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Marcin B, Katarzyna SA, Ivan K. The role of beta-adrenoreceptors in postoperative ileus in rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4851-4857. [PMID: 38157026 PMCID: PMC11166813 DOI: 10.1007/s00210-023-02918-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
The aim of the research was to evaluate the influence of antagonists of specific beta-adrenergic receptor subtypes on bowel motility following abdominal surgery in rat model of postoperative ileus. Bowel motility was measured by the intestinal transit of Evans blue introduced via orogastric tube after surgical procedures of skin incision, laparotomy and laparotomy with gut manipulation. Male rats were given individual adrenergic receptor subtypes antagonists intraperitoneally, and the influence of administered agents on intestinal transit of Evans blue was then evaluated. No statistically significant differences in the length of intestine in tested rats were observed. Propranolol administered prior to surgical procedure has shown protective effect on Evans blue migration in rats undergoing laparotomy and gut manipulation. Intestinal dye transit for propranolol doses of 10, 30 and 45 mg/kg was 18.00 ± 1.88c m, 23.75 ± 1.71 cm and 22.5 ± 2.43 cm, respectively, and for last two doses, statistically significant increase of dye passage was noted, compared to Evans blue transit of 11.00 ± 2.43 cm in the control group. No acceleration of dye migration was seen following administration of beta1-, beta2- and beta3-selective adrenergic receptor antagonist metoprolol, ICI 118.551 and SR58894A, respectively. Our research confirmed that propranolol at high doses, as seen by other researchers, improved bowel motility in early phase of postoperative ileus. That slight acceleration of intestinal dye transit after surgery with gut manipulation is rather connected with membrane-stabilizing action, than the receptor blocking effect, as this effect was not observed after the application of selective antagonists of respective subtypes of beta-adrenergic receptor.
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Affiliation(s)
- Bitel Marcin
- Department of Pharmacology, Faculty of Medicine, Medical University of Gdańsk, Dębowa Str. 23, 80-204, Gdańsk, Poland
| | | | - Kocić Ivan
- Department of Pharmacology, Faculty of Medicine, Medical University of Gdańsk, Dębowa Str. 23, 80-204, Gdańsk, Poland.
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Khawaja ZH, Gendia A, Adnan N, Ahmed J. Prevention and Management of Postoperative Ileus: A Review of Current Practice. Cureus 2022; 14:e22652. [PMID: 35371753 PMCID: PMC8963477 DOI: 10.7759/cureus.22652] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2022] [Indexed: 01/09/2023] Open
Abstract
Postoperative ileus (POI) has long been a challenging clinical problem for both patients and healthcare physicians alike. Although a standardized definition does not exist, it generally includes symptoms of intolerance to diet, lack of passing stool, abdominal distension, or flatus. Not only does prolonged POI increase patient discomfort and morbidity, but it is possibly the single most important factor that results in prolongation of the length of hospital stay with a significant deleterious effect on healthcare costs in surgical patients. Determining the exact pathogenesis of POI is difficult to achieve; however, it can be conceptually divided into patient-related and operative factors, which can further be broadly classified as neurogenic, inflammatory, hormonal, and pharmacological mechanisms. Different strategies have been introduced aimed at improving the quality of perioperative care by reducing perioperative morbidity and length of stay, which include Enhanced Recovery After Surgery (ERAS) protocols, minimally invasive surgical approaches, and the use of specific pharmaceutical therapies. Recent studies have shown that the ERAS pathway and laparoscopic approach are generally effective in reducing patient morbidity with early return of gut function. Out of many studies on pharmacological agents over the recent years, alvimopan has shown the most promising results. However, due to its potential complications and cost, its clinical use is limited. Therefore, this article aimed to review the pathophysiology of POI and explore recent advances in treatment modalities and prevention of postoperative ileus.
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Buscail E, Deraison C. Postoperative Ileus: a Pharmacological Perspective. Br J Pharmacol 2022; 179:3283-3305. [PMID: 35048360 DOI: 10.1111/bph.15800] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 11/29/2022] Open
Abstract
Post-operative ileus (POI) is a frequent complication after abdominal surgery. The consequences of POI can be potentially serious such as bronchial inhalation or acute functional renal failure. Numerous advances in peri-operative management, particularly early rehabilitation, have made it possible to decrease POI. Despite this, the rate of prolonged POI ileus remains high and can be as high as 25% of patients in colorectal surgery. From a pathophysiological point of view, POI has two phases, an early neurological phase and a later inflammatory phase, to which we could add a "pharmacological" phase during which analgesic drugs, particularly opiates, play a central role. The aim of this review article is to describe the phases of the pathophysiology of POI, to analyse the pharmacological treatments currently available through published clinical trials and finally to discuss the different research areas for potential pharmacological targets.
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Affiliation(s)
- Etienne Buscail
- IRSD, INSERM, INRAE, ENVT, University of Toulouse, CHU Purpan (University Hospital Centre), Toulouse, France.,Department of digestive surgery, colorectal surgery unit, Toulouse University Hospital, Toulouse, France
| | - Céline Deraison
- IRSD, INSERM, INRAE, ENVT, University of Toulouse, CHU Purpan (University Hospital Centre), Toulouse, France
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Katagiri N, Sakai R, Izutsu T, Kawana H, Sugino S, Kido K. Postoperative Pain Management in Patients With Ulcerative Colitis. Anesth Prog 2020; 67:158-163. [PMID: 32992337 DOI: 10.2344/anpr-67-01-06] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 11/14/2019] [Indexed: 12/26/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease. Pain management can be challenging in patients with IBD because there are limitations on the use of analgesics. Use of nonsteroidal anti-inflammatory drugs is not recommended in patients with IBD because there is risk of relapse of IBD and an overall increase in disease activity. Opioids, although frequently used for treating severe acute pain, can have additional risks and complications in patients with IBD such as ileus, toxic megacolon, and narcotic bowel syndrome. Furthermore, little information is available in the literature on pain management in these patients undergoing noncolorectal surgery. This report describes 2 patients with UC in whom postoperative pain following oral and maxillofacial surgery was managed by intravenous patient-controlled analgesia with pentazocine. Apart from the development of acute dystonia in 1 case that was likely due to the use of droperidol for prevention of postoperative nausea and vomiting, postoperative pain was well controlled by pentazocine in both patients without any complications or UC exacerbations.
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Affiliation(s)
- Norika Katagiri
- Department of Anesthesiology, Kanagawa Dental University Hospital, Yokosuka, Kanagawa, Japan
| | - Ryutaro Sakai
- Department of Anesthesiology, Kanagawa Dental University Hospital, Yokosuka, Kanagawa, Japan
| | - Takashi Izutsu
- Department of Oral and Maxillofacial Surgery, Yamagata Prefectural Central Hospital, Yamagata City, Yamagata, Japan
| | - Hiromasa Kawana
- Department of Oral and Maxillofacial Implantology, Kanagawa Dental University Hospital, Yokosuka, Kanagawa, Japan
| | - Shigekazu Sugino
- Department of Anesthesiology and Perioperative Medicine, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Kanta Kido
- Department of Anesthesiology, Kanagawa Dental University Hospital, Yokosuka, Kanagawa, Japan
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5
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Hong GS, Stein K, Lysson M, Kalff J, Wehner S. A comparative study about the immunomodulatory effects of tramadol and metamizole in a murine model of postoperative ileus. Lab Anim 2019; 53:610-618. [PMID: 30907232 DOI: 10.1177/0023677219832919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
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.
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Affiliation(s)
- Gun-Soo Hong
- Department of Surgery, University of Bonn, Bonn Germany
| | - Kathy Stein
- Department of Surgery, University of Bonn, Bonn Germany
| | | | - Joerg Kalff
- Department of Surgery, University of Bonn, Bonn Germany
| | - Sven Wehner
- Department of Surgery, University of Bonn, Bonn Germany
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Anaya-Prado R, Pérez-Navarro JV, Corona-Nakamura A, Anaya-Fernández MM, Anaya-Fernández R, Izaguirre-Pérez ME. Intestinal pseudo-obstruction caused by herpes zoster: Case report and pathophysiology. World J Clin Cases 2018; 6:132-138. [PMID: 29988868 PMCID: PMC6033747 DOI: 10.12998/wjcc.v6.i6.132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/27/2018] [Accepted: 05/15/2018] [Indexed: 02/05/2023] Open
Abstract
Herpes zoster (HZ) infection occurs in approximately 10% to 30% of individuals. Visceral neuropathies secondary to HZ can cause cystitis and urinary retention. But colonic pseudo-obstruction can also occur. Peripheral neuropathy may reveal segmental motor paresis of either upper or lower limbs, the abdominal muscles or the diaphragm. We report the case of a 62-year-old male patient who presented with abdominal distention and cutaneous vesicular eruption on the left side of the abdominal wall. Plain X-rays and computed tomography scan showed distended small bowel. A diagnosis of intestinal pseudo-obstruction was made secondary to segmental paresis of the small intestine and visceral neuropathy. Conservative management was successful and the patient was discharged uneventfully. Intestinal pseudo-obstruction ought to be considered when dealing with non-obstructive (adynamic) conditions of the digestive tract associated with HZ infection; since early recognition may help to avoid unnecessary surgery.
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Affiliation(s)
- Roberto Anaya-Prado
- Department of Surgery at Western Medical Center, the Mexican Institute of Social Security, Guadalajara, JAL 44340, México
- Division of Research at Autonomous University of Guadalajara, Guadalajara, JAL 45200, México
| | - José V Pérez-Navarro
- Department of Surgery at Western Medical Center, the Mexican Institute of Social Security, Guadalajara, JAL 44340, México
| | - Ana Corona-Nakamura
- Department of Infectious Diseases at Western Medical Center, the Mexican Institute of Social Security, Guadalajara, JAL 44340, México
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Hestehave S, Munro G, Christensen R, Brønnum Pedersen T, Arvastson L, Hougaard P, Abelson KSP. Is there a reasonable excuse for not providing post-operative analgesia when using animal models of peripheral neuropathic pain for research purposes? PLoS One 2017; 12:e0188113. [PMID: 29166664 PMCID: PMC5699849 DOI: 10.1371/journal.pone.0188113] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 11/01/2017] [Indexed: 12/26/2022] Open
Abstract
Introduction The induction of neuropathic pain-like behaviors in rodents often requires surgical intervention. This engages acute nociceptive signaling events that contribute to pain and stress post-operatively that from a welfare perspective demands peri-operative analgesic treatment. However, a large number of researchers avoid providing such care based largely on anecdotal opinions that it might interfere with model pathophysiology in the longer term. Objectives To investigate effects of various peri-operative analgesic regimens encapsulating different mechanisms and duration of action, on the development of post-operative stress/welfare and pain-like behaviors in the Spared Nerve Injury (SNI)-model of neuropathic pain. Methods Starting on the day of surgery, male Sprague-Dawley rats were administered either vehicle (s.c.), carprofen (5.0mg/kg, s.c.), buprenorphine (0.1mg/kg s.c. or 1.0mg/kg p.o. in Nutella®), lidocaine/bupivacaine mixture (local irrigation) or a combination of all analgesics, with coverage from a single administration, and up to 72 hours. Post-operative stress and recovery were assessed using welfare parameters, bodyweight, food-consumption, and fecal corticosterone, and hindpaw mechanical allodynia was tested for assessing development of neuropathic pain for 28 days. Results None of the analgesic regimes compromised the development of mechanical allodynia. Unexpectedly, the combined treatment with 0.1mg/kg s.c. buprenorphine and carprofen for 72 hours and local irrigation with lidocaine/bupivacaine, caused severe adverse effects with peritonitis. This was not observed when the combination included a lower dose of buprenorphine (0.05mg/kg, s.c.), or when buprenorphine was administered alone (0.1mg/kg s.c. or 1.0mg/kg p.o.) for 72 hours. An elevated rate of wound dehiscence was observed especially in the combined treatment groups, underlining the need for balanced analgesia. Repeated buprenorphine injections had positive effects on body weight the first day after surgery, but depressive effects on food intake and body weight later during the first week. Conclusion Post-operative analgesia does not appear to affect established neuropathic hypersensitivity outcome in the SNI model.
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Affiliation(s)
- Sara Hestehave
- Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Neurodegeneration In Vivo, H. Lundbeck A/S, Valby, Denmark
- * E-mail:
| | - Gordon Munro
- Department of Neurodegeneration In Vivo, H. Lundbeck A/S, Valby, Denmark
- Department of Neurology, Danish Headache Center, Glostrup Research Institute, Glostrup, Denmark
| | - Rie Christensen
- Department of Neurodegeneration In Vivo, H. Lundbeck A/S, Valby, Denmark
| | | | | | | | - Klas S. P. Abelson
- Department of Experimental Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Fu XY. Gastrointestinal motility dysfunction in critically ill patients: Pathogenesis, clinical assessment, and treatment. Shijie Huaren Xiaohua Zazhi 2017; 25:2583-2590. [DOI: 10.11569/wcjd.v25.i29.2583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal motility dysfunction is a common clinical complication in ICU patients, which can lead to difficulty in enteral nutrition, vomiting, diarrhea, increased intra-abdominal pressure, ventilator associated pneumonia, intestinal flora displacement, and other adverse reactions. The clinical features of gastrointestinal dysfunction mainly include gastric emptying disturbance, intestinal dysfunction, and gastrointestinal motility disorders. The causes of gastrointestinal motility dysfunction in ICU patients are complex and the clinical evaluation of gastrointestinal dysfunction is difficult. These factors have led to the fact that gastrointestinal motility monitoring techniques have not been widely used in clinical practice. Timely detection and correction of gastrointestinal motility dysfunction in ICU patients can improve outcomes. This article reviews the etiology, clinical evaluation, and treatment of gastrointestinal motility dysfunction in ICU patients.
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Affiliation(s)
- Xiao-Yun Fu
- Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical College, Zunyi 563000, Guizhou Province, China
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Cho JS, Kim HI, Lee KY, An JY, Bai SJ, Cho JY, Yoo YC. Effect of Intraoperative Dexmedetomidine Infusion on Postoperative Bowel Movements in Patients Undergoing Laparoscopic Gastrectomy: A Prospective, Randomized, Placebo-Controlled Study. Medicine (Baltimore) 2015; 94:e959. [PMID: 26091461 PMCID: PMC4616550 DOI: 10.1097/md.0000000000000959] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Sympathetic hyperactivation is one of the causes of postoperative ileus, which occurs frequently after abdominal surgery and adversely influences the patient's prognosis. We aimed to investigate whether dexmedetomidine (DEX) could attenuate postoperative ileus in patients undergoing laparoscopic gastrectomy. Ninety-two patients were randomized to the control (n = 46) or DEX group (n = 46). DEX was administered at a loading dose of 0.5 μg/kg for 10 minutes, followed by an infusion rate of 0.4 μg/kg/h from insufflation of the pneumoperitoneum to the end of surgery. The primary goal was to compare postoperative bowel movements by evaluating the time to first flatus. The balance of the autonomic nervous system, duration of postoperative hospital stay, and pain scores were assessed. The time to first flatus was shorter in the DEX group compared with the control group (67.2 ± 16.8 hours vs 79.9 ± 15.9 hours, P < 0.001). The low-frequency/high-frequency power ratio during pneumoperitoneum increased in the control group, compared with baseline values and the DEX group. The length of postoperative hospital stay was shorter in the DEX group compared with the control group (5.4 ± 0.7 days vs 5.8 ± 1.1 days, P = 0.04). Patients in the DEX group had lower pain scores and required fewer analgesics at 1 hour postoperatively. DEX facilitated bowel movements and reduced the length of hospital stay in patients undergoing laparoscopic gastrectomy. This may be attributed to the sympatholytic and opioid-sparing effects of DEX.
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Affiliation(s)
- Jin Sun Cho
- From the Department of Anesthesiology and Pain Medicine (JSC, K-YL, SJB, JYC, YCY); Department of Surgery (H-IK, JYA); and Anesthesia and Pain Research Institute (K-YL, SJB, YCY), Yonsei University College of Medicine, Seoul, Republic of Korea
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HOPSTER-IVERSEN C, HOPSTER K, STASZYK C, ROHN K, FREEMAN D, RÖTTING AK. Influence of mechanical manipulations on the local inflammatory reaction in the equine colon. Equine Vet J 2011:1-7. [DOI: 10.1111/j.2042-3306.2011.00378.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Holschneider DP, Bradesi S, Mayer EA. The role of experimental models in developing new treatments for irritable bowel syndrome. Expert Rev Gastroenterol Hepatol 2011; 5:43-57. [PMID: 21309671 PMCID: PMC3124306 DOI: 10.1586/egh.10.88] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Irritable bowel syndrome (IBS) is characterized by chronic, recurrent abdominal pain and altered bowel habits and is currently defined by symptom criteria and the absence of detectable organic disease. The underlying pathophysiology remains incompletely understood. Despite considerable efforts by the scientific community and the pharmaceutical industry to develop novel pharmacological treatments aimed at chronic visceral pain, the traditional approach to identifying and evaluating novel drugs for this target have largely failed to translate into effective IBS treatments. However, several novel drugs aimed at normalizing bowel movements have produced clinical effects, not only on the primary target, but also on pain and discomfort. While some of the commonly used experimental animal models for the pain dimension of IBS have some face and construct validity, the predictive validity of most of the models is either unknown, or has been disappointing. A reverse translational approach is proposed, which is based on identification and characterization of brain endophenotypes in patients, followed by translation of these endophenotypes for pharmacological studies in rodent models.
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Affiliation(s)
- Daniel P Holschneider
- VA Greater Los Angeles Healthcare System, LA, CA, USA
- Departments of Psychiatry and the Behavioral Sciences, Neurology, Cell & Neurobiology, Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Sylvie Bradesi
- VA Greater Los Angeles Healthcare System, LA, CA, USA
- UCLA Center for Neurobiology of Stress, Departments of Medicine, Physiology and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA
| | - Emeran A Mayer
- VA Greater Los Angeles Healthcare System, LA, CA, USA
- UCLA Center for Neurobiology of Stress, Departments of Medicine, Physiology and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA
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Comparison of the effect of epidural and intravenous patient-controlled analgesia on bowel activity after cesarean section: a retrospective study of 726 Chinese patients. ACTA ACUST UNITED AC 2009; 47:22-7. [PMID: 19318296 DOI: 10.1016/s1875-4597(09)60016-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Epidural patient-controlled analgesia (EPCA) and intravenous patient-controlled analgesia (IVPCA) have been used widely in parturients after cesarean section. Although many studies have demonstrated the safety and effectiveness of both EPCA and IVPCA, their effects on bowel activity of patients who have undergone cesarean section delivery have not yet been investigated. The purpose of this study was to compare the effect of EPCA and IVPCA on bowel activity after cesarean section. METHODS We collected data from 726 parturients who consented to receive either EPCA or IVPCA for postoperative analgesia following cesarean section delivery. All patients used postoperative PCA for at least 2 days. The analgesic solution for EPCA was 0.05% bupivacaine plus fentanyl (3 microg/mL), and that for IVPCA was 0.1% morphine. The patients were assessed by visual analog pain scale (VAS) scores at rest and in a dynamic state, time to first flatus passage after the surgery, and overall satisfaction after completion of the PCA course. Student's t test was used to determine intergroup differences. RESULTS There were statistically significant differences between the EPCA and IVPCA groups in the time to first flatus passage, overall satisfaction and VAS scores at rest and in a dynamic state. Patients in the EPCA group had a shorter time to first flatus passage, higher overall satisfaction and lower VAS scores. In addition, regional anesthesia offered an apparently shorter time to first flatus passage in comparison with general anesthesia. CONCLUSION PCA is safe and effective in alleviating postoperative pain following cesarean section. EPCA offers a faster return of bowel activity, lower VAS scores, and better patient satisfaction than IVPCA.
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de Jonge WJ, Greaves DR. Immune modulation in gastrointestinal disorders: new opportunities for therapeutic peptides? Expert Rev Gastroenterol Hepatol 2008; 2:741-8. [PMID: 19090735 DOI: 10.1586/17474124.2.6.741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Inflammation is the response of vascularized tissues to injury, irritation and infection. Nearly always, the inflammatory response is successfully resolved and, when necessary, a process of wound healing is initiated. Nowhere in the body is this homeostatic process more challenging than in the gastrointestinal (GI) tract, where the microbial flora sits in very close proximity to the mucosal immune system, separated only by an epithelial cell barrier. Delicate regulatory systems of the mucosal immune system determine mucosal permeability and response to bacterial flora, and aberrations in this system result in acute or chronic inflammatory conditions. Examples of such are two commonly occurring inflammatory GI disorders: inflammatory bowel disease and postoperative ileus. Inflammatory bowel disease is the result of a chronic and excessive mucosal immune response, whereas postoperative ileus represents a transient condition of GI tract paralysis that is the result of an inflammatory response to abdominal surgery. The clinical management of both conditions is very challenging and depends heavily on the possibility of modulating the host immune response. In this brief report, we highlight the role of neuropeptides in GI physiology and immune regulation, discuss a recently discovered endogenous anti-inflammatory pathway mediated by the ChemR23 receptor and speculate on the therapeutic potential of peptides that bind G-protein-coupled receptors in the management of inflammation in the GI tract.
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Affiliation(s)
- Wouter J de Jonge
- Laboratory of Experimental Gastroenterology and Hepatology, Academic Medical Center Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Abstract
Asimadoline is a potent kappa-opioid receptor agonist with a diaryl acetamide structure. It has high affinity for the kappa receptor, with IC(50) of 5.6 nmol L(-1) (guinea pig) and 1.2 nmol L(-1) (human recombinant), and high selectively with kappa : micro : delta binding ratios of 1 : 501 : 498 in human recombinant receptors. It acts as a complete agonist in in vitro assay. Asimadoline reduced sensation in response to colonic distension at subnoxious pressures in healthy volunteers and in irritable bowel syndrome (IBS) patients without alteration of colonic compliance. Asimadoline reduced satiation and enhanced the postprandial gastric volume (in female volunteers). However, there were no significant effects on gastrointestinal transit, colonic compliance, fasting or postprandial colonic tone. In a clinical trial in 40 patients with functional dyspepsia (Rome II), asimadoline did not significantly alter satiation or symptoms over 8 weeks. However, asimadoline, 0.5 mg, significantly decreased satiation in patients with higher postprandial fullness scores, and daily postprandial fullness severity (over 8 weeks); the asimadoline 1.0 mg group was borderline significant. In a clinical trial in patients with IBS, average pain 2 h post-on-demand treatment with asimadoline was not significantly reduced. Post hoc analyses suggest that asimadoline was effective in mixed IBS. In a 12-week study in 596 patients, chronic treatment with 0.5 mg and 1.0 mg asimadoline was associated with adequate relief of pain and discomfort, improvement in pain score and number of pain-free days in patients with IBS-D. The 1.0 mg dose was also efficacious in IBS-alternating. There were also weeks with significant reduction in bowel frequency and urgency. Asimadoline has been well tolerated in human trials to date.
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Affiliation(s)
- M Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN 55905, USA.
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Schmidt J, Stoffels B, Nazir A, Dehaven-Hudkins DL, Bauer AJ. Alvimopan and COX-2 inhibition reverse opioid and inflammatory components of postoperative ileus. Neurogastroenterol Motil 2008; 20:689-99. [PMID: 18266613 DOI: 10.1111/j.1365-2982.2007.01078.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Our objective was to investigate the therapeutic potential of peripheral opioid antagonism with alvimopan and anti-inflammatory cyclooxygenase 2 (COX-2) inhibition in an animal model of postoperative ileus with pain management. Intestinal manipulation was conducted in mice and rats with or without postoperative morphine injection. Rodents were orally fed non-digestible fluorescein (FITC)-labelled dextran and transit measured after a period of 90 min. The immunomodulatory effects of morphine and alvimopan were determined on nitric oxide released from the organ cultured muscularis externa. Surgical manipulation of the intestine resulted in a delay in gastrointestinal transit after 24 h that worsened with exogenous morphine. Alvimopan did not significantly alter transit of control or manipulated animals, but significantly antagonized the transit delaying effects of morphine. However, when the inflammatory component was robust enough to obscure a further opioid induced delay in gastrointestinal transit, alvimopan ceased to be effective in improving postoperative intestinal function. Cyclooxygenase 2 inhibition significantly diminished the inflammatory component of postoperative ileus. Surgical manipulation resulted in an increased release of nitric oxide from the inflamed isolated muscularis externa in 24-h organ culture which was not altered by morphine or alvimopan. Two distinct mechanisms exist which participate in postoperative bowel dysfunction: a local inflammatory response which is antagonized by COX-2 inhibition, and a morphine-induced alteration in neural function which can be blocked with alvimopan.
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Affiliation(s)
- J Schmidt
- Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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16
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Abstract
Ileus and colonic pseudo-obstruction cause functional obstruction of intestinal transit, without mechanical obstruction, because of uncoordinated or attenuated intestinal muscle contractions. Ileus usually arises from an exaggerated intestinal reaction to abdominal surgery that is often exacerbated by numerous other conditions. Colonic pseudo-obstruction is induced by numerous metabolic disorders, drugs that inhibit intestinal motility, severe illnesses, and extensive surgery. It presents with massive colonic dilatation with variable, moderate small bowel dilatation. Both conditions are initially treated with supportive measures that include intravenous rehydration, correction of electrolyte abnormalities, discontinuation of antikinetic drugs, and treatment of other contributing disorders. Specific therapies for colonic pseudo-obstruction include neostigmine (an anticholinesterase) for pharmacologic colonic decompression and colonoscopic decompression.
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Affiliation(s)
- Mihaela Batke
- Division of Gastroenterology, Department of Medicine, William Beaumont Hospital, MOB 233, 3601 West Thirteen Mile Road, Royal Oak, MI 48073, USA.
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17
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Abstract
Opioid analgesics are the mainstay in the treatment of moderate-to-severe pain, yet their use is frequently associated with adverse effects, the most common and debilitating being constipation. Opioid-induced motor stasis results from blockade of gastrointestinal peristalsis and fluid secretion, and reflects the action of the endogenous opioid system in the gut. Methylnaltrexone and alvimopan are new investigational drugs that selectively target peripheral mu-opioid receptors because they are poorly absorbed in the intestine and do not enter the brain. Clinical studies have proved the concept that these drugs prevent opioid-induced bowel dysfunction without interfering with analgesia. As reviewed in this article, opioid receptor antagonists with a peripherally restricted site of action also hold therapeutic promise in postoperative ileus and chronic constipation due to the fact that they have been found to stimulate intestinal transit.
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Affiliation(s)
- Peter Holzer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria.
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18
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Fruhwald S, Holzer P, Metzler H. Intestinal motility disturbances in intensive care patients pathogenesis and clinical impact. Intensive Care Med 2007; 33:36-44. [PMID: 17115132 DOI: 10.1007/s00134-006-0452-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2006] [Accepted: 10/17/2006] [Indexed: 12/26/2022]
Abstract
BACKGROUND Gastrointestinal motility disturbances in critically ill patients are frequent in the ICU setting, causing considerable discomfort and are associated with increased rates of morbidity and mortality. This review focuses on the pathophysiological basis of intestinal motility, the major patterns of pathological motility alterations, the impact on patient outcome, and current therapeutic options. DISCUSSION Intestinal motility is controlled by the enteric nervous system, modulated by hormones and extrinsic afferent and efferent neurons. Pathological motility disturbances can affect the stomach, small bowel, and colon separately or in combination. Changes in esophageal motor activity contribute to the aspiration of gastric juice, whereas early enteral feeding most frequently fails due to gastric intolerance. Disturbances in digestive and interdigestive motility patterns and the inability to switch motor activity from the interdigestive to the digestive pattern also contribute to feeding disability and thus to increased morbidity and mortality as well. CONCLUSIONS The therapeutic options for motility disturbances in critically ill patients include the adjustment of electrolyte imbalances, tailored fluid management, early enteral feeding, appropriate management of catecholamines and drugs used for analgosedation, and prokinetic drugs. Unfortunately, the therapeutic options for treating motility disturbances in ICU patients are still limited. This situation requires careful assessment of ICU patients with respect to gut motility disturbances and their pathophysiological mechanisms and an individually tailored treatment to prevent further aggravation of existing motility disturbances.
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Affiliation(s)
- Sonja Fruhwald
- Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 29, 8036, Graz, Austria.
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19
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Abstract
Investigations in the pathophysiology and treatment of postoperative ileus continue to evolve. Bowel rest is no longer a mandatory component of postoperative recovery. Tolerance of enteral nutrition and normalization of the abdominal examination are more accurate indications of the resolution of postoperative ileus than passage of flatus or first bowel movement. A multimodal "fast track" recovery approach incorporated into a clinical pathway provides a more rapid return of intestinal function and shortened hospital stay in patients undergoing major, uncomplicated gastrointestinal surgery.
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20
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Abstract
Use of opioid analgesics is associated with a number of side effects, especially opioid-induced gastrointestinal dysfunction. The extensive use of these compounds and the significant negative impact of the resulting gastrointestinal dysfunction on patients' quality of life make it an important clinical issue. In recent years our understanding of the mechanisms of opioid-induced gastrointestinal dysfunction has advanced greatly. This article reviews the underlying pathophysiological mechanisms of specific gastrointestinal adverse effects of opioids. The role of endogenous opioid peptides in certain gastrointestinal diseases is also discussed. A better understanding of the pathophysiological mechanisms of opioid-induced bowel dysfunction should lead to the development of newer opioid analgesics and improved regimens resulting in reduced gastrointestinal adverse effects.
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Affiliation(s)
- Sangeeta R Mehendale
- Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA
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21
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The FO, de Jonge WJ, Bennink RJ, van den Wijngaard RM, Boeckxstaens GE. The ICAM-1 antisense oligonucleotide ISIS-3082 prevents the development of postoperative ileus in mice. Br J Pharmacol 2005; 146:252-8. [PMID: 15997238 PMCID: PMC1576259 DOI: 10.1038/sj.bjp.0706303] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Intestinal manipulation (IM) during abdominal surgery triggers the influx of inflammatory cells, leading to postoperative ileus. Prevention of this local muscle inflammation, using intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-1-specific antibodies, has been shown to shorten postoperative ileus. However, the therapeutic use of antibodies has considerable disadvantages. The aim of the current study was to evaluate the effect of ISIS-3082, a mouse-specific ICAM-1 antisense oligonucleotide, on postoperative ileus in mice. Mice underwent a laparotomy or a laparotomy combined with IM after treatment with ICAM-1 antibodies, 0.1-10 mg kg(-1) ISIS-3082, saline or ISIS-8997 (scrambled control antisense oligonucleotides, 1 and 3 mg kg(-1)). At 24 h after surgery, gastric emptying of a 99mTC labelled semi-liquid meal was determined using scintigraphy. Intestinal inflammation was assessed by myeloperoxidase (MPO) activity in ileal muscle whole mounts. IM significantly reduced gastric emptying compared to laparotomy. Pretreatment with ISIS-3082 (0.1-1 mg kg(-1)) as well as ICAM-1 antibodies (10 mg kg(-1)), but not ISIS-8997 or saline, improved gastric emptying in a dose-dependent manner. This effect diminished with higher doses of ISIS-3082 (3-10 mg kg(-1)). Similarly, ISIS-3082 (0.1-1 mg kg(-1)) and ICAM-1 antibodies, but not ISIS-8997 or higher doses of ISIS-3082 (3-10 mg kg(-1)), reduced manipulation-induced inflammation. Immunohistochemistry showed reduction of ICAM-1 expression with ISIS-3082 only. ISIS-3082 pretreatment prevents postoperative ileus in mice by reduction of manipulation-induced local intestinal muscle inflammation. Our data suggest that targeting ICAM-1 using antisense oligonucleotides may represent a new therapeutic approach to the prevention of postoperative ileus.
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Affiliation(s)
- Frans O The
- Department of Gastroenterology and Hepatology, Academical Medical Center, Meibergdreef 9, 1055 AZ, Amsterdam, The Netherlands
| | - Wouter J de Jonge
- Department of Gastroenterology and Hepatology, Academical Medical Center, Meibergdreef 9, 1055 AZ, Amsterdam, The Netherlands
| | - Roel J Bennink
- Department of Nuclear Medicine, Academical Medical Center, Amsterdam, The Netherlands
| | - Rene M van den Wijngaard
- Department of Gastroenterology and Hepatology, Academical Medical Center, Meibergdreef 9, 1055 AZ, Amsterdam, The Netherlands
| | - Guy E Boeckxstaens
- Department of Gastroenterology and Hepatology, Academical Medical Center, Meibergdreef 9, 1055 AZ, Amsterdam, The Netherlands
- Author for correspondence:
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22
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Sanger G, Holzer P. Endogenous Opioids and the Gastrointestinal Tract. SEMINARS IN COLON AND RECTAL SURGERY 2005. [DOI: 10.1053/j.scrs.2006.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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23
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Gray AC, Coupar IM, White PJ. Comparison of opioid receptor distributions in the rat ileum. Life Sci 2005; 78:1610-6. [PMID: 16289621 DOI: 10.1016/j.lfs.2005.07.048] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2005] [Accepted: 07/26/2005] [Indexed: 11/20/2022]
Abstract
The cellular expression patterns of mu-, delta- and kappa-opioid receptors in the rat ileum were examined using fluorescence immunohistochemistry. Double-labelling was used to examine cellular receptor co-localisation as a pre-requisite for intracellular molecular interactions, such as heterodimerisation. Tissues were stained as whole-mount preparations. Strong, broadly distributed immunoreactivity (ir) was observed for each receptor in the myenteric and submucous plexuses. Although intracellular mu- and delta-ir patterns differed in ganglion neurons, mu/delta co-expression was extensive in these cells. mu/delta co-expression was also observed in interstitial cells, which were diffusely distributed in submucous plexus preparations but generally located adjacent to myenteric plexus structures. Punctate kappa-ir was seen broadly in nerve fibres in both plexuses, suggesting localisation in varicosities. Neuronal mu/kappa co-localisation was not apparent, although kappa-ir fibres were often apposed against mu-ir cells. mu/kappa co-localisation was detected in interstitial cells in submucous plexus preparations. Similarities in mu and delta expression patterns might reflect similar functional properties previously detected for these receptors. This study indicates that the rat gastrointestinal tract might provide a useful tool for the future study of molecular interactions between opioid receptor types.
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Affiliation(s)
- A C Gray
- Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, 381 Royal Pde, Parkville, Victoria 3052, Australia
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24
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Moore BA, Overhaus M, Whitcomb J, Ifedigbo E, Choi AMK, Otterbein LE, Bauer AJ. Brief inhalation of low-dose carbon monoxide protects rodents and swine from postoperative ileus. Crit Care Med 2005; 33:1317-26. [PMID: 15942350 DOI: 10.1097/01.ccm.0000166349.76514.40] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Carbon monoxide (CO), an endogenous byproduct of heme metabolism, is produced at high levels in injured tissue via induction of heme-oxygenase-1 activity, where it contributes to the modulation of proinflammatory processes. Alone, CO has potent anti-inflammatory effects in models of acute and chronic inflammation. In rodents, inhalation of low concentrations of CO (250 ppm) for 24 hrs protects against postoperative gastrointestinal ileus. The current study determined whether shorter exposures and lower concentrations were equally protective and whether CO treatment would be effective in a large animal species (swine) managed under conditions approximating the clinical setting. DESIGN Dosing studies were first performed in rats by exposing them to CO (30-250 ppm) or air by inhalation for 1 or 3 hrs before anesthesia. An effective dosing regimen was then selected for testing in swine. Postoperative ileus in both species was induced by laparotomy and mild compression (running) of the small intestine. MEASUREMENTS AND MAIN RESULTS In rats, inhalation of 75 ppm CO for 3 hrs before anesthesia and surgery ameliorated the surgically induced delay in gastrointestinal transit to levels achieved using 250 ppm for 24 hrs. Swine treated with 250 ppm CO for the same time period exhibited significantly improved postoperative intestinal circular muscle contractility in vitro and gastrointestinal transit in vivo. Carboxyhemoglobin concentrations measured after termination of CO exposure averaged 5.8% (baseline, 1.5%). No deleterious effects on heart rate, oxygen saturation, blood chemistries, and serum electrolytes were observed. CONCLUSIONS These findings demonstrate that inhalation of a low concentration of CO before surgery attenuates postoperative ileus in rodents and, more importantly, in a large animal species without risk to well-being during surgery or perioperatively. Exposures need not be prolonged, with significant benefit occurring with a 3-hr pretreatment.
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Affiliation(s)
- Beverley A Moore
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA
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25
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Abstract
Postoperative gastrointestinal (GI) tract dysfunction (PGID) is common and is associated with increased patient suffering and cost of care. The pathogenesis of PGID is complex and multifactorial. Traditional measures intended to reduce the incidence of PGID, such as the use of prokinetic drugs, nasogastric tube drainage, and the avoidance of early fluid and/or food intake, are apparently not beneficial. The administration of larger volumes of IV fluids to achieve predetermined increases in cardiac output has been shown in randomized trials to improve gut perfusion and reduce the incidence of PGID. A multimodal approach that includes limited surgical incision, regional local anesthesia, early mobilization, and enteral feeding has been associated with a dramatic reduction in postoperative complications, PGID, and length of hospital stay. However, none of these approaches has been validated in adequately powered multicenter prospective randomized controlled trials.
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Affiliation(s)
- Michael G Mythen
- Department of Anaesthesia and Critical Care, University College London, United Kingdom; and Portex Anaesthesia, Intensive Care and Respiratory Unit, Institute of Child Health, University College London, United Kingdom
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26
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Abstract
Postoperative ileus is an iatrogenic condition that follows abdominal surgery. Three main mechanisms are involved in its causation, namely neurogenic, inflammatory and pharmacological mechanisms. In the acute postoperative phase, mainly spinal and supraspinal adrenergic and non-adrenergic pathways are activated. Recent studies, however, show that the prolonged phase of postoperative ileus is caused by an enteric molecular inflammatory response and the subsequent recruitment of leucocytes into the muscularis of the intestinal segments manipulated during surgery. This inflammation impairs local neuromuscular function and activates neurogenic inhibitory pathways, inhibiting motility of the entire gastrointestinal tract. The mechanisms underlying the recruitment of the inflammatory cells, and their interaction with the intestinal afferent innervation, are discussed. Finally, opioids administered for postoperative pain control also contribute to a large extent to the reduction in propulsive gastrointestinal motility observed after abdominal surgery.
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Affiliation(s)
- A J Bauer
- Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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27
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Sanger GJ, Tuladhar BR. The role of endogenous opioids in the control of gastrointestinal motility: predictions from in vitro modelling. Neurogastroenterol Motil 2004; 16 Suppl 2:38-45. [PMID: 15357850 DOI: 10.1111/j.1743-3150.2004.00556.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastrointestinal motility can be assessed in vitro by investigating the effects of drugs or gene knockouts on intestinal propulsion, and on neurone-mediated responses evoked by electrical field stimulation (EFS). The latter predominantly measure enteric motor activity and can detect prokinetic activity of exogenous agents. Some evidence suggests that naloxone has prokinetic activity when evaluated for an ability to modulate responses to EFS, but the effects are inconsistent across different species or intestinal regions. Models of intestinal peristalsis measure an integrated sensory-motor nerve function and possess more intact neuro-neuronal connections. In such preparations, the effects of naloxone also suggest a prokinetic property but again, this is inconsistent. By contrast, consistent prokinetic activity of naloxone is apparent in models where peristalsis is compromised by drug-induced suppression of motor nerve activity or by modulation of endogenous processes using receptor antagonists or inappropriate intraluminal distension. These data suggest that endogenous opioids play little or no role in normal intestinal physiology, but suppress intestinal motility when motor function is compromised. Consequently, drugs that antagonize opioid receptors may exert prokinetic activity in conditions where intestinal motility is reduced, such as constipation. Further work is required to elucidate the opiate receptor(s) involved.
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Affiliation(s)
- G J Sanger
- Neurology and Gastroenterology CEDD, GlaxoSmithKline, Harlow, Essex, UK.
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28
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Affiliation(s)
- James C Nunley
- Department of Surgery, Madigan Army Medical Center, Tacoma, Washington, USA
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29
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Patierno S, Raybould HE, Sternini C. Abdominal surgery induces μ opioid receptor endocytosis in enteric neurons of the guinea-pig ileum. Neuroscience 2004; 123:101-9. [PMID: 14667445 DOI: 10.1016/j.neuroscience.2003.08.052] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Immunohistochemistry and confocal microscopy were used to investigate mu opioid receptor (muOR) internalization in enteric neurons of the guinea-pig ileum following abdominal surgery. The following surgical procedures were performed under halothane or isofluorane anesthesia: a) midline abdominal skin incision, b) laparotomy or c) laparotomy with intestinal manipulation. Gastrointestinal transit was evaluated by using a non-absorbable marker and measuring fecal pellet output. In neurons from normal and control (anesthesia alone) animals, muOR was predominantly at the cell surface. muOR endocytosis following skin incision was not significantly different from controls (21.2+/-3.5% vs. 13.7+/-2.1%, mean+/-S.E.M.), whereas it was significantly increased by laparotomy (46.5+/-6.1%; P<0.01 vs. controls) or laparotomy plus intestinal manipulation (40.5+/-6.1%; P<0.01 vs. controls) 30 min following surgery compared with controls. muOR endocytosis remained elevated at 4 h (38.6+/-1.2%; P<0.01 vs. controls), whereas it was similar to controls at 6 and 12 h (17.5+/-5.8% and 11.2+/-3.0%). muOR endocytosis occurred in cholinergic and nitrergic neurons. Gastrointestinal transit was significantly delayed by laparotomy or laparotomy plus intestinal manipulation (12.8+/-1.2 and 13.8+/-0.6 h vs. 7.0+/-0.5 in controls; P<0.01), but was not significantly changed by skin incision (8.2+/-0.6 h). The findings of the present study support the concept that the noxious stimulation caused by abdominal surgery induces release of endogenous opioids thus resulting in muOR endocytosis in neurochemically distinct enteric neurons. muOR internalization can serve as indirect evidence of opioid release and as a means to visualize neuronal pathways activated by opioids.
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Affiliation(s)
- S Patierno
- CURE Digestive Diseases Research Center, Building 115, Room 224, Veterans Administration Greater Los Angeles Healthcare System, Digestive Diseases Division, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA.
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30
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Abstract
This article will review the pathophysiology of postoperative ileus, with emphasis on potential therapeutic targets, and examine the efficacy of pharmacologic and nonpharmacologic interventions. Proposed mechanisms include actuation of spinal and local sympathetic neural reflexes, inflammatory mediation, and exacerbation by anesthetic or surgical procedures. Some procedures or agents have shown clinical benefit, and these include use of laparoscopic surgery, thoracic epidurals, nonsteroidal anti-inflammatory drugs, and opiate antagonists. Other procedures may be helpful with low risk of adverse effects. These include early feeding and ambulation, laxatives, and possibly neostigmine.
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Affiliation(s)
- Brian Behm
- Division of Gastroenterology, University of California San Francisco, San Francisco, California, USA
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31
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32
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Bauer AJ, Schwarz NT, Moore BA, Türler A, Kalff JC. Ileus in critical illness: mechanisms and management. Curr Opin Crit Care 2002; 8:152-7. [PMID: 12386517 DOI: 10.1097/00075198-200204000-00011] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Nonobstructive ileus, signifying the impairment of coordinated propulsive intestinal motility, remains a frequently documented and almost inevitable consequence of open abdominal surgery and sepsis. Despite the frequency and major impact of ileus on morbidity and mortality, the exact underlying molecular and cellular mechanisms of this important clinical conundrum are still ill defined. Animal models suggest that both neuronal and local inflammatory responses within the intestinal muscularis mechanistically contribute to intestinal ileus. The neuronal mechanism appears to involve the enhanced release of nitric oxide from inhibitory motor neurons. Likewise, nitric oxide and prostaglandins are released from inflammatory cells (macrophages and monocytes) via the induction of nitric oxide synthase (iNOS) and cyclooxygenase-2. Recently, preliminary data have confirmed the existence of an intraoperative local muscularis inflammatory response during surgery in human patients.
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Affiliation(s)
- Anthony J Bauer
- Department of Medicine/Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15216, USA. tbauer+@pitt.edu
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33
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Abstract
Postoperative ileus (POI) is an inevitable adverse consequence of surgical procedures. In fact, prolonged POI can lead to patient discomfort, decreased mobility, delayed enteral feeding, and ultimately, prolonged hospitalizations and increased costs. It is believed that POI occurs as a result of inhibitory neural reflexes and inflammatory processes. The use of postoperative opioids also appears to contribute to ileus. Recently, the potential influence of endogenous opioids, in addition to exogenous opioids, on the pathogenesis of ileus has come to light and spurred investigations into new treatment strategies. Over the years, several treatment modalities have become accepted management options for POI; chief among these are nasogastric suction and prokinetic agents. However, data demonstrating that these agents reduce the duration of POI are limited. Of current treatment modalities, use of epidural local anesthetics appears to be the most effective means of reducing POI. Other potentially effective treatments include early enteral feeding and less invasive surgical procedures. Together, these techniques have reduced the length of stay after colonic surgery to 2 to 3 days. Future studies, including those incorporating investigational agents, such as kappa-opioid agonists and peripheral mu-opioid antagonists, into a multimodal regimen, may offer new treatment options to further impact POI duration.
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Affiliation(s)
- H Kehlet
- Hvidovre University Hospital, Department of Surgical Gastroenterology, DK-2650, Copenhagen, Denmark.
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34
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Lee J, Shim JY, Choi JH, Kim ES, Kwon OK, Moon DE, Choi JH, Bishop MJ. Epidural naloxone reduces intestinal hypomotility but not analgesia of epidural morphine. Can J Anaesth 2001; 48:54-8. [PMID: 11212050 DOI: 10.1007/bf03019815] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
PURPOSE Epidural morphine is associated with decreased bowel motility and increased transit time. Low doses of intravenous naloxone reduce morphine-induced pruritus without reversing analgesia, but the effect of epidural naloxone on bowel motility has not been studied. Therefore we evaluated bowel motility and analgesia when naloxone was co-administered with morphine into the epidural space. METHODS Forty-three patients having combined thoracic epidural and general anesthesia for subtotal gastrectomy were randomly assigned to one of two study groups. All received a bolus dose of 3 mg epidural morphine at the beginning of surgery, followed by a continuous epidural infusion containing 3 mg morphine in 100 ml bupivacaine 0.125% with either no naloxone (control group, n = 18) or a calculated dose of 0.208 microg x kg(-1) x hr(-1) of naloxone (experimental group, n = 25) for 48 hr. We measured the time to the first postoperative passage of flatus and feces to evaluate the restoration of bowel function, and visual analog scales (VAS) for pain during rest and movement. Scores were assessed at 2, 4, 8, 16, 24, 36 and 48 hr postoperatively. RESULTS The experimental group had a shorter time to the first postoperative passage of flatus (5 1.9 +/- 1 6.6 hr vs 87.0 +/- 19.5 hr, P < 0.001 ) and feces (95.3 +/- 25.0 hr vs 132.9 +/- 29.4 hr, P < 0.001). No differences were found in either resting or active VAS between the two groups. CONCLUSION Epidural naloxone reduces epidural morphine-induced intestinal hypomotility without reversing its analgesic effects.
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Affiliation(s)
- J Lee
- Department of Anesthesiology, Kangnam Saint Mary's Hospital, Seoul, Korea
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35
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Abstract
Fedotozine [(1R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]-N,N- dimethyl-n-propylamine, (2S,3S-tartrate] is derived from the arylacetamide series. As with other compounds of this series, fedotozine is more or less selective of kappa(1)-opioid receptors and particularly for the kappa(1a)-receptor subtype, where it acts as an agonist. Pharmacological studies have shown that fedotozine exerts a peripheral antinociceptive action, comparable with that of other kappa-agonists. Its main effects have been demonstrated at the level of the afferent nerve pathways originating from the gut. Fedotozine alters the processing of visceral sensations along these pathways and hence, the perception of gut stimuli at the brain level. It modifies reflexes induced in various pathological conditions, like experimental inflammation of the gut, chemically-induced peritonitis or post-operative ileus. Fedotozine also decreases the nociceptive reflexes triggered by noxious gut distension in animals. In humans, fedotozine decreases the perception of gut distension, both in physiological and pathological conditions. Clinical trials undertaken in patients with functional digestive disorders, non-ulcer dyspepsia and irritable bowel syndrome, have shown that fedotozine relieves abdominal pain in these patients in 6-week treatments. kappa-Opioid receptors remain an interesting area for future development of new treatments for abdominal pain in patients with functional digestive disorders.
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Affiliation(s)
- M Delvaux
- Gastroenterology Unit, CHU Rangueil, F-31403 Toulouse Cedex 04, France.
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36
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Abstract
BACKGROUND Postoperative ileus has traditionally been accepted as a normal response to tissue injury. No data support any beneficial effect of ileus and indeed it may contribute to delayed recovery and prolonged hospital stay. Efforts should, therefore, be made to reduce such ileus. METHODS Material was identified from a Medline search of the literature, previous review articles and references cited in original papers. This paper updates knowledge on the pathophysiology and treatment of postoperative ileus. RESULTS AND CONCLUSION Pathogenesis mainly involves inhibitory neural reflexes and inflammatory mediators released from the site of injury. The most effective method of reducing ileus is thoracic epidural blockade with local anaesthetic. Opioid-sparing analgesic techniques and non-steroidal anti-inflammatory agents also reduce ileus, as does laparoscopic surgery. Of the prokinetic agents only cisapride is proven beneficial; the effect of early enteral feeding remains unclear. However, postoperative ileus may be greatly reduced when all of the above are combined in a multimodal rehabilitation strategy.
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Affiliation(s)
- K Holte
- Department of Surgical Gastroenterology, Hvidovre University Hospital, Denmark
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37
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Abstract
Acute pseudo-obstruction may manifest clinically in one of three forms--acute gastroparesis, ileus, and acute colonic pseudo-obstruction (Ogilvie's syndrome). Though formerly associated primarily with the postoperative state, these entities are increasingly recognized in association with a wide variety of major medical problems. There are few controlled studies to guide the clinician in the management of these disorders. Treatment remains largely empirical, and time-honored, based primarily on "bowel rest," nasogastric decompression, and supportive care. While a wide variety of pharmacologic approaches have been advocated, few have been subjected to, or survived, the rigors of a properly controlled trial. Neostigmine is a notable exception, and has been shown to be effective in Ogilvie's syndrome. Perforation is a significant threat in megacolon; colonoscopic, or surgical decompression may, therefore, be indicated. Both are associated with significant risks in this context, but may prevent progression to perforation with its attendant mortality. New approaches seek to exploit current concepts in the pathophysiology of ileus and megacolon but have not, as yet, achieved efficacy in human studies.
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38
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Bonaz B, Rivière PJ, Sinniger V, Pascaud X, Junien JL, Fournet J, Feuerstein C. Fedotozine, a kappa-opioid agonist, prevents spinal and supra-spinal Fos expression induced by a noxious visceral stimulus in the rat. Neurogastroenterol Motil 2000; 12:135-47. [PMID: 10771495 DOI: 10.1046/j.1365-2982.2000.00188.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Fedotozine, a kappa opioid agonist, reverses digestive ileus caused by acetic acid (AA)-induced visceral pain in rats. The aims of this study were: to map, in conscious rats, central pathways activated by AA using Fos as a marker of neuronal activation; to characterize primary afferent fibres involved in this activation; and to investigate the effect of fedotozine on AA-induced Fos expression. AA (0.6%; 10 mL kg-1) was injected i.p. in conscious rats either untreated; pretreated 14 days before with capsaicin; pretreated 20 min previously with fedotozine; or pretreated 2 h prior to fedotozine with the kappa-antagonist nor-binaltorphimine (nor-BNI). Controls received the vehicle alone. 60 min after injection of AA, rats were processed for Fos immunohistochemistry. Visceral pain was assessed by counting abdominal cramps. AA induced Fos in the thoraco-lumbar spinal cord (laminae I, V, VII and X) and numerous brain structures such as the nucleus tractus solitarius, and paraventricular nucleus (PVN) of the hypothalamus, whereas almost no Fos labelling was observed in controls. Capsaicin pretreatment blocked AA-induced Fos in all structures tested. Fedotozine significantly decreased AA-induced abdominal cramps and Fos immunoreactivity in the spinal cord and PVN, this effect being reversed by nor-BNI pretreatment. AA induces Fos in the spinal cord and numerous brain nucuei, some of which are involved in the control of digestive motility in rats. This effect is mediated through capsaicin-sensitive afferent fibres and prevented by fedotozine most likely through a peripheral action on visceral afferents.
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Affiliation(s)
- B Bonaz
- Laboratoire de Physiologie, Section Neurophysiologie, Institut National de la Santé et de la Recherche Médicale, U318, Hôpital A. Michallon, Centre Hospitalier Universitaire, Grenoble, France.
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39
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Abstract
This paper is the twentieth installment of our annual review of research concerning the opiate system. It summarizes papers published during 1997 that studied the behavioral effects of the opiate peptides and antagonists, excluding the purely analgesic effects, although stress-induced analgesia is included. The specific topics covered this year include stress; tolerance and dependence; eating and drinking; alcohol; gastrointestinal, renal, and hepatic function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurologic disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunologic responses; and other behaviors.
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Affiliation(s)
- G A Olson
- Department of Psychology, University of New Orleans, LA 70148, USA
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