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.

TENS is a strategy that allows for interaction with the peripheral vascular system or with the autonomic nervous system.

The vagus nerve is the main nerve of the parasympathetic division of the autonomic nervous system. The vagus nerve regulates metabolic homeostasis by controlling heart rate, gastrointestinal motility and secretion, pancreatic endocrine and exocrine secretion, hepatic glucose production, and many other visceral functions over the brainstem. In addition, afferent and efferent branches of the vagus nerve are part of a neural reflex mechanism (the inflammatory reflex) that controls innate immune responses and inflammation during pathogen invasion and tissue injury [1, 2, 3]. Innate immune responses are activated by pathogen-associated and danger-associated molecular patterns. Activation of downstream signaling cascades results in increased production and release of tumor necrosis factor (TNF), IL-6 and other proinflammatory cytokines. These are implicated in extracellular pathogen clearance, vasodilatation, neutrophil recruitment, increased vascular permeability and induction of acute-phase proteins, such as C-reactive protein (CRP), and coagulation molecules. Proinflammatory progression is balanced by the release of IL-10, TGF-ß and other anti-inflammatory molecules.

Communication between the immune system and the brain is vital for controlling inflammation by the inflammatory reflex (the afferent vagus nerve signalling, which is activated by cytokines or pathogen-derived products, is functionally associated with efferent vagus nerve-mediated regulation of proinflammatory cytokine production and inflammation) [2, 3]. The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. The absence of this inflammatory reflex leads to excessive immune responses and cytokine toxicity. It could be shown that the severity of collagen-induced arthritis can be reduced by neurostimulation of the cholinergic anti-inflammatory pathway, supporting the rationale for testing this approach in human inflammatory disorders [4]. Koopman et al. have shown that the vagus nerve stimulation (up to four times daily) for the reduction of the frequency of epileptic seizures had an effect also on the activity of rheumatoid arthritis. The vagus nerve stimulation significantly inhibited the TNF production for up to 84 days [5]. These results establish that vagus nerve stimulation modulates TNF production and reduces inflammation in humans. Gürgen et al. found that distinctive decreases of pro-inflammatory cytokines observed in the dermis in the vagus nerve stimulation group suggest that TENS shortened the healing process by inhibiting the inflammation phase in an animal model on wound healing in terms of the expression levels of pro-inflammatory cytokines [13]. We intend to investigate the effect of perioperative vagus nerve stimulation by application of the Neurostimulator V by Ducest in patients undergoing Whipple operation (pancreaticoduodenectomy).