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The Independent Monthly Newspaper for Gastroenterologists

Volume 65, Number 11 • November 2014

For Better Bowel Prep, Show, Don’t Tell

Malnutrition ‘Skeleton’ Still Rattling In Hospital Closets

Patient video improves cleansing before colonoscopy

Progress report cites awareness gaps among caregivers

BY MONICA J. SMITH

BY MARIE ROSENTHAL

hysicians responsible for educating patients about bowel preparation before colonoscopy may want to go beyond written instructions, according to research suggesting people may learn more from a video tutorial than from paper handouts. see Prep, page 36

Duke Protocol Reduces Colorectal SSIs by 75% BY MARIE ROSENTHAL

bundle of preventive measures can significantly reduce surgical site infections (SSIs) after colorectal surgery, but the strategy probably requires a “village” to be successful, a new study has found. see Duke, page 22

ne in three Americans enters a hospital malnourished, which increases their risk for adverse events, such as surgical site infections, postoperative pneumonia and the development of pressure ulcers. So with the Centers for Medicare & Medicaid Services (CMS) withholding payment to hospitals for 11 off these preventable conditions, hospitals and long-term care facilities should be looking at malnutrition as a contributing factor—or so one would think. Recent research shows that many facilities are missing an opportunity to address malnutrition, which is associated with increased rates of complications and readmission, prolonged hospital stays and greater mortality. In particular, malnourished patients are two to three times more likely to develop a surgical site infection or postoperative pneumonia ((Arch Surgg 2010;145:148-151) and twice as likely to develop a pressure ulcer (Nutrition 2010;26:896-901). Nearly half (45%) of patients who fall in the hospital are malnourished (J ( Hum Nutr Diett 2007;20:558-564).

“Malnutrition can increase the risk of hospitalacquired infections, increasing the patient’s length of stay and increasing their risk of morbidity and mortality. It can also interfere with the health care practitioner’s ability to adequately and successfully treat the patient while he or she is in the hospital,” explained Carmen Roberts, MS, RD, LDN, a clinical dietitian specialist at Johns Hopkins Bayview Medical Center, in Baltimore. see Malnutrition, page 25

I N S I D E

Public Stool Bank Aims To Increase Safety, Use of Fecal Transplants

Microbiome analysis may aid detection of CRC ......................... 5 To market your practice, befriend new media ........................... 18

BY DAVID WILD

Gastros sing a love song to POEM ............................................ 34

ou’re a gastroenterologist treating a patient with antibiotic-resistant Clostridium difficile, and you both are ready to consider a fecal microbiota transplant (FMT). You can’t simply order material online—or can you? A recently launched nonprofit stool bank, described by its founders as “like the Red Cross, but for stool,” offers physicians rigorously screened, tested and ready fecal preparations at a low cost.

How should you feel about ‘resect and discard’? .................... 38

EXPERT ROUNDTABLE GI Roundtable Talks the Survival of the Specialty .................... 14

see Bank, page 30 Brought to You by

NOVEMBER 2014

REPORT

Probiotic Therapy in the Management Of Common Gastrointestinal Conditions see insert at end of issue

Probiotic Therapy in the Management of Common Gastrointestinal Conditions n increasing appreciation disorders. These beneficial bacFaculty of the relationship between terial preparations are known as Darren Brenner, MD the intestinal microenvironment, probiotics—defined by the Food Assistant Professor in Medicinethe endogenous intestinal bacand Agriculture Organization and terial flora, and gastrointestinal the World Health Organization as Gastroenterology, Hepatology and Surgery (GI) health and disease has led “live microorganisms which when Northwestern Feinberg to the investigation of the therapresent in adequate amounts School of Medicine peutic potential of orally ingested confer health benefits on the Chicago, Illinois preparations of exogenous bachost.”5 Most probiotic microorteria (probiotics). ganisms belong to a group of This monograph provides a brief overview of this topic lactic acid–producing bacteria, such as, Lactobacillus and reviews clinical experience with the use of probiotand Bifidobacterium, or yeasts, such as Saccharomyces.6 ics in the treatment and prevention of diarrheal illnesses. These bacteria produce lactic acid through anaerobic digestion of saccharides, and can tolerate fluctuations in temperature and low pH environments; thus, this affords Overview of Intestinal Flora and them the ability to withstand the acidic milieu of the stomProbiotics ach and allows for transient colonization of the GI tract.7 The human GI system is home to a diverse array of Today, most probiotics are available or consumed as b t i M bacteria. Major j ffunctions ti off th the gutt microflora i fl iinclude l d di t dietary supplements l t or ffermented t d products. d t 8 metabolic activities that result in salvage of energy and The field of probiotics is associated with a number of absorbable nutrients, important trophic effects on intescommon misconceptions. The more general term probitinal epithelia and on immune function, and protection otics encompasses a large variety of products that difof the colonized host against invasion by pathogenic fer by the strains of bacteria or yeast included, dose, and/ microbes (Figure).1-4 Alteration in the intestinal microenvior delivery vehicle.9 There is a strain-specific relationship ronment and microflora can occur for a variety of reasons, between the probiotic chosen and its potential for elicitincluding antibiotic use, and can result in disruptions in ing a response for a particular health benefit.9 Despite the normal intestinal function as well as overgrowth of pathorange of potential health benefits observed with probiotics, genic microorganisms and subsequent infection.3 the effects described can only be attributed to the strain or strains tested, and not to probiotics as a whole. For this reaInsight into the role of intestinal flora in maintaining GI son consulting published literature and selecting the proper health has led to the recognition that oral administration organism for the desired health benefit is important. Prodof some types of exogenous bacteria can promote intesuct labeling should clearly define the strains included in a tinal homeostasis, as well as treat and prevent intestinal

Supported by an unrestricted grant from

Mary Igo, RN, MBA, CMPE

Colleen M. Schmitt, MD, MHS

Thomas M. Deas, D MD

Scott Ketover, MD, AGAF

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Quiet Launch for Potentially Practice-Changing Technology BY ADAM MARCUS

linicians in the state of Washington have become the first group in the United States to use the Sedasys system, an automated method of providing light to moderate sedation for patients undergoing certain gastrointestinal procedures. The FDA approved Sedasys (Ethicon US) in 2013 but required modifications to the technology, which the agency accepted earlier this year. Under the

current approval, the device—a propofol delivery system that monitors the effects of the drug in real time—may be used for patients undergoing screening colonoscopy and esophagogastroduodenoscopy. Although anesthesiologists do not have to be on hand when the system is in use, they must be immediately available for assistance or consultation if necessary. The device launched in September at Virginia Mason Medical Center in

Seattle, where clinicians using the system first underwent training in both the technology and the effects of propofol on the heart and lungs. According to the manufacturer, Sedasys has been shown to reduce the risk for oxygen desaturations—and to reduce the severity of such events—during procedures. The device also promotes rapid recovery from sedation, within 10 minutes for 99% of patients, the company said.

Is this machine the future of sedation?

Otto Lin, MD, director of quality improvement at Virginia Mason, and a gastroenterologist, said his institution started using Sedasys in September, in healthy, medically stable patients. “A lot of them are either patients we would have done with standard sedation—midazolam and fentanyl—and some patients who are difficult to sedate and would have required anesthesiologist-administered propofol if Sedasys was not available,” Dr. Lin said. The latter group commonly includes people who take chronic, high doses of narcotic pain medication; those with substance or alcohol abuse problems; and those with psychiatric issues such as post-traumatic stress disorder. Dr. Lin predicted that the system likely would significantly affect practice for gastroenterologists, at least those who work in a clinic setting with anesthesiologists on hand. “It really allows us to use propofol, which we believe is superior to midazolam and fentanyl, in outpatients without having the added cost of having anesthesiologists administer [the drug].” What’s more, because propofol is a fast-off drug, time to discharge is substantially less than with other sedation agents. “Propofol speeds up the flow in the unit,” Dr. Lin said. “Basically, patients are awake by the time they get to the recovery room.” And they are more satisfied with their care: “They’re not groggy for the rest of the day; they retain postoperative instructions better; and the people waiting to take them home don’t have to wait as long.” Dr. Lin noted that although using Sedasys for colonoscopies is straightforward, “with upper endoscopies there was a little bit of a learning curve. It takes a little bit of experience to get the timing perfect so that you have a seamless procedure. That probably took a week.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Statement of Ownership

Heard Here First

See page 1

Malnutrition can increase the risk of hospital-acquired

infections, increasing the patient’s length of stay and

increasing their

risk of morbidity and mortality. It can also

interfere with

practitioner’s and

the health care

ability to adequately

successfully treat

the patient

while he or she is in the hospital.

Vol. 65, No. 11 MEDICAL ADVISORY BOARD MANOOP S. BHUTANI, MD

GARY R. LICHTENSTEIN, MD

Houston, Texas

Philadelphia, Pennsylvania

ALAN F. CUTLER, MD

NIRMAL S. MANN, MD, PHD

Farmington Hills, Michigan

Sacramento, California

FREDRIC DAUM, MD

PETER R. MCNALLY, DO

Mineola, New York

Fort Carson, Colorado

STEVEN M. FABER, MD

TARUN MULLICK, MD

Elizabeth City, North Carolina

St. Charles, Illinois

RONNIE FASS, MD

JOEL E. RICHTER, MD

Cleveland, Ohio

Tampa, Florida

BARBARA B. FRANK, MD

DAVID ROBBINS, MD

Philadelphia, Pennsylvania

New York, New York

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ELLEN J. SCHERL, MD

New York, New York

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PRATEEK SHARMA, MD

Gainesville, Florida

Kansas City, Kansas

MYRON LEWIS, MD

JEROME H. SIEGEL, MD

Memphis, Tennessee

New York, New York

November 2014

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Microbiome Analysis May Improve Colon Cancer Detection BY DAVID WILD

ecal microbiome analysis may enhance the accuracy of noninvasive colorectal cancer screening, a recent study suggests. Investigators found that a combination of fecal microbiome analysis and fecal occult blood testing (FOBT) was significantly more accurate than FOBT alone in distinguishing between colorectal adenoma and carcinoma (CRC). Adding microbial analysis to demographic risk factors for colorectal cancer improved the identification of high-risk patients who should undergo colonoscopy, according to the study (Zackular JP, et al. Cancer Prev Res 2014 Aug 7. [Epub ahead of print]). “The findings of this paper are both interesting and important,” said Randall Burt, MD, emeritus professor of medicine at the University of Utah Huntsman Cancer Institute, in Salt Lake City, who was not involved in the research. “The results of this study alone do not yet justify using microbiome evaluation to guide screening strategies, but they are nonetheless exciting and indicate that further work in this area is certainly justified.” In the first phase of the study, co-investigator Patrick Schloss, PhD, associate professor in the Department of Microbiology and Immunology at the University of Michigan, in Ann Arbor, and his colleagues conducted gene sequencing to profile the microbial composition of stool from 30 healthy people, 30 subjects with adenoma and 30 with CRC. The groups were similar in age and medication use, but those with CRC were more likely to be white and male and to have higher body mass index (BMI). Dr. Schloss’ team isolated several microbial gene sequences that, when absent, were highly predictive of the presence of adenomas and CRC. After testing several models, they found that age and race risk factors along with the absence of five microbial gene segments accurately identified 90% of those with adenoma and ruled out 80% of those without adenoma—a 4.5-fold increase in the predictive accuracy over using only age and race as predictors (P=0.002). P Similarly, a model including age, race, BMI and the absence of six microbial gene segments was 90% sensitive and 83.3% specific in identifying CRC patients—a fivefold increase in accuracy compared with use of age, race and BMI alone (P=0.012). P “Incorporating microbial analyses in this way could help clinicians select individuals who should undergo colonoscopy,” Dr. Schloss said.

Microbiome Analysis and FOBT The investigators also examined whether microbiome analysis could be used to distinguish between individuals with adenoma and those with CRC. The absence of four specific microbial gene sequences discriminated between the presence of CRC and adenoma better than did FOBT, according to the study. Finally, a combination of microbiome analysis and FOBT further improved the

accuracy of distinguishing between adenoma and CRC, above and beyond either method alone. The investigators noted that previous research has shown that the abundance of several bacterial species, such as Fusobacterium and Bacteroides fragilis, is associated with colorectal cancer (Genome Res 2012;22:299-306). “In contrast, our study emphasizes that the depletion of potentially protective

bacteria—most importantly, species of Clostridium, Bacteroides and the Lachnospiraceae family of bacteria—also likely plays a role in colorectal cancer pathology,” Dr. Schloss’ team reported. Although the findings suggest that microbiome analysis may prove useful as part of a noninvasive CRC screening protocol, “we think it should complement, rather than replace, other colorectal cancer screening approaches,” Dr. Schloss said.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Bile Acid Malabsorption Seen as Major Unrecognized Cause of Diarrhea in Cancer Patients BY TED BOSWORTH CHICAGO—Poor absorption of bile acid is the cause of chronic diarrhea in a large proportion of cancer patients, new research shows. The study of 506 patients with diarrhea and a variety of cancer types found that 43% had bile acid malabsorption (BAM), suggesting an opportunity to substantially improve quality of life in patients with this complication. Characterized as a “landmark with significant patient numbers,” the study provides the basis for a more focused approach to complaints of diarrhea in patients with cancer, said Frank Phillips, MD, a trainee gastroenterologist at the Royal Marsden Hospital, in London, England, who presented at Digestive Disease Week 2014 (abstract 318). Led by Jervoise Andreyev, MD, PhD, a consultant gastroenterologist at the Royal Marsden Hospital, this was not the first study to associate BAM with diarrhea in this patient population, but the new data indicate that it has been an underappreciated source of the problem. In the study, patients referred to the clinic with chronic diarrhea were tested with selenium homocholic acid taurine (SeHCAT). SeHCAT is a radiolabeled bile acid analog that is readily measured with a gamma camera without the need to collect stool samples. Of the 506 patients referred over a four-year period, 34% had urologic cancers, 31% had cancers of the upper or lower gastrointestinal tract, 25% had gynecologic cancers and the rest had other cancers. Rates of BAM were particularly high in patients with cancers involving the upper pelvis. Among urologic malignancies, for example, BAM was more common in cancer of the bladder (50%) than the prostate (22%). In gynecologic cancers, the same was true for tumors involving the endometrium (42%) relative to vulvovaginal tissues (less than 20%). For gastrointestinal cancers, BAM was identified more frequently in those with disease of the lower tract (50%) than of the upper (35%). Chemotherapy may sensitize the terminal ileum to damage from radiation, according to Dr. Phillips. The role of this collateral damage is suspected because dysfunction of the terminal ileum is a well-established cause of BAM. High rates of BAM also were observed in patients with pancreatic cancer, particularly after a Whipple procedure, which can damage the bile duct and lead to adverse changes in bile metabolism. BAM was particularly common in

patients with hematologic malignancies and diarrhea. In this case, treatment with lenalidomide, which has been associated with altered bile acid metabolism, is a suspected cause. Far lower but still clinically meaningful rates of diarrhea were observed in other forms of cancer, such as breast and lung. Testing for BAM may still be justified

even in these groups when other causes of chronic diarrhea have been ruled out, Dr. Phillips said. In the United States, however, SeHCAT is not available. Stool analysis is an option, but many patients do not like collecting and submitting stool samples. The next best option may be an empiric course of bile acid sequestrant.

Several are available and an improvement in symptoms provides strong evidence of the underlying etiology. Although Dr. Phillips said he preferred a definitive diagnosis, relief of symptoms is the major goal. “Control of BAM to relieve chronic diarrhea improves quality of life and can prevent interruptions in cancer therapy,”

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Dr. Phillips said. He strongly recommended greater attention to BAM as a potential etiology in cancer patients with this complaint. John K. DiBaise, MD, professor of medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic, in Scottsdale, Ariz., agreed that the limited availability of a diagnostic test for BAM is a significant problem for patients with cancer-related diarrhea or another reason. He cited encouraging results with measurement of 7 alpha-hydroxy-4-cholesten-3

‘Control of [bile acid malabsorption] to relieve chronic diarrhea improves quality of life and can prevent interruptions in cancer therapy.’ —Frank Phillips, MD one, also called plasma C4 levels, which have correlated with SeHCAT in some initial studies, but he cautioned that this diagnostic test remains limited to the research setting so far.

Testing BAM with a therapeutic trial “seems reasonable,” but Dr. DiBaise remained cautious. Although he agreed that it might be the best option given the current lack of other choices, he

suggested that a response to bile acid sequestrants may be best characterized as “supportive evidence” for BAM as a cause in patients with diarrhea. “Use of bile acid sequestrants is often poorly tolerated and the response variable,” Dr. DiBaise said. “I find it difficult to strongly recommend this strategy without a definitive diagnosis or at least a very high index of suspicion.” Drs. Phillips, Andreyev and DiBaise reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

For Medical Trainees, More Contact With Drug Reps Boosts Prescribing of Brand-Name Meds BY MARTIN LEUNG

hysician trainees who are more receptive to pharmaceutical promotion and have less knowledge of evidencebased prescribing are likely to recommend brand-name drugs over generic alternatives, a national survey found. Led by Kirsten E. Austad, MD, researchers from the Brigham and

Women’s Hospital and Harvard Medical School, in Boston, asked first- and fourth-year medical students and thirdyear residents to answer evidence-based and marketed-drug questions to determine if interactions with pharmaceutical sales representatives would affect their medical knowledge and prescription drug preferences.

At least 14 trainees at each level per school were randomly selected—1,601 students (49% response rate) and 735 residents (42.9% response rate). All participants were asked how often they used different educational resources to learn about prescription drugs. Fourth-year students and residents were given multiple-choice questions

regarding appropriate initial therapy for clinical scenarios for patients with diabetes, hyperlipidemia, hypertension and sleeping difficulties. According to the researchers, “evidence-based answers followed widely used clinical guidelines, whereas marketed-drug answers favored brand-name drugs.”

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Respondents reported commonly using sources such as Google and Wikipedia. The team used survey answers to create an “industry relations index” to gauge each trainee’s level of acceptance of pharmaceutical promotion. They found that a “10-point industry relations index was associated with 15% odds of selecting an evidence-based

prescribing choice (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.79-0.92).” They reported a significant association between the industry relations index and increased odds of prescribing brand-name drugs (OR, 1.08; 95% CI, 1.00-1.16). The findings were published in JAMA Internal Medicine (2014;174: 1283-1290).

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Boxed Warning Trends Highlight Importance Of Adverse-Event Reporting BY MARTIN LEUNG

ore than one-third of recent drug approvals for novel therapeutics have boxed warnings, a new study found. Clinicians need to be aware of this growing number and must continue to report adverse events so new safety concerns are identified, according to the study researchers.

Boxed warnings, which are issued by the FDA and featured on the labeling of prescription drugs to describe potential adverse side effects and risks, are often used but “have not been well characterized,” according to researchers from the Department of Clinical Pharmacy at the University of California, San Francisco. The investigators examined 522 novel

therapeutics (441 pharmacologic and 81 biologic) approved between 1996 and 2012 to determine the frequency of premarket (present at the time of drug approval) and postmarket boxed warnings and safety-related withdrawals. They found that premarket warnings were more common among biologic than pharmacologic drugs (31% vs. 22%; odds

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

ratio, 2; 95% confidence interval, 1.23.3). Median time from approval to first postmarket boxed warning or withdrawal was 4.2 years—2.3 years for drugs with premarket warnings and 4.9 years for drugs without the cautionary language. They also found that the frequency of boxed warnings increased in the post2004 period. The researchers highlighted Merck’s voluntary recall of rofexcoxib (Vioxx), a nonsteroidal anti-inflammatory drug that was shown to increase the risk for cardiovascular events. The FDA also

pushed to strengthen drug safety surveillance at that time. The researchers noted that the study was limited in sample size and excluded biologic products under jurisdiction of the Center for Biologics Research and Evaluation. The study did not review all drugs approved since 1996, only those regulated by the Center for Drug Evaluation and Research. The findings were reported online on Aug. 15 in JAMA Intern Med [Epub ahead of print].

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Study Identifies Potential Noninvasive Biomarker for iGVHD BY KATE O’ROURKE BOSTON—Patients who develop graftversus-host disease after receiving stem cell transplants also may experience significant changes in their enteric flora, according to a new study that suggests that real-time monitoring of the gut microbiota may be the first noninvasive test for the potentially life-threatening complication.

Previous studies have suggested that gut bacteria are involved in initiating and perpetuating intestinal graft-versus-host disease (iGVHD), but their role is controversial (Leuk Lymphoma 2011;52:18441856). The new study found increases in Enterobacteriaceae and decreases in Clostridiaa in patients who developed iGVHD after stem cell transplantation. “This is a small study but it appears that medical therapies, particularly

specific antibiotics like clindamycin, can induce disruptive changes in the gut microbiota, and this seems to be associated with graft-versus-host disease,” said Andrew Koh, MD, assistant professor at the Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center, in Dallas, who led the study. “A biomarker test could really be helpful for diagnosing and ultimately treating patients.”

Dr. Koh presented the findings at a symposium titled “Probiotics Throughout the Lifespan” (poster 11), hosted by Harvard Medical School. Between 20% and 50% of patients who undergo a stem cell transplant experience GVHD, and as many as 30% of patients will die of the complication. iGVHD, which manifests as inflammatory colitis, occurs in 75% of GVHD cases (Blood 1998;92:2303). The disorder is

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H E PAT O L O G Y IN F O C U S

Guidance Equivocal On HCV Screening Of Baby Boomers

Despite Above Average Income, Gastros Report Job Dissatisfaction BY VICTORIA STERN

BOSTON—Recent evidence suggests that nonalcoholic fatty liver disease (NAFLD) is emerging as a significant public health problem. One study revealed an “alarming” rate of HCC related to NAFLD, even among

Gastroenterologists are the fourth most highly compensated physicians compared with doctors in 24 other medical specialties, according to an online survey conducted by Medscape in February 2013. Average annual income for gastroenterologists was up 13% in 2012 compared with 2011, coming in at $342,000. The three specialties that beat out gastroenterology in average yearly compensation were orthopedists at $405,000, cardiologists at $357,000 and radiologists at $349,000 (see Figure 1, page 28). But despite robust earnings, less than half (48%) of the gastroenterologists surveyed said they felt fairly compensated, the same percentage as that of physicians of all specialties who said they felt fairly compensated. The findings were based on responses collected in a third-party online survey of 21,878 U.S. physicians, 2% of whom were gastroenterologists. Most gastroenterologists who responded were men (84%) and board certified (96%), and 62% were aged 45 years or older.

see NAFLD, page 14

see Income, page 28

BY CHRISTINA FRANGOU Hepatologists have added their voices to the debate over screening for hepatitis C virus (HCV) infection and are urging the U.S. Preventive Services Task Force (USPSTF) to upgrade its current recommendation see HCV Screening, page 18

NAFLD Threatening Public Health BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

Investigational Device Prolongs Survival of Livers For Transplantation .................................................page 8

BY MONICA J. SMITH

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Ma Vis it y DD 19-2 us W bo 1, 20 oth 13 15 31

Effect of Preexisting Cardiovascular Disease On Outcomes After Liver Transplantation May Be Underestimated..........................................page 9

Patients with private insurance will no longer be responsible for any cost sharing in the event that a polyp is removed during a screening colonoscopy, according to a recent clarification, issued by the federal government, on preventive screening benefits under the Affordable Care Act (ACA). “This is very good news,” said Durado Brooks, MD, MPH, direcof Prostate and Colorectal Cancers at the American Cancer Society in

Retreatment of Hepatitis C With Interferon Alone May Increase Mortality ..........................................«>}iÊ£È Statins Linked to Reduction in Mortality From Liver Cancer.................................................«>}iÊÓ{

see Cost Sharing, page 32 PRINTER FRIENDLY VERSION AT GASTROENDONEWS.COM

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he e greatest ch hallenge for clinicians who

treat patients with inflamma atory bowel disease (IBD) is to move from symptomoriented (step--up) strategies toward preventio on-orie ented (early intervention) strategies aimed

ARUN SWAMINATH, MD

at tight inflammation control and alteration of the natural

Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

history of IBD. This review focuses on a personalized

BRIAN BOSWORTH, MD

acid (5-ASA) agents.

approach to the treatment of IBD using 5-aminosalicylic

Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

NewYork-Presbyterian Hospital/ Weill Cornell Medical Center New York, New York Weill Cornell Medical College New York, New York Columbia University College of Physicians and Surgeons New York, New York

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immunoinflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease. One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS •

2013

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

progressive, but early diagnosis and treatment may improve outcomes. No reliable noninvasive markers exist for iGVHD, which is diagnosed through evaluation of tissue obtained by upper endoscopy, rectal biopsy or colonoscopy. In the new study, Dr. Koh and his colleagues collected weekly stool samples from 10 pediatric cancer patients undergoing allogeneic stem cell transplants. They performed bacterial and fungal genomic sequencing using high-throughput DNA sequencing systems to determine the composition of the gut microbiota.

Four of the 10 patients developed iGVHD. Before developing iGVHD, patients had a significant growth of Enterobacteriaceae, proinflammatory bacteria and a decrease in anti-inflammatory Clostridia bacteria. These changes were not present in patients who did not reject the graft. Treatment with clindamycin, which is effective against Clostridia spp., was the only clinical characteristic significantly associated with the development of iGVHD. Dr. Koh said that much work needs to be done to validate the findings, but if

confirmed, clinicians may be able to test stool samples from patients suspected of having iGVHD for changes in Enterobacteriaceaee and Clostridia. Doing so may lead to a much more timely diagnosis of the disease. “You could do quantitative PCR [polymerase chain reaction] and get back the results in one to two days,” Dr. Koh said. “Currently, biopsy is the gold standard for diagnosing intestinal graft-versus-host disease, and it can take up to three weeks before you get a diagnosis. Early prompt treatment leads to better outcomes.”

Nelson Chao, MD, chief of the Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplant, at Duke Cancer Institute, in Durham, N.C., said the study was “interesting,” but pointed out that it had a small sample size. He said that if the results were validated in other studies, it could change the types of antibiotics that were given to cancer patients. In addition, he pondered whether fecal transplants—used to treat patients with C. difficile—could e be used to treat patients with iGVHD. But Dr. Koh was not a fan of the latter idea. “Stem cell transplant patients are so immunocompromised that if you throw bacteria back in the gut, some of the bacteria might escape and cause fatal infection,” he said.

‘It appears that medical therapies, particularly

with the best-read gastroenterology publication.

specific antibiotics like clindamycin, can induce disruptive changes in the gut microbiota, and this seems to be associated with graftversus-host disease.’ —Andrew Koh, MD

♦

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The Texas investigators plan to continue the research in humans as well as conduct studies in mice. “The problem with microbiome research is you show in disease condition A, this bacteria is up or down, but you don’t know whether it is causal or associative,” Dr. Koh said. “So, we are going back to a mouse model to study this further. We plan to treat mice with different antibiotics to examine whether we can increase or decrease the risk for GVHD, and then figure out the mechanism as to how this happens. Then, we will see if we can modulate the inflammation.” Drs. Koh and Chao reported no relevant financial conflicts of interest.

EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

GI Roundtable Talks the Survival of the Specialty y Mary Igo, RN, MBA, CMPE

Colleen M. Schmitt, MD, MHS

CEO, Digestive Health Specialists Tacoma, Wash.

Galen Medical Group Chattanooga, Tenn. President, American Society for Gastrointestinal Endoscopy (ASGE)

Thomas M. Deas, MD

Scott Ketover, MD, AGAF

Gastroenterology Associates of North Texas Fort Worth Past-President, ASGE

President and CEO Minnesota Gastroenterology Minneapolis

BY MONICA J. SMITH

BOSTON—In recent years, and particularly since the passage of the Affordable Care Act, there has been a trend toward consolidation in medicine. Hospitals and payors are merging into larger entities, and hospitals are acquiring independent providers and practices. This trend is driven by many forces, including the desire of younger physicians to work for institutions that can provide a steady salary and a bounded schedule; the increased complexity of managing private practices; and the presence of dominant, and sometimes predatory, hospitals and insurers in some regions.1 As articles in the lay and medical trade press have observed, in addition to the effect this trend may have on physician preference, livelihood and career path related to the work environment (good or bad), it may have a deleterious effect on the cost of health care. For one, large, consolidated entities are in a better position to negotiate and demand higher prices. Furthermore, the cost of care for procedures performed in a hospital outpatient setting is significantly higher than for procedures done in an office or ambulatory surgery center (ASC), so much so that the Centers for Medicare & Medicaid Services (CMS) has asked the Brookings Institute, a public policy think tank, to explore reducing facility payments for hospital outpatient services to the level of ASC facility payments, explained Klaus Mergener, MD, PhD, MBA, director of Digestive

Health Specialists, part of MultiCare Health Systems, in Tacoma, Wash. “All of this can eventually play into the hands of independent practices if they can survive long enough and position themselves as the high-quality, low-cost, efficient alternative to hospitals—at least for services that do not necessarily require hospital care,” Dr. Mergener added. A recurring theme of this year’s GI Roundtable, a meeting dedicated to exploring topics, issues and challenges relevant to the practice of gastroenterology, was what practices need to do or consider doing to stay viable, competitive, independent and successful. Gastroenterology & Endoscopy News invited experts, most of whom moderated sessions or gave presentations at the meeting, to share further insights on the topic.

GEN: Can most gastroenterology practices survive? Ms. Igo: To survive, the practice will need a strong business strategy and some reserves to invest in its infrastructure. The meaningful use money [for adoption of electronic health records] has encouraged people to invest in information technology, but it will take further

investment in assistance and in assessing processes. You can buy all the technology you want, but if you don’t have people to put it to work for you, you’re no better off than you were before. Smaller groups will need to band together if for no other reason than group purchasing and hiring consultants, human resources staff, coding and compliance support.

Dr. Schmitt: I think most practices will not only survive, but grow. Without question, our specialty is facing a number of challenges right now, but I think we’re hitting our stride when it comes to understanding what sets our professionals apart in terms of quality and value. I think our training programs have the proper focus, and our education efforts are doing a great job leading the way and helping folks like me, mid-career gastroenterologists, expand existing skill sets and develop new techniques to address old problems. We’re very fortunate to be led by some of the most innovative and talented thinkers in the medical profession, whose focus stays on quality and patient care. Dr. Deas: Practices both small and large can survive and do well because the demand for GI endoscopy services will continue to increase due to the aging population, the impact of colonoscopy on colon cancer prevention, and the cost-effectiveness of endoscopic services that replace more expensive surgical interventions. Dr. Ketover: I think independent GI practices can survive if they make themselves indispensable in their own marketplace. They can remain independent from the larger hospital systems or multi-specialty clinics if they provide a level of service that isn’t provided by everybody else, such as subspecialty service lines, quality metrics and demonstrating patient outcomes. All of those things will lead to a strong survival toolbox. see GI Roundtable, page 16

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EXPERT ROUNDTABLE

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

GI Roundtable continued from page 14

GEN: What will they need to do to thrive? Ms. Igo: Either grow internally or join forces with others. This decision requires a careful look at the group’s goals and objectives: solo practitioners who might want to ride it out and retire versus new MDs who are concerned about a long-term plan, or senior MDs wanting to continue a legacy. In a group, how are those decisions being made, by whom and how? What are the guiding principles? These are just some things to think about.

‘GI practices and our professional societies need to keep a focus on value, both near term and long term. Most payors, and I think even many patients, view this through the “cost” lens, but it’s incumbent on us to educate them and inform the patients and referring physicians about the metrics that really matter, such as elements of quality, and that just takes time.’ —Colleen M. Schmitt, MD, MHS

Dr. Schmitt: In my opinion, GI practices and our professional societies need to keep a focus on value, both near term and long term. Most payors, and I think even many patients, view this through the “cost” lens, but it’s incumbent on us to educate them and inform the patients and referring physicians about the metrics that really matter, such as elements of quality, and that just takes time. Education about what we do, why we do it, and—this is always important—when we should not do it, will set apart the practices that will thrive in this environment. Dr. Deas: They must focus on some key initiatives. For example, collaboration with other members of the health care community including hospitals, health plans, physician networks and organizations that are focusing on improved quality of care, transparency and cost-efficiency. Dr. Ketover: It comes back to being the indispensable GI provider in their marketplace, looking at how they care for patients and why the care they deliver is different from their competitors. Also, being able to demonstrate, through clinical outcomes or quality metrics, that the care they deliver is really the best in their region.

GEN: Should gastroenterologists join multi-specialty practices? Ms. Igo: It depends on your objectives. When you join a multi-specialty practice, your needs get buried with everyone else’s; you’re getting into a “one size fits all” system. Compensation systems for multi-specialty practices can be difficult unless they’re attached to something with deeper pockets, like a hospital or foundation. Having worked with single-specialty groups for the last 20 years, I would say that the MDs in these groups prefer to be compensated based on their specific work. Dr. Schmitt: I’m in a multi-specialty practice. Whether or not physicians should go it alone, merge or become employed is a complex and multi-faceted decision. Factors to consider in this decision must include long-term as well as short-term expectations. Areas that need to be really scrutinized include salary control, medical decision making and quality-of-life situations for the physician. There will always be trade-offs. As part of a multi-specialty practice, you do share the benefits of shared overhead, but you also lose some of the benefits we see in some streamlined and focused specialty practices. Dr. Deas: GI physicians may have several options within their health care community. They may be able to affiliate with other practices in an independent practice association, or align themselves as the GI providers of choice by primary care groups. They may link themselves to a hospital system by providing call coverage and/or oversight of the endoscopy unit. In some instances, they may choose to join a large single-specialty GI practice or multi-specialty practice. Dr. Ketover: I would say no, and my reasoning is that like other subspecialties with multiple service lines, I think gastroenterology gets diluted in a larger structure. In a multi-specialty clinic environment, gastroenterologists may secure their referral base from the other physicians in the clinic, but I think their specific GI interests, requests for capital investment and focus on developing clinical service lines that benefit patients get diluted by every other specialty’s needs.

GEN: What can you do on the political front to defend your practice’s best interests? Ms. Igo: Support your local congressional representatives as well as your state reps. Identify key committee members and make contact with them. A practice that I worked with in the past helped raise funds for our representative who was on the Ways and Means Committee, which plays a big role in CMS and other financial and funding decisions. Look for more opportunities to have discussions with these representatives. Invite them to tour your facilities, and provide them insight into the cost savings that GI practices provide. Dr. Schmitt: Given my background, the short answer is “listen and respond.” The ASGE and our sister

societies have the experts, consultants and volunteers who can analyze every eventuality that comes our way, but the effectiveness of our voice is only as strong as each member in the practices we represent. The legislatures care very much about what we have to say, because each of our practices is a business for each constituent physician. On the personal level, I would recommend that physicians get to know the legislators at the state and national levels, especially locally. They really do often seek our advice about bills that are on the table and for regulations, and we have the ability to respond to challenges that occur at the state level—but only if we know about them. Dr. Deas: Pay close attention to political and advocacy information from the GI societies: ASGE, the American College of Gastroenterology and the American Gastroenterological Association. When solicited to do so, contact your congressional representative on important issues. Dr. Ketover: Physicians and practices should focus on two areas: what happens at a national or federal level that affects practices through their relationship with CMS, and what happens at the state or regional level. It can be hard for practices that are by themselves to have an impact on a national level, but they can certainly be involved locally by knowing what is happening at their state house, and by knowing the policy and thought leaders around health care delivery in their state.

‘We need to be concerned that changes to financing policy don’t impede our ability to deliver highquality care for patients.’ —Scott Ketover, MD, AGAP

Most of the discussions these days focus on financing and less so on clinical care. I think that’s appropriate, given the situation we’re in with health care financing. But we need to be concerned that changes to financing policy don’t impede our ability to deliver high-quality care for patients. Incidentally, in the past five months, we’ve put together a trade association to help independent GI practices promote their model on a national basis, Digestive Health Physicians Association (www.dhpassociation.org). The association promotes the integrated model of independent GI care as the way to provide the highest quality at the lowest cost to our patients. The organization now includes 34 GI practices nationwide, just shy of 1,000 gastroenterologists. In July, we were up on Capitol Hill, meeting with congressional representatives to promote issues in support of independent practices. 1. Kirchhoff SM. Physician Practices: Background, Organization, and Market Consolidation. Washington, D.C.: Congressional Research Service; January 2, 2013. Accessed August 6, 2014. http://fas.org/sgp/crs/misc/R42880.pdf.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

For Marketing Your Practice, Make Friends With New Media BY MONICA J. SMITH

he rapid evolution of marketing technology might inspire nostalgia for an era when prominent placement in the Yellow Pages was all a practice needed. But those days are unlikely to return, and practices will need to incorporate online marketing in order to thrive, said Reed Hogan, MD, who addressed the topic at the GI Roundtable, a meeting geared toward helping gastroenterologists navigate the emerging health care landscape. “These new media marketing technologies are changing how we’re getting patients, how we’re communicating, how they ask questions and get answers,” said Dr. Hogan, of GI Associates and Endoscopy Center, in Jackson, Miss. “This is the way we’re going to practice in the future. You have to implement a plan that is intentional, and you have to have a partner who understands this landscape is rapidly changing.” For example, he pointed out, smartphones were a novelty in 2005; less than a decade later they have considerably changed the way people conduct personal research. Today, not only do 65% of people in the United States own a smartphone, they also increasingly favor them over their laptop or desktop computers when tracking down information. Patients use the Internet to find a doctor, more often than not via a mobile platform. With that in mind, Dr. Hogan’s practice enlisted the services of Aubrey Prince, CEO of Immerseme, a marketing strategy company, to help them update and develop their marketing plan. “Today’s marketing landscape requires a multifaceted approach to get your message out,” Mr. Prince said, listing branding, websites, search engine optimization and social media as the four elements that comprise this approach.

The Four Elements Branding goes beyond the logo, but that’s what most people think of first when trying to understand what, exactly, branding is, explained Mr. Prince. “The logo is the doorway to how people see you. You want to make sure current and potential patients know it’s you.” GI Associates’ logo debuted 26 years ago and has stayed fairly consistent and recognizable, Dr. Hogan said. “We want our logo to stand for quality and care. It has morphed a little over time … to reflect [changes in the practice, such as the addition of in-house] pathology and nutrition. But the main things are the color, the shape—not much variation. When you see that logo, you connect it with GI Associates.” Next, you need a current and interactive website. “Three-fourths of your patients today are going to look at your website before they come to see you,” Dr. Hogan said. “Patient loyalty is to their primary care doctors; when they need you, they’re going to use the Internet and you want to be on the front page.” There is a science to developing websites that attract and retain clients, Mr. Prince explained, but there are a few essential points to keep in mind. A website should be clean and easy to navigate; it should look different on a smartphone than it does on a desk- or laptop; and it should not overwhelm the visitor with text. At the same time, the website should be a valuable source of information for patients, said Jim Leavitt, MD, of Gastro Health, in Miami. “There are a lot of studies out there that show patients really want to get their medical information from their physician—a trusted

source,” he said. Optimally, a gastroenterology practice’s website will have internally generated information, as well as links to trusted sources, such as the American College of Gastroenterology and the Crohn’s and Colitis Foundation. “Another reason we absolutely need to have a website is to be able meet meaningful-use requirements for regulatory reasons—to be able to communicate with patients via a HIPAA-secure portal,” Dr. Leavitt said. He predicted that medical communications will become increasingly Web-dependent as health care focuses more on population health management, monitoring patients and keeping them healthy without necessarily seeing them in person. “There are a plethora of apps being developed now,” Dr. Leavitt said. “As more places acquire advanced population management tools, your ability to communicate with patients, even [to conduct] telemedicine through your portal, is going to be increasingly important.” Search engine optimization (SEO) is what leads patients to a practice’s website in the first place. SEO is basically driven by the content that grabs the attention of Google, which is where 80% to 85% of all Internet users start a search. “Text is the driving force behind search, so it’s important that your content is relevant and updated regularly, because Google loves content, but it loves updated content even more, as they regularly change their algorithm,” Mr. Prince said. GI Associates’ website, for example, contains about 200 pages with videos, Q&As and blogs. “It’s extremely interactive—we update our content constantly,” Dr. Hogan said. Note: Google can’t see pictures; images need to be tagged with file names to be detected. Finally, social media: “Facebook, Twitter, Pinterest. I didn’t believe in any of these,” Dr. Hogan said. “They kind of scared me. But social media is about capturing word of mouth, which is the most powerful marketing message you can get.” Making the most of social media means providing

more than just information. “They call it ‘social’ for a reason—you have to engage with them,” Mr. Prince said. “And whatever you put up on these platforms needs to be shareable and share-worthy.”

Enlisting Experts The concept of capturing word of mouth may be a bit slippery, but it can be done, although it may take the help of a dedicated professional, Dr. Leavitt said. His practice employs an in-house marketing specialist and also uses an external company to help them navigate the Internet marketing landscape and tailor their strategy. As an experiment to see how they could drive activity using Twitter, Gastro Health assigned its chief operating officer (COO) to respond to tweets relative to the practice. To do this, the COO used TweetDeck, a Twitter tool that identifies specific content and allows for the user to respond. “We used Crohn’s disease as a key word. So if that was mentioned [in a tweet], we could comment or add information to the subject line, and mention our practice if that was appropriate,” Dr. Leavitt said. “In less than a month, we had 3,000 people following us.” Twitter “is a really amazing tool to get your name out there and get people following you—to educate people in general,” he added. Although plenty of one- and two-person practices have websites, Dr. Leavitt acknowledged that the cost of hiring Internet marketing professionals may be prohibitive for smaller practices. “You’ll see [this type of service] becoming more and more accessible, and like any technology, the cost continues to go down. But being vibrantly involved in social media is an ongoing cost that most small practices would not be able to absorb,” he said. “But this is going to be big. When you go to a restaurant or to buy a car, you go online and look at reviews. That’s what patients do, and if they’re going to be there, we need to be there.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

New Treatments for Diabetic Gastroparesis Offer Promise BY CAROLINE HELWICK

ew treatments for diabetic gastroparesis appeared encouraging in two recent Phase II studies. One agent is still under development; the other is a novel formulation of the only FDA-approved product on the market for the condition, symptoms of which may, at some point, affect as many as half of patients with types 1 and 2 diabetes. At the late-breaking abstract session at the 2014 Digestive Disease Week (DDW), investigators reported that a 10-mcg twice-daily subcutaneous dose of RM-131 significantly accelerated gastric emptying (GE) and led to clinically meaningful reductions in vomiting. RM-131, also known as relamorelin (Rhythm Pharmaceuticals), is a selective ghrelin pentapeptide agonist under fast-track review by the FDA. RM-131 increases GE in patients with diabetes and is believed to be 15 to 130 times more potent than ghrelin, a gastric hormone that stimulates gastrointestinal activity. “RM-131 met the study’s primary end point for gastric emptying, as well as key secondary end points,” said Anthony Lembo, MD, of Beth Israel Deaconess Medical Center, in Boston, who reported the findings. Emptying improved by an average of 23 minutes from baseline after four weeks of twice-daily subcutaneous injections at the 10-mcg dose, Dr. Lembo reported. The randomized, double-blind, placebo-controlled 28-day study (abstract 929a) involved 204 patients with a mean body mass index (BMI) of 33 kg/m2 , a Gastroparesis Cardinal Symptom Index (GCSI) of at least 2.6, and a history of nausea and/or vomiting at least once a week. Approximately 12% of patients had type 1 diabetes. The screening GE breath test was performed at baseline and day 28 of the study. Symptoms were recorded daily, and the researchers analyzed a composite of nausea, abdominal pain, bloating and early satiety. After a one-week run-in phase, patients were randomized to placebo before breakfast and before the evening meal; placebo before breakfast and RM-131 before the evening meal (i.e., RM-131 10-mcg once daily) or RM-131 before both meals (i.e., RM-131 10-mcg twice daily). Changes in the placebo arm were significantly less than those observed in the active treatment group. The primary end point was change from baseline in GE breath test half-emptying time, which

indirectly measures GE by determining concentrations of 13C-octanoid acid. In the modified intention-to-treat population (who received at least one dose), the change from baseline was –22.9 minutes with 10 mcg twice daily (P<0.001) and –7.5 with placebo, an absolute difference between the arms of 15.4 minutes. In the 10-mcg once-daily group, the change from baseline was much less, –5.9 minutes, an insignificant difference over baseline measurement. Twice-daily treatment also reduced weekly vomiting episodes by 63% (P=0.033) P and vomiting severity by 58% (P=0.005) P compared with placebo. A strong placebo effect was present for symptoms of nausea, abdominal pain, bloating and early satiety, and in the composite end point. “The effects of RM-131 were numerically greater, but not significantly different from placebo,” Dr. Lembo said.

Most Benefit Seen in Vomiting Subgroup Approximately 60% of the study population reported vomiting at baseline, with a mean of five to six episodes per week. RM-131 had a significant effect in this subgroup of 119 patients, reducing mean GE breath test by 30.6 minutes over baseline, and vomiting episodes by 63%. “We did this subgroup [post hoc] analysis because vomiting is the most bothersome symptom and often brings the patient in for treatment,” Dr. Lembo said. In contrast to the overall population, for the four subjective patient-reported symptoms, “a clear separation from placebo was demonstrated,” Dr. Lembo reported. The composite score separated from placebo within one week, and was statistically significant at weeks 2, 3 and 4 of the study. Overall, there were no safety concerns with the drug, which had no effect on weight, Dr. Lembo said. Adverse events were reported by 43% of the placebo group, 48% of the once-daily treatment arm and 37% of the twicedaily group. Pankaj Jay Pasricha, MD, professor of medicine at Johns Hopkins University and director of the Johns Hopkins Center for Motility Disorders and Digestive Diseases, in Baltimore, said, “There are few drugs with positive results in diabetic gastroparesis, and I hope this one moves forward.”

Metoclopramide Nasal Spray Metoclopramide is the only FDAapproved drug for treating symptoms of gastroparesis. A nasal spray formulation

Table. Change ge e in n mGCSI-DD mGCSImGCSI mGCS mG GCS GC GCS Totall Score From Baseline Baselin Basel to Week 4 (Intention-to-Treat) tionPopulation

Placebo

10 mg EVK-001

P Value

14 mg EVK-001

P Value

All patients (N=287)

–1.0

–1.2

0.1504

–1.2

0.3005

Women (n=203)

–0.8

–1.2

0.0247

–1.3

0.0215

Men (n=84)

–1.4

–1.2

0.4497

–0.9

0.2174

mGCSI-DD, modified daily dietary version of the Gastroparesis Cardinal Symptom Index

(EVK-110) is being developed to provide reliable systemic absorption, even when patients are experiencing a disease flare. Systemic concentrations are about 85% of the orally administered dose. “A prior head-to-head study suggested the nasal spray has advantages over an orally administered tablet, including better symptom control in diabetic patients with gastroparesis,” said Henry P. Parkman, MD, director of the GI Motility Laboratory at Temple University School of Medicine, in Philadelphia, who presented Phase IIb results at DDW (abstract 71). “This Phase IIb study was the largest clinical study in diabetic gastroparesis with metoclopramide. The results were encouraging and quite unexpected,” Dr. Parkman said. “Metoclopramide nasal spray provided a significant clinical benefit in reducing the symptoms of diabetic gastroparesis in women, whereas in men it did not.” More than 80% of patients with diabetic gastroparesis are women, Dr. Parkman noted, so the latest findings are “important new information. Metoclopramide nasal spray has the potential to address an unmet need for patients.” The multicenter, double-blind, placebo-controlled trial compared two doses (10 and 14 mg) of metoclopramide nasal spray in 287 patients with symptomatic diabetic gastroparesis (mean age 51; 71% women). The primary end point was change from baseline to week 4 in the modified daily dietary version of the GCSI total score (nausea, early satiety, bloating and upper abdominal pain). “Overall, the primary efficacy end point was not statistically significant,” Dr. Parkman said (Table). “This appeared to be due to the high placebo response, primarily in male patients. Females, but not males, had statistically significant

improvement in symptoms for both doses of intranasal metoclopramide.” For the primary end point, an interaction test between treatment and sex was statistically significant (P=0.038), P suggesting the effect of the drug differs between men and women, he said. “The observed differences in efficacy by gender were not related to severity of baseline disease or other demographic characteristics,” he added. Dr. Parkman said the patients tolerated the nasal spray well at both doses. “There were no dose-limiting toxicities and fewer than 10% of patients dropped out, including 5% due to adverse events,” he said. The majority of adverse events were mild or moderate, and there were no deaths or reports of tardive dyskinesia, he added. “These two studies offer potentially very exciting new options for the treatment of a very common problem for a large number of diabetic patients,” said David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, in Norfolk. He said the lack of tardive dyskinesia and tremor with the metoclopramide nasal spray is notable. “Improving gastric emptying in these patients is important for both symptom relief as well as glycemic control,” Dr. Johnson said. “At present, we have very limited effective options for these patients, and these data address a huge unmet therapeutic need.” Dr. Lembo has served on advisory committees or review panels for AstraZeneca, Forest Research Institute and Salix Pharmaceuticals, and consulted for Ironwood Pharmaceutical and Prometheus Laboratories. Dr. Parkman has consulted for Evoke Pharma. Drs. Pasricha and Johnson reported no relevant financial conflicts of interest.

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Corticosteroid, PPI Found Effective For Eosinophil-Related Esophageal Conditions BY TED BOSWORTH CHICAGO—A pair of new studies offers clinicians guidance on pharmacologic strategies for the treatment of often stubborn conditions of the esophagus related to eosinophils. Topical corticosteroids were found effective for acute control of eosinophilic esophagitis (EoE), and proton pump inhibitors (PPIs) were found effective for long-term control of PPI-responsive esophageal eosinophilia (PPI-REE). For the respective conditions, which may or may not be related, the clinical studies appear to provide guidance on pharmacologic treatment. “So far, there is no approved therapy for EoE, even though efficacy with both systemic and topical corticosteroids has been shown previously,” said Stephan Miehlke, MD, of the Center for Digestive Diseases at the Internal Medicine Center, in Hamburg, Germany. Presenting his data on budesonide at Digestive Disease Week 2014 (abstract 55), Dr. Miehlke said the goal of the study was to compare two methods of delivering topical corticosteroids to the esophagus. For the multicenter trial, which had a double-dummy design, 76 adults with EoE were randomized into four groups: a budesonide effervescent tablet (BET) 1 mg twice daily; the same tablet in a dose of 2 mg; budesonide viscous suspension (BVS) 2 mg twice daily; or placebo. The ‘There is a growing study included two weeks of treatment and two weeks of follow-up. The primary end body of evidence point of the trial was histologic remission, that PPI-REE cannot defined as an eosinophil count less than 16 per high-powered field (HPF). be distinguished Histologic remissions were achieved in from EoE on the all patients on BET 1 mg, 93.8% of those basis of any clinical, on BET 2 mg, 93.8% on BVS and none on placebo. The efficacy rates for all active endoscopic or treatments were significantly different histological finding.’ from placebo (P<0.0001), but not from each other. Endoscopic and dysphagia —Stuart Spechler, MD scores also improved in all active treatment groups at the end of treatment, but the improvement for dysphagia after two weeks of followThe other study examined the long-term efficacy of up remained significantly improved relative to placebo PPIs in patients with PPI-REE (abstract 58). Spanish (P=0.0196) P only in patients who received the lowest researchers evaluated 40 adults with PPI-REE, with a dose of BET. minimum follow-up of 12 months and a median followThe researchers observed no serious adverse events, up of 27 months (79 months maximum). The diagnosis but three patients in each of the corticosteroid groups of PPI-REE initially was made on histologic response to developed infections that may have been related to a double dose of PPI therapy in 22 patients and a quatreatment. druple dose in 18 patients. After diagnosis, the mainteAll of the therapies were effective, but Dr. Miehlke nance therapy was double-dose PPI in 19 patients and said patients preferred BET to BVS. Because the single dose in 21 patients. higher-dose BET was not more effective than the 1 mg Over the course of follow-up, 26 patients (63%) maintablet, the trial results suggest that a two-week course of tained both symptomatic and histologic responses, with the low dose is the most practical approach for achieving less than 15 eosinophils per HPF, on their PPI treatrapid histologic remission. ment, said Javier Molina-Infante, MD, of the Division of

Gastroenterology at the Hospital San Pedro de Alcantara, in Caceres, who led the study. Of 14 relapses, eight occurred in patients receiving double-dose PPIs. In 10 patients who relapsed, eosinophilia was observed exclusively at the distal esophagus; eight regained histologic remission after going on quadruple-dose PPI therapy. By combining the 63% of patients who maintained a long-term clinical and histologic remission on relatively low doses of PPI with the 20% who regained histologic remission with increased doses of PPI, the study suggests that more than 80% of adult PPI-REE patients achieve long-term control with PPI therapy, according to the researchers. Dr. Molina-Infante added that the study provides one of the longest follow-ups for judging the efficacy of PPIs in sustained control of PPI-REE. Although Dr. Molina-Infante suggested that PPI-REE may be a distinct entity from EoE, at least one expert disagreed. Stuart Spechler, MD, chief of gastroenterology at the VA North Texas Healthcare System, in Dallas, said that “there is a growing body of evidence that PPI-REE cannot be distinguished from EoE on the basis of any clinical, endoscopic or histological finding.” In fact, drawing an analogy with ulcerative colitis, he said the term “PPI-REE” eventually may be dropped. “Many patients with ulcerative colitis do not respond to mesalamine but, in those who do, we do not abandon the diagnosis to label the condition ‘mesalamine-responsive inflammatory bowel disease,’” said Dr. Spechler, who also is professor of medicine at the University of Texas Southwestern Medical Center, also in Dallas. “It will be interesting to see how this issue plays out over the next several years.” In the meantime, he said the studies offer valuable information. Although the finding that an effervescent budesonide tablet is effective, safe and preferred over the viscous suspension is “intriguing,” he said the long-term PPI study adds to evidence that benefit in EoE may not be based on acid control. “Recent data suggest that PPIs have anti-inflammatory effects that are independent of their effects on stomach acid, and those anti-inflammatory effects might explain why an immune/antigen-mediated disorder like EoE can respond to PPIs,” Dr. Spechler explained. This most recent trial “suggests that PPIs retain their longterm efficacy in most patients, although dose escalations may be required.” Dr. Miehlke has received research funding from Dr. Falk Pharma GmbH. Dr. Molina-Infante has received consulting fees from Casen Fleet. Dr. Spechler reported no relevant financial conflicts of interest.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Duke continued from page 1

“You cannot do this alone,” said co-investigator Christopher R. Mantyh, MD, a colorectal surgeon and surgical oncologist in the Department of Surgery, Duke University Medical Center in Durham, N.C. “I had a lot of buy-in from people, and there was not much pushback at all.” In the study, a group of preventive measures was bundled and implemented pre-, during and post-colorectal surgery, which resulted in an almost 75% reduction in both superficial SSIs (5.7% after the intervention vs. 19.3% before; P<0.001) and postoperative sepsis (2.4% vs. 8.5%; P P=0.009) (JAMA Surgg 2014 Aug. 27. [Epub ahead of print]). Bundles, which combine specific interventions, have become popular in infection control, according to Joseph Kuti, PharmD, associate director of clinical and economic studies at the Center for Anti-Infective Research and Development at Hartford Hospital in Hartford, Conn., whose area of research is the use of bundles to improve outcomes in patients with infection. “By putting the bundle through as a package, the intent is that every single piece of the bundle will be followed,” said Dr. Kuti, who is also president of the Society of Infectious Diseases Pharmacists. “We think the sum is greater than the whole,” Dr. Mantyh explained. “If you did one [intervention], you might see a small improvement. If you add together five or 12 of these actions, there is an even greater improvement. I do not think any one action would move the needle significantly.” The colon and rectum are full of bacteria, so anytime a surgical procedure is performed in those areas, there is a high risk for infection; the risk for SSI from such surgical contamination ranges from 15% to 30%, according to the paper. The first step was recognizing this as a problem and not the norm. “It was an acceptable fact of life that when you operated on the colon or the rectum, you would see a surgical site infection in about one-fourth of your patients,” Dr. Mantyh said. After Duke began participating in the American College of Surgeons National Surgical Quality Improvement Program, which provides prospective 30-day postsurgical outcomes data, the physicians became aware that their 20% rate of infection was a little higher than some other institutions. “When I initially tried to start this in 2010, I was kind of doing this on my own, and I met a lot of failure,” Dr. Mantyh admitted. “My realization was that I had to involve other folks, such as nursing and anesthesia, and once I did that, it became a lot easier.”

The (Medical) Village A multidisciplinary team, including surgeons, anesthesiologists, clinic nurses, operating room (OR) staff, unit nurses, house staff and hospital midlevel providers were involved in either putting together the bundle or its implementation. The team looked at the entire colorectal surgery process from pre-op to post-op before deciding which measures to include in the bundle (Table). Some of the measures were evidence-based and others were commonsense ideas that presented little risk to patients, but had the potential to reduce infections, Dr. Mantyh said. “We chose these [actions] for our bundle because they were easy to do, low cost and everyone was on board

Table. Perioperative Actions for Bundling Pre-Op (5 measures) Educate patients about SSI preventive measures and objectives. Have patient shower with chlorhexidine. Perform mechanical bowel prep with oral antibiotics. Administer ertapenem within 1 h of incision. Standardize preparation of surgical field with chlorhexidine alcohol. During surgery (6 measures) Use fascial wound protector. Change gown and gloves before fascial closure. Have a dedicated wound-closure tray. Limit OR traffic. Maintain euglycemia. Maintain normothermia during surgery. Post-Op (5 measures) Remove sterile dressing within 48 h. Wash incision daily with chlorhexidine. Maintain euglycemia. Maintain normothermia in the early preoperative period. Reinforce patient education about SSI preventive measures and objectives. OR, operating room; SSI, surgical site infection Source: JAMA Surgery 2014 Aug. 27. [Epub ahead of print].

with them,” he said. (The largest cost was a $10,000 outlay for 10 fascial closure tray packages.) A few areas saw heavy discussion among the team members. One was the use of mechanical bowel preparation and prophylactic antibiotics. “This is a controversial area,” Dr. Mantyh said. “There are some studies that show it does not improve SSI rates, maybe even makes them worse, and some that show it does [improve rates]. But the most recent data that have come out in the last few years [Dis Colon Rectum 2012;55:1160-1166] indicate that it is beneficial to decrease the SSI rates if you provide the bowel prep with antibiotics.” After a discussion with the infectious disease staff, the team also decided to limit OR traffic. “Anesthesia and surgery had to get together and make sure we did not have extraneous people coming and going through the OR because the ID [infectious disease] people said that was a great way to introduce airborne bacteria into your room,” he said. Another controversial area was the use of fascial

wound protectors with reports in the literature both supporting and not endorsing their use. “We felt that if we began to use them especially for our open cases, it could decrease the bacterial count in the subcutaneous space,” Dr. Mantyh said. (For a positive study on the protectors, see Surg Infectt 2010;11:501-503.) The input surrounding the antibiotic choice demonstrates the type of interaction that was used throughout the process. As a teaching hospital, Duke residents are frequently provide postoperative care. “We found that our residents were redosing antibiotics inappropriately,” he said. A discussion with the infectious disease physicians led to the idea of using ertapenem (Invanz, Merck) because it is only dosed once before surgery. When they talked with the pharmacist, however, there was some concern about super selection of bacteria with this drug. But a review found that this was not an issue at Duke, so the idea was brought before the team and added to the bundle. see Duke, page 24

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The SEE CLEAR I study was a phase 3, randomized, multicenter, assessor-blinded, noninferiority study in patients preparing for colonoscopy. The primary endpoint was an evaluation of overall colon cleansing with Prepopik vs a comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets) using modified Aronchick and Ottawa scales. The secondary endpoint was an evaluation of the quality of cleansing of the ascending, mid (transverse and descending), and rectosigmoid segments of the colon. Patients were also required to complete a questionnaire that included the questions: “How easy or difficult was it to consume the prescribed bowel preparation?” and “Would you ask your doctor for this preparation again if you needed another colonoscopy in the future?”1 ‡ Prepopik was studied in a head-to-head clinical trial to demonstrate non-inferiority with a split-dose regimen vs a day-before regimen of 2L PEG+E plus 2x 5 mg bisacodyl tablets.2

INDICATION AND IMPORTANT SAFETY INFORMATION Prepopik® for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. • Prepopik is contraindicated in the following conditions: patients with severely reduced renal function, gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should be advised on the importance of adequate hydration, and post-colonoscopy lab tests should be considered if a patient develops significant vomiting or signs of dehydration after taking Prepopik • Patients with electrolyte abnormalities should have them corrected before treatment. Use caution when prescribing for patients who are at risk for seizures, or arrhythmias, including those patients with a history of prolonged QT, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy. Caution should also be used in patients with impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function, electrolyte imbalance and/or water retention • Oral medication administered within one hour of the start of administration of Prepopik solution may be flushed from the GI tract and the medication may not be absorbed. Prior or concomitant use of antibiotics with Prepopik may reduce its efficacy. Tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be

taken at least 2 hours before and not less than 6 hours after administration of Prepopik to avoid chelation with magnesium. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of additional stimulant laxatives with Prepopik may increase this risk • Prepopik should not be used if gastrointestinal obstruction or perforation is suspected. Prepopik is not for direct ingestion. Each packet must be dissolved in 5 ounces of cold water and administered at separate times, in addition to additional clear fluids, according to the dosing regimen. In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common treatment-emergent adverse reactions (>1%) following Prepopik administration

Please see brief summary of Prescribing Information following this advertisement. References: 1. Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study. Gastrointest Endosc. 2013;78(1):132-141. http://dx.doi.org/10.1016/ j.gie.2013.02.024. 2. Prepopik® Prescribing Information. August 2014. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

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Duke continued from page 22

“The great thing about ertapenem is you give one dose preoperatively and that’s it. With that single act, we got in compliance with perioperative antibiotics,” Dr. Mantyh said. They began implementing the bundle on July 1, 2011 and the adherence to the protocol was very high. In addition to the staff buy-in, the bundle had a champion in Dr. Mantyh, who met regularly with various departments to

review recent SSI results and address any implementation problems. Use of the team approach to determine and implement the bundle and the champion were probably instrumental in the program’s success, Dr. Kuti said. “This is about culture change,” Dr. Kuti said. “You need lots of education, and the support from key opinion leaders, well-respected individuals and the administration. Then you need to collect

Aspiration Patients with impaired gag reÀex and patients prone to regurgitation or aspiration should be observed during the administration of PREPOPIK. Use with caution in these patients. Not for Direct Ingestion Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen. The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances. INDICATIONS AND USAGE PREPOPIK® (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, CONTRAINDICATIONS adverse reaction rates observed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: be directly compared to rates in clinical trials of another drug and may • Patients with severely reduced renal function (creatinine clearance not reÀect the rates observed in practice. less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and vomiting were the most common adverse reactions (>1%) • Gastrointestinal obstruction or ileus following PREPOPIK administration. The patients were not blinded to • Bowel perforation the study drug. Since abdominal bloating, distension, pain/cramping, • Toxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing • Gastric retention preparations, these effects were documented as adverse events in • An allergy to any of the ingredients in PREPOPIK the clinical trials only if they required medical intervention (such as a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS diagnostic procedures, met the criteria for a serious adverse event), Serious Fluid and Serum Chemistry Abnormalities or showed clinically signi¿cant worsening during the study that was Advise patients to hydrate adequately before, during, and after the not in the frame of the usual clinical course, as determined by the use of PREPOPIK. Use caution in patients with congestive heart investigator. failure when replacing Àuids. If a patient develops signi¿cant vomiting PREPOPIK was compared for colon cleansing effectiveness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters (2L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, all lab tests (electrolytes, creatinine, and BUN) and treat accordingly. administered the day before the procedure. Table 1 displays the most Approximately 20% of patients in both arms (PREPOPIK, 2L of PEG common adverse reactions in Study 1 and Study 2 for the PREPOPIK + E plus two x 5-mg bisacodyl tablets) of clinical trials of PREPOPIK Split-Dose and Day-Before dosing regimens, respectively, each as had orthostatic changes (changes in blood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seven days post colonoscopy. Table 1: Treatment-Emergent Adverse Reactions observed in at Fluid and electrolyte disturbances can lead to serious adverse events Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte abnormalities should be corrected before treatment with PREPOPIK. In addition, use caution when prescribing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen for patients who have conditions or who are using medications that Reaction increase the risk for Àuid and electrolyte disturbances or that may PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adverse events of seizure, arrhythmia, and renal with 2 x (N=296) with 2 x 5-mg (N=305) impairment. n (% = n/N) 5-mg n (% = n/N) bisacodyl Seizures There have been reports of generalized tonic-clonic seizures with the use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of Àuid and electrolyte abnormalities. Use caution when prescribing PREPOPIK for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, patients with known or suspected hyponatremia. Use in Patients with Renal Impairment As in other magnesium containing bowel preparations, use caution when prescribing PREPOPIK for patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal anti-inÀammatory drugs). These patients may be at increased risk for renal injury. Advise these patients of the importance of adequate hydration before during and after the use of PREPOPIK. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

bisacodyl tablets (N=302) n (% = n/N) Nausea 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) * 2L PEG + E = two liters polyethylene glycol plus electrolytes solution. **abdominal bloating, distension, pain/cramping, and watery diarrhea not requiring an intervention were not collected tablets (N=298) n (% = n/N)

‘Phenomenal’ Results To determine whether the bundle helped reduce SSIs, the Duke researchers conducted a retrospective study and looked at surgeries performed between

arrhythmias, and prolonged QT in the setting of Àuid and electrolyte abnormalities. This includes patients receiving drugs which may be associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used in patients on nonsteroidal anti-inÀammatory drugs (NSAIDS) or drugs known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin re-uptake inhibitors, antipsychotic drugs and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance. Consider additional patient evaluations as appropriate. Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of PREPOPIK solution may be Àushed from the GI tract and the medication may not be absorbed. Tetracycline and Àuoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of PREPOPIK to avoid chelation with magnesium. Antibiotics Prior or concomitant use of antibiotics with PREPOPIK may reduce ef¿ f cacy of PREPOPIK as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies with PREPOPIK have been performed in pregnant rats at oral doses up to 2000 mg/kg/day (about 1.2 times the recommended human dose based on the body surface area), and did not reveal any evidence of impaired fertility or harm to the fetus due to PREPOPIK. The reproduction study in rabbits was not adequate, as treatment-related mortalities were observed at all doses. A pre and postnatal development study in rats showed no evidence of any adverse effect on pre and postnatal development at oral doses up to 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, PREPOPIK should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PREPOPIK is administered to a nursing woman. Pediatric Use The safety and effectiveness of PREPOPIK in pediatric patients has not been established.

Geriatric Use In controlled clinical trials of PREPOPIK, 215 of 1201 (18%) patients were 65 years of age or older. The overall incidence of treatmentemergent adverse events was similar among patients 65 years of age ( 3%) and patients <65 years of age ( 1%). Among all patients 65 years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities was greater in the PREPOPIK group (81.1%) than in the comparator In general, PREPOPIK was associated with numerically higher rates group (70.9%). of abnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing 2L of PEG + E plus two x 5-mg bisacodyl Renal InsufÀ f ciency tablets. These shifts were transient in nature and numerically similar Patients with impaired renal function or patients taking concomitant between treatment arms at the Day 30 visit. medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor Postmarketing Experience blockers, or non-steroidal anti-inÀammatory drugs) may be at The following foreign spontaneous reports have been identi¿ed during increased risk for further renal injury. Advise these patients of the use of formulations similar to PREPOPIK. Because these events are importance of adequate hydration before during and after the use reported voluntarily from a population of uncertain size, it is not always of PREPOPIK. Consider performing baseline and post-colonoscopy possible to reliably estimate their frequency or establish a causal laboratory tests (electrolytes, creatinine, and BUN) in these patients. relationship to drug exposure. In patients with severely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. The Allergic reactions signs and symptoms of hypermagnesemia may include, but are not Cases of hypersensitivity reactions including rash, urticaria, and limited to, diminished or absent deep tendon reÀexes, somnolence, purpura have been reported. hypocalcemia, hypotension, bradycardia, muscle, respiratory paralysis, complete heart block, and cardiac arrest. Electrolyte abnormalities There have been reports of hypokalemia, hyponatremia and OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation The patient who has taken an overdose should be monitored carefully, prior to colonoscopy. and treated symptomatically for complications.

Cardiac Arrhythmias There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing PREPOPIK for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal ECGs should be considered in patients at increased risk of serious Abdominal pain, diarrhea, fecal incontinence, and proctalgia have been reported with the use of PREPOPIK for colon preparation cardiac arrhythmias. prior to colonoscopy. There have been isolated reports of reversible Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis aphthoid ileal ulcers. Ischemic colitis has been reported with the use Osmotic laxatives may produce colonic mucosal aphthous ulcerations of PREPOPIK for colon preparation prior to colonoscopy. However, a and there have been reports of more serious cases of ischemic colitis causal relationship between these ischemic colitis cases and the use requiring hospitalization. Concurrent use of additional stimulant of PREPOPIK has not been established. laxatives with PREPOPIK may increase this risk. The potential for mucosal ulcerations should be considered when interpreting Neurologic colonoscopy ¿ndings in patients with known or suspected inÀammatory There have been reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients. bowel disease. Use in Patients with SigniÀcant Gastrointestinal Disease If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering PREPOPIK. Use with caution in patients with severe active ulcerative colitis.

data and analyze that data after implementation to demonstrate the intervention worked and can therefore be expanded—in this case, expanded to the other colorectal surgeons.”

DRUG INTERACTIONS

Manufactured by: Ferring Pharmaceuticals (China) Co., Ltd. No. 6 HuiLing Lu (Ferring Road) National Health Technology Park Zhongshan City, Guangdong Province, CHINA Manufactured for: Ferring Pharmaceuticals Inc. Parsippany, N.J. 07054

www.ferringusa.com 1-888-FERRING Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Use caution when prescribing PREPOPIK for patients with conditions ©2014 Ferring B.V. or who are using medications that increase the risk for Àuid and All rights reserved. Printed in USA. electrolyte disturbances or may increase the risk of seizure, PK/069/2014/US(1)

Jan. 1, 2008 and Dec. 31, 2012. They reviewed the medical records of 559 patients—346 underwent colorectal surgery before implementation of the bundle and 213 underwent surgery after implementation—and found that the bundle was associated with a substantial reduction in SSIs. Indeed, the nearly 75% reduction in SSIs documented in the JAMA Surgery study was “a phenomenal” result, said Ira L. Leeds, MD, MBA, who wrote an accompanying editorial in the journal. But he stressed that “one needs to interpret them in the right context. Their SSI rate going into the [research] was something they made an intentional effort to reduce.” Results like this require changing behavior and that can be difficult, especially in medicine, added Dr. Leeds, the Halsted Surgical Resident at Johns Hopkins University School of Medicine, in Baltimore. “Even within a single health care institution, there are awfully high fences between departments, and these firm and sharp divisions really make it difficult to implement something system-wide. “This bundle was built from the ground up. There was a physician champion, but he got buy-in from the nursing staff, the techs. On top of that, they invited comment from all the people who are involved in the procedure,” he said, adding that the future of quality improvement in health care will require grassroots interventions like this. For Duke, Dr. Mantyh said, the bundle has become the standard of care for colorectal surgery, and surgeons in other areas with a high SSI rate, such as hepatobiliary surgery, are reviewing the results. “We are beginning to look at these other areas, but each is a little different,” he said, so the bundle would have to be tweaked by the staff in that department. Dr. Leeds said that is the way infection prevention should be done. These interventions are less about duplication and mandates and more about a process and buy-in, he explained. “When the people who are ultimately responsible for the performance measure are the people designing the program, it becomes infused with a sense of ownership you cannot mandate.” He said people lampoon “committee think,” but a deliberative process can help improve quality. “Everyone in the operating room plays a very specific role, and they see things from very different perspectives. Unless you engage each of those individuals, you are going to end up with a solution that is not optimized for each individual’s role.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Malnutrition continued from page 1

“Of course, there is never one thing that influences a patient’s stay in the hospital, but malnutrition can be a significant factor,” said Melissa Parkhurst, MD, associate professor in the Department of Internal Medicine at the University of Kansas Medical Center, in Kansas City, and medical director of Nutrition Support Services at the University of Kansas Hospital. “The data we have over a number of years consistently show that one in three patients enters the hospital already meeting the criteria for malnourishment,” said Dr. Parkhurst, who is also the clinical representative in the Alliance to Advance Patient Nutrition, an interdisciplinary partnership dedicated to raising awareness about malnutrition in hospitals. “We know that if left unattended, about two-thirds will experience further decline while they are in the hospital.” Also worrisome are the statistics showing that even well-nourished individuals will experience some type of nutritional decline when they enter the hospital because of their illness, poor appetite, dietary restrictions, gastrointestinal problems and other issues, according to Dr. Parkhurst. “There are multiple reasons why malnutrition in the hospital is an issue,” she said. “The hospital care of a patient is a complex system with a lot of moving parts and a lot of things that are competing for the attention of the physician, nurses and administrators. Then on top of that, you add a lack of general understanding of the cost of malnutrition and lack of awareness and inaction.” These factors make it easy for malnutrition to fall under the caregivers’ radar, she explained. Many patients are placed on NPO (nothing by mouth) orders for long periods, or they are taken for radiographs or other diagnostic tests or procedures during mealtimes and frequently miss meals. Others stop eating because they do not like the food, feel nauseated, are experiencing medication-related

changes in taste, are depressed or in pain, or have another issue. Patients’ lack of adequate caloric intake may go unnoticed over time and, if interventions are put into place, they are not always tracked to see if they are working. It happens every day in hospitals and long-term care facilities across the country, Dr. Parkhurst said.

The Skeleton in the Closet Malnutrition in the hospital is not a new problem. In a landmark 1984 study, Charles E. Butterworth Jr., MD, referred to malnutrition as the “skeleton in the hospital closet” because it remains underrecognized and often goes untreated (Nutr Todayy 1974;9:4-8). Because one in three people enters the hospital already meeting the criteria for malnourishment (Int J Environ Res Public Health 2011;8:514-527), and malnutrition has been linked to increased morbidity and mortality, the Joint Commission mandates that a nutrition assessment be done when a person enters the facility. However, the group does not provide any guidance about the management of the patient once he or she is identified, which is how that patient falls through the cracks, Dr. Parkhurst pointed out. If a patient is identified as being malnourished, often he or she is discharged before a full nutritional assessment is performed because the average time for such an evaluation is five days after admission, which is also the average hospital length of stay ((J Parenter Enteral Nutr 2011;35:209-216). “Dietitians need to do an assessment within a timely fashion of the screening coming back at risk,” Dr. Parkhurst said. “And the dietitian’s recommendations, which are only implemented about 40% of the time, need to be followed up by the physician-led team.” The Alliance to Advance Patient Nutrition recently issued a progress report on alleviating hospital-based

‘Let’s catch these patients who are already at risk, who are showing signs of malnutrition when they hit the door, and make sure we have a plan in place quickly to intervene and track [their progress].’ —Melissa Parkhurst, MD

malnutrition (http://www.malnutrition. com/progressreport). The report highlights some of the obstacles impeding progress in recognizing and treating malnutrition, as well as recommends a roadmap for institutions to follow. To change the paradigm will require direct, system-wide and sustained intervention, according to the report, released in August 2014. Among the recommendations are: • Hospital administrators and staff must view nutrition as a priority for improving care, quality and cost. • Clinicians’ roles must be redefined to include nutrition, giving them the power to address patient’s nutritional needs.

By the Numbers: Fixing Malnutrition Growing evidence associates the effective treatment of malnutrition in the hospital with:

25%

28%

2-day

reduction in the incidence of pressure ulcers

fewer overall complications

decrease in avoidable hospital readmissions

reduction in the average hospital length of stay

¦ ¦ ¦ ¦

• The electronic health record (EHR) should be leveraged to standardize nutrition documentation and communicate nutrition care plans. • Someone should take responsibility for the patient’s nutritional status. The process begins with the screening, Dr. Parkhurst said. A simple, easy-to-use tool tied to the EHR should be used. Once a patient is identified as malnourished, the dietitian must quickly perform a full assessment and make recommendations. Someone on the care team must act on these recommendations and periodically check the patient’s nutritional status. Finally, during the huddle, nutritional status should be one of the issues discussed by the health care team. All members of the health care team should be part of the screening and treatment of malnutrition, according to Johns Hopkins’ Ms. Roberts. Nurses and physicians can screen patients on admission and during history taking as well as do a physical for nutritional risk factors and to identify the need for nutritional intervention if needed, as well as educational requirements during the hospital stay. “Dietitians are experts at assessing the patient’s nutritional needs and providing appropriate nutritional interventions,” she said, which could include recommending therapeutic diets, providing education to the patient and caregivers, see Malnutrition, page 28

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HEPATOLOGY

Fecal Transplants for IBD Show Mixed Results in Trials

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BY DAVID WILD

BY DAVID WILD Probiotics may be associated with a reduced risk for hepatic encephalopathy, researchers in India have found. But at least one expert questioned the strength of the findings.

see Probiotics, page 11

Studies Challenge Conventional Wisdom In Biliary Stent Cost BY TED BOSWORTH Chicago—Two randomized trials of metal versus plastic stents for drainage of biliary duct obstruction have reached the same conclusion: Self-expanding metal stents, although they carry higher acquisition costs, are no more expensive than plastic stents because they see Stents, page 13

Chicago—Fecal transplant has reached a critical milestone: testing in the first randomized controlled trial of the therapy to treat inflammatory bowel disease. Although this step might be good for science, the news was not quite so encouraging for patients. The treatment did not appear to be better than placebo transplant at alleviating symptoms of ulcerative colitis (UC), according to the researchers. “Although we did not find a statistically significant effect of FMT [fecal microbiota transplantation] in active UC, there is the possibility that FMT may be effective when administered longer than six weeks,” the researchers said, noting that there were no major adverse events. The study, led by Paul Moayyedi, MBChB, PhD, MPH, acting director of the Farncombe Family Digestive Health Research Institute and director

of the Division of Gastroenterology at McMaster University, in Hamilton, Ontario, Canada, was one of several trials of FMT whose results were presented at Digestive Disease Week (DDW) 2014. In the trial, the researchers randomized 27 patients with mild to moderate UC to receive an FMT enema and 26 patients to receive a placebo

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I N S I D E EXPERTS’ PICKS

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Extending Conventional Endoscopy in Barrett’s Esophagus Using Narrow Band Imaging See page 26

EDUCATIONAL REVIEW Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection?

Advanced Colonoscopic Imaging: Do New Technologies Improve Adenoma Detection? MOHAMMAD TITI, MD

NEIL GUPTA, MD

PRATEEK SHARMA, MD

Division of Gastroenterology and Hepatology Veterans Affairs Medical Center University of Kansas School of Medicine Kansas City, Kansas

Division of Gastroenterology and Hepatology Loyola University Medical Center Maywood, Illinois

Division of Gastroenterology and Hepatology Veterans Affairs Medical Center University of Kansas School of Medicine Kansas City, Kansas

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Dr. Sharma has received grant support from CDX Labs, Cook Medical, NinePoint Medical, and Olympus Inc. Drs. Titi and Gupta report no relevant financial conflicts of interest.

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CRC and have shown a reduction on in mortality within the screened population.2 However, colonoscopy remains imperfect and several studies have raised concerns about the miss rate of adenomatous polyps during screening. The overall miss rate is approximately 20%, and ranges from 6% for large (10 mm) adenomas to 26% for diminutive (<5 mm) lesions.3 Missing these adenomas is one of the proposed mechanisms in the development of interval colon cancers that occur within the screened population.4 Improving detection of adenomas during colonoscopy therefore may be the key to more effective screening.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • AU G U ST 2 0 14

Rise in colectomy for constipation raises alarm ...... page 37

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Are Hospitals Still Striking Out on Key Med Safety Standards? BY DAVID WILD

ospitals appear to be in a two-year slump when it comes to complying with potentially lifesaving medication safety standards. That was the message espoused during a recent Institute for Safe Medication Practices (ISMP) webinar, where the lagging statistics on medication safety were front and center. Indeed, as many as 35% of hospitals surveyed by the Joint Commission in 2013 did not comply with medication-related standards in 2013, according to data provided by webinar presenters. The rates of noncompliance remained nearly unchanged between 2012 and 2013, and the most frequent issues were related to

drug storage, ordering, pharmacist order reviews, improper labeling and medication reconciliations (Table). The findings prompted Darryl Rich, PharmD, MBA, a medication safety specialist at the ISMP in Horsham, Pa., to urge pharmacy directors to work with other departments to avoid potential consequences of noncompliance. “In my experience, hospitals that are accredited by the Joint Commission and receive a report showing noncompliance with a lot of medication management standards typically hold the pharmacy director responsible, even when the issues involve other departments,” said Dr. Rich, who moderated the ISMP webinar. “Unfortunately, I have known of pharmacy directors who were fired because of a poor report.”

Table. Noncompliance With Top Medication Standards Scores in 2013 Standard Number

Description

2012a

2013b

MM.03.01.01

Medication storage

35%

MM.04.01.01

Medication orders

26%

22%

MM.05.01.01

Pharmacist review

15%

16%

NPSG.03.04.01

Labeling in procedures

14%

13%

NPSG.03.06.01

Medication reconciliation

MM.01.01.03

High alert medications

MM.05.01.09

Medication labeling

MM.05.01.07

Medication preparation

a b

1,483 full surveys in 2012. 1,413 full surveys in 2013.

Pat Adamski, RN, MS, MBA, the director of projects in the Division of Healthcare Improvement at the Joint Commission, who shared these findings on compliance during the ISMP webinar, said that a common struggle emerged during field reviews. “Many of the issues we observed were related to poor communication between pharmacists, nurses and physicians,” she said. “Organizations can have defined policies and protocols in place, but if they’re not doing a good job of communicating these [steps] to everyone, they’ll get into trouble.”

Storage Wars Gaps in communication may have been partly responsible for rates of noncompliance with the Joint Commission’s medication storage standard (Medication Management [MM] standard 03.01.01), Ms. Adamski said. She reported that Joint Commission surveyors found medication carts left unattended in unlocked rooms, and discovered instances of unauthorized personnel and former employees having access to locked medication areas and automated dispensing devices.

“If staff are using bio-identification for automated dispensers, they need to be reminded to log out when they’re done,” Ms. Adamski said. “That’s a gap in communications that can be easily fixed.” Other issues of noncompliance with the medication storage standard included storage of drugs that were not clearly labeled as to their contents, expiration dates and applicable warnings. “We primarily saw this with sterile, injectable multidose vials, which need to be relabeled with a revised date after the multidose vial is accessed the first time,” she explained. These instances of noncompliance also may be partly a function of some confusion regarding the definition of a “revised date,” Ms. Adamski said. For those seeking clarity on the matter, she pointed to the Joint Commission’s FAQ section on the topic (http://bit.ly/XBnGhr), which states that “multidose vials are to be discarded 28 days after first use unless the manufacturer specifies otherwise.” Another storage issue that Joint Commission surveyors found, and that could compromise the safety and efficacy of see Safety Standards, page 28

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Safety Standards continued from page 27

drugs, is storage at temperatures outside the range specified by manufacturers. “Although we’ve been seeing greater diligence in recording and monitoring temperatures, the problem we’re finding now is that there is sometimes no evidence that steps were taken in light of documented temperature fluctuations,” Ms. Adamski said. Pharmacists can help mitigate the risk for administering compromised medications by developing and communicating clear protocols that outline what personnel need to do and who they need to notify if they notice temperature fluctuations, she suggested. Within the medication storage standard, Ms. Adamski said Joint Commission surveyors found expired drugs were sometimes in storage areas. “One step that can reduce the likelihood of stocking expired medications is to ask staff to inspect the medication areas in units or departments they don’t work in, to see it with fresh eyes,” she said. “You get so used to your own area that you can miss things.” Outside of the pharmacy storage area, Joint Commission surveyors found drugs that had not been delivered to patient care areas in the most ready-toadminister form, as one of the elements of the medication storage standard specifies. Following this dictum limits the number of times an agent is manipulated and handled before administration, and therefore reduces the likelihood of contamination or dosing errors, Ms. Adamski explained.

Other instances of noncompliance with this standard that surveyors found included standing orders without the required approvals, orders that were not patientspecific and orders that were not based on the most upto-date evidence, Ms. Adamski said.

Ordering Issues

In 16% of surveyed hospitals, Joint Commission surveyors found medication orders that had not been appropriately reviewed by a pharmacist. Ms. Adamski said there are exceptions that allow orders to be filled without pharmacist review (MM.05.01.01), but hospitals need to clearly define and document what those exceptions are, based on the requirements detailed in the elements of performance (EPs). “We don’t want to delay care, but we need hospitals to develop clear policies and guidelines regarding which scenarios do not require pharmacist order reviews,” she explained.

Nearly one-fourth of surveyed hospitals failed to comply with the medication ordering standard (MM.04.01.01), according to Ms. Adamski. The most frequent type of noncompliance with this standard was improper implementation of medication order policies. “It’s always a challenge to have people follow written policies, especially when they’re in a time crunch,” she observed. Time crunches may have led some staff to place orders without complete instructions as to the route of administration, frequency of use and titration measures, as Joint Commission surveyors found was sometimes the case. Ms. Adamski reiterated the importance of clear communication, urging pharmacy nursing and medical directors “to work with front-line staff to understand why they’re not following policies.”

Appropriate labeling in these settings is particularly crucial if agents are not being “immediately administered,” Ms. Adamski said. “The definition of ‘immediately administered’ is that an authorized staff member prepares or obtains the medication, takes it directly to the patient, and administers it to the patient without a break in the process.”

Medication Reconciliation

Medication Reviews Can Be Tricky

Improper Labeling Joint Commission surveyors also found improperly labeled agents in procedural areas in 10% of surveyed hospitals (National Patient Safety Goal 03.04.01).

Six percent of hospitals failed to fully comply with the Commission’s medication reconciliation standard (NPSG 03.06.01), although some of these were related to the absence of written policies and procedures, Ms. Adamski said. She noted that individual hospitals may decide on the type of information to collect during medication reconciliations, and that this can even vary across departments and scenarios, but surveyors require clear documentation of these policies and evidence that staff is implementing them. Notably, surveyors found instances in which staff had obtained medication information from patients but failed to complete the most crucial element of the reconciliation process. “In some cases, they were not comparing the information they received from medication histories to the in-hospital orders,” she noted. “Collecting the information isn’t good enough—you need to make sure you’re doing something with it by identifying and resolving any discrepancies.” Ms. Adamski concluded by singling out a standard with relatively low rates of noncompliance but potentially profound implications if not properly followed. “If you do nothing else, please get your organization to talk about what process you have in place to perform medication management systems evaluations [MM 08.01.01],” she urged. The standard calls for organizations to collect data on the performance of their medication management systems, to identify points that carry safety risks and to address weaknesses using best practices and published evidence. “Rip apart your processes and evaluate or assess everything,” Ms. Adamski said. “If you do a good job of evaluating your medication management system, the rest of the standards will fall into place.” Ms. Adamski and Dr. Rich reported no relevant financial conflicts of interest.

Malnutrition continued from page 25

and making recommendations to the physician for supplemental nutrition if needed during the patient’s hospital stay. Some malnutrition occurs because of nausea, vomiting, diarrhea and altered taste from medications. Pharmacists can conduct a medication reconciliation and side-effect profile, and make recommendations that might foster calorie intake. They also can assist with IV nutritional support if needed, Ms. Roberts said. Even therapists should help recognize if patients are not eating properly and

report that to the health care team. They also can recommend adaptive devices that might make eating easier for patients with handicaps. Social workers can assist the patient in locating community resources if needed. “Providing the patient with community and outpatient resources is an essential part of treating nutritional problems and ultimately avoiding readmission for these conditions,” Ms. Roberts said. “The ultimate goal is to move the patient from the acute environment and to provide them

with the resources in the community to ultimately treat any long-term nutritional problems.” These efforts can pay off. Studies show a 25% reduction in the incidence of pressure ulcers ((Ageing Res Rev 2005;4:422-450), 14% reduction in overall complications (Cochrane Database Syst Rev 2009;CD003288) and a 28% reduction in avoidable hospital readmissions ((Arch Intern Med 2001;161:1549-1554) when adequate nutrition is maintained in hospitalized

patients. Well-nourished patients also experience an average reduction in the hospital length of stay of about two days ((Am J Medd 2006;317:495-501). “Let’s catch these patients who are already at risk, who are showing signs of malnutrition when they hit the door, and make sure we have a plan in place quickly to intervene and track [their progress],” Dr. Parkhurst said. The Alliance to Advance Patient Nutrition accepts major funding from Abbott Nutrition, which is a founding partner.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Bank continued from page 1

“For the first time, clinicians will be able to offer FMT for C. difficile patients not responding to standard therapy without the need to develop in-house screening and processing methods,” said Zain Kassam, MD, MPH, chief medical officer at OpenBiome, in Medford, Mass. As the first FDA-approved stool bank, OpenBiome represents a significant milestone in the evolution of the treatment, said pioneering FMT researcher Lawrence Brandt, MD, professor of medicine and surgery at Albert Einstein College of Medicine and emeritus chief of the Division of Gastroenterology at Montefiore Medical Center, in New York City. “OpenBiome deserves lots of credit.” Freeing institutions from the need to identify and screen donors, and test and prepare stool for administration will ensure greater specimen consistency and potentially safer FMT, he noted.

It’s ‘like the Red Cross, but for stool.’ “Typically, when one is obtaining a patient-selected donor, the lab only conducts tests as requested, which may or may not be comprehensive,” said Dr. Brandt, who is not affiliated with OpenBiome. “OpenBiome’s protocol is very comprehensive.” Although there have been several instances of donor-to-patient norovirus transmission due to inadequate pathogen screening ((Am J Gastroenterol 2013;108:1367), Dr. Brandt said drawing connections between donor stool and post-transplant illness in recipients has been a challenge. “Clinicians don’t always test patients for the presence of infectious diseases and pathogens before performing FMTs,” Dr. Brandt said, urging this practice to be followed.

The OpenBiome Protocol Dr. Kassam, who is affiliated with the Massachusetts Institute of Technology, in Boston, and OpenBiome co-founder Mark Smith, PhD, also from MIT, shared the organization’s methodology at the American College of Gastroenterology’s 2014 James W. Freston Conference on microbiome-related research (abstract 16). OpenBiome developed its protocol after extensive consultations with gastroenterologists, infectious disease physicians, microbiologists, bioinformatics experts and patient advocates with an interest in FMT. The protocol begins by screening donors, including administering a

105-item questionnaire, conducting a clinical assessment, and analyzing their stool for pathogens using 20 serological and stool-based assays (Figure). The OpenBiome team also analyzes stool microbial composition using 16S ribosomal RNA sequencing, a widely used method for classifying organisms. To ensure ongoing safety, they prospectively monitor the donors’ health status, and both blood and stool undergo repeat testing every 60 days. Specimens are cryopreserved and quarantined until both screens are passed, and they are shipped on dry ice to the treating physician.

Dr. Kassam said the OpenBiome protocol “marks a significant improvement in the safety and rigor of screening and processing donor stool.”

Cost and Availability Advantages As of early September, OpenBiome had provided more than 950 stool specimens to 100 hospitals in 31 states. The wide network places more than 82% of the American population within a four-hour drive of a hospital offering FMT with OpenBiome’s product, Dr. Kassam said. A large distribution network leverages economies of scale, Dr. Kassam said, making the treatment’s $250 price

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

tag significantly lower than the $600 to $1,400 that most institutions pay when they conduct pre-FMT screening and testing themselves. “Our product is far below typical costs for stool that is less rigorously screened and processed,” Dr. Kassam emphasized. “Moreover, institutions may need to conduct the process multiple times if individual donors don’t pass the screening process.”

role that OpenBiome might play. “The clinical efficacy of FMT is clear, and efforts by OpenBiome and others will help move it forward,” he said. OpenBiome’s protocol is publicly available at www.openbiome.org. Dr. Kassam is chief medical officer at OpenBiome. Dr. Brandt reported receiving research funding from OpenBiome and is a consultant to CIPAC LLC, a company that is commercializing microbiota for FMT. Drs. Floch and Longman reported no relevant financial conflicts of interest.

Furthering the Science of FMT In addition to serving a clinical function, OpenBiome is moving the science of FMT and the microbiome further along, Dr. Kassam said. The organization is set to launch the prospective STOOL (Safety of fecal microbiota Transplantation: OpenBiome Outcomes & Longitudinal follow-up) study. The study will use post-FMT efficacy and safety outcomes data submitted by clinicians administering the organization’s specimens. Those data will be correlated with stool profiles, Dr. Kassam said. The findings will improve donor screening protocols and may provide a better understanding of the types of organisms that are most clinically beneficial or detrimental, he added. The organization’s rigorous microbiome sequencing could boost understanding of FMT in other ways, too, said Randy Longman, MD, PhD, a physician at NewYork-Presbyterian Hospital and assistant professor of medicine at Weill Cornell Medical College, in New York City, who has a clinical interest in FMT. “Rigorous characterization of microbial composition by 16S rRNA sequencing of donor samples will be critical to understanding the mechanism of this therapy, and ultimately enhancing safety and efficacy,” said Dr. Longman, who is not associated with OpenBiome. Although the FDA is currently limiting FMT to patients with C. difficile who have not responded to standard antibiotics, Dr. Kassam said clinicians with investigational new drug approval for use of FMT for other indications can use OpenBiome’s stool specimens as part of their studies. Utilizing standardized specimens will make research data more reliable, said Martin Floch, MD, who is clinical professor of medicine in the Department of Digestive Diseases, at Yale School of Medicine, in New Haven, Conn. “FMT protocols and studies for indications like IBD [inflammatory bowel disease] and obesity will need to be written and conducted very carefully, and public stool banks like OpenBiome will help in doing so,” said Dr. Floch, who has written several articles and a book on the microbiome and FMT, and is not involved with OpenBiome. Dr. Longman echoed the important

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Patients With Psychiatric Illness Require Close Watch After Bariatric Surgery BY LOUISE GAGNON MONTREAL—Patients with psychiatric illness who are choosing bariatric surgery require close psychiatric follow-up after surgery, according to the medical director of a community-based internal medicine weight management clinic. A study conducted in Brazil and presented at a poster session at the

International Federation for the Surgery of Obesity and Metabolic Disorders looked at six cases in which patients committed suicide or attempted suicide after bariatric surgery. The study did not specify the form of weight loss surgery that each patient underwent. Three of the six patients who underwent the surgery had an anxiety disorder

and had previous psychiatric treatment, a fact that needs to be given consideration, said Sean Wharton MD, PharmD, medical director of the Wharton Medical Clinic, and an internist at Toronto East General Hospital in Toronto, Ontario, Canada, and Hamilton Health Sciences in Hamilton, Canada, who was not involved with the study.

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The study investigators noted the patients had psychological follow-up until the third month after their operations. They also noted all but one patient committed or attempted suicide one year after surgery, which led them to conclude the surgery does not immediately spur patients to an act of suicide. “They absolutely need follow-up care for their psychiatric illness [postsurgery],” Dr. Wharton said. “They will need longterm follow-up for their psychiatric illness. Their psychiatric illness does not go away after [bariatric] surgery.” The poster research suggested that obese patients who seek bariatric surgery have a greater burden of psychiatric illness than obese patients who do not choose the surgery. Dr. Wharton stressed that patients should not discontinue their psychiatric medications before or after bariatric surgery. Many mood-stabilizing therapies that psychiatric patients are exposed to produce the undesirable side effect of weight gain, but newer pharmacologic therapies have been designed to have a weightneutral effect on patients, he said. Clinicians should favor initiation of weight-neutral medication in their newly diagnosed psychiatric patients and may consider switching to a weightneutral medication in patients whose psychiatric illness is well controlled, Dr. Wharton said. A preferred strategy, however, would be to maintain psychiatric patients on their medication if they are stabilized, and treat the associated weight gain with lifestyle interventions like dietary modification and exercise. Surgical centers should ensure that psychiatric patients who opt for bariatric surgery are seen by a mental health care professional, Dr. Wharton added.

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Intragastric Balloons for Weight Loss May Obviate Endoscopy BY LOUISE GAGNON MONTREAL—One of the emerging approaches for weight loss in obese patients is the use of the intragastric balloon, and research on several forms of intragastric balloons was highlighted at the 2014 meeting of the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO).

of the balloon through the GI tract. Dr. Gaur noted that investigators also observed a signal for weight loss with the device in the patients, who had a mean body mass index (BMI) of 31.0 kg/m2. The lack of need for endoscopy or anesthesia could mean that clinicians, such as gastroenterologists and endocrinologists, would be able to offer the

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Shantanu Gaur, MD, chief scientific officer at Allurion Technologies in Wellesley, Mass, discussed the Elipse intragastric balloon, a technology that includes a capsule and an attached delivery catheter. Patients swallow the capsule, and the balloon fills with 450 mL of bacteriostatic water. The catheter is then removed. “It opens up [in the stomach] and empties on its own,” Dr. Gaur told attendees. Dr. Gaur pointed out that the Elipse has distinct advantages over other intragastric balloons. “The difference with our device, compared to other intragastric balloons, is that it does not require endoscopy or anesthesia,” he said. Intragastric balloons pose a risk for spontaneous deflation and bowel obstruction, but this risk is lessened with this novel design, Dr. Gaur noted. “There is no secondary procedure required to remove the balloon,” he said. “The balloon passes through the GI [gastrointestinal] tract and is excreted [without endoscopy].” A study in eight patients was designed to assess the safety of the device, and investigators observed the safe passage

device to their patients, Dr. Gaur said. Manufacturers of the device plan to initially seek commercial approval outside the United States. Data on the use of the ReShape Duo, a dual intragastric balloon treatment where two balloons are connected, were also presented at the IFSO meeting. Single intragastric balloons have been shown to lose efficacy after about three months, which has prompted the design of novel technologies such as dual intragastric balloons. The device is filled with 900 cc of saline, with 450 cc in each balloon, said Gontrand Lopez-Nava, MD, a gastroenterologist based at Madrid Sanchinarro University Hospital, in Madrid. Sixty patients with a mean baseline BMI of 38.9 kg/m2 and a mean weight of 107.4 kg who participated in the study experienced a mean total body weight loss of 13.5%, or 14.4 kg. Investigators noted one balloon deflation. The manufacturer of the ReShape Duo, ReShape Medical, submitted a premarket approval application for the device to the FDA in July.

them to stay that way. Learn more at UPMCPhysicianResources.com/Crohns.

UPMC is afﬁliated with the University of Pittsburgh School of Medicine.

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Gastros Sing Praises of POEM New procedure promises to broaden scope of endoscopic practice BY MONICA J. SMITH

Images courtesy of Johns Hopkins Medicine

NEW YORK— —The introduction of per-oral endoscopic myotomy (POEM) to the pool of achalasia treatments has stirred excitement among endoscopists eager to learn and offer the novel procedure, but clinicians should consider several factors when discussing therapeutic options with a patient, said Felice Schnoll-Sussman, MD. She spoke at the 2013 meeting of the New York Society for Gastrointestinal Endoscopy. POEM may offer a treatment for achalasia that can eliminate the need for a traditional surgical procedure. “POEM appears safe and effective in early reports in the literature,” Dr. Schnoll-Sussman said. “But expertise is variable, and its place in the armamentarium remains unclear.” No treatment can restore peristalsis to the esophageal body. As a result, treatments for achalasia basically are

palliative: The goal is to strike a balance between the amelioration of symptoms and the risk for reflux. An important recent advancement in the diagnosis of achalasia is the availability of high-resolution esophageal manometry (HRM), which has changed how achalasia is diagnosed, Dr. Schnoll-Sussman said. “[It has] changed the way we look at esophageal motility by allowing for a more detailed assessment of peristalsis and the lower esophageal sphincter pressure,” she said. “We can now quantify the adequacy of relaxation at the [esophagogastric] junction, the IRP [integrated relaxation pressure].” This technology has shown that achalasia can be divided into three clinically relevant subtypes. Whereas no significant pressurization occurs in subtype 1 (classic achalasia), a pattern of panesophageal pressurization occurs throughout the esophagus in subtype 2. In the notoriously difficult-to-treat subtype 3 achalasia,

“we can see where there is rapidly propagated pressurization generated in the esophagus,” Dr. SchnollSussman said. “This is important because the different subtypes may respond differently to various treatments. “We need a tailored approach to treating achalasia, and these are the principles that guide me: the patient’s age, their gender and the institutional expertise, which is important when we’re talking about techniques that require exceptional endoscopic skill,” she added. Patient preference and the achalasia subtype also are important to consider, she said.

Nonsurgical Treatments Botox. Dr. Schnoll-Sussman said the gastrointestinal community tends to overuse botox for achalasia. It may be safe, easy to administer and associated with few side effects, but its durability is short. The effects of Botox wane after about two years, so it probably is best for patients with a short life expectancy or those who are unwilling or poor surgical candidates, Dr. SchnollSussman said. That said, life expectancy can be hard to estimate. Dr. Schnoll-Sussman continues to see a patient aged 98 years, whom she initially treated with botox 10 years ago. “She really outlived botox, but it worked for her. She’s been well the entire time, and she comes back and requests botox every six months.” Pneumatic dilation. Serial graded dilations improve symptoms in up to 90% of patients, and the results are comparable to that of a surgical Heller myotomy in patients with achalasia subtype 2 and likely type 1. Dr. Schnoll-Sussman offers pneumatic dilation for patients with types 1 and 2 achalasia who are fit enough for surgery but don’t want it. “The two most important things to consider with pneumatic dilation are clinical expertise and the availability of surgical back-up,” she said. “We are always nervous about perforations in these patients; but when you look at the data, in the hands of experienced [endoscopists], the perforation rate is very low, about 1% to 2%.” POEM. The procedure is a natural orifice transluminal endoscopic surgery (NOTES) approach to the Heller myotomy. “It combines the minimal invasiveness of an endoscopic treatment with the durability of laparoscopic Heller myotomy, which, when performed at high-volume centers, can have efficacy as high as 60% to 70% as far out as 15 to 20 years,” said Stavros N. Stavropoulos, MD, chief of endoscopy at Winthrop-University Hospital, in Mineola, N.Y. To perform a POEM procedure, the surgeon or endoscopist injects saline into the esophageal mucosa, then makes a small incision in the mucosa with an electrical endoscopic submucosal dissection (ESD) knife. The clinician inserts the endoscope into the submucosa through the hole and dissects a tunnel within the submucosa down to the gastric cardia. The clinician then returns the endoscope to about 3 cm beyond the mucosotomy and performs a myotomy. After the endoscope is withdrawn, the entrance to the tunnel is closed with clips. Worldwide, POEMs are performed by both surgeons and gastroenterologists, but the first POEMs done in the United States, when the technique made its debut

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

in 2009, were performed by a gastroenterologist—Dr. Stavropoulos. POEM is growing rapidly in this country, with both gastroenterologists and surgeons performing the procedure now, albeit with a slight preponderance of surgeons. Dr. Stavropoulos’s POEM series, currently the largest Western single-operator series, has shown good outcomes for most patients, despite inclusion of a large number of technically challenging and highrisk patients, he said. A word practitioners often used to describe POEM is “elegant,” which may explain some of the interest that U.S. endoscopists have in learning the procedure. But it is not particularly easy to learn, for several reasons. Proficiency hinges on facility with ESD, which is more commonly performed in places with a high incidence of early gastric cancer, such as Japan, where POEM was first performed in people in 2008.

not be the best procedure for any given patient. A major concern is the risk for gastroesophageal reflux disease associated with POEM. “Achalasia patients tend not to be very symptomatic with acid reflux,” Dr. Stavropoulos said. “In fact, most of our POEM patients have great clinical response, and therefore do not see the utility of additional tests or procedures. However, we know that objective testing is critical, so we were able to convince 52 patients to come back for endoscopy and pH studies.” Dr. Stavropoulos’s team

found that 32% of post-POEM patients had reflux esophagitis, and 33% had a positive pH study. Regarding the broader impact of POEM, Dr. Stavropoulos said it was much more than a technical advance restricted to the niche of rare esophageal motility disorders. He sees POEM revolutionizing adoption of ESD in the United States and spawning many NOTES procedures using the submucosal tunnel technique, such as pyloromyotomy for gastroparesis and

‘We’re not at a point where we can say every patient should be offered a POEM. There is variability in the way people are trained, in the way it’s performed, in the length of the myotomy and in whom it’s offered to—these are all important things to consider.’ —Felice Schnoll-Sussman, MD

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“We don’t often see lesions like that here, so the ability to gain training in one of the essential components for POEM is a lot different for U.S. endoscopists,” Dr. Schnoll-Sussman said. Furthermore, achalasia is relatively rare, and it may be a challenge to perform the procedure often enough to attain proficiency. Dr. Stavropoulos’ team undertook a complex study to define the POEM learning curve, and determined that an operator experienced in ESD required 40 cases to achieve competence in POEM and 60 cases to achieve mastery. “We’re not at a point where we can say every patient should be offered a POEM,” Dr. Schnoll-Sussman said. “There is variability in the way people are trained, in the way it’s performed, in the length of the myotomy and in whom it’s offered to—these are all important things to consider.” Even in the best hands, POEM may

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full-thickness endoscopic removal of gastrointestinal tumors. “With POEM, gastroenterologists are learning to linger in the previously taboo spaces of the mediastinum and peritoneum. In the very precise, standardized steps of POEM, they get increasingly confident with managing insufflationrelated complications and closing large perforations—the essential skills for NOTES,” he said. “POEM opens the door to a whole new world of NOTES interventions and POEM offshoots.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Prep continued from page 1

The quality of bowel preparation is notoriously variable, and experts agree that there’s substantial room for improvement in the practice. Dilip Bearelly, MD, assistant professor of clinical medicine at the University of Missouri, in Columbia, and his colleagues started investigating alternative modes of patient education when they observed inadequate preparation in an unacceptable number of their patients. “There seemed to be an opportunity to do things differently,” said Dr. Bearelly, who presented his group’s findings at the 2014 meeting of the American College of Gastroenterology (abstract P1810). Dr. Bearelly and his colleagues randomized 298 individuals scheduled for screening colonoscopy to receive either the practice’s usual written instructions, or to receive the paper handout plus an instructional video (right). The 11-minute video—burned on a disk—covers the same instructions as the written materials, but in an interactive format that depicts a typical patient asking questions of one of the practice’s doctors. The quality of bowel preparation between the two groups differed significantly (P=0.0098). Cecal intubation was 96% in the intervention group compared with 89% in the control group, and the adenoma detection rate was 53% and 42% in the two groups, respectively. Patients in the intervention group had a Boston Bowel Preparation Score (BBPS) of 6.99±1.87, whereas those in the control group had a score of 6.43±2.54, although the difference was not statistically significant. A BBPS of 6, with a minimum of 2 in each segment, was considered adequate. “We used 6, rather than 5, because physicians are not comfortable with any segment being less than 2,” Dr. Bearelly explained. “You can’t assume there are no polyps in one segment [where visibility is poor] just because you can see the other segments.” Although patients who viewed the instructional video fared better in their bowel preparation, they did not receive more or different instruction from those who had not. “The information in the video was the same as the information in the paper. We think the key was using examples of what the impact [of quality bowel preparation] would be and why it’s important to have a clean colon,” Dr. Bearelly said. A cost analysis of the intervention showed most of the expense was related to developing and mailing the video. “If this video was developed once and made

available by social media, there would be virtually no cost associated with it,” Dr. Bearelly said. The researchers concluded that their study, along with others, emphasizes the importance of presenting patients quality instructions in easy-to-understand formats, but that the value of direct communication by a provider cannot be underestimated. David Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School, in Norfolk, commended the Missouri researchers for their study. “About 25% of colonoscopies are believed to be inadequate because of poor bowel preparation,” he said. “Doctors tend to blame the patient, but the patient says, ‘I did everything you told me to.’ We need to find a way to move the bar on that 25%.” According to guidelines compiled by the U.S. Multi-Society Task Force on Colon Cancer, of which Dr. Johnson is a member, health care providers should give both oral and written instructions and ensure that the proper supports are in place to help patients achieve optimal preparation. “This navigation tool is an example of that concept, and its success is demonstrated by the clinical results,” Dr. Johnson said. “But it would be inappropriate to say that [video] is the best media. There is variation in patient acceptance and interpretation,” he continued. “Some may respond better to a video, some to a written instruction, some to being called by a nurse who goes over instructions with them the day before.”

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Is ‘Resect and Discard’ Gaining Acceptance? BY CAROLINE HELWICK

or diminutive polyps, is “resect and discard” ready for widespread use, or are there too many unknowns for clinicians to adopt the approach in their practices? According to colonoscopy expert Douglas K. Rex, MD, the concept is safe, rational and cost-saving, and the approach should move forward, although GI pathologist Robert H. Riddell, MD, argued for a more cautious approach. The two spoke on the subject at Digestive Disease Week 2014. Dr. Rex is Distinguished Professor of Medicine at Indiana University School of Medicine, and director of endoscopy at Indiana University Hospital, both in Indianapolis. Dr. Riddell is head of the Sections of Gastrointestinal Pathology and Immunopathology, and professor of laboratory medicine and pathobiology, at the University of Toronto, in Ontario, Canada.

Elements of New Approach

More importantly, interobserver variability is high, an observation that has led some post-polypectomy guidelines to not include villous elements and dysplasia as stratifiers of risk. Furthermore, cancer is rare in polyps 5 mm or smaller, Dr. Rex added, and on this point, the literature and “our day-to-day, and year-to-year experience” are consistent. For computed tomography colonography, the presence of polyps that size is not even reported, he said.

Clearing the Colon Is Most Important What determines outcomes, Dr. Rex emphasized, is not so much the histology of a tiny polyp, but how well the colon is cleared. “What is almost certainly less important is whether the diminutive polyp has highgrade dysplasia or villous elements, and whether it is hyperplastic or sessile serrated,” he said.

autofluorescence as adequate for the everyday application of resect and discard. “But recently, we have seen studies suggesting that PIVI criteria are not met by endoscopists in community practices,” Dr. Rex acknowledged (Ladabaum U, et al. Gastroenterologyy 2013;144:81-91; Schachschal G, et al. Gutt 2014;63:458-465). He suggested that the endorsement of PIVI by societies and a means of credentialing performance may be needed for resect and discard to move forward. “Perhaps, in reality, what we most need is motivation,” Dr. Rex added. “What happens in clinical practice often depends on the reimbursement environment, and we may need reimbursement for endoscopic interpretation. A bundled payment approach that includes the cost of pathology may make resect and discard more attractive. I believe resect and discard can, and should, go forward, and that widespread acceptance will occur when financial incentives are aligned.”

‘A cost analysis suggests this approach

Too Many Unknowns “Resect and discard” refers to a leads to substantial savings, as much as practice in which polyps less than Dr. Riddell responded that resect and $1 billion per year in the United States.’ a certain size threshold—in the discard transfers the diagnosis of colorec—Douglas K. Rex, MD United States, 5 mm or smaller— tal cancer from the pathology lab to the are evaluated during colonoscopy endoscopy suite, making it in effect a by narrow-band imaging or another point-of-care test. “Point-of-care tests modality. The clinician determines are tightly regulated,” he said. the probable diagnosis, and assum“How will we guarantee the ing a high level of confidence, he or universal quality of this test?” ‘How will we guarantee the universal quality she may choose to resect and disDr. Riddell asked. “Will each card the lesion instead of sending endoscopy unit need to be of this test? Will each endoscopy unit need the tissue to the pathologist. accredited? Will each endosto be accredited? Will each endoscopist The resect and discard concopist need to demonstrate his need to demonstrate his or her own diagnostic cept seeks to reduce expenditures or her own diagnostic compecompetence? How will this be done?’ by eliminating unnecessary testtence? How will this be done? ing when the diagnosis is certain, What will be the cost of this? —Robert H. Riddell, MD reserving the lab for uncertain diagHow will we prove maintenance noses, Dr. Rex said. “A cost analyof competence? If you argue that this sis suggests this approach leads to approach will not need accrediting, you substantial savings, as much as $1 billion per year in the In view of these considerations, the American may find opposition from the College of United States in one study [Kessler WR, et al. Endoscopy Society for Gastrointestinal Endoscopy established American Pathologists, clinical laboratories 2011;43:683-691],” he said. its PIVI (Preservation and Incorporation of Valuable and other bodies.” Dr. Rex argued that resect and discard is now sup- endoscopic Innovations) goals: Discarding polyps below Guidelines are in place because of the need to preported by evidence. Polyp differentiation, which is 5 mm with high confidence, along with sending low- cisely know the pathology of colorectal lesions and to central to the strategy, can be learned by motivated confidence diminutive polyps and those under 5 mm to be able to identify those containing invasive carcinoma, endoscopists. Pathology reports are not always reliable. pathology, is associated with more than a 90% agreement which often is not obvious, because size is not a perfect And adoption of the approach will result in huge cost with surveillance intervals established by pathology. The indicator, Dr. Riddell pointed out. There are also rare savings. The endoscopist can be confident about deter- second concept in PIVI is that diminutive hyperplas- instances when the unexpected occurs. mining the presence or absence of cancer and differen- tic polyps can be left in place if the negative predictive “There are less common things that can easily be tiating between conventional or serrated adenomas. The value for adenomas exceeds 90%. This approach is cost- missed by this technique,” Dr. Riddell said, for example, pathologist typically determines whether cancer is pres- effective, he reiterated. neuroendocrine polyps in the rectum, metastatic carcient and evaluates histology, but not all this information The confidence of the endoscopist cannot be overem- nomas presenting as small polyps, and lymphomas and is reliable, he maintained, especially the degree of dyspla- phasized, if cost-effectiveness is to be demonstrated, Dr. melanomas in the gastrointestinal tract. sia and the presence of villous elements in conventional Rex added. “When your pretest probability is extremely “Can we assume that all these variants really do get adenomas, and the differentiation between hyperplastic high for the diagnosis,” he said, “ordering a confirmatory picked up and sent to pathology?” he asked. “Throwing and sessile serrated polyps among serrated lesions. test is money that is wasted.” these away is not without its consequences.” Dr. Rex said he also is concerned about the lack of Dr. Riddell also offered a few “intangibles,” asking the standard definitions to describe the degree of dysplasia Can Targets Be Met? gastroenterologists in attendance, “Are you comfortable in conventional adenomas and what distinguishes a sesThe use of appropriate imaging techniques can help with never knowing what you are dealing with? And are sile serrated polyp from one that is hyperplastic. endoscopists meet the PIVI goals, according to numer- you happy having your own polyps thrown out?” That’s a “moving target,” he said. “We recently discov- ous studies and two recent meta-analyses (Wanders LK, Dr. Rex has financial relationships with American BioOpered for sub-centimeter polyps, even expert pathologists et al. Lancet Oncoll 2013;14:1337-1347; McGill SK, et al. tics, Boston Scientific, Braintree Laboratories Inc, Checkwere not necessarily using the same definition for high- Gutt 2013;62:1704-1713) that have established narrowCap, EndoAid, Epigenomics, Exact Sciences, grade dysplasia in conventional adenomas [Lasisi F, et band imaging, I-Scan, flexible spectral imaging color Given Imaging and Olympus America. Dr. Riddell has a al. Dig Liver Diss 2013;45:1049-1055].” enhancement (FICE), confocal laser microscopy and commercial interest in Santarus.

GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Calcium Absorption Plunges After Gastric Bypass, Study Shows BY ROSEMARY FREI, MSC

alcium absorption appears to decline precipitously after gastric bypass surgery, according to a new study, suggesting that people who undergo the procedure may need to boost their intake of the nutrient. The study showed a decline in average fractional calcium absorption (FCA) from normal levels, of 33% at baseline to 7% six months after surgery. This drop occurred despite the fact that patients had optimized levels of 25-hydroxyvitamin D, which facilitates calcium absorption in the small intestine. Bone mineral density also decreased significantly, although the reduction was not significantly correlated with the fall in FCA. “The skeleton of the gastric bypass patient experiences mechanical unloading with weight loss, as well as hormonal and nutritional changes,” said Anne Schafer, MD, assistant professor of medicine at the University of California, San Francisco, who led the study. “The dramatic decrease in calcium absorption—with corresponding increase in parathyroid hormone and bone turnover marker levels that we also observed in our study—is part of this big picture,” Dr. Schafer said. Dr. Schafer’s group presented their findings at the 2014 annual meeting of the American Society for Bone and Mineral Research. The study involved 33 men and women who were scheduled for Roux-en-Y gastric bypass. The patients had an average age of 45 years and a mean body mass index of 45 kg/m2. All participants received 1,200 mg per day of calcium in the form of chewable supplements. Six months after surgery, the patients had lost an average of 26% of their preoperative weight. Furthermore, their FCA dropped by an average of 26%. The mean 25-hydroxyvitamin D level remained relatively stable through supplementation, decreasing from 42 to 36 ng/mL. The patients with the highest percentage weight loss at six months’ follow-up had the largest reductions in FCA. This finding was independent of age, sex and race. Bone mineral density as measured by x-ray imaging fell by 4.9% at the femoral neck (P<0.01) and by 4.4% at the total hip (P<0.01). Mean levels of parathyroid hormone increased from 46 to 52 pg/ mL (P=0.01). P In addition, mean levels of serum C-terminal telopeptide—a marker of bone resorption—rose from 0.292 to 0.975 ng/mL (P<0.01), and patients with the greatest increases had lower FCA (P<0.01) after surgery. Bone mineral density did not fall with FCA—a finding stressed by Arvinpal Singh, MD, medical director of Emory

Bariatric Center, in Atlanta, who was not involved in the study. What’s more, FCA is known to decrease with increasing calcium intake—meaning it might be premature for physicians to start counseling patients to consume more calcium. “Either six months isn’t long enough to see an association between decreased FCA and decreased bone mineral density post-op, or there may be other variables involved,” Dr. Singh said. “Many would

argue that bone health or bone mineral density is more a product of calcium homeostasis/balance than calcium intake, and several factors may be playing a role in this population. Of course, exercise improves bone density and reduces the resorption of calcium from the bone,” he added. “Sodium, sodas, caffeine, smoking and excess protein increase calcium resorption from bone and promote loss of calcium from kidneys.”

Dr. Schafer acknowledged those factors, but said she remained concerned about the implications of the reduction in calcium. “I worry about its longterm effects on bone health,” she said. “Our results suggest that gastric bypass patients may need higher calcium intakes to prevent perturbations in calcium homeostasis, although the specific approach to calcium supplementation needs to be established.”

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Eat Some Lettuce and See Me in the Morning: The Endless Search for Pain Relief BY A.J. WRIGHT

ne constant throughout human history, unlimited by time or place, has been the search for pain relief. We have reached a point in the modern world where anesthetics, narcotics, over-the-counter pain relievers, etc., can give some measure of comfort in many painful situations. Yet, the search for improvement continues in neuroscience and pharmacology. The discovery, in the 1840s, that ether and chloroform vapors could offer significant pain relief during surgery enabled development of the idea in the West that pain did not always have to be endured. Yet, a vast literature created over the centuries and around the world documents earlier, less successful efforts at pain relief. Contemporary research in ancient and medieval manuscripts continues to uncover medical practices from cultures around the world, including recipes for treatments of many types of pain. Although published in 1946, Edgar S. Ellis’ book “Ancient Anodynes: Primitive Anaesthesia and Allied Conditions” is an excellent overview of the field. He covers pain relief by physical, psychological, inhalation and local methods. He cites many examples from the past: biological materials such as the poppy, belladonna, cannabis, hellebore, hemlock, garlic, curare and mandrake; various uses of alcohol; inhalation of different substances and mixtures; and snow or cold water. One interesting effort that Ellis notes is the “sleeping apple,” a ball made of a mix of substances and described by authors ranging from the Roman physician Dioscorides in the first century A.D. to Italian scholar Giambattista della Porta in the 17th century. As he catalogs this enormous number of pain relief methods, Ellis often expresses his skepticism about their efficacy. Perhaps many had placebo value. A method similar to the sleeping apple was the “soporific sponge,” or spongia somnifera. The sponge contained a mixture of herbals and was placed over the patient’s face or under the nostrils prior to surgery. Inhalation of the fumes allowed painless surgery while the patient was unconscious. Herbs used included poppy, hemp, henbane and mandragora. Recipes for this method from the Arab world date back to the 11th century; others appeared in Italy, Germany and Spain into the 16th century. The earliest known example is from the Bamburg Antidotarium of the ninth century. This collection of medical recipes contains a very specific one for the sponge. Ingredients included an ounce of opium, eight ounces

The path of burning pain from René Descartes, L’homme [1664] Source: National Library of Medicine

Two works by George Cruikshank, “The Headache” and “The Cholic,” ca. 1835. Source: National Library of Medicine

of mandrake leaf juice, three ounces of henbane juice, and green juice from hemlock. Mixed with an appropriate amount of water, this concoction soaked into a sponge that was allowed to dry. When needed, the sponge could be re-soaked in warm water for an hour, and was then ready to be placed under a patient’s nostrils for pain relief. Sleeping potions of various kinds found their way into medieval and Renaissance literature, as well. Boccaccio’s “The Decameron,” Shakespeare’s “Othello” and “Antony and Cleopatra,” Marlowe’s “The Jew of Malta” and “The Arabian Nights,” among others, feature such plot devices. How widely they were actually used in medicine remains unknown. For instance, the great 16thcentury French surgeon Ambroise Paré did not use any such pain-relieving methods. One would imagine that the spread of the recipe books throughout Europe during these centuries would have alerted physicians to the sponge and other pain relievers, if they had been truly effective. In 1847, the Lancet published an abstract of an article by a French physician named Dauriol, who claimed to have used a sponge recipe to achieve surgical anesthesia. In 1888, British physician Benjamin W. Richardson used a mandrake–alcohol mix for experiments on pigeons, rabbits and his own lips, noting a gentle sleep in the animals—unless too high a dose produced death. Scopolamine and other alkaloids in the plant no doubt

helped produce the effects that he noted. Medical historian Plinio Prioreschi is a modern-day researcher who expressed skepticism about the sponge’s effectiveness in producing anesthesia for surgery, in a 2003 article in Medical Hypotheses. In their research in Old and Middle English scientific and medical manuscripts, Linda Voigts and Patricia Kurtz found some 40 anesthetic recipes. Thirteen of them apparently had limited circulation due to what must have been recognized as their dangerous ingredients. However, they found 27 examples of a brief recipe for “a drynke that men callen dwale to make a man to slepe whyle men kerven him.” In their book chapter, Voigts and Robert P. Hudson note that the word “dwale” could mean several things in Middle English: deception or delusion; a dazed or unconscious condition; a fool; the nightshade plant; or a soporific drink. The last meaning is used by Chaucer in “The Reeve’s Tale.” The drink recipes are fairly consistent across the examples that the researchers found. Ingredients included swine gall, hemlock juice, wild nept, lettuce, poppy, henbane and vinegar. After boiling, the mixture could be stored until needed, after which three spoonfuls were to be mixed with a gallon of wine. The authors’ discussion of these ingredients, and the relationship of this recipe to others, is fascinating. An example of a surgical anesthetic used in Japan well before 1846 has

become well known in the West in recent decades. Seishu Hanaoka was a surgeon born in 1760 and died in 1835. Hanaoka improved herbal recipes for pain relief that came from China to the point where he was able to use the oral anesthetic in major surgeries. His formula is known as Tsusensan: two main ingredients were mandarage of the Datura genus and Aconitum japonicum. The patient drank the hot liquid, and in two to four hours was ready for surgery. The effects lasted six hours or longer depending on the dose. Hanaoka left records of dozens of surgeries, including many for breast cancer. His illustrated “Surgical Casebook” is available on the U.S. National Library of Medicine’s website (www.nlm.nih.gov). As with so many things, we tend to look at past efforts at pain relief with amusement. Yet, many of these recipes contained active ingredients recognized much later. Visitors from the past would no doubt be amazed at what we moderns can do to relieve pain, and they could easily appreciate our continuing efforts to find even better methods than we have now.

Additional Reading Bergman NA. Anesthetics of the ancients. In: Bergman NA. The Genesis of Surgical Anesthesia. Schaumburg, IL: Wood LibraryMuseum of Anesthesiology; 1998:1-28. Voigts LE, Hudson RP. A surgical anesthetic from late medieval England. In: Campbell SD, et al. Health, Disease, and Healing in Medieval Culture. New York, NY: St. Martin’s Press; 1992:34-56.

A.J. Wright is a librarian in the anesthesiology department at the University of Alabama at Birmingham.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Hydroxyethyl Starch Linked to AKI in Liver Transplant Patients BY MICHAEL VLESSIDES MONTREAL—Patients undergoing orthotopic liver transplant who receive 6% hydroxyethyl starch (HES) have an increased risk for acute kidney injury (AKI) compared with those who receive 5% albumin. Researchers recommended that the starch derivative not be used in this patient population. “Back in 2010, our Pharmacy and Therapeutics Committee recommended that we transition from albumin to hydroxyethyl starch for all surgical procedures,” said Joseph Whiteley, DO, assistant professor of anesthesiology at the Medical University of South Carolina, in Charleston. “However, a recent study [N Engl J Medd 2012;367:1901-1911] found an association between the colloid and acute kidney injury. Given that kidney injury following liver transplantation is a very common complication, this retrospective study was our attempt to gauge whether hydroxyethyl starch does, indeed, lead to increased postoperative acute kidney injury in this patient population.” Dr. Whiteley and his colleagues performed a retrospective, cross-sectional

analysis of the institution’s electronic anesthesia records, surgical dictations and perioperative laboratory records. Postoperative AKI was determined by the RIFLE criteria (i.e., risk, injury, failure, loss and end-stage renal disease). AKI was classified one of three ways—risk, injury or failure—based on change in serum creatinine from preoperative baseline to peak level by postoperative day 7. As Dr. Whiteley reported at the 2014 annual meeting of the International Anesthesia Research Society (abstract S-132), the records of 174 orthotopic liver transplant patients were reviewed. Of these, 50 received only 5% albumin, 25 received both albumin and HES, and 99 received only HES. There was a statistically significant association between the type of colloid administered and AKI. Indeed, patients who received HES were three times more likely to develop AKI within seven days of surgery than their counterparts who received albumin (adjusted odds ratio, 2.94; 95% confidence interval, 1.13-7.7; P=0.027). The linear association between P any colloid use and the development of AKI was statistically significant (P=0.048). P

No difference was found in 30-day mortality between the three groups. “The way we administer colloids at our institution is largely protocol-driven,” he explained. “We use arterial waveform analysis to determine fluid responsiveness to hypotension. We all keep central venous pressure at around 10. We try to keep hematocrit levels between 24 and 30. So we are all pretty uniform how we treat these patients.” James Findlay, MBChB, director of liver transplant anesthesia at Mayo Clinic, in Rochester, Minn., was not surprised by these findings, given recently

published trials and meta-analyses that demonstrate an association between the use of HES for resuscitation in ICU patients and renal injury. “The ICU studies also suggest an increased mortality with the use of hydroxyethyl starch; although this was not a finding in Dr. Whiteley’s study, I would be concerned that the renal injury reported could translate into worse outcomes in larger series of patients,” he said. “With the available evidence, I don’t think the continued use of hydroxyethyl starch is justified in liver transplantation. If colloids are required, I’d favor using 5% albumin.”

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GASTROENTEROLOGY & ENDOSCOPY NEWS • NOVEMBER 2014

Participation Low for Trials in Lung Cancer, CRC BY TED BOSWORTH CHICAGO—Only about 25% of patients receiving chemotherapy for advanced lung or colorectal cancer participate in a discussion about the option of entering a clinical trial, according to a survey of a large sample of patients. Of those who have that discussion, less than 30% enroll. Low rates of participation in clinical trials have been reported before, but data from a survey presented at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 6509) suggest that clinicians may carry much of the responsibility. The data were presented by Kenneth L. Kehl, MD, now an oncology fellow at the University of Texas MD Anderson Cancer Center, in Houston, who initiated this work under the direction of Nancy Keating, MD, associate professor of health care policy at Harvard Medical School, in Boston. According to the data, the vast majority of patients depend on clinicians to hear about trials. Specifically, more than 90% of those who decided to participate in a clinical trial first heard of the opportunity from a health care provider. Notably, that participation was much greater among patients who characterized decision making in their cancer care as shared or patient-controlled, rather than physician-controlled. The survey was conducted through the Cancer Care Outcomes Research and Surveillance (CanCORS) consortium, which has assembled a nationally representative population at participating

By the numbers Trial participation rates low for late-stage lung and CRC patients.

74.3% Did not discuss clinical trial

25.7% Discussed clinical trial

7.6% Participated in clinical trial

centers across the United States. Of the 7,887 patients with lung and colorectal cancer who were asked if they participated in a discussion of clinical trials, only 1,114 (14.1%) responded affirmatively. Among the 2,173 patients treated with chemotherapy for stage III or IV disease, the proportion rose to 25.7%, of which less than one-third enrolled. A multivariate analysis found that a college education and an income greater

than $60,000 nearly doubled the likelihood of having a discussion about trial participation. A significant inverse relationship existed between the likelihood of participating in a discussion about a trial and increasing age, and participation in such discussions was significantly lower among minority ethnic groups as well. Despite these differences, once the discussion occurred, none of these factors affected participation in trials.

The main implication of this study is that clinicians need to take the lead in introducing the option of a clinical trial when the limitations of standard therapies are well known. Dr. Kehl emphasized the “underlying reality that before a patient enrolls in a clinical trial, he or she must first learn about the possibility.” Drs. Kehl and Keating reported no relevant financial relationships.

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REPORT Probiotic Therapy in the Management of Common Gastrointestinal Conditions disorders. These beneficial bacn increasing appreciation Faculty terial preparations are known as of the relationship between Darren Brenner, MD probiotics—defined by the Food the intestinal microenvironment, Assistant Professor in Medicineand Agriculture Organization and the endogenous intestinal bacthe World Health Organization as terial flora, and gastrointestinal Gastroenterology, Hepatology, and Surgery “live microorganisms which when (GI) health and disease has led Northwestern Feinberg present in adequate amounts to the investigation of the theraSchool of Medicine confer health benefits on the peutic potential of orally ingested Chicago, Illinois host.”5 Most probiotic micropreparations of exogenous bacteria (probiotics). organisms belong to a group This monograph provides a brief overview of this topic of lactic acid–producing bacteria, such as Lactobacillus and reviews clinical experience with the use of probiotand Bifidobacterium, or yeasts, such as Saccharomyces.6 ics in the treatment and prevention of diarrheal illnesses. These bacteria produce lactic acid through anaerobic digestion of saccharides, and can tolerate fluctuations in temperature and low pH environments; thus, this affords Overview of Intestinal Flora and them the ability to withstand the acidic milieu of the stomProbiotics ach and allows for transient colonization of the GI tract.7 The human GI system is home to a diverse array of Today, most probiotics are available or consumed as b t i Major bacteria. M j functions f ti off the th gutt microflora i fl include i l d di t dietary supplements l t or fermented f t d products. d t 8 metabolic activities that result in salvage of energy and The field of probiotics is associated with a number of absorbable nutrients, important trophic effects on intescommon misconceptions. The more general term probitinal epithelia and on immune function, and protection otics encompasses a large variety of products that difof the colonized host against invasion by pathogenic fer by the strains of bacteria or yeast included, dose, and/ microbes (Figure).1-4 Alteration in the intestinal microenvior delivery vehicle.9 There is a strain-specific relationship ronment and microflora can occur for a variety of reasons, between the probiotic chosen and its potential for elicitincluding antibiotic use, and can result in disruptions in ing a response for a particular health benefit.9 Despite the normal intestinal function as well as overgrowth of pathorange of potential health benefits observed with probiotics, genic microorganisms and subsequent infection.3 the effects described can only be attributed to the strain or strains tested, and not to probiotics as a whole. For this reaInsight into the role of intestinal flora in maintaining GI son consulting published literature and selecting the proper health has led to the recognition that oral administration organism for the desired health benefit is important. Prodof some types of exogenous bacteria can promote intesuct labeling should clearly define the strains included in a tinal homeostasis, as well as treat and prevent intestinal

REPORT specific probiotic product. In addition, some may feel that where some is good, more is better.9 This is not the case with probiotics; more is not necessarily better. Prevailing research states that patients should be directed to the dose that has been studied in published literature.10

Clinical Experience With Probiotics Clinical studies have investigated the use of probiotics in the prevention and treatment of various GI conditions including infectious diarrhea, travelers’ diarrhea, antibiotic-associated diarrhea, Clostridium difficile–associated diarrhea, and irritable bowel syndrome.

Infectious Diarrhea Acute infectious diarrhea is characterized by defecation 3 or more times per day or at least 200 g of stool per day lasting less than 14 days and may be accompanied by nausea, vomiting, abdominal cramping, systemic symptoms, and malnutrition.11 In the United States, the bacterial pathogens responsible for the most cases of diarrhea include Salmonella, Campylobacter, Shigella, Escherichia coli, and viral infections, whereas cases caused by Vibrio, Yersinia, Listeria, Cyclospora, and other bacteria are less common.11,12 An estimated 99 million episodes of acute diarrhea, 8 million doctor visits, and 250,000 hospitalizations occur each year.13 Multiple studies have demonstrated the benefit of certain strains of probiotics in the treatment of acute infectious diarrhea. A meta-analysis of data from 1,306 individuals in 11 randomized controlled trials (RCTs) showed that Saccharomyces boulardii reduced the duration of diarrhea by approximately 24 hours and reduced hospital length of stay by approximately 20 hours.14 Furthermore, adverse effects (AEs) associated with S. boulardii were not reported in any of the trials.14 Another meta-analysis of 56 studies of acute infectious diarrhea in adults and children evaluated multiple strains of S. boulardii, Lactobacillus rhamnosus, and L. acidophilus; the use

of probiotics resulted in a roughly 24-hour decrease in the duration of diarrheal illness.15-17 There was also evidence of a decreased risk for diarrheal illness lasting 4 days or more (relative risk [RR], 0.41) and a reduction in stool frequency by day 2. Of the 43 studies that provided AE data, no significant AEs were identified.17 Based on these data, the investigators concluded that probiotics were safe and have clear benefit in terms of shortening the duration and reducing stool frequency in acute infectious diarrhea.17 Other studies have investigated whether probiotics also have a primary or secondary preventative effect against acute infectious diarrhea. Sur and colleagues studied 3,758 asymptomatic children in India, who received a 12-week course of L. casei Shirota or placebo with an additional 12 weeks of follow-up.18 Overall, 674 children who received placebo developed diarrhea compared with 608 receiving the probiotic. This resulted in a probiotic protective efficacy ([1-hazard ratio] ×100) of 14% and a number needed to treat (NNT) of 14.18 Another group studied the efficacy of probiotics in the prevention of nosocomial diarrhea in hospitalized patients. Hojsak and colleagues conducted a randomized, double-blind trial of L. rhamnosus GG or placebo in 742 hospitalized children.19 Probiotic therapy resulted in a reduced risk for gastroenteritis (RR, 0.40), vomiting episodes (RR, 0.5), and episodes of GI infections lasting more than 2 days (RR, 0.40).19 Children in day care centers often are exposed to pathogens that confer an increased risk for infectious diarrhea. Various studies have been conducted to investigate the efficacy of probiotics in the prevention of acute infectious diarrhea in this population. In a meta-analysis of over 1,100 participants, all probiotics tested were found to be safe. Strains of Bifidobacterium lactis, Streptococcus thermophilus, L. reuteri, L. rhamnosus, and L. acidophilus have been studied in this population; their efficacy in preventing diarrheal episodes in infants and children attending day care centers was only modest.20 Finally, probiotics also might have efficacy in the secondary

Figure. General therapeutic mechanisms of probiotics for enteric infections. B, B cell; DC, dendritic cell; IEC, intestinal epithelial cell; M, M cell; MAC, macrophage; T, T cell; TJ, tight junction Reprinted from Gastroenterology 140/1, Predis GA, Hill C, Guerrant RL, et al. Probiotics, enteric and diarrheal diseases, and global health, pages 8-14, Copyright 2001, with permission from Elsevier.

REPORT prevention of acute infectious diarrhea. For example, Billoo and colleagues have shown that children receiving a 5-day treatment course with S. boulardii following an acute infection experience a 50% reduction in rates of recurrent diarrheal episodes over the subsequent 2-month period.21

Travelers’ Diarrhea Travelers’ diarrhea (TD) is a subset of acute infectious diarrhea defined as acute diarrhea acquired by persons during international trips—this usually occurs during visits to developing countries. TD may occur in 20% to 50% of international travelers and is frequently caused by a bacterial pathogen, such as enterotoxigenic E. coli.22,23 In a meta-analysis of 12 RCTs and over 5,000 participants, primarily studying Lactobacillus species and strains such as L. rhamnosus GG. McFarland reported that probiotic therapy resulted in a significant reduction in the risk (RR, 0.85) for TD.24,25

Antibiotic-Associated Diarrhea Antibiotic-associated diarrhea is defined as otherwise unexplained diarrhea that occurs in association with the administration of antibiotics. Depending on the antibiotic or antibiotics used, the frequency of this complication ranges from 2% to 25% among patients taking a single antibiotic, and up to 43% among patients taking a combination of antibiotics.26,27 In a Cochrane meta-analysis of nearly 2,000 individuals from 10 RCTs, the most commonly studied probiotic was S. boulardii. Probiotic therapy resulted in a significant reduction in the incidence of antibiotic-associated diarrhea (RR, 0.49).28,29 Furthermore, the efficacy of probiotics in the prevention of antibiotic-associated diarrhea varies with dosage. In a study of 255 adult inpatients, those receiving 2 probiotic capsules per day of 50 billion colony-forming units (CFU) of live organisms (L. acidophilus CL1285 + L. caseii LBC80R Bio- K + CL1285) had a lower incidence of antibiotic-associated diarrhea (15%) than those who received only one capsule (28.2%) or those who received placebo (44.1%).30

Clostridium difficile–Associated Diarrhea C. difficile–associated diarrhea is due to overgrowth of toxinproducing C. difficile organisms and is sometimes classified as a subset of antibiotic-associated diarrhea. The incidence of this infection has increased markedly over the past decade, and can result in severe complications including bowel perforation and death.31,32 Because C. difficile is a spore-forming organism, it can be difficult to eradicate and is associated with a significant risk for recurrence.32 In a 2013 Cochrane review of 23 trials investigating 4,213 adult or pediatric patients receiving antibiotic therapy for any reason, probiotic prophylactic therapy was associated with a significant reduction in the subsequent development of C. difficile–associated diarrhea compared with the placebo group (2% vs 5.5%; RR, 0.36).33-35 The most commonly used probiotic strains were S. boulardii and L. rhamnosus GG. Probiotics also may offer promise as an adjunctive therapy for recurrent C. difficile infection. Indeed, one study demonstrated a significant reduction in recurrent C. difficile diarrhea with the addition of S. boulardiii 3 ×1010 CFU daily for 4 weeks versus the addition of placebo to conventional therapy (RR, 0.43).36 However, another study suggested that there was a significant reduction in recurrent C. difficile infection with S. boulardii (1 g/day; relative to placebo) only when used in combination with high-dose vancomycin (2 g/day; RR, 0.43).34

Irritable Bowel Syndrome Irritable bowel syndrome is a functional bowel disorder characterized by abdominal discomfort or pain associated with changes in bowel frequency and/or consistency.37 Two systematic reviews on the use of probiotics for the treatment of irritable bowel syndrome reported that it was difficult to draw conclusions on the efficacy of most probiotics tested due to suboptimal study designs. 38-40 However, 2 well-designed studies using Bifidobacterium infantis 35624 (1×108 CFU/mL) identified significant alleviation in abdominal pain/discomfort, bloating/distention, and/or bowel movement difficulty compared with placebo.41,42 Recently, the American College of Gastroenterology Task Force

Table. Third Yale Workshop Recommendations for Probiotic Use in Diarrhea-Associated Illness Effectiveness a

Specific Strain of Organism

Infectious (childhood)— treatment

Saccharomyces boulardii, LGG, Lactobacillus reuteri SD2112

Infectious—prevention

S. boulardii, LGG

AAD—prevention

S. boulardii, LGG, combination of Lactobacillus casei DN114 G01, Lactobacillus bulgaricus, Streptococcus thermophilus

Recurrent CDAD—prevention

B/C

S. boulardii, LGG, bacteriotherapy

CDAD—prevention

LGG, S. boulardii

Bifidobacterium infantis 35624, VSL#3

B. animalis, L. plantarum 299V

Clinical Condition Diarrhea

IBS

A: strong, positive studies in literature; B: positive controlled studies with presence of some negative studies not supporting primary outcome; C: some positive studies, but inadequate amount of work to establish certainty. AAD, antibiotic-associated diarrhea; CDAD, Clostridium difficile–associated diarrhea; IBS, irritable bowel syndrome; LGG, Lactobacillus rhamnosus GG

Reprinted from Floch MH, Walker A, Madsen K, et al. Recommendations for probiotic use—2011 Update. J Clin Gastroenterol. 2011;45(suppl):S168-S171, with permission. Based on references 41,42,44-52.

REPORT on IBS published its most recent meta-analysis and systematic review on probiotic use. In 35 RCTs, 3,452 patients were evaluated, and probiotics were shown to be beneficial in reducing overall symptoms, flatulence, abdominal pain, and bloating with a NNT of 7 for single strains and 8 for combination probiotics. The majority of the included studies used combination probiotics (19), while single-organism studies included strains of Lactobacillus (8) and Bifidobacterium (3).43

20. Guandalini S. J Clin Gastroenterol. 2011;45(suppl):S149-S153. 21. Billoo AG, Memon MA, Khaskheli SA, et al. World J Gastroenterol. 2006;12(28):4557-4560. 22. Caeiro JP, DuPont HL. Drugs. 1998;56(1):73-81. 23. Centers for Disease Control and Prevention. http://www.cdc.gov/ ncidod/dbmd/diseaseinfo/travelersdiarrhea_g.htm. Accessed October 7, 2014. 24. McFarland LV. Travel Med Infect Dis. 2007;5(2):97-105. 25. Hilton E, Kolakowski P, Singer C, et al. J Travel Med. 1997;4(1):41-43.

Conclusion

26. Wistrom J, Norrby SR, Myhre EB, et al. J Antimicrob Chemother. 2001;47(1):43-50.

Alterations in the intestinal microenvironment and endogenous flora play an important pathophysiologic role in many GI disorders. Probiotic therapies may promote intestinal health through multiple mechanisms of action and are proving useful in the management and prevention of various GI conditions. However, the benefits of probiotics are strain specific. The Third Yale Workshop has published recommendations for probiotic use in various clinical conditions, including specific probiotic strains and graded levels of evidence (Table).44-53 Furthermore, probiotic therapy is well tolerated with minimal or no adverse events demonstrated across clinical trials. Additional well-designed controlled studies are necessary to elucidate both the specific strains and dosages appropriate for the treatment of a spectrum of GI illnesses.

27. Bartlet JG. Antibiotic-associated diarrhea. Clin Infect Dis. 1992; 15(4):573-579. 28. Johnston BC, Supina AL, Ospina M, et al. Cochrane Database Syst Rev. 2007;(2):CD004827. 29. Kotowska M, Albrecht P, Szajewska H. Aliment Pharmacol Ther. 2005;21(5):583-590. 30. Gao XW, Mubasher M, Fang CY, et al. Am J Gastroenterol. 2010; 105(7):1636-1641. 31. Gupta A, Khanna S. Infect Drug Resist. 2014;7:63-72. 32. Mayo Clinic. http://www.mayoclinic.org/disease-conditions/c-difficile/ basics/definition/CON-20029664?p=1. Accessed October 7, 2014. 33. Goldenberg JZ, Ma SS, Saxton JD, et al. Cochrane Database Syst Rev. 2013;(5):CD006095. 34. Surawicz CM, McFarland LV, Greenberg RN, et al. Clin Infect Dis. 2000;31(4):1012-1017.

References

35. Rusczczynski M, Radzikowski A, Szajewska H. Aliment Pharmacol Ther. 2008;28(1):154-161.

1. Guarner F, Malagelada JR. Lancet. 2003;361(9356):512-519. 2. Gorbach SL. Galveston: University of Texas Medical Branch at Galveston; 1996. 3. Festi D, Schiumerini R, Birtolo C, et al. Dig Dis. 2011;29(6):518-524. 4. Predis GA, Hill C, Guerrant RL, et al. Gastroenterology. 2001;140(1):8-14. 5. Rastogi P, Saini H, Dixit J, et al. J Maxillofac Surg. 2011;2(1)6-9. 6. Sreeja V, Prajapati JB. Probiotics Antimicrob Proteins. 2013;5(2):81-91. 7. Sarowska J, Choroszy-Król I, Regulska-Ilow B, et al. Adv Clin Exp Med. 2013;22(5):759-766. 8. National Institutes of Health. http://nccam.nih.gov/health/probiotics/ introduction.htm. Accessed October 7, 2014. 9. World Gastroenterology Organization Global Guidelines. http:// www.worldgastroenterology.org/assets/export/userfiles/probiotics_ FINAL_20110116.pdf. Accessed September 26, 2014. 10. Kligler B, Cohrssen A. Am Fam Physician. 2008;78(9):1073-1078. 11. Thielman NM, Guerrant RL. N Engl J Med. 2004;350(1):38-47. 12. Crim SM, Iwamoto M, Huang JY, et al. MMWR. 2014;63(15):328-332. 13. Deshpande A, Lever DS, Soffer E. http://www.clevelandclinicmeded. com/medicalpubs/diseasemanagement/gastroenterology/acute-diarrhea/. Accessed October 7, 2014. 14. Dinleyici EC, Eren M, Ozen M, et al. Expert Opin Biol Ther. 2012;12(4): 395-410. 15. Htwe K, Yee KS, Tin M, et al. Am J Trop Med Hyg. 2008;78(2): 214-216. 16. Fang SB, Lee HC, Hu JJ, et al. J Trop Pediatr. 2009;55(5):297-301. 17. Allen SJ, Martinez EG, Gregorio GV, et al. Cochrane Database Syst Rev. 2010;(11):CD003048. 18. Sur D, Manna B, Niyogi SK, et al. Epidemiol Infect. 2011;139(6): 919-926. 19. Hojsak I, Abdovi S, Szajewska H, et al. Pediatrics. 2010;125(5):e1171-e1177.

36. McFarland LV, Surawicz CM, Greenberg RN, et al. JAMA. 1994; 271(24):1913-1918. 37. Longstreth GF, Thompson WG, Chey WD, et al. Gastroenterology. 2006;130(5):1480-1491. 38. Brenner DM, Moeller MJ, Chey WD, et al. Am J Gastroenterol. 2009;104(4):1033-1049. 39. Moayyedi P, Ford AC, Talley NJ, et al. Gut. 2010;59(3):325-332. 40. Quigley EM. J Clin Gastroenterol. 2008;42(suppl 2):S85-S90. 41. O’Mahony L, McCarthy J, Kelly P, et al. Gastroenterology. 2005; 128(3):541-551. 42. Whorwell PJ, Altringer L, Morel J, et al. Am J Gastroenterol. 2006; 101(7):1581-1590. 43. Ford AC, Quigley EM, Lacy BE, et al. Am J Gastroenterol. 2014 [Epub ahead of print]. 44. Floch MH, Walker WA, Madsen K, et al. J Clin Gastroenterol. 2011; 45(suppl):S168-S171. 45. Guandalini S, Pensabene L, Mona Z, et al. J Ped Gastroenterol Nutr. 2000;30(1):54-60. 46. Szajewska H, Skorka A, Dylag M. Ailiment Pharmacol Ther. 2007; 25(3):257-263. 47. Surawicz CM. J Clin Gastroenterol. 2008;42(suppl 2):S64-S70. 48. Doran SI, Himmerd PL, Gorbach SL. J Clin Gastroenterol. 2008; 42(suppl 2):S58-S63. 49. Hickson M, D’Souza AL, Muthu N, et al. BMJ. 2007;335(7610):80. 50. Katz JA. J Clin Gastroenterol. 2006;40(3):249-255. 51. Brandt LJ, Reddy SS. J Clin Gastroenterol. 2011;45(suppl):S159-S167. 52. Guyonett D, Chassany O, Ducrotte P, et al. Aliment Pharmacol Ther. 2007;26(3):475-486. 53. Niedzielin K, Kordecki H, Birkenfeld B. Eur J Gastroenterol Hepatol. 2001;13(10):1143-1147.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, P&G Personal Health Care, and the author neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature. Copyright © 2014, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Disclosure: Dr. Brenner reported that he has served as a consultant for AstraZeneca, Forest, Ironwood, P&G Personal Health Care, Salix, and Perrigo; and he has served on the speakers bureau for Forest, Ironwood, P&G Personal Health Care, and Salix.