acute pancreatitis ( ap ) is a common acute abdominal disease that may be caused by a variety of etiologies , such as gallstones , high - fat diets , and immune factors . . however , approximately 20% of patients with ap may develop severe acute pancreatitis ( sap ) , which is associated with rapid progression , frequent complications , and exceptionally high mortality . numerous studies have shown that the intestinal function disorder occurring in the early stage of ap results in decreased intestinal motility . this intestinal function disorder is thought to be related to the systemic inflammatory response , intestinal ischaemia - reperfusion injury , and stimulation of local fluid collection in the retroperitoneal space and abdominal cavity . decreased intestinal motility decreased intestinal motility worsens gastrointestinal bloating , increases intra - abdominal pressure ( iap ) , and probably induces abdominal compartment syndrome ( acs ) , a fatal complication of ap . it can also lead to the alteration of intestinal flora , which dramatically increases the risk of enterogenous infection . in addition , intestinal motility is closely associated with the implementation of enteral nutrition ( en ) . decreased intestinal motility in fact , en has been confirmed as one of the most important treatments for ap and is closely associated with the prognosis . thus , the clinical study of ap has focused on how to reduce the incidence of intestinal motility disorders and promote their recovery . in the past decade , the important role of enhanced recovery after surgery ( eras ) has become widely recognized . the underlying goals of this approach are to reduce morbidity , enhance the rate of recovery , and shorten the postoperative length of stay ( los ) . sham feeding is a method used in eras for promoting the recovery of gastrointestinal motility . research has shown that sham feeding can activate the cephalic - vagal reflex and thus promote gastrointestinal motility by humoral and nervous stimulation . at present , sham feeding can be also be effective after colon   and breast surgeries . however , there is limited evidence regarding whether sham feeding also plays a role in the treatment of ap . therefore , this prospective , randomized , controlled trial was performed to investigate the efficacy and safety of gum chewing , a type of sham feeding , in the early treatment of ap . this was a single - center , randomized , controlled trial registered in the chinese clinical trail registry ( chictr - och-13003427 ) . all of the pancreatitis patients admitted to chengdu military general hospital were screened for trial eligibility . the patients enrolled in this study were randomly assigned into either the sham - chewing group or the control group . this study was conducted in accordance with the principles of the declaration of helsinki , and the study protocol was approved by the institutional review board of chengdu military general hospital ( lkpz201413 ) . the following inclusion criteria were used : ( 1 ) ap was diagnosed consistent with the revised atlanta classification   and ( 2 ) ages between 18 and 70 years . the exclusion criteria were as follows : ( 1 ) ap subsequent to a second disease , endoscopic retrograde cholangiopancreatography ( ercp ) , or suspected malignancy of the pancreas or biliary tree , ( 2 ) medical history of immune deficiency and abdominal operation or diagnosis of pancreatitis first made during surgery , or ( 3 ) inability to provide informed consent . numbered opaque envelopes were used for concealment , kept at a central location , and opened sequentially . randomization , opening of envelopes , and allocation were all performed by a statistician who was not involved with the study . however , it was difficult to keep the sham feeding completely blind to the patients , ward nurses , and the research assistant without a suitable placebo - control . patients allocated to the sham feeding group were instructed to chew gum for 15 min 4 times a day ( usually at 8 : 00 , 12 : 00 , 16 : 00 , and 20 : 00 ) . these treatments mainly included early fluid resuscitation , targeted antibiotic therapy , early en , and the management of local and systemic complications . further step - up interventions , consisting of percutaneous catheter drainage , minimally invasive debridement , and open laparotomy , were utilized for those patients who developed infected peri - pancreatic necrosis . the primary outcome of this study was to determine the effectiveness and safety of sham feeding in the treatment of ap . the following outcome variables were analyzed as secondary outcomes : return of gastrointestinal function ( time to first flatus and time to passage of feces ) , the details of en ( time to full tolerance of oral diet and time to achieve the energy target ) , iap , hospitalization days , and medical expenses . baseline characteristics ( including age , sex , and etiology ) , laboratory test results , and several clinical scores were recorded at admission . acute physiology and chronic health evaluation ii ( apache ii ) score and systemic inflammatory response syndrome ( sirs ) were defined by the atlanta classification . iap > 20 mmhg associated with new - onset organ failure or acute worsening of existing organ failure was defined as acs . statistical analysis was performed using spss , version 16.0 for windows ( spss inc . , for normally distributed data , variables were compared using student s t - test for 2 groups . for skewed data , proportional variables were compared using the pearson  test or the fisher exact test , as appropriate . this was a single - center , randomized , controlled trial registered in the chinese clinical trail registry ( chictr - och-13003427 ) . all of the pancreatitis patients admitted to chengdu military general hospital were screened for trial eligibility . the patients enrolled in this study were randomly assigned into either the sham - chewing group or the control group . this study was conducted in accordance with the principles of the declaration of helsinki , and the study protocol was approved by the institutional review board of chengdu military general hospital ( lkpz201413 ) . the following inclusion criteria were used : ( 1 ) ap was diagnosed consistent with the revised atlanta classification   and ( 2 ) ages between 18 and 70 years . the exclusion criteria were as follows : ( 1 ) ap subsequent to a second disease , endoscopic retrograde cholangiopancreatography ( ercp ) , or suspected malignancy of the pancreas or biliary tree , ( 2 ) medical history of immune deficiency and abdominal operation or diagnosis of pancreatitis first made during surgery , or ( 3 ) inability to provide informed consent . numbered opaque envelopes were used for concealment , kept at a central location , and opened sequentially . randomization , opening of envelopes , and allocation were all performed by a statistician who was not involved with the study . however , it was difficult to keep the sham feeding completely blind to the patients , ward nurses , and the research assistant without a suitable placebo - control . patients allocated to the sham feeding group were instructed to chew gum for 15 min 4 times a day ( usually at 8 : 00 , 12 : 00 , 16 : 00 , and 20 : 00 ) . these treatments mainly included early fluid resuscitation , targeted antibiotic therapy , early en , and the management of local and systemic complications . further step - up interventions , consisting of percutaneous catheter drainage , minimally invasive debridement , and open laparotomy , were utilized for those patients who developed infected peri - pancreatic necrosis . the primary outcome of this study was to determine the effectiveness and safety of sham feeding in the treatment of ap . the following outcome variables were analyzed as secondary outcomes : return of gastrointestinal function ( time to first flatus and time to passage of feces ) , the details of en ( time to full tolerance of oral diet and time to achieve the energy target ) , iap , hospitalization days , and medical expenses . baseline characteristics ( including age , sex , and etiology ) , laboratory test results , and several clinical scores were recorded at admission . acute physiology and chronic health evaluation ii ( apache ii ) score and systemic inflammatory response syndrome ( sirs ) were defined by the atlanta classification . iap > 20 mmhg associated with new - onset organ failure or acute worsening of existing organ failure was defined as acs . statistical analysis was performed using spss , version 16.0 for windows ( spss inc . , for normally distributed data , variables were compared using student s t - test for 2 groups . for skewed data , proportional variables were compared using the pearson  test or the fisher exact test , as appropriate . from may 2014 to december 2015 , a total of 312 patients were assessed for eligibility , and 108 of them were excluded based on the inclusion and exclusion criteria . therefore , a total of 103 patients in the sham feeding group and 101 in the control group were included ( figure 1 ) . the demographic data ( age , sex , and etiology ) from the 2 groups were comparable ( table 1 ) . the etiology was mainly from hyperlipemia ( 39.8% in the sham feeding group and 36.6% in the control group ) and gallstone ( 30.1% in the sham feeding group and 27.7% in the control group ) . in addition to the demographic data , the severity of ap in the sham feeding group was similar to that in the control group ( p0.05 ) . there was no difference between the 2 groups in the intervals from onset of symptoms to admission ( p0.05 ) . in addition , there was also no significant difference in the body - mass index ( bmi ) and serum albumin between the sham feeding group and the control group ( p0.05 ) . although the mortality in the control group ( 5.9% ) was slightly higher than that in the sham feeding group ( 4.9% ) , there was no significant difference between the 2 groups ( p<0.05 ) . there were also no differences between groups in the proportion of patients who developed infected necrosis and needed further interventions , which were 18.4% and 19.8% , respectively . the average los was 22.7 days for all patients . in the sham feeding group , the number of days in hospital were 21.915.9 and days in the icu were 3.32.9 . in the control group , the number of days in the icu ( 3.63.1 ) was similar to the sham feeding group ( p0.05 ) , and the days spent in hospital ( 23.717.3 ) were more than that of the sham feeding group ( p<0.05 ) . the average total cost during hospitalization was significantly higher in the control group than in the sham feeding group ( p<0.05 ) . the results suggest that the patients instructed to chew gum recovered from pancreatitis more quickly but without better outcomes . the time to first flatus , time to passage of feces , and time to begin enteral feeding in the sham feeding group were all shorter than those in the control group ( 2.91.3 vs. 3.31.2 , 4.12.1 vs. 4.81.9 , 2.71.5 vs. 2.91.6 , respectively ) . however , no differences were found between groups except in the time to passage of feces ( p<0.05 ) . the incidences of gastrointestinal adverse events after refeeding in the 2 groups were similar ( p0.05 ) , except for vomiting . the patients in the sham feeding group took less time to achieve their nutrition target ( 25 kcal / kg / d ) and fully tolerated an oral diet ( p<0.05 ) . no differences were observed in the change of iap and the incidence of acs between both groups ( p<0.05 ) . moreover , weight and serum albumin decreased more significantly 1 week after admission in the control group ( p<0.05 ) . decreased intestinal motility is commonly observed in clinical practice during the early stage of ap . the etiology of this gastrointestinal disorder is believed to be multifactorial . during this period , the fluid collections , which are rich in inflammatory factors , including tnf- , il-1 , and il-10 , accumulate in the peritoneal cavity and around the retroperitoneal pancreatic space . local tissue hypoxia prompted by blood flow redistribution induces gastrointestinal edema and weak smooth muscle motility . in addition , inflammatory mediators such as vasoactive intestinal peptide , substance p , and nitric oxide are released in association with the stress response . all of the above factors directly or indirectly contributed to the reduced bowel motility and ileus . once the intestinal motility decreases , digestive secretions and gases accumulate inside the bowel , leading to increased iap . an iap higher than 20 mmhg may induce acs and thus affect respiration and circulation functions . in ap patients with accompanying acs , the mortality rate drastically increases . the decrease in intestinal motility can also result in delayed gastrointestinal emptying and subsequently induced nausea and vomiting , leading to electrolyte disturbance and acid - base imbalance . in addition , research has confirmed that decreased intestinal motility is associated with an obvious imbalance of the intestinal flora . the aerobic and anaerobic organisms become unbalanced and the normal bio - barrier is broken after intestinal motility decreases . decreased bowel movements and mucus flow are also more beneficial for the retention and reproduction of pathogenic bacteria . second hit  . translocated bacteria and endotoxins activate monocytes and macrophages to release excessive cytokines and inflammatory mediators , possibly inducing sirs . in addition , early en has been recognized as one of the most important treatments for ap , especially sap . early en has been proven to be related to suppression of negative nitrogen balance in the acute inflammation phase , the promoted restoration of the intestinal barrier function , and the decreased occurrence of enterogenous infection . furthermore , decreased gastric motility can also lead to the development of en intolerance , causing delayed or failed en . however , en has been reported to be associated with better clinical outcomes , and delayed or failed en can result in a prolonged hospital stay and poor prognosis . therefore , reducing the incidence of intestinal motility disorders and promoting motility restoration has become a major research topic in the treatment of ap . for example , prokinetic agents ( e.g. , serotonin receptor agonists such as itopride ) , traditional chinese medicine ( e.g. , da - cheng - qi decoction and qing - yi decoction ) , and some mechanical stimulations ( e.g. , electrical stimulation )   have been proven to improve gastrointestinal motility in previous studies . however , the clinical safety , efficacy , and convenience of these strategies have not been well studied . sham feeding is a method used in eras for promoting the recovery of gastrointestinal motility . research has shown that sham feeding can activate the cephalic - vagal reflex and thus promote gastrointestinal motility by both humoral and nervous stimulation . gum chewing mimics food intake and is thought to be an inexpensive and convenient type of sham feeding . it has also been suggested that the hexitols in sugar - free gum may play a role in resolving ileus through their osmotic effects . at present , sham feeding via gum chewing has been utilized in postoperative management following multiple surgeries and has been proven to be safe and efficacious . therefore , we speculated that sham feeding might be safe and efficacious in the treatment of ap as well . we also considered that sham feeding had the potential to promote intestinal motility without significantly increasing the burden on the digestive tract , as well as preventing adverse gastrointestinal events . according to our current study , the los and hospital costs for the sham feeding group were reduced , although there was no significant effect on mortality . moreover , the incidence of gastrointestinal adverse events , including nausea , vomiting , abdominal pain , and diarrhea , significantly decreased in the sham feeding group . the implementation of en also showed improvement in the sham feeding group . compared with the control group , the sham feeding group was able to reach the nutritional targets ( 25 kcal / kg / d ) earlier , with better nutritional indicators . meanwhile , the proportion of patients who terminated or delayed en because of en intolerance was significantly lower in the sham feeding group . thus , for the first time , we demonstrated the effectiveness and safety of sham feeding in patients with ap . first , as a single - center study , the sample size was relatively small , which is a potential source of bias . second , the type of chewing gum was not uniformly required during the study design ; as a result , the subjects chewed different types of gum , and the substances in the gum ( e.g. , with or without sugar ) may have affected the results of the study . furthermore , the en performed in our study was slightly different from that recommended in international guidelines . many current guidelines recommend that for patients with mild or moderate ap , no en is needed , but for severe ap , en should be started within the first 48 or 72 h after disease onset . in our clinical practice , however , intolerance to early en ( especially within 36 h after disease onset ) is more common , which may be explained by differences in ethnicity or en formula . thus , in our current study , a relatively compromised en formula was used . for patients with ap , clinicians with extensive clinical experience decided on the mode and starting time of en based on disease conditions : oral feeding was applied for patients with mild ap , whereas tube feeding was applied for patients with more severe conditions . en was typically started within 4872 h after admission , which was slightly later than is recommended in the guidelines . in summary , this prospective , randomized , controlled trial is the first to confirm that sham feeding is effective and safe for treating ap . in addition , other aspects ( including pain management , minimally invasive surgery , early activities , and early en ) of eras may also be applicable in the clinical management of ap . with this in mind , in our future studies we will further investigate the application of eras in the management of ap .
backgroundthe correlation between sham feeding and acute pancreatitis ( ap ) has only been examined in limited studies . we aimed to investigate the efficacy and safety of sham feeding in the early stage of ap.material/methodsa randomized 
 controlled clinical trial was performed . 
 equal groups of ap patients were recruited . 
 patients in the sham feeding group received chewing gum 4 times a day after admission . 
 all patients in the trial received standard treatment consistent with the guidelines for ap . 
 the primary outcomes were mortality , length of stay ( los ) , and medical expenses . 
 secondary outcomes were the incidence of complications and other adverse events , return of gastrointestinal function , the details of enteral nutrition and intra - abdominal pressure.resultsfrom may 2014 to december 2015 , a total of 204 patients were recruited . 
 the los and hospital costs in the sham feeding group were reduced , although mortality was equivalent between groups . 
 the return of gastrointestinal function occurred earlier in the sham feeding group , with no complications related to gum chewing.conclusionssham feeding with chewing gum is safe and efficacious in the early stage of ap .