A comparative study about the immunomodulatory effects of tramadol and metamizole in a murine model of postoperative ileus.

Postoperative ileus (POI) is a common complication after abdominal surgery characterized by motility disturbances leading to increased morbidity and mortality in surgical patients. Intestinal manipulation of the murine small bowel is an established animal model resulting in an increased postsurgical inflammation within the intestinal muscular externa and a delayed gastrointestinal transit. Some analgesics have been shown to affect inflammation. In this study, we compared the immunomodulatory effects of two different analgesics. Mice were treated with tramadol, metamizole or saline as a control in our established POI model. The postoperative inflammatory response was assessed by gene expression of pro-inflammatory cytokines at different time points and immunocytes extravasation into the muscularis externa. Functional motility analyses were performed by a gastrointestinal transit measurement. Metamizole application reduced the pro-inflammatory response after surgery and improved gastrointestinal motility, while tramadol showed no alteration in cytokine gene expression, influx of immunocytes and gastrointestinal transit compared with the controls. In conclusion. we suggest tramadol as analgesia in immunological studies on POI in mice as it does not affect the underlying inflammation of POI.

Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice.

BACKGROUND: The cholinergic anti-inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non-invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. METHODS: Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c-fos+ cells. Gene and protein expression of IL-6, MCP-1, IL-1ß as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL-6, TNFα, and IL-1ß serum levels were analyzed 3 hours after lipopolysaccharide administration. RESULTS: tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia-induced IL-6 and TNF-α release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. CONCLUSION: tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non-invasive approach for treatment of POI.

Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa): a prospective clinical trial.

PURPOSE: Postoperative ileus (POI) is a common complication after abdominal surgery. Invasive stimulation of the cervical vagus nerve is known to reduce inflammatory response and ameliorated POI after surgery in a mouse model. However, the transcutaneous vagus nerve stimulation (tVNS) is a possible non-invasive approach. In this clinical study, we aimed to investigate the effect of tVNS on the activation of the stomach muscle in humans. METHODS: Patients requiring open laparotomy were screened for this prospective proof of concept clinical study. After open laparotomy, muscle activity of the stomach was measured by a free running electromyography (EMG) before and during tVNS on the ear. Frequency and amplitude of compound gastric action potentials were the electrophysiological parameters we assessed to reveal the changes in electro motor gastric activity. Gastrin levels as a surrogate marker for vagus nerve activation was analyzed before, 1 and 3 h after tVNS. RESULTS: Fourteen patients were included, no severe adverse events and no medical device related adverse events occurred. tVNS led to significant reduction of action potential frequency and significant elevation of action potential amplitude in the stomach compared to control. Gastrin levels were significantly elevated 3 h after tVNS compared to levels before tVNS. CONCLUSION: Application of tVNS is a safe and feasible procedure during surgical intervention. Our results provide evidence that tVNS activates efferent visceral vagal fibers. Therefore, this low risk and easy to perform method could be useful to prevent postoperative ileus. CLINICAL TRIAL REGISTER NUMBER: DRKS00013340.

Advantages of laparoscopic compared to conventional surgery are not related to an innate immune response of peritoneal immune activation: an animal study in rats.

PURPOSE: Laparoscopic surgery (LS) has proved superior compared to conventional surgery (CS) regarding morbidity, length of hospital stay, rate of wound infection and time until recovery. An improved preservation of the postoperative immune function is assumed to contribute to these benefits though the role of the local peritoneal immune response is still poorly understood. Our study investigates the peritoneal immune response subsequent to abdominal surgery and compares it between laparoscopic and conventional surgery to find an immunological explanation for the clinically proven benefits of LS. METHODS: Wistar rats (N = 140) underwent laparoscopic cecum resection (LCR; N = 28), conventional cecum resection (CCR; N = 28), laparoscopic sham operation (LSO; N = 28), conventional sham operation (CSO; N = 28), or no surgical treatment (CTRL; N = 28). Postoperatively, peritoneal lavages were performed, leukocytes isolated and analyzed regarding immune function and phagocytosis activity. RESULTS: Immune function was inhibited postoperatively in animals undergoing LCR or CCR compared to CTRL reflected by a lower TNF-α (CTRL 3956.65 pg/ml, LCR 2018.48 pg/ml (p = 0.023), CCR 2793.78 pg/ml (n.s.)) and IL-6 secretion (CTRL 625.84 pg/ml, LCR 142.84 pg/ml (p = 0.009), CCR 169.53 pg/ml (p = 0.01)). Phagocytosis was not affected in rats undergoing any kind of surgery compared to CTRL. Neither cytokine secretion nor phagocytosis activity differed significantly between laparoscopic and conventional surgery. CONCLUSIONS: According to our findings the benefits associated with LS compared to CS cannot be explained by differences in the postoperative peritoneal innate immune response. Further studies are needed to elucidate the causes for a more favorable postoperative outcome in patients after LS compared to CS.

Development of a standardized laparoscopic caecum resection model to simulate laparoscopic appendectomy in rats.

BACKGROUND: Laparoscopic appendectomy (LA) has become one of the most common surgical procedures to date. To improve and standardize this technique further, cost-effective and reliable animal models are needed. METHODS: In a pilot study, 30 Wistar rats underwent laparoscopic caecum resection (as rats do not have an appendix vermiformis), to optimize the instrumental and surgical parameters. A subsequent test study was performed in another 30 rats to compare three different techniques for caecum resection and bowel closure. RESULTS: Bipolar coagulation led to an insufficiency of caecal stump closure in all operated rats (Group 1, n = 10). Endoloop ligation followed by bipolar coagulation and resection (Group 2, n = 10) or resection with a LigaSure™ device (Group 3, n = 10) resulted in sufficient caecal stump closure. CONCLUSIONS: We developed a LA model enabling us to compare three different caecum resection techniques in rats. In conclusion, only endoloop closure followed by bipolar coagulation proved to be a secure and cost-effective surgical approach.