Ignite Creation Date:
2024-05-06 @ 6:40 PM
Last Modification Date:
2024-10-26 @ 2:52 PM
Study NCT ID:
NCT05743530
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-02-24
First Post:
2023-02-15
Brief Title:
Effect of Perioperative Neurostimulation in Patients Undergoing Whipple Operation Pancreaticoduodenectomy on Acute Postsurgical Inflammatory Response ENSWAPI-trial
Sponsor:
Medical University of Graz
Organization:
Medical University of Graz
Study Overview
Official Title:
Effect of Perioperative Neurostimulation in Patients Undergoing Whipple Operation Pancreaticoduodenectomy on Acute Postsurgical Inflammatory Response ENSWAPI-trial
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this clinical trial is to test whether electrical stimulation of the vagus nerve via a device placed on the top of the external ear can reduce the postoperative inflammatory reaction after Whipples surgery pancreatoduodenectomy
Detailed Description:
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 patients death In order to avoid destruction by ones 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 n275 showed the development of postoperative sepsis in 4 n11 which had an abdominal focus in 29 n8 and other localizations in 11 n3 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 pgml 8 IL-6 is particularly important in chronic inflammatory conditions such as rheumatoid arthritis inflammatory bowel disease Castlemanns disease haematopoietic diseases and after physical stress such as surgery or chemotherapy Increased levels of serum andor 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
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 n275 showed the development of postoperative sepsis in 4 n11 which had an abdominal focus in 29 n8 and other localizations in 11 n3 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 pgml 8 IL-6 is particularly important in chronic inflammatory conditions such as rheumatoid arthritis inflammatory bowel disease Castlemanns disease haematopoietic diseases and after physical stress such as surgery or chemotherapy Increased levels of serum andor 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None