Obesity, Surgery, and Perioperative Inflammation Research: Where is it Going?

Dr. Schumann is Associate Professor of Anesthesiology, Tufts University School of Medicine, Department of Anesthesiology, Tufts Medical Center, Boston, Massachusetts.

Funding: No funding was provided.

Disclosures: The authors report no conflicts of interest relevant to the content of this article.

ABSTRACT
Obesity has been recognized as a pro-inflammatory condition. This article reviews the current scientific information available regarding the course of the perioperative inflammatory response exemplified by three markers of this response: TNF-a, Interleukin-6, and C-reactive protein. In this nascent territory of research, many questions remain. However, opportunities for possible postoperative outcome improvement are becoming more obvious, and targets for modulation of the perioperative inflammatory response need to be identified, as well as the potential role of different anesthetic regimens in this context.

Introduction
Obesity, which is now accepted as at least a low-grade, pro-inflammatory state, is increasingly becoming a focus of investigation in the recent scientific literature for its impact on perioperative outcomes. Measurements of pro-inflammatory cytokines, including tumor-necrosis factor-a (TNF-a), c-reactive protein (CRP), and interleukins (IL), such as IL-6 and IL-8, have been used to characterize this pro-inflammatory state. These cytokines have also been found to be physiologic, acute-phase reactants in response to stressors, such as surgery and the perioperative environment. The degree of this perioperative physiologic stress response may be related to adverse postoperative short- and long-term clinical outcomes. Therefore, there is great interest among individuals in the medical community in how to reduce this stress response, particularly for patients with obesity, and how to measure its effects.

Pro-inflammatory Cytokines and Body Mass Index.

Park et al[1] found significantly higher baseline levels of TNF-a, CRP, and IL-6 in subjects with “simple” obesity (defined as not having any obvious medical comorbidities or metabolic syndrome) compared to normal-weight controls. A significant correlation of all three markers (TNF-a, CRP, and IL-6) existed with body mass index (BMI), waist and hip circumference, and waist to hip ratio. Within the group with obesity, CRP significantly correlated with BMI and IL-6 with visceral adipose tissue.[1]

Several studies have investigated these same markers prior to, and then weeks and months following bariatric surgery and its attendant weight loss, showing their postoperative decline.[2] Less information is available regarding these cytokines’ immediate perioperative behavior, and relating cytokine changes to clinical outcomes.

In a study of normal-weight patients by Maruna et al,[3] TNF-a and IL-6 peaked in the first 24 hours after colon resection in cancer patients and open cholecystectomy in an otherwise healthy group whereas CRP reached its peak in 48 hours. Larger elevations were noted following the more invasive colon surgery.[3] Similar results were reported for two methods of hernia repair with different degrees of surgical invasiveness, although no BMI information was available in that study.[4]

Analogous changes have been reported within the population with morbid obesity (BMI≥40kg/m2). Nguyen et al[5] examined the previously mentioned markers in patients undergoing either laparoscopic or open gastric bypass and found an increased stress response in the open group as determined by TNF-a, IL-6, and CRP.[5] Chung et al[6] examined TNF-a and IL-6 in the patients with morbid obesity following laparoscopic gastric bypass and in normal-weight patients after laparoscopic gastrectomy in the first 24 hours. Interestingly, although cytokine levels increased in both groups, the patients with morbid obesity exhibited significantly lower changes from baseline.[6]

Perioperative Outcomes
Overweight and moderate obesity in a nonbariatric general surgical population comports a lower adjusted mortality risk compared to normal-weight patients.[7] This is a phenomenon also known as the “obesity paradox.” However, a more refined analysis of outcomes in the context of morbid obesity with its associated comorbidities seems to suggest that the metabolic syndrome (a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes) may be an important distinction within this population and may explain some of these paradoxical findings.
Glance et al[8] demonstrated the impact of the modified metabolic syndrome on perioperative outcomes in patients with different BMIs undergoing non-cardiac surgery in a large cohort from the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. In this study, the detrimental effects of this comorbidity are defining.[8] Patients with metabolic syndrome had a 2 to 2.5-fold higher cardiac adverse event risk and a 3 to 7-fold increased risk of acute kidney injury depending on their BMI.

Postprocedural Outcomes
There are limited data on the postprocedural course of cytokines adjusted for the presence of metabolic syndrome.
Van Guilder et al[9] found a significant baseline elevation of IL-6, CRP, and TNF-a between patients with obesity and metabolic syndrome versus those without. Curiously, they found that the patients with obesity without metabolic syndrome did not have significantly higher TNF-a and IL-6 compared to normal-weight subjects. Marso et al[10] reported a heightened inflammatory response following elective percutaneous coronary intervention in patients with metabolic syndrome compared to those without as determined by TNF-a and IL-6.[10]

Questions and Considerations
Obesity and perioperative inflammation research is an exciting nascent territory, and its initial results have opened the door to many more interesting questions and possible targets for interventions to improve outcomes. The data provoke many questions, such as the following:
1.    What do these perioperative changes in pro-inflammatory cytokines really mean?
2.    Are the observed changes in the levels of TNF-a, CRP, and IL-6 desirable as a normal physiologic response to surgical trauma, guaranteeing a normal immune response and wound healing, or are they indicating inflammatory and immune activation that may be detrimental?
3.    Which markers are important for outcomes?
4.    Which markers should be measured and possibly modulated?
5.    How are these acute phase reactants integrated into the cellular inflammatory response and balanced with the physiologic anti-inflammatory humoral and cellular reaction to surgical trauma?
6.    How does the perioperative treatment itself change the course of inflammatory cytokine levels and possibly the outcomes associated with these changes ?

Anesthetic agents and techniques have been found to affect the perioperative cytokine and immune response.[11,12] Preoperative administration of a dose of steroids has been shown to significantly decrease postoperative IL-6 and CRP levels as well as shift the balance toward elevated anti-inflammatory IL-10 levels in hepatic resection patients.[13] This leads us to ask if nonsteroidal anti-inflammatory drugs (NSAIDs), other perioperative medications, or preoperative diet and lifestyle interventions could have the same effect and if there is a connection with clinical outcomes.

To complicate matters, measurement of these interesting cytokines is performed with a variety of non-standard test kits and assays, many of which have very specific specimen collection and storage requirements. For this reason, many studies chose to measure levels at least twice from the same specimen. This makes comparison of specific cytokine levels between studies very difficult or impossible. In addition, the expression of many markers of interest follows a circadian variance that is not always accounted or corrected for in the literature.

With regards to obesity as a pro-inflammatory condition, these questions, and the early findings in anesthetic and perioperative care described previously represent one core area of interest for the anesthesiologist, and anesthesiology as a medical specialty is called upon to contribute.

Conclusion
In summary, the area of obesity, perioperative inflammation, and outcomes research is very intriguing but still in its infancy with many questions and obstacles remaining before results can be meaningfully integrated into daily clinical practice. The opportunity for translational research is abundant. The International Society for the Perioperative Care of Obese Patients (ISPCOP) is one professional organization that could and should capitalize on these opportunities, which are in direct concert with its mission.

References
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Category: Anesthetic Aspects of Bariatric Surgery, Past Articles