relationship of obesity with sepsis. Finally, most of the studies identified were retrospective cohort studies. To limit confounding effect, wherever available, we have reported the adjusted risk estimates. However, there may be residual confounding from other unmeasured factors. 6. Conclusions Our review of the current clinical evidence of association of obesity with sepsis mortality revealed mixed results. Three studies reported no significant association between obesity and mortality, 1 study observed increased mortality among obese patients with bacteremia,
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whereas 3 studies found decreased mortality among obese patients. Clinicians are faced with a number of challenges while managing obese patients with sepsis and should be mindful of the impact of obesity on antibiotics administration, fluid resuscitation, and ventilator management. The currently available experimental and clinical evidence is not conclusive and indicates that there are differences in biology, treatment interventions, and epidemiology in obese and nonobese patients with sepsis. Future research should be directed toward studying larger cohorts and toward developing an individualized approach to guide the clinician in treatment interventions that influence outcomes of patients with sepsis. References [1] Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29(7):1303–10. [2] Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. Natl Vital Stat Rep 2013; 61(4):1–117. [3] Lagu T, Rothberg MB, Shieh MS, Pekow PS, Steingrub JS, Lindenauer PK. Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007. Crit Care Med 2012;40(3):754–61. [4] Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014;311(8):806–14. [5] Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013;309(1):71–82. [6] Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005;366(9497):1640–9. [7] Savva SC, Lamnisos D, Kafatos AG. Predicting cardiometabolic risk: waist-to-height ratio or BMI. A meta-analysis. Diabetes Metab Syndr Obes 2013;6:403–19. [8] Oliveros H, Villamor E. Obesity and mortality in critically ill adults: a systematic review and meta-analysis. Obesity 2008;16(3):515–21. [9] Akinnusi ME, Pineda LA, El Solh AA. Effect of obesity on intensive care morbidity and mortality: a meta-analysis. Crit Care Med 2008;36(1):151–8. [10] Prescott HC, Chang VW, O'Brien Jr JM, Langa KM, Iwashyna T. Obesity and 1-year outcomes in older Americans with severe sepsis. Crit Care Med 2014;42(8): 1766–74. [11] Wurzinger B, Dunser MW, Wohlmuth C, Deutinger MC, Ulmer H, Torgersen C, et al. The association between body-mass index and patient outcome in septic shock: a retrospective cohort study. Wien Klin Wochenschr 2010;122(1–2):31–6. [12] Kuperman EF, Showalter JW, Lehman EB, Leib AE, Kraschnewski JL. The impact of obesity on sepsis mortality: a retrospective review. BMC Infect Dis 2013;13(1):377. [13] Wacharasint P, Boyd JH, Russell JA, Walley KR. One size does not fit all in severe infection: obesity alters outcome, susceptibility, treatment, and inflammatory response. Crit Care 2013;17(3):R122. [14] Arabi YM, Dara SI, Tamim HM, Rishu AH, Bouchama A, Khedr MK, et al. Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study. Crit Care 2013;17(2):R72. [15] Huttunen R, Laine J, Lumio J, Vuento R, Syrjanen J. Obesity and smoking are factors associated with poor prognosis in patients with bacteraemia. BMC Infect Dis 2007;7:13. [16] Gaulton TG, Weiner MG, Morales KH, Gaieski DF, Mehta J, Lautenbach E. The effect of obesity on clinical outcomes in presumed sepsis: a retrospective cohort study. Intern Emerg Med 2014;9(2):213–21. [17] Cottam DR, Mattar SG, Barinas-Mitchell E, Eid G, Kuller L, Kelley DE, et al. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg 2004;14(5):589–600. [18] Vachharajani V, Vital S. Obesity and sepsis. J Intensive Care Med 2006;21(5):287–95. [19] Vachharajani V, Russell JM, Scott KL, Conrad S, Stokes KY, Tallam L, et al. Obesity exacerbates sepsis-induced inflammation and microvascular dysfunction in mouse brain. Microcirculation 2005;12(2):183–94. [20] Singer G, Stokes KY, Terao S, Granger DN. Sepsis-induced intestinal microvascular and inflammatory responses in obese mice. Shock 2009;31(3):275–9. [21] Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257(1):79–83. [22] Venkatesh B, Hickman I, Nisbet J, Cohen J, Prins J. Changes in serum adiponectin concentrations in critical illness: a preliminary investigation. Crit Care 2009;13(4):R105. [23] Vachharajani V, Cunningham C, Yoza B, Carson Jr J, Vachharajani TJ, McCall C. Adiponectin-deficiency exaggerates sepsis-induced microvascular dysfunction in the mouse brain. Obesity 2012;20(3):498–504. [24] Teoh H, Quan A, Bang KW, Wang G, Lovren F, Vu V, et al. Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality. Am J Physiol Endocrinol Metab 2008;295(3):E658–64. [25] Koch A, Sanson E, Voigt S, Helm A, Trautwein C, Tacke F. Serum adiponectin upon admission to the intensive care unit may predict mortality in critically ill patients. J Crit Care 2011;26(2):166–74. [26] Walkey AJ, Rice TW, Konter J, Ouchi N, Shibata R, Walsh K, et al. Plasma adiponectin and mortality in critically ill subjects with acute respiratory failure. Crit Care Med 2010;38(12):2329–34. [27] Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000;62:413–37.
524
V. Trivedi et al. / Journal of Critical Care 30 (2015) 518–524
[28] Behnes M, Brueckmann M, Lang S, Putensen C, Saur J, Borggrefe M, et al. Alterations of leptin in the course of inflammation and severe sepsis. BMC Infect Dis 2012;12: 217. [29] Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB, Gold P, et al. Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion. J Clin Endocrinol Metab 1998;83(1):280–3. [30] Yousef AA, Amr YM, Suliman GA. The diagnostic value of serum leptin monitoring and its correlation with tumor necrosis factor-alpha in critically ill patients: a prospective observational study. Crit Care 2010;14(2):R33. [31] Dossett LA, Dageforde LA, Swenson BR, Metzger R, Bonatti H, Sawyer RG, et al. Obesity and site-specific nosocomial infection risk in the intensive care unit. Surg Infect 2009;10(2):137–42. [32] Hourigan JS. Impact of obesity on surgical site infection in colon and rectal surgery. Clin Colon Rectal Surg 2011;24(4):283–90. [33] Yuan K, Chen HL. Obesity and surgical site infections risk in orthopedics: a metaanalysis. Int J Surg 2013;11(5):383–8. [34] Bishara J, Farah R, Mograbi J, Khalaila W, Abu-Elheja O, Mahamid M, et al. Obesity as a risk factor for Clostridium difficile infection. Clin Infect Dis 2013;57(4):489–93. [35] Semins MJ, Shore AD, Makary MA, Weiner J, Matlaga BR. The impact of obesity on urinary tract infection risk. Urology 2012;79(2):266–9. [36] Wang HE, Griffin R, Judd S, Shapiro NI, Safford MM. Obesity and risk of sepsis: a population-based cohort study. Obesity 2013;21(12):E762–9. [37] Littleton SW. Impact of obesity on respiratory function. Respirology 2012;17(1):43–9. [38] Fezeu L, Julia C, Henegar A, Bitu J, Hu FB, Grobbee DE, et al. Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis. Obes Rev 2011;12(8):653–9. [39] Morgan OW, Bramley A, Fowlkes A, Freedman DS, Taylor TH, Gargiullo P, et al. Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A (H1N1) disease. PLoS One 2010;5(3):e9694. [40] Inoue Y, Koizumi A, Wada Y, Iso H, Watanabe Y, Date C, et al. Risk and protective factors related to mortality from pneumonia among middle-aged and elderly community residents: the JACC study. J Epidemiol 2007;17(6):194–202. [41] Corrales-Medina VF, Valayam J, Serpa JA, Rueda AM, Musher DM. The obesity paradox in community-acquired bacterial pneumonia. Int J Infect Dis 2011;15(1):e54–7. [42] Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41(2):580–637. [43] Longo C, Bartlett G, Macgibbon B, Mayo N, Rosenberg E, Nadeau L, et al. The effect of obesity on antibiotic treatment failure: a historical cohort study. Pharmacoepidemiol Drug Saf 2013;22(9):970–6. [44] Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy 2007;27(8):1081–91. [45] Falagas ME, Karageorgopoulos DE. Adjustment of dosing of antimicrobial agents for body weight in adults. Lancet 2010;375(9710):248–51.
[46] Blouin RA, Warren GW. Pharmacokinetic considerations in obesity. J Pharm Sci 1999;88(1):1–7. [47] Nawaratne S, Brien JE, Seeman E, Fabiny R, Zalcberg J, Cosolo W, et al. Relationships among liver and kidney volumes, lean body mass and drug clearance. Br J Clin Pharmacol 1998;46(5):447–52. [48] Janson B, Thursky K. Dosing of antibiotics in obesity. Curr Opin Infect Dis 2012; 25(6):634–49. [49] Blouin RA, Bauer LA, Miller DD, Record KE, Griffen Jr WO. Vancomycin pharmacokinetics in normal and morbidly obese subjects. Antimicrob Agents Chemother 1982; 21(4):575–80. [50] Hall II RG, Payne KD, Bain AM, Rahman AP, Nguyen ST, Eaton SA, et al. Multicenter evaluation of vancomycin dosing: emphasis on obesity. Am J Med 2008;121(6):515–8. [51] Rich BS, Keel R, Ho VP, Turbendian H, Afaneh CI, Dakin GF, et al. Cefepime dosing in the morbidly obese patient population. Obes Surg 2012;22(3):465–71. [52] Ross AL, Tharp JL, Hobbs GR, McKnight R, Cumpston A. Evaluation of extended interval dosing aminoglycosides in the morbidly obese population. Adv Pharm Sci 2013; 2013:194389. [53] Rae L, Pham TN, Carrougher G, Honari S, Gibran NS, Arnoldo BD, et al. Differences in resuscitation in morbidly obese burn patients may contribute to high mortality. J Burn Care Res 2013;34(5):507–14. [54] Nelson J, Billeter AT, Seifert B, Neuhaus V, Trentz O, Hofer CK, et al. Obese trauma patients are at increased risk of early hypovolemic shock: a retrospective cohort analysis of 1,084 severely injured patients. Crit Care 2012;16(3):R77. [55] McCallister JW, Adkins EJ, O'Brien Jr JM. Obesity and acute lung injury. Clin Chest Med 2009;30(3):495–508 [viii]. [56] Bahammam AS, Al-Jawder SE. Managing acute respiratory decompensation in the morbidly obese. Respirology 2012;17(5):759–71. [57] Gong MN, Bajwa EK, Thompson BT, Christiani DC. Body mass index is associated with the development of acute respiratory distress syndrome. Thorax 2010;65(1):44–50. [58] O'Brien Jr JM, Welsh CH, Fish RH, Ancukiewicz M, Kramer AM, National Heart L, et al. Excess body weight is not independently associated with outcome in mechanically ventilated patients with acute lung injury. Ann Intern Med 2004;140(5):338–45. [59] Morris AE, Stapleton RD, Rubenfeld GD, Hudson LD, Caldwell E, Steinberg KP. The association between body mass index and clinical outcomes in acute lung injury. Chest 2007;131(2):342–8. [60] Hibbert K, Rice M, Malhotra A. Obesity and ARDS. Chest 2012;142(3):785–90. [61] Muir M, Heese GA, McLean D, Bodnar S, Rock BL. Handling of the bariatric patient in critical care: a case study of lessons learned. Crit Care Nurs Clin North Am 2007; 19(2):223–40. [62] Newell MA, Bard MR, Goettler CE, Toschlog EA, Schenarts PJ, Sagraves SG, et al. Body mass index and outcomes in critically injured blunt trauma patients: weighing the impact. J Am Coll Surg 2007;204(5):1056–61 [discussion 62–4]. [63] Olson M, Pohl C. Bedside and radiologic procedures in the critically ill obese patient. Crit Care Clin 2010;26(4):665–8.