A CASE REPORT

Submucosal Tunneling Endoscopic Resection (STER) Prevents Esophagectomy for Esophageal Mass

January 2021 • Volume XLV, Issue 1
Bo Hyung Yoon,Justin Robbins,Alexander Schlachterman

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Traditionally, upper gastrointestinal (GI) tract tumors have been treated with conventional surgical techniques. More recently, interventional endoscopic techniques have been utilized in the management and resection of these tumors with lower perioperative risks. Here, we describe our experience with submucosal tunneling endoscopic resection (STER) for a large esophageal tumor. A 55 mm mass was successfully removed by STER with pathology revealing a leiomyoma. No procedural or postoperative complications were noted. This early experience suggests that STER is a safe and efficient alternative technique for treating upper gastrointestinal tract mass.

INTRODUCTION

Submucosal esophageal tumors describe a subclass of esophageal masses that originate from the submucosal layer and muscularis propria. The most common types include leiomyomas, gastrointestinal stromal tumors (GISTs), and lipomas. The incidence of these tumors has been relatively low (<1% of all esophageal masses); however, it has increased with widespread use of endoscopic techniques.1 Indications for resection of these masses include dysphagia, obstruction, pain, or cases in which diagnostic testing does not rule out malignancy. 2 Throughout the late 1900s and early 2000s, surgical intervention was the only option for resection of these masses. Over the last decade, interventional endoscopy has become more widely utilized as a reasonable alternative to surgery.

Submucosal tunneling endoscopic resection (STER) was introduced in 2011 for the treatment of upper GI submucosal tumors originating from the muscular propria layer as a viable alternative to surgical (open or laparoscopic) resection.3 STER is a direct offshoot of the endoscopic tunneling technique and received wide clinical adoption while peroral endoscopic myotomy (POEM) became standard practice.4 Compared to more invasive approaches, STER offers the advantage of preserving mucosal integrity with decreased risk of perforation in resection of submucosal esophageal tumors.

Case Presentation

A 70-year-old female presented for treatment options regarding a subepithelial esophageal lesion. In March 2018, the patient underwent an upper endoscopy for dysphagia and weight loss, revealing a moderately severe extrinsic compression in the middle third of the esophagus. After a gap in care, an upper endoscopy with endoscopic ultrasonography performed in August 2019 showed a subepithelial lesion in the proximal esophagus arising from the muscularis mucosa and extending into the submucosa. The lesion was a single oval hypoechoic and heterogenic mass measuring 27 mm x 14 mm with well-defined margins in the upper to mid esophagus, 20 cm from the incisor. Fine-needle aspiration was concerning for granular cell tumor given spindle cell on cytology.

In February 2020, the patient underwent STER under general anesthesia. An upper endoscope was used to evaluate the entire esophagus, and a 55 mm mass was identified at 21 cm to 27 cm from the incisors (Figure 1a). White light and narrow band imaging with near focus was utilized to evaluate the lesion. An upper endoscope with distal cap was used, and injection of lifting agent (Orise, BSCI) 6 cc was used for incision at 20 cm from the incisors. An initial 10 mm incision was made with an ERBE hybrid-T knife with continued injection, dissection, and hemostasis of small vessels. The tumor was fully dissected with intact mucosa, muscle, and capsule surrounding the lesion (Figure 1b). A rescue net was used to remove the lesion after extending the incision site as the lesion was 20 mm in diameter. The resected tumor was sent for analysis (Figure 1c). The tunnel was evaluated for bleeding, and hemostasis was achieved. Eight TTS (through the scope) clips (360, BSCI) were used for full closure of the mucosectomy site (Figure 1d).

The tumor was fixed in formalin which was then processed. Immunohistochemical stains were performed including smooth muscle actin, desmin, C-KIT, DOG1 and S-100. The pathology of the tumor was diffusely positive for smooth muscle actin and desmin, while negative for C-KIT, DOG1 and S-100, consistent with leiomyoma. Followup with annual surveillance with endoscopy was recommended.

Post-procedure esophagram did not show any leak, and no post-procedural bleeding occurred. She was continued on ciprofloxacin and metronidazole for seven days prophylactically.

DISCUSSION

STER differs from conventional laparoscopic surgery as it utilizes the space between the gastrointestinal mucosa and muscularis propria layers for manipulation. STER aligns with the true definition of a NOTES (natural orifice transluminal endoscopic surgery) procedure. In our case report, we showed that a 55 mm esophageal mass was successfully treated by STER. The lesion was completely resected with no complications. The patient was discharged after a 23-hour observation.

Although interventional endoscopic technology has rapidly developed in the last decade, surgery is still preferred for the removal of larger submucosal esophageal tumors.5 Some studies have described their experience with endoscopic techniques including STER.1,6,7 A study from China shared the experience of 24 cases with large symptomatic submucosal tumors, size ranging from 3.5 to 6.5 cm, in the esophagus who underwent STER. Wang et al. reported procedure-related complications in eight patients including pneumoperitoneum, pneumothorax and small pleural effusion.7 Given the high-risk endoscopic procedure, the safety of STER is closely related to the experience of the operator. Marcella et al. reported a retrospective single-center study with 97 patients who underwent endoscopic treatment for subepithelial tumors with majority of which were smaller than 5 cm in size and concluded that endoscopic management was effective and safe.8

CONCLUSION

STER is safe and effective for treatment of large symptomatic submucosal tumors in the esophagus. It can be used to achieve the complete curative resection of lesions with a low rate of complications while also providing accurate pathological evaluations. We hope this report will encourage STER as a more frequent therapeutic choice for treatment of large symptomatic tumors in the esophagus.

References

  1. Jain D, Desai A, Mahmood E, Singhal S. Submucosal tunneling endoscopic resection of upper gastrointestinal tract tumors arising from muscularis propria. Annals of gastroenterology. 2017; 30: 262-272.
  2. Ko WJ, Song GW, Cho JY. Evaluation and endoscopic management of esophageal submucosal tumor. Clinical endoscopy. 2017; 50(3): 250-253.
  3. Xu M, Cai M, Zhou P, et al. Submucosal tunneling endoscopic resection: a new technique for treating upper GI submucosal tumors originating from the muscularis propria layer (with videos). Gastrointestinal Endoscopy. 2012; 75(1): 195-199.
  4. Zhang X, Modayil R, Criscitelli T, et al. Endoscopic resection for subepithelial lesions—pure endoscopic fullthickness resection and submucosal tunneling endoscopic resection. Translational gastroenterology and hepatology. 2019; 4.
  5. Zhang J, Huang K, Ding S, et al. Clinical applicability of various treatment approaches for upper gastrointestinal submucosal tumors. Gastroenterol Res Pract. 2016; 2016.
  6. Du C, Linghu E. Submucosal tunneling endoscopic resection for the treatment of gastrointestinal submucosal tumors originating from the muscularis propria layer. Journal of Gastrointestinal Surgery. 2017; 21(12): 2100- 2109.
  7. Wang G, Yu, G, Xiang Y, et al. Submucosal tunneling endoscopic resection for large symptomatic submucosal tumors of the esophagus: A clinical analysis of 24 cases. The Turkish Journal of Gastroenterology. 2020; 31(1): 42.
  8. Marcella C, Sarwar S, Ye H, et al. Efficacy and Safety of Endoscopic Treatment for Gastrointestinal Stromal Tumors in the Upper Gastrointestinal Tract. Clinical Endoscopy. 2020.

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BOOK REVIEWS

A Patient’s Guide to Managing a Short Bowel (4th Edition)

January 2021 • Volume XLV, Issue 1

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Author: C.R. Parrish
Publication Year: 2016
Price: Free.
Book funded by Shire

Carol Rees Parrish MS, RDN provides a practical overview of short bowel syndrome (SBS) focusing on common problems and management approaches in A Patient’s Guide to Managing a Short Bowel (4th Edition) (publishing support from Shire, 2016). The book is well organized and written using friendly, easily understandable language. It provides high yield practical advice that can be readily incorporated into daily life. Patients will surely appreciate the numerous tables throughout the book highlighting various dietary options, both desirable and undesirable, the numerous oral rehydration solutions, including home recipes, and sample meal plans that have been organized by the presence or absence of a colon. The book also provides examples of common over-the-counter medications containing sugar thus potentially acting as unrecognized drivers of stool output. Through concrete and useful examples of everyday do’s and don’ts, patients can feel empowered and knowledgeable regarding their care.

For those seeking a deeper understanding or more information, Parrish offers ample online resources both embedded within the text and also listed in a table at the end of the book; however, the reader should note that many of these resources are more than 8-10 years old, and new information is likely available for some of the referenced topics. Additionally, the mental model of intestinal failure has been updated to consider short bowel syndrome distinct from other functional causes not related to resection or loss of bowel, such as chronic intestinal pseudoobstruction. Although much of the information presented within the book is applicable to both pediatric and adult patients with SBS, the target audience appears to be an adult population as there is no discussion regarding the unique nutritional considerations for infants and toddlers with SBS. Despite this, parents of children with SBS will still likely find the information helpful. Overall, A Patient’s Guide to Managing a Short Bowel offers practical information and recommendations, most notably related to nutritional interventions, for patients living with SBS in a way that is concise, applicable, and easily accessible.

Ethan A. Mezoff, MD
Assistant Professor of Clinical Pediatrics
Colleen B. Flahive, MD
Pediatric Gastroenterology Fellow
The Ohio State University College of
Medicine
Nationwide Children’s Hospital
Columbus, Ohio

John Pohl, M.D., Book Editor, is on the Editorial Board of Practical Gastroenterology

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FRONTIERS IN ENDOSCOPY, SERIES #69

Advances in Endoscopic Management of GERD: A Brief Review on TIF Procedure

January 2021 • Volume XLV, Issue 1
Mahmoud Mahfouz,Erika L. Graff,Tara Keihanian,Rajnish Mishra,Mohit Girotra

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INTRODUCTION

Gastroesophageal reflux disease (GERD) is arguably the commonest gastrointestinal (GI) pathology encountered by gastroenterologists, and primary care physicians, with prevalence reported to be up to 27.8% in the North America.1 GERD greatly impacts quality of life due to missed work days and leisure activities,2 and resultant increase in health-care costs with frequent clinic visits, diagnostic testing and medication use.

Lifestyle and dietary modifications are highly recommended as initial management strategy for GERD symptoms.3 Recommendations include exercise and weight loss for obese/overweight individuals, cessation of smoking and alcohol use, elevation of head-end of bed to 30 degrees, eliminating late night meals and avoiding trigger foods.4 Such modifications have physiologic effects on the GI tract, including decreased pressure on the gastroesophageal junction (GEJ)5 and normalization of lower esophageal sphincter (LES) pressure.6 First-line medical management of GERD is an eight-week trial of proton-pump inhibitor (PPI) therapy. In PPI non-responders or patients with “troublesome” dysphagia, the American Gastroenterological Association (AGA) recommends early endoscopic evaluation with biopsies for further assessment.7

Since medical therapy only alters the pH of the gastric refluxate, GERD may persist despite optimized medical therapy. Historically, surgical fundoplication and bariatric surgery, specifically the Roux-en-Y technique were the most common approaches to mitigate this issue. Surgery is usually reserved for those with desire for medication discontinuation, esophagitis persistent despite optimal therapy and structural abnormalities such as hiatal hernia.8 Surgery is predictably offered to patients with typical symptoms, who demonstrate abnormal esophageal pH, as evidence suggests that these patients are more likely to have resolution of their symptoms.9 Complications of traditional surgical Nissen fundoplication, as well as newer partial fundoplications, include dysphagia and gasbloat syndrome.10 Regurgitation and heartburn have been noted to recur in up to 29% and 35% of patients, respectively, after 10 years.11-12

In the last few years, new innovations in the field of endoscopy have resulted in several endoscopic strategies attempting to bridge the gap between medical (PPI) and surgical (Nissen and others) management of chronic GERD. The three procedures approved by the Food and Drug Administration (FDA) include Stretta, which delivers thermal energy to multiple sites in the LES and gastric cardia, producing a tissue-tightening effect related to heat-induced fibrosis, MUSE (Medigus Ultrasonic Surgical Endostapler), which uses 5 standard surgical staples (instead of fasteners) in 3 staggered rows to attach the gastric fundus to the esophagus, creating an anterior partial fundoplication, and TIF (Transoral Incisionless Fundoplication), which is anatomically and functionally similar to fundoplication, wherein the gastric fundus is folded up and around the distal esophagus and anchored with polypropylene fasteners. TIF targets the main anatomical mechanism involved in the pathophysiology of GERD, by reconstructing the GE valve (GEV). The goal of TIF procedure is to create a true flap valve around the GEJ by creating a 270-degree endoscopic fundoplication,13 and has shown favorable outcomes with low rates of adverse events, thus providing hope to poor surgical candidates.

Patient Selection for TIF Procedure

There are two commonly practiced approaches for endoscopic assessment of anti-reflux barrier of the GEJ; one by measuring the axial length of the hiatal hernia,14 and second by assessing the GE flap valve graded by the Hill classification, on a scale of I–IV, with higher value reflecting more severe disruption of the GEJ and less LES pressure.15 The endoscopic measurement of axial length of hiatal hernia can be less accurate due to effects of breathing and the physiological dynamics in the area,16 and for this reason, Hill approach is considered better and more accurate.

Traditionally, the presence of typical GERD symptoms and a positive response to PPI therapy increase the chances of superior outcomes following anti-reflux surgery.17 However, ~ 60% GERD patients report satisfaction with lifestyle modifications and/or medical therapy, and those with inadequate response and poor quality of life typically seek alternative treatment plans, including TIF. Conversely, for both typical and atypical symptoms of GERD, elevated pre-operative GERD health-related quality of life (GERDHRQL) score on PPI was found to be a predictor of successful outcome of TIF in patients with persistent symptoms despite medical therapy.18 This conundrum forms the pivotal challenge in appropriate patient selection.

Similar to the workup for surgical approach (Nissen fundoplication), pre-TIF assessment to support objective evidence of GERD must include pH impedance testing (i.e. pathologic acid reflux on ambulatory pH monitoring in the upright and supine positions), esophageal manometry (i.e. exclusion of motility disorders) and esophagogastroduodenoscopy (EGD) (i.e. mild Los Angeles Class A or B esophagitis).19 Excellent outcomes were reported in a prospective, randomized, multicenter TEMPO (TIF EsophyX vs Medical PPI Open Label) study when TIF was performed on GERD patients with Hill grades I/ II anatomy and effective esophageal motility.19-20 In this study, patients with severe erosive esophagitis (Los Angeles grade C or D), and hiatal hernias with Hill Grade > II were excluded. Moreover, lower success rates were reported in the RESPECT (Randomized EsophyX® vs. Sham/ Placebo Controlled Trial) trial, when patients with Hill grade III/IV hiatal hernias were included.21 Therefore, an optimal TIF candidate is one with chronic GERD with partial or complete symptom control on PPI therapy, and minimal anatomical distortion of the GEJ (absent or < 2 cm hiatal hernia or Hill grades I/II) and preserved motility. With appropriate patient selection, TIF can fill the “therapeutic gap” that exists between PPI and surgical options (laparoscopic fundoplication).

The TIF procedure might not be an ideal option for those with abnormal anatomy, which would prohibit the insertion and safe advancement of the EsophyX device, such as the presence of esophageal stricture/stenosis, esophageal diverticula or paraesophageal hernia. The procedure is also not advised for patients with bleeding disorders or esophageal varices, due to high risk of bleeding. Furthermore, patients with esophageal dysmotility, large hiatal hernias (> 2 cm) with Hill grade III-IV (if cannot be surgically repaired), active esophageal infection (fungal or bacterial) or inflammation (severe esophagitis), morbid obesity (BMI > 35), limited neck mobility and cardiopulmonary or other contraindications for endoscopy and/or general anesthesia should be excluded.

Evolution of TIF Procedure

The TIF procedure currently performed in the United States is a result of several years of evolution and development. The original iteration of this procedure was known as endoluminal fundoplication (ELF), first performed in 2005 in Europe, and within 2 years it was cleared to be used in the United States by the Food and Drug Administration (FDA).22-23 ELF involved a fundus-to-fundus fundoplication, with all fasteners deployed below the Z-line, to allow reduction of small hiatal hernia while fashioning longitudinal gastro-gastric plication, without creating a wrap.24 ELF paved path for the next generation of procedure (TIF 1.0), which allowed esophago-gastric fundoplication around the GEJ using the EsophyX device (EndoGastric Solutions, Redmond, WA, USA), wherein the fasteners were placed up to 1 cm above the Z line (just proximal to the GE junction), but again, a wrap was not performed.24 This technique underwent several refinements to reach its current format (TIF 2.0) which uses the EsophyX Z device (launched in 2017) to successfully replicate the principles and outcomes of traditional surgical fundoplication. TIF 2.0 combines partial fundoplication around the distal esophagus with fashioning a rotational wrap of the cardia and fundus circumferentially around the distal esophagus, and the fasteners are placed 1-3 cm above the Z-line.23

Description of TIF 2.0 Procedure25

The TIF 2.0 procedure ideally requires 2 operators; one to control the gastroscope and provide visualization, while the second to control the EsophyX Z device.

The procedure is performed under general anesthesia, with usage of a paralytic agent to induce muscle relaxation to minimize intraoperative diaphragmatic sliding movements. Also, mechanical ventilation with application of positive end-expiratory pressure (PEEP) is important to separate the diaphragmatic surface, which facilitates plication. Supine patient position is often favored to decrease liver pressure on the GE junction, and carbon dioxide (CO2 ) insufflation is preferred over air given less patient discomfort and safer profile in case of perforation.

Steps of TIF 2.0 procedure include:

(i) A pre-TIF EGD is performed to carefully examine the esophagus, stomach and duodenum, confirm the established diagnosis, and also document the anatomical landmarks including Z-line, diaphragmatic impingement and hiatal hernia (axial length and Hill grade) (Figure 1A.).

(ii) The EsophyX Z device is prepared for use by lubricating the channels of the device with mineral oil and lubricating the external parts of the device with water-soluble lubricant.

(iii) The gastroscope is inserted through the central channel of the EsophyX Z device, and the platform is then gently glided through the patient mouth into the stomach under constant visualization (Figure 1B.).

(iv) The tissue mold is closed and the scope is advanced 10-15 cm beyond the tissue mold and retroflexed to allow visualization of the GEJ throughout the procedure.

(v) GEV reconstruction starts with engagement of helical retractor into the tissue slightly distal to the Z-line, and then using the tissue mold of the device, the gastric fundus is circumferentially folded around the distal esophagus. All tissuemanipulating elements are then locked.

(vi) An integrated suction apparatus is activated to gently grasp the distal esophagus to position it in the abdominal cavity, distal to the diaphragm, as the EsophyX Z device is rotated to wrap the gastric fundus toward the lesser curvature of the stomach. Subsequently, two H-Shaped nonabsorbable fasteners are deployed above the GEJ, through apposed layers of esophageal and fundus tissue to anchor the repair (Figure 1C.)

(vii) The EsophyX Z device is rotated on its long axis and this sequence (retract, wrap and appose) is repeated to implant approximately 20 fasteners to create fusion of the esophageal and fundus tissues to create the final product, which is a full thickness, omega shaped, partial circumferential (270-degree wrap) gastroesophageal fundoplication (Figure 1D.).

OUTCOMES OF TIF PROCEDURE
(a) GERD symptoms and HRQL improvement

Resolution of typical GERD symptoms, such as heartburn and regurgitation, appears to be sustained after TIF in long-term follow-up studies. Normalization of reflux symptoms index scores has been reported in 73% in 6 months and 65% in 2-year follow-up.26-27

Two key long-term clinical studies evaluating the efficacy of TIF in the United States are TEMPO and RESPECT trials. In TEMPO trial (cross over trial between incomplete responders to PPI therapy and TIF 2.0 therapy), complete elimination of regurgitation was reported in 65% patients at 6 months, 87% at 3 years and 86% at 5 years.28-29 In comparison, RESPECT trial (TIF 2.0 versus a sham procedure with PPI therapy), 67% had improvement of regurgitation in 6 months and 72% remained asymptomatic in 12 months.21

Multiple meta-analyses,30-31 with pooled estimates from over 1000 patients, demonstrate a statistically significant improvement in GERDHRQL after TIF procedure (mean difference = 17.72; 95% CI: 17.31-18.14). A recent metaanalysis by Huang et al. abstracted from 13 prospective studies and 5 randomized control trials was remarkable for a decreased total number of reflux episodes, without reported gas-bloat symptoms after TIF compared to the PPI/sham groups.32 Passaretti et al. extended the follow-up to 10 years, and showed persistence of improved mean GERD-HRQL scores after TIF.33

Based on the current literature, TIF offers promising results for long-term symptomatic control in patients with typical GERD symptoms and presence of < 2 cm Hill grade I-II hiatal hernia. Additionally, TEMPO trial was also remarkable for improvement of atypical GERD symptoms, such as hoarseness, throat clearing, excess throat mucus, dysphagia, and cough in 80% of patients at 5-year follow-up.29 Based on these results, the TIF procedure appears to be a valuable alternative for well-selected patients with significant atypical symptoms.

(b) Anti-secretory (PPI) Medication Cessation

PPI cessation is considered a robust measure of symptom and quality of life (QoL) improvement in patients with chronic GERD. Complete cessation of PPIs was reported in up to 71% patients in 3 years and 46% patients 5 years after TIF in the TEMPO trail,28-29 and similar trends were observed in the RESPECT trial as well.21 Ten year follow-up data from a separate cohort was equally reassuring, with rates of patients who successfully stopped or halved anti-secretive therapy 2, 3, 5, 7, and 10 years after the TIF procedure being 86.7 %, 84.4 %, 73.5 %, 83.3 %, and 91.7 %, respectively.33 Similarly, patients remained in clinical remission off anti-secretory therapy for significantly longer period of time after TIF (60% at 6 months), when compared to sham procedure.27

(c) Objective Physiological Outcomes

TIF has been shown to achieve normalization of acid exposure in the distal esophagus in up to 69%35 in European studies,34 and 57% in the United States TIF registry.27 TIF also heals esophagitis in between 77-100% of patients, which is arguably a more clinically relevant metric.21,29 However, along the lines of previous observations evaluating GERD therapies,35-37 recent TIF studies confirm a poor correlation between post-TIF symptom control and pH normalization.19,21

In addition, TIF is thought to decrease the number of postprandial transient LES relaxation (TLESR) episodes, resulting in significant reduction in the GEJ distensibility.38 It also selectively reduces liquid-containing reflux episodes, whereas gas reflux events remain unaffected. This accounts for gas ventilation following the TIF procedure while avoiding gas bloat symptom commonly accompanying laparoscopic Nissen fundoplication.

(d) Durability

Different iterations of TIF have been successfully performed over a decade now, with constant improvisations in its technique and equipment. In literature, TIF failures have been defined as persistent GERD symptoms or worsening GERDHRQL scores. Previous per-oral incisionless fundoplication techniques (ELF and TIF 1.0, both of which created plication without a wrap) reported higher failure rate (~ 36%)39-40, with 5% re-operation rate in the TEMPO trial,29 which is comparable to 5-6% re-operation rates of surgical fundoplication.41 This occurred for a variety of reasons, including lack of wrap around the plication, device malfunction at implantation and persistent symptoms due to hiatal hernia or displaced TIF valve.29 TEMPO and RESPECT trials in the US,21,28-29 and randomized sham trial in Europe33 have provided long-term (5 and 10 year) durability data on TIF 2.0, and supported nonsignificant change in symptom control over time.

(E) Safety and Adverse Events and Post-Operative Care

Across all studies, a 2.4% complication rate for TIF has been reported.32 The most common reported complications include perforation, bleeding, pleural effusion and dysphagia.32 Mortality directly related to TIF procedure is extremely uncommon, with only one reported death till date.42 Traditional anti-reflux surgeries have higher incidence of post-operative dysphagia, bloating and excess flatulence in comparison to TIF procedure. In fact, preexisting dysphagia, gas bloat, and flatulence reportedly improved after TIF.29 Although, minor adverse events such as post-operative nausea and abdominal discomfort are common after TIF, major adverse events such as pleural effusion, mediastinitis, abscess, and esophageal perforation are possible.43-44

(f) Treatment Failure and Surgical Revision

Similar to surgical fundoplication, treatment failure and recurrent symptoms after TIF procedure have been reported, with up to 5-18% patients requiring surgical revision after TIF failure.29,45-46 In TEMPO 5-year follow-up, surgical revision was required in 5% after the initial TIF procedure.29 However, post-TIF failure surgical revision is challenging. In order to safely perform Nissen fundoplication, the TIF wrap needs to be freed by cutting the fasteners, however due to scar tissue and adhesions, surgery carries higher risk of complications especially gastric wall injuries such as perforation, bleeding, abscess formation. Furnée et al. reported 27% gastric perforation during surgical revision after failed TIF procedure,45 which is higher than 13% reported gastric perforation after Nissen revision47 and 2% observed gastric perforation during primary anti-reflux surgery.48-49 Furthermore, incidence of dysphagia in post-TIF surgical revision patients appears high.45

Patients with hiatal hernia > 2 cm were excluded from the TEMPO clinical trial.29 Testoni et al. included patients with any Hill grade or hiatal hernia size in their 6-year trial, and noted that patients with Hill grade II-IV or hiatal hernia > 2cm had less favorable response at 12 months.50 Number of fasteners released also has been reported as an independent factor in predicting optimal outcome after the TIF procedure.50 [Testoni et al.; responders vs non-responders: (10 ± 2 vs. 14 ± 2; p = 0.01)]. Furthermore, Rabach et al. postulated that anatomic structures around the GE junction such as the phreno-esophageal ligament and esophageal fat pad are not amenable to endoscopic correction, resulting in long term TIF failure.51 Moreover, Bell et al. noted hiatal hernia recurrence, disrupted wrap, traction and adhesion from the fasteners during revision laparoscopic anti-reflux surgery, thereby explaining TIF failure.52

(g) Cost and Coverage

For years TIF was considered an experimental option in lieu of surgical approach, and hence not covered by Medicare/Medicaid or commercial insurances, requiring patients to pay ballpark of the cost out of pocket. As TIF procedure evolved over years, with establishment of its efficacy and long term beneficial effects through clinical trials, the Centers of Medicare and Medicaid Services (CMS) announced on January 1, 2018 coverage of TIF 2.0 procedure with the EsophyX device at all Medicare Administrative Contractors.53 More commercial insurers followed the lead to support reimbursing TIF procedure. Despite having a universal CPT code (43210) and increasing support from CMS and other private insurers, a great deal of communication and written approval requests is usually required before scheduling the procedure.53

Post-operative Care after TIF Procedure

In most centers, patients are admitted in the hospital for a short observation after TIF procedure, with care emphasizing on control of sub-sternal discomfort/ pain and aggressive management of nausea to prevent disruption of plication with vomiting/ retching. Additionally, patients are monitored for bleeding or any delayed cardiopulmonary complications or post-procedure infections/leaks. If patient develops any leukocytosis or features of systemic inflammatory response syndrome (SIRS) like tachycardia, fever, tachypnea, contrast studies (gastrograffin based) are performed to investigate a possible leak. If immediate post-operative course is uneventful, then patient is placed on a stepwise dietary plan, entailing a 2 week full liquid diet, 1 week puree diet, 1 week soft diet followed by modified regular diet avoiding hard dried food, and finally regular diet in the 6th week. This graduated regimen is believed to promote optimal healing response by improving esophageal muscular strength and peristaltic coordination in the postoperative period.

Combined TIF and Laparoscopic Hiatal Hernia Repair (LHHR)

Patients with hiatal hernias > 2 cm may become candidates for TIF if the hernia can be reduced to ≤ 2 cm. Clinical data extrapolated from existing studies have demonstrated that concomitant LHHR immediately followed by TIF 2.0 procedure is safe and effective in patients requiring repair of both anatomical defects.21,28-29,33-34

Although comprehensive literature on this combined (TIF+LHHR) approach is still evolving, but, in available studies, it appears to have similar symptom control and normalization of esophageal pH, without the gas-bloat syndrome that deterred patients from undergoing anatomic repair in the past.43,54

TIF versus Laparoscopic

Nissen Fundoplication (LNF) Current data is lacking a parallel long-term controlled clinical trial evaluating the utility and response to TIF versus LNF. Most recently Richter et al. published a systematic review and network meta-analysis to summarize the efficacy of TIF vs LNF vs PPI use. GERD-HRQL were noted to be higher in TIF recipients, however patients with LNF procedure had higher LES pressure (0.78 vs 0.72) and decreased percent time pH <4 in longterm (0.99 vs 0.32).55

Laparoscopic Magnetic

Sphincter Augmentation (LINX) Another minimally invasive procedure that has shown promising result is laparoscopic magnetic sphincter augmentation, also know as the LINX procedure. The device was approved by the FDA in 2012, and consists of an expandable dynamic ring of magnetic beads, which increases the length and pressure of the esophagogastric junction. Patients with LA class A or B esophagitis are the best candidates for LINX procedure; in contrary, any size hiatal hernia requires repair before the LINX procedure. The least favorable candidates for the LINX procedure are those with gastroparesis, prior upper abdominal surgeries, metal allergies or presence of pacemaker or defibrillator.51 Similar to TIF, LINX procedure has also shown promising result in improvement of GERD-HRQL to 3.3-6 post procedure.56-60 Acid exposure improvement after LINX has been reported between 50-80%. PPI secession reported to be achieved in 72-85.3% of patients in long term studies.56-60 In comparison to TIF, LINX procedure has higher side effect profile; dysphagia has been reported in up to 70% of cases, regurgitation in 50% as well as inability to belch. To date, there is no prospective controlled trial comparing efficacy of LINX procedure with TIF procedure.

Conclusion

To summarize, TIF is a minimally invasive incisionless endoscopic procedure, which has demonstrated promising outcome in long-term symptomatic management of chronic GERD, with a shorter recovery time and superior safety profile compared to surgical equivalent options. With over 22,000 TIF 2.0 procedures performed worldwide using the latest iteration of EsophyX Z device, along with coverage benefit for all Medicare beneficiaries throughout the United States (using CPT code 43210 EGD esophago-gastric fundoplasty + APC 5331 Complex GI procedures), and increasing support from other insurance carriers, TIF 2.0 appears to be well positioned to fill the ‘therapy gap’ between medical treatments (PPI) and invasive surgical procedures (laparoscopic Nissen fundoplication) for management of chronic GERD.

References

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  6. Ness-Jensen E, Lindam A, Lagergren J, Hveem K. Tobacco smoking cessation and improved gastroesophageal reflux: a prospective population-based cohort study: the HUNT study. Am J Gastroenterol. 2014. 109(2): p. 171-7.
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  10. Du X, Wu JM, Hu ZW et al., Laparoscopic Nissen (total) versus anterior 180° fundoplication for gastro-esophageal reflux disease: A meta-analysis and systematic review. Medicine (Baltimore), 2017. 96(37): p. e8085.
  11. Broeders JA, Rijnhart-de Jong HG, Draaisma WA, Bredenoord AJ, Smout AJ, Gooszen HG. Ten-year outcome of laparo scopic and conventional nissen fundoplication: randomized clinical trial. Ann Surg, 2009. 250(5): p. 698-706.
  12. Dallemagne B, Weerts J, Markiewicz S, et al. Clinical results of laparoscopic fundoplication at ten years after surgery. Surg Endosc, 2006. 20(1): p. 159-65.
  13. Chang KJ, Bell R. Transoral Incisionless Fundoplication. Gastrointest Endosc Clin N Am, 2020. 30(2): p. 267-289.
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  16. Kahrilas PJ, Kim HC, Pandolfino JE. Approaches to the diagnosis and grading of hiatal hernia. Best Pract Res Clin Gastroenterol. 2008;22(4):601-16.
  17. Campos GM, Peters JH, DeMeester TR, et al., Multivariate analysis of factors predicting outcome after laparoscopic Nissen fundoplication. J Gastrointest Surg, 1999. 3(3): p. 292-300.
  18. Bell RCW, Fox MA, Barnes WE, et al. Univariate and multivariate analyses of preoperative factors influencing symptomatic outcomes of transoral fundoplication. Surg Endosc, 2014. 28(10): p. 2949-58.
  19. Trad KS, Simoni G, Barnes WE, et al. Efficacy of transoral fundoplication for treatment of chronic gastroesophageal reflux disease incompletely controlled with high-dose protonpump inhibitors therapy: a randomized, multicenter, open label, crossover study. BMC Gastroenterol, 2014. 14: p. 174.
  20. Trad KS, Barnes E, Simoni G, et al. Transoral incisionless fundoplication effective in eliminating GERD symptoms in partial responders to proton pump inhibitor therapy at 6 months: the TEMPO Randomized Clinical Trial. Surg Innov, 2015. 22(1): p. 26-40.
  21. Hunter JG, Kahrilas PJ, Bell RCW, et al. Efficacy of transoral fundoplication vs omeprazole for treatment of regurgitation in a randomized controlled trial. Gastroenterology, 2015. 148(2): p. 324-333.e5.
  22. Cadière GB, Rajan A, Rqibate M, et al. Endoluminal fundoplication (ELF) – evolution of EsophyX, a new surgical device for transoral surgery. Minim Invasive Ther Allied Technol, 2006. 15(6): p. 348-55.
  23. Cadière GB, Buset M, Muls V, et al. Antireflux transoral incisionless fundoplication using EsophyX: 12-month results of a prospective multicenter study. World J Surg, 2008. 32(8): p. 1676-88.
  24. Bazerbachi F, Krishnan K, Abu Dayyeh BK. Endoscopic GERD therapy: a primer for the transoral incisionless fundoplication procedure. Gastrointest Endosc, 2019. 90(3): p. 370-383.
  25. Endogastric solutions – https://www.endogastricsolutions. com/technology/safety-info/
  26. Bell RCW, Mavrelis PG, Barnes WE, et al. A prospective multicenter registry of patients with chronic gastroesophageal disease receiving transoral incisionless fundoplication. J Am Coll Surg 2012; 215: 794–809.
  27. Bell RC, Barnes WE, Carter BJ, et al., Transoral incisionless fundoplication: 2-year results from the prospective multicenter U.S. study. Am Surg, 2014. 80(11): p. 1093-105.
  28. Trad KS, Fox MA, Simoni G, et al. Transoral fundoplication offers durable symptom control for chronic GERD: 3-year report from the TEMPO randomized trial with a crossover arm. Surg Endosc. 2017 Jun;31(6):2498-2508. doi: 10.1007/ s00464-016-5252-8. Epub 2016 Sep 21.
  29. Trad KS, Barnes WE, Prevou ER, et al. The TEMPO Trial at 5 Years: Transoral Fundoplication (TIF 2.0) Is Safe, Durable, and Cost-effective. Surg Innov, 2018. 25(2): p. 149-157.
  30. McCarty TR, Itidiare M, Njei B, Rustagi T. Efficacy of transoral incisionless fundoplication for refractory gastroesophageal reflux disease: a systematic review and meta-analysis. Endoscopy, 2018. 50(7): p. 708-725.
  31. Richter JE, Kumar A, Lipka S, Miladinovic B, Velanovich V. Efficacy of Laparoscopic Nissen Fundoplication vs Transoral Incisionless Fundoplication or Proton Pump Inhibitors in Patients With Gastroesophageal Reflux Disease: A Systematic Review and Network Meta-analysis. Gastroenterology, 2018. 154(5): p. 1298-1308.e7.
  32. Huang X, Chen S, Zhao H, et al. Efficacy of transoral incisionless fundoplication (TIF) for the treatment of GERD: a systematic review with meta-analysis. Surg Endosc 2017;31(3):1032–44.
  33. Testoni PA, Testoni S, Distefano G, Mazzoleni G, Fanti L, Passaretti S. Transoral incisionless fundoplication with EsophyX for gastroesophageal reflux disease: clinical efficacy is maintained up to 10 years. Endosc Int Open, 2019. 7(5): p. E647-e654.
  34. Håkansson B, Montgomery M, Cadiere GB, et al., Randomised clinical trial: transoral incisionless fundoplication vs. sham intervention to control chronic GERD. Aliment Pharmacol Ther, 2015. 42(11-12): p. 1261-70.
  35. Milkes D, Gerson LB, Triadafilopoulos G. Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal and intragastric pH in patients with gastroesophageal reflux disease (GERD). Am J Gastroenterol, 2004. 99(6): p. 991-6.
  36. Velanovich V, Karmy-Jones R. Measuring gastroesophageal reflux disease: relationship between the Health-Related Quality of Life score and physiologic parameters. Am Surg, 1998. 64(7): p. 649-53.
  37. Markus PM, Horstmann O, Kley C, Neufang T, Becker H. Laparoscopic fundoplication. Surg Endosc, 2002. 16(1): p. 48-53.
  38. Rinsma NF, Smeets FG, Bruls DW, et al. Effect of transoral incisionless fundoplication on reflux mechanisms. Surg Endosc, 2014. 28(3): p. 941-9.
  39. Witteman BP, Strijkers R, de Vries E, et al. Transoral incisionless fundoplication for treatment of gastroesophageal reflux disease in clinical practice. Surg Endosc. 2012;26(11):3307- 3315.
  40. Muls V, Eckhardt AJ, Marchese M, et al. Three-year results of a multicenter prospective study of transoral incisional fundoplication. Surg Innov. 2013;20:321-330.
  41. Dallemagne B, Sanchez MA, Francart D, et al. Long-term results after laparoscopic reoperation for failed antireflux procedures. Br J Surg. 2011 Nov;98(11):1581-7.
  42. Demyttenaere SV, Bergman S, Pham T, et al. Transoral incisionless fundoplication for gastroesophageal reflux disease in an unselected patient population. Surg Endosc. 2010 Apr;24(4):854-8.
  43. Ihde GM, Besancon K, Deljkich E. Shortterm safety and symptomatic outcomes of transoral incisionless fundoplication with or without hiatal hernia repair in patients with chronic gastroesophageal reflux disease. Am J Surg 2011; 202: 740–747.
  44. Barnes WE, Hoddinott KM, Mundy S, Williams M. Transoral incisionless fundoplication offers high patient satisfaction and relief of therapyresistant typical and atypical symptoms of GERD in community practice. Surg Innov 2011; 18: 119–129.
  45. Furnée EJ, Broeders JA, Draaisma WA, et al. Laparoscopic Nissen fundoplication after failed Esophyx fundoplication. Br J Surg 2010; 97:1051–1055
  46. Perry KA, Linn JG, Eakin JL, Onders RP, Velanovich V, Melvin WS. Transoral incisionless fundoplication does not significantly increase morbidity of subsequent laparoscopic Nissen fundoplication. J Laparoendosc Adv Surg Tech A 2013; 23:456–458
  47. Furnee EJ, Draaisma WA, Broeders IA, Gooszen HG. Surgical reintervention after failed antireflux surgery: a systematic review of the literature. J Gastrointest Surg 2009; 13: 1539– 1549.
  48. Chrysos E, Tsiaoussis J, Athanasakis E, Zoras O, Vassilakis JS, Xynos E. Laparoscopic vs open approach for Nissen fundoplication. A comparative study. Surg Endosc 2002; 16: 1679– 1684.
  49. Bais JE, Bartelsman JF, Bonjer HJ, et al. Laparoscopic or conventional Nissen fundoplication for gastro-oesophageal reflux disease: randomised clinical trial. The Netherlands Antireflux Surgery Study Group. Lancet 2000; 355: 170– 174.
  50. Testoni PA, Testoni S, Mazzoleni G, Vailati C, Passaretti S. Long-term efficacy of transoral incisionless fundoplication with Esophyx (Tif 2.0) and factors affecting outcomes in GERD patients followed for up to 6 years: a prospective single-center study. Surg Endosc. 2015 Sep;29(9):2770-80.
  51. Rabach L, Saad AR, Velanovich V. How to choose among fundoplication, magnetic sphincter augmentation or transoral incisionless fundoplication. Curr Opin Gastroenterol. 2019 Apr 24.
  52. Bell RC, Kurian AA, Freeman KD. Laparoscopic anti-reflux revision surgery after transoral incisionless fundoplication is safe and effective. Surg Endosc. 2015 Jul;29(7):1746-52.
  53. Endogastric solutions- https://www.endogastricsolutions.com/ tif-procedure/reimbursement/
  54. Janu P, Shughoury AB, Venkat K, et al. Laparoscopic Hiatal Hernia Repair Followed by Transoral Incisionless Fundoplication With EsophyX Device (HH + TIF): Efficacy and Safety in Two Community Hospitals. Surg Innov. 2019 Dec; 26(6):675-686.
  55. Richter JE, Kumar A, Lipka S, Miladinovic B, Velanovich V. Efficacy of Laparoscopic Nissen Fundoplication vs Transoral Incisionless Fundoplication or Proton Pump Inhibitors in Patients With Gastroesophageal Reflux Disease: A Systematic Review and Network Meta-analysis. Gastroenterology. 2018 Apr;154(5):1298-1308.e7.
  56. Lipham JC, DeMeester TR, Ganz RA et al. The LINX(R) reflux management system: confirmed safety and efficacy now at 4 years. Surg Endosc 2012; 26: 2944–9.
  57. Bonavina L, Saino G, Bona D, Sironi A, Lazzari V. One hundred consecutive patients treated with magnetic sphincter augmentation for gastroesophageal reflux disease: 6 years of clinical experience from a single center. J Am Coll Surg 2013; 217: 577–85.
  58. Schwameis K, Schwameis M, Zorner B et al. Modern GERD treatment: feasibility of minimally invasive esophageal sphincter augmentation. Anticancer Res 2014; 34: 2341–8.
  59. Smith CD, DeVault KR, Buchanan M. Introduction of mechanical sphincter augmentation for gastroesophageal reflux disease into practice: early clinical outcomes and keys to successful adoption. J Am Coll Surg 2014; 218: 776–81.
  60. Ganz RA, Edmundowicz SA, Taiganides PA et al. Long-term outcomes of patients receiving a magnetic sphincter augmentation device for gastroesophageal reflux. Clin Gastroenterol Hepatol 2016; 14(5): 671–77.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #206

Pediatric Short Bowel Syndrome:Nutritional Care

January 2021 • Volume XLV, Issue 1
Danielle Wendel,Rachel Kay,Erin Walsh,Simon Horslen

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Short bowel syndrome (SBS) is the most common cause of pediatric intestinal failure. The goal of treatment for SBS is intestinal rehabilitation involving the transition from parenteral nutrition to enteral autonomy. In order to achieve this, intestinal adaptation must occur with resulting structural and functional changes. Enteral feeds are a necessary factor in the promotion of adaptation. Children with SBS have significant malabsorption necessitating close monitoring of growth and laboratory studies in order to prevent deficiencies and maintain adequate growth. With the many complexities of this vulnerable population, it is important to have a multidisciplinary approach to their care as demonstrated by the success of intestinal rehabilitation programs.

Introduction

Intestinal failure occurs when the intestine is unable to absorb the necessary fluid and nutrition to support growth and development. The most common etiology of intestinal failure is short bowel syndrome (SBS), a term used to describe a critical loss of functional bowel length. Pediatric SBS often occurs as a result of surgical resection secondary to acquired gastrointestinal issues such as necrotizing enterocolitis or volvulus, or congenital anomalies such as gastroschisis and/ or intestinal atresias (see Table 1). The goal of intestinal rehabilitation is to promote adaptation, the process by which the remaining intestine undergoes functional and histological changes in order to increase absorption after resection.1 One of the most important stimulators of adaptation is intestinal exposure to nutrients. Over time, if carefully monitored and managed, most children with SBS will be able to transition from parenteral nutrition (PN) dependence to enteral autonomy.2

Nutrition Assessment

A thorough nutrition assessment is important for the management of pediatric patients with SBS. See Table 2 for baseline nutrition evaluation components. Nutrition reassessment should occur regularly with frequent reevaluation for the child on home PN. Evaluation can decrease in frequency according to the patient’s specific needs, but even older children who have become enterally autonomous require a full nutritional assessment at least annually. Management by a multidisciplinary team (including physician, pediatric surgeon, registered nurse, registered dietitian, and pharmacist) has been shown to improve morbidity and mortality for patients with SBS as well as decrease reliance on PN.3,4

Growth goals for patients with SBS are the same as other pediatric patients although growth failure is common.5-7 Weight gain at a lower percentile for age is acceptable while on PN if linear growth is tracking consistently along the child’s established growth curve. Children with SBS are at particularly high risk for growth failure in the first two years of life and during their adolescent years, both periods of high-expected growth.5,7 Some children who progress to enteral autonomy in their childhood years may require re-initiation of PN in their adolescent years if they demonstrate growth delays or other nutrient deficiencies.

Calculating Nutritional Needs

Provision of adequate calories and nutrients can promote age appropriate growth and development. Avoidance of overfeeding patients who are PNdependent is also critical in the prevention of intestinal failure associated liver disease (IFALD).8 Calories should be decreased for patients with excessive weight gain or those with weight-forlength or BMI >95th percentile for age. Generally, calories from PN are not reduced with introduction of enteral nutrition (EN) until tolerance and weight gain is established with feeds. As a result of malabsorption, enterally autonomous children with SBS may require enteral intake up to 200-250 kcal/kg/day in order to achieve adequate growth9,10 (Table 3).

Protein needs for these patients are also higher than expected for age due to increased gastrointestinal losses. Infants who are PN dependent may require up to 4 g/kg/day while older children may require 2-3 g/kg/day of protein from a combination of intake types even into adolescent years to maintain appropriate growth and development.9,10

Fluid needs to maintain hydration are typically higher than age matched controls due to high GI losses. Actual fluid needs may vary depending on the length of remaining bowel, portion of remaining bowel (those with preserved colon often have lower fluid requirements), and total daily stool or ostomy output. Some patients who are enterally autonomous may have even higher fluid requirements of up to 150-200 mL/kg due to higher GI losses. Furthermore, these increased losses often necessitate a higher sodium provision, both parenterally while receiving PN, and enterally, after enteral autonomy is attained.

Laboratory Monitoring

With the significant risk of nutrient deficiencies, regular laboratory monitoring is required. This is especially important for patients who are on parenteral nutrition. There is significant variation in the frequency of lab monitoring recommended by different intestinal rehabilitation centers and authors.11-13 See Table 4 for a suggested lab monitoring protocol.

Parenteral Nutrition

Careful management of PN by multidisciplinary intestinal rehabilitation teams has allowed for significant improvements in survival as a result of decreases in complications associated with PN and the required central venous access.14 Recent advances in PN include:

  • New lipid formulations that have helped decrease IFALD and,
  • Careful management of micronutrient delivery.

However, challenges remain with frequent product shortages of nearly all PN components.

Until recently, the only FDA-approved intravenous lipid emulsion (IVLE) in the U.S. was soybean oil-based Intralipid™ (Baxter/Fresenius Kabi). These products contain high levels of proinflammatory omega-6 fatty acids and hepatotoxic phytosterols shown to contribute to development and progression of IFALD.15 In order to minimize these negative effects, Intralipid™ doses are often restricted to 0.5-1.0g/kg/day with improvement in liver disease. This change typically necessitates an increase in glucose infusion rates to make up for lost lipid calories. High glucose infusion rates can further contribute to IFALD. To help address these issues, Omegaven™ (Fresenius Kabi), a fish oil-based lipid emulsion consisting of only omega-3 fatty acids, was introduced in the early 2000s. Because it was found to successfully reverse cholestasis in IFALD,16 Omegaven™ was FDA-approved in 2018 for use in children with PN-associated cholestasis. Concerns have been raised regarding development of fatty acid abnormalities related to the isolated provision of omega-3 fatty acids long-term. Recently the FDA approved SMOFlipid™ (Fresenius Kabi) for use in adults. It is currently being widely used off-label for children with SBS. SMOFlipid™ is a mixedlipid emulsion consisting of 30% soy, 30% MCT, 25% olive, and 15% fish oil. Studies of children with intestinal failure have shown prevention of IFALD with SMOFlipid™.17-19 Fish-oil lipid emulsion may still be necessary to treat cholestatic IFALD if it develops despite use of SMOFlipid™. While Omegaven™ is typically dosed at 1 gm/kg/ day, SMOFlipid™ has been shown to be safe at higher doses allowing for an improved balance of calories. There is evidence that at least 2 g/kg/day of SMOFlipid™ is necessary to prevent and treat essential fatty acid deficiency.20,21 With changes in the amount of fatty acids provided with various IVLE, it is suggested that the individual levels of fatty acids, specifically linoleic acid, alphalinolenic acid, Mead acid, and the triene-to-tetraene ratio all be taken into account when considering the fatty acid status of a patient.22 Table 5 compares the contents of the three IVLE commonly used in pediatric SBS.23

Enteral Nutrition

In order to promote adaptation and prevent intestinal atrophy, enteral feeds are started as soon as possible after intestinal resection.24,25 Some children can achieve nutritional goals by mouth while others may require a feeding tube. With the heterogenous nature of SBS, there is no optimal feeding regimen or advancement schedule that is appropriate for all patients, although in general, initial trophic feeds are started and advanced slowly. Advancement is continued if stool frequency and volume does not drastically increase. For patients with an ostomy, goal output is typically <30-40ml/kg/day, although patients may tolerate higher amounts without significant dehydration or electrolyte imbalances as long as the output and laboratory studies are carefully monitored.

Human breast milk is preferred as it contains growth factors, immunoglobulins, and other components that stimulate adaptation.26 If breast milk is not available, elemental formula has historically been used, although there is evidence in animal studies that more complex nutrients promote adaptation.27 Human studies have been small and do not clearly show benefit of one type of feeding over another.25 With a lower osmotic load, children with SBS often tolerate larger volumes of lower caloric density formula, so it is our practice to start with dilute standard infant formula. Typically, this involves starting with 15 kcal/oz formula for infants and 20 kcal/oz for older children and delaying increasing caloric density until tolerating goal volume feeds and PN is being weaned.

The increased interest in whole food-based formulas has brought us commercially available, nutritionally complete products that resemble a blenderized feed. While some patients require blenderized feeds to be diluted, as they often have a high caloric density, others, especially those with a colon segment, tolerate them well. There is a likely benefit from the significant fiber content in many blenderized formulas which not only acts as a prebiotic, but slows down intestinal transit allowing more time for absorption, and provides the fuel for colonocytes to make short chain fatty acids providing additional calories to the patient.28,29

Children with SBS are at high risk for developing oral aversion due to their complicated medical history and the limitations on enteral feeds early on. It can also be a limiting factor in the ability to wean a patient off of PN as patients tend to tolerate larger amounts of food orally even if they do not tolerate larger volumes or more calorically dense formula. In order to avoid oral aversion, it is important to start oral feeds as early as possible even if the feed volume is minimal. With improvements in long-term PN management, there is less pressure to quickly advance enteral feeds allowing infants to develop the necessary oral skills. Although many programs use gastrostomy tubes for slow continuous feeding, delay of gastrostomy placement may help achieve these early oral feeding goals and prevent development of oral aversion by focusing all feeding efforts on the oral route. If patients are being tube fed, feeds can be held to allow for bottle feeds several times per day. A nocturnal regimen can give the child time off the pump during the day and help to stimulate hunger to aid in oral intake.

As the child approaches 6 months corrected age, age-appropriate foods should be introduced with a focus on vegetables, proteins, and complex carbohydrates. Children with SBS need to follow a diet low in sugar (natural, added, sugar alcohols [sorbitol, mannitol, xylitol, erythritol], or artificial sweeteners) as sugars and sweeteners can create an osmotic load contributing to increased stool output. Sugars can also worsen small intestinal bacterial overgrowth which can cause diarrhea, abdominal distention, emesis, poor growth, intestinal bleeding, and may contribute to IFALD.30 While some sugar and artificial sweeteners may be tolerated, following the recommendation to avoid sweet tasting food in young children may prevent them from developing a preference for sweet foods.

Micronutrient Deficiencies

Children with SBS are at high risk for multiple micronutrient deficiencies while receiving full PN, during the transition to enteral nutrition, and once enterally autonomous.31 In recent years, PN component shortages have become more common resulting in deficiencies.32 In order to address individual trace element deficiencies in PN-dependent patients, it is important to be able to adjust them individually. Use of commercially available standard pediatric PN trace element solutions can also result in manganese and chromium toxicity as these micronutrients are both found as contaminants in PN. For these reasons, separate dosing of trace elements is recommended for pediatric SBS patients.

The degree of micronutrient risk and deficiencies vary depending on the length of bowel and which portions of the intestine remain. Those with loss of the terminal ileum are at higher risk for fat soluble vitamin deficiencies, vitamin B12 deficiency, as well as essential fatty acid deficiency. With increased overall gastrointestinal losses, patients are also at risk of sodium, magnesium, and zinc deficiencies. While there are numerous deficiencies seen in SBS, some of the most common include iron, fat-soluble vitamins, vitamin B12, and iodine.

Iron

Iron deficiency is the most common deficiency seen in SBS. Iron infusions are often needed for those receiving significant amounts of PN and enteral supplementation in those off PN. Iron is not typically included in PN, although iron dextran has been added to lipid-free PN by some groups.33 While children who have reached enteral autonomy will likely tolerate enteral iron supplementation, children receiving full PN support will likely require IV iron infusions to treat and prevent iron deficiency. Iron sucrose has traditionally been used anywhere from weekly to monthly in order to replete and maintain iron stores. More recently ferric carboxymaltose has been used in patients with inflammatory bowel disease with iron deficiency. It is given at a higher dose than iron sucrose and has structural alterations that lead to longer duration of drug activity.34 Hypophosphatemia, which can be severe and symptomatic, has been associated with ferric carboxymaltose making it essential to follow patient labs and clinical status in the weeks following infusion.35,36 With careful monitoring, ferric carboxymaltose may help SBS patients require less frequent infusions (and line access) with improved iron status.

Fat-soluble Vitamins

Fat malabsorption is a common complication of SBS and a factor in the development of fatsoluble vitamin deficiencies. The doses of fatsoluble vitamins required for enterally autonomous patients can be quite high secondary to significant malabsorption. Vitamin A deficiency tends to respond well to enteral supplementation while vitamin E often requires a water-soluble formulation to optimize absorption. The dose of vitamin D included in the parenteral multivitamin is rarely enough to prevent vitamin D deficiency requiring additional supplementation.37 With no separate parenteral form of vitamin D available in the United States, vitamin D deficiency that is refractory to enteral supplementation may require transition to calcitriol. There is a significant amount of vitamin E in both SMOFlipid™ and Omegaven™, typically preventing vitamin E deficiency until patients are off intravenous lipids (Table 5).

Vitamin B12

Vitamin B12 requires the terminal ileum for foodbound B12 absorption. Deficiency can lead to megaloblastic anemia and irreversible neurologic changes. As it is supplemented in PN, deficiency is often not an issue until patients are enterally autonomous. For monitoring, it is important to check both a B12 and methylmalonic acid level, as serum B12 levels can be unreliable.38 Elevated methylmalonic acid levels are found in B12 deficiency, but can also be seen in small intestinal bacterial overgrowth so it is important to evaluate the patient’s entire clinical picture when interpreting these labs.39,40 Supplementation for children with SBS is most reliable in the injectable and nasal forms although sublingual preparations may be used as well. Oral B12 supplements are typically not useful in SBS due to significant malabsorption, the loss of the distal ileum in many patients, and the small amount of B12 that is passively absorbed when given in high doses via the oral route.38

Iodine

Iodine is another micronutrient of concern for children who are fully dependent on PN (>70% of calories provided by PN) as it is not routinely included in PN solutions in the United States and is important for growth and development. Monitoring of thyroid hormones, thyroglobulin, as well as urine iodine levels can help identify patients with iodine deficiency.11,41 Iodine deficiency should be considered for urinary iodine levels <100 mcg/L; <50 mcg/L indicates moderate, and <20 mcg/L, severe deficiency.42 Repletion of iodine can be difficult to achieve in children who are fully PN dependent, as they will not likely absorb an enteral supplement such as iodized salt. The use of ultradilute potassium iodide or topical iodine may be useful.43

Conclusion

Nutritional management is a major focus of intestinal rehabilitation in children with pediatric SBS. Multidisciplinary intestinal rehabilitation programs have been shown to improve the care and outcomes for this medically and surgically complex population. With careful monitoring of growth and nutritional lab values, prevention of complications associated with PN, and transition to enteral feeds with slow advancement, intestinal adaptation and enteral autonomy is achievable in most children with SBS.

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  20. Carey AN, Rudie C, Mitchell PD, et al: Essential fatty acid status in surgical infants receiving parenteral nutrition with a composite lipid emulsion: a case series. J Parenter Enteral Nutr. 2019;43(2):305- 310.
  21. Memon N, Hussein K, Hegyi T, et al: Essential fatty acid deficiency with SMOFlipid reduction in an infant with intestinal failure-associated liver disease. J Parenter Enteral Nutr. 2019;43(3):438-441.
  22. Gramlich L, Ireton-Jones C, Miles JM, et al: Essential fatty acid requirements and intravenous lipid emulsions. J Parenter Enteral Nutr. 2019;43(6):697-707.
  23. Vanek VW, Seidner DL, Allen P, et al: A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions. Nutr Clin Pract. 2012;27(2):150-92.
  24. Castillo RO, Feng JJ, Stevenson DK, et al: Altered maturation of small intestinal function in the absence of intraluminal nutrients: rapid normalization with refeeding. Am J Clin Nutr. 1991;53(2):558-61.
  25. Olieman JF, Penning C, Ijsselstijn H, et al: Enteral nutrition in children with short-bowel syndrome: current evidence and recommendations for the clinician. J Am Diet Assoc. 2010;110(3):420-6.
  26. Pereira-Fantini PM, Thomas SL, Taylor RG, et al: Colostrum supplementation restores insulin-like growth factor -1 levels and alters muscle morphology following massive small bowel resection. J Parenter Enteral Nutr. 2008;32(3):266-75.
  27. Bines JE, Taylor RG, Justice F, et al: Influence of diet complexity on intestinal adaptation following massive small bowel resection in a preclinical model. J Gastroenterol Hepatol. 2002;17(11):1170-9.
  28. Kles KA, Chang EB: Short-chain fatty acids impact on intestinal adaptation, inflammation, carcinoma, and failure. Gastroenterology. 2006;130(2 Suppl 1):S100-5.
  29. Samela K, Mokha J, Emerick K, et al: Transition to a tube feeding formula eith real food ingredients in pediatric patients with intestinal failure. Nutr Clin Pract. 2017;32(2):277-81.
  30. Rodriguez D, Ryan P, Toro Monjaraz EM, et al: Small intestinal bacterial overgrowth in children: A state-of-the-art review. Front Pediatr. 2019;7(1):1-19.
  31. Ubesie AC, Kocoshis SA, Mezoff AG, et al: Multiple micronutrient deficiencies among patients with intestinal failure during and after transition to enteral nutrition. J Pediatr. 2013;163(6):1692-6.
  32. Smith A, Feuling MB, Larson-Nath C, et al: Laboratory monitoring of children on home parenteral nutrition: a prospective study. J Parenter Enteral Nutr. 2018;42(1):148-55.
  33. Lee D, Barsky D, Hughes R, et al: Evaluation of the safety of iron dextran with parenteral nutrition in the paediatric inpatient setting. Nutr diet. 2017;74(5):471-5.
  34. Laass MW, Straub S, Chainey S, et al: Effectiveness and safety of ferric carboxymaltose treatment in children and adolescents with inflammatory bowel disease and other gastrointestinal diseases. BMC gastroenterology. 2014;14:184.
  35. Wolf M, Chertow GM, Macdougall IC, et al: Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight. 2018;3(23):e124486.
  36. Anand G, Schmid C: Severe hypophosphataemia after intravenous iron administration. BMJ Case Rep. 2017 Mar 13;2017:bcr2016219160.
  37. Ubesie AC, Heubi JE, Kocoshis SA, et al: Vitamin D deficiency and low bone mineral density in pediatric and young adult intestinal failure. J Pediatr Gastroenterol Nutr. 2013;57(3):372-6.
  38. Stabler SP: Vitamin B12 deficiency. N Engl J Med. 2013;368(21):2041-2.
  39. Jimenez L, Stamm DA, Depaula B, et al: Is serum methylmalonic acid a reliable biomarker of vitamin B12 status in children with short bowel syndrome: a case series. J Pediatr. 2018;192:259-261.
  40. Davis ET, Strogach I, Carobene M, et al. Paradoxical Elevation of Both Serum B12 and Methylmalonic Acid Levels in Assessing B12 Status in Children with Short-Bowel Syndrome. JPEN J Parenter Enteral Nutr. 2020 Jan 27.
  41. Cicalese MP, Bruzzese E, Guarino A, et al: Requesting iodine supplementation in children on parenteral nutrition. Clin Nutr. 2009;28(3):256-9.
  42. Johnsen JC, Reese SA, Mackay M, et al: Assessing selenium, manganese, and iodine status in pediatric patients receiving parenteral nutrition. Nutr Clin Pract. 2017;32(4):552-6.
  43. Ikomi C, Cole CR, Vale E, et al: Hypothyroidism and iodine deficiency in children on chronic parenteral nutrition. Pediatrics. 2018;141(4):e20173046.

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FROM THE LITERATURE

Incidence of Colorectal Cancer and Advanced Adenoma in Patients with Acute Diverticulitis

January 2021 • Volume XLV, Issue 1

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The incidence of colorectal cancer (CRC) and advanced adenoma (AA) were examined in patients with diverticulitis, compared with patients undergoing screening colonoscopy.

CT scans from January 1, 2008 to May 1, 2013 were evaluated at the University of Pittsburgh Medical Center (UPMC) to identify those with confirmed acute diverticulitis. Subsequent surgical, colonoscopy and pathologic reports were abstracted to identify those with a diagnosis of AA and CRC. The incidence of neoplasia was compared with that reported for screening colonoscopy from a meta-analysis (N = 68,324), and from colonoscopy examinations at UPMC between 2013 and 2015 (N = 28,573).

A total of 5,167 abdominal/pelvic CT scan reports identified 978 patients with acute diverticulitis, among which 474 (48.5%) patients had undergone at least one colonoscopy or gastrointestinal surgery to April 2015. The CRC rate in patients with diverticulitis (13/474 – 2.7%), was significantly higher compared with the metaanalysis (0.8%) and UPMC (0.3%).

The AA rate (19/474, 4%), was similar to the rate in the meta-analysis (5%), but significantly lower than at UPMC (7.7%). The incidence of AA or CRC in complicated diverticulitis (10/141, 7.1%), did not differ significantly from the incidence of AA or CRC in uncomplicated diverticulitis (22/332, 6.6%).

It was concluded that CRC after diverticulitis was significantly higher than that observed at screening colonoscopy and was not limited to complicated disease. Colonoscopy is advisable after the diagnosis of diverticulitis.

Tehranian, S., Klinge, M., Saul, M., et al. “Prevalence of Colorectal Cancer and Advanced Adenoma in Patients with Acute Diverticulitis: Implications for Follow-Up Colonoscopy.” Gastrointestinal Endoscopy, 2020; Vol. 91, pp. 634-640.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #205

Enhanced Recovery after Surgery (Eras) and Immunonutrition: An Evidence-based Approach

December 2020 • Volume XLIV, Issue 12
Jeff Friedman,Robert Thiele

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Nutrition is increasingly understood to play an essential role in optimization of perioperative outcomes. Pre-surgical nutritional status has a profound impact on perioperative outcomes and in the critically ill patient population, early adequate enteral nutrition has a clear positive impact on outcomes including mortality. Not surprisingly, nutritional optimization is a focus of many “Enhanced Recovery After Surgery” (ERAS) protocols. Additionally, manufacturers have developed “disease-specific” nutritional formulations designed for individual patient populations (e.g. acute respiratory distress syndrome). One such disease-specific category includes “immunonutrition” (IMN) formulations, most of which include arginine and are designed to enhance immune function in patients exposed to an immunological threat (e.g. undergoing surgery). While there are some theoretical benefits of IMN, a lack of credible, prospective data in the perioperative patient population suggest it would be premature to recommend their use in surgical patients, either within or outside of the context of an ERAS protocol. Furthermore, their safety in critically ill patients has recently been questioned, making it even harder to justify the routine use of these costly agents given the lack of data to support them.

INTRODUCTION

Perioperative management has experienced a sea change over the last two decades with the arrival and implementation of Enhanced Recovery After Surgery (ERAS) protocols. ERAS is a conceptual framework grounded on the application of evidence-based principles to improve outcomes in surgical patients. While ERAS was originally developed for patients undergoing colorectal surgery,1 it has since expanded to a variety of other surgical subspecialties including thoracic surgery.2 A key feature of ERAS is the development of standardized protocols based on best available evidence. Originally, ERAS for colorectal surgery focused on achievement of adequate pain control without excessive use of opioids, rational fluid management (either goal-directed or “restrictive”), early ambulation and feeding.1 Not all early ERAS (or “fast track”) protocols addressed fluid management.3 However, around the time of ERAS development, the benefits of restrictive4 or goaldirected5 fluid management strategies became clear, and later, all protocols6,7 addressed this important component of enhanced recovery. Many of these interventions were tried “all at once” and it was impossible to tease out the relative contribution of each to the observed improvement in outcomes, which included reductions in length of stay and surgical complications.1

With the advent and success of ERAS, interest has grown in understanding which components have the greatest impact, as well as whether other areas of the perioperative experience are being overlooked (e.g. the potential for pre-habilitation). Perioperative nutritional state is of particular interest for several reasons:

  • First, all of the core concepts of ERAS (opioid minimization [less ileus], rational fluid administration [less bowel edema], ambulation [accelerated GI recovery], and early oral intake), either directly or indirectly impact nutrition
  • Second, preoperative nutritional status is a powerful predictor of a variety of surgical complications;8,9 and,
  • Third, an enormous body of data from the ICU literature suggests that critically ill patients survive longer when they receive early, adequate nutrition.10

While there are distinct differences between surgical and critically ill patients, there is also extensive overlap in these patient populations that cannot be ignored. The recent development of “disease specific” nutrition formulations (e.g. omega-3 enhanced diets for acute respiratory distress syndrome11) is a testament to the crucial role played by nutrition in patients who are critically ill, undergoing surgery (or both). One of the more intriguing disease-specific dietary strategies is immune modification (referred to as immunonutrition [IMN]).

From the perspective of the patient as well as the clinician, increased certainty regarding the risks and benefits of a surgical procedure is desirable.

The nutritional screening strategies described below are inexpensive to perform and can help riskstratify surgical patients. However, whether and how nutritional status can be normalized in a short time period, whether or not this leads to improved outcomes, and how much this intervention costs are less clear.

In 2018, the American Society of Enhanced Recovery (ASER) released guidelines on nutrition as a component of ERAS.12 This review will discuss those guidelines as well as additional evidence that has been subsequently published. The primary purpose of this manuscript is to discuss evidence supporting the use of IMN in ERAS protocols, however it is not possible to discuss IMN in isolation, thus other nutritional concepts (e.g. screening) will be covered as well.

Previously Published Guidelines

Current recommendations for perioperative nutrition come from three sources: the ESPEN Clinical nutrition in surgery guideline,13 the American College of Surgeons (ACS) Strong For Surgery campaign14 and the 2018 ASER perioperative nutrition guidelines.12 The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines are the most comprehensive (37 recommendations) and focus on ERAS patients undergoing cancer surgery. The ESPEN guidelines include recommendations for nutritional screening, attention to perioperative nutrition, and use of IMN in malnourished patients undergoing major cancer surgery. The Strong for Surgery (S4S) campaign is a multifaceted perioperative optimization platform, of which nutrition is but one component.14 S4S includes three nutritional components – a clinical screening questionnaire (and registered dietitian referral if positive), preoperative albumin screening in all patients undergoing inpatient procedures, and use of IMN supplements in any patient undergoing complex surgical procedures. The 2018 ASER recommendations are similar to the S4S guidelines (with several important differences) and are also more prescriptive (Table 1).

Actionable recommendations proposed by ASER include12

  1. Nutritional screening with a clinical questionnaire (and serum albumin if triggered by the questionnaire).
  1. Dietitian referral with a positive screen.
  2. Lean body mass evaluation by CT if available.
  3. Oral nutritional supplements (ONS) for “at risk” patients (either high in protein or IMN).
  4. Placement of a home feeding tube for “at risk” patients in whom ONS is not possible.
  5. Parenteral nutrition for when enteric nutrition is not possible in “at risk” patients.
  6. Consideration of IMN in any patient undergoing elective major abdominal surgery

The use of albumin was discussed in all three sets of guidelines. Albumin, which is clearly correlated to surgical outcomes,3 has been used to quickly and inexpensively measure nutritional risk, but has unfortunately been misconstrued as a universal marker of malnutrition. Albumin is a negative acute phase reactant and in isolation is not a sensitive or specific marker for malnutrition.15-17 The utility of albumin as a modifiable risk factor has not been thoroughly explored and deserves further research.

The guidelines differ somewhat on their recommendations related to administration of nutrition before surgery. ESPEN writes that “Patients with severe nutritional risk shall receive nutritional therapy prior to major surgery” and that “Peri- or at least postoperative administration of specific formula enriched with immunonutrients (arginine, omega-3-fatty acids, ribonucleotides) should be given in malnourished patients undergoing major cancer surgery.” However, they also acknowledge that “There is currently no clear evidence for the use of these formulae enriched with immunonutrients vs. standard oral nutritional supplements exclusively in the preoperative period”.13 S4S suggests that any patient undergoing complex surgery receive supplementary IMN for a week preoperatively, and supports this assertion with a compendium of studies available on their website. The ASER Guidelines, in contrast, recommend some type of high protein oral nutrition before major surgery and that IMN be considered, but noted in the online supplementary data file that “The role of IMN was an area of great controversy in our discussions. Without question, additional definitive clinical trials comparing IMN to high protein ONS in the preoperative setting and preop IMN alone versus pre- and post-op IMN versus post-op IMN alone are needed. Further, additional trials of IMN within ERAS pathways are needed. Ultimately, a definitive, adequately-powered, randomized, multi-center trial of IMN is needed to finally define the previously observed benefits of perioperative IMN in many smaller trials”.12

The recommendation to prioritize protein intake over consumption of calories in the pre-operative period is based on solid experimental evidence showing that the addition of protein to a diet can have an anabolic effect,18 as does consumption of food sources that cist primarily of protein.19 There is at least one prospective randomized controlled trial in critically ill surgical patients demonstrating that a hyperproteineic, hypocaloric diet leads to improved sequential organ failure assessment (SOFA) scores despite receiving similar amounts of calories prior to surgery.20

The recommendation to consider IMN was based on a shakier foundation. The ESPEN guidelines cite 15 meta-analyses published between 1992 to 2012 and note that “the methodological analysis of these meta-analyses and the included RCTs raise reservations to give a strong recommendation for the general use of immunomodulating formulae.” As the ASER manuscript notes, perioperative IMN was recently supported by a Cochrane Systematic Review published in 2012 (6 trials, 549 participants), which compared IMN to either no nutritional support or standard support and concluded “Seven trials evaluating IMN nutrition were included in the review, of which 6 were combined in a metaanalysis. These studies showed a low to moderate level of heterogeneity and significantly reduced total post-operative complications (risk ratio [RR] 0.67). 21” However, a more recent meta-analysis published in 2014 (7 trials, 404 participants), also included in the ASER manuscript, compared IMN to ONS and concluded that “When compared to ONS, preoperative IMN was not associated with reduced wound infection (OR 0.97, 95% CI 0.45 to 2.11), all infectious complications (OR 0.71, 95% CI 0.30 to 1.68), non-infectious complications (OR 1.25, 95% CI 0.64 to 2.43), or LOS (mean difference 0.07 days, 95% CI -2.29 to 2.43)”.22 A key difference between these two more recent meta-analyses is that the Cochrane Review included trials in which IMN was compared to no nutritional support, whereas the 2014 meta-analysis only included trials comparing one nutrition intervention against another.

Update on the Evidence

Significant work has been completed and published in the literature since publication of the S4S and ASER guidelines in 2018. Though the effects of nutrition protocols have been of interest throughout the medical community, particular attention to the role of nutrition in improved outcomes has been focused within surgical and critical care populations. In 2018, two Cochrane Reviews of IMN trials were published describing recent work in the head and neck cancer population (high risk for decreased nutritional intake)23 and the acute respiratory distress syndrome (ARDS) critical care populations,24 respectively. The head and neck cancer (19 trials, 1099 participants) review found no evidence for differences in LOS, postoperative infection, mortality, or adverse events between patients receiving IMN and standard nutrition.23 There was some weak evidence that patients receiving IMN were less likely to develop postoperative fistulae. The review of the effects of IMN in adults with ARDS (10 trials, 1015 participants) concluded that there were no differences in all-cause mortality between IMN and those patients receiving standard nutrition.24 Additionally, the effect of IMN with omega-3 fatty acids and antioxidants on LOS and number of ventilator days was inconclusive. Both reviews noted that the quality of evidence ranged from low to very low due to small sample sizes, wide confidence intervals, high risk of bias, and clinical and methodological heterogeneity. Neither review quantified adherence or compliance. In addition to the Cochrane Reviews described above, the authors of this update conducted a search of the available literature (PubMed) for randomized control trials of IMN in the surgical and critical care populations between 2016 and 2020, identifying 23 additional prospective RCTs, only 12 of which studied IMN in the surgical or critical care populations. The results of these studies are summarized below in Table 2. Greater than half of the studied populations were oncological populations, including colorectal, hepatopancreaticobiliary, gastric, esophageal, urological, and head and neck cancer patients. Other studies included total knee arthroplasty, traumatic brain injury, surgical ICU, neurocritical care, elective craniotomy, pelvic exenteration, and ICU patients. With one exception, the included studies were small, with 12 of the 23 studies reporting less than 100 total participants and multiple studies reporting intervention and control groups of less than 20 participants each. Intervention and control nutrition protocols differed widely across the studies, as did reported primary and secondary outcomes. Conclusions on significant effects of IMN on mortality, LOS, postoperative infections, and complications were mixed. Additionally, reported results were of varying quality with levels of significance and confidence intervals inconsistently reported.

Limitations of the Literature

Though interest in perioperative nutrition (and IMN in particular), has grown exponentially, the current literature remains fractured and limited. Much of the early work in IMN has occurred within the various critical care populations. While critically ill patients differ from those presenting for elective surgery, it is reasonable to at least draw some inferences from the critical care literature given the size and quality of critical care trials focused on nutrition as well as similarities between populations. A recent, larger trial of early versus late parenteral nutrition in critically ill populations unable to achieve caloric goals by the enteric route demonstrated an increased complication rate in the early parenteral nutrition group.25 On the other hand, a more recent study of critically ill patients able to tolerate enteral nutrition, but randomized to enteral vs. parenteral nutrition showed no difference between the two routes.26 Whether or not these studies can be generalized to elective surgical procedures is not known. IMN may yet prove beneficial to both or either populations, but extrapolation of results across differing populations may not prove efficacy in improved outcomes.

Drover et al.’s 2011 systematic review of arginine-supplemented diets highlights the difficulties associated with analysis of the IMN data. Many of the studies included in this analysis were small (e.g. 20 subjects per group), and not all were blinded.27 Many of the studies included in these analyses were funded by commercial entities that produce the products in question,28-33 received some other form of industry support,34 or failed to report who funded the study.35 Some of the authors of these systematic reviews have, appropriately, disclosed the receipt of industrysponsored research grants, honoraria, or consulting fees related to nutrition research.36

The relationship between industry and academia is complex and a detailed analysis is beyond the scope of this review. We, along with many other authors, acknowledge that in order for an effective therapeutic agent to make it to the bedside, a commercial entity needs to produce it. The massively important role of the pharmaceutical industry in funding cutting edge research is undeniable and their continued contributions to science must be acknowledged. That said, industrysponsored studies do present unique challenges in terms of conflict of interest management, which are certainly not limited to the nutrition literature and have been described in detail elsewhere.37-40 We find the Oxepa® (Abbot Laboratories, Abbott Park, IL) experience particularly instructive. In 2008, an industry-sponsored, highly favorable meta-analysis of Oxepa® in critically ill patients was published in Journal of Parenteral and Enteral Nutrition, based on three small studies including 296 subjects.41 Three years later a single larger, randomized controlled trial including 276 subjects and sponsored by the National Heart, Lung, and Blood Institute (NHLBI) was negative.11

In fact, the critical care literature is filled with small, high impact studies which have subsequently been disproven,42-47 and thus, while the majority of the IMN data is promising, it is prudent to wait for the results of large, independent, multicenter studies before recommending widespread adoption of this promising (albeit expensive) therapeutic modality. The Oxepa® experience should give clinicians pause before practice changes are made based on small, industry-funded trials, as the potential for bias is higher.

Also important is reconciliation of the mostly favorable perioperative arginine data with data from other patient populations – in both critically ill patients and those suffering myocardial infarctions, arginine supplementation may also have the potential to cause harm.48-50 This may be, in part, due to the complex nature of arginine metabolism and its variety of effects in humans.48 Further complicating the interpretation of IMN data are the lack of data to even support basic perioperative nutrition as compared to no nutrition. The abovereferenced Cochrane review was only able to identify three studies (263 subjects) comparing preoperative oral nutrition to no intervention (as opposed to standard oral supplementation), with no difference in outcomes.2

For ERAS specifically, the reality is that there is not enough data directly comparing IMN to either standard supplementation or no intervention in the context of an established ERAS pathway to make any meaningful determination as to efficacy. There is one moderate sized trial comparing IMN to other nutritional products in the context of ERAS. Moya et al. randomized 264 patients to IMN versus a hypercaloric hypernitrogenous supplement starting 7 days before surgery and finishing 5 days post-operatively and found a significant reduction in infectious complications (attributable solely to decreased surgical site and deep wound infections) although no difference in length of stay or re-admission rates.51 Of note, the surgical site infection rate reported by the authors in the control group was considerably higher (~ 3X) than that reported by other authors.7,52

Recommendation

While we agree with much of the ESPEN, S4S, and ASER recommendations, based on the most up-to-date analysis of the literature, we believe that the evidence does not support the use of IMN in the context of ERAS at this time for the following reasons:

  1. There is only one trial specifically studying the use of IMN in ERAS.51
  2. Data on IMN in other populations (surgical, critical care) are equivocal.13,24
  3. There is some data that IMN can be harmful in certain populations.53-57
  4. The use of IMN incurs cost (3-5 x that of standard ONS) which might be more effectively used (e.g. for registered dietitian consultation in high risk patients) in a healthcare environment in which expenses are increasingly constrained.

Future work should be focused first on larger multicenter randomized control trials, adequately powered for analysis of both primary and secondary outcomes, specifically studied in patients enrolled in ERAS programs. These trials should also explicitly report the “dose” of IMN actually received by the patient (many published trials do not actually report this). Much of the perioperative nutrition literature is based on studies conducted outside the context of ERAS. What is not known and deserves further investigation is whether or not nutritional assessment and intervention is useful in patients who receive care in a structured pathway that encourages enteral intake of carbohydratecontaining fluids up to two hours before surgery, in addition to other modifications (opioid minimization, rational fluid administration, and ambulation), when compared to traditional care.

Additionally, though mortality, LOS, and postoperative complications have been the most commonly studied outcomes to date, greater emphasis should be placed on economic analysis. In an era of increasing cost constraints and limited resources, the cost of any potential intervention must also be weighed. These two competing realities (the desire to improve outcomes while decreasing costs) have been captured by the term “value,” which indexes marginal improvements to cost. Going forward, it is increasingly expected that healthcare systems will make investments in equipment, supplies, and infrastructure that offer them the largest return on investment. Expensive interventions with weak or no evidence will likely be abandoned, and these cost-savings reinvested in proven technologies and strategies.

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  40. Young NS, Ioannidis JP, Al-Ubaydli O. Why current publication practices may distort science. PLoS Med. 20085(10):e201.
  41. Pontes-Arruda A, Demichele S, Seth A, et al. The use of an inflammation-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr. 2008;32(6):596-605.
  42. Pro CI, Yealy DM, Kellum JA, et al. A randomized trial of protocolbased care for early septic shock. N Engl J Med. 2014;370(18):1683-93.
  43. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-77.
  44. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-97.
  45. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-67.
  46. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-56.
  47. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999;341(6):403-9.
  48. Dioguardi FS. To give or not to give? Lessons from the arginine paradox. J Nutrigenet Nutrigenomics. 2011;4(2):90-8.
  49. Luiking YC, Deutz NE. Exogenous arginine in sepsis. Crit Care Med. 2007;35(9 Suppl):S557-63.
  50. Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295(1):58-64.
  51. Moya P, Soriano-Irigaray L, Ramirez JM, et al. Perioperative Standard Oral Nutrition Supplements Versus Immunonutrition in Patients Undergoing Colorectal Resection in an Enhanced Recovery (ERAS) Protocol: A Multicenter Randomized Clinical Trial (SONVI Study). Medicine (Baltimore). 2016;95(21):e3704.
  52. Grant MC, Yang D, Wu CL, et al. Impact of Enhanced Recovery After Surgery and Fast Track Surgery Pathways on Healthcare-associated Infections: Results From a Systematic Review and Meta-analysis. Ann Surg. 2017;265(1):68-79.
  53. Atkinson S, Sieffert E, Bihari D. A prospective, randomized, doubleblind, controlled clinical trial of enteral immunonutrition in the critically ill. Crit Care Med. 1998;36:1164-1172.
  54. Bower RH, Cerra FB, Bershadsky B, et al. Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: Results of a multicenter, prospective, randomized, clinical trial. Crit Care Med. 1995;23:436-449.
  55. Kieft H, Roos AN, van Drunen JDE, et al. Clinical outcome of immunonutrition in a heterogeneous intensive care population. Intensive Care Med. 2005;31:524-532.
  56. Dent DL. Immunonutrition may increase mortality in critically ill patients with pneumonia: results of a randomized trial. Crit Care Med. 2003;30:A17.
  57. Bertolini G, Iapichino G, Radrizzani D, et al. Early enteral immunonutrition in patients with severe sepsis: results of an interim analysis of a randomized multicentre clinical trial. Intensive Care Med. 2003;29:834- 840.

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MEDICAL BULLETIN BOARD

Redhill Biopharma Extends Talicia® Unrestricted National and Regional Commercial Coverage to over 40 Million Additional Americans

December 2020 • Volume XLIV, Issue 12

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Talicia® unrestricted access in the U.S. now extends to over 70% of commercial lives covered Approximately 35% of Americans are affected by H. pylori infection, a Group 1 carcinogen and the strongest risk factor for gastric cancer; eradication of H. pylori has been shown to reduce the risk of gastric cancer by up to 75% Talicia addresses the high and growing resistance of H. pylori bacteria to commonly used antibiotics

TEL AVIV, Israel and RALEIGH, N.C., RedHill Biopharma Ltd. (Nasdaq: RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company, today announced that it has increased unrestricted national and regional commercial coverage for Talicia® (omeprazole magnesium, amoxicillin and rifabutin)[i] to more than 40 million additional Americans.

“With this addition of unrestricted coverage for over 40 million more lives, Talicia is now available to over 70% of commercial lives. The unrestricted commercial coverage achieved for Talicia to date far exceeds our expectations at such an early stage following the product’s launch. We continue to work diligently to increase unrestricted coverage of Talicia, in an effort to make a significant difference in ending sub-optimal treatment of H. pylori,” said Rick Scruggs, RedHill’s Chief Commercial Officer. “Antibiotic resistance is a major issue in the treatment of H. pylori infections and yet, despite current guideline recommendations from the American College of Gastroenterology calling for use of the most effective first-line treatment, physicians are still prescribing treatment regimens containing antibiotics such as clarithromycin that face high levels of bacterial resistance. This growth in unrestricted commercial access helps change that dynamic by increasing access to Talicia to more than 167 million Americans.”

RedHill has previously announced listings of Talicia as a preferred brand on the national formularies of Prime Therapeutics, EnvisionRx, and Express Scripts.

About Talicia
(omeprazole magnesium, amoxicillin and rifabutin)

Talicia is the only rifabutin-based therapy approved for the treatment of H. pylori infection and is designed to address the high resistance of H. pylori bacteria to clarithromycin-based standard-of-care therapies. The high rates of H. pylori resistance to clarithromycin have led to significant rates of treatment failure with clarithromycin-based standard-of-care therapy and are a strong public health concern, as highlighted by the FDA and the World Health Organization (WHO) in recent years.

Talicia is a novel, fixed-dose, all-in-one oral capsule combination of two antibiotics (amoxicillin and rifabutin) and a proton pump inhibitor (PPI) (omeprazole). In November 2019, Talicia was approved by the U.S. FDA for the treatment of H. pylori infection in adults. In the pivotal Phase 3 study, Talicia demonstrated 84% eradication of H. pylori infection in the intent-to-treat (ITT) group vs. 58% in the active comparator arm (p<0.0001). Minimal to zero resistance to Talicia was detected in RedHill’s pivotal Phase 3 study. Further, in an analysis of data from this study, it was observed that subjects who were confirmed adherent[ii] to their therapy had response rates of 90.3% in the Talicia arm vs. 64.7% in the active comparator arm[iii].

Talicia is eligible for a total of eight years of post-approval U.S. market exclusivity under both its Qualified Infectious Disease Product (QIDP) designation and New Clinical Investigation exclusivities. In addition, Talicia is protected by a robust U.S. patent portfolio which provides patent protection until at least 2034, with additional patents and applications pending and granted in various territories worldwide.

About H. pylori

H. pylori bacterial infection affects approximately 35%[iv] of the U.S. population, with an estimated two million patients treated annually[v]. Worldwide, more than 50% of the population is affected by H. pylori infection, which is classified by the WHO as a Group 1 carcinogen, remains the strongest known risk factor for gastric cancer[vi] and a major risk factor for peptic ulcer disease[vii] and gastric mucosa-associated lymphoid tissue (MALT) lymphoma[viii]. More than 27,000 Americans are diagnosed with gastric cancer annually[ix], while eradication of H. pylori has been shown to reduce the risk of gastric cancer by up to 75%[x]. Eradication of H. pylori is becoming increasingly difficult, with current standard-of-care therapies failing in approximately 25-40% of patients who remain H. pylori-positive due to high resistance of H. pylori to antibiotics commonly used in standard combination therapies[xi].

About RedHill Biopharma

RedHill Biopharma Ltd. (Nasdaq: RDHL) is a specialty biopharmaceutical company primarily focused on gastrointestinal and infectious diseases. RedHill promotes the gastrointestinal drugs, Movantik® for opioid-induced constipation in adults[xii], Talicia® for the treatment of Helicobacter pylori (H. pylori) infection in adults[xiii], and Aemcolo® for the treatment of travelers’ diarrhea in adults[xiv]. RedHill’s key clinical late-stage development programs include: (i) RHB-204, with an ongoing Phase 3 study for pulmonary nontuberculous mycobacteria (NTM) disease; (ii) opaganib (Yeliva®), a first-in-class SK2 selective inhibitor targeting multiple indications with a Phase 2/3 program for COVID-19 and Phase 2 studies for prostate cancer and cholangiocarcinoma ongoing; (iii) RHB-104, with positive results from a first Phase 3 study for Crohn’s disease; (iv) RHB102 (Bekinda®), with positive results from a Phase 3 study for acute gastroenteritis and gastritis and positive results from a Phase 2 study for IBS-D; (v) RHB-107 (upamostat), a Phase 2-stage serine protease inhibitor with a planned Phase 2/3 study in symptomatic COVID-19 and targeting multiple other cancer and inflammatory gastrointestinal diseases; and (vi) RHB-106, an encapsulated bowel preparation.

More information about the company is available at:
redhillbio.com

IMPORTANT SAFETY INFORMATION

Talicia contains omeprazole, a proton pump inhibitor (PPI), amoxicillin, a penicillinclass antibacterial, and rifabutin, a rifamycin antibacterial. It is contraindicated in patients with known hypersensitivity to any of these medications, any other components of the formulation, any other beta-lactams or any other rifamycins.

Talicia is contraindicated in patients receiving delavirdine, voriconazole or rilpivirine-containing products.

Serious and occasionally fatal hypersensitivity reactions have been reported with omeprazole, amoxicillin and rifabutin.

Acute Tubulointerstitial Nephritis has been observed in patients taking PPIs and penicillins.

Clostridioides difficile-associated diarrhea has been reported with use of nearly all antibacterial agents and may range from mild diarrhea to fatal colitis. Talicia may cause fetal harm and is not recommended for use in pregnancy. It may also reduce the efficacy of hormonal contraceptives. An additional non-hormonal method of contraception is recommended when taking Talicia. Talicia should not be used in patients with hepatic impairment or severe renal impairment.

Cutaneous lupus erythematosus and systemic lupus erythematosus have been reported in patients taking PPIs. These events have occurred as both new onset and exacerbation of existing autoimmune disease.

The most common adverse reactions (≥1%) were diarrhea, headache, nausea, abdominal pain, chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis.

To report SUSPECTED ADVERSE
REACTIONS, contact RedHill Biopharma INC.
at 1-833-ADRHILL (1-833-237-4455) or FDA at
1-800-FDA-1088 or fda.gov/medwatch.

Full prescribing information for Talicia is
available at:
Talicia.com

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements may be preceded by the words “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company’s control and cannot be predicted or quantified, and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties including, without limitation, the risk that the Company will be unable to secure additional pharmacy benefit management’s formulary coverage for Talicia®, as well as other risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company’s research, manufacturing, pre-clinical studies, clinical trials, and other therapeutic candidate development efforts, and the timing of the commercial launch of its products and ones it may acquire or develop in the future; (ii) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its pre-clinical studies or clinical trials, including the development of a commercial companion diagnostic for the detection of MAP; (iii) the lack of sufficient financial resources which may result in material adverse impact on the Company’s research, manufacturing, preclinical studies, clinical trials, and other therapeutic candidate development activities including delay or termination of preclinical or clinical activities or of any other such activities (iv) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its preclinical studies or clinical trials (v) the extent and number and type of additional studies that the Company may be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (vi) the manufacturing, clinical development, commercialization, and market acceptance of the Company’s therapeutic candidates and commercial products; (vi) the Company’s ability to successfully commercialize and promote Talicia®, and Aemcolo® and Movantik®; (vii) the Company’s ability to establish and maintain corporate collaborations; (viii) the Company’s ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (ix) the interpretation of the properties and characteristics of the Company’s therapeutic candidates and the results obtained with its therapeutic candidates in research, pre-clinical studies or clinical trials; (x) the implementation of the Company’s business model, strategic plans for its business and therapeutic candidates; (xi) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and commercial products and its ability to operate its business without infringing the intellectual property rights of others; (xii) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; (xiii) estimates of the Company’s expenses, future revenues, capital requirements and needs for additional financing; (xiv) the effect of patients suffering adverse experiences using investigative drugs under the Company’s Expanded Access Program; (xv) competition from other companies and technologies within the Company’s industry; and (xvi) the hiring and maintaining employment of executive managers. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company’s filings with the Securities and Exchange Commission (SEC), including the Company’s Annual Report on Form 20-F filed with the SEC on March 4, 2020. All forwardlooking statements included in this press release are made only as of the date of this press release. The Company assumes no obligation to update any written or oral forward-looking statement, whether as a result of new information, future events or otherwise unless required by law.

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MEDICAL BULLETIN BOARD

Fujifilm Earns Fda “breakthrough Device” Designation for Endosurgical Image Enhancement Technology

December 2020 • Volume XLIV, Issue 12

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Company announces development of new image processing technologies designed to enhance visualization during therapeutic procedures

Lexington, MA – FUJIFILM Medical Systems U.S.A., Inc., a leading provider of endoscopic imaging solutions, announced that the U.S. Food and Drug Administration (FDA) granted its Breakthrough Device Designation – reserved for medical devices that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions – for Fujifilm’s new, in-development, endoscopic light and image processing technology. Although not yet 510(k) cleared, the goal of Fujifilm’s indevelopment image processing technology is to arm surgeons with the resources needed to care for patients at risk for ischemic states of the gastrointestinal tract.

“Leveraging our 80+ year imaging legacy, we develop technologies designed to enhance visualization and guide healthcare providers as they make critical clinical decisions caring for their patients,” says Taisuke Fujita, General ManagerEndoscopy, FUJIFILM Medical Systems U.S.A., Inc. “We’re proud to receive this designation through the FDA’s Breakthrough Devices Program on the heels of several advancements in 2019, and we look forward to bringing more innovations to the endoscopic and endosurgical markets in the years to come.”

Fujifilm’s new image processing technology is being developed to enhance endosurgical visualization and will be an upgrade to the ELUXEO Surgical System-the company’s in-market video imaging system which leverages 4-LED multi-light technology to enable advanced visualization modes including White Light Endoscopy, Linked Color Imaging (LCI), and Blue Light Imaging (BLI). These imaging modes are designed to improve visualization, detection, and characterization during procedures.

In gastrointestinal procedures such as colorectal surgeries, anastomosis is performed following resections, sometimes resulting in a serious complication – anastomotic leaks. One of the major causes of anastomotic leaks is necrosis of ischemic tissue where the anastomosis is performed, and Fujifilm’s new technology is designed to assist physicians in identifying ischemic areas of tissue.

Anastomotic leaks can result in septic complications, and are shown to have a 10% higher mortality rate as compared to patients who did not develop anastomotic leaks (14% vs. 4%). In a Medicare data analysis of more than 200,000 patients who underwent colorectal surgery between January 1, 2013 and August 31, 2015, care admission costs for patients with anastomotic leaks were reported more than $30,500 greater and the length of stay was 12 days longer as compared to those without. The commercial analysis of both the bariatric and colorectal populations trended similarly to the Medicare population in regards to all outcomes measured. These staggering statistics have led industry to research and develop technologies to prevent and/or reduce anastomotic leaks.

“For decades Fujifilm has invested in the research and development of technologies to improve patient outcomes and reduce healthcare costs, and in recent years, we’ve elevated our focus in endosurgery,” says Stephen Mariano, Vice President of Global Endosurgical R&D, FUJIFILM Medical Systems U.S.A., Inc. “We look forward to working with the FDA as we prioritize the development and access of some of our exciting endosurgical innovations.”

About Fujifilm

FUJIFILM Medical Systems U.S.A., Inc. is a leading provider of innovative diagnostic imaging products and medical informatics solutions that meet and exceed the evolving needs of healthcare facilities today and into the future. It’s ever expanding medical imaging solutions span digital radiography (DR), detectors, portables and suites, mammography systems with digital breast tomosynthesis, computed tomography solutions for oncology and radiology applications, technologically advanced flexible and surgical endoscopy and fluoroscopy solutions. Fujifilm enables interoperability through its Systems Integration offering as well as its comprehensive, AI-supported Synapse® Enterprise Imaging portfolio, which includes the TeraMedica Division of Fujifilm. Fujifilm’s in vitro diagnostics (IVD) portfolio includes clinical lab reagents, and biomarkers to assess the risk for the development of hepatocellular carcinoma in patients with chronic liver disease. FUJIFILM Medical Systems U.S.A., Inc. is headquartered in Lexington, Massachusetts.

For more information, please visit:
fujifilmhealthcare.com

FUJIFILM Holdings Corporation, Tokyo, Japan, brings cutting edge solutions to a broad range of global industries by leveraging its depth of knowledge and fundamental technologies developed in its relentless pursuit of innovation. Its proprietary core technologies contribute to the various fields including healthcare, graphic systems, highly functional materials, optical devices, digital imaging and document products. These products and services are based on its extensive portfolio of chemical, mechanical, optical, electronic and imaging technologies. For the year ended March 31, 2020, the company had global revenues of $22.1 billion, at an exchange rate of 109 yen to the dollar. Fujifilm is committed to responsible environmental stewardship and good corporate citizenship.

For more information, please visit:
fujifilmholdings.com

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FROM THE LITERATURE

Cognitive Deficit and White Matter Changes in Celiac Disease

December 2020 • Volume XLIV, Issue 12

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To validate previous reports over the presence and prevalence of brain injury in patients with celiac disease, neuropsychological dysfunction in patients with celiac disease included in the National UK Biobank was carried out, containing experimental medical data from 500,000 adults in the United Kingdom.

Biobank participants with celiac disease (N = 104; mean age 63 years; 65% female) were matched with healthy individuals (N = 198; mean age 63 years; 67% female) for age, sex, level of education, body mass index and diagnosis of hypertension. All participants were otherwise healthy.

Scores were compared from five cognitive tests and multiple choice responses in 6 questions about mental health between groups using the t test and chi-squared analyses. Groupwise analyses of MRI brain data included a study of diffusion tensor imaging metrics (mean diffusivity, fractional anisotropy, radial diffusivity, axial diffusivity), voxelbased morphometry and Mann-Whitney U comparisons of Fazekas grades.

Compared with controlled individuals, participants with celiac disease had significant deficits in reaction time and significantly higher proportions had indications of anxiety, depression, thoughts of self-harm and healthrelated unhappiness. Tract-based spatial statistics analysis showed significantly increased axial diffusivity in widespread locations, demonstrating white matter changes in brains of participants with celiac disease. Voxel-based morphometry and Fazekas grade analyses did not differ significantly between groups.

It was concluded in an analysis of data from the UK Biobank that participants were found with celiac disease to have cognitive deficit, indications of worsened mental health, and white matter changes, based on analyses of brain images. These findings support the concept that celiac disease is associated with neurological and psychological features.

Croall, I., Sanders, D., Hadjivassiliou, M., Hoggard, N. “Cognitive Deficit and White Matter Changes in Persons With Celiac Disease: A Population-Based Study.” Gastroenterology 2020; Vol. 158, pp. 2112-2122.

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FROM THE LITERATURE

Family History of Colorectal Cancer and Prevalence of Advanced Colorectal Neoplasia in Screening

December 2020 • Volume XLIV, Issue 12

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To evaluate the clinical significance of family history (FH) of colorectal cancer (CRC) in first degree relatives (FDRs) in screening stratified by different age groups, investigation of the relationship between FH and the presence of advanced colorectal neoplasia (ACN), and screened individuals in different age groups were evaluated.

Data from screened individuals aged 40 to 45 years (N = 2263), and 55 to 69 years (N = 2621), who underwent their first-ever screening colonoscopy, were analyzed. The relationship between FH and ACN was examined and a multivariate logistic regression analysis incorporating other baseline characteristics was performed.

Among individuals age 40 to 55 years, the prevalence of ACN was significantly higher in 249 individuals with affected FDRs than in those without (5.6% vs 1.6%), with an adjusted odds ratio of 3.7. The prevalence was particularly high in those having FDRs with CRC mortality (7.3%). Among individuals age 55 to 69 years, the prevalence of ACN was not significantly different between 291 individuals with affected FDRs and those without (5.8% vs 5.8%). However, individuals with two FDRs with CRC and mortality showed a high prevalence of ACN (17.4% and 42.9%, respectively).

It was concluded that an FH of CRC in FDRs was associated with a higher prevalence of ACN in younger individuals with a particularly high impact of FH on CRC mortality. In contrast, the impact of FH was weaker in older individuals, except those having two FDRs with CRC on mortality.

Sekiguchi, M., Kakujawa, Y., Nakamura, K., et al. “Family History of Colorectal Cancer and Prevalence of Advanced Colorectal Neoplasia in Asymptomatic Screened Populations in Different Age Groups.” Gastrointestinal Endoscopy 2020; Vol. 91, pp. 1361-1370.

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