Obal, D., Wadhwa, A. the Obesity Paradox

The obesity paradox: does it exist in the perioperative period? Detlef Obal, MD, PhD, DESAa,b,c, Anupama Wadhwa, MBBS, MSc, FASAc,d

At least 30% of the surgical population consists of patients who hypertension, and hyperlipidemia, and an increased risk of fulfill the definition of obesity, mirroring the obesity epidemic in thrombosis and inflammation, leading to higher mortality rates.7 – the general population in the United States.1 3 Nearly 74% of the However, neither BMI nor waist circumference reflects the participants in the American College of Surgeons National metabolic and inflammatory profiles of the patient. Therefore, a Surgical Quality Improvement Program (NSQIP) had an abnor- new definition of obesity was introduced emphasizing the term mally high body mass index (BMI), including 17% of patients adiposopathy and acknowledging individual body fat composi- younger than 18 years of age.4,5 This development is of particular tion and functionality.8 According to the definition of adiposo- concern as obesity is associated with an increased risk of meta- pathy, 4 different types of phenotypes are distinguished as bolic syndrome, hypertension, coronary artery disease (CAD), follows: and diabetes mellitus. However, physicians, nutritionists, and the (1) Normal weight obese (NWO). general public struggle with definitions of obesity based only on (2) Metabolically obese with normal weight (MONW). total body weight proportionate to height and, therefore, BMI. (3) Metabolically healthy obese (MHO). This leads to the question of whether BMI can adequately (4) Metabolically unhealthy obese (MUO) or “at risk” obese describe the physical condition of and potential risks in our patients suffering from complications directly related to patients. obesity. BMI: an outdated measurement? MHO patientCopy According to the World Health Organization (WHO), obesity is a MHO patients were first described in the 1980s as a subgroup of “ condition in which percentage body fat is increased to an extent obese patients without the presence of hypertension, hyperlipi- ” in which health and well-being are impaired. On the basis of demia, or T2DM characterized by insulin resistance.9,10 The BMI [ie, body weight in kilograms divided by the square of the incidence of MHO is estimated to be between 6% and 40%.11,12 2 height in meters (kg/m )], patients are considered to be obese if A preserved insulin sensitivity is the hallmark of these patients.12 the total body weight reaches 20% above the ideal body weight. Insulin resistance can be calculated by a homeostatic model fi However, the usefulness of BMI, or the Quetelet index, rst assessment of insulin resistance (HOMA-IR), the product of described by Belgian statistician Adolphe Quetelet, has been fasting glucose (mg/dL) and fasting insulin levels (uIU/mL). fi questioned in recent years as this almost 200-year-old classi ca- HOMA-IR <3.16 is categorized as MHO and ≥ 3.16 as MUO.13 tion is based solely on an arithmetic approximation. BMI ignores On the basis of healthy white adipose tissue expansion, MHO the complex interaction of genetic lifestyle, dietary habits, energy individuals are relatively immune to the pathologic consequences exposure nutritional and metabolic factors, and adipocyte associated with obesity and associated lipotoxic side effects.14,15 metabolism resulting in different body compositions (eg, body They have lower C-reactive protein and high adiponectin fl – frame and muscularity, uid retention, sarcopenia in aging or levels.16 18 Ortega et al19 extracted data from the Aerobics disease, spinal deformities) and relativeAuthor's quantities of body fat and Center Longitudinal Study including 43,265, mainly male, muscle. Percentage and type of distribution of adipose tissue and Caucasian adults with a BMI ≥ 18.5 kg/m2. MHO individuals the duration of obesity may play a major role in determining demonstrated a higher level of fitness as indicated by their max- metabolic abnormalities, leading to a higher cardiovascular risk imal exercise capacity on a treadmill. After adjustment for BMI, and higher mortality in some subsets of patients.6,7 Waist cir- body fat percentage, and fitness level, MHO individuals had a cumference has been used to predict the extent of visceral fat, 38% lower risk of all-cause mortality than their MUO counter- which is associated with increased insulin resistance [conse- parts. Interestingly, there was no difference between MHO and quently, type 2 diabetes mellitus (T2DM)], hepatic steatosis, metabolically healthy normal-weight participants in terms of the all-cause mortality. Furthermore, fat distribution in the trunk, a Department of Anesthesiology, Pain, and Perioperative Medicine, Stanford chest, abdomen, and subcutaneous regions in the upper body University, Stanford, California, bStanford Cardiovascular Institute, Stanford, California, cOutcomes Research Consortium, Cleveland, Ohio and dDepartment of (android phenotype) had stronger associations with diabetes, Anesthesiology, University of California San Diego, San Diego, California CAD, gout, and uric acid renal stones, whereas reduced peri-

ADDRESS CORRESPONDENCE TO: Anupama Wadhwa, MBBS, MSc, FASA, Department of hepatic and visceral fat accumulation occurred more frequently in 20 Anesthesiology, University of California, San Diego, 200 West Arbor Drive, 430 MPF MHO patients. Other characteristics of MHO patients are the bldg., San Diego, CA 92122. E-mail: [email protected] absence of hypertension, a reduced intima to media thickness Volume 58, Number 3, 14-20, DOI: 10.1097/AIA.0000000000000278 ratio of the carotid artery, and a favorable lipid, inﬂammation, 19,21 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. hormonal, and liver enzyme proﬁle. After adjusting for

Copyright r 2020 Wolters Kluwer Health, Inc. All rights reserved. This paper can be cited using the date of access and the unique DOI number which can be found in the footnotes. Obal and Wadhwa. International Anesthesiology Clinics (2020) 58:3 www.anesthesiaclinics.com

fitness and several confounding variables, Guo and Garvey22 seem to have a survival advantage if they belong to the “slightly” found that MHO participants had a lower risk (30% to 50%, obese cohort. For example, Lee and colleagues found that com- estimated by hazard ratios) of all-cause mortality, nonfatal and pared with normal-weight nursing home residents, overweight fatal cardiovascular disease, and cancer mortality than their Chinese nursing home residents (BMI > 25 kg/m2, using the Asia MUO peers. However, this finding has been challenged by the Pacific cut-off) had the lowest mortality, whereas underweight European Prospective Investigation into Cancer and Nutrition residents had a significantly higher mortality (hazard ratio = study (EPIC-CVD), which revealed that overweight and obese 1.53, 95% confidence interval = 1.33-1.76).36,37 Similar findings individuals had higher CAD risk than lean people irrespective of are observed in elderly patients, either admitted for exacerbation metabolic health.23 Ten percent of the adult US population has a of COPD or suffering from dementia, patients with pulmonary normal BMI, but increased body fat content, and the incidence of artery hypertension, patients with exacerbation of CAD or MHO is estimated to be between 6% and 19% in children and CHF, or patients requiring intensive care in the perioperative adolescents.13,24,25 setting.36,38,39 In contrast, patients with noncatabolic medical conditions do not benefit from obesity or an additional energy support. For Obesity paradox example, Galesanu et al40 studied the impact of obesity on sur- Nonbariatric surgery presents with specific challenges in the vival in patients attending a rehabilitation program for COPD. patient with morbid obesity, both technically and in terms of After controlling for their lung function, a previously observed fi short-term and long-term outcomes. There is an increase in bene t from obesity disappeared. Similar results were found by fi obesity-related disorders that require non-bariatric surgery.26,27 Zafrir and colleagues when investigating the signi cance of BMI fi If an increased BMI is associated with an increased cardiac risk, in patients with CHF on their rst visit to the heart failure clinic, fi then it would be expected to carry a higher rate of perioperative that is, at an early stage of the disease. The authors did not nd an advantage in survival in obese patients after they adjusted for complications. Data from NSQIP suggest that patients with 41 higher BMI stay longer in the hospital, suffer more frequently age. Even in patients suffering from myocardial infarction or stroke, obesity did not improve patients’ outcomes or from postoperative surgical site infections, and undergo more 42–46 frequent reoperations.4 Despite this, a “paradoxical” survival prognosis. Thus, the obesity paradox remains a con- benefit has been observed in the surgical obese population, both troversial concept in different types of medical specialties and – for cardiac and noncardiac surgery.28 31 Decreased 30-day medical conditions. fi mortality has been observed in obese compared with underweight Nevertheless, surgical procedures pose a signi cant stress to fi patients, mostly due to a decrease in noncardiac causes, whereas patients and their metabolic pro les during elective and urgent/ emergentCopy surgical procedures. Therefore, it remains attractive to the mortality in severely obese patients is mostly from cardiac causes.4,32 The increased morbidity and mortality in the extremes examine whether obesity contributes to better outcomes and a fi of BMI lead to a U-shaped curve with mortality on the y-axis and survival bene t for surgical patients with morbid obesity. BMI on the x-axis. The obesity paradox, the concept that MHO patients have a Role of adipose tissue as a survival factor after fi similar cardiovascular risk pro le as normal-weight patients and general surgery a survival benefit compared with underweight patients, has been questioned by several investigators. In a recent population-based It is an appealing concept that obesity might provide potential prospective cohort study, including a total of 6299 men and energy reserves during acute catabolic illness that might result in women without evidence of cardiovascular disease at baseline, decreased mortality of surgical patients.47 In a small study, Jörgen MHO individuals were not at an increased risk of acute myo- and colleagues observed that the basal rate of lipolysis was cardial infarction compared with normal-weight individuals, but doubled and there was a 50% increase in the lipolytic effects of were more likely to develop congestive heart failure (CHF).33 catecholamines after surgical trauma. This effect on the regula- This paradoxical survival benefit has been criticized, as <10% of tion of lipolysis was studied in isolated fat cells obtained before published studies actually measuredAuthor's the body composition and 24 hours after elective cholecystectomy in 12 patients who of participants rather than BMI. An analysis solely on the basis of were not obese and otherwise healthy. The actions of various BMI might not appropriately account for patients with decreased agents that selectively stimulate lipolysis at different early or late muscle mass and lean tissue, which has been associated with a steps in the cyclic adenosine monophosphate system beyond the poor prognosis.34 Banack and Kaufman identified 4 major flaws adrenoceptors were also increased by about 50% after surgery in studies postulating an obesity paradox: (1) incorrect reference (P < 0.01). These changes occurred without altering the beta- values were used (ie, a lower overall BMI reference range), (2) adrenergic receptor density, suggesting that patients with addi- stratification bias, a type of selection bias that can often be tional fat reserves might be able to mobilize additional energy in observed in confounding variables that share common causes the absence of obesity-induced side effects, which may in turn with the proposed outcome, (3) data originating from observa- result in beneficial outcomes after surgery.48,49 However, cate- tional and cross-sectional studies instead of randomized, cholamines activate both β-receptors and α2-receptors, meaning prospective controlled trials, and (4) BMI rather than body fat that the net effect of stress is dependent on the balance between composition and lean muscle tissue being used in most studies both receptor systems. Under normal conditions, β-receptor– that suggest the existence of an obesity paradox.35 mediated lipolysis predominates.48 Interestingly, in patients According to current data, the obesity paradox seems to be an undergoing cholecystectomy, the properties of the β-adrenocep- underlying disease-specific phenomenon in which patients with tors were not altered as determined by radio-ligand binding and disease conditions dominated by a “catabolic” metabolic state isoproterenol sensitivity. In untreated control participants, the

anti-lipolytic properties of catecholamines were also not changed that may allow future studies to determine a patient’sabilityto when they were given the same type of postoperative nutrition as cope with surgical stress on the basis of his or her individual sub- surgical patients.48 Therefore, it seems that the recognized cutaneous fat reservoirs.59 increased lipolytic activity of adipocytes might be caused by Our classical view on adipocytes has been extended toward their modification at more distal steps in the cyclic adenosine mono- important role in lipid and glucose metabolism, in which they phosphate system after moderate surgical trauma (eg, cholecys- release bioactive proteins (eg, adipokines and myokines) and tectomy), which may involve the protein kinase/hormone modulate cardiovascular risk factors related to obesity.59,60 At this sensitive lipase complex. point, however, it is unclear to which extent different adipose tissue Another question is whether the location of the adipose tissue components (ie, brown or white adipose tissue, subcutaneous and plays a role. Patel and Abate suggested that the location of adi- visceral fat depots) might contribute to an improved outcome after pose tissue (subcutaneous vs. visceral) may be a major con- surgical procedures. Early studies investigating the effect of over- tributor to free fatty acid (FFA) flux. An increased level of feeding in the perioperative period via total parenteral nutrition circulating FFA blocks the glucose uptake by skeletal muscle, suggest that both lipogenesis and lipolysis occur simultaneously.49 resulting in insulin resistance.50,51 Furthermore, for each mole of However, experimental evidence from the same author suggests adenosine triphosphate producing FFA, oxidation consumes that surgically stressed individuals provided with additional energy more oxygen than needed by carbohydrates, leading to a dis- activate a futile cycle of lipogenesis and lipolysis involving primarily turbed energy balance. By contrast, accumulation of fat in the brown adipose tissue instead of visceral, white adipose tissue. subcutaneous depot is an independent predictor of lower cardi- Current studies and concepts (eg, enhanced recovery after surgery) ovascular and diabetes-related mortality and protects against are attempting to determine whether preoperative high carbohy- 52,53 impaired glucose metabolism. Interestingly, removal of drate-based caloric intake results in improved postoperative visceral fat depots (eg, omentum) results in improvements in oral outcome, supporting the concept that an endogenous energy glucose tolerance, insulin sensitivity, and fasting plasma glucose, “backpack” carried by MHO patients might be beneficial for 54 with insulin levels doubling or tripling. Similar data were recovery during perioperative stress/catabolism. observed by McLaughlin et al,55 who found that increased visceral adipose tissue results in insulin resistance, whereas increased subcutaneous fat tissue seems to protect against insulin resis- Obesity Paradox in Surgical Populations tance. Wang et al56 proposed that the differences between visceral Is insulin sensitivity changed by anesthetic agents? and subcutaneous fat tissue in terms of lipotoxicity and insulin resistance are based on disturbed expansion and storage of lipids Previous animal studies suggest that volatile anesthetics might within the adipocytes. Interestingly, fat tissue expansion can inhibit basalCopy and glucose-stimulated insulin secretion, increasing occur either by an increase in the volume of pre-existing adipo- perioperative insulin resistance.61 These changes are dose cytes (hypertrophy) or by hyperplasia through recruitment of new dependent and rapidly reversible, but it remains questionable preadipocytes. Data in rodents suggest that visceral fat expands whether these changes affect patient outcomes after surgery. predominantly by adipocyte hypertrophy, whereas subcutaneous Yasuda et al62 studied propofol-anesthetized rats in which insulin depots undergo adipocyte hyperplasia. This difference is impor- sensitivity, insulin-stimulated glucose uptake, and hepatic glucose tant as hyperplasia leads to small adipocytes, which are more output were determined by a hyper-insulinemic euglycemic 56 insulin sensitive and provide enhanced lipid-storage capacity. clamp. Compared with the awake rats, the propofol-anesthetized Preliminary data suggest that fat distribution might be deter- rats showed decreased insulin-stimulated glucose uptake in ske- mined by the expression of estrogens, which direct fat increase letal muscle and the heart, but not in the liver or adipose tissue, toward subcutaneous hyperplasia by increasing adipocyte pro- suggesting that fat tissue might not be affected by propofol during 57 genitor cells. The vascular supply of subcutaneous adipose general anesthesia. Interestingly, insulin action at the liver was tissue consists of a higher capillary density and angiogenesis almost completely suppressed in lean and 6-week fat-fed male compared with visceral fat depots, which prevents tissue hypoxia mongrel dogs under propofol anesthesia.63 In summary, animal during expansion and, subsequently, alters hypoxia-inducible data suggest that central and peripheral insulin sensitivity Author'sfl factor activation of adipokine expression, proin ammatory decrease under general anesthesia, which might explain a larger 58 macrophage recruitment, and insulin resistance. Estrogens not energy reserve in MHO patients compared with lean patients. only influence the distribution and mass of adipose tissue but also influence the metabolic activity by selective neural modulation, Are surgical outcomes affected in patients with metabolically leading to “browning,” that is, higher light reflection caused by healthy obesity? an increased number of mitochondria.57 Brown adipose tissue is metabolically more active due to increased number of mito- Criteria for bariatric surgery are based on weight, BMI, and the chondria. These observations are important as women accumu- presence of components of metabolic syndrome. There are no late energy reserves in the subcutaneous areas to prepare for specific criteria to perform bariatric surgery in metabolically adipose tissue mobilization required for lactation. Thus, one healthy patients with morbid obesity. There are emerging data on could speculate that these mechanisms provide additional energy the prognosis and outcomes of patients after bariatric and non- for patients undergoing surgical procedures and increased periopera- bariatric surgery and how they vary in patients with different tive stress. Therefore, it will be beneficial in the future to determine metabolic profiles. MHO patients have a smaller neck cir- patients’ adipose tissue distribution. Fortunately, multiple noninvasive cumference, lower fasting blood glucose, lower insulin and tri- methods have been established (ie, ultrasound, magnetic resonance glyceride levels, and higher HDL levels.64 In a retrospective imaging, positron emission tomography-computed tomography, analysis, 150 of 710 MHO patients had neither hypertension nor and positron emission tomography-magnetic resonance imaging) diabetes. However, almost 89% of these patients had developed

hepatic steatosis, 20% had liver fibrosis, and 7% had nonalco- weight patients, suggesting that an obesity paradox does not exist holic steatohepatitis. This challenges the notion of MHO as a in patients suffering from CAD with poor cardiovascular metabolically healthy state. Bariatric surgery is now considered health.83 In contrast, Hartrumpf et al84 studied 15,000 patients one of the best options to achieve significant weight loss and undergoing cardiac surgery and found the lowest mortality rates significant metabolic alterations leading to cure of T2DM and in the overweight group and the highest in-hospital mortality in other comorbidities.65,66 Bariatric surgery is recommended for the underweight group. In addition, Takagi et al’s85 data suggest adults with a BMI of 40 kg/m2 or more and in those with a BMI of that being overweight (but not obese) is associated with a 10% 35 kg/m2 with comorbidities.67 It is considered to be the most reduction in mid-to-long term mortality after CABG surgery. effective treatment for sleep-disordered breathing, and morbid Recent developments in cardiovascular surgery shifted away obesity and its associated metabolic abnormalities. Bariatric from on-pump to off-pump cardiac valve replacements. surgery also improves the histologic and biochemical parameters Interestingly, patients classified as overweight or obese by BMI in of nonalcoholic fatty liver disease including insulin resistance, a Japanese study were associated with early, not mid-term, post- altered glucose metabolism, hypertension, plasma FFA, transa- transcatheter aortic valve implantation survival, whereas a recent 68 minases, steatohepatitis, and fibrosis of the liver. Bariatric Norwegian study suggests a negative correlation between BMI surgery effectively reduces neck and waist circumference, and survival.86,87 enhances sleep architecture, and reduces obstructive sleep apnea Recent observations from Lopez-Delgado and colleagues sug- 69 in patients with severe obesity. Nevertheless, recent evidence gest that overweight patients have a better 1-year survival than suggests additional nutritional support as many patients suffer normal-weight patients. In their prospective study, 2499 patients fi 70,71 from micronutrient de ciencies after successful surgery. were divided into 4 groups on the basis of BMI. Although the Pelascini and colleagues retrospectively studied MHO, meta- patients with higher BMI presented with worse oxygenation and a bolically healthy morbidly obese (MHMO), and metabolically higher risk of perioperative myocardial infarction, they could not unhealthy morbidly obese (MUMO) patients undergoing gastric find any difference in in-hospital mortality between BMI groups, bypass surgery. Their goal was to determine whether surgical challenging the notion that obesity protects patients undergoing management could be based on stratification of obese individuals 88 89 72 cardiac surgery. Similar results were presented by Ho et al, according to their metabolic health phenotype. MHMO who did not find any survival benefit after elective cardiac surgery patients were generally females with a history of previous bar- in patients with higher BMIs. In contrast, Johnson et al31 found iatric surgery. The most common metabolic disorder in the that in 78,762 patients undergoing first-time CABG or combined MHMO group was low-grade inflammation. The authors found CABG/aortic valve replacement surgery, overweight and obese a favorable effect on glycemia and an improvement in HOMA-IR patients had a lower incidence of mortality and adverse perio- in MHMO patients compared with the MUMO patients. Weight Copy perative outcomes compared with normal weight, underweight, loss with Roux-en-Y gastric bypass had beneficial effects on the and morbidly obese patients. In an attempt to explain their find- metabolic alterations encompassed by the metabolic syndrome, ings, the authors suggest that malnourished or cachectic patients but the effects were more prominent in the MHMO group even were older, with a higher prevalence of comorbidities, and that the 24 months after surgery. They argue that these 2 phenotypes are – higher BMI patients were treated sooner.19,90 93 just different stages of disease evolution. In addition, bariatric surgery positively changes insulin resistance, lipid profile, inflammation, and adipokines, factors often Orthopedic Surgery 7 associated with nonalcoholic fatty liver disease. Interestingly, Whiting et al94 analyzed the NSQIP database to evaluate the Roux-en-Y gastric bypass results in improvement of insulin predictive value of BMI on perioperative complications after resistance and reduction of hepatic lipid content even before a orthopedic trauma surgery. After analyzing 53,219 orthopedic reduction in weight is recognized. Although several mechanisms trauma patients, the authors found that patients with morbid have been discussed, it appears that guiding food directly to the obesity were more likely to suffer from wound dehiscence, deep location of GLP-1 increases peptide tyrosine-tyrosine secretion wound infection, and major complications compared with nor- and reduces hunger and food intake by abolishing ghrelin 73–76 Author'smal-weight patients. Interestingly, patients with obesity had the secretion in the stomach. In addition, an increase in bile acids lowest number of minor, major, and total complications. This and a change in the microbiota positively impact energy home- – trend was confirmed after a multivariate analysis, which revealed ostasis after bariatric surgery.77 79 a significant increase in complications in patients at both ends of the BMI extremes.94 In contrast, Zhang et al95 analyzed 91,000 Obesity paradox in specific surgery types records of patients who underwent nonurgent hip surgery and found that obese patients were less likely to die and suffer from Cardiac surgery cardiac and respiratory complications compared with patients In the adult heart, the major pathway for adenosine triphosphate with a normal BMI. production is fatty acid oxidation for increasing glucose delivery In a prospective study of elective hip surgery patients, Flodin during stress or injury, such as exercise or ischemia.80,81 Indeed, et al96 analyzed the 1-year survival after hip fracture. Confirming under pathological conditions, the heart shows a severe mal- previous retrospective data and the existence of an obesity function of different metabolic pathways including the tri- paradox, the authors found that patients with a higher BMI carboxylic acid cycle and beta-oxidation.82 Benedetto carried out returned to a normal, independent life more frequently than a retrospective analysis in patients undergoing coronary artery normal-weight patients.97 These results raise an interesting bypass graft (CABG) surgery and found that long-term survival in question: does the obesity paradox actually reflect the physiolo- obese and severely obese patients was worse than that in normal- gical benefit of obesity or are the benefits a result of a more

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