Effect of Perioperative Neurostimulation in Patients Undergoing Whipple Operation (Pancreaticoduodenectomy) on Acute Postsurgical Inflammatory Response [ENSWAPI-trial]

Following surgery, inflammation normally is a balanced event, which is resolved in a timely manner. But, disrupted immune regulation can result in continuous proinflammatory cytokine activity and excessive or chronic inflammation. In the case of major surgical interventions, the inflammatory reaction is not limited to the area of surgery, but takes place systemically via various mediators. The cytokines IL-1, TNF-α and IL-6, which are formed by the leukocytes, are responsible for associated clinical symptoms like fever, fatigue and general feeling of illness. By crossing the blood-brain barrier, IL-6 initiates the synthesis of prostaglandin E2 (PGE2), and IL-6 also facilitates energy mobilizations in muscle and fat tissue. The release of acute phase proteins from the hepatocytes of the liver is also effected via cytokines. These include fibrinogen and C-reactive protein (CRP), which are involved in the removal of entered microorganisms with opsonization and complement fixation. However, if too many of these cytokines are present or if they are released for prolonged periods, this can lead to an intensified inflammatory process, which is also called systemic inflammatory response syndrome (SIRS) if certain criteria are met. These criteria include systemic activation of the coagulation cascade, disseminated intravascular coagulation (DIC), Acute Respiratory Distress Syndrome (ARDS) and Multi Organ Failure (MOF). In the worst case, this ends with the patient's death. In order to avoid destruction by one's own immune system, pro-inflammatory mediators are only released for a short time. In addition, the organism forms anti-inflammatory mediators such as Transforming Growth Factor Beta (TGF-ß) and IL-10, which is formed by the TH2 subtype of CD4 positive T lymphocytes. They counteract the inflammatory process by downregulating the immune response and thus limiting the destruction of the tissue.

A well-functioning immune system is essential for surgery. The interaction of inflammation and anti-inflammation ensures the destruction of the destroyed tissue and prevents penetrating microorganisms from developing an infection. An excessive pro-inflammatory reaction can lead to a SIRS, a possibly reactive strong post-operative immunosuppression facilitates the penetration of pathological microorganisms and thus predisposes to infection. Unfortunately, postoperative infectious and non-infectious postoperative complications do occur in spite of preventive treatment with antibiotics immediately before or during surgical treatment and have so far been treated upon their occurrence during the postoperative recovery period.

An analysis on postoperative morbidity associated with inflammation in pancreatic surgery (own database (n=275)) showed the development of postoperative sepsis in 4% (n=11), which had an abdominal focus in 2.9% (n=8) and other localizations in 1.1% (n=3). Postoperative pneumonia has been reported to occur after pancreatic resection in 1-6% of cases and has been associated with both pancreatic fistula and delayed gastric emptying (DGE), and has been reported to be associated with a very high 90-day-mortality [6]. IL-6 is a major mediator of inflammation, and it is important to elucidate that IL-6 is part of a complex, interdepending network of cytokines released in inflammatory conditions [7]. In healthy adults, IL-6 concentrations in the plasma are <10 pg/ml [8]. IL-6 is particularly important in chronic inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, Castlemann's disease, haematopoietic diseases and after physical stress such as surgery or chemotherapy. Increased levels of serum and/or tumor IL-6 are also seen in a number of malignant conditions, both haematopoietic malignancies and solid tumors including breast, cervical, esophageal, head-and-neck, ovarian, prostate, colorectal, pancreatic, hepatocellular, gall bladder, non-small-cell lung cancer and multiple myeloma, reflecting the immunological involvement in cancer. Several studies have shown IL-6 to be a prognostic indicator of survival as well as predictive in response to therapy in many types of cancer [9, 10]. A high IL-6 level is generally associated with a poorer outcome and with more severe symptoms in regards to cancer as well as the development of anti-cancer drug resistance [11, 12].

Endogenous mechanisms that prevent or neutralize excessive proinflammatory reactions could lead to novel therapeutic options.

Transcutaneous electrical neurostimulation (TENS) is a non-invasive physiotherapeutic resource for pain management, but evidence on the effectiveness of this device at reducing proinflammatory cytokines in the blood is unclear.