Page 49 – Practical Gastro

SUFFERN, NY – CDx Diagnostics, innovator of the WATS^3D diagnostic tissue test for the detection and surveillance of Barrett’s esophagus (BE), a known precursor to esophageal adenocarcinoma (EA), recognizes and supports the goals of Esophageal Cancer Awareness Month in helping to educate patients and physicians about the role of screening and surveillance in enabling early detection of this highly lethal cancer. EA is one of the most rapidly increasing and fatal cancers in the United States, but patients should know that advances such as WATS3D in combination with high-definition endoscopes and endoscopic therapies enable improved detection and treatment that can save many lives every year.

WATS^3D is a clinically proven diagnostic test used by gastroenterologists and surgeons for sampling and analyzing esophageal tissue. WATS^3D takes tissue from a greater percentage of the target esophageal surface area than standard forceps biopsy and has been shown to sharply increase the detection of precancerous cells. The Company is proud to play a leading role in preempting EA, and has now processed more than 200,000 WATS^3D tests.

“Gastroenterologists now have the diagnostic and therapeutic tools to help prevent esophageal adenocarcinoma,” said Dr. Anthony Infantolino, a gastroenterologist at Thomas Jefferson MedicalCenter in Philadelphia. “The key is finding precancerous cells before cancer can develop and WATS^3D is a game changer in this area. With a larger tissue sample and advanced computeridentification of unhealthy cells, pathologists can arrive at a diagnosis sooner and with more confidence and agreement about their finding.”

While the United States cancer death rate recently hit 25 years of decline, EA is one of the fastest growing and most fatal cancers in the United States. It is estimated that approximately 17,650 new cases of EA will be diagnosed this year and approximately 16,080 people will die from this disease. In many cases, with raised awareness, screening, physician training and the addition of WATS^3D, EA is now a potentially preventable disease. It joins the growing list of preventable cancers including cervical cancer, melanoma and sporadic colon cancer.

The Key to Preventing Esophageal Adenocarcinoma:

Consultation with a Gastroenterologist or Foregut Surgeon
Detection of Precancerous Cells (Dysplasia)
Removal of Precancerous Cells

WATS^3D has been adopted by nearly 1,000 gastroenterologists and foregut surgeons from leading academic and community centers across the United States and has been clinically proven to increase detection of esophageal dysplasia (ED) and BE by more than 200% and 100% respectively.

“I am so thankful that my gastroenterologist used WATS^3D along with standard forceps biopsy,” said Bob Webb, a patient with chronicgastroesophageal reflux disease (GERD) and BE.“While the standard biopsy results came back negative for precancerous cells, WATS^3D found high grade dysplasia which are precancerous cells that can progress to cancer. My doctor was able to remove these cells, and thanks to WATS3D I feel I have really dodged a bullet.”

“The more than 200,000 WATS performed to date in the United States have spared many Americans from developing EA, a cancer that is frequently fatal,” said Mark Rutenberg, Founder and CEO of CDx Diagnostics. “Esophageal Cancer Awareness Month plays a critical role in further reducing the morbidity and mortality of EA byhelping to educate the public about the well-definedconnection between heartburn and cancer and about the role that screening and surveillance play in early detection and removal of precancerous cells before they can progress to EA. I hope that patients will take Esophageal Cancer Awareness Month as a catalyst to discuss their GERD symptoms with their primary care physician and consult with a gastroenterologist to understand their status and cancer risks.”

To learn more about WATS^3D, visit their website

GASTROINTESTINAL MOTILITY AND FUNCTIONAL BOWEL DISORDERS, SERIES #26

Rumination Syndrome in the Setting of a Nissen Fundoplication: Its Atypical Clinical and Diagnostic Features

Zorisadday Gonzalez,

Richard W. McCallum

Rumination syndrome is a behavioral disorder characterized by the subconscious regurgitation of recently ingested food into the mouth. Although a widely unrecognized disorder, rumination syndrome should be an important consideration in the differential diagnosis of postprandial regurgitation and vomiting resistant to treatment.

Zorisadday Gonzalez, MD, Adult Hospitalist, Presbyterian Healthcare Services, Presbyterian Healthcare Services Richard W. McCallum, MD, FACP, FRACP (AUST), FACG, AGAF, Professor of Medicine and Founding Chair, Division of Gastroenterology, Director, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

INTRODUCTION

Rumination syndrome is a functional gastrointestinal disorder characterized by effortless regurgitation of recently ingested food back into the mouth within 5-20 minutes of ingestion, followed by re-swallowing or spitting of the food bolus.¹ We report a case of a 20-year old male with history of a Nissen fundoplication as an infant who presented with a three month history of severe postprandial abdominal pain and nausea resulting in significant weight loss. Extensive work-up was unrevealing including numerous imaging, diagnostic, and laboratory studies. A thorough physical examination and history confirmed a diagnosis of rumination syndrome, an atypical presentation given his prior fundoplication history. Although a widely unrecognized disorder, rumination syndrome should be an important consideration in the differential diagnosis of postprandial regurgitation and vomiting resistant to treatment.

Presentation

A 20-year old male presented to the hospital with three months of severe postprandial abdominal pain, early satiety, and intractable nausea resulting in a 20 pound weight loss. The onset of his symptoms were within 5-20 minutes of food ingestion. He denied fevers, diarrhea, dysphagia, melena, hematochezia or change in stool caliber. He denied bulimic behavior and did not desire losing weight. His past medical history was significant for severe reflux as an infant resulting in failure to thrive, and underwent a Nissen fundoplication at that time. As a result of his fundoplication, he was unable to regurgitate food or vomit. His family history was negative for gastrointestinal (GI) malignancy. He had recurrent emergency department (ED) visits with these symptoms and had visited numerous physicians without definite diagnosis. Proton pump inhibitors, opioids, and anti-emetics were ineffective in alleviating his symptoms. He had recently experienced several stressful situations at home. Extensive laboratory testing, upper endoscopy, upper gastrointestinal and small bowel series, computed tomography (CT) angiogram of the abdomen and pelvis, gastric emptying study, and CT of the head failed to explain his symptoms. He refused nasogastric tube feeding. Total parenteral nutritional therapy was initiated to support both hydration and nutrition. He was transferred to the University Medical Center (UMC) at Texas Tech University Health Sciences Center after two weeks without clinical improvement. Physical exam findings were remarkable for postprandial contraction of the rectus abdominis muscle. Following meal intake, the patient was noted to burp and belch as he attempted to ruminate, but he was unsuccessful because of his fundoplication. A jejunostomy tube was ultimately placed in approximation of his fundoplication. Biopsy of antral smooth cells obtained during jejunostomy placement revealed normal number of Cajal cells implying normal gastric emptying. The patient was educated on behavioral therapy and discharged home. At two month follow up, he endorsed marked improvement of his gastrointestinal symptoms with diaphragmatic breathing skills, and his jejunostomy tube was removed. At five months follow up, he reported complete resolution of symptoms and was tolerating food well. He had gained weight and had returned to work and school.

Discussion

Rumination syndrome is the subconscious and effortless regurgitation of recently ingested food from the stomach back into the mouth with subsequent spitting out of the regurgitant or remastication with re-swallowing.¹ Episodes occur within 5-20 minutes after ingestion and symptoms can last up to one to two hours.⁷ These patients often describe their symptoms as vomiting and are therefore incorrectly diagnosed with GERD or another upper gastrointestinal disorder such as gastroparesis or dyspepsia. Furthermore, the presence of additional GI symptoms including abdominal discomfort, nausea, or heartburn does not exclude the diagnosis of rumination syndrome which can further confound the differential diagnosis.⁵ Many of these patients undergo extensive, invasive, and costly testing before a diagnosis is reached. Even though rumination syndrome can imitate GERD or gastroparesis, a careful history can help differentiate the diagnosis. In rumination syndrome, symptoms always occur in the early postprandial period as opposed to GERD or gastroparesis where symptoms occur late postprandially. Additionally, anti-reflux medications do not improve symptoms of rumination syndrome. In gastroparesis, nausea and/or retching usually precede vomiting which is not always the case in rumination syndrome. Another gastrointestinal disorder which can present with effortless postprandial regurgitation is achalasia, although these patients present with dysphagia which is not seen in rumination syndrome. The epidemiology of rumination syndrome is limited because many providers are not aware of this diagnosis and is therefore rarely recognized. Although early observations were mostly described in infants and developmentally disabled patients, it is now recognized in healthy patients of normal intellect and of all ages.⁵ Psychological disturbances have been postulated to play a role around symptom onset of rumination, and therefore a psychiatric evaluation should be considered in patients with a suspected eating disorder.^4,7

The pathogenesis of rumination syndrome is not well understood. The hallmark feature is a coordinated combination of lower esophageal relaxation and increased intra-abdominal pressure coupled with negative intrathoracic pressure.^6,7 This subsequently leads to the reversal of the esophagogastric pressure gradient allowing food to come back up the esophagus and into the mouth. Diagnostic findings on manometry include reflux events associated with an increase in gastric pressures > 30 mm Hg caused by voluntary yet unintentional contraction of the abdominal wall muscles. Although postprandial high resolution impedance pH manometry can support a diagnosis, this test is not required to make diagnosis.⁵ A thorough history and physical examination are key to diagnosing rumination syndrome. Brisk contraction of the abdominis rectus muscle prior to regurgitation can be appreciated on exam. Rumination syndrome has been recognized as its own unique category under functional gastrointestinal disorders and should be diagnosed based on the Rome IV criteria outlined in Table 1.1

Treatment for rumination syndrome consists of reassurance and behavioral therapies including diaphragmatic breathing exercises during and after meals to target abdominal wall contraction and prevent the urge to regurgitate.^2,3 This technique allows for habit reversal, and has been proven to be effective in most patients.⁷ There are no known effective medications in the treatment of rumination syndrome.

Our case was unique in that our patient had a Nissen fundoplication procedure as an infant and was therefore unable to regurgitate or vomit any food. Attempts to regurgitate food only led to severe epigastric pain and nausea which led to fear of eating resulting in significant weight loss. To our knowledge, this is the first case of rumination syndrome in a patient with a prior fundoplication. Interestingly, in a case series of five patients with rumination syndrome whose symptoms had been resistant to medical and psychiatric interventions, Oelschlager et al. reported complete elimination of symptoms in all five patients after performing a Nissen fundoplication.² However, this was a very small sample size and fundoplication is not a recommended treatment for rumination syndrome.

CONCLUSION

Rumination syndrome is a behavioral disorder characterized by the subconscious regurgitation of recently ingested food into the mouth. It is widely unrecognized due to the limited awareness of this condition. Patients with prior fundoplication anatomy may further mask this diagnosis due to their inability to bring up undigested food. A thorough history and physical exam are key in diagnosing rumination syndrome with brisk contractions of the rectus abdominis muscles on exam prior to regurgitation. The mainstay of treatment includes diaphragmatic breathing with behavioral therapy.

FRONTIERS IN ENDOSCOPY, SERIES #52

Hemobilia: Evaluation and Management

Douglas G. Adler,

Taylor Frost

Hemobilia should be suspected in patients with evidence of upper GI bleeding in the setting of a history of prior hepatobiliary intervention or malignancy. Here we discuss the management of hemobilia which can often be managed conservatively with transfusions and the correction of any underlying coagulopathy. However, in patients with persistent bleeding, angiography with selective embolization is the first line therapy to achieve hemostasis but endoscopic biliary stenting and surgical interventions may be warranted.

Taylor Frost MD, Douglas G. Adler MD, FACG, AGAF, FASGE University of Utah School of Medicine Gastroenterology and Hepatology, Salt Lake City, UT.

CASE VIGNETTE

A 68 year old man with chronic pancreatitis developed splenic vein thrombosis with extensive peripancreatic collateral vessels, including around the pancreatic head and duodenal wall. The patient presented with new jaundice and melena and was referred for ERCP. ERCP was performed and revealed ampullary varices with active hemobilia, consistent with variceal erosion and hemorrhage into the distal common bile duct. (Figures 1 and 2) A fully covered metal stent was placed across the distal CBD to produce tamponade on the bile duct, which stopped the bleeding temporarily. (Figure 3) The patient was referred to surgery for splenectomy, which was performed to good effect. The stent was subsequently removed.

Etiology

As a clinical entity, hemobilia can develop from a wide variety of conditions and has been reported in patients with hereditary architectural vascular disease, auto-immune or inflammatory conditions, and malignancy.^1,2,3,4,5,6 However, historically the vast majority of cases have arisen in patients who suffered from abdominal trauma.7 In recent years, with the advent of percutaneous and endoscopic procedures, there has been a shift over time towards iatrogenic cases, and most cases of hemobilia in the modern era are secondary to interventional procedures.^8,9 Hemobilia has been reported as a complication of many procedures including, but not limited to, percutaneous and transjugular liver biopsy, percutaneous transhepatic biliary drainage and cholangiography, radiofrequency ablation of hepatocellular carcinoma, endoscopic retrograde cholangiopancreatography (ERCP) as well as surgical procedures including laproscopic cholecystectomy, liver resection, and liver transplantation.^10,11,12

Mechanism of Injury

Typically, hemobilia occurs when there is direct trauma to the biliary tree and the hepatic blood supply. This then leads to the formation of a fistula followed by a bleeding event, which is often immediate.^13,14 Delayed bleeding has also been reported in some patients. In cases of delayed hemobilia, the initial trauma of the procedure and subsequent inflammation can lead to the formation of a pseudoaneurysm in an adjacent blood vessel. The pseudoaneurysm can then, due to poor structural integrity, rupture or fistulize at a later date, which effectively expands the time between the initial injury and subsequent presentation of hemobilia.¹⁵ Furthermore, both arterial and venous vessels can be affected and have been implicated as sources of hemobilia.^16,17

Incidence and Presentation

Hemobilia can present on a spectrum ranging from an immediate bleed with hemodynamic compromise to minor upper gastrointestinal bleeding that may not even be noticeable clinically. Furthermore, symptoms may not be temporally related to the inciting event, i.e., the initial trauma may have occurred months prior to symptom onset. To complicate this further, hemobilia can present as an intermittent gastrointestinal bleed, which may further impede accurate diagnosis. Quincke’s triad of abdominal pain, upper gastrointestinal bleeding and jaundice has been described as the classical presenting symptoms but may only be present in 20-30% of patients.⁹ For these reasons, the incidence of hemobilia by procedure type or technique is not well understood.

In a retrospective review of 333 patients who underwent percutaneous biliary drainage, Savader et al. (1992) found that 13 patients developed hemobilia with symptom onset ranging from 1 day to 1.8 years following catheter placement. (Figure 4) However, the incidence of hemobilia in percutaneous procedures has been estimated to range from 2.3 – 3.9% in two moderate sized retrospective reviews of percutaneous biliary drainage and 0.005% in those who underwent percutaneous liver biopsy in a large multicenter retrospective study of 68,276 patients.^18,19,20 Hemobilia following transjugular liver biopsy is relatively rare and has been reported at 0.006% in a retrospective review of 601 patients.²¹

Post endoscopic hemobilia has not been well described in the literature. To our knowledge, there are no large retrospective studies that have examined hemobilia following endoscopy. Of the reported cases, hemobilia appears to most commonly follow biliary stenting and may be more prevalent among patients who received metal stents as compared to those who received plastic stents.^{22,23,24,25,26} (Figure5) Hepatic artery pseudoaneurysm from traumatic stent placement has been reported following biliary stenting and is thought to be the mechanism that promotes hemobilia.15 Otherwise, hemobilia has been reported in patients with malignancy or underlying architectural vascular disease who undergo ERCP.^27,28 To complicate matters further, there are no known risk factors that may aid in the identification of those with an increased likelihood of developing hemobilia as a complication of endoscopy.

Management

Currently, there are three main methods that can be utilized in the definitive treatment of hemobilia: surgical intervention, biliary stenting, and angiography followed by selective embolization. The approach to management may change depending upon hemodynamic stability, the suspected source of bleeding, and the inciting event.

Historically, surgical intervention with segmental liver resection, pseudoaneurysm repair, and/or nonselective arterial ligation was the mainstay of treatment. However, more recently surgery has been reserved to patients with extensive liver trauma, hemodynamically instability, and those who develop hemocholecystitis or have failed alternative therapies.²⁹

Endoscopic biliary stenting has been reported to be successful in the treatment of hemobilia but is often a poor choice for definitive therapy as the location of the bleed must be readily identifiable, extrahepatic, and easily accessible.³⁰ Covered and non-covered self-expandable metal stents have seen some success in the treatment of massive hemobilia that occurs from bile duct varices or primary tumor bleeding due to extrahepatic malignancy.^31,32 In these patients, the stent will generally be left in place for a prolonged period of time (or forever) unless the patient develops another complication such as stent obstruction or cholangitis. It is believed that expandable stents are able to distribute pressure over the communicating venous vessel and thereby provide a tamponade effect to achieve hemostasis.

Angiography with selective embolization was first described in 1976 and now represents the first line therapy to achieve hemostasis as it is noninvasive and has a high success rate with an associated low morbidity.^33,34 Furthermore, angiography with selective embolization is the only intervention that can both delineate the vascular anatomy and the location of the pseudoaneurysm or fistula and guide therapeutic intervention. Although one drawback is that false negative studies may occur if there is intermittent bleeding.¹⁵Embolization is typically achieved through the injection of Gel-foam, polyvinyl alcohol particles or steel coils at the site of the lesion.³⁴ Inadvertent embolization of adjacent arteries leading to fatal ischemic disease has been reported but occurs infrequently.³⁵ A caveat to these treatment modalities may exist in patients who develop hemobilia secondary to percutaneous biliary drainage. In this scenario, success with repeated drain flushing followed by an upsizing of the percutaneous catheter may provide a tamponade effect.³⁶ Regardless of which treatment modality is performed, initial evaluation should be directed at hemodynamic stabilization and resuscitation.

After hemostasis is achieved and the patient is hemodynamically stable, attention is often shifted to the clearance of blood from the biliary tree if clinically indicated. However, in minor hemobilia, patients can often be managed conservatively with the correction of any underlying coagulopathy and volume resuscitation with intravenous fluids or transfusions. In those who experience persistent minor hemobilia without a recognizable vascular lesion on imaging, it is reasonable that ERCP be performed, as there may be an identifiable lesion of the distal biliary tree, which could be amendable to biliary stenting. In patients with minor hemobilia, most intrabiliary blood will dissolve under the influence of flowing bile. However, if intrabiliary blood becomes immiscible it is prone to forming a pure clot, which may lead to biliary obstruction and would warrant nasobiliary drainage or ERCP with sphincterotomy and ductal clearance.³⁷

Hemocholecystitis is a feared complication of biliary obstruction as it may necessitate the need for surgical intervention, which carries an increased risk of mortality. Furthermore, it has been hypothesized that even transient obstruction may favor the reflux of blood clots into the cystic duct. Thus, if biliary ductal dilatation is demonstrated on imaging then decompression through either a nasobiliary drain or endoscopic sphincterotomy with clot extraction should be pursued.³⁶

In instances of major hemobilia, surgical intervention is warranted as this approach allows for the identification and selective ligation of the bleeding vessel. If a bleeding vessel cannot be visualized then nonselective ligation of the hepatic vasculature with intraoperative bleed surveillance may be pursued.³⁸ Nonselective ligation allows for gross localization of the source of hemobilia, which can then guide more precise interventions. In rare instances, both ligation and selective embolization can be insufficient in controlling the bleed and partial hepatectomy may be required.³⁹

Discussion

Hemobilia should be suspected in patients with evidence of upper GI bleeding in the setting of a history of prior hepatobiliary intervention or malignancy. The management of hemobilia will depend upon the presenting symptoms and the acuity of the bleeding itself but should initially focus on hemodynamic stabilization. Hemobilia can often be managed conservatively with transfusions and the correction of any underlying coagulopathy. However, in patients with persistent bleeding, angiography with selective embolization is the first line therapy to achieve hemostasis but endoscopic biliary stenting and surgical interventions may be warranted. Biliary dilatation on imaging may represent obstruction and should warrant biliary decompression with either nasobiliary drainage or ERCP with sphincterotomy and clot extraction. Hemocholecystitis carries an increased risk of mortality and is a feared complication of hemobilia with biliary obstruction. The presence of hemocholecystitis or bleeding unresponsive to less invasive therapies should warrant urgent surgical intervention.

NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #186

Part IV Enteral Feeding: Hydrating the Enterally-Fed Patient – It isn’t Rocket Science

Andrew P. Copland,

Carol Rees Parrish,

Stacey McCray

Enteral nutrition (EN) provides primary sustenance to thousands of individuals each day in the hospital, long term care, and home settings. In addition to determining appropriate nutrient requirements, assessing hydration needs is every bit as important. Unfortunately, specific guidelines for clinicians to determine fluid needs do not exist and the equations routinely used are without evidence. The purpose of this article is to approach hydration in the stable EN-fed patient from a practical approach, as well as to review the body’s physiologic need for water.

Carol Rees Parrish, MS, RDN, Nutrition Support Specialist, Digestive Health Center Stacey McCray, RDN, Coordinator, Nutrition Support Training Programs, Digestive Health Center Andrew P. Copland, MD, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, University of Virginia Health System, Charlottesville, VA

The following two scenarios occur all too often:
CASE 1

80 y/o male admitted from clinic with failure to thrive and to rule out a possible GI bleed. His medical history includes stage III, SCC of tongue with dysphagia (PEG-dependent), CVA without deficits, and constipation secondary to opioid use. No renal, hepatic or cardiac history. He was recently discharged (5 days prior) for a similar issue. His wife reported that during that admission he was NPO the first 3 days for workup, and the day of discharge his tube feedings were restarted. Intravenous fluids (IVF) were not given other than during an EGD. A GI bleed was ruled out both admissions.

Home EN Regimen:

1.5 cal/mL product, 1 can x 5 per day via PEG
H2O: 240mL after each feeding

Height: 5′ 10″ (178 cm)
Weight history:
Current weight: 138# (62.7kg)
UBW: 164#(74.5 kg)
IBW: 166# (75 kg)
Lab values: See Table 1

Nutrition Assessment:
Patient with weight loss due to both lost enteral feeding time and a component of dehydration. Dehydration suspected due to back to back admissions, NPO status for procedures without IV support, elevated BUN/creatinine ratio, and the patient’s report that the IV nurse has had a difficult time finding a vein for a blood draw. Both primary team and GI consult service agreed that his initial presumed “GI bleed” was non-contributory (no change in hematocrit), and that he most likely had just gotten behind on fluids. He also needs more calories than his current regimen provides. Nutrition team made the following recommendations:

1. D5, 1/2 normal saline @ 75mL/hr x 2 liters, then reassess if he needs an additional liter.
2. Whenever NPO, provide D5, ? NS @ 75 mL/hr for maintenance.
3. When patient is allowed to resume EN, start:
- 1.5 cal/mL product, 300mL per feeding at: 0600, 1000, 1400, 1800, 2200.
- Provide 120mL water before and after each feeding; some of that water may be used for medication flushes as needed.

CASE 2

An 85 year old male was admitted with diarrhea (+ for Clostridium difficile), mental status changes, and acute renal failure. He is status post a recent stroke, PEG tube-dependent, and was discharged to a skilled nursing facility two weeks earlier. No prior history of renal, hepatic or cardiac disease.

EN Regimen at initial discharge 2 weeks earlier:

1.5 cal/mL product, 1 can x 6 per day via PEG
H2O: 240mL after each feeding

See Table 2 for a chronology of his BUN/creatinine ratio.

Nutrition Assessment:
While this patient’s EN regimen and water flushes would normally meet all of his nutrition and hydration needs, his dehydration resulted from not only leaving the hospital already behind on hydration, but also from staggering stool/electrolyte losses as the C. diff infection took hold. He required several liters of volume repletion IV fluids before his BUN/creatinine ratio normalized and his weight was back to near baseline of his last discharge.

Nutrition team made the following recommendations:

1. Resume patients EN regimen of:
- 1.5 cal/mL product, 1 can x 6 per day via PEG
- 120mL water before and after each feeding; some of that water may be used for medica?tion flushes as needed.

INTRODUCTION

“There is plenty of water in the universe without life, but there is no life without water.”
Sylvia A. Earle

Dehydration is a common primary or secondary diagnosis upon hospital admission^1-4 and is associated with untoward clinical consequences (see Table 3). In 2004, Xiao reported that the number of hospitalizations for dehydration in both community dwelling and long term care elderly had increased to over 500,000 cases annually.⁵ Patients admitted to acute care facilities with a diagnosis of dehydration experience a much higher morbidity and mortality (hazard ratio = 6.04).⁶ In a recent systemic review, dehydration was one of the most common causes of unplanned, but preventable contacts for outpatients with head and neck, gastrointestinal, and esophageal cancers undergoing radiotherapy.¹ In 2013, Drake found that >43,000 Medicare beneficiaries receiving EN were admitted for acute care hospitalization with dehydration and/or malnutrition.³ Dehydration was substantially more common than malnutrition; >two-thirds of these patients (67%) were admitted with dehydration in the absence of malnutrition. The financial costs of dehydration are significant; the Agency for Healthcare Research and Quality lists dehydration as one of the top 10 most common preventable diagnoses with an estimated annual cost of $1.6 billion due to hospital related charges.⁷

Subclinical or chronic underhydration is a common finding in elderly nursing home residents whether on EN or oral intake alone.⁸ Bennett documented chronic dehydration in 48% (89/185) of elderly patients presenting to an emergency department.² While many patients have disease states or other factors that cause them to become dehydrated in the long term care setting prior to admission,⁹ Snyder and Borra et al reported as many as 40% of patients developed dehydration after hospital admission.^10,11 El-Sharkawy found 37% (69/200) of older patients (≥65 years) admitted to a large teaching hospital were dehydrated on admission; 22 (11%) were still dehydrated at 48 hours.⁶ Cases of patients being discharged inadequately hydrated have also been reported; the incidence of iatrogenic dehydration after admission to the hospital was 3.5% in one study12 and 2.1% in a later study.⁷ Crary showed that use of modified dysphagia diets as well as tube feeding was significantly associated with poor hydration status at discharge (66% and 50% respectively).¹³ Leibovitz found that 75% of patients orally fed with feeding difficulties and 18% of EN-fed patients had markers of dehydration and went on to remark, “Dehydration in the EN-fed patient is surprising since the accepted view is that these patients should be sufficiently hydrated”.⁹ Clearly, having enteral access does not ensure adequate nutrition or hydration. Finally, Vivanti compared fluid delivery from food, enteral, and parenteral routes in hospitalized patients with dysphagia against calculated requirements and demonstrated that while enteral and parenteral fluids were a significant source of fluid, calculated fluid requirements were still not achieved in the majority of patients.¹⁴ This further sets our patients up for readmission or increased morbidity and mortality. We can, and must, do better.

The purpose of this article is to arm the clinician with a practical, common sense approach to assessing hydration in the vulnerable EN-fed population and to provide suggestions to improve identification and intervention in order to prevent its occurrence in the first place.

A Word About Dehydration and Lab Values

The intent of this article is not to detail the different types of dehydration, differentiate between volume depletion vs. dehydration, or provide a complete guide to assessing laboratory values (although a nice review is available elsewhere).¹⁵ However, there are some basic concepts that are helpful to keep in mind.

There is no absolute or universal definition for dehydration, and dehydration may manifest in various ways.^16-19 This contributes to the difficulty clinicians encounter when trying to assess hydration status in the acute care setting. Interviews with physicians revealed no standard process for assessing dehydration.¹⁸ In the most basic terms, hypovolemia (salt and water loss) and dehydration (water loss), are often used interchangeably,²⁰ and patients frequently have a combination of volume depletion and dehydration.¹⁵ Clinical signs and symptoms have poor sensitivity and specificity¹⁷ and have limited value in making a diagnosis of dehydration; therefore, they should not be relied on to treat or diagnose dehydration. Rather, the diagnosis should be made based on a combination of laboratory values, clinical assessment, and the knowledge of the patient’s history; in particular, paying attention to extra losses such as vomiting/diarrhea, as well as times when a patient has limited access to water (this would include water from EN, oral intake, and IV fluids).

Laboratory values can provide helpful insight to hydration status. In the straightforward patient (no renal, hepatic or cardiac disease), a rising blood urea nitrogen (BUN)/creatinine ratio (albeit a soft target), is an early sign that the patient is getting behind on hydration. Following the trend of BUN levels over time can be useful. This trend is often underappreciated despite frequent routine labs evaluations particularly during inpatient stays. The kidneys filter urea and excrete nitrogen through the urine. Increased BUN levels can be caused by increased urea production, decreased urea elimination, or a combination of the two. This rise is often transient and may be caused by low blood flow due to dehydration, although there are a myriad of other causes (see Table 4).

Increased serum creatinine is usually a function of renal failure or intrinsic renal disease; only in severe dehydration will creatinine rise as a result of acute kidney injury. In the setting of normal renal function, a rising BUN with stable creatinine (a widening BUN/creatinine ratio), can be an early indicator of worsening hydration status. An elevated BUN/creatinine ratio will be present in most cases of encroaching dehydration,¹⁷as will a drop in weight over a short time period (if accurate weights can be obtained). The kidneys play a very important role in regulating fluid balance and function most efficiently in the presence of an abundant supply of water.²¹ It makes sense to supply adequate water to protect these vital organs.

Why Do Our Patients Get Dehydrated In the Hospital?

There are numerous factors in the acute care setting that set our patients up to become dehydrated, remain dehydrated, or even though once rehydrated early on in the hospitalization, over time become dehydrated again. Table 5 lists many of the most common causes of dehydration in the hospital setting. In addition to the more obvious reasons, such as vomiting, diarrhea, or increased ostomy output, there are more subtle situations that may go unnoticed; for example, the patient on a dysphagia diet with thickened liquids, or the patient who is repeatedly NPO (but not consistently enough for clinicians to notice). At times, a patient might not have been fully rehydrated after an episode of dehydration; as a result, they never catch up to baseline. In these cases, even if the EN prescription should meet maintenance hydration requirements, the patient may remain dehydrated, or even become more dehydrated over time. It is critical to understand that patients, particularly EN-fed patients in acute and subacute settings, have limited control over their access to water.

Some patients have extra fluid losses (and therefore increased water and sometimes sodium needs) that may go unnoticed without careful evaluation. A number of ‘note to self’ moments can occur when doing a visual assessment of a patient; these should trigger a closer assessment of hydration status. These observations may include:

Excessive perspiration (diaphoresis), noted by a glistening, shiny, or wet appearance to their skin.
Patients with amyotrophic lateral sclerosis, or other such neurological conditions may experience excessive saliva production (sialorrhea), or just an inability to control their oral secretions evidenced by frequent dabbing of their mouth with tissue or the fact they carry a towel with them.
Head and neck cancer patients who carry a cup to spit in because they cannot swallow their saliva
24/7 rotating fan to keep the patient cool

In any of the above situations, additional fluid will be needed. Many of these fluid losses are difficult to quantify and are not always noted in the medical record. These fluid losses can can add up over the course of a day. The bottom line is, if the healthcare team does not consider all of these fluid losses, the patient’s volume and hydration status will suffer. Intake and Output (I and O) records are very important in these patients and some clinicians assume that if .I’s = O’s then hydration and volume status are steady; however, it is important to account for insensible losses over and above the standard “outs” and to keep in mind that I and O records might be incomplete. Iatrogenic causes of dehydration may be the consequences of treatments or just the result of being a patient in the hospital. Medications, such as Lactulose for hepatic encephalopathy, may cause excessive stool loss. Hospitalized patients often remain NPO for procedures for an extended period of time without the addition of maintenance IVF. An all too common scenario goes something like this:

1. NPO at midnight
2. Procedure is bumped from late morning, to afternoon, then to the next day
3. It is too late for meals to arrive and/or EN to be restarted
4. NPO at midnight again

If maintenance IVF is not started in the interim, dehydration will follow. In patients whose sole source of nutrition and hydration is EN, it is up to the health care team to ensure adequacy of both. Since it is well documented that hospitalized patients do not receive full EN support for a myriad of reasons,22-24 to assume that water flushes are always given would be folly. Despite this, in a survey of 173 treating physicians, 60% expected improved hydration as one of the benefits of initiating EN.25 Evidence for Determining Hydration Requirements in Enterally-Fed Patients

Healthcare professionals are taught various equations to determine hydration (water) requirements (Table 6). Unfortunately, these equations have never been validated, and as such are without evidence to support their use.²⁶ These calculations can result in dramatically different fluid recommendations depending on the one used (Table 7). They also do not take into consideration clinical assessment, sources of additional loss, or other common sense factors. In addition, these equations presume that the individual/patient is “euhydrated” or adequately hydrated at the time of the calculation. Unfortunately, patients are often behind in their hydration when EN begins (or become so after EN is initiated) for the many reasons discussed above.

Assessing Hydration Status in Our Hospitalized, Enterally-Fed Patients (aka, “The Down and Dirty” Approach)

If the water equations we have been using for years are unsupported by evidence (and may actually be harmful if clinicians solely rely on the numbers and not clinical assessment resulting in over- or underhydration), what should clinicians do? It begins with good clinical judgment and objective data. There are some basic assessment techniques and key tools for the clinician to keep in mind in the acute care setting (see Table 8).

First, it is helpful to think about basic maintenance fluid requirements and what these are supporting. Basic water intake requirements are generally 1800-3000mL/day (IVF rate of 75-125mL/hour). This is why standard IVF are set to run at 75-125mL/hour. This amount of fluid supports daily ongoing, routine losses (27):

Urine: 1200-2000mL
Feces: 100mL
Skin, Lungs: 500-800mL

Of course additional fluid replacement above and beyond maintenance requirements is necessary to replace any additional losses. An accurate account of ins and outs (I and O) is vital. This can be encouraged and enforced through physician orders, strict I and O orders, and ongoing education and collaboration with the nursing staff. Common sources of fluid loss in the hospitalized patient include: vomiting, diarrhea, ostomy/fistula output, drains, gastric suction/venting, draining wounds, and bleeding. Patients with burns, fever, open tracheostomies, or diaphoresis will have increased baseline hydration needs (see Table 5). Finally, there are numerous interruptions throughout a hospitalization where our patients can get behind on fluids (Table 8). It is up to the healthcare team to monitor these.

All sources of fluid provision and intake should be documented in I and O records in every EN-dependent patient. This includes any oral intake, enteral fluids, IVF, and fluids given with medications. The amount of enteral fluid actually received may differ significantly from what is ordered. Frequent procedures or NPO status is important to note, as well as restrictive diet orders which may include thickened liquids or fluid restrictions. In the stable, non-critically-ill patient, twenty-four hour urine output should be quantified with a goal of >1200mL per day. Urine color may also give clues about hydration status. Patients who are unable to drink if thirsty are at higher risk than those who can drink freely. Simply asking the patient if he or she feels thirsty can be an important part of the hydration assessment. Frequent ED visits or admissions for dehydration are signs that the current hydration plan is not working.

After a full assessment of Ins, Outs, current hydration status, and level of risk of dehydration, a plan can be implemented. Table 9 includes practical tips to meet hydration goals once fluid needs have been determined. Always ensure that the patient is adequately rehydrated before implementing a maintenance plan. The hydration prescription should also include concrete endpoints to monitor such as urine output, lab values, or other clinical tools discussed in this article. Patients and caregivers can be educated regarding the fluid goals and can play an important role in meeting these goals. Finally, evaluation of hydration status is not a one-time event, but must be reevaluated over time and as the clinical status changes.

When To Recognize It Is Not about the Nutrition and Hydration Prescription

Just as important as knowing how to assess and monitor hydration in our patients is accepting when the clinical situation is not about simple nutrition and hydration, but rather a medical matter. Critically ill patients in the ICU may have complicating issues such as severe intravascular volume depletion, third spacing of extracellular fluids, renal failure, and severe electrolyte abnormalities,28-30 which require comprehensive care directed by intensivists and other medical specialists to determine the best course of action. This is not a situation for a dietitian to use standard calculations and advise the team on how much fluid to provide or use the invalid “water deficit equation”.³¹ Of course, once the primary team determines the amount of free water needed, the nutrition team may be asked to provide recommendations to best meet those hydration goals and develop a regimen that provides more or less fluid as indicated. When patients leave the intensive care unit and transition to the acute setting, the role of the nutrition team in monitoring hydration and ensuring hydration needs are met becomes important. It takes a village to keep our patients adequately hydrated. IVF are often discontinued, input and output are not measured as meticulously, and things can slip through the cracks. The nutrition team also plays a vital role in developing a successful nutrition and hydration plan for the patient transitioning to home.

Cirrhosis, heart failure, and acute or end-stage renal disease are also circumstances where hydration status is more complex, and standard equations and assessment techniques do not apply. Severe hypernatremia is another situation in which the nutrition team should defer to the medical team for treatment. While there is a desire to treat hypernatremia, “the natural way,” i.e., via the GI tract with higher and higher water boluses more often, there are many reasons why this practice should be avoided and IVF should be used.³²

For serum sodium < 150mmol/L, it is reasonable to try enteral water replacement up to 1 liter in divided doses (for example, 250mL every 6 hours, or 165mL every 4 hours).
For serum sodium > 150mmol/L, IV hydration should be given carefully in a controlled and reliable fashion, using dextrose 5% in water or another hypotonic fluid as appropriate for the individual patient.

CONCLUSION

Dehydration is a serious problem in the acute care setting which leads to increased health care costs and increased complications for our patients. Dehydration is both preventable and reversible. Calculations to estimate hydration requirements in EN-fed patients commonly used in practice today are not evidence based, nor do they take into consideration changes in the patient’s condition, NPO status, or a myriad of other factors. Clinicians’ time would be better spent completing a clinical assessment and focusing on strategies to ensure adequate fluid delivery. A systematic, stepwise approach and better understanding of the signs and symptoms of dehydration will help prevent dehydration in the EN-fed patient population throughout hospitalization and at the time of discharge. In other words, clinicians must pay attention to this most basic requirement of our patients: water.

MEDICAL BULLETIN BOARD

LabCorp’s DoseASSURE® Portfolio Provides Most Expansive Biologics TDM Menu Combined with Expert Guidance

BURLINGTON, NC — LabCorp® (NYSE: LH), a leading global life sciences company that is deeply integrated in guiding patient care, announced a new assay in its therapeutic drug monitoring (TDM) DoseASSURE® portfolio. The new Certolizumab Concentration and Anti-Certolizumab Antibody DoseASSURETM CTZ assay, helps physicians monitor individual drug response for patients who are on Certolizumab, a biologic drug used to treat certaininflammatory diseases, such as rheumatoid arthritis and Crohn’s disease.
Biologic drugs are complex, protein-based therapies that can be used to treat certain inflammatory diseases and are among the fastest growing class of drugs available today. However, the expense of these medications and the variability in patient response can present numerous challenges. LabCorp’s DoseASSURE® portfolio helps address these challenges by providing quantitative,patient-specific measurement which can guide patienttherapy. With the launch of the DoseASSURE CTZ, LabCorp now has the most comprehensive biologics TDM menu in the industry, targeting the largest number of biologic drugs.

“Biologic drugs can be life-changing, but individual patient response to biologics can vary greatly,” said David P. King, LabCorp’s chairman and CEO. “LabCorp’s DoseASSURE portfolio helps to deliver on the promise of precision medicine by enabling more effective and more individualized treatment plans that can improve clinical outcomes at reduced costs.”

Studies demonstrate the use of TDM can improveefficacy and prolong successful response to biologictreatment. Accordingly, appropriate use of TDM can diminish the need for disease-related surgery and hospitalization by reducing the risk of treatment failure.

“Our expanding DoseASSURE portfolio demonstrates our commitment to providing world-class diagnostic and patient management solutions for physicians and patients,” said Marcia Eisenberg,Ph.D., chief scientific officer of LabCorp Diagnostics.“LabCorp adds value because our diagnostics expertise and available clinical decision support tools help clinicians integrate biologic drugs and the associated diagnostics into optimal patient care.”

DoseASSURE® TDM Portfolio

LabCorp’s TDM DoseASSURE portfolio includes eight assays measuring 10 biologic therapies —including Adalimumab, Infliximab, Infliximab-dyyb, Infliximab-abda, Etanercept, Rituximab, Golimumab,Vedolizumab, Ustekinumab, and Certolizumab.

Adalimumab and Anti-Adalimumab Antibody, DoseASSURE ADL
Certolizumab and Anti-Certolizumab Antibody, DoseASSURE CTZ
Etanercept and Anti-EtanerceptAntibody, Dose ASSURE ETN
Golimumab and Anti-Golimumab Antibody,DoseASSURE GOL
Infliximab and Anti-Infliximab Antibody,DoseASSURE IFX
Rituximab and Anti-Rituximab Antibody,DoseASSURE RTX
Ustekinumab and Anti-Ustekinumab Antibody,DoseASSURE UST
Vedolizumab and Anti-Vedolizumab Antibody,DoseASSURE VDZ

For more information about LabCorp’s DoseASSURE portfolio, please visit the online test menu at LabCorp’s website

About LabCorp

LabCorp (NYSE: LH), an S&P 500 company, is a leading global life sciences company that is deeply integrated in guiding patient care, providing comprehensive clinical laboratory and end-to-end drug development services. With a mission to improve health and improve lives, LabCorp delivers world-class diagnostic solutions, brings innovative medicines to patients faster, and uses technology to improve the delivery of care. LabCorp reported revenues of more than $11 billion in 2018. To learn more about LabCorp, visit: LabCorp’s website

MEDICIAL BULLETIN BOARD

Vedolizumab Superior to Adalimumab in Achieving Clinical Remission and Mucosal Healing at Week 52 in Patients with Moderately to Severely Active Ulcerative Colitis

Osaka, JAPAN – Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) announced results from the Phase 3b head-to-head VARSITY study which demonstrated that the gut-selective biologic vedolizumab (Entyvio®) was superior to the anti-tumornecrosis factor-alpha (anti-TNFα) biologic adalimumab(Humira®) in achieving clinical remission* in patients with moderately to severely active ulcerative colitis at week 52. Data showed that 31.3% (n=120/383) of patients receiving vedolizumab intravenous (IV) achieved the primary endpoint of clinical remission compared to 22.5% (n=87/386) of patients treated with adalimumab subcutaneous (SC) at week 52, with thedifference being statistically significant (p=0.0061).These results were announced as an oral presentation (OP34) on Saturday March 9, 2019 from 09:40-09:50, at the 14th Congress of the European Crohn’s and Colitis Organisation (ECCO) in Copenhagen, Denmark.

Furthermore, treatment with vedolizumab wasassociated with significantly higher rates of mucosalhealing** at week 52, with 39.7% of patients receiving vedolizumab achieving mucosal healing compared to 27.7% treated with adalimumab (p=0.0005). Anon-statistically significant difference in favor ofadalimumab was seen in the percentage of patients using oral corticosteroids at baseline who discontinued corticosteroids and were in clinical remission*** at week 52. While the study was not powered to compare the safety of the two biologics, patients treated with vedolizumab (62.7%) had a lower rate of overall adverse events over 52 weeks than patients treated with adalimumab (69.2%), with a lower rate of infections reported in patients treated with vedolizumab (33.5%) as compared to adalimumab (43.5%). The rate of serious adverse events was also lower in vedolizumab- treated patients than adalimumab (11.0% vs. 13.7% respectively).

“The VARSITY study addresses critical questions concerning the selection of biologic therapy in ulcerative colitis,” said Dr. Bruce E. Sands, primary investigator of the VARSITY study and Chief of the Dr. Henry D. Janowitz Division of Gastroenterology at Mount Sinai Hospital and the Icahn School of Medicine at Mount Sinai in New York. “The goal of treatment in ulcerative colitis is to achieve clinical remission and mucosalhealing, and these results clearly highlight the benefitsseen with vedolizumab versus adalimumab on these important outcomes. The results also showed lower rates of overall and serious adverse events including infections in patients treated with vedolizumab than adalimumab.”

“As the first clinical study to directly compare the efficacy and safety of two commonly used biologictherapies in patients with ulcerative colitis, VARSITY provides invaluable knowledge to help inform physicians’ treatment decisions when initiating biologic therapy,” said Jeff Bornstein, M.D., Executive MedicalDirector, Takeda. “This is also the first time we haveseen a direct comparison between two medicines with distinct modes of action in ulcerative colitis, the gut- selective anti-alpha4beta7 integrin vedolizumab andthe anti-TNFα adalimumab. This is an exciting time inthe landscape of ulcerative colitis treatment, as head- to-head clinical data has not previously been available to guide treatment decisions around biologic therapies.”

VARSITY is a phase 3b, randomized, double-blind, double-dummy, multi-center, active-controlled studyto evaluate the efficacy and safety of vedolizumab IVcompared to adalimumab SC at week 52 in patients with moderately to severely active ulcerative colitis. The study randomized 769 patients (vedolizumab n=383 or adalimumab n=386), all of whom had inadequate response with, loss of response to, or intolerance tocorticosteroids, immunomodulators, or one TNFα-antagonist other than adalimumab prior to being enrolled. Patients were randomized into one of two treatment groups, vedolizumab IV and placebo SC or adalimumab SC and placebo IV. Patients in the vedolizumab group were administered vedolizumab IV 300 mg at weeks 0, 2, 6 and every 8 weeks thereafter until week 46, along with placebo SC at week 0 and every 2 weeks until week 50. The adalimumab group were administered adalimumab SC 160 mg at week 0, 80 mg at week 2 and 40 mg every 2 weeks until week 50, along with placebo IV at weeks 0, 2, 6 and every 8 weeks thereafter until week 46. Dose escalation was not permitted in either treatment arm during the study.* Primary endpoint: Clinical remission is defined as a complete

Mayo score of ≤2 points and no individual subscore ˃1 point. ** Secondary endpoint: Mucosal healing is defined as Mayo endoscopic subscore of ≤1 point. Mayo score: instrument designed to measure disease activity of ulcerative colitis. *** Secondary endpoint: Corticosteroid-free clinical remissionis defined as patients using oral corticosteroids at baseline(week 0) who have discontinued oral corticosteroids and are in clinical remission at week 52.

About Ulcerative Colitis

Ulcerative colitis (UC) is one of the most common formsof inflammatory bowel disease (IBD). UC is a chronic, relapsing, remitting, inflammatory condition of thegastrointestinal tract that is often progressive in nature, and involves the innermost lining of the large intestine. UC commonly presents with symptoms of abdominal discomfort and loose bowel movements, including blood or pus. The cause of UC is not fully understood; however, recent research suggests hereditary, genetics, environmental factors, and/or an abnormal immune response to microbial antigens in genetically predisposed individuals can lead to the condition.

About Entyvio® (vedolizumab)

Vedolizumab is a gut-selective biologic and is approved as an intravenous (IV) formulation. It is a humanizedmonoclonal antibody designed to specifically antagonizethe alpha4beta7 integrin, inhibiting the binding of alpha4beta7 integrin to intestinal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but not vascular cell adhesion molecule 1 (VCAM-1). MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract. The alpha4beta7 integrin is expressed on a subset of circulating white blood cells. These cells have been shown to play a rolein mediating the inflammatory process in ulcerativecolitis (UC) and Crohn’s disease (CD). By inhibiting alpha4beta7 integrin, vedolizumab may limit the abilityof certain white blood cells to infiltrate gut tissues.

Vedolizumab IV is approved for the treatment of adult patients with moderately to severely active UC and CD, who have had an inadequate response with, lost response to, or were intolerant to either conventionaltherapy or a tumor necrosis factor-alpha (TNFα)antagonist. Vedolizumab IV has been granted marketing authorization in over 60 countries, including the United States and European Union, with more than 260,000 patient years of exposure to date.

Therapeutic Indications

Ulcerative colitis

Vedolizumab is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventionaltherapy or a tumor necrosis factor-alpha (TNFα)antagonist.

Crohn’s Disease

Vedolizumab is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventionaltherapy or a tumor necrosis factor-alpha (TNFα)antagonist.

Important Safety Information
Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Special warnings and special precautions for use
Vedolizumab should be administered by a healthcare professional prepared to manage hypersensitivity reactions, including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering vedolizumab. Observe patients during infusion and until the infusion is complete.

Infusion-related reactions

In clinical studies, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity. If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of vedolizumab must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines). If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated (e.g., epinephrine and antihistamines). Once the mild or moderate IRR subsides, continue the infusion. Physicians should consider pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the next infusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize their risks.

Infections

Vedolizumab is a gut-selective integrin antagonist with no identified systemic immunosuppressive activity. Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier. Vedolizumab treatment is not to be initiated in patients with active, severe infections such as tuberculosis, sepsis, cytomegalovirus, listeriosis, and opportunistic infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with vedolizumab. Caution should be exercised when considering the use of vedolizumab in patients with a controlled chronic severe infection or a history of recurring severe infections. Patients should be monitored closely for infections before, during and after treatment. Before starting treatment with vedolizumab, screening for tuberculosis may be considered according to local practice. Some integrin antagonists and some systemic immunosuppressive agents have been associated with progressive multifocal leukoencephalopathy (PML), which is a rare and often fatal opportunistic infection caused by the JohnCunningham (JC) virus. By binding to the α4β7 integrinexpressed on gut-homing lymphocytes, vedolizumabexerts an immunosuppressive effect specific to thegut. Although no systemic immunosuppressive effect was noted in healthy subjects, the effects on systemicimmune system function in patients with inflammatorybowel disease are not known. Healthcare professionals should monitor patients on vedolizumab for any new onset or worsening of neurological signs and symptoms, and consider neurological referral if they occur. If PML is suspected, treatment with vedolizumab must bewithheld; if confirmed, treatment must be permanentlydiscontinued. Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression ofdeficits usually leads to death or severe disability overweeks or months.

Malignancies

The risk of malignancy is increased in patients with ulcerative colitis and Crohn’s disease. Immunomodulatory medicinal products may increase the risk of malignancy.

Prior and concurrent use of biological products

No vedolizumab clinical trial data are available for patients previously treated with natalizumab. No clinical trial data for concomitant use of vedolizumab with biologic immunosuppressants are available. Therefore, the use of vedolizumab in such patients is not recommended.

Vaccinations

Prior to initiating treatment with vedolizumab all patients should be brought up to date with all recommended immunizations. Patients receiving vedolizumab may receive non-live vaccines (e.g., subunit or inactivated vaccines) and may receive live vaccines only if thebenefits outweigh the risks.

Adverse reactions include: nasopharyngitis, headache, arthralgia, upper respiratory tract infection,bronchitis, influenza, sinusitis, cough, oropharyngealpain, nausea, rash, pruritus, back pain, pain in extremities, pyrexia, fatigue and anaphylaxis.
Please consult with your local regulatory agency for approved labeling in your country.
For U.S. audiences, please see the full Prescribing Information including Medication Guide for ENTYVIO®.
For EU audiences, please see the Summary of Product Characteristics (SmPC) for ENTYVIO®.

Takeda’s Commitment to Gastroenterology

Gastrointestinal (GI) diseases can be complex, debilitating and life-changing. Recognizing this unmet need, Takeda and our collaboration partners have focused on improving the lives of patients through the delivery of innovative medicines and dedicated patient disease support programs for over 25 years. Takeda aspires to advance how patients manage their disease. Additionally, Takeda is leading in areas of gastroenterology associatedwith high unmet need, such as inflammatory boweldisease, acid-related diseases and motility disorders. Our GI Research & Development team is also exploring solutions in celiac disease and liver diseases, as well asscientific advancements through microbiome therapies.

About Takeda Pharmaceutical Company Limited

Takeda Pharmaceutical Company Limited (TSE:4502/ NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly- innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Neuroscience, and Rare Diseases. We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people’s lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions.

For more information, visit Takeda Pharmaceutical’s website

FROM THE PEDIATRIC LITERATURE

Preventing Perinatal Transmission of Hepatitis C

Hepatitis C virus (HCV) infection is increasingin young adults, and better screening processes during pregnancy are warranted in order toprevent a subsequent increase in HCV infections in newborns. The authors used data from the “Recovery, Empowerment, Social Services, Prenatal care, Education, Community, and Treatment” (RESPECT) project from Boston Medical Center which cares for pregnant women with substance use disorders. Specifically, women with an opioid use disorder and who delivered a live birth from 2006 to 2015 were followed to see how well follow up occurred in a HCV cascade ofcare. The HCV cascade of care had managementcomponents utilized for both women and infants. Women who had live births were assessed for HCV infection. If they were HCV seropositive, they underwent HCV RNA testing to determine if they had viremia so that they could be linked to medical care. Subsequently, infants born to HCVseropositive mothers were screened per AmericanAcademy of Pediatrics guidelines, and all children with positive HCV antibody testing or RNA testing were linked to medical care, including consultationwith a pediatric infectious disease service. Motherswith and without HCV infection were compared, and multivariable logistic regression was used to determine various factors associated with linking to HCV care, including maternal age, race, distance from the medical center, HIV status, behavioral health diagnosis, tobacco use, substance use disorder, and opioid agonist therapy.

A total of 879 women with an associated opioid use disorder met inclusion criteria for the study and 510 subjects (68%) were HCV seropositive.Women who were seropositive were significantly more likely to be white, non-Hispanic, have a concomitant HIV infection, have used tobacco during pregnancy, and have been prescribed opioid agonist therapy at time of delivery. It was notedthat 369 of HCV seropositive women (72%) hadHCV RNA testing, but only 107 women who had positive HCV RNA testing (41%) were linked tosubsequent HCV care.

Additionally, 404 infants were included in the analysis who were born to mothers with positive HCV seropositivity. Only 180 infants (45%) finished testing for an HCV infection, and only5 of these infants (2.8%) were diagnosed withan HCV infection (and all of these infants were subsequently linked to care). Increased completion of HCV screening in infants was significantly associated with maternal HIV co-infection. Maternal methadone maintenance therapy also was associated with completion of HCV screening on univariate analysis only.

This study demonstrates that there are areasin the care chain warranting improvement forwomen and their infants with HCV positivity so that complete testing and potential referral for treatment can occur. This study shows that linking high-risk individuals to care has the opportunity to improve HCV treatment. It would be interesting to see how this care model would work in othergeographic regions of the United States.

Epstein R, Sabharwal V, Wachman E, Saia K, Vellozzi C, Hariri S, Linas B. Perinatal transmission of hepatitis C virus: defining the cascade of care. Journal of Pediatrics 2018; 203: 34-40

FROM THE LITERATURE

Screening for Pancreatic Cancer

Murray H. Cohen

A meta-analysis of prospective cohort studies to determine the diagnostic yield and outcomes of abdominal imaging screening for asymptomatic individuals at high risk for pancreatic cancer, based on family history or genetic variants was carried out.

Through a systematic review of electronic databases and conference proceedings through July 2017, prospective cohort studies (greater than 20 patients), of asymptomatic adults with alifetime risk greater than 5%, including specificgenetic-associated conditions, who were screened by endoscopic ultrasound (EUS) and/or MRI to detect pancreatic lesions. The primary outcomewas identification of high-risk pancreatic lesions(high-grade pancreatic intraepithelial neoplasia, high-grade dysplasia, or adenocarcinoma) at initial screening and overall incidence during followup.

Summary estimates were reported as incidence rates per 100 patient-years.

A total of 19 studies were identified, comprising7085 individuals at high-risk for pancreatic cancer. Of these, 1660 patients were evaluated by EUS or MRI. A total of 59 high-risk lesionswere identified; 43 had no carcinomas; 28 duringthe initial examination and 15 during follow-up surveillance. A total of 257 patients underwent pancreatic surgery. Based on this meta-analysis, the overall diagnostic yield screening for high-riskpancreatic lesions was 0.74 per 100 patient-years,with moderate heterogeneity among studies. The number needed to screen to identify one patientwith a high-risk lesion was 135. The diagnosticyield was similar for patients with different genetic features at increased risk, and whether patients were screened by EUS or MRI.

Corral, J., Mareth, K., Riegert-Johnson, D., Daas, A., Wallace, M. “Diagnostic Yield from Screening Asymptomatic Individuals at High Risk for Pancreatic Cancer: A Meta-Analysis of Cohort Studies.” Clinical Gastroenterology and Hepatology 2019; Vol. 17, pp. 41-53.

Assessment of Fibrosis and Steatosis in NAFLD

To determine the diagnostic accuracy of vibration- controlled transient elastography (VCTE), which measures liver stiffness, a prospective study of393 adults with NAFLD was carried out within one year of liver histology analysis from 7/1/2014 through 7/31/2017.

Liver stiffness measurement (LSM) cut-off values for pairwise fibrosis stage and controlledattenuation parameter cut-off values for pairwise steatosis grade were determined using cross- validated area under the receiver operating characteristics curve (AUROC) analyses.Diagnostic statistics were computed at a sensitivity fixed at 90% and a specificity fixed at 90%.

LSM identified patients with advanced fibrosis with an AUROC of 0.83 and patients with cirrhosis with an AUROC of 0.93. At a fixed sensitivity, a cut-off LSM of 6.5 kBa excluded advancedcirrhosis with a negative predictive value of 0.99.At a fixed specificity, LSM identified patients with advanced fibrosis with a positive predictive valueof 0.71 and patients with cirrhosis with a positivepredictive value of 0.41.

Controlled attenuation parameter analysis detected steatosis with an AUROC of 0.76. In contrast, the VCTE was less accurate indistinguishing lower fibrosis stages, higher steatosis grades, or the presence of NASH.

It was concluded in a prospective study ofadults with NAFLD, VCTE was found to accurately distinguish advanced vs earlier stages of fibrosis,using liver histology as the reference standard.

Siddiqui, M., Vuppalanchi, R., Van Natta, M., et al for the NASH Clinical Research Network. “Vibration-Controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease.” Clinical Gastroenterology and Hepatology 2019; Vol. 17, pp. 156-163.

Transient Elastography in Apparently Healthy Individuals and Changes
in Liver Stiffness

A systematic review was carried out to determine the range of liver stiffness measurements (LSMs) examined by transient elastography in healthy individuals and individuals who are susceptible tofibrosis. Data was collected from 16,082 individuals in 26 cohorts, identified from systematic searches of MBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements.

Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis based on ultrasound examination was known for most participants.

Participants with a BMI less than 30 wereexamined with a medium probe and those witha BMI greater than 30 were examined with the extra-large probe. Linear regression models wereconducted after adjusting for potential confoundingfactors of LSMs. Several sensitivity analyses werecarried out.

LSM ranges for healthy individuals wereestablished, measured with both probes. They didnot change significantly in sensitivity analysesof individuals with normal platelet counts andnormal ALTs in men and women. Multivariate analysis factors that modified LSMs with statistical significance included diabetes, dyslipidemia(decrease), waist circumference, level of AST and systolic blood pressure at examination time.Significant increases in LSMs were associated witha metabolic syndrome in individuals examinedby either probe. Diabetes in obese individuals increased the risk of LSMs in range associated with advanced fibrosis.

It was concluded that a comprehensive setof LSM ranges measured by TE in large cohortsof healthy individuals and persons susceptibleto hepatic fibrosis regression analyses identified factors associated with increased LSMs obtainedby TE with the medium and extra-large probes.

Bazurbachi, F., Haffar, S., Wang, Z., et al. “Range of Normal Liver Stiffness and Factors Associated with Increased Stiffness Measurements in Apparently Healthy Individuals.” Clinical Gastroenterology and Hepatology 2019; Vol. 17, pp. 54-64.

Thermal Ablation of Endoscopic
Mucosal Resection

Endoscopic mucosal resection (EMR) is performed to remove large laterally spreading colonic lesions with a high risk of progression to CRC. Because endoscopically invisible micro-adenomas at the margins of the EMR site might contribute toadenoma recurrence that occurs at 15-30% ofpatients who undergo surveillance, determinationof the efficacy of adjuvant thermal ablation of theEMR mucosal defect margin in reducing polyp recurrence was carried out.

A prospective study of 390 patients with largelaterally spreading colonic lesions (greater than20 mm/N = 416), referred for EMR at 4 tertiarycenters in Australia was carried out. After complete excision by EMR, lesions were randomly assigned. The thermal ablation of the post-EMR mucosaldefect margin (N = 210), or no additional treatment (N = 206), surveillance colonoscopies wereperformed with standardized photo documentation and biopsies of the scar after 5 to 6 months. Patient, procedure and lesion characteristics were similar between the groups. The primary endpoint wasdetection of lesion recurrence at first surveillancecolonoscopy.

A significantly lower proportion of patientswho received thermal ablation of the post-EMR mucosal defect margin had evidence of recurrenceat first surveillance colonoscopy (10/192; 5.2% and controls 37/176; 21%). The relative risk ofrecurrence in the thermal ablation group was 0.25 compared with the control group. Rates of adverse events were similar between the groups.

In this multicenter, randomized trial, it was concluded that thermal ablation in the post-EMRmucosal defect margin significantly reduced polyp recurrence at first surveillance colonoscopy,compared with no additional treatment.

Klein, A., Tate, D., Jayasekeran, V., et al. “Thermal Ablation of Mucosal Defect Margins Reduces Adenoma Recurrence After Colonic Endoscopic Mucosal Resection.” Gastroenterology 2019; Vol. 156, pp. 604-613.

Common Sense Pediatric Gastroenterology: A Practical Guide

John Pohl

Author: Timothy Blaufuss, DO
Publisher and year: BlaufCo, LLC Publishing, 2018
ISBN-13: 978-1719239653
Price: $19.99 (Paperback)

Common Sense Pediatric Gastroenterology: A Practical Guide, authored by Dr. Tim Blaufuss, was envisioned during a home call, when heidentified the need for a resource for commonpediatric gastroenterology related clinical questions. Dr. Blaufuss recently completed his pediatric gastroenterology fellowship at Children’s Mercy Hospital, Kansas City, MO, and has joined Sanford Health, Fargo, ND. This book primarily targets pediatric gastroenterology trainees; however, pediatricians, residents and currentpediatric gastroenterologists also will find this book beneficial.

The book is well-written in a bulleted format with extensive use of helpful tables, algorithms,flowcharts and formulas. The writing style makesthis book extremely easy to navigate, especially when tending to phone calls after hours. This pocket- sized, 50-60 page, light-weight book is divided into two major sections, namely Gastroenterology and Hepatology. These sections are further divided into

various topics and subtopics. A reference section highlighting crucial articles as they pertain to particular topics has been incorporated as well. The section on hepatology has an impressive outline for the work-up of laboratory abnormalities, and it addresses not only common biliary, autoimmune and infectious etiologies but also less common metabolic liver diseases and benign/malignant liver masses. The book concludes with a Quick Medication Guide where the most commonly used GI drugs, their doses, and common indicationsare efficiently tabulated. Most recent guidelinesand up-to-date evidence from a variety of sources have been used to formulate the book. In addition to addressing common symptoms, pathologies, and diseases, more rare clinical entities as well as their diagnosis, management, and treatment pearls also are discussed. In spite of being concise, this book is comprehensive and detailed. Of course, this book will maintain its applicability when updated frequently. In future editions, inclusion of endoscopy and histology pearls with imagesmight prove beneficial to readers.

In summary, this book cannot be applauded enough for its crisp format and thorough presentation of topics both common and rare. We would highly recommend this book to every budding pediatric gastroenterologist as a pocket guide for daily use.

FELLOW's CORNER

A Case of Small Bowel Intussusception in an Adult

Devendra Enjamuri,

Arkady Broder,

Sonmoon Mohapatra

Sonmoon Mohapatra, Devendra Enjamuri, Arkady Broder, Department of Gastroenterology and Hepatology, Saint Peter’s University Hospital – Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ.

CASE PRESENTATION

A 36-year-old male presented to the hospital with severe diffuse abdominal pain that was intermittent, with no significant aggravating or relieving factors. He also reported nausea and few episodes of non-bloody vomiting preceding the event. There was no weight loss, fever, chills, or constipation. There was no associated co-morbid conditions or previous history of abdominal surgery. Clinical examination showed normal vital signs. His abdomen was distended, and hyperactive bowel sounds were noted on auscultation. Investigations: complete blood count (CBC) and electrolytes were normal. Contrast-enhanced computed tomography (CT) scan and upper gastrointestinal series (UGI) with gastrografin of the abdomen is shown in Figure I. Follow up single balloon enteroscopy was performed (Figure II). He subsequently underwent surgery. The gross surgical specimen and histology is shown in Figure III and Figure IV respectively.

Questions

1. What is the radiological diagnosis?
2. a) What is the endoscopic diagnosis?
b) What does the histology show?
3. What is the most common cause of this finding in adults?
4. What are the non-obstructive causes of this disease?

Discussion

1. This paper illustrates an unusual case of intussusception in an adult with the lead lesion being a hamartoma. Figure I shows a focal mass like a filling defect in the small bowel lumen (3.2 cm in maximal diameter) acting as a lead point of the intussusception. Adult intussusception represents 5% of all cases of intussusception and only 1-5% presents with intestinal obstruction. Although the cause of intussusception in children is largely idiopathic, the majority of the adult cases is non-idiopathic and are associated with a pathological structural lead point. Adult intussusception is commonly diagnosed by CT scan.1 Ultrasonography (USG) can be performed alternatively if the CT scan is unavailable. “Doughnut” or “pseudo kidney” signs may be present on the USG suggesting intussusception.1 The “target sign” and “crescent sign” are some other specific abdominal radiographic findings.
2. a) Single balloon enteroscopy showed a large polypoid mass in the mid-jejunum [Figure II]. The patient underwent segmental small bowel resection (jejunal) including a regional lymph node removal [Figure III]. 3. b) Pathology showed a central core of smooth muscle extending into the polyp in an arborizing fashion, which was covered by normal small bowel mucosa suggesting Peutz-Jeghers polyp [Figure IV].
4. The most common causes of small bowel intussusception in adults include malignancies (commonly metastatic), benign tumors (such as adenomatous polyps, fibromas, lipomas, hamartomas, leiomyomas), adhesions and lymphoid hyperplasia.²
5. Non-obstructive diseases such as cystic fibrosis, scleroderma, celiac disease, inflammatory bowel disease, appendicitis, pancreatitis and rectal foreign bodies may also cause intussusception in adults.² A hamartomatous polyp is diagnosed as a solitary Peutz-Jeghers polyp (PJP) when it does not meet the WHO criteria of Peutz-Jeghers syndrome (PJS). PJS is a rare clinical entity characterized by distinct mucocutaneous pigmentation and intestinal hamartomatous polyps. PJS is commonly seen in the 2^nd and 3^rd decade whereas solitary PJP is diagnosed often in the 4^thdecade.³ A mutation of the LKB1/STK11 gene is found in 50-94% of the patients with PJS. There is an increased risk of gastrointestinal malignancies in patients with PJS. An increased prevalence of malignancies has been shown in PJS with a relative risk for gastrointestinal cancer of 13 (95% confidence interval, 2.7-38.1) and non-gastrointestinal cancer of 9 (95% confidence interval, 4.2-17.3).⁴ No optimal screening strategy has yet been described. Some proposed screening strategies include upper gastrointestinal endoscopy every 2 years beginning at age 10, colonoscopy every 3 years starting at age 25, and small-bowel screening starting at age 10.⁴