Medical Hypotheses xxx (2014) xxx–xxx
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Nicotine gum chewing: A novel strategy to shorten duration of postoperative ileus via vagus nerve activation q Z. Wu a,⇑, G.S.A. Boersema a, J. Jeekel b, J.F. Lange a a b
Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Neuroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 29 April 2014 Accepted 9 June 2014 Available online xxxx
a b s t r a c t Postoperative ileus (POI) is a transit cessation of bowel motility after surgery. Substantial evidences suggest that gum chewing accelerate the recovery of bowel motility after surgery. Perioperative nicotine administration reduces postoperative opioid use and prevents postoperative nausea and vomiting. Nicotine gum chewing combines stimulation of the cephalic-vagal reflex by gum chewing, and activation of the cholinergic anti-inflammatory pathway by nicotine administration. We therefore hypothesized that nicotine gum chewing reduces POI and improves patient outcomes such as shortening the length of hospitalization as well as saving medical costs. As nicotine gum is commercially available, inexpensive, and has been in use for many years without any severe side effects, it may have a wide clinical application in POI prevention. Ó 2014 Published by Elsevier Ltd.
Introduction Postoperative ileus (POI) is a common complication after abdominal surgery. It is a transit cessation of bowel mobility after surgery. Clinical manifestation of POI include nausea, vomiting, abdominal distension, and lack of flatus and defecation [1]. Delayed recovery of bowel function leads to other serious morbidity such as pulmonary complications, hospital-acquired infections, and longer hospitalization, and it also lead to higher medical cost [2]. The economic burden of POI in the USA health care system is estimated to surpass $1.5 billion per year [3]. Numerous risk factors such as previous surgery, general anesthesia and postoperative opioid consumption have been reported, contributing to prolonged bowel dismotility [4]. Targeting on them, multimodal fast-track perioperative care programs such as Enhanced Recovery After Surgery (ERAS) including adequate pain relief, minimal invasive surgery, and early enteral nutrition, are now being implemented with promising results. Previous research revealed that surgical procedures trigger two different phases of POI: an early neurogenic phase and a late inflammatory phase. The latter one is considered to be a more clinically relevant cause of gastrointestinal dismotility [4], but efficient strategies targeting
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it remains unavailable in clinical practice. In experimental studies anti-inflammation therapy with stimulation of the vagus nerve showed promising results in preventing POI. Activation the vagus nerve increases bowel motility by controlling inflammatory cell recruitment via the cholinergic anti-inflammatory pathway [1,4,5]. With the promising experimental results, different strategies of vagus nerve stimulation (e.g. physiological, pharmacological, and electrical stimulation) are now being attempted in human patients. The hypothesis Nicotine chewing gum may have double effect on stimulating the vagus nerve via physiological pathways by chewing, and via pharmacological pathways by the nicotine administration. Although no direct evidence is available to date, accumulative data from clinical and experimental studies are in favor of the hypothesis: nicotine gum chewing reduces the time of POI and improve patient’s outcomes via vagus nerve activation. We evaluated the current evidence supporting this hypothesis in the following parts. Evaluation of the hypothesis Part I. Influence of gum chewing in preventing POI
This work is supported by Stichting Coolsingel, Rotterdam, The Netherlands.
⇑ Corresponding author. Address: Erasmus MC, Laboratory of Experimental Surgery, Room Ee-173, Postbus 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31 10 70 43 683; fax: +31 10 70 44 746. E-mail address:
[email protected] (Z. Wu).
Gum chewing is a form of sham feeding, which mimics the cephalic phase of digestion, stimulates the gastrointestinal motility via the vagal pathways [6]. In addition to the vagal pathway,
http://dx.doi.org/10.1016/j.mehy.2014.06.011 0306-9877/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Wu Z et al. Nicotine gum chewing: A novel strategy to shorten duration of postoperative ileus via vagus nerve activation. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.06.011
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Z. Wu et al. / Medical Hypotheses xxx (2014) xxx–xxx
ingesting contents of maxitols in sugar-free chewing gum may also accelerate the intestinal transit [7]. Since Asao et al. first demonstrated that gum chewing stimulated bowel motility and aided early recovery from POI in surgical patients [8], many randomized clinical trials have reported similar results [2,9–12]. In general, consensus has been reached that gum chewing reduces the duration of POI in abdominal surgery in the recent decade [13]. The postoperative gum chewing is supported by many systemic reviews and meta-analysis [6,14–17], which reported that chewing gum could shorten both POI duration and postoperative hospitalization for approximately one day [18]. Importantly, gum chewing is not only beneficial in POI prevention after gastrointestinal surgery. It has shown satisfactory results in the prevention of POI in other types of intra-abdominal surgery (e.g. gynecological operations) as well [19,20].
Consequences of the hypothesis and conclusion Substantial evidence suggests gum chewing accelerates the recovery of bowel motility after surgery. Nicotine gum chewing combines the stimulation of the cephalic-vagal reflex by gum chewing, and the activation of the cholinergic anti-inflammatory pathway by nicotine administration, it might be beneficial to the prevention of POI. As nicotine gum is commercially available, inexpensive, and has been in use for many years without any severe side effects, it may have a wide clinical application in POI prevention. Nicotine gum chewing may reduce POI via activating the vagal pathway and result in better patient outcomes such as shortening the length of hospitalization as well as saving medical costs.
Funding Part II. Influence of perioperative administration of nicotine Nicotine, a selective cholinergic agonist, is an essential regulator of the cholinergic anti-inflammatory pathway [21]. In animal models, nicotine has been shown to improve survival rates of sepsis by stimulating a7 nicotinic acetylcholine receptor (nAchR) [22]. Experimental studies have also shown the effect of specific a7 receptor agonist that ameliorates POI in rats [5], while other nAchR also play important roles mediating the cholinergic antiinflammatory pathway [5,23]. Despite the nicotine replacement therapy (NRT), nicotine administration has also been investigated for other medical indications, and many of them provide us indirect evidence of its possible effect on preventing POI. Perioperative administration of nicotine (e.g. nicotine patch) has been shown to reduce postoperative nausea and vomiting [24–26], which are common clinical manifestations of POI. Prevention of those symptoms may significantly accelerate the recovery of bowel function after surgery. Preoperative nicotine administration also reduces postoperative opioid consumption [27–30], while reducing opioid consumption is an important strategy of shortening POI [1,4,31]. This effect might be more evident to smoker patients because they may require more opioid compared to nonsmoker patients after surgery [32– 34]. Given that approximately 25–40% of colorectal patients are smokers [35,36], respective recommendations of nicotine gum chewing (i.e. dosage, frequency) should be considered between smoker and non-smoker patients due to their different requirements in postoperative analgesia and varied responses to nicotine administration. It is important to notice that postoperative nausea and vomiting are strongly influenced by opioid administration in a dosedependent pattern [37]. Also, the a7 nicotinic receptor seems to mediate the nicotine-induced analgesia [38], so its activation by nicotine administration may benefit the control of both postoperative pain and POI. One main concern of perioperative nicotine use is its potential systemic influence or intoxication [39], especially in non-smoker patients. However, no obvious adverse events (e.g. cardiovascular events) were reported in the studies included in Part II, many of which only included non-smoker patients. There was no significant difference between the groups in postoperative heart rate, arterial blood pressure, respiratory rate, or oxygen saturation after temporal nicotine administration [28,29]. The effective nicotine dosage in those studies were lower than that in NRT, let alone the dosage in cigarette smoking [40]. However, localized side effects such as dislike the taste, irritation of the tongue, mouth, and throat, and occasional nausea caused by nicotine gum chewing should be expected [41]. But the incidence of these side effects is now much lower than it was with the earlier forms of the gum.
This work is supported by Stichting Coolsingel, Rotterdam, The Netherlands.
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Please cite this article in press as: Wu Z et al. Nicotine gum chewing: A novel strategy to shorten duration of postoperative ileus via vagus nerve activation. Med Hypotheses (2014), http://dx.doi.org/10.1016/j.mehy.2014.06.011