Gastrointestinal Motility And Functional Bowel Disorders, Series #14

Intestinal Malrotation Volume I: The Pediatric Perspective

February 2016 • Volume XL, Issue 2
Eduardo D. Rosas-Blum,Aldo Maspons

Read Article

In this article we discuss the following questions: Are there asymptomatic patients that should be screened for malrotation? If malrotation is found, what should the next step be? Should an elective Ladd’s procedure be performed or should observation be instituted?

Eduardo D. Rosas-Blum1 Aldo Maspons1 Paul L. Foster School of Medicine, Texas Tech University Health Science Center at El Paso,Department of Pediatric, Division of Gastroenterology, Hepatology, and Nutrition1 El Paso, TX

Intestinal malrotation is a rare congenital abnormality that occurs when the normal rotation and fixation of the intestines does not occur.1 About 90% of the cases of malrotation are diagnosed before the first birthday with the majority of the diagnosis being made in the first month of life.2 The most common complication of intestinal malrotation is midgut volvulus which could lead to intestinal necrosis and be potentially fatal if not promptly diagnosed and surgically treated.3 The reported incidence for malrotation is estimated at 1/6,000 live births1 while the absolute incidence is unknown. Autopsy studies have reported an incidence as high as 1 % of the total population.2

The spectrum of intestinal malrotation includes non-rotation, incomplete rotation, reversed rotation, and mesocolic hernia. Non-rotation is characterized by incomplete counterclockwise rotation of the midgut around the superior mesenteric artery (SMA). Essentially the small bowel is on the left of the abdomen, the colon on the right, and the cecum displaced anteriorly and midline. This type of malrotation has an increased risk for midgut volvulus. Incomplete rotation occurs when the intestine only rotates 180 degrees rather than the total 270 degrees. The duodenojejunal junction is on the right and the cecum is in the upper abdomen just left of the SMA; the same risk of midgut volvulus is present. Reversed rotation and mesocolic hernia are rare and difficult to diagnose. Both conditions can present with chronic abdominal symptoms or acute bowel obstruction in the absence of previous abdominal surgeries.4

Most of the patients have an asymptomatic malrotation which sometimes is incidentally found while testing, specifically imaging for other clinical conditions. Symptomatic malrotation usually present early in life with bilious emesis and abdominal pain as the most common symptoms. Other symptoms may include hematemesis and rectal bleeding. Older children with symptomatic malrotation have more vague symptoms that include: anorexia or nausea, intermittent apnea, failure to thrive, constipation, and diarrhea.3 It is important to suspect intestinal malrotation in older children that present with recurrent episodes of abdominal pain associated with symptoms of intestinal obstruction pain, irritability, vomiting, or failure to thrive.

For patients who are symptomatic as a result of malrotation, surgery is the treatment of choice. When it comes to asymptomatic malrotation, there is a lack of consensus. There are no prospective studies and only retrospective chart reviews and computer modeling.5 The questions that often arise are:

  • 1. Are there asymptomatic patients that should be screened for malrotation?
  • 2. If malrotation is found, what should the next step be? Should an elective Ladd’s procedure be performed or should observation be instituted 5? Surgery is a consideration in these asymptomatic patients because volvulus is a theorhetical risk.

Graziano et al. summarized the available literature and concluded that there was a lack of evidence to support screening asymptomatic patients for malrotation. Also, there was minimal evidence to screen those patients with heterotaxy syndrome (HS).6 Patients with HS have cardiac and visceral malpositionining. In these patients, volvulous most commonly occurs in the first year of life and most cases occur in the first month of life.7,8 A recent literature review performed by Landisch, et al. found that 47% of patients with HS have intestinal rotation abnormalities on upper gastrointestinal series, but only 1.2% have an increased risk of developing volvulus.7 Pockett et al. found that 57% of patients with HS have serious complications and argued against prophylactic Ladd procedure.

What is true is that prospective data is needed and in the interim, we recommended that with each malrotation, the physician carefully weigh their experience and how it coincides with patient outcomes. From a pediatric gastroenterology perspective, we follow our field’s common adage-once a malrotation, always a malrotation. We therefore observe until clinical symptoms tell us otherwise.

Liver Disorders, Series #4

Primary Biliary Cholangitis

January 2016 • Volume XL, Issue 1
Duminda Suraweera,Courtney Reynolds,Shehan Thangaratnam,Gaurav Singhvi

Read Article

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic, cholestatic, inflammatory liver disease characterized by destruction of intrahepatic bile ducts resulting in progressive liver damage. The etiology of PBC is still not fully understood but likely involves both environmental and genetic factors. Here we provide a review of the etiology, pathogenesis, natural history, diagnosis and management of primary biliary cholangitis.

Download Tables, Images & References

A Case Report

An Unusual Presentation of Myopathy in Celiac Disease

January 2016 • Volume XL, Issue 1
John R. Stroehlein,Martin Poliak,Huamin Wang

Read Article

Although celiac disease in adults is more often manifest by non-gastrointestinal pathology or nutritional deficiency, indeterminate gastrointestinal symptoms combined with hepatopathy and myopathy can be an indication of celiac disease despite a normal anti TTG and serum IgA. This case illustrates a.) the importance of small bowel biopsy to render a diagnosis of celiac disease and b.) the potential for myopathy to occur without overt myositis, obvious nutritional deficiencies or metabolic bone disease. Celiac disease should be considered and pursued as a diagnostic possibility when the cause of weight loss and myopathy is indeterminate.

Although rare, the development of combined myopathy and hepatopathy from celiac disease is of clinical importance and requires consideration when gastrointestinal symptoms are associated a combination of markedly elevated creatine kinase and loss of muscle mass. This is illustrated by the following case which calls attention to the possibility of celiac disease as the basis for myopathy and hepatopathy.

A 66 year-old Caucasian female with a history of breast cancer developed acute onset of diarrhea beginning in February 2011. Her history included stress related irritable bowel symptoms, not necessarily with diarrhea, and reflux managed with a proton pump inhibitor. Recent upper and lower endoscopy were reported to be normal. She was empirically treated with ciprofloxacin and metronidazole by her primary physician. Her diarrhea improved but did not resolve and was followed by myalgia, fatigue, noticeable muscle loss without muscle tenderness and general weakness without electrolyte abnormalities. Subsequent treatment with a yogurt based probiotic, hyoscyamine and rifaximin were unsuccessful. Notable physical exam findings were limited to loss of muscle mass. She was referred for evaluation 6 months later; at that time, stool evaluation (C. difficile, ova and parasites and culture) was negative but lactoferrin was positive. Colonoscopy with biopsies performed elsewhere in October 2011 was negative for microscopic colitis. Her with consistently normal alkaline phosphatase and bilirubin. A normal gamma glutamyl transpeptidase (GGT) and negative viral serology prompted evaluation of the creatine kinase which proved to be 355 U/L and rose to 561 U/L as of December. Duodenal biopsies obtained during esophagogastroduodenoscopy (EGD) revealed chronic inflammatory change, villous atrophy and intraepithelial lymphocytosis, suggestive of celiac disease (Figure 1A & 1B). A gluten free diet was initiated and was followed by prompt normalization of all biochemical abnormalities with subsequent 35 pound weight gain and restoration of muscle mass. All of the patient’s symptoms resolved and have remained resolved, and the liver enzymes and creatine kinase have remained normal (Figure 2).

This index case exemplifies the possibility for myopathy to occur as a consequence of celiac disease. The possibility of myopathy was initially considered when the GGT was normal despite significant elevation of the ALT and AST. Additionally, duodenal biopsies are often necessary to establish the diagnosis of celiac disease in the absence of hypokalemia or other electrolyte abnormalities.1 Prior case reports of celiacinduced myopathy have been reported in children.2-3 Celiac disease associated myopathy may be more commonly encountered alongside other manifestations of gluten-sensitive enteropathy including metabolic bone disease4-6 and polyneuropathy7 or, even more rare, myelopathy. There has been interest in the association of myotonic dystrophy and celiac disease although the response to gluten restriction is not predictable. Our case was not characterized by the aforementioned associations nor was there evidence of an inflammatory myopathy, which is often associated with higher levels of creatine kinase and elevation of the sedimentation rate. Although response to gluten restriction is not assured, the mere fact that there is no specific treatment for otherwise idiopathic inflammatory myopathy renders the association with celiac disease to be of more than passing interest.8

The association between celiac disease and neuromuscular disorders is not well defined; however, it is clear that celiac disease can manifest primarily if not exclusively with neuromuscular pathology. Myopathy is the third most common neuromuscular disorder associated with sprue and second only to ataxia and peripheral neuropathy.9 In addition to a clinical association between celiac disease and neuromuscular manifestation is the presence of IgA deposits against transglutaminase 2 observed in muscle in a patient with celiac disease.10 Interestingly, the antigen that endomysial antibodies recognize is tissue transglutaminase type 2. It is important to recognize the possibility that celiac disease can present with extra intestinal manifestations including unexplained myopathy.

Download Tables, Images & References

Frontiers In Endoscopy, Series # 24

Extension of a Prior Biliary or Pancreatic Sphincterotomy: Efficacy, Outcomes, and Adverse Events

January 2016 • Volume XL, Issue 1
Sheeva Parbhu,Douglas G. Adler

Read Article

Endoscopic sphincterotomy (ES) is a complex procedure performed under direct endoscopic observation. ES is performed for a variety of both biliary and pancreatic disorders, including the treatment of biliary and pancreatic leaks, to facilitate the placement of biliary or pancreatic stents, as a precursor to cholangioscopy and/or pancreatoscopy, and to treat suspected sphincter of Oddi dysfunction. The need for repeat sphincterotomy can arise in clinical practice and interventionalists should be prepared to perform this when it is needed. In this article we discuss the efficacy, outcomes, and adverse events associated with these procedures.

Sheeva Parbhu, MD, Douglas G. Adler MD, FACG, AGAF, FASGE, University of Utah School of Medicine, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Huntsman Cancer Center, Salt Lake City, UT

INTRODUCTION

Endoscopic sphincterotomy (ES) is one of the most fundamental maneuvers performed in ERCP, with over 150,000 biliary sphincterotomies performed annually in the United States.1 ES is a complex procedure performed under direct endoscopic observation. Facilitating the removal of common bile duct stones is the most common indication, but ES is performed for a variety of both biliary and pancreatic disorders, including the treatment of biliary and pancreatic leaks, to facilitate the placement of biliary or pancreatic stents, as a precursor to cholangioscopy and/or pancreatoscopy, and to treat suspected sphincter of Oddi dysfunction, among others (see Table 1).2,3

ES, also known as sphincterotomy or papillotomy, involves retrograde cannulation of the bile or pancreatic duct via the ampulla of Vater. In the vast majority of sphincterotomies, ES is performed after deep access to the desired duct has been achieved and a guidewire is in place in the duct. The biliary or pancreatic sphincter is then incised by a sphincterotome via electrocautery delivered through the cutting wire incorporated into the sphincterotome itself.

Less commonly, a needle knife instead of a sphincterotome is used in order to perform ES, usually in cases where standard techniques to achieve ductal access have failed. Other variations of the technique include a precut sphincterotomy (cutting with a sphincterotome without deep access already established) as well as transpancreatic sphincterotomy also known as a trans- septal sphincterotomy. In rare cases, an interventional radiologist can assist in a combined percutaneous- endoscopic procedure by passing a guide-wire in an antegrade manner through the bile duct and into the duodenum to allow the endoscopist to achieve ductal access and perform sphincterotomy.1

Complications of Initial Biliary Sphincterotomy

Complications related to performing ES vary greatly, from approximately 6-22% in multiple studies.4,5,6 Freeman et al. conducted the largest prospective study, consisting of 2347 patients analyzing complications of ES. They identified difficult cannulation of the duodenal sphincter, use of precut sphincterotomy, suspected sphincter of Oddi dysfunction and presence of cirrhosis as significant factors associated with an increased odds ratio of procedure-related complications. The authors concluded that complications were related to the technical skill of the endoscopist, indicating that these procedures may be safest in centers in that perform ES on a regular basis.1 Complications are likely less common with high volume providers.

A different study that investigated the risk of post- ERCP pancreatitis (PEP) in the setting of ES identified a relative increase in risk in younger patients and patients who received an increased number of contrast injections into the pancreatic duct.7 More recent retrospective data has identified the co-morbid conditions of chronic kidney disease (possibly with associated platelet dysfunction from uremia), hypertension and ischemic heart disease as risk factors in post-procedural bleeding after ES.8

The type of current used for electrocautery has also been described as a risk factor for complications related to ES. Pure current provides better tissue cutting quality, whereas mixed current combines pure current with low-voltage coagulating current in alternating short bursts, achieving cutting and coagulation simultaneously.9,10 Multiple prospective randomized trials have been unable to identify a clearly superior method of electrocautery in relation to specific side- effects.11,12 A meta-analysis of 4 trials and over 800 patients identified no significant difference in rate of pancreatitis, however pure current was noted to be associated with more episodes of bleeding compared to the mixed current technique.13

Specific complications related to performing ES are most commonly classified as early (occurring within 30 days of the procedure) or late (occurring > 30 days after the procedure). The overall rate of early complications has been quoted around 7-10% in various studies, and most commonly includes bleeding (both immediate and delayed hemorrhage), pancreatitis, and rarely, duodenal perforation.1,13,14 A major late complication of ES is papillary restenosis, which can occur months to years after initial ES. This complication is rare but has been noted in 1-4% of patients, and can be successfully treated with repeat ERCP and ES.2,3,15 Ascending cholangitis is another late ES complication managed by repeat ERCP.3 Recurrent stones can also be seen in these patients, but it is unclear if this represents a procedure-related complication or the natural course of stone-related disease.15

Throughout the literature there is mention of the long-term risk of patients with ES developing cholangiocarcinoma, presumably through chronic inflammation resulting in malignant transformation or through sample error as those undergoing ERCP are more likely to have underlying biliary disease in the first place. However, several studies with long-term follow up (greater than 10-15 years) have been unable to confirm this suspected link. 5,15,16,17

Repeat Biliary Sphincterotomy
When and Why?

A problem for any endoscopist who performs ERCP is the occasional need to extend a previous sphincterotomy. This can occur at any time, from days to years after the initial procedure.

The need for a repeat procedure can be divided into the “early” and the “late” time period, although what exactly is meant by these terms has been variably defined in the literature. A retrospective review of 248 patients defined an early post-procedure period of 1-3 days, and differentiated it from the period 4-10 days after the original sphincterotomy.18 Although seemingly arbitrary and not based on rigorous evidence, this division was made because of the anecdotal experience that re-intervention within 3 days may be met with increased technical difficulty. This increase in difficulty is thought to be related to persistent edema from recent trauma, as well as the potential presence of an adherent clot, which can obscure vision and carries with it a higher risk of bleeding.19 Alternatively, Mavrogiannis et al conducted the largest prospective study to date and used 0-8 days as the early re-intervention group, whereas the late reintervention group had a repeat procedure between 9 days to 7 years from the initial ES.20 This was done because several early studies had identified a high risk of bleeding in patients within 8 days of ES, attributed to increased papillary vascularity during that time.21

Regardless of the specific timing, early extension of prior ES can be performed for several different indications. The most common reason to extend a biliary sphincterotomy is to facilitate the removal of biliary stones that could not be removed on a prior ERCP. (Figures 1 and 2) Other patients need their sphincterotomy extended and completed after it was interrupted during the initial procedure due to various complications (bleeding, severe edema, periampullary diverticulum, and cardiopulmonary complications related to sedation). Another reason for extension of ES is to complete a sphincterotomy after the precut technique has been used.19

Although the exact definition of a “late” extension of previous sphincterotomy may be debated, it is commonly needed in the setting of papillary stenosis which can develop after a prior biliary ES, although true papillary stenosis is a rare development. Sphincterotomy extension can also be necessary to remove common bile duct stones that recur.20

Papillary stenosis may cause jaundice or other associated conditions like stone formation and/or cholangitis. The development of stenosis at the site of prior sphincterotomy is thought to be due to inadequate incision of the sphincter muscle or excessive scar tissue formation. It is frequently seen in patients who have had extraction of multiple or large stones compared to patients who have sphincter of Oddi dysfunction or pass single, small stones.22 It could also be related to fibrotic reaction at the site of incision, as previous studies have shown that mean length of incision does decrease over time, indicating an active area of tissue growth and re- modeling.23 Late extension is sometimes not possible, as Bourke et al first described the phenomenon of a papillary orifice that is seemingly buried in the duodenal wall. In this situation, the papillary stenosis extends along the bile duct beyond the biliary orifice, and the lesion is not amenable to further extension.24 This situation is, fortunately, extremely uncommon.

Outcomes, Safety and Adverse Events

The largest prospective study of extending a biliary ES followed 250 patients who underwent sphincterotomy as primary treatment for choledocholithiasis. Of those, 81 (32%) underwent extension of their initial ES. 66 of these patients underwent a “late” extension (9 days to 7 years after initial procedure), while the remaining 15 had an early extension within 8 days of the first ES. 80 out of the 81 patients had successful clearance of stones from the bile duct after repeat ES, with mechanical lithotripsy utilized in one case. The authors concluded that extension of a previous sphincterotomy is an efficient treatment for recurrent biliary stones. It should be noted that the cohort represented a homogenous group of patients with choledocholithiasis, and patients with other indications for repeat ES were excluded.20

This study concluded that repeat ES was a safe procedure, with an overall complication rate which was no different when compared to the initial sphincterotomy group (2.5% vs 8.4%, p > 0.05). Other common complications, including bleeding, cholangitis and perforation were found to be the same in both groups, with no deaths reported in either group. The repeat ES group did, however, have statistically significant fewer episodes of pancreatitis (0% vs 4.8%, p < 0.05). This suggests that extension of previous sphincterotomies may have less risk of pancreatic injury than initial ES, possibly explained by cutting on the upper edge of the previous cut, thus avoiding the pancreatic orifice. There was a trend (although not statistically significant) towards a higher risk of bleeding in early repeat ES vs late repeat ES. Both cases of bleeding in this cohort occurred when repeat ES was performed within 3 days of initial ES.20

A similar study aimed to examine whether repeat ERCP was safe and feasible in treating recurrent choledocholithiasis. Resembling the design of Mavrogiannis et al, the study excluded patients with concomitant hepatolithiasis, choledochal cysts or bile duct strictures. Of 84 patients who underwent repeat ERCP for post-ES recurrent choledocholithiasis, 69 patients received a repeat sphincterotomy. Biliary duct clearance was achieved in 100% of these patients. Early adverse events were noted in 2 (2%) patients. This low complication rate consisted of cases of mild pancreatitis and mild hemorrhage.25

In addition to confirming that repeat ES is indeed a safe procedure in the short-term, this study was unique in that it also included long-term follow up (mean 11.7 years) after repeat ERCP. Choledochal complications, consisting of recurrent choledocholithiasis and cholangitis were noted in 30 patients during this follow- up period. While this rate of 36% is higher than the complication rates reported after initial ES (6-22%), the authors explained this by identifying independent risk factors not related to the procedure. Multivariate analysis found that early recurrent choledocholithiasis (within 5 years), a dilated bile duct ( >15mm) and periampullary diverticulum were independent risk factors predictive of these recurrent stone disease and cholangitis.25 While this study confirmed that repeat ERCP and ES are safe and effective means of managing recurrent biliary disease, the simple fact that patients require a repeat procedure seems to put them at increased risk for further complications and future procedures.

A more recent study investigating the safety and efficacy of repeat ES was described by Hisai et al.26 They describe a series of 76 patients who underwent repeat ES, 25 of whom had a repeat procedure within 8 days of the initial procedure (“early” extension), and 51 who received a “late” extension ( > 9 days after initial procedure). This delineation of early and late was the same as described by Mavrogiannis et al.20 While recurrent choledocholithiasis was the most common indication for repeat ES (67/81 patients, 83%), this study included patients requiring ES for other indications, including biliary strictures and papillary stenosis. Repeat ES was technically successful in all cases, with an overall complication rate of 5.4%. Complications consisted of bleeding (2 patients), mild pancreatitis (2 patients) and cholangitis (1 patient). The overall complication rate, including pancreatitis, was no different between the two groups, and there were no procedure-related deaths. The authors concluded that repeat ES is safe, effective and was not associated with an increased risk of bleeding as they had hypothesized.26

Pancreatic Sphincterotomy
Indications for and Complications of Initial Pancreatic Sphincterotomy

The sphincter of Oddi can be anatomically divided into the bile duct (biliary) sphincter, the pancreatic duct sphincter, and the ampullary sphincter, encompassing the distal most portion of the ampulla. In biliary endoscopic sphincterotomy, the pancreatic sphincter is left intact.27 Pancreatic sphincterotomy was first described in 1976 and can be performed in conditions such as pancreas divisum, chronic pancreatitis, to perform pancreatoscopy, to facilitate the evaluation of pancreatic malignancy, to enable the remoal of pancreatic stones (pancreaticoliths), and to treat suspected pancreatic sphincter of Oddi dysfunction.28,29

Pancreas divisum is a relatively common congenital abnormality of the pancreatic ductal system, occurring in about 7% of the population in the United States.29 While typically asymptomatic, it can be associated with recurrent acute or chronic pancreatitis, as well as chronic abdominal pain. Most studies evaluating the success of pancreatic ES in these patients consist of retrospective case series measuring pain burden, and the success rates vary widely from 32%-86%.30,31 Of note, pancreatic sphincterotomy in patients with pancreas divisum is performed on the minor papilla, which is distinct from pancreatic ES for other indications.

Pancreatic ES of the major papilla is useful in chronic pancreatitis, as it can improve pancreatic drainage via facilitating the removal of stones and endoscopic of strictures in the pancreatic duct.29 While technical success rates of the procedure are high ( > 85%), the number of patients who clinically improve after the procedure is lower, around 50% in several studies.32,33

A more controversial indication, the treatment of sphincter of Oddi dysfunction, is another indication for pancreatic ES, biliary ES, or both. In patients with abnormal sphincter manometry, clinical improvement after ES has been quoted as 85%-95% in earlier studies.34,35 A recent, widely publicized, randomized sham controlled, multicenter trial studied over 200 patients with sphincter of Oddi type III dysfunction. Their results were far less enthusiastic and demonstrated that in these patients, pancreatic and/or biliary ES does not improve outcomes, and sphincter manometric pressure is not predictive of pain relief, lessening the enthusiasm for this procedure in some circles.36

The major early complications associated with pancreatic ES are bleeding, cholangitis and pancreatitis.29 As would be expected, the overall rate of pancreatitis in patients undergoing pancreatic ES is higher than the risk after ERCP without pancreatic ES. Overall, the rate of pancreatitis following pancreatic ES is around 10-12%, while the rate of post-ERCP pancreatitis has been quoted at approximately 3% in expert hands, and is likely higher in the hands of low volume providers.37,38,39 The incidence of pancreatitis after pancreatic ES can be affected by other factors, including pancreatic duct stent placement, difficulty of cannulation of the pancreatic duct, and whether the pancreatic sphincterotomy was performed on the major or minor papilla.40 Stent-related complications, including parenchymal changes, infection, perforation, occlusion and stone formation can be seen in follow- up if stents are left in the pancreatic duct too long, but are not related to the sphincterotomy itself.41 Late complications such as papillary stenosis and proximal ductal strictures are exceedingly rare, and can similarly be treated with repeat pancreatic ES.

Repeat Pancreatic Sphincterotomy

Pancreatic ES is performed far less frequently than biliary ES. This is due to less commonly encountered indications for the procedure, as well as operator concern regarding the technical difficulties and the perceived increased occurrence of complications.40 As a result, the literature is sparse regarding incidence, safety and specific complications in regards to repeat endoscopic pancreatic sphincterotomy. Still, repeat pancreatic sphincterotomy is a valid procedure that is sometimes clinically indicated, most commonly to allow removal of pancreatic duct stones. (Figure 3)

Jakobs et al. retrospectively identified 171 patients who underwent pancreatic ES for therapy of chronic pancreatitis over the span of 11 years.42 The procedure was technically successful on the first attempt in 147 patients (86%). In the remaining 24 patients, repeat pancreatic ES (maximum of 3 attempts) was successful in 20 (83%) patients. During the long-term follow- up period, a repeat pancreatic sphincterotomy was necessary in 17/167 patients (10%), and was successful in all patients. Indications for repeat sphincterotomy were an inadequate pancreatic duct orifice for removal of pancreatic duct stones (13 patients), retrieval of a pancreatic duct stent (2 patients) or transpapillary insertion of a larger pancreatic stent (2 patients).42

A similar retrospective study by Joo et al. identified 46 patients who underwent pancreatic ES.40 While a majority (26/46 or 57%) of patients received pancreatic ES for the indication of chronic pancreatitis, 10/46 (22%) were undergoing evaluation for possible malignancy, for cases of pancreatic divisum (4/46) (9%), and for treatment of pancreatic pseudocyst (3/46) (7%). The procedure was successful in 96% (44/46) of patient, and the authors only reported one late complication of re-stenosis of the pancreatic duct, which developed after 38 months. The need for repeat sphincterotomy in only 2% (1/46) of patients is explained by the authors as being due to the heterogenous characteristics of the study cohort, as well as the relatively large amount of patients (12/46 or 26%) that were lost to follow-up.40

A recent large prospective study examining the effectiveness of ES in patients with chronic pancreatitis prospectively followed a 41 patient sub-set who received a pancreatic ES in addition to ductal dilation and/or stent placement. The mean follow-up period was 4.8 years, and there were no reported long-term complications that required repeat pancreatic ES. While the study’s primary aim was to compare outcomes in patients who underwent different modalities of treatment, it contributes to the conclusion that pancreatic ES is a safe and effective procedure without significant long- term complications.32

Initial and Repeat Sphincterotomy of the Minor Papilla

In contrast, pancreatic ES performed on the minor papilla in patients with pancreatic divisum (PD) is considered a separate clinical and technical entity. For patients with symptomatic PD, it is postulated that obstruction at the site of the accessory pancreatic duct, or minor papilla, is an important predisposing factor for symptomatic disease. By receiving therapy to relieve the obstruction and improve pancreatic drainage, it is thought that symptoms such as pain and recurrent acute pancreatitis may be relieved.43 Successful endoscopic therapy via pancreatic ES, which consists of resolved pain and decreased instances of pancreatitis, has been reported to occur in up to 60-80% of patients in some studies. This varies based on patient characteristics and this number is likely elevated due to some degree of publication bias.44,45

Pancreatic ES at the minor papilla incurs similar risks of acute complications, including pancreatitis, bleeding and perforation.46 The rate of pancreatitis, however, has been noted to be higher in patients undergoing pancreatic ES of the minor papilla, with some studies citing an incidence in over 30% of patients.47 More recent studies have shown that if the intervention is performed by an experienced endoscopist at a large referral volume center, the rate of pancreatitis may decrease significantly, to below 10%.44,48 The rate of re-stenosis in these patients is a significant long-term complication, ranging from 16-20%. This results in the need for re-intervention, often with repeat pancreatic ES.45,49

In a large retrospective review of 184 patients, Atwood et al compared differences in outcomes between needle-knife sphincterotomy and standard pull-type sphincterotomy of the minor papilla.44 Complication rates and outcomes were the same in both groups, with the authors indicating that endoscopist preference and comfort plays a large role in which technique is safest. Re-stenosis rates were around 20%, and were not different between the two groups. In this study, median follow-up over the span of 5-6 years identified 28 patients (21%) who required repeat pancreatic ES. A majority of these patients received their repeat procedure within a year of the index procedure, and the need for a repeat ES did not seem to be a risk factor for further complications.44

Another retrospective study that included 113 patients attempted to evaluate long-term clinical outcomes in patients who underwent ES of the minor papilla. Over a median follow-up range of 47 months, the overall success rate was 62%. While primary success (no need for repeat procedure) was noted in 49/113 (43%) patients, another 47/133 (42%) patients required at least one more ERCP. While the authors did not publish data regarding how many of those patients needed a repeat or extension of minor papilla ES, they did mention restenosis as a complication seen in follow- up that was safely treated via a repeat ES.50

Maple et al. described a retrospective study of 64 patients undergoing minor papilla ES to compare a wire- assisted technique compared to the aforementioned needle-knife or pull-type sphincterotomies. While no significant difference existed between the techniques, the published data included a sub-set of patients who required re-intervention. The authors reported 11/64 (17%) patients who required a repeat intervention on the minor papilla. No complications were reported in these procedures, and all were technically successful.51

CONCLUSION

Endoscopic sphincterotomy remains a fundamental maneuver during ERCP, and the need for repeat sphincterotomy can arise in clinical practice and interventionalists should be prepared to perform this when it is needed. Complications of extension of an ES tend to be linked to characteristics of the patients, the indication for the procedure, and the technical skill and experience of the endoscopist. Patients who undergo biliary ES tend to be at risk to undergo further endoscopic therapy, likely related to their underlying disease process and not the sphincterotomy itself. Distinct “early” and “late” re-interventions are well described in the setting of biliary ES, and studies have shown that these repeat procedures are safe and effective. While the field still lacks multiple prospective clinical trials to confirm this, repeat biliary ES is a necessary procedure that can be performed without excessive risk of adverse events.

Although sparse and lacking randomized prospective data, the summation of the literature regarding extension of a prior pancreatic ES supports the fact that it can also achieve good outcomes when patients are properly selected. Some pancreatic ES patients do require repeat procedures, and while re- intervention is also relatively safe, it is a fact that should be taken into account when deciding on initial therapy.

Download Tables, Images & References

A CASE REPORT

Insulinoma Diagnosed with Endoscopic Ultrasound

December 2015 • Volume XXXIX, Issue 12
Brijesh B. Patel,Thure Caire,Prasad Kulkarni

Read Article

We present two cases of insulinoma diagnosed by endoscopic ultrasound (EUS) after initial imaging was unrevealing. Both patients presented with refractory hypoglycemia and were found to have high c-peptide and insulin levels suspicious for insulinoma with evaluation for factitious causes (sulfonylurea, and meglitinides screening) being ruled out. However, imaging with computed tomography (CT) or magnetic resonance imaging (MRI) was not revealing of lesion location. Subsequently, EUS was pursued. In each case, EUS was able to localize and biopsy the lesion in the head of the pancreas and immunohistochemistry confirmed the diagnosis. Both patients underwent definitive treatment and had uneventful recovery. These cases highlight the utility of EUS in diagnosing and localizing insulinoma.

Brijesh B. Patel, M.D.1,2 Thure Caire, M.D.1,2 Prasad Kulkarni, M.D.1,2 1University of South Florida, Division of Digestive Diseases and Nutrition Tampa General Hospital, 2Veteran’s Administration Department of Gastroenterology

INTRODUCTION

Insulinomas are rare neuroendocrine tumors (NET) with an annual incidence ranging from 1 to 4 people per million per year. Although rare, they are the most common of the NETs, with a higher female predominance and typical presentation in the 5th decade of life.1 Only 5-10% of insulinomas are malignant. After gastrinoma, insulinoma is the second most common functioning pancreatic tumor, accounting for 10-30% and are associated with multiple endocrine neoplasia (MEN type 1).2 They are usually small in size < 2 cm.3

The clinical presentation of insulinoma may include diaphoresis, tremor, palpitations and uncharacteristic hunger. This may progress to more severe neuro- glycopenenic symptoms including confusion, behavioral changes, personality changes, visual disturbances, seizure, coma and death.4,5 The clinical Whipple’s triad is used to clinically diagnose one with insulinoma which includes: symptoms known or likely to be caused by hypoglycemia, low plasma glucose measured at the time of the symptoms and relief of these symptoms when the blood glucose is raised to normal.6

In many cases, insulinomas can be localized by non invasive imaging modalities such as CT or MRI. If unrevealing more invasive modalities need to be utilized, such as EUS and insulin sampling via selective arterial calcium stimulation (SACS) and somtostain receptor scintigraphy. While there is no head to head comparison of EUS and SACS, the sensitivity with SACS may exceed 90% and it is a provocative test with operator dependence and high cost.7 C peptide levels, sulfonylurea testing and meglitinides screening are used to rule out factitious causes. If tissue is available, immunohistochemistry (IHC) for insulin chromogranin and synaptophysin aid in confirming the diagnosis. No matter what diagnostic modality one uses, the treatment includes surgical resection vs. enucleation. The pharmacological treatments are available for patients who are poor surgical candidate but only surgery is curative.8 The medical management includes frequent carbohydrate meals, octreotide and diazoxide or somatostatin analogs help control hypoglycemic symptoms in only 50-60% of patients.9,10

The most common cause of hypoglycemia in adults is iatrogenic; factitious use of anti-diabetic agents such as sulfonoureas or insulin. In healthy adults other causes include lack of hormones such as cortisol or glucagon or hyperinsulinism secondary to nesidioblastosis or autoimmune insulin hypoglycemia.11-14 One of the rare causes of hypoglycemia includes tumors secreting endogenous analogs causing such symptoms. NETs are rare functional tumors of pancreas, they represent a small percentage of all pancreatic tumors (1.3%) but their incidence is rising.15 Insulinomas causes hypoglycemic episodes secondary to excess endogenous insulin production leading to metabolic derangements. They may exert these effects even when <1cm in size.

We present 2 cases that exemplify the importance of EUS in accurate diagnosis and location of insulinomas after primary imaging modality was unable to localize the lesion.

CASE # 1

A 65 year old male veteran with past medical history significant for prostate cancer s/p radical prostatectomy presented with episodes of dizziness and weakness. Initially the patient was found to have blood glucose (BG) levels of 40-60s mg/dL and he was unable to raise his glucose levels despite frequent snacks (every 2-3 hours). On presentation, he underwent CT of the abdomen and pelvis which was unremarkable. With consistently low BG levels, his labs revealed an insulin level > 40 mcU/mL (normal 2-25 mcU/mL), c- peptide level of 8 ng/mL (normal 0.78-1.89 ng/mL) and an octreotide scan was negative. With a high suspicion for insulinoma (given the negative sulfonylurea screen) our patient underwent EUS- with fine needle aspiration (FNA). A 14 mm x 16 mm homogenous lesion was noted in the head of the pancreas (Figure 1). The biopsy revealed plasmacytoid neoplastic cells (Figure 2) with pathology positive for chromogranin, synaptophysin and pankeratin and negative for CK 7, CK 19, CK 20 and CDX2. With IHC and staining, a diagnosis of pancreatic endocrine neoplasm was made, and with aspirate positive for insulin, the diagnosis of insulinoma was confirmed (Figure 3). Subsequently the patient underwent enucleation and is currently symptom-free.

CASE # 2

A 67 year-old female with past medical history significant for hypothyroidism, hypertension, recurrent hypoglycemia and hypoglycemia associated seizures was referred for EUS/FNA. She had been having recurrent episodes of hypoglycemia and witnessed seizures for two years. An abdominal MRI at an outside facility was normal. Her laboratory evaluation revealed an insulin level of 203 mcU/mL (normal 2-25 mcU/mL), c-peptide 44 ng/mL (normal 0.78- 1.89 ng/mL) and proinsulin 149.9 pmol/L (normal <18 pmol/L). Screening was negative for sulfonylureas and meglitinides. She underwent EUS/FNA which showed a well-circumscribed hypo- to isoechoic 8.4 mm x 9.6 mm lesion in the head of the pancreas (Figure 4). FNA showed cytology consistent with tumor cells positive for synaptophysin and chromogranin, findings again suggestive of pancreatic neuroendocrine tumor. Similarly this patient underwent surgical resection and IHC was positive for insulin stains and patient is symptom-free.

DISCUSSION

These cases highlight the importance of endoscopic ultrasound in the diagnosis of the insulinoma. The diagnosis can be made via biochemical assays and routine blood work although localizing the tumor may prove to be a challenge. The conventional imaging modality such as high resolution pancreatic protocol CT and MRI are often beneficial to localize the lesion. At this time, these modalities are more widely available than EUS. A small number of insulinomas still remain occult after conventional CT scan and MRI fail to identify them.9 The sensitivity of CT and MRI has been reported to be 33%-64% and 40%-90%, respectively with MRI being more sensitive and specific when compared to CT.16-18 A study by Bonato et al. showed that CT was able to localize insulinoma in 4/16 patients with size > 1.5 cm and largest being 12 cm.19 Both of our cases had hypoglycemia on presentation with abnormal biochemical assay and negative sulfonylurea and meglitinides screen. After initial imaging CT scan and MRI were unable to identify or localize the lesion and strong clinical evidence supportive of insulinoma, EUS localized the lesion and obtained tissue that was helpful to the diagnosis. Preoperative use of EUS for insulinoma allows precise targeting of the lesion, preventing intra-operative (including unnecessary total pancreatectomy) complications, length of operating time and post-surgical complications. With this modern approach, EUS/FNA may also enable carbon-particle tattooing for easy localization. Overall sensitivities up to 94 % are reported in the localization of tumors using EUS.17 When combined with high resolution CT and EUS the sensitivity increases to 100 %.20 Even with expert surgical experience, there is still a 10-20 % rate of not being able to detect lesion intra-operatively making pre-operative localization very important. The idea is that with precise location the surgical management resection vs. enucleation is more feasible. Key draw backs for EUS is that it is highly operator dependent, available only in tertiary care centers and has limited utility in localizing lesions in the tail or the distal body of the pancreas or if the tumors are pedunculated or if tumors are extra-pancreatic. Although with advent of intraductal ultrasound, these areas can be readily visualized with its detection rate as high as 90 % of lesion measuring 1-3 mm although it is not widely available.21,22 Both of our cases involved lesions in the head of the pancreas. The importance in these cases is that use of EUS aided in the diagnosis and precise localization of even very small (<1 cm) tumors.

Histopathologically, insulinomas stain positive for insulin, pro-insulin, chromogranin A, synaptophysin, neuron specific enolase and cytokeratin.23 Our patients’ IHC were positive for chromogranin, synaptophysin and pankeratin. Although these markers can be used to identify insulinoma, the importance lies in localizing where the biopsy needs to be taken which can be aided with EUS.

Other techniques such as somatostain receptor scintigraphy, selective arterial calcium stimulation and hepatic venous sampling are also used to diagnose previously missed tumors. Selective arterial calcium stimulation with hepatic venous sampling for insulin quantification has shown a high sensitivity (93%) for localization, these techniques can get cumbersome and yield can be significantly low.7 Combination with EUS allows one major advantage of tattooing and biopsy once tumor is localized.

These cases identify the crucial role of EUS in identifying the lesions which not only confirmed the diagnosis but also aided in the operative resection of the tumors. With the help of EUS, blind surgical approaches are rarely performed. The most common complication post surgery was noted to be hyperglycemia as expected, pancreatic psuedocyst formation, pancreatic fistula, wound infection and the longest hospital stay was 40 days.19 Once the tumor is identified the curative approach is still enucleation and or distal or partial pancreatectomy. Since the incidence of NET rising it will be critical in identifying the lesions that are missed or are too small to be seen on imaging. Our cases exemplify the important aspects in using primary EUS in diagnosing of insulinoma and management. In addition, cases such as ours can help spread awareness about the utility of EUS in diagnoses that are not amenable per primary imaging modality with strong clinical suspicion for NETs and target the lesion with tattooing for enucleation. Future studies need to be performed that will quantitate variables such as length of hospital stay, pre, intra, and post-operative complications when EUS is used in diagnosis vs. blind approach.

Download Tables, Images & References

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #13

Utilization of Complementary and Alternative Medicine in Irritable Bowel Syndrome

December 2015 • Volume XXXIX, Issue 12
Christine Yu,Richard W. McCallum

Read Article

In the field of gastroenterology, there is scant evidence-based-medicine available for review in regards to alternative therapeutic options to treat or manage gastrointestinal disorders. The intent of this article is to first bring awareness to fellow gastroenterologists that numerous complementary therapies and alternative modalities to treat gastrointestinal disorders do exist and then to emphasize that utilizing such treatments may be of some benefit to our patients, specifically in patients with irritable bowel syndrome.

As gastroenterologists trained in Western medicine, our fund of knowledge and sensitivity to the concepts and applications of integrative, complementary, alternative, holistic, naturopathic or herbal medicines is quite limited. When endoscopic procedures, imaging and pharmacologic therapies fail to alleviate a patient’s symptoms, we find ourselves with few options in what we can offer our patients. There are numerous complementary modalities that can be considered as treatment for patients when western therapies fail or as adjunctive treatment in settings of partial responders. In the field of gastroenterology, there is scant evidence-based- medicine available for review in regards to alternative therapeutic options to treat or manage gastrointestinal disorders. Finding double-blinded randomized clinical trials for alternative treatments is almost impossible for multiple reasons, including the extensive funding needed to orchestrate such studies, although the new Center for Complementary Medicine at the NIH will potentially be a source of funding for these types of studies. The intent of this article is to first bring awareness to fellow gastroenterologists that numerous complementary therapies and alternative modalities to treat gastrointestinal disorders do exist and then to emphasize that utilizing such treatments may be of some benefit to our patients, specifically in patients with irritable bowel syndrome.

Christine Yu MD, ABIHM, Richard W. McCallum MD, FACP, FRACP, FACG, AGAF Texas Tech University Health Sciences Center, Department of Internal Medicine, Division of Gastroenterology, El Paso, TX

INTRODUCTION

In the past few decades, there have been an increased interest and utilization of complementary and alternative medicine (CAM) for treatment of all medical issues, including gastrointestinal disorders. There is a vast array of different terminology used when speaking of CAM ranging from holistic medicine, homeopathy, herbal medicine, botanical medicine, essential oils, aromatherapy, nutritional supplements including vitamins and minerals, probiotics, acupuncture, biofeedback therapy, Aruvedic therapy and body-mind therapy, to name a few. Most of these modalities have been used for thousands of years prior to the existence of modern western medicine by civilizations all over the world. Many patients may be utilizing CAM but forget to tell their physicians unintentionally or, most times, intentionally because they fear that their physicians will tell them that they should not take it or participate in such therapies for various reasons. For the most part it is true that there is limited evidence-based medicine available for CAM but also, many physicians are not aware or knowledgeable of such therapies, thus not recommending CAM to their patients. Recently there was an article published in the American Journal of Gastroenterology that found that CAM was used by 42% of respondents with a GI condition from the 2012 National Health Interview Study and over 80% of patients who used CAM found it helpful.1 The GI conditions mentioned in the study were abdominal pain, acid reflux/ heartburn, digestive allergy, liver condition, nausea/vomiting and ulcer. The most commonly used modalities were herbs, supplements and mind body and manipulative therapies. Because of this explosive utilization of CAM therapies in recent years, the Center of Complementary and Alternative Medicine in National Institutes of Health has engendered opportunities to support rigorous scientific research in relevant topics and help integrate proven complementary and alternative approaches into conventional medicine.2 This will undoubtedly lead to more scientific and more rigorous controlled trials to increase credibility for CAM. Irritable bowel syndrome (IBS) is recognized to occur in about 15% of people in the United States and up to 75% are females. IBS is defined as chronic or recurrent abdominal pain that is associated with constipation, diarrhea or both. The etiology of this disease is unclear and multifactorial in nature but has been found to be associated with abnormal peristalsis, infections, food insensitivities, altered neural sensitivity and inflammation. There have been studies indicating that up to 50% of patients suffering from IBS have utilized CAM therapy.3 In this article, we will review specific modalities of CAM that have been found to be beneficial in IBS beginning with the traditional first line approach- fiber- which actually relies on this CAM concept.

Fiber

Increasing fiber intake through either diet or via supplementation is most often the first recommendation we give to IBS patients.4 Soluble fiber, but not insoluble fiber, is thought to be beneficial. Soluble fiber consists of pectins, gums and mucilages but is usually administered as psyllium. Psyllium husk is the outer coat of psyllium seed known in India as ispaghula seed from the plant Plantago ovata.5 It is found in fruits, vegetables, whole grains, seeds and nuts. When mixed with water, it forms
a gel and is fermented by colonic bacteria, yielding metabolites that might decrease gut intracolonic pressure and gut transit time. Insoluble fiber which is found in wheat bran and corn bran, undergoes stool bulk and decreases transit time. Dietary fiber recommendations for adults generally range from 20 to 35 grams/day.6 Likely benefits from fiber intake include increase stool weight, normalization of defecation frequency,
improved glycemic control in patients with diabetes, lower blood cholesterol levels, with protective roles regarding diverticulosis, constipation, colon cancer and cardiovascular disease.4 The proposed mechanism of action for fiber in the treatment of IBS and constipation is acceleration of oroanal transit and decrease in intracolonic pressures either as a direct effect or by binding bile acids.7

Systematic review of clinical trials of fiber for IBS have found no clear beneficial effects for fiber supplementation or bulking agents. The American College of Gastroenterology Functional Gastrointestinal Disorders Task Force recommendations are that fiber is appropriate for the treatment of constipation dominant IBS but may not be recommended for the treatment of all subsets of IBS.8 A similar meta-analysis of therapies for IBS does not recommend use of bulking agents except as adjuvants.9

Herbals for IBS

The Cochrane Collaboration performed a review of herbal medicines for IBS and found that there were 75 randomized controlled trials in approximately 8000 patients. Although only 3 of those studies were judged to be of high quality, there were several Chinese and Ayurvedic preparations that were found to be better than placebo. There were also no serious adverse effects for any of the herbal preparations.10

Chinese Herbal Preparations – Traditional Chinese Medicine (TCM)

IBS patients were treated with either a standardized combination herbal formula, an individualized herbal formula or placebo. Both treatment groups showed a substantial benefit over placebo after 16 weeks of therapy, and the individualized treatment showed continued benefit 14 weeks after treatment ended. The mechanisms of the herbal formula’s action are unknown.11

Tong sie yao fang (TXYF) is a combination of commonly used TCM. A meta-analysis of different variations of this formula included 12 Chinese studies examining its use in IBS.12, 13 TXYF was found to be more effective than placebo but the trials were heterogeneous, generally of poor quality and the TXYF formula itself was inconsistent. There were 3 trials from the English language literature using different TCM herbal formulas containing TXYF ingredients and two demonstrated efficacy,11,13 but one did not.14

STW 5 (iberogast) and STW 5-II are a combination of nine herbs that are commonly used as digestive aids. A trial compared 208 patients with IBS who received STW 5, STW 5-II, a single-plant extract or placebo. Abdominal pain and IBS symptom scores were significantly improved among patients that received STW 5.15

Padma Lax, a Tibetan herbal digestive formula has been used in Europe for decades. In a trial involving 61 constipation-predominant IBS patients, screened for celiac disease or lactose intolerance, reported global improvement in 76% of those using Padma Lax versus 31% of those receiving placebo.16 In a Cochrane systematic review of herbal medicines for the treatment of IBS, Padma Lax, STW 5, and certain formulations of TXYF were shown to improve global IBS symptoms when compared to placebo.10

A systematic review of 22 randomized controlled
trials (RCTs) focused on the safety concerns with herbal
medicine and demonstrated that adverse events occurred
in 2.97% of patients, none of which was considered of
a serious nature. Of note, the authors did caution that
most of these trials were not of acceptable quality and
there might have been underreporting of adverse events.
Thus, clinicians should weigh the potential benefits and
risks of these therapies when advising patients.17

Ginger (Zingiber Officinalis Roscoe)

Ginger is one of the most common herbal medicines that are used for a variety of GI conditions, including IBS. Ginger was found to be the most popular alternative medicine in one study of IBS patients18 but there has not been any well conducted study examining its efficacy.

Ginger root is the rhizome of the perennial plant Zingiber Officinalis Roscoe. Ginger contains approximately 1-3% oils. Dosing is usually standardized according to gingerol content which is assumed to have antiemetic, analgesic, sedative and antibacterial effects.19,20 Ginger is recognized by the American Food and Drug Administration relatively safe and is exempt from premarket review or approval before marketing.

As an antiemetic, studies have shown that ginger is effective in treating nausea and vomiting in pregnancy, after surgery and also during chemotherapy. Ginger has also been shown to improve gut motility as well as abdominal pain.21 Therefore, theoretically, ginger may be useful in reducing stool changes in IBS as well as pain.

A double-blinded randomized controlled trial was performed comparing the efficacy of ginger in treating IBS patients compared to placebo.22 This study had three groups: patients that received 1 gram of ginger daily, 2 grams of ginger daily and/or placebo for 28 days. There were 57.1% responders to placebo, 46.7% to 1 gram and 33.3% to 2 grams of ginger. Adequate relief was reported by 53.3% on placebo as well as both ginger groups combined. Side effects were mild and reported in 35.7% in the placebo group and 16.7% in the ginger groups. This double blind randomized controlled trial suggests that although ginger is well tolerated, it did not perform better than placebo. Larger trials are needed for further evaluation.

Peppermint oil (Mentha Piperita Linnaeus)

Peppermint is a leafy, green plant. Peppermint oil, which has been used for thousands of years, is extracted from the leaves and stems.23 The active ingredients in peppermint are organic oils including menthol, which act as smooth muscle relaxers in the GI tract, likely on calcium channels. Peppermint oil is available in enteric coated capsules (containing 0.2ml of oil) and in liquid dropper form. The capsule form is preferred because direct consumption of the oil can reduce pressure in the lower esophageal sphincter theoretically leading to reflux. The recommended dose is one to two capsules three times daily for adults 15 to 30 min prior to meals.

In a study by Liu et al, IBS patients treated for one month with peppermint oil (Colpermin) had improved abdominal pain, distension, frequency of
bowel movements and flatulence over a placebo control group. Symptom improvements after Colpermin were significantly better than after placebo.24 A meta-analysis of four randomized placebo controlled trials with approximately 400 subjects which showed peppermint oil to be superior to placebo for symptom reduction. The number needed to treat to prevent persistent symptoms was 2.5.25 Another study that looked at patients taking four capsules daily for four weeks, showed symptom improvement in 75% of patients compared to 38% of those taking placebo (P<.01).26

Peppermint oil is generally considered safe but there have been reports of renal failure or death if very high doses are taken, although the exact doses are not quantified. According to the FDA poisonous plant database, the lethal dose of peppermint oil that would cause death in 50% of the patients was 300 ml/kg. Common side effects at clinical doses include allergic reactions, rash, nausea, vomiting, perianal burning and heartburn. Drug interactions include potential interaction with medications metabolized through the cytochrome P450 1A2 system such as cyclosporine and simvastatin.27 The safety of peppermint oil during pregnancy has not been demonstrated.

There has been a recent study supporting the use of peppermint oil (IBgard®) which is a capsule of sustained release microspheres of Ultramen®, an ultra-purified peppermint oil, the results of which were presented at the 2015 DDW meeting.28 IBgard® capsules contain L-menthol, the principal component of peppermint oil, with targeted delivery to the small intestines. A US-based, four week, placebo-controlled, multi-centered, randomized trial was completed which studied 72 patients with IBS-D and IBS-M. 79% of patients reported a reduction in unbearable or severe abdominal pain at four weeks and even showed a reduction in total IBS symptoms at 24 hours. 93% of patients were satisfied with the relief from their IBS symptoms in a post-study assessment and side effects were comparable to placebo. This agent – IBgard®-is now officially approved for treating patients.

Mind-body therapies

Brain-gut interactions are increasingly recognized in the pathogenesis of IBS and almost half of IBS patients have comorbid psychiatric disorders.29 Mind-body therapies are directed at using the connection between the brain and body to either alter how the mind perceives symptoms or to change the symptoms themselves. A systematic review of psychological treatments included controlled trials of cognitive-behavioral therapy (CBT),
biofeedback therapy, stress management, hypnotherapy, progressive muscle relaxation and relaxation; of these, hypnotherapy and CBT are supported by the most clinical evidence.30

CBT teaches patients that they have a choice in how they respond to their internal and external environments. Patients undergoing CBT are trained to recognize and correct thoughts and behaviors that amplify symptoms or undermine well-being. This is often combined with psychological strategies for coping with symptoms and illness.29,31 For example, patients who normally respond to abdominal cramping by anger and frustration may, through CBT, decide to respond to the cramping by sitting down and performing some breathing exercise while calming the mind instead of having his or her usual response.

A review of CBT for IBS found that when looking at 16 trials, all but three showed significant behavioral improvement in IBS symptoms. Most of these studies had small number of patients included in the study. The author concluded that “overall, the weight of evidence from published trials show CBT to be more beneficial than routine medical care for the treatment of IBS, and possibly more beneficial than attention-placebo control conditions (i.e. giving additional support as in education and emotional support)”.32

Therapeutic suggestions have been given to patients in a state of deep relaxation and narrow focus since the 19th century.33 Gut-directed hypnotherapy is a specific technique that combines suggestions related to emotional well-being and intestinal health. Its use in IBS was first reported in a small trial of 30 patients, in which improvements in symptoms were greater after seven weekly sessions of hypnotherapy than they were with supportive psychotherapy.34 Hypnosis teaches patients to place themselves in a relaxed state and give themselves suggestions about how their mind or body should respond. For example, patients who have chronic abdominal pain may be asked to associate a color with the pain; patients often choose the color red. A medical hypnotherapist will then work with patients in a relaxed state to image that red, painful color in his or her abdomen slowly changing to a more calming and comfortable blue color, and during that change, imagining the pain also diminishing. Patients will practice this with the hypnotherapist so that when the pain occurs outside the therapist’s office, they can use this technique on their own.35

A Cochrane review in 2007 looked at multiple studies using hypnotherapy for IBS.36 The results were positive in that the studies showed a beneficial effect of hypnotherapy. Another review looked at 14 studies, which found that 80% of the subjects had improvement of IBS symptoms with hypnotherapy but only six of the included trials had a control.37 There is strong evidence supporting the use of hypnotherapy for treatment of
IBS. Safety and potential long-term benefits add to its appeal.38 The evidence also suggests that some patients may be more “hypnotizable” than others,39 but it is reasonable to advise patients to consider a trial with a
therapist trained in gut-directed hypnotherapy.

Mind-body therapies are useful modalities for treatment of IBS given they are unlikely to have side effects and most patients respond well, especially in children, where the data is strongest for a positive effect.

Acupuncture

Acupuncture has been used in Asia for thousands of years and is becoming more and more popular in the United States since the 1970s. Acupuncture is a therapeutic modality in TCM. Acupuncture uses small needles to pierce the skin at designated acupuncture points and is often used with electrical stimulation from devices that are similar to transcutaneous electrical nerve stimulation (TENS) unit. The physiology of acupuncture can be related to local changes in pain chemicals, such as substance P, bradykinin, central release of endogenous opioids, norepinephrine and serotonin. It has been used to treat several gastrointestinal symptoms in functional and organic diseases, and has been shown to influence visceral reflex activity, acid secretion and gastric emptying.40 Brain-gut disturbances make it reasonable to consider treating the disorder with acupuncture.40,41

A study showed that electroacupuncture could attenuate chronic visceral hypersensitivity in rats.42 Although animal studies have shown positive effects with acupuncture, human trials have had mixed results. There is difficulty in assessing the appropriate controls including needles used, sham procedures utilizing acupuncture points pay also result in some stimulation of these points, and it is difficult to blind either the patients or the clinician as to whether or not patients have had acupuncture. There have been studies that have found that patients treated with acupuncture were equivalent to sham acupuncture where some studies used non-acupuncture points as “sham control” and others used telescopic needles that did not penetrate the skin. Some used a standard set of points for the
intervention while others used different points for each patient that was selected after an assessment by a blinded acupuncturist. There has been one study that showed that acupuncture and psychotherapy were more effective that psychotherapy alone43 and another study reported that acupuncture was superior to the herbal formula TXYF.44

In 2006, the Cochrane Collaboration reviewed 6 acupuncture trials and found that overall the scientific quality of the studies was poor, and the results showed acupuncture to be no more effective than sham acupuncture in treating symptoms of IBS. It had recommended further studies before drawing definite conclusions.41 There was a subsequent study which showed that the IBS patients in both acupuncture and sham acupuncture groups improved significantly when compared with the waitlist group. However, they found no statistical different in the change in symptoms between the acupuncture and sham acupuncture groups.45,46

Side effects of acupuncture usually tend to be transient and mild; they include sensation, aching at the sites of needle insertion, bleeding and infection.

A new modality, non-needle electroaccupuncture, has been described in the literature for treatment of various conditions including nausea, vomiting and gastroparesis. This might be a future direction for the treatment of GI conditions including IBS for patients who are afraid of needles and to decrease possible side effects of acupuncture. In addition, needless acupuncture

  • typically a vibrating signal from an electrode – can
    be applied by the patient at home frequently (e.g.
    before meals). Traditional acupuncture is limited to
    certain days of therapy and effects cannot be sustained.
    Finally, the cost of acupuncture is a hurdle for the needle
    approach in the USA.
    Probiotics

The World Health Organization defines probiotics as “live organisms that when administered in adequate amounts confer a health benefit on the host”.47 The phenomenon of ingesting probiotic products started 100 years ago, when the first reports showed beneficial effects of probiotic bacteria on human health. Since then, probiotic preparations have become an essential element in the prevention and treatment of certain disease. Probiotic microorganisms are primarily lactic acid-producing bacteria (i.e. Lactobacillus, Bifidobacterium). Some probiotics have been shown to have anti-inflammatory properties, as evidenced by a recent article of efficacy of VSL#3 in Crohn’s patients,48,49 while others have been shown to modulate
visceral hypersensitivity.50,51

A systematic review and meta-analysis was completed were 35 RCTs were identified using probiotics in IBS, involving 3,452 patients. Fourteen trials were at a low risk of bias with the remainder being unclear. Nineteen trials used a combination of probiotics; eight used Lactobacillus, three Bifidobacterium, two E.coli, one Streptococcus, one Saccharomyces and one either Lactobacillus or Bifidobacterium. The systematic review and meta-analysis demonstrated that probiotics were effective therapies for IBS, in terms of both improvement in overall symptoms and improvement in global symptom, abdominal pain, bloating and flatulence scores. The number needed to treat to improve symptoms was 7. The most evidence was found to support the use of combinations of probiotics and L.planatarum DSM 9843. There was also a trend toward beneficial effect of Bifidobacterium in terms of improvement in global IBS symptoms and pain scores, although which particular strain or species remains unclear. Adverse effects were rare but more common in the probiotics group when compared to placebo.52

Treatment with a probiotic containing L.plantarum 299 v (Lp 299 v) significantly reduced the main symptoms of IBS, such as abdominal pain, discomfort and bloating. Lp 299 v was administered once daily for four weeks.53 Another study showed that long-term supplementation with probiotics like Bifidobacterium bifidum MIMBb75 and Saccharomyces boulardii could cause up to a 20% improvement compared to the placebo group.54,55,56It has been found that formulations containing VSL#3 have reduced flatulence while lactobacillus GG may potentially reduce the risk of
diarrhea. The clinical effects of B.infantis 35,624 strain have been confirmed to be beneficial as well, showing that a preparation administered to patients at a dose of 100,000,000 CFU showed at least 20% decrease in all
major IBS symptoms compared to placebo.57

General recommendations from the American College of Gastroenterology as well as expert consensus panels from both the United States and in Europe are similar. There is reasonable rationale for why probiotics may work as treatment for IBS and the FDA has granted probiotics GRAS status (generally recognized as safe). A therapeutic trial of probiotics is reasonable. Daily oral doses of 10-100 billion bacteria are most common. Side effects are believed to be negligible but caution is advised in preterm infants, immunocompromised patients, and critically ill patients in the ICU.

Fecal Enemas

Transplantation of stool for the treatment of gastrointestinal disease was first reported in 4th-century China by Ge Hong, who described the use of human fecal suspension by mouth for patients who had food poisoning or severe diarrhea.58 In the 16th century, Li Shizhen described oral administration of fermented fecal solution, fresh fecal suspension, dry feces and infant feces for the treatment of severe diarrhea, fever, pain, vomiting and constipation. In the 17th century, fecal microbiota transplantation (FMT) began to be used in veterinary medicine, both orally and rectally, and was later termed “transfaunation”.59

The pathogenesis of irritable bowel syndrome (IBS) is multifactorial and now believed to involve a complex interplay among the brain-gut axis, immune system and intestinal microbiota.60 Perturbation of the intestinal microbiota has been shown to result in altered GI motility and visceral hypersensitivity, which have been observed in patients with IBS and are thought to play a role in disease pathophysiology.61 Additionally, observations have been made that link preceding gastroenteritis, small bacterial overgrowth (SIBO) and IBS, further implicating intestinal microbiota in the development of IBS.60 Probiotics have been reported to improve post infectious IBS in animal models.62 Hence there has been interest in restoring the intestinal microbiota in IBS patients. FMT, or donated feces, may prove more beneficial, since they are the ultimate
human probiotic.

In a series of 55 patients with IBS and IBD treated with FMT, cure was reported in 20 (36%) patients, decreased symptoms in 9 (16%) patients, and no response in 26 (47%) patients. In another series, 45 patients with chronic constipation were treated with colonoscopic FMT and subsequent fecal enema infusions, 89% of whom (40 of 45 patients) reported relief in defecation, bloating, and abdominal pain immediately after the procedure. Normal defecation, without laxative use, persisted in 18 (60%) of 30 patients who were contacted 9 to 19 months later. In a recent study of 13 patients who underwent FMT for refractory IBS (9 IBS-diarrheal, 3 IBS-constipated, 1
IBS-mixed), 70% of patients reported improvement or resolution of symptoms, including abdominal pain (72%), bowel habit (69%), dyspepsia (67%), bloating (50%) and flatus (42%).63 FMT resulted in improved quality of life in 46%. Conclusions of all these trials are limited by the lack of any control arm.

In another study of patients with refractory IBS, FMT resolved or improved symptoms in 70% of our patients with refractory IBS, including abdominal pain (72%), bowel habit (69%), dyspepsia (67%), bloating (50%) and flatus (42%). FMT also resulted in improved quality of life (46%).63

In 2013, the US Food and Drug Administration (FDA) announced that fecal microbiota would require an investigational drug application (IND) to perform FMT for any indication. This decision to apply IND requirements made FMT largely unavailable to the community physician. Currently, FDA regulations permit a treating physician to perform FMT for Clostridium difficile infection (CDI) in patients who are unresponsive to standard therapy, without an IND, provided that the physician obtains adequate informed consent. The FMT product must be obtained from a donor known to either the patient or the treating licensed healthcare provider. Finally, the donor and the donor’s stool must be qualified by screening and testing performed under the direction of the licensed healthcare provider. The FDA still requires an IND for the use of FMT to treat all other GI and non-GI diseases.64

In the only long-term follow-up study of FMT in IBS patients to date, which was a combined effort from 5 medical centers, 77 patients who had had FMT and were followed for more than 3 months experienced and maintained a 91% primary cure rate and a 98% secondary cure rate, the latter defined as cure enabled by use of antibiotics to which the patient had not responded before the FMT or by a second FMT.64,65,66,67

In summary, FMT in IBS is undoubtedly work in progress. The patient may inquire with our Dr. Google society, yet at this stage there is no controlled trial data. Therefore our recommendation regarding this treatment
is “let’s wait”.

CONCLUSION

This is an attempt at a brief overview of the most common alternative therapies available to treat IBS. Although it is in no way comprehensive, gastroenterologists should be aware of the various alternative treatments available for our patients. There are many instances where our IBS patients come to us already on various Western medications and they are responding to some degree but are searching for more improvement in their quality of life or they initially responded well but now seem to be less sustained by usual medical approaches. At these encounters when the patients says, “Doctor, should I go to the Mayo Clinic?” the answer should be a resounding “No. We have a lot more options to try, specifically the following…” At that point, you can consider trying various complementary therapeutic options, often in the setting of the patient personally requesting alternative treatment approaches.

One important concept to emphasize from the beginning is the necessity to establish a good doctor- patient relationship and hence trust. To enhance this relationship, the clinician must remember to first and foremost listen to their patients. Although we are specialists in gastroenterology, we must not forget that in the end, we are treating the whole patient, not just their GI symptoms. To achieve this goal, the patient must be an active participant in his or her treatment strategy. IBS is a life-long disease where the goal is to maximize the good days since there is no magic cure. All possible approaches and therapies may be needed and in this review, we endorse and subscribe to them all, including those treatments with evidence supporting nontraditional therapies.

Download Tables, Images & References

NUTRITION ISSUES IN GASTROENTEROLOGY, #147

Transition to Ready to Hang Enteral Feeding System

December 2015 • Volume XXXIX, Issue 12
Mallory Foster,Wendy Phillips,Wendy Phillips,Carol Rees Parrish

Read Article

Nursing time and supply costs to administer enteral feeding are substantial. One major academic medical center recently converted from an open system (OS) to a closed, or “ready to hang” (RTH) system for enteral feeding. This article reviews that transition from an OS to RTH and documents the costs, nursing perceptions, and lessons learned in the process.

Healthcare costs in the United States are soaring. Efforts to improve patient care, safety, and outcomes are ongoing goals particularly when they also result in a reduction in the cost of care. Enteral feeding is the primary means of providing nutrition support to patients who cannot meet their needs orally; nursing time and supply costs to administer that care are substantial. One major academic medical center recently converted from an open system (OS) to a closed, or “ready to hang” (RTH) system for enteral feeding. This article reviews that transition from an OS to RTH and documents the costs, nursing perceptions, and lessons learned in the process.

Mallory Foster, Dietetic Intern, University of Virginia Health System Dietetic Internship Program Capstone Project Wendy Phillips, MS, RD, CNSC, CLE, FAND, Director, Nutrition Systems, Regional Clinical Nutrition Manager, Morrison Healthcare Carol Rees Parrish MS, RD, Nutrition Support Specialist, University of Virginia Health System, Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, VA

INTRODUCTION

Healthcare costs in the United States are the highest in the world1 and have become a major concern in recent years. At the same time, undiagnosed and untreated malnutrition in the hospital setting is an often undetected contributor to the growing cost of medical care in this country, as it can lead to further health complications and increased length of stay.1 Thus, efforts to advance nutrition care should be emphasized as a means to improve patient outcomes and decrease the cost of healthcare. Nutrition care practices and protocols should be reevaluated routinely to ensure that resources are used effectively and efficiently.

Enteral feeding is the primary means of providing nutrition support to patients who cannot meet their needs orally. Enteral nutrition (EN) is a cost-effective way of delivering nutrition support,2 has inherent benefits to the gastrointestinal (GI) tract, and is the standard of nutrition care over parenteral nutrition.3 Thus, anything that can be done to improve the efficiency, safety, and delivery of EN is a worthwhile goal.

Open Vs. Ready to Hang System

EN delivery is available in two main systems: an open system (OS) or a “ready to hang” system (RTH), also sometimes called a “closed system.” Using an OS, formula from cans or bottles is “bolused” into a feeding tube with a syringe, or poured into a feeding bag, then administered via a feeding tube into the stomach or intestine using a feeding pump or gravity drip. RTH comes in a sterile, pre-filled formula container (typically 1 liter) that is spiked by the feeding tube, and then fed to the patient via a feeding pump.4 Boluses can also be delivered using RTH by setting the feeding pump to deliver boluses at predetermined times. Both systems have advantages and disadvantages in several areas, including cost, ease of use, and nursing time required.

COST

Factors to consider when evaluating the cost difference between an OS and RTH include actual cost of the formula and tubing, nursing labor, transportation to hospital units, storage, and waste.

OS has been used for many years to deliver EN to patients. Based on current pricing contracts between the Medical Center and formula companies, OS costs less compared to the same volume of a RTH formula.4,5 OS is also convenient when a small volume of formula is needed, as is the case with bolus feeding or in the pediatric population,4 yet it can lead to increased labor and equipment cost.4-8 According to nursing procedures at some facilities, including the hospital in question, only the amount of formula that will be infused within 4 hours (although in the real world, we know how hard this is to achieve) is to be hung at one time in an OS. So nurses must refill feeding bags frequently, up to 6 times per day.9 The tedious protocol (see Table 1) may also occasionally lead to missed EN if the nurse
is unable to refill the bag in a timely manner when it runs out. Additionally, OS requires more handling than the RTH prior to administration, potentially increasing the risk of bacterial contamination.4-8,10-13 Proper prevention methods to decrease the chance of bacterial contamination in the OS increase nursing time.7 The additional time used to ensure an OS system is safe could be spent conducting other nursing tasks.

RTH, also known as a closed system, was developed with the express purpose to reduce the nursing time required to administer EN and to decrease the risk of bacterial contamination by requiring less handling.5,7 Most studies cite an increased amount of nursing time related to an OS as compared to a RTH;4-6 in fact, Luther et al.6 estimated that administering formula using the OS doubles the required nursing time when compared to RTH in a hospital intensive care unit due to the additional steps required to administer the OS (See Table 1). Per manufacturer guidelines, RTH containers are approved to hang for up to 48 hours, yet available tubing sets are only approved to hang for 24 hours; hence, all RTH formula containers must be discarded at 24 hours as they cannot be spiked more than once.7,8 Regardless, 24 hours is a significant improvement over every 4 hours – or up to 6 times per day – if a patient is on a continuous feeding regimen. Although RTH formula has a higher cost when compared to the same volume of OS formula,4,5,7 cost savings may be realized through decreased nursing time, a potential decrease in nosocomial infection, and improvement in delivery of EN to patients.4 Actual practices at individual hospitals should be evaluated to determine if transition to a RTH from an OS achieves these goals.

Handling of EN Contamination of EN

Contamination of EN can occur during preparation if modular supplements (such as protein powder/liquid) are added to the formula, when the feeding is transferred to the administration container, during assembly of the feeding system, and during administration to the patient.5,7,11 Clean technique and proper hand washing should always be used to prepare and deliver formula in both an OS and RTH.2

Potential risk reduction from nosocomial infection from contamination of EN influences some clinicians in the selection of an OS vs. RTH. Whereas only the formula itself is sterile in an OS (not the bag it hangs in), the entire RTH system is sterile because it is not exposed to the outside environment; it is therefore associated with a decreased risk of contamination.13,14 However, prospective trials demonstrating this perceived benefit are not available. C. difficile infection is one of the most life-threatening infections associated with hospitalized patients, especially those on EN.17,18 Any measures that can be taken to prevent bacterial contamination and a culture of safe practices surrounding the use of EN should be the goal.

Both OS and RTH EN formulas are sterile when packaged, however, once administration has begun, retrograde movement of bacteria from the GI tract via the feeding tube is possible in both systems,7,12 as the GI tract is a source of a myriad of microbes.7 Studies have shown that retrograde movement of bacteria in EN feeding systems is very slow, and while bacterial contamination has been found in the distal portions of the feeding tube closest to the patient, bacteria did not reach the feeding container over a 48 hour hang time.7,12

Storage

RTH formula containers should not have long-term exposure to light as some nutrients in the formula such as riboflavin, vitamin B6, and vitamin A are photosensitive. Recommended storage of RTH containers is on covered
shelves or in a closed cabinet prior to use to avoid vitamin degradation. The opaque packaging of the OS protects the formula from light during storage.

Volume of EN Delivered

Others have reported an association between longer hang times in the RTH and increased percentage of prescribed EN actually received by the patient.19,21 Perhaps because of the longer hang time, Atkins and Phillips20 found that, on average, an OS provided patients with 74% (range 43-104%) of the ordered EN volume compared to 84% (range 59-101%) with RTH
at one major academic medical center. Though small, (n=60), this study suggests that the RTH may provide patients with a greater volume of their nutrient needs, and confirms results found in other studies.19,21

Product Waste

Formula waste can be a significant cost regardless of which system is used, and the limited research in this area is mixed. Some studies have shown that the RTH leads to decreased formula waste because the EN can hang longer and thus the full volume is delivered to the patient.2,4,7 However, others have noted that RTH can lead to increased formula waste if the entire volume of the container is not used within the recommended
hang time or if hospital culture is difficult to change from years of switching all bags, tubing, etc. at a certain time each day regardless of expiration time of hanging formula.4 Further studies are needed to determine whether one feeding system generates less wasted formula than another.

Cost Analysis

To evaluate the difference in cost between the OS and RTH, purchasing data for an eight month period after transition from the OS to RTH was obtained from the hospital storeroom purchasing department. A small inventory of OS supplies and formulas continued to be purchased even after the transition to the RTH system since not all formulas are available in RTH
containers and because OS containers are used for teaching those patients discharged home on the bolus feeding method. Total cost for formula and supplies for both the OS and RTH systems during the 8 month study period was $109,297.54. For practical purposes of this descriptive study, it was assumed that the same actual volume of formula would have been purchased had the OS alone been used during the study period, the expenses for formula and related supplies would have been $104,470.16. Therefore, RTH cost $4,827.38 more over the 8 month period than would have been spent on the OS system. Since the study period was 8 months, the monthly average increase in overall cost is $603.42 (see Table 2).

Feeding supply costs were also factored in. Total expenses for feeding supplies after the transition to the RTH system, including the cost of bags and tubing required to deliver water flushes as well as the remaining OS products (excluding enteral formula), during the 8 month period were $52,795.99. Had the OS continued to be used, the money that would have been spent on the equivalent tubing and bags would have been $54,549.64 (see Table 2), for a difference of $1,753.65 in favor of RTH. Overall, considering cost of formula and supplies, the OS would have cost the Medical Center $3,073.73 less during the 8 months under consideration. On the other hand, nursing time with each system, a considerable expense, was not factored into the cost differences. An interesting finding was the total expenditure on the feed/flush bags vs. the feed bag alone (see Table 3).

Nursing Satisfaction Survey An Unexpected, but Important Finding

Cost analysis is an important component of evaluating the transition to a RTH, but also important is the effect on nursing satisfaction. A nursing satisfaction survey (see Table 4) was distributed on six hospital units
(n=92). Survey results showed nurses perceive that RTH requires less time to prepare, hang, and manage when compared to OS, which is consistent with other studies6,21 (see Table 5). Nurses also reported that RTH was easier to use, and they perceived formula waste to be comparable between systems. Overall, respondents overwhelmingly preferred the RTH over the OS system: 88% compared to 12%. Nurses play a vital role in patient care, therefore anything that makes their job easier, takes less time, and improves nursing satisfaction is always a worthy goal.

Open text comments left on surveys and visits to nursing units also provided valuable feedback. Nurses reported confusion about which tubing sets to use and the appropriate hang time of RTH EN. Additionally, they reported that the appropriate feeding sets were sometimes difficult to find. Based on these comments, the clinical nutrition team was able to provide improved guidance for nursing staff and in the future expect to see a decrease in costs based on improved selection of appropriate tubing and more efficient use of RTH.

Limitations and Lessons Learned

Actual nursing time associated with delivery of EN was not quantified, making it impossible to attach a monetary value to the nursing time required. The number of patients receiving EN and volume ordered and
delivered were not recorded for the RTH or OS. Amount of wasted formula and supplies due to administration error, confusion about hang times, expiration, labeling errors, or other unknown factors were not evaluated because data was based on retrospective purchasing information. However, total costs spent by an institution on supplies required to deliver EN should be measured and tracked, especially related to administration error and supply management. Evaluating data obtained from the purchasing department, as in this study, provides a place to start.

Comments recorded on the nursing satisfaction survey and visits to the unit supply room’s revealed opportunities for education and process improvement. In the future, observing actual delivery of EN using the RTH and conducting a root cause analysis of systemic issues needed to improve delivery will be used to improve EN practices. Designing clean supply rooms so all supplies are located in a standardized location on all units with clear labeling is important at all healthcare facilities. Nursing education should be delivered in regular intervals in collaboration with both the nutrition and nursing staff, to include overcoming the barriers identified in this project as well as factors identified ia other means related to EN feeding (see Table 6).

CONCLUSION

When considering the advantages and disadvantages of an OS or RTH EN feeding system, the most important factors to consider are patient outcomes, ease of use, safety, and cost. Review of the literature reveals that both the OS and RTH can be safely delivered to patients when proper procedures are followed. A RTH may also provide patients with a greater percentage of their nutrient needs, ultimately leading to improved nutritional status and improved patient outcomes, but this will require further study. Although a RTH is more expensive per unit of volume when compared to the OS, it is possible that if the RTH saves nursing time, it may in fact be significantly less expensive due to savings on labor costs. Other factors that need to be considered are whether there is a decrease in infectious risk and waste. Although insufficient evidence exists to determine if a RTH is superior to OS in terms of cost, it clearly increases nursing satisfaction, and has been shown to increase delivery of EN which could also decrease hospital costs by reducing the incidence of malnutrition.

Download Tables, Images & References

FRONTIERS IN ENDOSCOPY, SERIES # 23

Image-Enhanced Endoscopy for Neoplasia Surveillance in Inflammatory Bowel Disease

December 2015 • Volume XXXIX, Issue 12
Margaret Blayney,Michael Chiorean

Read Article

The risk of colon cancer is increased in patients with both ulcerative colitis and Crohn’s colitis and therefore surveillance colonoscopy is recommended in patients with elevated risk factors for neoplasia. The guidelines developed during the era of standard white light endoscopy recommend targeted biopsies of visible neoplastic lesions as well as random biopsies to detect invisible dysplasia. The practical adoption of these guidelines has been thwarted by low yield and limited effectiveness in preventing colon cancer. Image-enhanced endoscopy and particularly chromoendoscopy have demonstrated an increased diagnostic yield for dysplasia while essentially eliminating the need for random biopsies. Although very promising, additional studies are needed to assess the utility of image-enhanced endoscopy and to demonstrate the superiority of these techniques in preventing colon cancer in IBD.

Margaret Blayney, MD1 Michael Chiorean, MD2 1Department of Internal Medicine and 2Division of Gastroenterology and Hepatology, Virginia Mason Medical Center, Seattle, WA

INTRODUCTION

It is well established that both ulcerative colitis (UC) and Crohn’s disease (CD) involving the colon increase the risk of colon cancer (CRC) although the magnitude of the incremental risk varies considerably with the epoch and the study population.1-5 Risk factors for colorectal neoplasia include duration and anatomic extent of disease, family history of colon cancer, persistence and degree of inflammation, coexistent primary sclerosing cholangitis and possibly male sex. 1-4,6-9 In contrast to sporadic colorectal neoplasia, colitis- associated neoplasms are more frequently multifocal and flat, thus being more challenging to diagnose particularly in an inflamed colon. Furthermore, colon cancer in patients with colitis tends to occur at a younger age compared to non-IBD patients.10-12 As is the case with sporadic colon cancer, dysplasia is believed to be the precursor of the majority of cases of colitis-associated carcinomas and thus surveillance guidelines have been developed by several professional societies based on limited supportive evidence. In the era of standard- definition white light endoscopy, these guidelines called for surveillance colonoscopy every 1-2 years after 8-10 years of established disease, with removal of all visible “suspicious” lesions and adjacent biopsies around lesions removed from within the area of colitis. In addition, random 4-quadrant biopsies every 10 cm were recommended in order to increase the detection of “flat” or invisible dysplasia. Based on a mathematical model developed in the early ’90s, a minimum of 32 random biopsies were required to achieve a sensitivity of 90% for detecting dysplasia or carcinoma.13,14 Aside from the tedious and time consuming approach, this strategy has never been clearly shown to be effective in preventing or increasing survival from colon cancer in patients with IBD. The yield of random biopsies for dysplasia obtained using both standard- and especially high- definition white light endoscopy (WLE) is extremely low (< 1:500 biopsies).15,16 In a large retrospective series from the St Mark’s hospital, more than 50% of the colon cancers detected in a cohort of patients enrolled in a surveillance program were interval cancers.11,17 Moreover, given the considerable costs associated with frequent colonoscopies and multiple biopsies, any marginal benefit of surveillance may not be cost- effective.18,19 Therefore, not surprisingly, many studies showed that the compliance with these guidelines was poor.15,20

Chromoendoscopy for IBD Surveillance

Since a substantial proportion of colon cancers in IBD can be attributed to missed or unrecognized neoplastic lesions using white light colonoscopy and the yield of random biopsies is extremely low, several image-enhancing techniques have been developed in order to maximize dysplasia detection and to facilitate the performance of targeted biopsies and polypectomies. Chief among these has been dye-based chromoendoscopy (CE) which has been evaluated in multiple prospective and retrospective studies mostly from referral centers. CE consists in the application of dye onto the colonic mucosa via either a catheter or using the water-jet channel provided with most colonoscopes. The stained mucosa enables a superior visualization of both elevated and depressed polypoid and non-polypoid lesions. In addition, particularly with the use of high- definition endoscopy, the pit pattern of the glandular crypts becomes visible and may help differentiate between neoplastic and hyperplastic or inflammatory pathology21,22. Indigo carmine at concentrations of 0.2- 0.4% and methylene blue at a concentration of 0.1% are the most commonly utilized dyes. Indigo carmine is commercially available both as a solution and as a powder – which is less expensive – although recent FDA restrictions on the use of non-sterile compounds in medical practice have limited drastically the use of the latter. Methylene blue is available as a 1% solution in vials containing either 1 or 10 mL and, in contrast to indigo carmine, is an absorptive dye which can penetrate the epithelial cell cytoplasm.23

Chromoendoscopy Technique

The technique of chromoendoscopy has been well described elsewhere.24-26 Most experts recommend the inspection of the colon mucosa on insertion using either standard or high-definition WLE. This allows a good evaluation of the level of disease activity, lavage and suction of excess fluid from the colon, and the identification of gross abnormalities that can be sampled or removed upon withdrawal. A solution of 5 or 10% N-acetyl cysteine may be sprayed during the introduction of the scope in order to wash off the mucus layer and allow a superior staining of glandular crypts and an improved visualization of subtle abnormalities.27 Once in the cecum, the stain is sprayed on withdrawal, either using the water-jet device provided with the scope or a dedicated spray catheter introduced through the operative channel.24 The water-jet device is faster and less messy but uses a larger volume of dye compared to the spray catheters (average 250 mL). A disadvantage of spray-catheters is that they have to be removed and reintroduced each time a lesion that requires an intervention is discovered thus increasing the down-time during the procedure. In our center, we prefer sequential segmental staining of the colonic mucosa after the excess fluid was adequately removed. An excellent quality of the prep is paramount and the use of anti-motility agents is optional. Most experts recommend against the use of random biopsies in patients with adequate mucosal healing.27 When significant inflammation or distortion of the lumen (including strictures) is present, or in patients with PSC, random biopsies should still be considered.

Diagnostic Yield of Chromoendoscopy

Regardless of the agents utilized, CE increases the yield of dysplasia by 2-5 fold per procedure compared to standard or HD WLE (Table 1). The per patient incremental yield for dysplasia with CE and targeted biopsies vs. WLE with random biopsies is approximately 7% with a number needed to test of 14. Conversely, the odds ratio for missed lesions with CE compared
with WLE is 0.07.26 Although no head to head studies are available, data suggests that indigo carmine and methylene blue produce equivalent results.28 Using decision-analytic models, CE was found to be both more effective and less costly compared with WLE regardless of the surveillance interval.29 Given the consistent superiority of CE for neoplasia detection,
some professional societies such as the British Society of Gastroenterology and the European Crohn’s and Colitis Organization have endorsed CE with targeted biopsies as the preferred surveillance method in patients with UC and Crohn’s colitis.30

Despite its obvious advantages, there has been a relatively slow uptake of chromoendoscopy in gastroenterology practices in the United States. Among the shortcomings, the most frequently cited are lack of basic knowledge and expertise, lack of opportunities for training during or after fellowship, a relatively slow and steep learning curve, variation in detection and resection skills, additional equipment requirements, the need for additional time for lengthy procedures and lack of specific procedure codes for reimbursement. The increased procedure time associated with CE – average 10 minutes – may be offset in part by obviating the need for random biopsies. In addition, some IBD thought leaders have questioned the significance of the incremental yield of CE for neoplasia as prospective outcomes studies evaluating the utility of CE for colon cancer prevention have not been performed. This seems somewhat counterintuitive as a very similar outcome, the adenoma detection rate, is widely considered a quality indicator of the adequacy of screening colonoscopy in the general population.31 Furthermore, there is ample indirect evidence of the benefit of CE from one of the largest and oldest UC surveillance programs in the world. A recent 40 year retrospective review of the data from the St Mark’s Hospital in the UK has shown that, although the rate of colectomy for dysplasia has decreased during the era of chromoendoscopy, the number of cases of interval cancer and advanced (Duke’s stage C and D) colon cancer diagnosed during surveillance has also decreased.32 This implies that more patients with ulcerative colitis who are diagnosed with dysplasia at surveillance colonoscopy are able to preserve their colon after the dysplastic lesions are removed, without the risk of dying from colon cancer. Furthermore, the negative predictive value of CE seems to be substantially higher compared with WLE; patients diagnosed with high-grade dysplasia or cancer during surveillance were twice as likely to have had a previous normal white light colonoscopy than a normal chromoendoscopy.32 Taken together, this data suggests that CE may be more effective at reducing the cancer risk compared with WLE. Obviously this is heavily dependent on the success of removing neoplastic lesions as they are identified.

Narrow Band Imaging for IBD Surveillance

Narrow-band imaging (NBI) available on the Olympus endoscopy system utilizes an electronically activated filter placed in front of the light source which allows only limited wavelengths of 415 nm and 540 nm (narrow band) of the white light spectrum to reach the mucosa. The blue-green light has a lower depth of penetration in the colon tissue and coincides with the optimal absorption wavelengths of hemoglobin. This makes blood vessels in the lamina propria appear darker against the white background of the mucosa and superficial submucosa.33-35 Angiogenesis and abnormal capillary patterns have long been associated with neoplasia and thus NBI is considered superior to WLE for differentiating between neoplastic and hyperplastic polyps.36 However, what may be an advantage in a healthy colon can become a limitation when evaluating mucosa in patients with colitis as the vascular pattern is diffusely distorted due to chronic inflammation. In addition, the pit pattern with NBI is not as neatly seen as with chromoendoscopy. NBI has been evaluated for IBD neoplasia surveillance in a few studies and was found not to be superior to high-definition WLE and was inferior to CE for detecting neoplasia in patients with chronic colitis (Table 2). The obvious advantage of all forms of “electronic chromoendoscopy” is that they are extremely accessible and easy to use; however their potential application in IBD surveillance is unclear.

The SCENIC Consensus Statement

As of 2010, the American Gastroenterology Association has endorsed colonoscopy with multiple random biopsies as the standard method for dysplasia detection in IBD based on the available evidence at that time.13 However, major advances in this field in the last decade have resulted in a significant variation in guideline recommendations among different gastroenterological societies throughout the world. In 2015, an international multi-disciplinary panel of experts was convened with the goal of developing unifying consensus guidelines for the diagnosis and management of dysplasia in patients with IBD. This process was based on an extensive critical review of the literature, used Institute of Medicine standards of guideline development and incorporated the GRADE methodology.37 In order to standardize reporting for both clinical practice and research purposes, the panel recommended abandoning the confusing terms of DALM (dysplasia-associated lesion or mass) and ALM (adenoma-like mass) in favor of ‘endoscopically resectable’ or ‘non-resectable’and ‘polypoid’ or ‘non-polypoid’ lesions. The defining elements of the appearance and resectability of a lesion are diameter, height, symmetry and appearance of the margins, along with endoscopic and histologic evidence of successful removal. Needless to say, these features are therefore, to some extent subjective and operator-dependent. The other recommendations of the SCENIC consensus panel regarding the detection and management of dysplasia in IBD are listed in Table 3. Overall, the SCENIC panel has endorsed chromoendoscopy and high-definition imaging as superior methods for neoplasia detection in IBD; however the panel stopped short of relinquishing the need for random biopsies. The SCENIC authors acknowledge the controversy surrounding this issue as well as the technological and logistic hurdles for adopting chromoendoscopy as the standard surveillance method. Nevertheless, these guidelines represent a big first step in the right direction which will undoubtedly create the foundation for further research in this field.

CONCLUSION

In conclusion, despite its rather modest contributions in routine screening colonoscopy, CE is an endoscopic technique with fairly obvious advantages for dysplasia detection in patients with inflammatory bowel disease at high risk for neoplasia. There is a mounting level of evidence supporting its superior performance for surveillance in patients with chronic colitis. Over time, additional studies will likely strengthen the evidence on improved outcomes for dysplasia diagnosis and management and ultimately, survival from colon cancer and improvement in the quality of life in patients with IBD. While easier to use and more accessible than dye- based chromoendoscopy, electronic chromoendoscopy such as narrow band imaging has an as yet undefined role in colorectal neoplasia surveillance in IBD.

A CASE REPORT

Syphilitic Hepatitis

November 2015 • Volume XXXIX, Issue 11
Lauren M. Bleich,Howard L. Taubin

Read Article

Lauren M. Bleich, MD, MPH Gastroenterology Fellow Bridgeport Hospital Yale New Haven Health, Department of Medicine, Section of Gastroenterology Howard L. Taubin, MD, Attending Physician Clinical Faculty, Bridgeport Hospital Yale New Haven Health, Department of Medicine, Section of Gastroenterology

A 21 year-old homosexual male presented to his primary care physician with a five-day history of right upper quadrant abdominal pain exacerbated by meals. He also endorsed generalized pruritis, dark urine and fatigue. He denied fever, chills, nausea or vomiting. He had no significant past medical history, and denied taking medications or supplements. His social history was significant for a history of intravenous (IV) drug use in the past and several tattoos. On physical exam, he exhibited mild tenderness to palpating in the epigastrum but the exam was otherwise unremarkable. Blood work demonstrated abnormal liver enzymes including aspartate transaminase (AST) 314U/L, alanine transaminase (ALT) 627U/L, alkaline phosphatase 317U/L, total bilirubin 2.1mg/dL and GGT 654U/L. Synthetic hepatic function was preserved with an INR of 1.0. Abdominal ultrasound was significant for increased echogenicity suggestive of fatty infiltration. A complete hepatitis panel including Hepatitis B DNA and Hepatitis C RNA viral loads were normal.

The patient’s alkaline phosphatase continued to increase over the next few weeks and peaked at 590U/L, while the AST and ALT decreased but did not return to the normal range. Two weeks after the patient’s initial presentation, he returned with symptoms including night sweats, a maculopapular palmar rash, and a painless penile chancre. A skin biopsy was performed of the left palm, which demonstrated the presence of spirochetes, consistent with the diagnosis of secondary syphilis (Figure 1). Rapid plasma reagin (RPR) and fluorescent treponemal antibody-absorption (FTA-ABS) tests were both reactive. The patient was treated with a single dose of benzathine penicillin G 2.4 million units intramuscularly and his symptoms resolved. Repeat liver enymes three months later were normal including an alkaline phosphatase of 47U/L.

Described by William Osler as the great imitator, syphilis is thought to originate from the area now known as Haiti.1 The New World theory proposes that Christopher Columbus acquired the disease and carried it to Europe in the 1400s. By 1495, syphilis was widespread throughout the continent. In 1905, Treponema pallidum was linked to the disease. Throughout history, many famous people are thought to have been infected with syphilis, including Naopleon Bonaparte, Vincent Van Gogh, Beethoven and Mussolini.

Early syphilis is a reportable infection in the United States. It is estimated that one fourth of syphilis cases in the United States were reported in HIV-infected patients.2 In the early 1990s, a mini epidemic of syphilis occurred, corresponding with increasing number of HIV cases. In 2010, the rates of infection are highest among the group of men age 20-24, and African American men are 15 times more likely to be infected than their Caucasian counterparts.3 Syphilis continues to remain a worldwide issue. In 2009, according to the World Health Organization, there were 3-4 million new cases of syphilis in each Southeast Asia, Sub-Saharan Africa and Latin America.4

Transmission of Treponema pallidum usually occurs through direct contact with an infectious lesion during sexual intercourse. The spirochete accesses the new host via disrupted epithelium at sites of minor trauma. Early lesions of primary syphilis, including chancres, mucous patches, and condyloma lata, are infectious and transmission occurs in one-third of patients exposed to these lesions. Syphilis can also be acquired by passage through the placenta. Median incubation time before the onset of clinical symptoms is approximately three weeks, but can range from 3 to 90 days.

The natural course of untreated syphilis is well documented in history. In the late 19th century, a Norwegian physician described the progression of infection in over 1,400 patients with primary and secondary syphilis. Between 1932 and 1972, data was collected on 431 African American men with untreated syphilis in Tuskegee, Alabama. Although separate stages, there is no clear demarcation between primary and secondary syphilis. As many as one-third of patients with secondary syphilis will still have a primary chancre present. It had been reported that up to 60% of patients with secondary syphilis do not recall having a skin lesion.5 This is particularly the case in the female population, where primary lesions tend to be internal.

Before 1980, only a few cases of syphilitic hepatitis were reported in the literature. Clinical manifestations are varied, but include jaundice, dark urine, malaise, anorexia and arthralgias, similar to our patient’s presentation. The most common finding is an abnormally disproportionate elevation of the alkaline phosphatase. Minor elevations of AST, ALT and bilirubin can be seen as well. Histologic preservation of the liver architecture is usually seen, with occasional granulomas and focal hepatocyte necrosis. Treponema pallidum organisms within the liver biopsy confirm the diagnosis, however more commonly the spirochete is demonstrated within other tissue samples. Non-treponema tests including RPR and VDRL are used for primary screening. Secondary treponemal testing (ie: FTA-ABS) are used to confirm the diagnosis.

Clinical symptoms of syphilitic hepatitis are likely due to dissemination of Treponema pallidum from the site of primary infection to the liver. The pathogenesis of liver injury is not well understood. Hypotheses include direct injury by the spirochete to the portal venous system and an immune complex-mediated autoimmune reaction.6

Treatment for primary, secondary and latent syphilis includes a single dose of benzathine penicillin G (2.4 million units IM). If the duration of latent syphilis is unknown, the patient should be treated with 3 doses of benzathine penicillin G at 1-week intervals. A patient’s symptoms should decline along with liver function abnormalities when appropriate treatment is given, thereby confirming the diagnosis. A Jarisch- Herxheimer reaction may occur within 24 hours of treatment. This acute febrile reaction, accompanied by headache and myalgia, is thought to be the result of pyrogens released from the dying spirochete into the body. All patients should have re-examination of clinical symptoms and serologies at six and twelve months following treatment. Syphilitic hepatitis should not lead to sequelae of chronic liver disease.

Download Tables, Images & References

A SPECIAL SUPPLEMENT

Efficacy, Safety and Tolerability of Rectal Therapies in Ulcerative Proctitis and Ulcerative Proctosigmoiditis A Special Supplement

November 2015 • Volume XXXIX, Issue 11
Elisa McEachern,Brian P. Bosworth

Read Article

Ulcerative colitis (UC) is a chronic condition in which inflammation extends proximally from the rectum along the colonic mucosa. Most patients experience alternating periods of active disease and clinical remission. In patients with ulcerative proctitis or ulcerative proctosigmoiditis, inflammation is limited to the rectum, or rectum and sigmoid colon, respectively. Induction of clinical remission is the primary goal of treatment for patients with active UC, whereas maintenance therapy is recommended for patients with UC in remission.

Ulcerative colitis (UC) is a heterogeneous disease that varies in the extent of affected colon and the severity of symptoms. Studies have suggested that at the time of diagnosis, approximately 46% of patients have inflammation limited to the rectum (ulcerative proctitis) or limited to the rectum and the sigmoid colon (ulcerative proctosigmoiditis). For distal forms of UC, a number of treatment options are available, including rectal and oral formulations. Rectal therapies (i.e., suppositories, foams, enemas) may be recommended for the management of patients with distal forms of UC, either as monotherapy, or in combination with oral therapies. First-line treatment for patients with distal UC is often 5-aminosalicylic acid rectal therapies, and is supported by a history of safety and efficacy in this patient population. However, second-generation corticosteroid (i.e., budesonide, beclomethasone dipropionate) rectal therapies have also been developed to treat active distal forms of UC. Despite the demonstrated safety and efficacy of rectal therapies for the induction and maintenance of remission of UC, rectally administered agents are widely underused and associated with nonadherence to treatment. However, decreased dosing frequency and the introduction of formulations of rectal agents that improve retention may increase use of rectal therapies and help to overcome barriers associated with nonadherence. Data support the use of rectal therapies for the induction and maintenance of remission of distal forms of UC.

Elisa McEachern, BS and Brian P. Bosworth, MD; Jill Roberts Center for Inflammatory Bowel Disease, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY. Elisa McEachern reports no conflicts. Brian Bosworth has received research grants from Pfizer Inc., Salix Pharmaceuticals, Inc., and Takeda Pharmaceutical Company Limited. Acknowledgments: Technical editorial and medical writing assistance was provided under the direction of the authors by Sophie Bolick, PhD, Synchrony Medical Communications, LLC, West Chester, PA. Funding for this support was provided by Salix Pharmaceuticals, Inc., Raleigh, NC.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon, characterized in most patients by alternating periods of active disease and clinical remission.1 Common clinical symptoms of active UC include diarrhea, rectal bleeding, urgency, abdominal pain, and tenesmus. In one study, diarrhea was the most common symptom observed in patients with active UC, affecting approximately 65% of patients, with abdominal pain reported in approximately 34% of patients.2 The majority of patients with active distal UC had rectal bleeding (i.e., 70% of patients with ulcerative proctitis [UP] vs. 33 to 37% of patients with more extensive disease). In another study, 96% of patients with active UC passed blood and mucus in their stool.3 Thus, management of symptoms of active UC, which may cause concern for patients, is one of the goals of treatment.4,5

The prevalence of UC has been estimated between 206 and 263 per 100,000 persons in the United States, thus UC affects approximately 600,000 individuals.6-8 While diagnosis of UC can occur anytime, age at diagnosis typically has a bimodal distribution, with the first peak observed during the 20s and 30s, and a second, smaller, peak occurring during the 60s and 70s.9 Although it is not clear whether differences in incidence based on sex are apparent, some studies have suggested that males have slightly greater incidence of UC versus females.9,10 In general, patients with UC have the potential for a relatively long and variable disease course, associated with a substantial economic burden. Overall total costs for UC were estimated to be $390 to $920 million in the United States (in 2010 US dollars), with mean annual direct expenditures (health insurance and patient out-of-pocket costs) estimated at $8700 per patient.11

Whereas the etiology of UC remains to be elucidated, both genetic and environmental factors are thought to play a role in the development of the disease. A number of susceptibility loci associated with genes involved in barrier function and inflammatory and immune responses have been implicated as potential genetic risk factors for UC.12-18 Further, environmental exposures (e.g., hormone therapy, smoking status) have been associated with both increased and decreased risk of UC.19-22

Ulcerative colitis is a heterogeneous disease that varies in severity (i.e., mild to fulminant) and extent of the colon affected.23 Inflammation typically extends proximally from the rectum along the colonic mucosa.1 At the time of diagnosis, approximately 46% of patients had inflammation limited to the rectum (UP) or to the rectum and the sigmoid colon (ulcerative proctosigmoiditis [UPS]).2,23,24 Disease extent is not static, as approximately 45% of patients with an initial diagnosis of UP or UPS progressed to left-sided colitis or pancolitis after 5 years,2 and approximately 20% and 54% of patients with an initial diagnosis of UP experienced proximal extension of disease after 5 and 10 years, respectively.25

Most patients begin an intermittent disease course after resolution of symptoms associated with an initial disease flare.26,27 Approximately 40 to 50% of patients with UC are in clinical remission at any given point in time, and 90% of patients experienced relapsing disease within 25 years of diagnosis.26 However, 83% of patients with UC experienced disease relapse within 10 years; 54, 71, and 57% of patients with UP relapsed within 1 year, between 1 and 5 years, or between 5 and 10 years after diagnosis, respectively.27 Treatment choice affects the disease course of patients with UC, both during active disease and during disease in remission.26

Rectal Therapies for Treatment of Ulcerative Colitis

For patients with UC, the goal of treatment is multifaceted and includes symptom resolution, mucosal healing, induction and maintenance of remission, improvement in quality of life, and prevention of infirmity, surgery, and hospitalization.1,4,28-32 Approaches to treatment depend on the extent and severity of disease, but the initial goal of treatment is induction of clinical remission.4,5 Mild to moderate active distal colitis is typically treated with oral 5-aminosalicylic acid (5-ASA), rectal 5-ASA or steroids, or a combination of oral and rectal therapies.4,5 Maintenance therapy is recommended for patients with UC in remission, to reduce the risk of symptomatic relapse.5 Rectal 5-ASA is recommended as first-line therapy for the maintenance of remission of UP, and recommended as an option for patients with left-sided colitis.5 Oral 5-ASAs are also effective at maintaining remission as monotherapy and in combination with rectal 5-ASA.5 Rectal therapies differ in their proximal distribution: suppositories are limited to the rectum,33,34 whereas foams and enemas have been shown to reach to the proximal sigmoid colon and splenic flexure, respectively.34-38 In patients with UP, suppositories may be the most effective method for targeting the rectum.5 For the sigmoid or descending colon, enema and foams may be considered, with the greatest distribution of drug in these locations occurring within 2 hours of administration of enema or foam in patients with UPS or left-sided colitis.35

5-ASAs

Sulfasalazine, a combination of the antibiotic sulfapyridine with the anti-inflammatory salicylate, was developed in the 1930s as a potential treatment for rheumatoid arthritis.39 Whereas the efficacy of sulfasalazine in rheumatoid arthritis was limited, sulfasalazine was subsequently found to have efficacy in UC.40,41 Sulfasalazine was widely prescribed for the treatment of UC in subsequent decades, but its use was associated with some toxicity (e.g., nausea, vomiting, anorexia, headache).42 A seminal study by Azad Khan et al43 demonstrated that 5-ASA was the active moiety of sulfasalazine. Sulfasalazine is not well absorbed in the small intestine and passes through to the colon, where colonic bacteria cleave the diazo bond, releasing 5-ASA and sulfapyridine.44-47 Ingesting a pure 5-ASA moiety administered orally does not reach the colon intact,42,48 and thus oral 5-ASAs have been developed with pH- dependent and delayed-release mechanisms to facilitate colonic delivery of active drug.42-44 The advantage of these agents is a reduction in adverse effects compared with sulfasalazine.49,50 However, unmodified 5-ASA can be administered rectally; for distal forms of UC, this allows direct delivery to the site of inflamed mucosa, while minimizing systemic absorption.51

Overall, the safety and efficacy of rectal 5-ASA for the induction and maintenance of remission of distal UC have been well established.52,53 In randomized, double-blind, placebo-controlled studies, clinical and endoscopic remission were achieved by a greater percentage of patients with UP, UPS, left-sided UC, pancolitis, or distal UC receiving 5-ASA suppositories compared with placebo after 4 weeks (Table 1).54-68 In addition, a once-daily dosing regimen had comparable efficacy with 2- or 3-times daily dosing of 5-ASA suppositories after 6 weeks in patients with active UP.57-59 However, patients preferred once-daily administration compared with 3-times daily administration of suppository.57 Furthermore, a greater percentage of patients with UP, UPS, or left-sided UC maintained remission for at least 1 year, and up to 2 years, with 5-ASA suppositories.60-62

In randomized, double-blind studies, 5-ASA enemas had greater efficacy than placebo in patients with active UP, UPS, or distal UC after 6 weeks.63,64 Remission or improvement (clinical, endoscopic, or histologic) was achieved by a greater percentage of patients on 5-ASA enema therapy for 4 weeks compared with placebo.65 Patients receiving 5-ASA enemas demonstrated improvement in the physician’s global assessment score and a decrease from baseline in the mean disease activity index (DAI) score after 6 or 8 weeks.63,64,66 In a study of patients with mild to moderate active UP and UPS receiving either 5-ASA enema or foam for 4 weeks, the majority of patients achieved clinical remission, and there was no apparent difference in the efficacy of 5-ASA enema or foam.67 5-ASA enemas were also efficacious for the maintenance of remission for at least 46 weeks compared with placebo in a clinical study of patients with left-sided UC.68 Finally, in addition to demonstrated efficacy, 5-ASA suppositories and enemas had a favorable safety profile in a number of clinical studies.54,55,57-64,66-68

Corticosteroids

Truelove first described the efficacy of rectal corticosteroids (i.e., hydrocortisone) for the induction of remission of UC in 1956.69 In this study, 67% of patients with mild to moderate UC receiving hydrocortisone enemas nightly for up to 3 weeks achieved clinical remission, usually within days of initiating treatment. Corticosteroids are efficiently absorbed across the colonic mucosa, with an estimated 30 to 50% of administered hydrocortisone enema absorbed through the rectal mucosa.70,71 Thus, the potential for serious adverse effects (e.g., diminished adrenal function, hypothalamic-pituitary-adrenal [HPA] axis suppression, metabolic bone disease, ophthalmologic impairment, cushingoid features, metabolic issues) associated with long-term corticosteroid treatment must be considered.4,72 Second-generation rectal corticosteroid therapies, including budesonide and beclomethasone dipropionate (BDP), with high first-pass hepatic metabolism (∼90% for budesonide)73 and limited systemic toxicity,74 have since been developed.

Budesonide

Patients with active UP, UPS, left-sided UC, or distal UC achieved remission, and endoscopic and histologic improvement, following treatment with budesonide enema for 4, 6, or 8 weeks (Table 2).75-83 However, a greater percentage of patients treated with 5-ASA enema compared with budesonide enema achieved clinical remission after 4 and 8 weeks.77 A similar percentage of patients with active UP or UPS achieved clinical remission with budesonide foam and budesonide enema after 4 weeks.81 However, the majority of patients preferred the foam to enema (83.6 vs. 6.2%, respectively). A significantly greater percentage of patients receiving budesonide foam achieved remission, a Mayo rectal bleeding subscore of 0, and endoscopic improvement (Mayo endoscopy subscore ≤ 1) after 6 weeks compared with placebo.80 Further, a greater percentage of patients with distal UC or UP maintained remission with twice-weekly administration of budesonide enema compared with placebo for 6 months.76 However, it is unknown what effect increased frequency of dosing will have on the percentage of patients maintaining remission of UC. Once- or twice-daily administration of budesonide foam or enema 2 mg or 8 mg for 4, 6, or 8 weeks was safe and, notably, did not adversely affect the HPA axis in most patients with active distal UC.75,78-80,82,83 However, in one study, twice-daily dosing with rectally administered budesonide for 8 weeks significantly increased the incidence of impaired adrenal function compared with once-daily dosing.76 It should be noted that studies have not explored the safety profile of these agents beyond 1 year.

Several baseline factors associated with response to treatment with budesonide enemas or foams have been identified.80-82 Less severe disease at baseline was associated with improved response to treatment, as patients with mild disease (not defined) at baseline had significantly greater odds of achieving clinical remission after 8 weeks of treatment than patients with more severe disease (odds ratio [OR], 4.25; 95% confidence interval [CI], 1.72-10.48).82 Further, a second study demonstrated that a greater percentage of patients with less severe disease at baseline (i.e., clinical activity index [CAI] ≤ 8) achieved clinical remission (defined as CAI ≤ 4) following treatment with budesonide foam or budesonide enema for 4 weeks compared with patients with more severe disease (i.e., CAI >8; foam, 59 vs. 49%, respectively; enema, 71 vs. 47%, respectively; OR, 1.4; 95% CI, 1.01-2).81 However, extent of disease (i.e., UP or UPS) and disease duration (i.e., ≤5 years or >5 years) had no significant association with achievement of clinical response with budesonide foam or budesonide enema after 4 weeks.81 Finally, a significantly greater percentage of patients receiving budesonide foam achieved remission (i.e., Mayo endoscopy subscore ≤1, rectal bleeding subscore = 0, and improvement or no change in stool frequency subscore) compared with placebo when subgroup analyses of baseline disease (i.e., moderate disease, established disease, and extent of disease [UP, UPS]) and demographic (i.e., age, sex, white race, and smoking history) characteristics were conducted.80

The absence of exposure to previous therapeutic modalities was also associated with improved response to either budesonide foam or hydrocortisone foam, as patients who had not previously received treatment with rectal 5-ASA had significantly greater odds of achieving clinical remission compared with patients with prior exposure to rectal 5-ASA (OR, 2.97; 95% CI, 1.05-8.37).82 However, a second study reported that a greater percentage of patients with previous response (not defined) to oral or rectal 5-ASA achieved clinical remission (CAI =4) after 4 weeks of treatment with budesonide foam compared with patients with no previous response to oral or rectal 5-ASA, although the findings were not significant.81 Lastly, a randomized, double-blind, placebo-controlled study of budesonide foam found that remission was achieved with budesonide foam versus placebo regardless of a previous (baseline) 5-ASA use.80

Beclomethasone Dipropionate

Rectal formulations of BDP are safe and efficacious for the induction of remission of active UP, UPS, or distal UC, with improvement or induction of remission following treatment with BDP enema comparable with that of 5-ASA enema after 4 to 6 weeks (Table 3).84-92 A comparable percentage of patients with active, distal UC receiving BDP enema or foam, or 5-ASA enema or foam, achieved remission or response at 4 or 8 weeks.86 In both studies, patients in all groups achieved significant improvement from baseline in the DAI (total and subscale) scores and endoscopy scores after 4, 6, or 8 weeks of treatment.84,86 The safety profiles of BDP and 5-ASA were favorable in patients with UP or UPS.84,86

Whereas BDP enema and 5-ASA enema induced clinical and endoscopic improvement in the majority of patients with UP, and histologic improvement in approximately half of patients, after 28 days, the combination of BDP and 5-ASA resulted in greater efficacy than monotherapy, with all patients experiencing clinical, endoscopic, and histologic improvement.87 The efficacy of BDP enema was examined in patients with UC in 3 randomized, double-blind studies.88-90 Mulder et al89 found no differences in clinical, endoscopic, or histologic improvement between groups receiving BDP or prednisolone after 4 weeks, while van der Heide et al88 demonstrated improvement from baseline only in endoscopic scores in patients receiving prednisolone enema after 4 weeks. Further, a similar percentage of patients receiving BDP and prednisolone enemas achieved clinical and endoscopic remission after 4 weeks.90 However, in these studies, the safety profile of BDP was more favorable than that of prednisolone, with significant decreases from baseline in mean basal cortisol concentrations occurring after treatment with prednisolone, but not BDP.88-90

Clinical remission, clinical response, and endoscopic improvement were achieved by a comparable percentage of patients receiving either BDP enema or betamethasone (BMT) enema in 2 randomized, double- blind studies of patients with active, distal UC after 20 to 28 days.91,92 However, BDP had a more favorable safety profile compared with BMT, with steroid-related adverse events and suppression of adrenal function occurring with greater frequency following treatment with BMT.

Rectal and Oral Combination Therapy

Patients with more extensive active UC may benefit from a combination of oral and rectal 5-ASA therapies, as opposed to monotherapy with an oral or rectal 5-ASA (Table 4).93-98 Rectal therapies target sites of inflammation typically affected by distal forms of UC,24,33,35 but D’Incà et al.93 found that mucosal concentrations of 5-ASA following the administration of both oral and rectal drugs were greater in the sigmoid colons of patients with UC compared with when oral 5-ASA had been administered alone. Thus, in patients who are refractory to rectal therapies alone, a combination of oral and rectal therapies may be warranted.4,5

The addition of 5-ASA enema to oral 5-ASA therapy significantly increased the rate of remission compared with oral 5-ASA therapy alone after 8 weeks in patients with extensive mild to moderate active UC.94,95 However, the percentage of patients with extensive mild to moderate active UC achieving clinical or endoscopic remission after treatment with a combination of 5-ASA enemas plus oral 5-ASA for 6 weeks was similar to that of patients receiving 5-ASA enemas alone.96 The majority of patients receiving either 5-ASA combination therapy or oral 5-ASA alone achieved mucosal healing after 4 weeks.95 Resolution of rectal bleeding within 7 days of study initiation occurred in a greater percentage of patients receiving combination 5-ASA therapy versus oral 5-ASA monotherapy.

The combination of oral 5-ASA therapy and 5-ASA enemas had greater efficacy than oral 5-ASA monotherapy in 2 randomized, controlled studies of patients with UC in remission for up to 1 year.97,98 A greater percentage of patients with UC maintained remission following treatment with a combination of oral 5-ASA therapy and weekend 5-ASA enema compared with oral 5-ASA alone.97 Similarly, the combination of oral 5-ASAs with twice-weekly 5-ASA enemas was more efficacious for the maintenance of remission of UC after 12 months compared with oral 5-ASA monotherapy.98 Further, the results of a case- control study of patients receiving the combination of oral 5-ASA 1.6 g/day with twice-weekly 5-ASA 2 g/50 mL enemas for a median treatment period of 6 years demonstrated that patients receiving combination therapy had a significantly lower incidence of relapse (1.59 vs. 2.76, respectively; p = 0.034) and fewer hospitalizations.99 The safety profile of combination oral and rectal therapies for the induction and maintenance of remission of UC was favorable.94,96-98

Limitations Associated with the Use of Rectal Therapy

Rectal 5-ASAs are efficacious both for the induction and maintenance of remission in patients with mild to moderate distal UC, and rectal corticosteroids have demonstrated efficacy for the induction of remission in patients with active, distal UC. However, rectal therapies for UC are currently underused. A European study noted that a comparable percentage of patients with UP received oral or rectal therapy (29.5 vs. 25.6%, respectively); however, a greater percentage of patients with UPS received oral versus rectal treatment (42.8 vs. 6.9%, respectively).100 The percentage of patients with UP and UPS receiving combination oral and rectal therapy was 13.2% and 17.4%, respectively. Further, during 1992-2009, the number of prescriptions for all 5-ASAs increased 72%, yet those for rectally administered 5-ASAs remained generally at the same level, with a decline in the overall 5-ASA market share from 11% to 9%.101 Oral 5-ASAs accounted for ∼70% of 5-ASA prescriptions in 2009. Patients with UC, prescribed rectal therapies at time of diagnosis, have a high rate of discontinuation of therapy, often as soon as 1 month. Data from a US health insurance database demonstrated that patients with newly diagnosed UC, or UP and UPS were commonly prescribed oral 5-ASA (53%) or 5-ASA suppositories (42%), respectively.102 Within 1 month, approximately 40% of patients with UC discontinued treatment with oral 5-ASAs, and approximately 70% of patients with UP and UPS discontinued treatment with rectal therapy.

Underuse of rectal therapy may be related to a combination of patient preference for oral therapy and potential inconvenience and technical issues with administration of rectal agents.103,104 An important aspect of any treatment is patient adherence.101

Adherence to any treatment is particularly challenging during periods of remission in patients with UC, as demonstrated by prescription refill data that estimated that only approximately 40% of patients with UC were adherent to oral 5-ASAs.105 Other factors associated with a greater likelihood of nonadherence to treatment among patients with UC included less extensive disease and receiving >4 concomitant therapies (OR, 2.5; 95% CI, 1.4-5.7). Patients with UC receiving rectal therapy reported difficulty with use during work hours (OR, 4.4; 95% CI, 1.5-12.5; p = 0.003), pain and bloating (OR, 2.8; 95% CI, 1.20-6.54; p = 0.013), and difficulty with use (OR, 2.4; 95% CI, 1.00-5.73; p = 0.043) as reasons for nonadherence. Additional issues were associated with the use of rectal therapy, including retention of the medication (i.e., duration, position), leakage, and stained clothing with enemas,106 and difficulty with administration and with anal or rectal pain that occur in some patients using suppositories.61

Nonadherence to treatment has implications for the course of a patient’s disease, significantly increasing the risk of relapse compared with patients who are adherent to treatment (relative risk [RR], 1.4; 95% CI, 1.08-1.94; p = 0.014). Patient nonadherence to enemas was signif.icantly higher compared with oral therapies (68% vs. 40%, respectively; p = 0.001).107 However, in a clinical trial comparing enemas and foams, the majority of patients receiving enemas and foams reported no retention problems, unpleasant feeling, rectal or abdominal pain, or flatulence.81 Thus, although the issue of adherence to therapy is complex, providing patients with treatment options that include less frequent dosing and simplified administration may improve adherence and, ultimately, lead to more favorable outcomes for patients.104

Adherence is an ongoing issue in the overall management of UC.105,108,109 Common issues associated with nonadherence to treatment in patients with UC may be overcome by allowing for more flexible dosing regimens (i.e., weekend dosing) and addressing problems with insertion and retention with different formulations of rectal therapies. Rectal therapies (i.e., budesonide foam) have shown favorable safety profiles in clinical trials and are preferred by patients to enemas.81,83 These therapies have the potential to provide additional safe and efficacious options for healthcare providers treating UC. The most effective way to preserve adherence is to forge a therapeutic bond with the patient and discuss the duration of therapy. Additionally, seeing patients at least every 6 months may improve adherence to both oral and rectal treatment regimens.

In conclusion, this review of published data of rectal therapies, including 5-ASAs and corticosteroids, supports that these agents are well tolerated, safe, and efficacious for the induction and maintenance of remission of distal forms of UC. Furthermore, combination oral and rectal therapy is also well tolerated and efficacious for the induction of remission in patients with mild to moderate extensive UC compared with oral therapy alone, and should be considered in appropriate patient populations. Rectal therapies are an underused, yet valuable part of the management paradigm for patients with distal forms of UC. They may be appropriate as monotherapy or in combination with oral therapy for the induction or maintenance of remission of mild to moderate UC, depending on disease extent and patient considerations.

Funded by an unrestricted educational grant from Salix, a Division of Valeant Pharmaceuticals North America LLC.

Download Tables, Images & References

hacklinkJojobet Girişivermectin tabletMadridbet girişMadridbet girişMadridbetbaşakşehir masaj salonumeritbetbetsmoveCasibom GirişsuperbetinikimislimeritbetsuperbetinTophillbetcasibomJojobet GirişcasibomCasibom GirişHoliganbetmatbetgalabetGamdomMarsbahisCasibomJojobet