Page 13 – Practical Gastro

Peter D.R. Higgins

Acute severe ulcerative colitis (ASUC) will affect at least one in four patients with ulcerative colitis,

requiring hospitalization and induction therapy to achieve remission. The initial assessment should

include measurement of inflammation, testing for infection, and evaluating for toxic megacolon. All

patients will need prophylaxis against venous thromboembolism, and most will require significant

IV hydration. Early endoscopy with biopsies will rule out cytomegalovirus (CMV) and herpes

simplex virus (HSV) and help assess severity. First line therapy with intravenous corticosteroids

is effective in 2/3rds of patients, while rescue therapy with cyclosporine or infliximab is effective

in 80% of the remaining 1/3rd. Roughly 10% will require colectomy in the initial hospitalization,

and another 5% will need a colectomy in the next 90 days. Close monitoring after discharge and

timely adjustment of maintenance therapy to maintain remission is essential in these high-risk

patients. First line small molecule therapies in high-risk patients may help reduce colectomy rates.

How is severe UC defined?

Severe ulcerative colitis was defined by Truelove and Witts in 19551 which reported on the use of cortisone in severe UC. Severe UC was defined as six or more bowel movements per day with visible blood in stools, and one or more of the following: fever > 100F/37.8C, tachycardia > 90 bpm, anemia (hemoglobin<= 10.5), or an ESR >= 30 mm per hour. Neither C-reactive protein (CRP) nor fecal calprotectin (FCP) were standard measurements in 1955. Kedia, et al.2 used the Truelove and Witts criteria to validate a laboratory definition of severe UC and found that an FCP > 782 mcg/g of stool could identify severe UC with a sensitivity of 84% and a specificity of 88%. CRP is often elevated in severe UC, and when positive, can be followed daily as a marker of response to therapy. FCP and ESR change more slowly than CRP and are less helpful as rapid dynamic markers of response to therapy.

What is acute severe UC?

In theory, acute severe UC indicates a flare of rapid onset, but the rapidity is not defined. As a practical definition, we generally define patients hospitalized for severe flares as having acute severe UC. In practice, this may include some patients with more chronic, ongoing flares, who have not responded to outpatient steroids or previous inpatient therapy with IV corticosteroids. These patients who have failed prior steroids (and/or prior biologics) are at particularly high risk for colectomy.

Admission and initial assessment

The initial assessment should include measurement of inflammation with CRP and FCP, testing for infection, usually including Clostroides difficile testing and a stool polymerase chain reaction (PCR) panel for enteric infection, and evaluating for toxic megacolon with abdominal x-ray, a complete blood count and differential, chemistries to detect baseline electrolyte and liver problems, and physical exam for toxic megacolon and dehydration.

Infection with C. diff can be detected with PCR and antigen testing for toxin, though detected C. diff may be merely colonization, may activate a UC flare, or may be the primary driver of diarrhea. Decisions about when to treat C. diff and hold corticosteroid therapy can be difficult. In general, mild inflammation and a positive toxin antigen test should favor treatment with vancomycin for C. diff without starting steroids. A sigmoidoscopy more consistent with UC rather than C. diff, and a lack of substantial improvement on vancomycin after 48 hours should trigger initiation of corticosteroids. The absence of toxin antigen, more severe inflammation, and a scope consistent with active UC should favor early initiation of corticosteroids, even if this means co-treatment with vancomycin to cover Clostroides difficile.

Stool PCR testing for other enteric infections and PCR for CMV are controversial, as many of the positive tests will be “red herrings” in the setting of a UC flare and may not be driving the clinical presentation. The presence of nausea or vomiting in the setting of a positive norovirus test suggests that this is a real infection, and occasional E. coli infections do occur in UC, particularly with recent steroid exposure. Very high CMV titers confirmed on biopsy can be primary CMV infections, especially after an extended course of corticosteroids. C. diff remains the most common colonic infection in UC and should be suspected as the primary driver when diffuse abdominal pain and fever are present and minimal or no blood in stool is seen.

The initial abdominal film should be evaluated for colonic thumbprinting and the presence of free air under the diaphragm. Ideally these should be rare when patients present early in a flare, but the risk of perforation rises over time in patients who have failed outpatient or inpatient steroid therapy, and this is especially important in readmissions or hospital transfers. An abdominal exam suspicious for rebound, or a very high (or surprisingly low) white blood cell count with thumbprinting should precipitate an early call to your surgical colleagues to get them on board.

Risk assessment

Patients with ASUC are at increased risk of colectomy if they have failed prior steroids or biologics, are younger or former smokers, require early admission after diagnosis, have extensive colitis or deep ulcerations, have high CRP and ESR, or have low hemoglobin or albumin. The number of positive Truelove and Witts additional criteria (anemia, fever, tachycardia, ESR) have also been shown to be predictive of colectomy (Table 1).3 Early endoscopy (usually a flexible sigmoidoscopy with biopsies in the first 12 hours) can help prognosticate severity, and biopsies can help rule out CMV and HSV as infectious causes of colitis.

Empiric therapy and prevention of complication

All acute severe UC patients should receive empiric therapy to improve their symptoms and prevent complications. All patients should receive medical prophylaxis for venous thromboembolism, as both active severe UC and the use of corticosteroids increase the risk of venous thromboembolism (VTE). Patient mobility should not be a reason to avoid therapy with enoxaparin or unfractionated heparin, as these risk factors are unchanged by mobility. Confirm daily dosing with the patient, the responsible, nurse, and the medication administration record.

Nearly all patients will be dehydrated upon admission, due to self-restriction of food and fluids to reduce bowel moments, in addition to many watery bowel movements. This should be ameliorated with infusion of IV fluids initially at 1 L per hour until thirst is no longer present, and urine output is frequent and clear. Patients with heart failure, renal failure, or other contraindications to volume infusion should be started at a lower rate and monitored closely.

Most patients will have a limited appetite at the time of admission and should not force food intake. Many will be able to tolerate small amounts of high protein liquid nutrition, e.g., Boost or Ensure, until their appetite returns. When able to tolerate food, patients should start slowly with a high protein, low residue diet, often provided as a high protein breakfast at each meal and advance to full diet as tolerated. Many patients have severe urgency at theinitial presentation, and can benefit from a bedside commode, and twice daily 5-ASA suppositories to reduce this symptom. Patients in the hospital benefit from protected sleep time. Consider providing night quiet hours, limiting vitals and blood draws when possible, and dosing intravenous steroids early in the day (e.g., 6 AM and 2 PM for bid dosing) to reduce sleep disturbance. Discuss with each patient the common side effects of steroids and their effects on sleep, anxiety, depression, and PTSD. Each inpatient stay is also an opportunity for education, particularly on therapies for UC and surgical options for UC. Encourage patients to keep a pad and pen nearby to write down questions during the day. I often use the IBD School videos on YouTube to address particular education topics tailored to each patient.

First line therapy

When patients are first admitted to the hospital, and infection testing is pending, first line therapy with methylprednisolone, a corticosteroid, at a standard dose of 30 mg bid, is recommended. There is no evidence that doses higher than 1 mg per kilogram per day add any benefit. Alternative dosing schedules of once daily, three times daily, four times daily, or continuous dosing do not seem to have any additional benefit, though more frequent dosing may interfere with sleep.

Over time, an increasing number of ASUC patients are presenting with prior biologic (usually anti-TNF) failure. Recent case-control data in high-risk patients with prior biologic failure treated with first line tofacitinib 10 mg three times daily in combination with intravenous solumedrol suggest initial presentation, and can benefit from a bedside commode, and twice daily 5-ASA suppositories to reduce this symptom. Patients in the hospital benefit from protected sleep time. Consider providing night quiet hours, limiting vitals and blood draws when possible, and dosing intravenous steroids early in the day (e.g., 6 AM and 2 PM for bid dosing) to reduce sleep disturbance. Discuss with each patient the common side effects of steroids and their effects on sleep, anxiety, depression, and PTSD. Each inpatient stay is also an opportunity for education, particularly on therapies for UC and surgical options for UC. Encourage patients to keep a pad and pen nearby to write down questions during the day. I often use the IBD School videos on YouTube to address particular education topics tailored to each patient.

First line therapy

All patients should be advised that colectomy is a reasonable option even at first line, as some patients will choose a one-time colectomy over lifelong maintenance medication. It is important for all patients to meet the local colorectal surgeons, usually on day two of admission, and to meet the wound care ostomy nurse, who will mark a site for optimal ostomy placement. A key part of patient education is to establish that colectomy is a reasonable therapeutic option, and to re-emphasize this regularly during the course of the hospital stay.

Reassessment at 72 hours

Patients should be monitored closely during their first 72 hours on steroids, including daily measurements of CRP, and tracking of bowel movements. The patient should be counseled on the options of colectomy and rescue therapy and should be prepared to make a decision on the next step if needed at 72 hours. There are three indices developed to estimate the likelihood of success of intravenous, steroids, and 72 hours. The CRP should be collected at 72h on steroids, and the most recent 24-hour bowel movement count used to calculate the Travis, Lindgren, and Ho prognostic indices, as described in the Michigan Severe UC Protocol.5 If these all indicate low risk of colectomy, you should plan a transition to oral corticosteroids, advance to full diet, and plan for a maintenance therapy. If any one of these indices indicates high risk, the patient should be prepared to choose between colectomy and rescue therapy, so that either option can be started in a timely fashion.

Rescue therapy options

The two best studied rescue therapies after corticosteroids have failed in ASUC are cyclosporine and infliximab, which had equivalent 98-day outcomes in the CYSIF trial. One of the challenges of starting any biologic medication in ASUC is the protein leak across the damaged colon. Infliximab has been shown to leak into stool effluent at a high rate, lowering drug levels in ASUC patients. Small molecules (methylprednisolone, cyclosporine, Jak inhibitors), in contrast, bind to receptors inside of cells. This lowers their serum level, and the amount of drug available to leak out of the colon. This makes the small molecules more attractive for induction of remission in ASUC. Limited data from a GETAID study suggest a high (79% at 3 months) success rate with tofacitinib after prior corticosteroid and biologic failure.6

A second problem with using biologics for induction of remission in ASUC is the low trough levels that frequently result with a leaky colon. Particularly for older biologics prone to formation of anti-drug antibodies like infliximab, this increases the risk of forming blocking antibodies, making it more attractive to achieve induction with small molecules, and start biologics after the colon leak has been slowed.

The third limitation of using a biologic for rescue therapy is that these drugs have a long half-life and tend to stay around for weeks at a time. If one is considering salvage therapy with a different medication, this compounds immunosuppression from steroids, the biologic rescue drug, and the addition of a 3rd salvage drug. It is usually wiser to use small molecules with more rapid washout for first and second line therapy if a 3rd line salvage therapy is being considered.

Assessing rescue therapy

The outcome from rescue therapy should be assessed between 72 and 108 hours after initiation. Daily CRP and a repeat FCP will be helpful, as these should continue to trend downward and enter the normal range. Bleeding in bowel movements should cease, and the number of bowel movements should be reduced. If bowel symptoms plateau, and CRP and/or FCP rise, these are bad prognostic signs, and generally mean colectomy in the very near future. In patients who have been on corticosteroids for some time and have a worsening of inflammation, it can be worth rechecking for CMV and/or rescoping with a flexible sigmoidoscopy to help inform the decision about colectomy.

Should you salvage?

Some patients, especially those new to ulcerative colitis, may resist the idea of colectomy, even after failure of corticosteroids and rescue therapy. The plan for next option should be an ongoing discussion during rescue therapy, with clear recommendation of colectomy as the standard of care. Salvage therapy entails significant risks, with multiple immunosuppressive medications that increase the risk of both infection and death. There are very limited data on salvage therapy with a 3rd immunosuppressive medication and some case series have documented high rates of infection, and occasional deaths. These risks may be decreased by the rapid washout of prior small molecules and may be increased by prior biologic therapies with long half-lives.

Patients need to be aware of the risks of multiple immunosuppression, and there must be a clear plan for an exit to a long-term maintenance therapy that is acceptable to the patient before any salvage therapy is attempted. It must be clear to both the patient and the provider colectomy is the standard of care after failure of rescue therapy, as the data on salvage therapy is very limited, and includes significant negative outcomes.

Preparing for colectomy

Preparing a patient for a colectomy is an ongoing process during each admission for ASUC. Colostomy must be presented as a viable therapeutic option, and a good ostomy site should be marked early in the stay by a wound ostomy care nurse. If there has been no previous imaging of the small bowel, CT or MRI should be done to evaluate for Crohn’s disease rather than ulcerative colitis. An ongoing discussion with the surgeons should begin on day two of admission, and patient education about surgical options should be ongoing. When a decision is made to proceed to colectomy, immunosuppressive medications (including corticosteroids) should be stopped, and if possible, given time to wash out before surgery. When possible, nutritional status should be optimized, and an elective colectomy is always preferred over toxic megacolon, perforation, or an emergent colectomy.

Preparing for discharge

For the patient who achieves induction of remission during the hospitalization, planning for a successful discharge should begin as soon as the patient turns the corner. You should expect no blood in the stool and a CRP below 10 mg/L. Patient should be able to advance to a full diet without recurrence of symptoms. The patient should be able to stop all intravenous therapy and transition to oral therapy. Note that switching from 60 mg daily methylprednisolone to 60 mg prednisone is a drop of 20% in efficacy, while a transition to 40 mg prednisone is an 88% drop in efficacy. The patient should be able to walk around and maintain normal activity levels as if they were at home for 24 hours before discharge. After 24 hours on oral therapy, there should not be a sudden rise in CRP, and you should obtain a new FCP to establish a new baseline. Note that while CRP often rapidly normalizes, FCP (along with mucosal healing) may take months to normalize. Some practitioners will obtain a repeat flexible sigmoidoscopy, especially in high-risk patients, to establish a new baseline and to estimate the time to complete mucosal healing. It is important to obtain insurance approvals of all maintenance therapies, and schedule infusions if needed, before the patient leaves the hospital.

After discharge

After induction of remission and discharge, it is important to monitor patients closely, as there is a high rate of recurrence and readmission. We typically monitor CRP, FCP, and symptoms for any recurrence at 1, 3, and 6 weeks. We standardize our symptom collection with the UC-PRO instrument in Epic. The typical discharge plan will start the patient on prednisone at a dose of 40 or 60 mg (for more severe cases) daily, with tapering by 5 mg per week. There is sone data suggesting that effective induction of remission with cyclosporine may not need a prednisone taper,7 though this needs further study to determine if this is generalizable and whether this applies to other small molecules like JAK inhibitors. It is also important to check in on the patient after discharge to make sure that they have actually started their maintenance medication on schedule, without any insurance hiccups, and that they are tolerating this well. Readmissions and subsequent ASUC admissions increase the risk of colectomy, as documented by Dinesen.3

References

1. Truelove & Witts. Cortisone in ulcerative colitis; final report on a therapeutic trial. BMJ. 1955; 2(4947): 1041- 1048.

2. Kedia, S, et al. Potential of Fecal Calprotectin as an Objective Marker to Discriminate Hospitalized Patients with Acute Severe Colitis from Outpatients with Less Severe Disease. Dig Dis Sci. 2018; 63(10): 2747-2753.

3. Dinesen, L., et al. The pattern and outcome of acute severe colitis. J Crohns Colitis. 2010; 4(4): 431-437.

4. Berinstein, J.A., et al. Tofacitinib for Biologic-Experienced Hospitalized Patients With Acute Severe Ulcerative Colitis: A Retrospective Case-Control Study. Clin Gast Hep. 2021; 19(10): 2112-2120.

5. Higgins, P.D.R., et al. University of Michigan Severe Ulcerative Colitis Protocol, version 2.99. June 3, 2022, website updated annually. https://www.med.umich.edu/ ibd/docs/severeucprotocol.pdf

6. Uzzan, M., et al. Tofacitinib as salvage therapy for 55 patients hospitalised with refractory severe ulcerative colitis: A GETAID cohort. Aliment Pharmacol Ther. 2021; 54(3): 312-319.

7. Tarabar, D., et al. A Prospective Trial with Long Term Follow-up of Patients With Severe, Steroid-Resistant Ulcerative Colitis Who Received Induction Therapy With Cyclosporine and Were Maintained With Vedolizumab. Inflamm Bowel Dis. 2022; 28(10): 1549-1554.

Cholangioscopy

Wissam Kiwan,

James Buxbaum

Key Points

• Cholangioscopy has evolved substantively over the last few decades to enable a single operator to directly examine the biliary tree using digital platforms.

• Cholangioscopy-guided intraductal therapy with electrohydraulic or laser lithotripsy is a safe and effective treatment for difficult bile duct stones.

• Cholangioscopy with guided biopsies represents a powerful diagnostic tool for indeterminate biliary strictures and new diagnostic criteria and technology promises that its role will increase.

• The adverse event rates of cholangioscopy are acceptable when it is performed by trained endoscopists using appropriate precautions including judicious biliary stent use.

Technology to enable direct visualization of the bile duct has gone through several stages of revision.1 While widespread clinical use has emerged only over the past 5-10 years, the first percutaneous cholangioscopy was reported in 19512 and peroral exam in 1976.3 It was first utilized for laser and electrohydraulic lithotripsy in the late 1980’s.4,5

The first commercially available cholangioscopes used a mother-baby system that required a high degree of coordination between two endoscopists: one controlling the mother duodenoscope and the other controlling a slim through-the-channel baby scope. The major limitations of this system were the fragility of the cholangioscopes, suboptimal image quality and limited maneuverability related to the need for two operators.6

Direct peroral cholangioscopy with ultraslim cholangioscopes, which did not pass through a “mother” scope, provided higher resolution images, and mitigated challenges associated with fragility. However, the technical success was low and inconsistent, due to the need to anchor a flexible scope through the mouth deeply into the biliary tree. Specific problems included unstable position, requirement for a large sphincterotomy, and the lack of the ability to examine the bile ducts beyond the bifurcation of the main hepatic duct given the scope size and need to inflate an anchoring balloon in the biliary tree itself.7,8

These issues limited widespread use. In 2007, a cholangioscope which could be passed via the accessory channel and controlled by a single operator was introduced. These devices used a reusable fiberoptic cable in a disposable scope.9 A channel in the scope enables passage of a biopsy forceps and introduction of laser and electrohydraulic lithotripsy probes.10 The most recent major innovation in cholangioscopy has been the introduction of a single-use, digital imaging version of the single-operator cholangioscopes (DSOC) which provided a higher image quality, simplified assembly and a flexible introduction system (Figure 1).1,11

Over the past decade, cholangioscopy has become a widely used tool in academic and community medical centers. In this article, we will address its role in biliary disease. It represents a primary tool for difficult choledocholithiasis, and the assessment of indeterminate biliary strictures. In addition to its major therapeutic and diagnostic roles, we will discuss technique, emerging applications, cost and safety of this technology.

BASIC CHOLANGIOSCOPY TECHNIQUE

Most contemporary cholangioscopic procedures are performed with a disposable DSOC via peroral approach during endoscopic retrograde cholangiopancreatography (ERCP). After testing the light and the dials of the cholangioscope, and flushing the channel with water for lubrication, the handle of the scope is strapped just below the duodenoscope working channel. An adequate sphincterotomy or balloon sphincteroplasty is indicated to allow passage of the cholangioscope. Then, the cholangioscope is advanced through the duodenoscope channel preferably over a previously inserted guidewire into the bile duct under fluoroscopic guidance. Once the cholangioscope is in a stable position in the distal or middle common bile duct, irrigation with sterile water allows visualization of the bile duct aided by four-way tip deflection. The cholangioscope is advanced over the guidewire to a targeted biliary site before the wire is removed to allow optimal visualization and to allow advancing any instruments through its channel if needed. It may be necessary to gently advance the duodenoscope forward to favor parallel alignment of the cholangioscope and the bile duct to allow deeper insertion. The locks on the duodenoscope and cholangioscope may need to be released to advance the cholangioscope.

These maneuvers may also be needed to advance instruments (i.e., electrohydraulic lithotripsy (EHL)/laser probe or biopsy forceps) through the cholangioscope channel. Another technique is to advance the cholangioscope gently forward at the same time as the instrument is passed through the working channel. Sometimes, it is necessary to advance the cholangioscope to the hilum to pass tools through its channel and then slowly back it distally toward the ampulla. Advancement of instruments (e.g., laser fiber and forceps) may be particularly difficult at the level of the cholangioscope traversing the duodenoscope elevator or deflected tip of cholangioscope. No force must be used to push instruments within the cholangioscope channel to avoid damage. Gentle advancement or withdrawal of the duodenoscope or cholangioscope and release of all locks is important to negotiate this challenge. Repetitive opening and closing of the forceps while advancing it through the cholangioscope channel may also facilitate successful advancement.

Attention must be paid to the duodenoscope position throughout the procedure and fluoroscopy should be obtained intermittently to determine the location of the cholangioscope and avoid accidentally falling out of the bile duct. To optimize visibility, contrast use before cholangioscopy should be minimized. Additionally, irrigation with water or saline should be kept to a level necessary to facilitate evaluation to reduce the risk of bacterial translocation and the development of cholangitis, although it is not clear from available evidence whether irrigation is a definite risk factor for biliary infection.12 The four-way dials may need to be locked when a certain intervention is considered, such as sampling of a lesion or performing lithotripsy in an oblique position. However, the use of dial locking should be used with caution to avoid ductal injury and must not be used whenever the cholangioscope is advanced up within the bile duct.

INDICATIONS FOR CHOLANGIOSCOPY

Management of Choledocholithiasis

ERCP is the primary treatment modality for bile ducts.13 A broad armamentarium of tools can be used through the duodenoscope channel to allow lithotripsy, stone removal and ductal clearance. These tools include extraction balloons, sweeping baskets, mechanical lithotripsy baskets, papillary dilation balloons, and biliary stents.14,15 Nevertheless, in approximately 10-15% of cases, fundamental techniques fail either due to very large stone size, extremely hard consistency, barrel or piston shape, faceted configuration or ductal features such as a diminutive orifice, distal narrowing or sigmoid shape.14, 16-19

Cholangioscopy-guided lithotripsy represents a core therapeutic approach for the most difficult bile duct stones (Table 1). There are two commonly used modalities used to perform direct intraductal lithotripsy: electrohydraulic lithotripsy (EHL) and pulsed laser lithotripsy (LL). These modalities are most frequently guided by peroral cholangioscopes. While they may also be guided by fluoroscopy or percutaneously-introduced cholangioscopes, the former is limited by relatively blind targeting and the latter by hemobilia and bile leaks. 20,21

EHL delivers high-energy shockwaves generated by high voltage electric sparks delivered via fiber advanced through the accessory channel of the cholangioscope. The bile ducts are irrigated with saline to allow transfer of energy to the stone and minimize buildup of thermal energy.22 The probe should be positioned about 2 mm from the stone and directed towards the center (Figure 2a) and typically application of energy will result in a shattering of the stone (Figure 2b). If a cavity forms in the center without fracture the EHL probe may be aimed at the resulting joints to disrupt the stone into small fragments (Figure 2c). In LL, the shockwave is generated by the creation of a plasma cloud by high energy pulsed light delivered through flexible fiber (via the cholangioscope) into an aqueous media (saline or water).23 An aiming light allows precise targeting and helps prevent bile duct injury (Figure 3a). Intermittent irrigation and suctioning of the bile duct to wash away the minute fragments allow optimal visibility during the lithotripsy and dissipate heat energy. When LL is performed, safety measures must be observed and the manufacturer’s instructions must be followed including proper eye protection.24 Several technical maneuvers to weaken stones are to drill centrally through its core (Figure 3b) versus cutting it horizontally by using a saw motion generated by rocking the laser probe back and forth using the cholangioscope controls (Figure 3c).

A randomized trial demonstrated that peroral-cholangioscopy-guided lithotripsy reduced the need for surgical removal of difficult bile duct stones by four-fold.25 A meta-analysis of 2,204 patients with difficult bile duct stones revealed that the overall clearance was 92% (95% CI 90-94%).13 While overall adverse events for intraductal therapy was 8% (95% 6-11%), this was comparable to the rate for difficult stone treatment by conventional (non-intraductal) methods, 9% (95% 8-11%). The comparative safety and efficacy of cholangioscopy-guided EHL and LL has been investigated in a multicenter, international, observational study.26 Complete ductal clearance was high and comparable in both methods (97% and 99%, respectively). However, the mean procedure time was longer in the EHL group as compared to LL group (74 min and 50 min; P < 0.001). Adverse events were reported in 3.7% and they included cholangitis, bleeding and abdominal pain. Another prospective, multicenter study on peroral cholangioscopy-guided lithotripsy with EHL or LL in patients with difficult bile duct stones showed that ductal clearance was achieved within a single session in 80% (95% CI 73 – 86%) of patients.27

Cholangioscopy may also enable stone removal without fluoroscopy and can be used to identify missed bile duct stones in the context of patients with marked ductal dilatation and other features which reduce sensitivity of cholangiography.28 Cholangioscopy guided intraductal therapy has also emerged as a safe and effective endoscopic approach for the dreaded scenario in which stones become impacted in lithotripsy baskets within the bile duct.29 While this problem used to frequently require surgery, in most cases effective intraductal lithotripsy of the impacted stone will result in a prompt release of the impacted apparatus (stone + basket) from the duct (Figure 4). Finally, baskets introduced directly through the cholangioscope may be used to target and remove stones, particularly if located in an obliquely oriented duct (Figure 5).30

Therefore, cholangioscopy with intraductal therapy has a well-defined role in the management of difficult stones to obviate the need for surgery (Figure 6). Additionally, in cases in which there is suspicion of retained stones or other diagnostic uncertainty it has a burgeoning role.

EVALUATION OF INDETERMINATE BILIARY STRICTURES

Indeterminate biliary strictures represent a major and frequently encountered challenge for advanced endoscopists. While the ERCP brush cytology and trans-papillary intraductal forceps biopsy have high (95-99%) specificity for malignancy, the sensitivity is suboptimal (<50%) for both techniques (Figure 7a-b).33,34

Fine needle aspiration of biliary strictures via endoscopic ultrasound (EUS-FNA) has a comparably high specificity, 97% (95% CI 94- 99%) and 80% (95% CI 74-86%), sensitivity.35 Furthermore, EUS-FNA specifically following negative ERCP-guided cytologic brushing and biopsy has a 77% sensitivity and 100% specificity (Figure 7c).36 Nevertheless, there is concern about malignant seeding for EUS-FNA of proximal or hilar biliary lesions, though trials suggest that this may be overstated.37 EUS-FNA is a contraindication for patients with cholangiocarcinoma who are potentially candidates for a liver transplant treatment protocol.38

Given that cholangioscopes are introduced via the “natural” papillary orifice and do not cross a tissue plane there is less concern for seeding. It provides an opportunity both for visual assessment and diagnostic sampling. The identification of cholangioscopic visual features associated with benign, inflammatory and malignant diseases of the bile ducts has been the subject of multiple studies.39-44 Intraductal mass lesions and irregular nodules are strongly suggestive of malignancy (Figure 8).43 Dilated and tortuous vessels have also been proposed as concerning features.39,42 Papillary and villous projections are suggestive of neoplasia,44 while a smooth glandular surface is consistent with benign etiology (Figure 9). Diffuse but symmetric and homogenous narrowing may suggest a non-neoplastic inflammatory process such as primary sclerosing cholangitis (Figure 10) or IgG4 mediated cholangiopathy. Systematic review and meta-analysis of the visual features suggest a pooled diagnostic sensitivity of 60.1% (95% CI 54.9%-65.2%) and specificity of 98.0% (95% 96.0-99.0%).45 Nevertheless, studies of interobserver agreement suggest only slight to fair agreement for most individual visual features.46

Several classification systems have been developed to better categorize the cholangioscopic impressions of the bile duct. The Monaco Classification was developed by a recent multicenter group of expert biliary endoscopists using direct peroral cholangioscopy and digital single-operator cholangioscopy.40 The interobserver agreement (IOA) was slight in scoring for ulceration, white linear bands, and pronounced pits. The IOA was fair in scoring for the presence of stricture, a lesion, mucosal changes, and abnormal vessels. The IOA was moderate in scoring for papillary projections. The presumptive diagnosis IOA was fair (κ = 0.31, SE = 0.02) (Table 2). The overall accuracy of Monaco Classification based on visual impression alone was 70%. An alternative classification system is the Carlos Robles Medrana (CRM) criteria.41 Recently, the authors of the Monaco and CRM criteria convened to develop the newest visual criteria for cholangioscopy, the Mendoza criteria.47 These include the presence of tortuous and dilated vessels, irregular nodularity, raised intra-ductal lesions, irregular or ulcerated surface, and friability. The authors report a diagnostic accuracy of 77% for the criteria, nevertheless these criteria require external validation. As the use of cholangioscopy expands and more studies on endoscopic features of bile duct diseases are performed, the accuracy of visual inspection will likely continue to improve over time.

In addition to direct visualization of the bile duct lumen, cholangioscopy allows targeted biopsies using small diameter forceps which pass through the working channel of the cholangioscope (Figure 11). Systematic review and meta-analysis of observational studies indicated that the pooled sensitivity and specificity of cholangioscopy guided biopsies is 60.1% (95% CI 54.9%-65.2%) and 98.0% (95% CI 96.0%-99.0%), respectively.45 In a recent multicenter randomized trial, DSOC-guided biopsy sampling significantly improved the sensitivity of a tissue diagnosis, 68.2%, versus ERCP guided brushing, 21.4%. Specificity was 100% for both modalities.48 Given small size of biopsies specimen it is recommended to take multiple biopsies from each biliary lesion. While meta-analysis indicates reduced yield for 2 or fewer biopsies, the precise number is undefined.49

Recently, a larger forceps passed via the cholangioscopes which obtains more tissue per pass has been introduced (Figure 11b). While the aim is to improve yield, improved performance has not yet been demonstrated in studies.50

Given favorable performance characteristics and minimal risk of seeding it is frequently utilized in the central diagnostic algorithm of biliary strictures in patients who are potentially resectable, candidates for transplantation, and those who have failed other diagnostic maneuvers (Figure 12).

FACILITATING THERAPY FOR CHALLENGING BILE DUCT STRICTURES

Successful guidewire placement is essential to allow therapeutic interventions during ERCP such as dilation and decompression using stents. Using different kinds of guidewires with different characteristics (e.g., angled vs. straight tip, wire size, stiffness) along with trying different scope positions often allows successful guidewire placement. However, in some cases these conventional techniques and instruments fail to reach the duct of interest. By enabling direct visualization of bule ducts, cholangioscopy allows selective passage of wires and subsequent therapy into very specific biliary targets (Figure 13).51-55 In addition, selective bile duct cannulation by direct cholangioscopic visualization mitigates the likelihood of extensive fluoroscopy use and may reduce procedure time.

OTHER INDICATIONS

An important and specialized scenario where direct visualization by POC has been successfully used is the evaluation of biliary complications after liver transplantation. Post-transplant strictures may have extremely oblique angulation or high-grade nature, particularly following living donor procedures, which may benefit from cholangioscopy.56,57 In addition to facilitating guidewire placement across difficult angulation or strictures, cholangioscopy may have a diagnostic role in post-transplant patients to identify surreptitious mural ulceration retained sutures, and stones or casts which are not apparent on cholangiography.57,58 It is unclear whether the utilization of POC for evaluation of biliary complications during first ERCP is warranted. Nevertheless, it is worth considering in cases that are not responsive to initial ERCP with interventions and when there is diagnostic uncertainty.

POC has been successfully used for a number of other indications. Prior to complex resection, it may be used to perform mapping which can guide surgery.59 It may also play an important diagnostic role to evaluate malignancy in choledochal cysts,60,61 guide tumor ablation with radiofrequency or photodynamic therapy62, and evaluate source of hemobilia.63-65 POC was also found beneficial in retrieval of migrated biliary stents.66 As technology, training and access to cholangioscopy grow, additional novel applications will emerge.

COST AND ADVERSE EVENTS

Cost and safety are additional vital considerations for the use of cholangioscopy in clinical practice. The cost of single operator cholangioscopes increased with conversion from fiberoptic to digital platforms. The cost of the latter many exceed $3000 per case which requires careful assessment of resource utilization. Definitive cost-effectiveness studies are needed. A model of the economic consequences of single-operator cholangioscopy in a Belgian hospital system found that early use of cholangioscopy-guided therapy for difficult stones could potentially result in cost savings by decreasing the overall number of procedures.67

Prospective studies of cholangioscopy indicate that bacteremia and cholangitis occur in 8.8% and 6.6%, respectively.68 While meta-analysis does not suggest a higher rate of overall adverse events than conventional ERCP for indications such as difficult bile duct stones,13 likelihood of cholangitis is greater. This increases with hilar and multifocal strictures.69 In high-risk settings, i.e., primary sclerosing cholangitis, complex stones, and proximal strictures, administration of peri-procedural antibiotics such as fluoroquinolones and 3rd or 4th generation cephalosporins in addition to bile duct stent should be considered. Cholangioscopy should be avoided in cases of purulent.

When laser lithotripsy is performed, sufficient irrigation and aspiration to optimize visibility along with strictly avoiding use of laser blindly are important precautions to avoid ductal injury. Other adverse events include post-ERCP pancreatitis, perforation, and bleeding, though the rates of these complications for cases with cholangioscopy do not appear to be significantly higher than adverse events from ERCP alone.9,12, 70-74

Another important consideration is the use of general anesthesia to protect airways when irrigation may increase the fluid content of the upper GI tract.

FUTURE DIRECTIONS

Rapid advancements in medical technology have already expanded the use of and role of cholangioscopy. Deep learning algorithms promise to increase the diagnostic power of cholangioscopy as do integration of image enhancement techniques from other types of endoscopy including narrow band imaging.75 Technical advances will also make scopes easier to use and intensify their therapeutic potential. Direct POC using a novel multi-bending ultra-slim scope shortens procedure time and may improve success rates.76 Slimmer, more flexible scopes may facilitate cholangioscopy’s role in patients with primary sclerosing cholangitis and high-grade strictures where success is lower. Additionally, it will likely emerge as a high precision ablative therapy with radiofrequency and photodynamic therapy and future modalities.77-79 Simpler less expensive devices to exclude residual stones will likely emerge which will have a complementary role with cholangioscopes with broader therapeutic capability.

CONCLUSION

Cholangioscopy has emerged as a core tool in diagnosis and management of neoplastic and non-neoplastic biliary diseases. It is especially important in the treatment of complex bile duct stones and evaluation of indeterminate strictures. An expanding role in biliary practice including treatment of early neoplasia, pre-operative staging, and exclusion of residual stones is emerging. While cost might still be a limiting factor in some practices, the proper utilization of this tool in the appropriate clinical context is likely cost-effective as it improves non-operative management of biliary disease.

Wissam Kiwan, MD Assistant Professor of Medicine Advanced & Therapeutic Endoscopy Division of Gastroenterology and Hepatology Saint Louis University, St. Louis, MO James L. Buxbaum, MD, FASGE Associate Professor of Medicine, Keck Medicine of the University of Southern California, Los Angeles, CA

References

1. Committee AT, Komanduri S, Thosani N, et al. Cholangiopancreatoscopy. Gastrointest Endosc 2016;84:209-21.

2. Roca J, Flichtentrei R, Parodi M. [Progress in the radiologic study of the biliary tract in surgery; cholangioscopy and cholangiography; utilization of apparatus; preliminary note]. Dia Med 1951;23:3420.

3. Rösch W, Koch H, Demling L. Peroral Cholangioscopy. Endoscopy 1976;08:172-175.

4. Ell C, Lux G, Hochberger J, et al. Laserlithotripsy of common bile duct stones. Gut 1988;29:746-51.

5. Leung JW, Chung SS. Electrohydraulic lithotripsy with peroral choledochoscopy. BMJ 1989;299:595-8.

6. Cotton PB, Kozarek RA, Schapiro RH, et al. Endoscopic laser lithotripsy of large bile duct stones. Gastroenterology 1990;99:1128-33.

7. Larghi A, Waxman I. Endoscopic direct cholangioscopy by using an ultra-slim upper endoscope: a feasibility study. Gastrointest Endosc 2006;63:853-7.

8. Moon JH, Choi HJ. The role of direct peroral cholangioscopy using an ultraslim endoscope for biliary lesions: indications, limitations, and complications. Clin Endosc 2013;46:537-9.

9. Chen YK, Pleskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bile-duct disorders: a clinical feasibility study (with video). Gastrointest Endosc 2007;65:832-41.

10. Chen YK, Parsi MA, Binmoeller KF, et al. Single-operator cholangioscopy in patients requiring evaluation of bile duct disease or therapy of biliary stones (with videos). Gastrointest Endosc 2011;74:805-14.

11. Shah RJ, Raijman I, Brauer B, et al. Performance of a fully disposable, digital, single-operator cholangiopancreatoscope. Endoscopy 2017;49:651-658.

12. Adler DG, Cox K, Milliken M, et al. A large multicenter study analysis of adverse events associated with single operator cholangiopancreatoscopy. Minerva Gastroenterol Dietol 2015;61:179- 84.

13. Committee ASoP, Buxbaum JL, Abbas Fehmi SM, et al. ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis. Gastrointest Endosc 2019;89:1075- 1105 e15.

14. Thomas M, Howell DA, Carr-Locke D, et al. Mechanical lithotripsy of pancreatic and biliary stones: complications and available treatment options collected from expert centers. Am J Gastroenterol 2007;102:1896-902.

15. Stefanidis G, Viazis N, Pleskow D, et al. Large balloon dilation vs. mechanical lithotripsy for the management of large bile duct stones: a prospective randomized study. Am J Gastroenterol 2011;106:278-85.

16. Manes G, Paspatis G, Aabakken L, et al. Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy 2019;51:472-491.

17. Kedia P, Tarnasky PR. Endoscopic Management of Complex Biliary Stone Disease. Gastrointest Endosc Clin N Am 2019;29:257-275.

18. Trikudanathan G, Arain MA, Attam R, et al. Advances in the endoscopic management of common bile duct stones. Nat Rev Gastroenterol Hepatol 2014;11:535-44.

19. Garg PK, Tandon RK, Ahuja V, et al. Predictors of unsuccessful mechanical lithotripsy and endoscopic clearance of large bile duct stones. Gastrointest Endosc 2004;59:601-5.

20. Neuhaus H, Hoffmann W, Zillinger C, et al. Laser lithotripsy of difficult bile duct stones under direct visual control. Gut 1993;34:415-21.

21. Ell C, Hochberger J, May A, et al. Laser lithotripsy of difficult bile duct stones by means of a rhodamine-6G laser and an integrated automatic stone-tissue detection system. Gastrointest Endosc 1993;39:755-62.

22. Arya N, Nelles SE, Haber GB, et al. Electrohydraulic lithotripsy in 111 patients: a safe and effective therapy for difficult bile duct stones. Am J Gastroenterol 2004;99:2330-4.

23. Patel KS, Calixte R, Modayil RJ, et al. The light at the end of the tunnel: a single-operator learning curve analysis for per oral endoscopic myotomy. Gastrointest Endosc 2015;81:1181-7.

24. Villa L, Cloutier J, Comperat E, et al. Do We Really Need to Wear Proper Eye Protection When Using Holmium:YAG Laser During Endourologic Procedures? Results from an Ex Vivo Animal Model on Pig Eyes. J Endourol 2016;30:332-7.

25. Buxbaum J, Sahakian A, Ko C, et al. Randomized trial of cholangioscopy-guided laser lithotripsy versus conventional therapy for large bile duct stones (with videos). Gastrointest Endosc 2018;87:1050-1060.

26. Brewer Gutierrez OI, Bekkali NLH, Raijman I, et al. Efficacy and Safety of Digital Single-Operator Cholangioscopy for Difficult Biliary Stones. Clin Gastroenterol Hepatol 2018;16:918-926 e1.

27. Maydeo AP, Rerknimitr R, Lau JY, et al. Cholangioscopy-guided lithotripsy for difficult bile duct stone clearance in a single session of ERCP: results from a large multinational registry demonstrate high success rates. Endoscopy 2019;51:922-929.

28. Ridtitid W, Luangsukrerk T, Angsuwatcharakon P, et al. Uncomplicated common bile duct stone removal guided by cholangioscopy versus conventional endoscopic retrograde cholangiopancreatography. Surg Endosc 2018;32:2704-2712.

29. Aloreidi K, Patel B, Atiq M. Intraductal cholangioscopy-guided electrohydraulic lithotripsy as a rescue therapy for impacted common bile duct stones within a Dormia basket. Endoscopy 2016;48:E357-E358.

30. Fejleh MP, Thaker AM, Kim S, et al. Cholangioscopy-guided retrieval basket and snare for the removal of biliary stones and retained prostheses. VideoGIE 2019;4:232-234.

31. Kim HJ, Choi HS, Park JH, et al. Factors influencing the technical difficulty of endoscopic clearance of bile duct stones. Gastrointest Endosc 2007;66:1154-60.

32. Christoforidis E, Vasiliadis K, Tsalis K, et al. Factors significantly contributing to a failed conventional endoscopic stone clearance in patients with “difficult” choledecholithiasis: a single-center experience. Diagn Ther Endosc 2014;2014:861689.

33. Navaneethan U, Njei B, Lourdusamy V, et al. Comparative effectiveness of biliary brush cytology and intraductal biopsy for detection of malignant biliary strictures: a systematic review and meta-analysis. Gastrointest Endosc 2015;81:168-76.

34. Hu B, Sun B, Cai Q, et al. Asia-Pacific consensus guidelines for endoscopic management of benign biliary strictures. Gastrointest Endosc 2017;86:44-58.

35. Sadeghi A, Mohamadnejad M, Islami F, et al. Diagnostic yield of EUS-guided FNA for malignant biliary stricture: a systematic review and meta-analysis. Gastrointest Endosc 2016;83:290-8 e1.

36. DeWitt J, Misra VL, Leblanc JK, et al. EUS-guided FNA of proximal biliary strictures after negative ERCP brush cytology results. Gastrointest Endosc 2006;64:325-33.

37. El Chafic AH, Dewitt J, Leblanc JK, et al. Impact of preoperative endoscopic ultrasound-guided fine needle aspiration on postoperative recurrence and survival in cholangiocarcinoma patients. Endoscopy 2013;45:883-9.

38. Heimbach JK, Sanchez W, Rosen CB, et al. Trans-peritoneal fine needle aspiration biopsy of hilar cholangiocarcinoma is associated with disease dissemination. HPB (Oxford) 2011;13:356-60.

39. Seo DW, Lee SK, Yoo KS, et al. Cholangioscopic findings in bile duct tumors. Gastrointest Endosc 2000;52:630-4.

40. Sethi A, Tyberg A, Slivka A, et al. Digital Single-operator Cholangioscopy (DSOC) Improves Interobserver Agreement (IOA) and Accuracy for Evaluation of Indeterminate Biliary Strictures: The Monaco Classification. J Clin Gastroenterol 2022;56:e94-e97.

NUTRITION REVIEWS IN GASTROENTEROLOGY

The Importance of Assessing Muscle Health – Practical Tools for Clinicians

Rebecca Lee,

Patricia Sheean

Human body composition is an emerging field of science that looks beyond body mass index to explore the different distributions of muscle and adipose tissue on health outcomes. Declines in skeletal muscle mass and function (e.g., sarcopenia) independently contribute to adverse health outcomes and often reflect poor muscle health. Therefore, it is imperative for clinicians to better understand the different methodologies to measure muscle mass, as well as muscle function. Familiarity with the array of existing and emerging clinical tools and measures is a critical step to help clinicians identify and address poor muscle health. This article briefly reviews practical and emerging body composition methodologies (bioelectrical impedanceanalysis, dual energy x-ray absorptiometry, ultrasound, computed tomography) and offers clinicians tools to measure, quantify, and address muscle health concerns in their patients.

INTRODUCTION

Skeletal muscle (SM), the primary component of lean soft tissue or lean mass (LM), serves as the major protein reserve in the human body. Although decreases in SM mass and function are part of the natural aging process, an ever-increasing body of research supports that decreases in muscle health (e.g., sarcopenia) independently contribute to adverse clinical outcomes. Addressing the presence of sarcopenia in acute and chronically ill patient populations is crucial as this condition negatively impacts individual health (e.g., self-care, treatment response, quality of life) and increases the financial burden on healthcare systems.1 While excess adiposity is often a focal point of care for many clinicians, and body mass index (BMI) is the common clinical metric used to evaluate obesity, sarcopenia is highly prevalent across the BMI spectrum.2 Therefore, it is imperative for clinicians to better understand the different methodologies to measure muscle mass and muscle function (referred to as muscle health). Familiarity with the available tools and measures can help clinicians to identify this highly prevalent, clinically significant condition.

Why Body Composition Matters

Human body composition analysis is an emerging field of science that looks beyond BMI to explore the different distributions of SM and adipose tissue on health outcomes. Compromises in muscle health are the hallmark feature of sarcopenia; a clinical condition characterized by low muscle strength and low muscle mass.1 The more recent inclusion of muscle function into patient assessments is intended to facilitate better application and integration into clinical practice. Sarcopenia is occult, often difficult to detect on physical examination (PE) and may not automatically trigger nutritional interventions. Other physiological indications that coexist and may contribute to the onset of sarcopenia may include chronic illness, inflammation, poor oral intake, a sedentary lifestyle, and declining functional status. Weight loss is not considered a reliable indicator to identify or screen for sarcopenia3 and currently, there is no consensus on how best to measure muscle health.

Clinicians are encouraged to use direct measures of muscle mass, as well as devices or tools to assess muscle function. It should be emphasized that further evaluation regarding the validity of assessment techniques for body composition applicable to a wide array of patient populations are recommended. This brief review intentionally focuses on the most common and emerging tools relevant to clinical practice. For a more in-depth appreciation on the development, use, strengths, and limitations of these and other body composition assessment tools, please refer to reference 4. Table 1 depicts several tools most applicable in the clinical setting.

Measurement Techniques to Assess Body Composition

Bioelectrical Impedance Analysis

Bioelectrical Impedance Analysis (BIA) uses low-intensity, electric conduction with single, multiple, or a spectrum (BIS) of frequencies to determine estimates of total body water (TBW). By using predictive equations, TBW is used to calculate estimated fat free mass (FFM) and fat mass (FM).5 For clarity, FFM encompasses LM and bone, while FM refers to the actual lipid content in adipose tissue.6 To use BIA or BIS, electrodes are placed on the hand, wrist, foot, and/or ankle and a low intensity electric current(s) is applied creating measures of reactance and impedance (Figure 1). Body tissues such as FM with low amounts of water and electrolytes will produce a high impedance, compared to LM which will have low impedance reflecting the high water and electrolyte content.5

Conventionally, BIA or BIS is a clinical favorite in multiple settings due to its low cost, portability, and noninvasive nature. However, BIA and BIS results are only considered valid and reliable when repeated measures are obtained over time and when steady state conditions have been met, especially those related to hydration and fluid status. For example, in patients with heart failure, a BIA measurement could produce falsely low estimates of body fat due to the increase in TBW. In contrast, an individual with decreased TBW such as dehydration, will produce falsely high measures of body fat as there is less conductivity measured. If clinicians or researchers decide to utilize BIA or BIS as a measurement tool, it is crucial to obtain baseline and follow up measures, and to consider the appropriate type of device, the intended target population for the device, and conditions of measurement (e.g., fasting requirements, fluid status, medications).5 Handheld and scale-type devices are readily available over the counter and easily incorporated into clinical practice. However, because manufacturers do not share their FFM and FM predictive equations, the same device must be used for follow-up measures to support valid comparisons.

Dual Energy X-Ray Absorptiometry

As the name implies, dual energy x-ray absorptiometry (DXA) relies on x-ray technology to procure information about bone density and body composition. It is conventionally used to diagnosis osteoporosis; however, since the 1980s DXA has gained popularity as a body composition assessment tool.7 DXA technology is based on two, low radiation photon energy x-rays measured with a detector after these two rays pass through the subject (Figure 1). The strength of photon x-ray beams is altered depending on the tissue they pass through, and thus this variation can be captured as body composition measurements. The ratio of the energy from the two beams can differentiate bone, FM, and LM. DXA is useful for measuring specific parts of the body and can provide insights on LM change, especially in appendicular regions.8

Similar to BIA, DXA can be used on a wide range of body sizes and body types and is non-invasive, yet it remains a greatly underutilized tool in the outpatient setting due to issues surrounding access and availability.7 The practicality of using DXA for body composition assessment in the acute or inpatient setting greatly limits its use. Unlike BIA, DXA instrumentation is expensive, requires a dedicated room, and requires technician certification. Conventionally, DXA scanning captures images of the femoral or lumbar spine, as these are reference standards for determining osteoporosis risk. Obtaining body composition data requires whole-body imaging, which is only performed if requested and would likely pose additional labor and cost burden.6 Whole-body images relay information on regional and total adiposity, as well as appendicular LM (e.g., LM of the arms and legs combined) and total LM (e.g., trunk, head, appendages). Appendicular LM is adjusted for height and used to diagnose sarcopenia, which ignores muscle function. Like BIA, the reliability of DXA can be compromised in individuals with hydration issues, should be completed when individuals are fasted,9 and the output may not differentiate adipose tissue types (visceral vs. subcutaneous fat). Since 1999, DXA is used to characterize body composition in the on-going National Health and Nutrition Examination survey, providing population reference values for adults and children.10 However, DXA imaging for clinical assessment of body composition is still considered ‘investigational’ and therefore not routinely covered by insurers.

Ultrasonography

There is growing interest in the utilization of ultrasound (US) as a body composition technique due to its portability, relative affordability, and ease in obtaining repeated measurements. Most work has focused on measuring visceral and subcutaneous adipose tissue (VAT and SAT, respectively), and more recently muscle.11 US uses high-frequency sound waves from tissues, where the amount of sound reflected depicts changes in acoustic impedance – the product of acoustic velocity and tissue density (Figure 1). As such, US can relay information about adipose tissue, muscle thickness and muscle cross-sectional area of measurement. Total body LM can be estimated via a regression equation using measures of muscle thickness from multiple sites. US can also be used to gauge “fatty infiltrated” muscle (also known as myosteatosis); a condition more common in persons with diabetes symbolizing metabolic and physiologic dysfunction.12

The biggest limitation of US lies in the reliability of the operator. Even with the advent of standardized techniques, determining the minimal vs. maximal compression of the transducer onto the skin site by the operator can vary, and alter the thickness and quantifications of SM and SAT.12 Similar to BIA, BIS, or DXA, hydration, specifically edema, can present challenges to obtaining accurate body composition measures using US. However, with US technique training, edema is no longer an absolute contraindication for using this technique.13 Differences in US transducers allow for varying ranges of tissue penetration and window width (e.g., linear vs. curvilinear), which may be beneficial for patients with severe obesity or fluid overload.12 While US has the potential to be utilized within multiple patient populations, issues surrounding inter- and intra-individual measurement variation continue to pose barriers for making this technique more applicable in the clinical setting.

Computed Tomography

Due to software advances, computed tomography (CT) images conducted for clinical (diagnostic or surveillance) purposes can be utilized to obtain precise information related to adipose tissue and SM. Specifically, VAT, SAT and intramuscular adipose tissue (IMAT) can be individually quantified or comprised to create total adipose tissue (TAT). Additionally, SM mass and SM quality can be ascertained from CT images to diagnose sarcopenia and myosteatosis, respectively. Given the widespread use of CT imaging in patient care, these images serve as a rich archive of body composition data and are increasingly employed in prevalence and outcomes research.14 Conventionally, CT images inclusive of the third lumbar (L3) region (e.g., abdominal and/or pelvic) are used to examine body composition.

While CTs are distinctly advantageous because of their superior precision relative to other body composition techniques, they remain largely a research tool. The barriers to utilizing CT images are immense, and include but are not limited to extensive training, access to the picture archiving and communications system to retrieve specific CT studies, expertise utilizing the body composition software, and/or personnel time for analyses. Due to concerns regarding radiation and expense, rarely are CTs advocated as prospective body composition technique.15 There are additional concerns related to the translation of these data to patient care (e.g., what are the implications of myosteatosis?) and a lack of clinically meaningful cut-points (e.g., high vs. low VAT). As such, advances are required to increase the immediate clinical applicability of body composition measures ascertained from CT imaging.

Physical Examination, Anthropometric Measurements, and Muscle Function

In instances where BIA, BIS, DXA, or US are not available, the use of anthropometric measurements and comprehensive PE are recommended to assess muscle health.11 Mid-upper arm and/or calf circumferences are easily obtained in the clinical setting and correlate with compromised muscle health. In addition, clinicians can be trained to evaluate qualitative signs of reduced muscle mass during their PE, taking a ‘head to toe’ approach focusing on the temples, neck, clavicle, shoulder, scapula, thigh, and calf areas (see Table 2). Nutrition focused PEs are a component of validated nutrition assessment tools, including the Subjective Global Assessment (SGA), and recommended by professional bodies such as the Academy of Nutrition and Dietetics (AND) and the American Society for Parenteral and Enteral Nutrition (ASPEN) to depict muscle wasting. However, PE and anthropometric measurements are more challenging in individuals with obesity and severe fluid abnormalities, as SM may be poorly differentiated.

To complement the anthropometric and PE information gathered, it is imperative to measure muscle function for a comprehensive picture of muscle health. Endorsed by the European Working Group on Sarcopenia in Older People, several tests can be conducted at the bedside or in clinic to assess muscle function (See Table 2).1 Because of the undue influence of non-nutritive factors (e.g., neurologic impairment), it is not advised to uniformly prioritize muscle function tests over muscle mass assessment.11 For example, some patients may be too impaired to hold the hand dynamometer or too unbalanced to perform a sit-to-stand test. Muscle function testing can substantiate or support PE, or other clinical findings, regarding muscle health and put into proper context of patient care.

Practical Applications for Clinicians

Preserving or improving LM and/or muscle function is the overarching goal for any patient, especially the aging. Simply recognizing compromises in LM occur across all BMI strata is vital for clinicians to appreciate. Clinicians are encouraged to look beyond BMI and focus their treatments on simple messaging and early intervention referrals.

Clinicians should take advantage of opportunities to assess eating patterns, honing in on nutrition-impact symptoms (e.g., taste change, gastrointestinal symptoms) or behaviors (e.g., skipping meals, eliminating of food groups) that preclude optimal oral intake. Additionally, incorporating methods to identify patients who report unstable socioeconomic status and/or food insecurity, as these factors increase the likelihood of inadequate dietary intake. Simple interventions, including calorically dense oral supplements or protein supplements (e.g., beverages, bars, powders) may be indicated at or between meals. Animal sources of protein have been shown to upregulate anabolic stimulation compared to plant-based proteins (apart from soy-based isolates) and possess higher levels of digestibility. Expert opinion recommends older adults with comorbid conditions aim to consume at least 65% of daily protein needs from animal sources, such as red meat, eggs, fish, poultry, and dairy. Patients following an exclusively plant-based diet (veganism or vegetarianism) should regularly incorporate soy or pea protein isolates as these plant proteins offer higher amino acid digestibility.16 Table 3 offers dietary intake probes and potential responses to support improved nutrition messaging.

In patient populations with sarcopenia or at high risk of sarcopenia, dietary protein intake and physical activity are typically low which negatively affect rates of muscle protein synthesis.13 Increasing physical activity, specifically progressive resistance exercise training, can preserve or build LM. A 3-month pilot study demonstrates the value of a supervised resistance exercise program significantly and positively impacting quality of life, pain, LM and physical functioning in older patients with advanced cancer.17 Referrals to physical therapy and/or exercise physiologists to assess and individualize functional interventions, as well as engagement with registered dietitians and social workers to reduce nutrition, psychological, and socioeconomic barriers to oral intake are recommended.

CONCLUSIONS

The landscape of clinical practice is shifting to recognize the importance of muscle health and its impact on outcomes. Clinicians should arm themselves with the knowledge and tools to assess muscle mass and muscle function, utilizing readily available quantitative measures (BIA or DXA), anthropometrics (mid-upper arm or calf circumference), and/or enhanced PE methods. Recommendations regarding consistent, adequate oral intake with high quality protein sources are advocated for any patient with documented or suspected compromises in muscle health. Interdisciplinary collaborations are key to optimizing care and combating the untoward effects of compromised muscle health.

References

1. Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31.

2. Prado CM, Cushen SJ, Orsso CE, Ryan AM. Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact. Proc Nutr Soc. 2016;75(2):188-98.

3. Prado CM, Lieffers JR, Bowthorpe L, Baracos VE, Mourtzakis M, McCargar LJ. Sarcopenia and physical function in overweight patients with advanced cancer. Can J Diet Pract Res. 2013;74(2):69-74.

4. Heymsfield S. Human body composition. 2nd ed. Champaign, IL: Human Kinetics; 2005. xii, 523 p. p.

5. Vineis MA PS. A review of biolectiral impedance analysis. Support Line: Dietitians in Nutrition Support. 2015;37(3):18-23.

6. Sheean P, Gonzalez MC, Prado CM, McKeever L, Hall AM, Braunschweig CA. American Society for Parenteral and Enteral Nutrition Clinical Guidelines: The Validity of Body Composition Assessment in Clinical Populations. JPEN J Parenter Enteral Nutr. 2020;44(1):12-43.

7. Shepherd JA, Ng BK, Sommer MJ, Heymsfield SB. Body composition by DXA. Bone. 2017;104:101-5.

8. Coltman A. Dual energy x-ray absorptiometry (DXA). Support Line: Dietitians in Nutrition Support. 2015;37(3):15-8.

9. Hangartner TN, Warner S, Braillon P, Jankowski L, Shepherd J. The Official Positions of the International Society for Clinical Densitometry: acquisition of dual-energy X-ray absorptiometry body composition and considerations regarding analysis and repeatability of measures. J Clin Densitom. 2013;16(4):520-36.

10. Kelly TL, Wilson KE, Heymsfield SB. Dual energy X-Ray absorptiometry body composition reference values from NHANES. PLoS One. 2009;4(9):e7038.

11. Barazzoni R, Jensen GL, Correia M, Gonzalez MC, Higashiguchi T, Shi HP, et al. Guidance for assessment of the muscle mass phenotypic criterion for the Global Leadership Initiative on Malnutrition (GLIM) diagnosis of malnutrition. Clin Nutr. 2022;41(6):1425-33.

12. McGhee B RH. Application of ultrasonography for measuring change in lean body mass in acute care. Support Line: Dietitians in Nutrition Support. 2015;37(3):3-5.

13. Sabatino A, Regolisti G, Bozzoli L, et al. Reliability of bedside ultrasound for measurement of quadriceps muscle thickness in critically ill patients with acute kidney injury. Clin Nutr. 2017;36(6):1710-5.

14. Amini B, Boyle SP, Boutin RD, Lenchik L. Approaches to Assessment of Muscle Mass and Myosteatosis on Computed Tomography: A Systematic Review. J Gerontol A Biol Sci Med Sci. 2019;74(10):1671-8.

15. Tolonen A, Pakarinen T, Sassi A, et al. Methodology, clinical applications, and future directions of body composition analysis using computed tomography (CT) images: A review. Eur J Radiol. 2021;145:109943.

16. Ford KL, Arends J, Atherton PJ, et al. The importance of protein sources to support muscle anabolism in cancer: An expert group opinion. Clin Nutr. 2022;41(1):192-201.

17. Cormie P, Newton RU, Spry N, Joseph D, Taaffe DR, Galvão DA. Safety and efficacy of resistance exercise in prostate cancer patients with bone metastases. Prostate Cancer and Prostatic Diseases. 2013;16(4):328-35.

18. National Institute of Health Motor Measures: NIH; 2019 [Available from: https://www.healthmeasures. net/explore-measurement-systems/nih-toolbox/obtain-and-administer-measures/demonstration-videos.]

FROM THE PEDIATRIC LITERATURE

Will COVID-19 Increase Pediatric IBD Cases Over Time?

The COVID-19 pandemic has led to many downstream consequences, and one such sequelae may be an increase in pediatric autoimmune disease, such as Type I diabetes mellitus. The authors of this study looked at pediatric SARS-CoV-2 infections during the COVID-19 pandemic as well as the subsequent occurrence of inflammatory bowel disease (IBD) in New York City children.

This study evaluated cases of pediatric IBD from four large academic pediatric gastroenterology (GI) centers in New York City from 2016 to 2022. Electronic medical record data was used to determine basic patient information including age grouping based on FDA approval of the SARS-CoV-2 vaccine. Pediatric cases of Crohn’s disease (CD) and ulcrative colitis (UC) were identified and followed while pediatric cases of IBD unclassified were excluded. A quarterly count analysis of both CD and UC cases using the Shapiro-Wilk test demonstrated normal distribution, and autoregressive integrated moving average modeling was used to predict trends in new pediatric IBD cases over a specific period during the pandemic (April 2020 – June 2022) based on known pediatric IBD cases found retrospectively during the defined pre-pandemic period (January 2016 – March 2020).

A total of 587 pediatric IBD patients were initially included in the study with 43.1% of patients being female. The median age of patients was 14 years (range of 2 to 21 years) with most patients being of white ethnicity (47.4%) and between 16 to 21 years of age (36.3%). Autoregressive integrated moving average modeling based on pre-pandemic new pediatric cases of UC forecast 1.91 new cases per month and 5.76 new cases per quarter through the pandemic period. However, the actual number of new pediatric UC cases was more than predicted during 3 monthly periods (range 5-6 cases per month) during the pandemic. Regarding pediatric CD cases, autoregressive integrated moving average modeling of pre-pandemic cases of CD forecast 4.67 new cases per month and 14 new cases per quarter during the pandemic period. However, more new pediatric CD cases compared to what was predicted were diagnosed during the 2020 third quarter, 2022 first quarter, and during 4 monthly periods (range 9-13 cases) during the pandemic. Significantly less cases of new IBD cases occurred in white patients during the study period while significantly more cases occurred in Hispanic patients.

This study suggests that the COVID-19 pandemic may have some unforeseen downstream effects for other disorders; namely, an increase in pediatric IBD cases after SARS-CoV-2 infection. The authors note that the rise in pediatric IBD cases seen in this study could be due to the overall increase in IBD prevalence worldwide, but in the setting of the New York City area where the COVID-19 pandemic was exceptionally severe, these findings provide data suggesting that SARS-CoV-2 contributes to perturbing the immune system which leads to increased cases of pediatric IBD. It would be interesting to see if vaccination status is associated with less IBD in pediatric patients long term.

Rosenbaum J, Ochoa K, Hasan F, Goldfarb A, Tang V, Tomer G, Wallach T. Epidemiologic Assessment of Pediatric Inflammatory Bowel Disease Presentation in NYC During COVID- 19. Journal of Pediatric Gastroenterology and Nutrition, 2023; e003740: Online ahead of print.

Do Abdominal Radiographs Help in the Diagnosis of Constipation in Children?

Constipation is a common cause for pediatric patients to be seen in general pediatric and pediatric gastroenterology clinics. Typically, there is no organic cause for constipation, and functional constipation really should be diagnosed by history and physical examination alone. Unfortunately, abdominal X-rays (AXR) are over-utilized in the work up of pediatric constipation despite recommendations to the contrary provided by European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). The authors of this study proposed that significant inter- / intraobserver variation exists in the interpretation of AXRs by physicians when an AXR is obtained to determine constipation in a child.

This study evaluated 100 AXRs obtained at a single pediatric emergency room over a three-year period. Images were blinded regarding patient information and were read by 2 senior physicians (defined as having at least 5 years of clinical experience) and 2 junior physicians (defined as having less than 5 years of clinical experience) in each of the following specialties: pediatric gastroenterology, radiology, and pediatric emergency medicine. All AXRs underwent subjective readings of findings by these 12 physicians, and then a subset of the AXRs were submitted to the same physicians for repeat subjective readings. Finally, these physicians were taught two separate scoring systems to objectively diagnose constipation using AXRs (the Barr scoring system and the Blethyn scoring system), and all AXRs were reinterpreted. Pediatric patients for this study were aged between 1 and 18 years old, and AXRs from patients with Hirschsprung disease and previous abdominal surgery were excluded.

When subjective interpretation of AXRs were evaluated, the Fleiss kappa coefficient demonstrated a value of 0.18 (poor agreement) between all physicians with only 40% of physicians having an agreement on radiology findings. Comparisons between specialties showed a kappa coefficient of 0.21 (41.5%), 0.11 (36.7%), and 0.26 (47.3%) in the fields of pediatric gastroenterology, radiology, and pediatric emergency medicine, respectively. Comparisons of subjectively reading repeat AXRs for each individual produced a kappa coefficient of 0.08 – 0.61 with only 33.3% – 73.4% agreement noted. Objective readings of AXRs also did not perform well as use of the Blethyn method produced a kappa coefficient value of 0.14 (38.4% agreement) while the Barr method produced a kappa coefficient value of 0.20 (60% agreement) among all 12 providers. It should be noted that Fleiss kappa values ˂ 0.40 indicated poor agreement, 0.40 – 0.75 indicated intermediate to good agreement, and ˃ 0.75 indicated excellent agreement.

This study demonstrates that using AXRs to diagnose constipation in children is not helpful and increases healthcare costs while exposing children to unnecessary radiation. The cornerstone of diagnosing constipation in children remains the history and physical examination, and AXRs should not be used as a diagnostic endeavor in such a scenario. More international exposure to both EPSGHAN and NASPGHAN consensus statements in the diagnosis and treatment of pediatric constipation is very much needed.

Yallanki N, Small-Harary L, Morganstern J, Tobin M, Milla L, Chawla A. Inter and Intraobserver Variation in Interpretation of Fecal Loading on Abdominal Radiographs. Journal of Pediatric Gastroenterology and Nutrition 2023; 76: 295-299.

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

FUNDAMENTALS OF ERCP, SERIES #5

Pancreatoscopy

Robert J. Sealock,

Mohamed O. Othman

Pancreatoscopy is an endoscopic procedure by which a small caliber endoscope or a catheter-based system is advanced from either the major or minor papilla into the pancreatic duct. Either system is typically advanced through a duodenoscope to allow for proper approach to the pancreatic duct orifice. We herein describe the history, technical aspects, setup, and technical success of pancreatoscopy for a variety of diagnostic and therapeutic indications.

1. History of pancreatoscopy

The use of per oral cholangiopancreatoscopy was reported in 1975^1,2 using 10Fr endoscope under duodenoscopic visualization. The initial devices were limited to diagnostic purposes with subsequent modifications to allow for tip deflection, irrigation, and the passage of accessories namely a biopsy forcep and lithotripsy fiber. These early systems were termed “mother-daughter” as the duodenoscope served as the “mother” while the smaller “daughter” pancreatoscope was inserted through the working channel. Limitations to these early devices were that two endoscopists were required with one operating the duodenoscope and the other the pancreatoscope. The fiberoptic cable was prone to breakage given that it was housed within a small caliber device. In an early series of 50 patients undergoing pancreatoscopy, technical success was a less-than-satisfying 70%³ and demonstrated the feasibility of examining not only normal intraductal anatomy but also those with intraductal calculi and tumors. The mother-daughter system remained in use for over 30 years in limited clinical capacity. In 2007, a single operator cholangiopancreatoscope (SpyGlass, Boston Scientific, Natick, MA) was introduced to facilitate direct visualization of bile and pancreatic duct. This initial system contained a reusable visualization probe which was inserted through a disposable delivery catheter which also contained injection and working channels. The disposable catheter also allowed for tip deflection using a handle that was modeled after a reusable endoscope. The initial clinical feasibility study⁴ was limited to biliary use but subsequent studies demonstrated technical success of this system in the evaluation and treatment of pancreatic duct pathology.

In 2015, a digital version of the SpyGlass system was introduced⁵ allowing for greater visual resolution and a 60% wider field of view. At the time of this publication, there are no existing competitors to SpyGlass available in the United States, but several products are in preclinical review.

2. Setup and specifications of disposable cholangiopancreatoscope and accessories

The single operator cholangiopancreatoscope uses a sterile and steerable disposable catheter with two irrigation channels, a 1.2mm working channel, and two diodes as a light source. The handle has two control knobs, which mimic that of a standard endoscope. (Figure 1) Aspiration through the working channel is achieved by attaching an empty Luer lock syringe to the dedicated suction line. There is also tubing for irrigation that is attached to the endoscope irrigation pump. Our practice is to reduce the irrigation pressure to at least 50% to minimize the volume and pressure of fluid entering the main pancreatic duct and side branches.

The cholangiopancreatoscope is attached to a proprietary image processor. The only adjustable function via the processor is the light source brightness but rarely is manual adjustment necessary. As opposed to the mother-daughter systems, optical contrast modes such as narrow band imaging are not available. Video output options include DVI, S-video and VGA.

The working channel will accommodate any accessory equal to or smaller than 3Fr which includes most electrohydraulic lithotripsy fibers (EHL), holmium laser fibers, microforceps, and dedicated snares and baskets for the SpyGlass system. (Figure 2).

3. Performing pancreatoscopy

Amongst ERCPists with experience in pancreatography, pancreatoscopy is a straightforward extension of their endoscopic toolbox. Positioning of the patient is the same for traditional ERCP with the patient placed in either prone or supine positioning. Left lateral decubitus position makes interpretation of fluoroscopic images difficult. Endotracheal intubation should be considered given the longer duration of time needed to complete ERCP with pancreatoscopy and saline irrigation of the pancreatic duct can reflux from the second portion of the duodenum into the stomach increasing the risk of pulmonary aspiration. General endotracheal anesthesia has been associated with a lower rate of sedation related adverse events amongst high-risk patients undergoing ERCP.⁶ Access to the pancreatic duct is obtained via the major ampulla in most patients although reports have documented access from the minor papilla in select cases.^7-10 The choice of guidewire diameter is at the discretion of the endoscopist as the single operator cholangiopancreatoscope will accommodate up to a diameter of 0.035 inches. A 260cm length wire is acceptable in most cases, but once pancreatoscopy is complete and subsequent devices are to be used while maintaining access to the pancreatic duct, a 450cm wire must be used for device exchange. In most cases, pancreatic sphincterotomy is necessary to pass the 10Fr (3.3mm) diameter scope into the pancreatic duct however in cases of main duct intraductal papillary neoplasm (MD-IPMN) freehand cannulation without wire or sphincterotomy is feasible. (Figure 3) A minimum duct diameter of 3mm is recommended to advance the cholangiopancreatoscope through the pancreatic duct. Saline irrigation is often required to clear debris and improve endoscopic visualization. If EHL is performed, intraductal saline is required for shock wave transmission. Once pancreatoscopy is completed, our practice is to place at least a prophylactic pancreatic duct stent without leading barb for mitigation of post-ERCP pancreatitis (PEP) which can be as high as 28% of patients.¹¹ Rectal indomethacin is also administered unless NSAID allergy is documented.

4. Indications, technical success, and clinical outcomes for pancreatoscopy

Diagnostic
1. Assessment of PD strictures
1. Evaluation of suspected MD-IPMN and extent of duct involvement
Therapeuticiii. Lithotripsy for PD stones

(Figure 4) Indications for pancreatoscopy mirror those of cholangiopathy and can be subdivided into diagnostic and therapeutic indications. Diagnostic applications include the assessment of pancreatic duct stricture and evaluation of suspected main duct intraductal papillary mucinous neoplasms. In addition to endoscopic visualization, pancreatic duct aspiration and directed biopsies can be obtained at the time of pancreatoscopy. (Video 1. See link below) https://practicalgastro.com/media/Main_Duct_IPMN.mp4 Therapeutic applications include guided lithotripsy for obstructing pancreatic duct stones, ablation of pancreatic duct strictures, and assessing treatment response for intraductal radiofrequency application.

In one of the largest series of pancreatoscopy in the evaluation of benign and malignant disease of the pancreatic duct, Shah et al. evaluated 79 patients with inconclusive pancreatic duct findings based on prior CT, MRCP or EUS and found that when optical findings were combined with pancreatoscopy guided biopsy and/or aspiration sensitivity and specificity for neoplasm was 91% and 95%, respectively. Technical success was 97% and adverse events occurred in 12%. In cases with inconclusive EUS guided FNA results of lesions involving the pancreatic duct, pancreatoscopy may provide an additional benefit in evaluating for neoplastic lesions.^13,14 Given the morbidity of total pancreatectomy, pancreatoscopy allows of precise delineation of the extent of involvement in cases of main duct IPMN thereby allowing for preservation of the uninvolved pancreas. In one of the first series to evaluate pre-operative use of cholangiopancreatoscopy, Tyberg et al. found that amongst 13 patients undergoing pre-operative pancreatoscopy for IPMN, pancreatoscopy changed surgical resection in 62% (8/13 pts) of patients.¹⁵ In a separate series of patients with main duct IPMN who underwent pancreatoscopy followed by surgery, 95% (18/19) of the patients had a negative surgical margin. However, there was no control group of patients that did not undergo pre-operative pancreatoscopy.¹⁶ As stated above, therapeutic applications of pancreatoscopy are focused on the treatment of intraductal complications of chronic pancreatitis, namely visualization, fragmentation, and removal of obstructing pancreatic duct stones. The ideal candidates for pancreatic duct stone fragmentation are those with pain from obstructive pancreatitis with upstream pancreatic duct dilation. Conventional techniques of stone removal via ERCP including balloon extraction should be considered, but for multiple or stones >5mm traditional endoscopic measures may not be successful. Pancreatoscopy guided fragmentation can be achieved using an electrohydraulic lithotripsy or a holmium laser fiber which is advanced through the working channel of the pancreatoscope. Published studies have not delineated the ideal candidate but in our experience, stones located in the pancreatic head and body are more easily treated. Intraductal stones are commonly situated proximal to strictures and fluoroscopically directed dilation using small caliber balloons is often necessary to visualize and treat stones. Even if complete stone clearance is achieved, we commonly place a prophylactic small caliber pancreatic duct stent without leading barbs to mitigate the risk of post-ERCP pancreatitis. In a multi-center retrospective study evaluating the efficacy of pancreatoscopy for intraductal stones amongst 109 patients, technical success was achieved in 90%, with a majority achieving complete stone clearance in a single session.¹⁷ Adverse events were 10% and included 5 cases of pancreatitis and 1 main pancreatic duct perforation that was treated with stent therapy.

Clinical success, defined as resolution or reduction in symptoms, was achieved in 88% but did not include a formal quality of life or pain survey. In a systemic review involving 383 patients, Saghir et al.¹⁸ found a pooled technical and clinical success rate of 76%. When comparing EHL vs. laser lithotripsy (LL), LL achieved a higher technical and clinical success rate of 89% and 88%, respectively. Only one study out of 16 used a formal quality pre and post procedure quality of life survey to assess pain outcomes. Most studies were retrospective and single center in design.

In summary, pancreatoscopy directed therapy for intraductal stones is effective amongst experienced operators, however, randomized studies comparing pancreatoscopy to alternative therapies including extracorporeal shockwave lithotripsy or surgery are needed.

5. Troubleshooting

One of the main limitations of pancreatoscopy is the difficulty in advancing the pancreatoscope catheter into a normal sized pancreatic duct. A minimal main pancreatic duct diameter of 4-5 mm is needed to allow easier advancement of the pancreatoscope. Endoscopists should be aware of the direction of the pancreatic duct during advancement of the pancreatoscope. Using the dials of the pancreatoscope to ensure the device is aligned along the axis of the pancreatic duct is crucial for easier advancement, even if the device is advanced over a guidewire. In terms of guidewires, the device could be advanced over a 0.025-inch guidewire into the main pancreatic duct; if the endoscopist encounters difficulty in pancreatoscope advancement, using 0.035 inch guidewires could provide the tension required to advance the pancreatoscope into the pancreatic duct. During pancreatic duct lithotripsy, endoscopists could encounter difficulty advancing the lithotripsy probe outside of the pancreatoscope due to bending of the pancreatoscope catheter. In these instances, it might be easier to advance the lithotripsy probe into the pancreatoscope channel to the tip of the device while the pancreatoscope is in the duodenal lumen. After ensuring that the lithotripsy probe reached the tip of the pancreatoscope, the endoscopist should advance the device into the main pancreatic duct to start lithotripsy. It is worth mentioning that lithotripsy of pancreatic duct stones obstructing the main pancreatic duct at the head of the pancreas could be challenging due to device instability or difficulty in visualization. Endoscopists should be aware that pancreatic duct stones embedded in pancreatic duct orifice may be better managed with other methods such as shock wave lithotripsy.

Future Directions

There are several prototypes of cholangio-pancretoscopes in the pipelines. It is expected that the next generation of cholangio-pancreatoscopes will have artificial intelligence capabilities which will aid in differentiating benign from malignant strictures. The working channel of the next generation cholangio-pancreatoscope will hopefully be large enough to accommodate therapeutic devices such as plastic or metal stents. Larger baskets, biopsy forceps, snare, injection needles or radiofrequency ablation probes could be advanced under direct visualization through next generation cholangio-pancreatoscopes to expedite diagnostic or therapeutic interventions.

CONCLUSION

In conclusion, pancreatoscopy is a useful diagnostic and therapeutic tool for patients with complex neoplastic and chronic conditions of the pancreatic duct with a favorable adverse event rate comparable to that of more conventional ERCP techniques.

References

Takekoshi T., Maruyama M., Sugiyama N., et al. Retrograde pancreatocholangioscopy. Gastrointest Endosc. 1975; 17: 678-683
Kawai K, Nakajima M, Akasaka Y, Shimamotu K, Murakami K. A new endoscopic method: the peroral choledocho-pancreatoscopy (author’s transl). Leber Magen Darm. 1976;6:121-124.
Nakajima M, Akasaka Y, Yamaguchi K, Fujimoto S, Kawai K. Direct endoscopic visualization of the bile and pancreatic duct systems by peroral cholangiopancreatoscopy (PCPS). Gastrointest Endosc. 1978 May;24(4):141-5.
Chen YK, Pleskow DK. SpyGlass single-operator peroral cholangiopancreatoscopy system for the diagnosis and therapy of bileduct disorders: a clinical feasibility study (with video). Gastrointest Endosc. 2007 May;65(6):832-41.
Navaneethan U, Hasan MK, Kommaraju K, Zhu X, HebertMagee S, Hawes RH, Vargo JJ, Varadarajulu S, Parsi MA. Digital, single-operator cholangiopancreatoscopy in the diagnosis and management of pancreatobiliary disorders: a multicenter clinical
experience (with video). Gastrointest Endosc. 2016 Oct;84(4):649-
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Smith ZL, Mullady DK, Lang GD, Das KK, Hovis RM, Patel RS, Hollander TG, Elsner J, Ifune C, Kushnir VM. A randomized controlled trial evaluating general endotracheal anesthesia versus monitored anesthesia care and the incidence of sedation-related adverse events during ERCP in high-risk patients. Gastrointest Endosc. 2019 Apr;89(4):855-862.
Shintani S, Maehira H, Inatomi O, Tani M, Andoh A. Peroral pancreatoscopy via the minor papilla in the diagnosis of intraductal papillary mucinous neoplasm. VideoGIE. 2020 Aug 13;5(12):673675.
Takeshita K, Asai S, Fujimoto N. Removal of dilated Santorini’s duct stones by peroral pancreatoscopy and electrohydraulic lithotripsy through the minor papilla. Dig Endosc. 2020 Jul;32(5):e98-e99.
Chew EY, Varghese BT, Sealock RJ. Pancreatic duct rendezvous with pancreatoscopy through the minor papilla. VideoGIE. 2018 Feb 21;3(4):132-134.
Brauer BC, Chen YK, Ringold DA, Shah RJ. Peroral pancreatoscopy via the minor papilla for diagnosis and therapy of pancreatic diseases. Gastrointest Endosc. 2013 Sep;78(3):545-9.
van der Wiel SE, Stassen PMC, Poley JW, De Jong DM, de Jonge PJF, Bruno MJ. Pancreatoscopy-guided electrohydraulic lithotripsy for the treatment of obstructive pancreatic duct stones: a prospective consecutive case series. Gastrointest Endosc. 2022 May;95(5):905-914.e2.
El Hajj II, Brauer BC, Wani S, Fukami N, Attwell AR, Shah RJ. Role of per-oral pancreatoscopy in the evaluation of suspected pancreatic duct neoplasia: a 13-year U.S. single-center experience. Gastrointest Endosc. 2017 Apr;85(4):737-745.
Yamao K, Ohashi K, Nakamura T et al. Efficacy of peroral pancreatoscopy in the diagnosis of pancreatic diseases. Gastrointest Endosc 2003; 57: 205-209
Kodama T, Koshitani T, Sato H et al. Electronic pancreatoscopy for the diagnosis of pancreatic diseases. Am J Gastroenterol 2002; 97: 617-622
Tyberg A, Raijman I, Siddiqui A, Arnelo U, Adler DG, Xu MM, Nassani N, Sejpal DV, Kedia P, Nah Lee Y, Gress FG, Ho S, Gaidhane M, Kahaleh M. Digital Pancreaticocholangioscopy for Mapping of Pancreaticobiliary Neoplasia: Can We Alter the Surgical Resection Margin? J Clin Gastroenterol. 2019 Jan;53(1):71-75.
Kishimoto Y, Okano N, Ito K, Takuma K, Hara S, Iwasaki S, Yoshimoto K, Yamada Y, Watanabe K, Kimura Y, Nakagawa H,
Igarashi Y. Peroral Pancreatoscopy with Videoscopy and NarrowBand Imaging in Intraductal Papillary Mucinous Neoplasms with Dilatation of the Main Pancreatic Duct. Clin Endosc. 2022 Mar;55(2):270-278.
Brewer Gutierrez OI, Raijman I, Shah RJ, Elmunzer BJ, Webster GJM, Pleskow D, Sherman S, Sturgess RP, Sejpal DV, Ko C, Maurano A, Adler DG, Mullady DK, Strand DS, DiMaio CJ, Piraka C, Sharahia R, Dbouk MH, Han S, Spiceland CM, Bekkali NLH, Gabr M, Bick B, Dwyer LK, Han D, Buxbaum J, Zulli C, Cosgrove N, Wang AY, Carr-Locke D, Kerdsirichairat T, Aridi HD, Moran R, Shah S, Yang J, Sanaei O, Parsa N, Kumbhari V, Singh VK, Khashab MA. Safety and efficacy of digital single-operator pancreatoscopy for obstructing pancreatic ductal stones. Endosc Int Open. 2019 Jul;7(7):E896-E903.
Saghir SM, Mashiana HS, Mohan BP, Dhindsa BS, Dhaliwal A, Chandan S, Bhogal N, Bhat I, Singh S, Adler DG. Efficacy of pancreatoscopy for pancreatic duct stones: A systematic review and meta-analysis. World J Gastroenterol. 2020 Sep 14;26(34):52075219.

DISPATCHES FROM THE GUILD CONFERENCE, SERIES #51

A Review of the Diagnosis and Treatment of Inflammatory Pouch Conditions

Marouf Hossain,

Maia Kayal

Pouch inflammation is common after restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) and is best described as a spectrum that includes acute and chronic pouchitis. Distinguishing between these conditions may be difficult given the extensive overlap of clinical symptoms, and treatment can be challenging due to limited evidence. The aim of this study is to review the diagnosis and treatment of inflammatory pouch disorders, focusing on acute pouchitis, chronic antibiotic dependent pouchitis, chronic antibiotic refractory pouchitis, Crohn’s disease like pouch inflammation and cuffitis.

INTRODUCTION

Despite advancements in medical therapy, ileostomy and preserves quality of life particularly surgery is still required in up to 15% of with respect to body image and social function.^2-4 patients with ulcerative colitis (UC).¹ Unfortunately, there are multiple inflammatory The most common surgery is the restorative proctocolectomy (RPC) with ileal pouch anal anastomosis (IPAA) which commonly involves the following three stages each separated by three months: (1) subtotal colectomy with end ileostomy, (2) proctectomy, pouch creation and proximal diverting ileostomy, and (3) ileostomy takedown and restoration of intestinal continuity. The RPC with IPAA avoids the need for a permanent ileostomy and preserves quality of life particularly with respect to body image and social function.^2-4

Unfortunately, there are multiple inflammatory The most common surgery is the restorative conditions that can occur after IPAA including acute pouchitis, chronic pouchitis, and cuffitis.⁵ These conditions can present with a variety of overlapping clinical symptoms that include increased stool frequency, urgency, abdominal or perineal pain, and hematochezia. A thorough evaluation with history, physical exam, laboratory studies and pouchoscopy is necessary to delineate the inflammatory condition as it can impact treatment and prognosis. The Pouchitis Disease Activity Index (PDAI) is the most commonly used index to assess the severity of pouch inflammation during pouchoscopy.⁶ The PDAI incorporates the following: (1) clinical features: stool frequency, urgency, abdominal pain, hematochezia, fever (2) endoscopic features: edema, granularity, friability, loss of vascular pattern, mucous exudate, ulceration and (3) histologic features: polymorphonuclear leukocyte infiltration and ulceration. A PDAI score > 7 confirms the diagnosis of pouchitis, however, the severity of patient’s symptoms may not correlate to the degree of inflammation characterized by the PDAI.⁷

Diagnosis and treatment of inflammatory pouch conditions can be challenging given the overlapping symptoms and limited evidence. The aim of this review is to discuss acute pouchitis, chronic antibiotic dependent pouchitis, chronic antibiotic refractory pouchitis, Crohn’s disease like pouch inflammation, and cuffitis and summarize their management.

Acute pouchitis

Acute pouchitis is defined as symptoms of increased stool frequency, urgency, abdominal pain and/ or hematochezia that last less than four weeks.⁸ Acute pouchitis is the most common type of pouch inflammation and occurs in up to 50% of patients within 10 years of surgery.⁹ Risk factors for acute pouchitis include genetic polymorphisms of the IL-1 receptor antagonist and NOD2/CARD15,¹⁰ the presence of perinuclear anti-neutrophils cytoplasmic (p-ANCA) antibodies,¹¹ smoking, and preoperative use of steroids.¹²

There are no approved medications for acute pouchitis, however, the mainstay of treatment is antibiotics. Although data are limited, the most commonly used antibiotics are ciprofloxacin and metronidazole. Studies have shown that a twoweek course of either antibiotic is associated with a reduction in PDAI score, however, ciprofloxacin is associated with a larger score reduction as well as fewer side effects (nausea, vomiting, peripheral neuropathy) than metronidazole.^13,14 Patients with acute pouchitis who do not initially respond to a standard two week course may be treated with an additional two week course or may be transitioned to alternative antibiotics such as tinidazole, rifampin, or amoxicillin-clavulanate.^8,15

Chronic pouchitis

Chronic pouchitis is defined as symptoms of increased stool frequency, urgency, abdominal pain and/or hematochezia that last greater than four weeks.¹⁶ Chronic pouchitis can be subclassified as chronic antibiotic dependent pouchitis (CADP) and chronic antibiotic refractory pouchitis (CARP). Approximately 10-20% of patients develop chronic pouchitis.⁵ Risk factors for chronic pouchitis include genetic polymorphisms of IL-1 and NOD2/CARD15,¹⁰ positive p-ANCA serology, an extensive UC history, and primary sclerosing cholangitis.¹⁷ Observational studies have also associated preoperative use of anti-tumor necrosis factor (TNF) agents¹⁸ and postoperative use of NSAIDs with chronic pouchitis.¹⁹

Chronic antibiotic dependent pouchitis (CADP)

CADP is defined as greater than four episodes of pouchitis per year or persistent symptoms that require long-term antibiotics to maintain remission.⁸ The most commonly used antibiotics for CADP are ciprofloxacin and/or metronidazole. In a cohort study of 44 patients with CADP, combined ciprofloxacin and metronidazole achieved clinical and endoscopic remission in 82% of patients.²⁰ Given risks of resistance, and tendinopathy and neuropathy with long-term ciprofloxacin and metronidazole use, patients with CADP should be tapered to the lowest effective dose.²¹ Rifaximin and probiotics (VSL#3) have also been shown to be effective in the management of CADP, though evidence is limited.^22-24

Chronic antibiotic resistant pouchitis (CARP)

CARP is defined as symptoms of pouchitis that fail to respond to a four-week course of antibiotics and require escalation of therapy to mesalamine, corticosteroids or biologics.⁸ The data to support the use of mesalamine in CARP are limited to a single case series of 16 patients that compared combined ciprofloxacin and metronidazole to oral, suppository, and enema mesalamine formulations. Approximately 50% of patients achieved clinical remission in the mesalamine group, however, clarity on which formulation was most efficacious in the case series was lacking.²⁵ Budesonide has been studied in greater breadth than mesalamine in patients with CARP, but still data is limited by small sample sizes. In a prospective study of 20 patients with CARP, treatment with budesonide for eight weeks resulted in a significant reduction in PDAI scores and a remission rate of 75%.²⁶ Patients with CARP who respond to budesonide may remain on the lowest effective dose or consider escalation to a biologic if the risks of maintenance budesonide are significant relative to other co-morbidities.

Biologic agents such as infliximab, adalimumab, vedolizumab, and ustekinumab are commonly used for the management of CARP. A meta-analysis including 15 studies with 311 patients with CARP treated with biologics reported a pooled rate of clinical remission of 65.7% with infliximab, 47.4% with vedolizumab, and 31.0% with adalimumab.²⁷ Vedolizumab has recently been shown to be effective in CARP in the first randomized, doubleblind, placebo-controlled trial, with superior rates of clinical and endoscopic remission and response compared to placebo.²⁸

There is currently insufficient evidence to recommend one biologic over another for CARP, however, it is important to consider a patient’s pre-colectomy biologic use. Patients exposed to anti-TNF agents pre-colectomy and then again post-IPAA for chronic pouchitis have lower rates of clinical remission and higher rates of pouch failure.²⁹

Crohn’s disease like pouch inflammation (CDLPI)

CDLPI is defined as inflammation of the pouch and pre-pouch ileum with or without fistulae and strictures of the proximal small bowel.⁸ CDLPI is a clinical diagnosis based on history, physical exam, pouchoscopy and imaging. It is important to review each patient’s surgical history as fistulae or strictures that develop within the first 12 months of ileostomy closure are not CDLPI but rather surgical complications.^30,31 Histologic evidence of granulomas in the pre-pouch ileum or pouch body are suggestive of CDLPI, but are not required for diagnosis as they are typically only found in about 10% of patients.³² Risk factors for CDLPI include a family history of Crohn’s disease, pouch duration, antibodies to Saccharomyes cerevisiae and CBir1 flagellin, and early, recurrent pouchitis within the first two years of ileostomy closure.^31,33,34

There is no consensus regarding the treatment of CDLPI given lack of large, randomized controlled trials. CDLPI is typically refractory to antibiotics and steroids, and biologics are firstline.³⁵ In a meta-analysis of adalimumab and infliximab for CARP and CDLPI, adalimumab and infliximab achieved a clinical remission rate of 52% at 12 months in patients with CDLPI, superior to the rates achieved in patients with CARP.³⁶ Ustekinumab and vedolizumab have also been shown to be effective with remission rates of approximately 80% in patients with CDLPI, though data is limited by relatively small sample sizes.^37,38 Unfortunately, given the difficulties in treating CDLPI and achieving remission, up to 45% of patients will experience pouch failure and require pouch excision and transition to a permanent end ileostomy.³⁹

Cuffitis

Cuffitis is defined as symptoms of increased stool frequency, hematochezia, tenesmus and urgency in the setting of the inflammation of the residual rectal cuff.⁸ Cuffitis occurs in up to 30% of patients post-IPAA, though may be underdiagnosed given the overlap of symptoms with pouchitis.⁴⁰ Cuffitis can be diagnosed using the Cuffitis Activity Index, which is adapted from the PDAI, incorporating clinical, endoscopic and histologic features specifically of the rectal cuff instead of the pouch.⁴¹ Cuffitis can be characterized into classic and non-classic based on etiology. Classic cuffitis is secondary to residual ulcerative colitis in the preserved rectal tissue, while non-classic cuffitis can be due to a variety of causes such as Crohn’s disease, ischemia or prolapse. Risk factors for cuffitis include history of toxic megacolon, fulminant colitis, pre-operative use of biologic agents and increased cuff length (³ 5cm).^40,42

The main stay treatment for cuffitis is topical mesalamine similar to proctitis. Treatment with mesalamine suppositories resulted in significant improvement in hematochezia as well as endoscopic and histologic inflammation of the rectal cuff.⁴¹ Patients with classic cuffitis that do not respond to topical mesalamine can consider topical corticosteroids, however, evidence is insufficient.⁴³

Approach to delineating the inflammatory pouch conditions

The clinical, endoscopic, and histologic features of acute and chronic pouchitis overlap significantly, and it can be difficult to delineate the conditions despite laboratory studies and pouchoscopy. The key to delineating acute and chronic pouchitis is history – specifically symptom duration and response to antibiotics. Acute pouchitis is the diagnosis in patients with symptoms lasting less than four weeks while chronic pouchitis is the diagnosis in patients with symptoms lasting greater than four weeks or recurring with antibiotic course completion. CDLPI is easier to delineate from acute and chronic pouchitis as the pre-pouch ileum is typically involved and strictures and/or fistulae may be present. In patients with suspected CDLPI based on pouchoscopy or physical exam, imaging with magnetic resonance (MR) enterography and MR pelvis should be considered to fully assess for strictures or fistulae. Histology is not a reliable way to make the diagnosis of any of these conditions as biopsies typically demonstrate chronic inflammation regardless of endoscopic inflammation.⁴⁴

CONCLUSION

There is a spectrum of inflammatory pouch conditions that can occur after RPC with IPAA and it is crucial to properly diagnose each in order to choose the appropriate therapy. A summary of the recommended evaluation to delineate between these conditions is presented in Figure 1, and a guide for recommended management options for each disorder is highlighted in Figure 2. Although data are limited, the choice of therapy is directly related to the diagnosis and options range from antibiotics to biologics.

References

Sofo L, Caprino P, Sacchetti F, Bossola M. Restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis: A narrative review. World J Gastrointest Surg. 2016;8(8):556-63 doi: 10.4240/wjgs.v8.i8.556.
Grieco MJ, Remzi FH. Surgical Management of Ulcerative Colitis. Gastroenterol Clin North Am. 2020;49(4):753-68 doi: 10.1016/j.gtc.2020.09.001.
Berndtsson I, Lindholm E, Oresland T, Borjesson L. Long-term outcome after ileal pouch-anal anastomosis: function and health-related quality of life. Dis Colon Rectum. 2007;50(10):1545-52 doi: 10.1007/s10350-007-0278-6.
Kuruvilla K, Osler T, Hyman NH. A comparison of the quality of life of ulcerative colitis patients after IPAA vs ileostomy. Dis Colon Rectum. 2012;55(11):1131-7 doi: 10.1097/DCR.0b013e3182690870.
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Shen B, Achkar JP, Lashner BA, et al. Endoscopic and histologic evaluation together with symptom assessment are required to diagnose pouchitis. Gastroenterology. 2001;121(2):261-7 doi: 10.1053/gast.2001.26290.
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Achkar JP, Al-Haddad M, Lashner B, et al. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol. 2005;3(1):60-6 doi: 10.1016/s15423565(04)00604-4.
Fleshner P, Ippoliti A, Dubinsky M, et al. A prospective multivariate analysis of clinical factors associated with pouchitis after ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol. 2007;5(8):952-8; quiz 887 doi: 10.1016/j.cgh.2007.03.020 [published Online First: 20070604].
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Segal JP, Poo SX, McLaughlin SD, Faiz OD, Clark SK, Hart AL. Long-term follow-up of the use of maintenance antibiotic therapy for chronic antibiotic-dependent pouchitis. Frontline Gastroenterol. 2018;9(2):154-58 doi: 10.1136/flgastro-2017-100913 [published Online First: 20180131].
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Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119(2):305-9 doi: 10.1053/gast.2000.9370.
Mimura T, Rizzello F, Helwig U, et al. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut. 2004;53(1):108-14 doi: 10.1136/gut.53.1.108.
Shen B, Fazio VW, Remzi FH, et al. Combined ciprofloxacin and tinidazole therapy in the treatment of chronic refractory pouchitis. Dis Colon Rectum. 2007;50(4):498-508 doi: 10.1007/s10350-006-0828-3.
Gionchetti P, Rizzello F, Poggioli G, et al. Oral budesonide in the treatment of chronic refractory pouchitis. Aliment Pharmacol Ther. 2007;25(10):1231-6 doi: 10.1111/j.1365-2036.2007.03306.x.
Chandan S, Mohan BP, Kumar A, et al. Safety and Efficacy of Biological Therapy in Chronic Antibiotic Refractory Pouchitis: A Systematic Review With Meta-analysis. J Clin Gastroenterol. 2021;55(6):481-91 doi: 10.1097/MCG.0000000000001550.
Travis S, Silverberg MS, Danese S, et al. OP04 Vedolizumab intravenous is effective across multiple treatment targets in chronic pouchitis: Results of the randomised, double-blind, placebo-controlled EARNEST trial. Journal of Crohn’s and Colitis. 2022;16(Supplement_1):i004-i05 doi: 10.1093/ecco-jcc/jjab232.003.
Kayal M, Lambin T, Plietz M, et al. Recycling of Precolectomy Anti-Tumor Necrosis Factor Agents in Chronic Pouch Inflammation Is Associated With Treatment Failure. Clin Gastroenterol Hepatol. 2021;19(7):1491-93 e3 doi: 10.1016/j.cgh.2020.07.008 [published Online First: 20200712].
Barnes EL, Kochar B, Jessup HR, Herfarth HH. The Incidence and Definition of Crohn’s Disease of the Pouch: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. 2019;25(9):1474-80 doi: 10.1093/ibd/izz005.
Kayal M, Kohler D, Plietz M, et al. Early Pouchitis Is Associated With Crohn’s Disease-like Pouch Inflammation in Patients With Ulcerative Colitis. Inflamm Bowel Dis. 2022;28(12):1821-25 doi: 10.1093/ibd/izac012.
Shen B, Kochhar GS, Kariv R, et al. Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium. Lancet Gastroenterol Hepatol. 2021;6(10):826-49 doi: 10.1016/S2468-1253(21)00101-1 [published Online First: 20210818].
Coukos JA, Howard LA, Weinberg JM, Becker JM, Stucchi AF, Farraye FA. ASCA IgG and CBir antibodies are associated with the development of Crohn’s disease and fistulae following ileal pouch-anal anastomosis. Dig Dis Sci. 2012;57(6):1544-53 doi: 10.1007/s10620-012-2050-6 [published Online First: 20120207].
Truta B, Li DX, Mahadevan U, et al. Serologic markers associated with development of Crohn’s disease after ileal pouch anal anastomosis for ulcerative colitis. Dig Dis Sci. 2014;59(1):135-45 doi: 10.1007/s10620-013-2866-8 [published Online First: 20131004].
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NUTRITION REVIEWS IN GASTROENTEROLOGY, SERIES #3

The Infant Formula Shortage: Reasons, Responses, and Resources for Clinicians

Tegan Medico

In the United States, regulatory and trade barriers contributed to an infant formula market dominated by a few domestic companies, such that a major recall in 2022 swiftly and profoundly reduced access nationally. Limited data points to an adverse impact broadly on households with formula-dependent infants, particularly those reliant on specialized formulas. To remedy the crisis, several federal actions aimed to augment the domestic formula supply and increase flexibility in formula purchasing by participants of the Supplemental Nutrition Program for Women, Infants, and Children. Clinicians in inpatient and outpatient pediatric care settings will benefit from an understanding of the systems that influence infant formula use and access to help provide families with safe recommendations and resources.

INTRODUCTION

In 2022, a widespread shortage of infant formula in the sociopolitical background for the recent infant the United States sent parents and clinicians into formula shortage, a review of known and theoretical a panic. An unprecedented crisis, the shortage safety concerns, the federal response, and practical aroused scrutiny of the conditions that set its stage, tips for clinicians.

History of Infant Formula
Commercialization

Commercial alternatives to human milk emerged following advances in science and technology of the Industrial Revolution.^1,2 Early infant formulas were expensive, and many were complicated to prepare.³ Energy density ranged widely.¹ Some products were accompanied by recipe books containing numerous preparation permutations based on a perceived clinical indication, variations were known as the “percentage method”.^1,4 The percentage method largely was implemented in hospitals and specialized commercial laboratories.¹ Hence, many physicians more simply recommended recipes amenable to home preparation that consisted of boiled milk or diluted evaporated milk and corn syrup or table sugar, a practice that persisted widely into the mid-20^thcentury.^1,3

Infant formulas with more straightforward preparation methods and improved nutritional compositions, achieved by the addition of cod liver or vegetable oils and vitamins, emerged in the 1920s and peaked in popularity in the early 1970s.¹ Breastfeeding rates reached a low with the increased usage of formulas: 25% initiation during the first week of life.⁵ Homemade formula preparation was a dwindling practice as well.^1,6

Regulation

Regulation of infant formula was an evolving endeavor beginning in 1938 with the Federal Food, Drug, and Cosmetic Act (FFDCA). The FFDCA established standards for food product identity, quality, and volume that were applicable to infant formulas, and it authorized oversight by the United States Food and Drug Administration (FDA).⁷ A 1941 amendment to the Act included infant formula labeling requirements¹ and a 1966 amendment included minimums for 11 vitamin levels following cases of vitamin B6 deficiency associated with a production change to a liquid concentrate.^1,8 By the time these latter changes were implemented in 1971, minimum concentrations (per 100 kilocalories of formula) for protein, fat, linoleic acid and 17 vitamins and minerals also were established.¹ A later reformulation oversight that resulted in 141 cases of hypochloremic metabolic alkalosis^9,10 gave way to the most comprehensive amendment to the FFDCA, the Infant Formula Act of 1980 and its 1986 amendment.

To date, the Infant Formula Act remains the most significant legislation concerning infant formula production and composition, and it is the most rigorous legislation for any food sold in the

United States. Notable provisions include:^11,12

infants defined as less than 12 months of age mandated alerts to the FDA prior to first manufacture and with any formulation changes
mandated scientific evidence of safety and efficacy across product shelf-life
standards for good manufacturing practices and quality control procedures
expanded nutrient minimums and maximums
standards for certain nutrient forms and ratios
updated product labeling requirements

The International Code of Marketing of Breast-milk Substitutes is a set of policy-aimed recommendations adopted by the World Health Organization to limit the marketing reach of infant formula manufacturers. The Code has not been adopted by the United States, nor has the United States produced any legislation pertaining to one or more of the Code’s specific articles.¹³

Nutritional Features of Infant Formula

All infant formulas marketed and sold in the United States must meet nutrient composition requirements set by the FDA, unless designated exempt. Nutrient composition requirements for non-exempt formulas are detailed in Title 21, Chapter 1B, Part 107, of the Code of Federal Regulations and are publicly available online.¹² Exempt formulas are intended to address specific medical and/or nutritional problems, such as low birth weight, cow milk protein-induced allergic proctocolitis, malabsorption, and inborn errors of metabolism.^12,14 Nutrient compositions of exempt formulas vary widely depending upon their unique indications. Some exempt formulas are medically compulsory, such that unavailability could pose a significant health risk, and they often require a prescription from a medical provider. The FDA status (exempt/non-exempt) is shown in Table 1, along with primary indications for use, major nutritional features, and contemporary brand examples.

Nutrients that are not required by the FDA, but nevertheless widespread in modern options domestically and abroad, include docosahexaenoic acid (DHA) and arachidonic acid (ARA) (long-chain fatty acids); oligosaccharides (prebiotics); taurine (amino acid); lutein (carotenoid); and carnitine (amino acid derivative). These components are targets of growing research interest related to infant nutrition.^15,16

Precursors to the Infant Formula Shortage Domestic Monopolies

Despite its comprehensiveness, the Infant Formula Act does not abide mutual recognition of foreign regulatory approval of infant formulas, though such provisions apply to pharmaceuticals.¹⁷ Without recognition of foreign regulatory approval, infant formulas produced in other countries must undergo FDA approval prior to legal sale in the United States. According to a report from the Congressional Research Service, few foreign companies have pursued and obtained FDA approval historically, ostensibly due to significant trade barriers—high tariffs, quota tariffs, and export caps—that threaten profitability in the United States market.¹⁸ These regulatory and trade barriers contribute to a domestic infant formula market dominated by a few companies: Abbott Nutrition (of Abbott Laboratories), Mead Johnson (of Reckitt Benckiser Group), Gerber Products Company (of Nestlé), and Perrigo. The latter is the major white label manufacturer of store-brand and boutique formulas. Although exact figures are unavailable, common estimation is that Abbott Nutrition held approximately 40% of the total infant formula market share¹⁹ and 75% of the amino acid formula market share.²⁰

Supplemental Nutrition Assistance Program for Women, Infants, and Children

Domestic monopolies are reinforced by contracts between infant formula manufacturers and state-level WIC (Women, Infants, and Children Program) agencies. Federally funded via the United States Department of Agriculture (USDA) Food and Nutrition Service (FNS), WIC is a nutrition assistance program that provides supplemental foods, including infant formula, to infants from lowincome families. It covers all 50 states, the District of Columbia, 33 Indian Tribal Organizations, American Samoa, Guam, the Commonwealth Islands of the Northern Marianas, Puerto Rico, and the U.S. Virgin Islands. The greatest program expense, the cost of infant formula, is contained via contracts between individual state programs or state consortia and a single infant formula company. Contracts are determined via a competitive bidding process. The winning company provides WIC with rebates for approximately 85% of retail price and in turn enjoys priority shelf space in WICparticipating retailers, thus recouping money in the non-WIC market via a “spillover effect”.^21-23

In 2022, 43% of infants in the United States participated in WIC.²⁴ An estimated 85-90% of participating infants receive formula as a program benefit.²⁵ Thirty-four states and the District of Columbia contracted with Abbott Nutrition,²³ thus directing a majority of total domestic infant formula sales toward Abbott products.

Abbott Nutrition Recall and Plant Closure

On February 17, 2022, Abbott Nutrition issued a largescale recall of its Similac^® and Elecare^®product lines. The recall followed troubling findings during an FDA inspection of one of Abbott’s primary plants in Sturgis, MI. The inspection was prompted by four reports of infant illness, including two deaths, from Cronobacter sakazakii infection. Additionally, a whistleblower report to the FDA in October 2021 detailed safety concerns at the Sturgis plant.²⁶ Although evidence was insufficient to determine a direct link between the Sturgis plant and the infected infants, the plant closed production shortly after issuing the recall. Under a consent decree with the FDA, it remained closed until June 2022 but closed again soon thereafter due to storm flooding. It resumed operations in July 2022.

Consequences of the Infant Formula Shortage Medical & Nutritional Risk

Availability of infant formulas following the Abbott Nutrition recall was largely gauged via retail data. Information Resources, Inc. (IRI) Worldwide and Datasembly reported out-ofstock figures of approximately 30-40% during the shortage peak.^27,28 However, out-of-stock rates ranged widely store-by-store and state-by-state providing a limited interpretation of the crisis.

There are two big limitations of out-of-stock rates in evaluating the full extent of the infant formula shortage. Foremost, the out-of-stock rate is more a measure of product variety on the shelves rather than overall quantity. Considering the uneven demand across formula brands because of WIC participants’ restrictions to specific products, overall quantities of the most in-demand formulas is important. A major WIC-approved formula outof-stock represents lack of access for a significant portion of infants. Furthermore, retail data does not capture formulas obtained through durable medical equipment companies (DMEs), WIC-contracted special formula distribution centers, medical clinics, and hospitals. Specialized formulas, such as those for inborn errors of metabolism, renal disease, and severe allergies, are not typically available or obtained via retail channels. At this time, there is no quantitative data to confirm the many anecdotes from families and clinicians who were challenged in accessing specialized formulas, nor is there data of medical emergencies directly related to the shortage or of the impact on specific patient populations. There is, however, data supporting adverse impact broadly. The United States Census Bureau’s Household Pulse Survey was developed to assess socioeconomic impacts of the SARS-CoV-2 (COVID-19) pandemic rapidly and continually. In 2022, questions specific to the infant formula shortage were included. First results for these questions from September 2022²⁹ revealed the following:

Of households with infants, 50.2% reported being affected by the infant formula shortage.
Of households with infants who used formula, 31.8% reported difficulty obtaining formula over the last 7 days, including 32.9% using routine infant formula, 32.6% using extensively hydrolyzed infant formula, 65.1% using amino acid formula, and 65.9% using metabolic formula.
Of households with infants who used formula, 6.2% reported having no formula on hand, and 18% reported having less than a week’s supply on hand.
Of households affected by the infant formula shortage, irrespective of income level, 8.1% reported watering down formula or making a homemade version. The household income categories with the highest rates of watering down or using homemade formula: <$25,000 (25.5%), $35,000-$49,999 (17.8%) and ≥ $200,000 (13.9%).

Federal Response

The impacts assessed by the Household Pulse Survey were likely mitigated by several federal actions in response to the shortage. These initiatives aimed to increase the domestic supply of infant formula and to increase flexibility in formula purchasing by WIC participants. Major actions are listed below.

Defense Production Act

On May 18, 2022, President Joseph Biden delegated authority to the Secretary of the HHS to invoke the Defense Production Act (DPA). By invoking the DPA, HHS was able to prioritize procurement of raw materials for infant formula production by

Abbott Nutrition and Mead Johnson.³⁰

Operation Fly Formula

Along with the DPA, President Biden announced Operation Fly Formula. A coordinated effort of the USDA, HHS, and Department of Defense, Operation Fly Formula was a series of air shipments of formulas sourced from other countries. As of October 5, 2022, 26 missions were completed.³¹

FDA Enforcement Discretion to Manufacturers

Most formulas imported via Operation Fly Formula were products previously not approved by the FDA for domestic sale. Announced on May 16, 2022, the FDA’s Enforcement Discretion to Manufacturers was essentially an accelerated and temporary approval of foreign formulas for sale in the United States on a case-by-case basis. Among the FDA criteria for review were nutritional composition, ingredients, product label and packaging, current or anticipated inventory, microbiological testing, and facility inspection history. A stop-gap approach, the FDA Enforcement Discretion to Manufacturers expired November 14, 2022, though some products approved before that date may remain in the United States market.³²

Access to Baby Formula Act

The Access to Baby Formula Act (ABFA) was passed on May 21, 2022. This amendment to the Child Nutrition Act of 1966 has two broad objectives. The first is to require state WIC agencies to include language in their infant formula rebate contracts regarding manufacturers’ plans to prevent supply disruption for WIC participants in the event of a recall. For example, the FNS recommends that “manufacturers be required to pay rebates on both contract brand and non-contract brand formula in any available unit size, type, or form”.³³

The second main objective of the ABFA is to give the USDA permanent authority to issue waivers for WIC program rules during emergencies, disasters, and supply chain disruptions.³³ Prior to the ABFA, state WIC agencies submitted individual requests to implement emergency waivers. Some states had done so with the COVID-19 pandemic, and they were able to invoke their existing emergency waiver to allow participants to access non-contract formula substitutes during the infant formula shortage. The ABFA allows for a more streamlined waiver process.

Tips for Clinicians
Formula Substitutions

See Table 2 for emergency guidance from governmental and professional organizations.
See Table 3 for a formula substitution matrix.
Formulas marketed for sensitivity/comfort have varying degrees of lactose reduction. There is no evidence supporting lactose reduction in infants apart from rare circumstances: galactosemia, an inborn error of metabolism that requires total lactose elimination; congenital disaccharidase deficiency; and transient lactose intolerance from acute gastroenteropathy.³⁴ Thus, the lactose contents of these formulas should not be used as a criterion for determining appropriate substitutions in most cases.
Toddler formulas are not regulated like infant formulas. They have varying calorie concentrations and may not be nutritionally complete. The nutritional composition of toddler formulas should be thoroughly evaluated prior to use, and use should be temporary (<1 week).

Foreign Formulas

Foreign formulas sold within the FDA Enforcement Discretion to Manufacturers may be used with confidence.
Safety, quality, and identity cannot be guaranteed for foreign formulas imported outside the FDA Enforcement Discretion.
See Table 4 for an updated list of FDAapproved foreign formulas.
Some foreign formulas are “staged”. “Stage 1” or “first milk” is for infants up to 6 months of age. Stage 2, “second”, or “follow-on” milk is for infants 6-12 months of age. Stages vary in nutritional composition, particularly iron. Guide caregivers to use the correct stage for their infant’s age.

Accurate and Safe Formula Preparation

Never dilute infant formula.
Scoop sizes are formula-specific and may not be interchanged. The mixing instructions for specialty formulas and imported formulas may differ.
Imported formulas may express water measurements as milliliters instead of ounces. Ensure caregivers understand how to convert between units (one fluid ounce contains 30 milliliters).
Families who were instructed to mix formula to a non-standard calorie concentration using a hospital- or clinic-provided recipe should receive updated mixing instructions with every formula change.
If non-standard mixing instructions are not immediately available, instruct families to prepare formula per can instructions until the specialized recipes can be conveyed.
Reinforce safe formula mixing methods to minimize the growth of harmful pathogens. See Infant Formula Preparation and Storage on the Centers for Disease Control and Prevention website (cdc.gov) for guidance.

Homemade Formulas and Milks

Ask caregivers whether they are making homemade formulas, as this practice has been reported by a significant percentage of households.²⁹
Discourage use of homemade formula. Although once a common practice, it was not without documented health consequences, including hypertonic dehydration, rickets, scurvy, and iron deficiency.^1,6 Contemporary variations of homemade formulas available on social media have been noted to contain unsafe ingredients,^35,36 and some have been implicated in cases of malnutrition, electrolyte disarray, acidosis, rickets, seizure, and cardiac arrest.^37-39

Emergency guidance from the American Academy of Pediatrics states that pasteurized whole cow milk or fortified soy milk may be used for infants older than 6 months and for no longer than one week.⁴⁰
Plant-based alternative milks, other than temporary use of soy milk described above, should not be used.
Raw milk from cows, goats, or other mammals, should never be given.

Human Milk

Select recommendations from the Academy of Breastfeeding Medicine include:⁴¹

Support those wishing to increase milk production by referring to a qualified lactation expert.
If accessible, consider pasteurized donor milk from milk banks certified by the Human Milk Banking Association of North America (visit hmbana.org for a map of milk bank locations).
Exercise caution with informal milk sharing. Consider the health of the donor, along with flash pasteurization methods.
Discourage online purchasing of human milk, especially from unknown donors.

Collaboration

As applicable, be familiar with state WIC program formularies and approved substitutions.
Be aware of current limitations in how WIC participants may access formula. For example, formulas may only be purchased at WICapproved retailers; online purchases are not currently a feature of the program. Some states offer ship-to-home services for specialty formulas.
As applicable, be familiar with DME company formularies and communicate with DME personnel to stay abreast of inventory changes. • Give input to hospital stakeholders involved in facility formula contract negotiations to optimize formula access.
Utilize registered dietitian/nutritionists (RDNs) with expertise in infant nutrition for guidance on the features and indications of various formulas, as well as for specialized mixing instructions.

Conclusion

The evolution of the infant formula industry has shaped, and has been shaped, by scientific advances, infant feeding trends, and regulatory constraints and liberties, both. The 2022 shortage experienced in the United States may reshape the domestic market and industry at large. Notwithstanding, at the time of this writing, the major trade and regulatory structures underpinning formula access in the United States remain intact. Time will tell whether the market diversity and resiliency will improve. Clinicians in inpatient and outpatient pediatric care settings will benefit from an understanding of the systems that influence infant formula use and access to help provide families with safe recommendations and resources.

References

Fomon SJ. Infant feeding in the 20th century: Formula and beikost. J Nutr. 2001;131(2).
Wargo WF. The history of infant formula: quality, safety, and standard methods. J AOAC Int. 2016;99(1):7-11.
Schuman A. A concise history of infant formula (twists and turns included). Contemp Pediatr. 2003; 2:91.
The Mellin’s Food Method of Percentage Feeding. Press of Mellin’s Food Company; 1908.
Martinez GA, Krieger FW. 1984 milk-feeding patterns in the United States. Pediatrics. 1985;76(6).
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Koletzko B, Baker S, Cleghorn G, et al. Global standard for the composition of infant formula: Recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr. 2005;41(5).
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Leo L, Khandekar A. Abbott aims to recapture baby formula market share. Reuters. July 20, 2022. Accessed November 11, 2022. https://www.reuters.com/business/ healthcare-pharmaceuticals/abbott-raises-2022-profitforecast-2022-07-20.
Bottemiller Evich H. “I don’t know how my son will survive”: Inside the dangerous shortage of specialty formulas. Politico. May 7, 2022. Accessed November 11, 2022. https://www.politico.com/ news/2022/05/07/i-dont-know-how-my-son-will-survive-inside-the-dangerous-shortage-of-specialty-formulas-00030787.
Choi YY, Ludwig A, Andreyeva T, Harris JL. Effects of United States WIC infant formula contracts on brand sales of infant formula and toddler milks. J Public Health Pol. 2020;41(3):303-320.
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Bottemiller Evich H. Whistleblower warned FDA about formula plant months before baby deaths. Politico. April 28, 2022. Accessed November 11, 2022. https://www.politico.com/news/2022/04/28/whistleblowerfda-baby-formula-00028569.
Snider M. Baby formula shortage continues: nearly 30% of popular brands sold out, stores ration sales. USA Today. April 9, 2022. Accessed October 29, 2022. https://www.usatoday. com/story/money/shopping/2022/04/09/baby-formula-shortage-2022-worsens/9525498002.
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U.S. Department of Health and Human Services. HHS Secretary Becerra Invokes Defense Production Act for Third Time to Further Increase Production of Infant Formula for American Families. Published May 27, 2022. Accessed October 29, 2022. https://www.hhs.gov/about/news/index. html.
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U.S. Food and Drug Administration. Enforcement Discretion to Manufacturers to Increase Infant Formula Supplies. Updated November 2, 2022. Accessed November 12, 2022. https:// www.fda.gov/food/infant-formula-guidance-documents-regulatory-information/enforcement-discretion-manufacturersincrease-infant-formula-supplies.
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SPECIAL ARTICLE

Patient-Related Adverse Events and Clinical Device Failures Associated with the Linx Magnetic Sphincter Augmentation Device: A MAUDE Database Analysis

Alexandra McMillan,

Daryl Ramai,

Douglas G. Adler

Abstract

Introduction: The Linx Medical Sphincter Augmentation Reflux Management System is a surgical option for the treatment of chronic gastroesophageal reflux disease (GERD). However, real life data regarding device failures and patient-related adverse events is lacking.

Methods

We analyzed device failures and patient-related adverse events reported to the FDA Manufacturer and User Facility Device Experience (MAUDE) database related to the Linx device from January 2011 to October 2021.

Results

We identified 499 reports describing 918 patient-related adverse events and 101 device failures with two duplicates excluded. The most reported patient-related adverse events were dysphagia in 275 patients (30%), odynophagia in 271 patients (29.5%), GERD in 135 patients (14.7%), adverse events not otherwise specified in 39 patients (4.2%) and erosion in 38 patients (4.1%). The most reported device failures were device removal for recurrence of symptoms in 61 patients (60.4%), Linx device opening unexpectedly in 14 patients (13.9%), Linx device removed without additional information reported in 9 patients (8.9%), Linx bead separation in 7 patients (6.9%) and device migration from the original site of implantation in 7 patients (6.9%).

Conclusion

Linx device implantation offers an alternative to other surgical and medical therapies in the treatment of refractory GERD; however, additional investigation of both short and long-term device failures and patient-related adverse events is necessary.

ABSTRACT

The Linx Medical Sphincter Augmentation Reflux Management System is a surgical option for the treatment of chronic gastroesophageal reflux disease (GERD). However, data regarding device failures and patient-related adverse events is lacking. We analyzed Linx device failures and patient-related adverse events reported to the FDA Manufacturer and User Facility Device Experience (MAUDE) database from January 2011 to October 2021. We describe 101 device failures and 918 patient-related adverse events in detail, providing valuable information for clinicians and patients considering Linx implantation.

INTRODUCTION

The Linx Medical Sphincter Augmentation Reflux Management System (Ethicon, Bridgewater, NJ) is a device created as a surgically-implanted option for the treatment of chronic gastroesophageal reflux disease (GERD). Linx was approved in 2012 by the U.S Food and Drug Administration (FDA) as a safe alternative to fundoplication for the treatment of patients with GERD.¹Compared to the previous surgical gold standard of Nissen fundoplication, the Linx device is designed to be implanted laparoscopically without altering foregut anatomy and is reversible via device removal.² Prior to antireflux surgery, increasing the dose of proton pump inhibitors in patients with GERD is a common treatment option to suppress acid secretion; however, some patients continue to have insufficient symptom control after dose adjustments.^2,3 The magnetic sphincter augmentation (MSA) device was developed as a long-term solution for GERD due to its specific design to augment lower esophageal sphincter length and provide support to patients with LES failure.⁴

The Linx device is a ring composed of interlinked titanium beads with magnetic cores that is surgically implanted around the gastroesophageal junction to reduce and/or prevent acid from entering the esophagus. The beads can temporarily separate in the context of ring expansion to allow food or liquid to pass into the stomach as well as belching and vomiting.⁵ The magnetic attraction between the beads allows the lower esophageal sphincter to remain closed and protect the esophagus from acid reflux and mucosal injury. The magnetic force when the beads are closed is 40 grams and when the beads are separated falls to 7 grams.⁶ Linx device implantation via laparoscopy occurs under general anesthesia and patients are able to return to a regular diet shortly after the procedure.⁷

According to Duke Health, approximately 6,000 Linx devices had been implanted globally by 2017 with the number of explants not reported.⁸ A study of the safety of magnetic sphincter augmentation published in 2021 noted 30,000 Linx devices have been implanted worldwide with a 7-year cumulative removal of 4.81%.⁹ The likelihood of removal was felt to be related to device size, with devices composed of a lower number of magnetic beads having a higher rate of removal.⁹ Due to the relative lack of data regarding Linx device failures and clinical adverse events, we undertook an analysis of the MAUDE database to assess these outcomes.

Methods

We performed an analysis of the FDA Manufacturer and User Facility Device Experience (MAUDE) database to report the device failures and clinical adverse events following Linx device implantation. The MAUDE database contains medical device reports submitted to the FDA by voluntary reporters, patients and healthcare professionals, or mandatory reporters, such as manufacturers; however, the medical device reports cannot be solely used to establish rate of events. The FDA works to include all reports received and updates the MAUDE database monthly. The database is available to the public at accessdata.fda.gov/scripts/ cdrh/cfdocs/cfmaude/search.cfm. We searched the MAUDE database from January 2011 to October 2021 for all reports related to the Linx device. The medical device reports were downloaded and individual reports were analyzed for device failures and clinical adverse events.

The event descriptions for each report were individually analyzed and categorized and data was collected on the type of device failure and clinical adverse events. Each device failure and clinical adverse event were assigned a number. When appropriate, some of the clinical adverse events were reclassified to correct for some differences in nomenclature. For example, pyrosis, regurgitation and heartburn were all classified under GERD. As the individual reports were analyzed, the numbers representing each device failure and clinical adverse event were assigned to the report. The total number of device failures and clinical adverse events associated with each report were calculated and organized into two tables.

Results

Our search of the MAUDE database identified 499 reports describing 918 patient-related adverse events and 101 device failures from January 2011 to October 2021 with two duplicates excluded.

Patient-related Adverse Events

Patient-related adverse events following Linx implantation are detailed in Table 1. The most reported patient-related adverse event following Linx implantation was dysphagia, which was reported in a total of 275 patients (30%). This was followed by odynophagia in 271 patients (29.5%) and GERD in 135 patients (14.7%). Thirty-nine patients (4.2%) had adverse events not otherwise specified in the event descriptions associated with the report. Erosion secondary to the device occurred in 38 patients (4.1%). Reports of erosion secondary to Linx device implantation include one or more of the magnetic beads eroding through the esophageal lumen. Thirty-eight patients (4.1%) experienced abdominal pain and 24 patients (2.6%) reported pain but the location was unspecified. Vomiting occurred in 16 patients (1.7%). Additionally, sixteen patients (1.7%) had chest pain while 14 patients (1.5%) reported a hiatal hernia. Nausea occurred in 7 patients (0.7%) and anxiety in 4 patients (0.4%). Three patients (0.3%) experienced headaches. Muscle spasms, weight change and flatus each occurred in 3 patients (0.3%). Inflammation, fatigue, allergy, aspiration, diarrhea, ulcer, infection, perforation and hemorrhage were reported for 2 patients (0.2%) each. The remaining adverse events each occurred in 1 patient (0.1%); pneumothorax, muscle weakness, eructation, abscess, laceration of the esophagus, adhesion, constipation, hypertension, obstruction, cardiac arrest, scar tissue formation, foreign body sensation and dry mouth.

Device Failures

Device failures following Linx implantation are detailed in Table 2. The most reported device failure, affecting 61 patients (60.4%), was device removal for recurrence of original symptoms such as dysphagia, odynophagia and GERD. This was followed by the Linx device opening unexpectedly through the interlinked titanium beads and/ or the locking clasp, after implantation around the lower esophageal sphincter in a total of 14 patients (13.9%). Nine patients (8.9%) had the Linx device removed without additional information reported in the event description associated with the report. Seven patients (6.9%) experienced Linx bead separation, where a magnetic bead disconnects from an adjacent wire link, after device implantation. Device migration from the original site of implantation occurred in 7 patients (6.9%). The reports include Linx device movement below the diaphragm or around the stomach leading to device removal. Unintended movement of the Linx device also occurred due to a hiatal hernia. In 1 patient (1.0%), the Linx locking device (a multi-directional locking clasp) mechanism failed. Additionally, in 1 patient (1.0%), there was a sizing tool failure during the procedure, which is used to approximate the Linx device to the circumference of the distal esophagus. Lastly, 1 patient (1.0%) experienced an implantation failure due to findings of impaired esophageal peristalsis during a motility study.

Discussion

This analysis of the MAUDE database over a 10year period reveals a variety of device failures and patient-related adverse events reported after Linx implantation. This is the first study exploring device failures and patient-related adverse events reported to the MAUDE database. One previous MAUDE analysis of the Linx device reported solely on the single and specific adverse event of erosion.¹⁰ Their study evaluated 9,453 Linx device implantations from 2007 to 2017 and included 29 reported cases of erosion with most patients experiencing newonset dysphagia.¹⁰ In our study, removal of the Linx device for recurrence of original symptoms and the Linx device opening unexpectedly were the most common reported device failures.

A study on Linx explantation in 435 devices from 2009 to 2017 from a single institution concluded that the most common reason for device removal in patients was recurrent GERD, which parallels our MAUDE database finding of removal for recurrence of the patient’s original symptoms.¹¹ Additionally, a review on magnetic sphincter augmentation for GERD noted postoperative dysphagia is a common reason for device removal.¹² In our study, dysphagia, odynophagia and GERD were the most commonly reported patient-related adverse events.

A literature review on the Linx device concluded that dysphagia was the most common patient related adverse event following MSA.¹³In addition, Linx device erosion through the esophageal lumen was reported as the most significant adverse event of the device due to its potential morbidity.¹³ Further, a safety analysis of the first 1000 patients treated with the MSA device for GERD also concluded dysphagia was the primary reason for device removal.¹⁴ In our study, dysphagia was also the most reported patient-related adverse event in 275 patients (30%). Further, our study revealed erosion secondary to Linx device implantation was a significant adverse event, occurring in 38 patients (4.1%). MAUDE database medical device reports have limitations. Not all reports contain complete data regarding the device failure or patient related adverse event. For this reason, some of the device failures were reported without specific information on the type of device failure. Those entries were categorized in our study as devices removed

without additional information. Additionally, patient related adverse events that were reported without further details were classified as adverse events not otherwise specified. Other MAUDE database limitations include lack of information on the frequency of device use and the potential for under-reporting of events.

With 101 device failures and 918 patient-related adverse events, our study highlights the importance of awareness of the potential adverse outcomes of Linx device implantation. Early reviews assessing the efficacy of the Linx device concluded that the device is a well-tolerated option for the treatment of GERD but also note the long-term safety of the device was, at that time, undetermined.^15,16,17 A more recent review stated the adverse event of esophageal endoluminal erosion was not fully appreciated in previous reviews and Linx device implantation should be used with restraint with regards to this potential injury.¹³ Although Linx device implantation has its own risks, laparoscopic removal of the device can be performed safely as a 1-stage procedure even within the context of esophageal erosion.¹⁸ Endoscopic removal of the Linx device is considered safe; however, potential complications from device implantation still need to be considered. A case report on esophageal penetration of the MSA device analyzed two cases of severe dysphagia due to migration of the device into the esophagus after implantation.¹⁹ The report concluded that the Linx device may migrate into the esophagus as seen in the two cases, yet the authors felt that the device was considered an effective treatment option for GERD and device removal is generally without diffculty.¹⁹ In our study, device migration from the original site of implantation occurred in 7 patients (6.9%) leading to device explantation.

The Linx device is widely used as an alternative to proton pump inhibitors. In a controlled clinical trial in 2012, the Linx device improved the quality of life in patients with GERD in 23 out of 23 patients and decreased dependence on proton pump inhibitors for refractory GERD in 20 out of 25 patients after 4 years.²⁰ Further, the Linx procedure is minimally invasive and the device can be easily removed, making it a potentially desirable surgical option for patients with chronic GERD.²¹ However, the current literature and this analysis suggests that the long-term safety of the device warrants further research.²²

CONCLUSION

Our study shows that the Linx device has complications which must be thoroughly discussed with patients prior to implantation. Although the Linx device offers patients an alternative to Nissen fundoplication and proton pump inhibitors for the treatment of refractory GERD, additional investigation of both the short and long-term device failures and patient-related adverse events are warranted.

References

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Bonavina L, Saino G, Lipham JC, Demeester TR. LINX(®) Reflux Management System in chronic gastroesophageal reflux: a novel effective technology for restoring the natural barrier to reflux. Therap Adv Gastroenterol. 2013;6(4):261- 268. doi:10.1177/1756283X13486311
Fass R. Alternative therapeutic approaches to chronic pro- ton pump inhibitor treatment. Clin Gastroenterol Hepatol. 2012;10(4):338-e40. doi:10.1016/j.cgh.2011.12.020
Reynolds JL, Zehetner J, Wu P, Shah S, Bildzukewicz N, Lipham JC. Laparoscopic Magnetic Sphincter Augmentation vs Laparoscopic Nissen Fundoplication: A Matched-Pair Analysis of 100 Patients. J Am Coll Surg. 2015;221(1):123- 128. doi:10.1016/j.jamcollsurg.2015.02.025
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Schizas D, Mastoraki A, Papoutsi E, et al. LINX® reflux management system to bridge the “treatment gap” in gastro- esophageal reflux disease: A systematic review of 35 studies. World J Clin Cases. 2020;8(2):294-305. doi:10.12998/wjcc. v8.i2.294
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Alicuben ET, Bell RCW, Jobe BA, et al. Worldwide Experience with Erosion of the Magnetic Sphincter Augmentation Device. J Gastrointest Surg. 2018;22(8):1442-1447. doi:10.1007/ s11605-018-3775-0
Tatum JM, Alicuben E, Bildzukewicz N, Samakar K, Houghton CC, Lipham JC. Removing the magnetic sphincter augmentation device: operative management and outcomes. Surg Endosc. 2019;33(8):2663-2669. doi:10.1007/s00464- 018-6544-y
Dunn C, Bildzukewicz N, Lipham J. Magnetic Sphincter Augmentation for Gastroesophageal Reflux Disease. Gastrointest Endosc Clin N Am. 2020;30(2):325-342. doi:10.1016/j.giec.2019.12.010
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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #50

A Practical Approach to Diagnosis and Treatment of Barrett’s Esophagus

March 2023 • Volume XLVII, Issue 3

Abhilash Perisetti,

Prateek Sharma

Barrett’s esophagus (BE) is a condition characterized by transformation of the normal squamous epithelium of the distal esophagus with abnormal columnar epithelium. It can be detected in patients with gastroesophageal reflux disease (GERD, 2.3% to 8.3%) or without GERD (1.2% to 5.6%). Common risk factors include older age (approximately 1.1% in individuals older than 50 years and 0.3% in those 50 years or younger), Caucasian race, male gender, cigarette smoking, positive family history and longstanding GERD. BE can progress to neoplasia and if left untreated, could develop adenocarcinoma. BE increases the risk (annual rate of 0.2% to 0.5%) of developing esophageal adenocarcinoma (EAC) and it remains critical for early identification and treatment of this precancerous condition. High-quality upper endoscopy remains an essential tool for early identification, treatment and surveillance of BE. Despite advances in the endoscopic recognition, there is approximately a 20-25% rate of missed lesions and an urgent need to improve the rate of neoplasia detection. Management of BE is dependent on presence or absence of neoplasia. Non-dysplastic BE is treated with regular endoscopic surveillance (3-5 years) compared to neoplastic BE which requires endoscopic resection and ablation. In this review, we aim to describe recent updates on the screening, surveillance, diagnosis and management of patients with BE.

Introduction

Barrett’s esophagus (BE) derives its term from a British surgeon Dr. Norman Rupert Barrett¹ who first described abnormal appearing esophageal lining in BE. The esophagus is normally lined by flat, stratified squamous epithelium which if exposed to chronic inflammation and tissue injury, could turn into mucus secreting tall and long columnar epithelium.² This metaplastic change (where a differentiated flat squamous epithelium transforms into another mature differentiated columnar cell type) is triggered by inflammation and chronic acid exposure. This change remains a precursor to dysplasia, a critical step for developing esophageal adenocarcinoma (EAC).3 The natural history of BE involves a risk of transformation to full blown EAC in 3% to 5% of patients during their lifetime. This rate accelerates when an individual develops dysplasia.

Screening

Screening refers to evaluating individuals with GERD (without a prior history of BE) with upper endoscopy for BE. On the contrary, surveillance involves a prior established diagnosis of BE and to assess the progression to EAC. An algorithm approach for screening and surveillance for BE have published in prior studies (Figure 1).⁴

Patients with chronic gastroesophageal reflux disease with one or more risk factors (male sex, smoking history, age > 50 years, obesity and positive family history) are at risk of developing BE. A meta-analysis of 44 cross-sectional studies⁵ included 26,521 GERD individuals, in whom the pooled prevalence of endoscopically suspected BE (suspected columnar epithelium in the esophagus without biopsy) was 12% (95% CI, 5.5%-20.3%) while histologically confirmed BE was 7.2% (95% CI, 5.4%-9.3%), short-segment (BE affecting 1 to 3 cm of the esophagus) was 6.7% (95% CI, 4.6%9.1%) and long-segment (BE affecting more than 3 cm of esophagus) was 3.1% (95% CI, 2.0%4.6%).⁵ Male sex is associated with higher BE pooled prevalence of 10.8% (95% CI, 6.6%15.9%) compared to females of 4.8% (95% CI, 2.7%-7.5%).⁵ Although the precise reason for this difference is unclear, possible contributors include a male-predominant gender bias including GERD related esophagitis, vulnerability of esophageal epithelium to acid exposure and estrogen induced acid protection in females.⁶ Prevalence of BE is higher in White individuals compared to Hispanics (6.1% vs. 1.7%; P = .002).⁷ Older individuals (>50 years) are at higher risk than younger individuals (50 years or younger). In a cohort of 29,374 patients, prevalence of BE was higher in older patients compared to younger individuals (1.1% vs. 0.3%; P = .02).⁸ Further, tobacco smoking increases the risk of BE with higher prevalence noted in cigarette smokers compared to nonsmokers (12% vs. 1.1%; P < .001).⁹ Obesity poses a risk for higher prevalence of BE compared to lean individuals. A study of 13,434 patients (mean body mass index [BMI] of 39 to 51.2) showed for every 1-point increase in BMI, there is a 0.15% increase in prevalence of BE. This is likely attributed to adipocytokines increasing the risk of inflammation in obese individuals. Patients with positive family history (of BE or EAC) are at a higher risk of BE.¹⁰

While screening can assess for BE and need for further surveillance, an important consideration should be given to overall life expectancy. If the patient overall life expectancy is less than 10 years, the value of screening decreases significantly.

Diagnosis of BE and Related Neoplasia

BE is primarily diagnosed by high-quality upper endoscopy followed by multiple biopsies of the columnar lined esophagus to confirm intestinal metaplasia. To minimize variability in measuring the extent of BE during endoscopy, the Prague criteria with methodological inspection of the diaphragmic area, upper end of gastric folds, circumferential and maximum extent of squamocolumnar area has been introduced.¹¹ Further, use of expert esophageal histopathologist could improve the interobserver variability for diagnosis of dysplasia in BE.¹² A high-definition endoscope could improve the detection of the visible and potentially curable lesions (BE-related neoplasia [BERN]). Multiple strategies are available to improve the detection of these subtle BERN lesions on upper endoscopy.¹³ High-quality endoscopy requires CLEAN-adequate cleaning [C], learning [L] slow withdrawal with inspection of BE segment, use of virtual chromoendoscopy [E], acquiring [A] education to identify BERN lesions (by webbased and interactive sessions), and use of quality metrics (neoplasia detection rate [NDR]), which could potentially enhance detection of these lesions (Figure 1).¹³ The evaluation of the BE requires extensive cleaning of the concerned segment and slow withdrawal during the inspection. Endoscopists with a mean inspection time longer than 1 minute per centimeter of BE detected more lesions compared to those with less than 1 minute inspection time (54.2% vs. 13.3%; P = .04).¹⁴

For individuals who cannot tolerate sedation, office-based procedures such as swallowed cellcollection devices (unsedated transnasal endoscopy, esophageal capsule endoscopy) have been advocated.¹² In unsedated transnasal endoscopy, an ultrathin endoscope is passed through the nose and advanced to the esophagus to evaluate for mucosal abnormalities. Non-endoscopic capsule sponge device (once swallowed, the capsule dissolves, compressed sponge emerges which is pulled out by a string for laboratory biomarker assessment) combined with biomarkers (trefoil factor 3, methylated DNA markers) can be used in individuals with chronic GERD.¹²

Missed Lesions

The visible lesions noted in the BE segment, also called BE-related neoplasia (BERN), are abnormalities noted on the BE surface mucosa (raised or abnormal pattern) indicative of dysplasia or invasive cancer. The prevalence of LGD remained relatively stable at approximately 1213%, HDG increased by 148% (2.7% [1990-1994] to 10% [2010 and beyond]).¹⁵ Further, prevalence of EAC increased by 112% (3.3% [1990-1994] to 7.6% [2010 and 2016]).¹⁵ This correlated with increase in BERN lesions from 5.1% [1990-1994] to 16.3% [2010-2019]. While this increase in prevalence of HGD or EAC could be theoretically related to increase in recognition of BERN lesions, further studies are needed to corroborate these findings. On the contrary, the rate of missed BERN lesions on endoscopy is an important finding to assess for potential targets for improving lesion detection. Recent studies reported a missed rate up to 23% from Netherlands (f lat BERN from community centers had higher grade when referred to expert centers), 27% from Australia (BE referral centers identified advanced BERN lesions with a prior diagnosis of LGD). A meta-analysis of 24 studies reported a missed rate of 25.3% (95% CI, 16.4%-36.8%) for EAC.¹⁶ These studies indicate an approximate missed rate of EAC/HGD as high as up to one-quarter of all cases suggestive of an area of huge improvement.

Progression of BE to EAC

The annual rate of progression of BE to EAC is dependent on length of BE segment, and the presence or absence of dysplasia. In a study involving 4097 patients with BE,¹⁷ the annual rate of progression to EAC in short-segment BE (nondysplastic) was 0.06% (95% CI, 0.01%-0.10%), in long-segment BE 0.31% (95% CI, 0.21%-0.40%).¹⁷ Similarly, a meta-analysis of 2694 patients with BE and LGD (low-grade dysplasia) found that annual incidence of HGD/EAC was 1.73% (95% CI, 0.99%-2.47%).¹⁸ The progression of BE to HGD/EAC is critical and risk stratification tools have been developed. In a study involving 4584 patients with BE in the US and Europe, Progression in Barrett Esophagus (PIB) score was developed.¹⁹ This scoring system (composed of 30-point score, validated externally) combines data from age, sex, tobacco smoking history, BE segment length and presence of any LGD. An annual progression risk is determined based on score, 0.13% (score: 0-10), 0.73% (score: 11-20), 2.1% (score: 21-40).

Prevention

Given that GERD is a risk factor for development and progression of BE to EAC, acid exposure elimination remains an important strategy for prevention. Aspirin (given its anti-inflammatory properties) have been used as a chemo preventative agent against multiple cancer including progression of BE to EAC. This combined with a proton pump inhibitor (PPI) could potentially reduce the progression of BE. To evaluate this, a large, randomized trial published (ASPECT trial) in Lancet²⁰ was conducted in the UK and Canada (84 centers, 2557 participants). Four groups: high-dose PPI with aspirin group, low dose PPI with aspirin group, twice-daily PPI group and daily PPI group. At 9 year follow up, the first group (high-dose PPI with aspirin) had overall reduced rates of a combination of: EAC, all-cause mortality and HGD without significant adverse events. High-dose PPI added the highest beneficial effect and combination with aspirin added another 38% benefit to the time to an event.²⁰ Health et al.²¹ studied Celecoxib (n= 49, 200 mg twice daily) vs. placebo (n = 51) to evaluate for change in dysplasia progression and found no difference at 4-year follow-up (-0.08% vs. -0.06%). Despite this benefit, given the risk of non-fatal, fatal bleeding events²² and cerebrovascular events, the American College of Gastroenterology (ACG) and American Gastroenterological Association (AGA) recommend against routine use of aspirin and/or nonsteroidal anti-inflammatory drugs for chemoprevention of BE.

Surveillance of BE

Management of BE includes surveillance endoscopy and treatment interventions (endoscopic resection and ablation). Surveillance refers to assessment for progression of EAC with an established diagnosis of BE in the past. The intervals for surveillance is dependent on the length of the BE segment. Major gastrointestinal societies recommend a 5-year surveillance for short segment (<3 cm) compared to 3-year surveillance for long segment (> 3 cm). Endoscopy image technology and pixel improvement resulted in high-definition white light endoscopy (HD-WLE) and chromoendoscopy (electronic or dye-based [acetic acid]). Acetic acid chromoendoscopy meets the Preservation and Incorporation of Valuable Innovations (PIVI) thresholds. A meta-analysis of 24 studies (2304 patients) with BE patients showed a sensitivity of 97% (95% CI, 95%-98%), negative predictive value (NPV, 98%, CI, 95%99%) and specificity of 85% (95% CI, 69%-93%) for acetic acid chromoendoscopy.²³ Additionally, American Society of Gastrointestinal Endoscopy (ASGE) recommended chromoendoscopy in addition to WLE for biopsy specimens. In a meta-analysis including 12 randomized trials and 2433 BE patients, a 9% (95% CI, 4.1%-14%) increase in dysplasia detection was noted with chromoendoscopy compared to WLE.²³

Endoscopic Resection

The initial step in endoscopic therapy includes either mucosal or submucosal resection. Prior to these advances, many of these esophageal lesions were treated surgically. Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are most commonly performed procedures when lesions are restricted to mucosa and superficial third of the submucosa respectively. EMR and ESD are both highly effective with ESD achieving a higher R0 resection at the expense of time and higher adverse events. Further, prior endoscopic therapy (mucosal resection or ablation) can lead to submucosal fibrosis which can make further endoscopic therapy challenging. In these cases, ESD could offer definitive treatment. Band mucosectomy is the most commonly performed EMR technique which could assist with resection for margin free removal. This technique involves evaluation of abnormal mucosal tissue and followed by targeted resection of visibly abnormal area. The resected area is assessed histologically for the depth and lateral margins for R0 resection. For welldifferentiated lesion restricted to mucosa, without submucosal or lymphovascular involvement, EMR could be considered curative. ESD is a technique characterized by dissecting lesions in the submucosa with ability to remove entire lesions with varying length and depth. Given the ability to target a wider area, it could theoretically lead to higher R0 resections. In a small randomized controlled trial of BE patients²⁴ with focal area of HGD or early EAC < 3 cm undergoing either ESD (20 patients) or EMR (20 patients), R0 (margin free of HGD/EAC) resection rates were higher in ESD compared to EMR (10/17 vs. 2/17, P = 0.01), but no difference was noted in neoplasia remission, recurrence or need for surgery.²⁴ Further, ESD was associated with longer procedure times with a mean ESD time of 83.3 minutes compared to EMR of 36.7 minutes limiting its generalizability.²⁴

Ablation Therapies

Endoscopic ablative therapy with heat (radiofrequency ablation [RFA], argon plasma photocoagulation [APC]) or cold (cryotherapy) have been used for BE patients with HGD or visible neoplastic lesions after resection.¹² RFA remains the most studied and established method of ablation for neoplastic BE and HGD.²⁵ RFA could be used after resection (EMR/ ESD) or without resection for absolutely flat HGD. A systematic review of 20 cohort studies (9 studies with RFA post resection and 11 studies with only RFA) noted complete eradication of neoplasia (CE-N) in 93.4% (for RFA post resection) and 94.9% for RFA only groups.²⁶ Complete eradication of intestinal metaplasia (CE-IM) was 73.1% for RFA post resection compared to 79.6% in RFA only group.²⁶ Rates of recurrence were 1.4% (EAC), 2.6% (dysplasia) and 16.1% (IM) for RFA post resection. For RFA only group, recurrence rates were 0.7% (EAC), 3.3% (dysplasia) and 12.1% (IM). Adverse events associated with RFA were post treatment stricture formation, bleeding and perforation. The risk of adverse events with RFA have been studied in a systemic review and meta-analysis of 9200 patients in 7 studies with rates significantly higher in RFA with resection (EMR) compared to RFA without resection (22.2% vs. 5%; relative risk, 4.4; P = .015).²⁷ For every 1-cm increase in the median BE length, there was a 25% (95% CI, 16-35%) increase in adverse events.²⁷ Nevertheless, mucosal resection (to remove the neoplastic BE) followed by RFA remains the standard of care for patients to achieve eradication of IM. Cryoablation involves the application of a cryogen such as liquid nitrogen spray or nitrous oxide via flexible catheter to achieve a temperature as low as ^__196 ⁰C. These extremely low temperatures cause ice crystallization and destruction of plasma cell membranes and denature the proteins. The tissue architecture and extracellular matrix (which are cryoresistant) are preserved reducing the underlying risk of tissue scaring, post-procedure pain and stricture formation. A multicentric nonrandomized and noncontrolled clinical trial of 120 patients using nitrous oxide cryoballoon focal ablation system achieved eradication of IM in 91% and dysplasia in 97%.²⁸ Post-procedure pain was well tolerated with a score of 2 which was considered mild (visual analog score of 0 [no pain] to 10 [most severe pain]) which resolved within 2 days. Some reported adverse events included post-procedure chest pain, stricture formation, bleeding and perforation.²⁹ Hybrid- Argon plasma coagulation (APC) uses injection therapy followed by heat for achieving eradication of metaplasia in BE. A randomized pilot study of 65 patients with BE showed that APC compared to RFA achieved ablation in BE patients in 55.8% vs. 48.3% (OR, 1.4 [95% CI, 0.5-3.6]) with comparable adverse events and quality of life scores.

Approach to Neoplastic BE

Endoscopic therapy remains first-line of treatment for high-grade dysplasia and early EAC (T1a and superficial T1b) lesions. In LGD, the risk of progression to EAC should determine the intensity of treatment versus surveillance. Given the variable risk of LGD patients progressing to EAC (0.02%11.4%), shared decision making based on the patient preferences, risk factors and annual progression risk could be considered. Surgical options (esophagectomy) could be considered for HGD or early EAC, however are associated with higher adverse events compared to endoscopic therapy. A systematic review of 870 patients (510 undergoing endoscopic therapy and 360 undergoing surgical esophagectomy) in 7 studies³⁰ showed no difference in rates of CE of dysplasia (314/334 in endoscopy arm vs. 237/241 in surgical esophagectomy arm, relative risk, 0.86 [95% CI; 0.91-1.01]). Survival rates and mortality did not differ between groups at 1 year and 5 years. However, adverse events (stricture formation, bleeding, perforation) were significantly lower in endoscopic therapy (66/510) compared to esophagectomy (90/360, relative risk, 0.38; 95% CI, 0.20-0.73; P = .004).³⁰ For lesions extending to superficial submucosa (early T1b), a multidisciplinary team approach is needed to assess the candidacy for ESD. Patients with lowrisk lesion (good to moderate differentiation), no lymphovascular invasion, and superficial submucosal lesion (up to 500-mm invasion) could be offered ESD in high-volume center with experienced advanced endoscopist. In an observational study of 61 patients with low risk T1b lesions with ESD, eradication of dysplasia was noted in 87% of patients with maintenance of eradication in 84% over a 47 month period.³¹

Limitations

This review aims to provide updated information on the diagnosis, treatment and management of BE. First, due to use of practice guidelines, they could be subjected to expert opinion bias. Second, since this review did not systematically search the literature, some relevant publications may have been missed. Observational data without randomized controlled trials could decrease the strength of recommendations.

The Future

Given the high miss rate of BERN lesions, artificial intelligence (AI) could be a promising tool in identifying subtle neoplastic lesions with improved sensitivity (>90%) and specificity (>80%).¹³ Use of machine learning with convolutional neural networks, deep learning can assess the lesion accurately for depth and precise mucosal patterns. This combined with areas in long segment BE could improve quality, blind spot assessment, could provide feedback and report quality metrics needed to reduce the missed BERN lesions. Use of highquality BE examination with CLEAN (cleaning, learning, endoscopic [virtual], acquiring and neoplasia detection metric [NDR quality metric assessment]) could further improve our ability to identify and manage these lesions effectively. Newer treatment modalities such as radiofrequency vapor therapy can generate heat therapy (vapor at 100 °C using a RF electrode) and could be used for ablation of the dysplastic segment, the efficacy and feasibility needs to be studied in the future.³²

References

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2021;53(11):1162-1168. doi:10.1055/a-1319-5550

FUNDAMENTALS OF ERCP, SERIES #4

ERCP Stone Extraction: Simple

March 2023 • Volume XLVII, Issue 3

Himmat S. Brar,

Amaninder S. Dhaliwal

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) was initially developed as a diagnostic procedure for visualizing the pancreatic and biliary ducts. However, it has evolved over the years into a predominantly therapeutic tool. The most common indication for undergoing ERCP is biliary stone disease. Choledocholithiasis refers to the presence of gallstones in the common bile duct (CBD). (Figures 1-3) Stones in the CBD can cause stasis and obstruction leading to bacterial translocation and cholangitis. The clinical presentation varies from biliary colic, cholangitis, and can also include biliary pancreatitis. Therefore, ERCP plays a vital role in managing choledocholithiasis and preventing and treating complications. ERCP is used to identify the stones often seen as a filling defect. The modalities used to identify stones are the injection of undiluted contrast, diluted contrast, and regular and occlusion cholangiograms.¹ Diagnostic ERCP is commonly performed with undiluted water-soluble contrast. The initial fluoroscopic images can reveal bile duct stones that manifest as a filling defect (an area where dye cannot go), often with a “meniscus sign,” or an arc of contrast at the level of the stone. Diluted contrast can be used if the bile duct is dilated, as the undiluted contrast can mask the small stones, although in practice the use of diluted or undiluted contrast during ERCP varies widely. An occlusion cholangiogram, whereby the bile duct is filled with contrast over an inflated occlusion balloon attached to an ERCP catheter, is performed in patients with suspected intrahepatic stones or stones proximal to a stricture or to prove duct clearance after stone removal. Bile duct stones will manifest as intraluminal filling defects, but other lesions can present as filling defects as well, including air bubbles, blood clots, parasites, mucus, tumors and neoplasms of the duct, and other etiologies. The patient’s clinical picture should be considered to make a definitive diagnosis.

Of utmost importance for stone extraction is for the operator to properly gauge the size of the exit passage. The size of the stone should be measured relative to the size of any intended or performed biliary sphincterotomy and the diameter of the bile duct. The sphincterotomy site should be adequate to allow for the stone to pass. Different methods can be used to measure the size of the ampullary orifice. One of the methods is by pulling a stone extraction balloon, inflated to the approximate size of the stone, through the sphincterotomy and the distal bile duct. The stone extraction should, in theory, be easily accomplished if the balloon passes easily and without resistance or deformation. However, stone extraction may prove to be difficult if there is resistance during the passage or the balloon becomes deformed during its transit through the distal CBD and the ampullary orifice-this suggests that the sphincterotomy itself may be inadequate and may need to be extended or completed. Another way of measuring sphincterotomy size is by pulling a fully bowed sphincterotome through the papilla. A bowed sphincterotome should be able to pass easily through the sphincterotomy, and with no resistance. If the sphincterotomy size is deemed inadequate even after what is felt to be a complete sphincterotomy has been performed, additional therapies such as balloon dilatation of the sphincterotomy and distal bile duct may be required for stone extraction.²

Balloon dilation of the bile duct itself is occasionally needed in patients harboring benign biliary strictures when the stone is proximal to the stricture or cases of intrahepatic stones. Biliary dilation balloons are used for dilation. These are low-profile balloons ranging from 4 to 10 mm in diameter and 2 to 4 cm in length that can be inflated to a single, fixed diameter (unlike esophageal dilation balloons, for example, which can often be inflated to several distinct sizes). Biliary dilation balloons can be placed over a guidewire across the biliary stricture in question and inflated using saline or dye to achieve effacement of the underlying stricture. A radio-opaque marker (or markers, depending on the vendor) placed at the end and/or in the middle of the balloon helps with proper positioning of the balloon across the stricture. The choice of balloon size is based upon the diameter of the bile duct. The balloon is visualized under fluoroscopy during inflation to provide an additional margin of safety. The disappearance of the waist (full effacement) during inflation would determine the effectiveness of the dilation and typically demonstrates if the dilation was successful. If there is distortion during inflation, it would suggest inadequate dilation or a recalcitrant stricture. Additional therapies, including stone fragmentation, may be warranted before attempting stone removal when the calculus itself is located above an incompletely dilated stricture. Alternatively, indwelling stents can be placed to allow biliary decompression, avoid cholangitis, and to prevent other complications until the stricture is adequately treated.³

Indications

(i) Common bile duct stones (ii) Intrahepatic duct stones

Contraindications

Medical conditions preventing the use of sedation in the patient
Anatomical – Gastric outlet obstruction that prevents the access to major papilla

Patient Preparation

Patients undergoing ERCP should be evaluated for their general fitness for the procedure itself as well as the sedation required to perform the procedure. In the United States, most ERCP procedures are performed under General Anesthesia or Monitored Anesthesia Care. Endotracheal intubation is preferred in patients with sepsis with unstable hemodynamics.⁴ Most patients can safely undergo ERCP, including young and old patients, cirrhotic and non-cirrhotic patients, children, and pregnant patients, depending on the circumstance.⁵

Positioning

There are several position options for patients undergoing ERCP: prone, supine, left lateral decubitus, or oblique. The positioning is determined by operator experience and preference as well as patient-related factors such as body habitus, neck mobility, or the presence of abdominal drains. The other factors that play a role in choice of patient position are anesthesia and airway considerations. The left lateral and oblique positions are sufficient for cases involving extrahepatic bile duct but can be less than ideal inadequate for patients requiring pancreatic duct or intrahepatic duct imaging.⁶ In these cases, either a prone or supine position is preferred. There have been studies that have compared prone and supine positioning during ERCP. A large randomized controlled trial at a tertiary center found no difference in cannulation rate or adverse events between the prone and supine groups, irrespective of operator skill.⁷ In addition, a retrospective study was performed with 649 patients undergoing ERCP: prone (n = 506) and supine (n = 143) with a mix of moderate and generalized anesthesia administered. The study found no difference between cannulation rate or adverse events between the prone and supine groups.⁸ In general, ERCP is usually performed in the prone position in the United States.

Antithrombotics

Many patients who need to undergo ERCP require antithrombotic or anticoagulant medications to treat other underlying illnesses, and practitioners of ERCP often must make decisions regarding if and when to stop and restart these medications so that the procedure can be performed. The decision to proceed with ERCP and whether to start or stop antithrombotic agents should be, in general, individualized and based on clinical urgency, the bleeding risk of the specific ERCP that needs to be completed, and the cardiovascular risk of holding the antithrombotics. For example, the active use of anticoagulants should not defer an ERCP procedure in cases of sepsis that require urgent ERCP i.e., a decompressive biliary stent can be quickly and safely placed in a patient on any anticoagulant and with any international normalized ratio (INR). This approach can save time in a critically ill patient but leaves for a later day the decision on how to manage anticoagulants so that the offending stone can be safely removed. One study has shown a threefold increase in organ failure in patients with cholangitis who waited for ERCP for > 48 hrs, further arguing for early intervention.⁹

Endoscopic sphincterotomy (ES), which is nearly universally practiced to facilitate the removal of bile duct stones in the United States, always carries a risk of causing acute or delayed bleeding, although the absolute risk of bleeding is low. Endoscopic papillary balloon dilatation (EPBD) without ES is a low-risk bleeding procedure, but carries an increased risk of causing pancreatitis, which can be severe. In non-urgent cases, antithrombotics and anticoagulants can be held prior to performing ES, whereas they can be continued in patients undergoing EPBD. In urgent cases, a plastic biliary stent can be placed for drainage without the need for ES to decrease the risk of bleeding. For patients with low cardiovascular risk who require ES, anticoagulation can frequently be held, whereas “bridging” with heparin can be considered in higher cardiovascular risk patients, although in practice bridging is rarely performed.

The 2016 ASGE guideline on the role of blood thinners in endoscopy provides a thorough review of this topic.¹⁰ The key concern generally involves weighing the risk of bleeding against the risk of a thromboembolic event. The primary risk factor for bleeding during ERCP is endoscopic sphincterotomy.¹¹ Therefore, it is unnecessary to discontinue antithrombotics if ERCP without ES is planned.

Antibiotics

The guidelines recommend using preprocedural antibiotics for immunocompromised patients, liver transplant patients, cholangitis and patients with biliary obstruction in whom incomplete drainage is anticipated (multiple stones or complex strictures).¹² The use of pre- and/or post-procedural antibiotics has shown lower rates of post-ERCP cholangitis in cases of biliary obstruction without cholangitis and anticipating complete drainage after ERCP.¹³ In many centers antibiotic prophylaxis is widely used for patients undergoing ERCP regardless of indication given the low cost and significant potential benefits.

Stone Extraction: Devices and Techniques

The choice of stone extraction device depends upon the number, size, and type of stones and the structure of the bile duct relative to the stone(s). The size of the stone and duct diameter can be estimated by comparing to the width of the duodenoscope, which is generally around 12mm.

ERCP Guidewires

Guidewires are the mainstay of ERCP. They are critical for duct cannulation, maintaining access to a desired duct, exchanging devices, guiding devices, dilating strictures, and placing stents; all of these maneuvers are employed during stone extraction cases. There are a variety of guidewires that are commercially available, and these differ widely in terms of materials, length, diameter, mechanical properties, and design.¹⁴

Broadly speaking, there are three general classes of guidewires available for ERCP: (1) Monofilament wires with stainless steel cores that are designed for rigidity. (2) Coiled wires are made of inner monofilament core and outer spiral core of stainless steel. The inner core provides stiffness, and the outer core provides flexibility. (3) Coated or sheathed wires made of stainless steel or nitinol monofilament cores with an outer sheath of Teflon, polyurethane, or other materials. Guidewires are advanced into the desired duct through a sphincterotome or a balloon catheter under endoscopic and fluoroscopic guidance. Most wires come with external markers of some type printed on their outer coatings to illustrate movement and measure depth of entry. Guidewire locking devices, that fit externally onto a duodenoscope, can be used to fix the proximal end of the guidewire (outside the patient) and reduce the risk of wire dislodgement.¹⁵ A summary of currently available guidewire types is listed in Table 1.

Sphincterotomy – Devices and Techniques

Biliary Sphincterotomy

Endoscopic sphincterotomy (ES) of the biliary sphincter is indicated for many biliary interventions and is critical for stone extraction. The sphincterotome itself helps in achieving deep bile duct cannulation and is then used to perform the sphincterotomy itself. Advantages of using sphincterotomes include the following: 1. When it is anticipated that a sphincterotomy will be needed, exchange to a sphincterotome from a straight biliary catheter is avoided. 2. A sphincterotome allows for the variable deflection of the catheter tip to facilitate biliary access during cannulation. Studies have shown a higher cannulation rate with sphincterotomes than with standard straight biliary catheters, with no difference in adverse effects.^16,17 A recent meta-analysis showed an increased cannulation rate and decreased risk of post-ERCP pancreatitis for guidewire-assisted cannulation compared with contrast-assisted cannulation, both of which are generally performed with sphincterotomes in the modern era.^18,19

Sphincterotomes (Figure 4) vary in the diameter and length of the tip, size, characteristics of the cutting wire, and shaft stiffness.²⁰ Tapered devices can be easily inserted into the papilla but also come with a potentially higher incidence of tissue trauma when compared to blunt tip devices. Modern sphincterotomes are considered to be “triple lumen devices” with one channel for contrast injection, one for guidewire access, and the third lumen in the catheter being the one that contains the cutting wire itself. As such, most sphincterotomes have a lumen for the guidewire and an integrated hub for contrast injection, thus allowing contrast injection without guidewire removal (as was required in the past with so called “double lumen devices”).

Sphincterotomy Procedure for Biliary Stone Extraction

The papilla is approached with the sphincterotome from a distance so that the pre-curved distal part can be seen exiting the endoscope. The tip of the sphincterotome is inserted into the papillary opening, and the device is maintained by the short, straight position of the duodenoscope. The subsequent bowing of the tip allows the insertion into the common bile duct opening. The S-shaped distal part of the common bile duct is overcome by straightening the tip and gently withdrawing the endoscope. The guidewire is passed into the bile duct under endoscopy and fluoroscopy guidance without contrast injection. A soft hydrophilic guidewire is preferred to reduce the risk of ductal injury. The unbowed sphincterotome can then be advanced to attain deep cannulation. The guidewire is then moved into the proximal biliary system to secure ductal access for maneuvers and the exchange of accessories.

Precut Sphincterotomy for Biliary Cannulation

Selective biliary cannulation (SBC) is the mainstay of therapeutic ERCP.²¹ Despite significant advancements in imaging techniques and newer designs of guidewires and sphincterotomes, the success rate for biliary cannulation has been around 85% using standard cannulation techniques for average providers.²² Precut sphincterotomy, which refers to cutting into the ampulla before deep biliary access has been obtained, is performed when biliary cannulation is not attained using standard techniques. Difficult SBC has been defined variously but can be considered to apply when the cannulation requires ≥10 attempts and/or takes more than 10 minutes to achieve cannulation.²³ Precut sphincterotomy increases the cannulation rate to approximately 98%.²⁴ A ‘precut’ is defined as an incision made into the CBD or the ampulla of Vater before attaining SBC during ERCP.²⁵

Endoscopic Papillary Balloon Dilatation

Endoscopic papillary balloon dilatation (Figure 5) is used to facilitate stone extraction with or without preceding endoscopic sphincterotomy. This technique is specifically helpful in achieving adequate opening (i.e., exit passage) to allow retrieval of stones, in cases of complicated anatomy (e.g., diverticulum), in cases of prior failed stone extraction, and in circumstances that prohibit sphincterotomy (e.g., coagulopathy) or extension of sphincterotomy. The dilation balloons (< 10 mm) include the Fusion dilation balloon (Cook Endoscopy, Winston Salem NC) and the Hurricane balloon (Boston Scientific, Natick MA). The balloon should not be dilated greater than the diameter of the proximal bile duct to avoid perforation. In addition, the dilation should be performed slowly and under fluoroscopy to evaluate for the disappearance of the “waist.” The balloon should be kept dilated for about 30 to 60 seconds after the disappearance of the waist according to some, but no hard and fast guidelines exist. However, a longer duration should be considered, as this may reduce the risk of pancreatitis (mainly when sphincterotomy is not performed). Balloon dilation with endoscopic sphincterotomy has comparable outcomes in terms of stone clearance. However, there is an advantage of overall lower risk of adverse events and pancreatitis than sphincterotomy alone.²⁶

Balloon Extraction

Stone extraction balloons are available in multiple sizes. The size varies from 8 to 20 mm depending upon the amount of air in the balloon. The exit site is gauged by inflating the balloon to the maximum diameter of the bile duct below the stone and pulled out to check for resistance or change in the diameter or any significant deformity of the balloon under the fluoroscopy. The shape can be distorted and become “sausage-shaped” in cases of chronic pancreatitis due to inflammation. Triple lumen catheters allow the catheter to pass over the guidewire. This provides an advantage as it maintains access to the biliary system while allowing for the injection of the contrast. The disadvantage is that the triple-lumen balloon shafts are stiffer than the double-lumen shafts. Prior to introducing the balloon catheter into the endoscope, the tip of the catheter should be slightly bent or curved to allow for easier cannulation of the bile duct. (Figures 6-10) The catheter is passed into the bile duct, and the images are obtained under fluoroscopy. The catheter is passed proximal to the stone, and the balloon is inflated. It is gently pulled back until the stone reaches the level of the papilla. Once at the papilla, the axis of traction is adjusted by aligning the scope with the axis of the bile duct. This has a mechanical advantage and also reduces damage to the duct. The tip of the endoscope is angled upwards against the sphincterotomy. While continuing the slow pulling of the catheter, the scope is angled downward, leading to the expulsion of the stone from the ampulla. If the removal of the stone is unsuccessful at the first attempt, the scope should be angled upward, and gentle traction should be applied along with the repetition of a similar downward movement of the scope. It is necessary to maintain the traction as the stone is getting expelled from the bile duct. More traction can be applied if required by bending the scope downward and rotating it to the right to expel the stone.

Occasionally, the inflated balloon can also cause resistance, and it is essential to deflate the balloon to the size of the bile duct or the sphincterotomy. This can be done by adjusting the flow inside the balloon by the stopcock. In the case of multiple stones, the most distal stones are removed first and then the proximal ones. This will avoid the impaction of the stone or rupturing of the balloon. The balloon should be adjusted according to the size of the bile duct. The other thing to be careful about is not to dislodge the wire. The balloon goes over the wire, and excessive movement can dislodge the wire. The balloon should be pulled gently, and excessive movement should be avoided to prevent dislodgement of the wire. However, if the guidewire access is lost, the balloon should be withdrawn, and the bile duct should be recannulated with the guidewire. There are multiple advantages (Table 2) and disadvantages (Table 3) of using the stone extraction balloon.

Basket Extraction

Wire baskets are commonly used for stone extraction. The baskets are available in different shapes and sizes and allow stone extraction for sizes ranging from 5 mm to 3 cm. A variety of baskets currently available (Table 4) are listed with their characteristics, advantages and disadvantages. However, stones that are larger than 2 cm require fragmentation before extraction. The most commonly used basket is the four-wire Dormia basket. It is made of braided steel and is hexagonal in shape. The stone is captured between the basket wires when it is closed. The stone is then removed by continuous gentle traction during basket withdrawal.²⁷ Smaller stones are difficult to capture due to the large spacing between the wires. Newer baskets with a modified design help in capturing smaller stones. So called “flower baskets” are divided into eight wires, with narrow space between the wires, allowing for better engagement of smaller stones. The eight-wired basket allows for better engagement of small stones than the four-wired basket. There are spiral baskets that are used for relatively small stones. The wires wind closely around the stone when the basket is opened. These spiral baskets are not designed for mechanical lithotripsy. The baskets for lithotripsy have stronger wires and metal sheets that provide support to crush the stone. The tension can be applied manually or using a crank handle to crush the stones. Dilute contrast is injected during the procedure, and the images are obtained to outline the stones in the bile duct. Care should be taken to avoid injecting excessive contrast due to the risk of displacing the stones proximally into the intrahepatic ducts or interfering with proper visualization. The singlelumen basket allows for the free flow of dilute contrast when it is opened. A double-lumen basket has different channels for injection of contrast and passage of a guidewire. The basket can also be advanced over an already positioned guidewire. This is mainly useful for removing stones in the intrahepatic duct or those that could have migrated to the intrahepatic ducts. The traditional guidewires run through the entire length of the basket catheter. Modern baskets are typically designed for shortwire systems. These involve only a part of the basket going over the guidewire. The wire is locked in position, and then the manipulation is done. A newer modification is the “ropeway” basket. It is a single lumen system and has a catheter attached to the tip of the basket, which allows only the tip (instead of the shaft) of the basket to go over the wire. The contrast is injected, and images are obtained to specify the location of the stone. (Figure 11) The stone can also be visualized on the cholangiogram. The basket in a closed position is inserted into the bile duct and is advanced proximal to the stone. Once the basket is in the duct, it is opened slowly above the stone. An alternative is to go all the way to the intrahepatic duct and then open the basket and pull back gently to capture the stone. Caution should be taken to avoid opening the basket below the stone as this can push the stone proximally into the intrahepatic duct, thus making extraction difficult. The basket is pulled back and manipulated along the stone to engage it. Once the stone is captured, the basket is partially closed to avoid losing the stone. The endoscope is pushed further into the duodenum to help align the basket’s axis with the bile duct. Continuous gentle traction is applied to the basket catheter until it reaches the distal bile duct or the level of sphincterotomy. The endoscope tip is angled upward to the sphincterotomy, and the traction is applied. Once the stone is at the papilla, the tip of the scope is turned down, and traction is applied to remove the stone. If the stone is not extracted, the same motion can be repeated with the steady traction of the basket. Furthermore, the scope tip should be turned down and rotated to the right once it has reached the tip, helping to extract the stone out of the bile duct. The basket is closed gently during extraction instead of the fully open basket. The closed basket allows all the wires to come together, and the overall force is transmitted along with the wire basket and along the distal bile duct. However, if the basket is withdrawn in a fully opened position, the loose wires tend to cut across the sphincterotomy rather than the axis of the common bile duct. This leads to bruising and submucosal tissue damage. In addition, caution should be taken to avoid closing the basket tightly around the stone. This can lead to embedding the wires to the stone’s surface, resulting in the impaction of the stone, especially in cases of large stones. In some instances, the wires cannot be freed from the stone, thus leading to the impaction of the basket. Another technique that can be applied to capture stones in a dilated bile duct is an aspiration. The basket is opened above the bile duct, and the aspiration of the contrast or bile is done as the basket is withdrawn. This creates a negative suction force and helps trap the stones within the basket wires. The same technique can be applied to smaller stones that are difficult to capture. The basket can be placed at the level of the papilla to keep the open sphincter. Suction is applied from the duodenum that helps in the movement and capturing of the stones in the basket. This can also be used for small stones in the hepatic duct. The basket can be placed at the bifurcation of the duct, and the suction is applied. This leads the stones to descend in the hepatic duct and into the basket placed in the bile duct, from where the stones are eventually removed. There are numerous advantages of the extraction basket. These include more effective traction and help remove medium to large stones.

However, there are some disadvantages of extraction baskets. Smaller stones or fragments are difficult to engage in the wires. The stones in the intrahepatic ducts may be difficult to capture because of the narrow diameter and less flexibility of the capture baskets. There is also a constraint in opening the basket in the narrow intrahepatic ducts. Thus, in these scenarios, extraction balloons are perhaps a better choice. The recent trials comparing the extraction balloons to extraction baskets have favored balloons for smaller (10 to 11 mm) stones.^28,29 However, the choice for smaller stone removal depends upon personal preference.

Comparing Balloon and Basket Extraction

Basket and balloon catheters are used for stone extraction. Nearly 85-90% of stones are easily retrieved by these methods following endoscopic sphincterotomy (EST), whereas difficulty is encountered in 10-15% of cases. The balloon catheter can capture small stones by obstructing the lumen. However, it cannot prevent small stones from slipping and impaction in the corner pocket at the distal third of the bile duct during stone extraction. Thus, the basket catheter has a better traction power than the balloon catheter.³⁰

The European guidelines recommend using either technique as there is minimal difference between overall outcomes with basket or balloon catheters. However, the American guidelines recommend balloon catheters over baskets due to the risk of adverse effects related to basket impaction.^31,32

Ishiwatari et al. performed a randomized control trial in Japan that primarily investigated the clearance rates between the basket or balloon catheters.³³ The complete clearance rates were 92.3% (72/78) in the balloon group and 80.0% (64/80) in the basket group. The difference in the rates between the two groups was 12.3 percentage points, indicating noninferiority of the balloon method (noninferiority limit −10%; P< 0.001 for noninferiority).

Ozawa et al. conducted another randomized control trial in Japan.³⁴ It was designed as a noninferiority study and compared basket extraction with balloon extraction. The study involved 184 patients over six institutions with bile duct stones < 11 mm in diameter. The primary aim of the study was the rate of complete stone extraction within 10 minutes. The rate of successful extraction within 10 minutes was 81.3% (74/91) in the basket group and 83.9% (78/93) in the balloon group (p = 0.7000). The complication rate was 6.6% in the basket group as compared to 11.8% in the balloon group (p = 0.3092). The complications included bleeding, pancreatitis, and cholangitis.

Ekmektzoglou et al. reported a randomized control trial from Greece.³⁵ It was a noninferiority study with 180 patients randomized into balloon and basket groups. The study primarily looked at the complete bile duct clearance rate with each method. 69 out of 82 patients (84.1%) achieved complete clearance in the basket catheter group compared to 79 out of 84 patients (94%) in the balloon catheter group (p = 0.047). The time required for clearance was shorter in the balloon group than the basket group. The study concluded that the balloon extraction was noninferior to basket stone extraction (OR 3.35, 95% CI [1.12, 10.05], P = 0.031). Takeshita et al. conducted a retrospective cohort study that primarily investigated the rates of post-ERCP pancreatitis.³⁶ 244 cases were divided into the group that used a retrieval balloon as the first choice (n =107) and a group that used a basket catheter as the first choice (n = 137). The groups were further subdivided into one device group and a multiple-device group. 104 cases achieved complete stone removal by only using a balloon, and 88 cases had complete stone removal by only using a basket catheter. 5/104 had pancreatitis in the balloon only group compared with 3/88 in the basket only group (4.8% vs. 3.4%; P = 0.73). The sub-analysis revealed that the use of additional extraction balloon was significantly higher than that of a basket catheter, suggesting that the complete stone retrieval rate using a single device was higher with an extraction balloon than the basket catheters. The study concluded that the choice of the device did not affect PEP occurrence. Gbreel et al. conducted a meta-analysis comparing balloon extraction and basket extraction.³⁷ The primary outcomes were divided into efficacy, including time to complete clearance, complete clearance, and clearance according to the number of stones. The secondary outcomes included pancreatitis, bleeding, perforation, and cholangitis. The analysis comprised 728 patients over four studies. The results revealed that the balloon catheter was better than the basket catheter in terms of incomplete bile duct clearance (RR = 0.91, 95% CI [0.85, 0.98], P = 0.01). It also found that the balloon catheter was better than basket for clearance of less than four stones (RR = 0.91, 95% CI [0.85, 0.99], P = 0.02) with no significant difference noted for more than four stones (RR = 0.77, 95% CI [0.48, 1.24], P = 0.29). The analysis concluded that a balloon catheter is better than a basket catheter for complete clearance with no significant difference in safety outcomes. A summary of all the included studies is shown in Table 5.

Adverse Effects

Extraction Balloons

Multiple adverse events can happen when using the extraction balloons. The most common is balloon rupture if pushed hard against the stone, although this is unlikely to cause actual patient injury. The other common complication is the impaction of the stone. The inflated balloon can get deformed alongside the stone and can slip out, leaving the stone impacted at the lower end of the common bile duct or the level of the papilla. The stone should be pushed proximally using accessories like forceps or the balloon itself to free the impacted stone. Alternatively, the sphincterotome can be used to extend the sphincterotomy, potentially liberating the stone. Another method is to use the needle knife to cut the bulging portion in the duodenum to free the stone from the bile duct. However, the balloon can be used if the stone is impacted at the distal bile duct but not the papilla. The inflated balloon is placed below the impacted stone, and the contrast is injected under pressure to push the stone proximally. Once the stone is freed, other therapies can be pursued to help in extraction. If the stone cannot be liberated, stenting should be done to provide adequate bile drainage to prevent cholangitis. The indwelling guidewire can be used to operate the balloon to maintain biliary access in case of failed extraction to ensure adequate drainage.

Extraction Basket

The most common adverse event while using the extraction basket is the migration of stones into the intrahepatic ducts. The stones in the bile duct can migrate proximally into the intrahepatic ducts. Therefore, capturing the stone from the intrahepatic duct can be challenging. Once this happens, balloon extraction should be used instead. A guidewire is used, and the required segment is cannulated. The wire is advanced into the intrahepatic duct, and the balloon is advanced over it. The balloon is then inflated proximal to the stone and pulled gently to bring the stone into the common hepatic duct or bile duct.

Further attempts can be made by balloon extraction or basket extraction to remove the stone. Although the basket can be used over the guidewire, the manipulation is difficult within the bile duct because of the basket’s stiffness and narrow diameter of the bile duct. In cases where it is difficult to extract the stone from the basket, care should be taken to avoid impaction. In this scenario, the basket is advanced proximally into the bifurcation zone of the duct and opened to free the stone as the wires open up. Once the stone is disengaged from the basket, the basket is closed gently and pulled back to avoid engaging the stone again. Once it is closed, it can be pulled out. However, the stone extraction would need further intervention with balloon extraction or lithotripsy.

The other complication of the basket extraction is the impaction of the stone in the bile duct or at the level of the papilla. This could occur due to large size of the stone, small exit passage (inadequate sphincterotomy), or inability to enlarge the sphincterotomy. In rare cases, the stone and basket impaction can happen at the level of the head of the pancreas. This occurs because of the narrow distal common duct. This would need emergent intervention involving lithotripsy to prevent complications. Emergent mechanical lithotripsy may be done using Soehendra lithotripter to either crush the stone or break the wires of the basket to allow its release.

Conclusion

Bile duct stones should be removed, even if asymptomatic, due to the high risk of obstruction, cholangitis, and pancreatitis. The biliary system is accessed via the sphincterotomy and sphincteroplasty. Basket and balloon catheters help remove most stones up to 1.5 cm in diameter. The use of guidance wire allows for proper access to the intrahepatic system, thus facilitating the removal of intrahepatic stones or migrated stones. Stones above a biliary stricture require balloon dilation of the stricture before successful removal. Mechanical lithotripsy is employed to break large stones and stones above a stricture to facilitate removal.

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