Biliary Stenting: old problems & new challenges

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take advantage of it. Barb in Texas

Biliary

stenting: old problems and new challenges.

F Binmoeller, 22 May 2006

A

new era in therapeutic endoscopy began with the first

endoscopic biliary stent placement by Soehendra in 1979, 5 years after the first sphincterotomy. Today the

technique of biliary stenting has been standardized

and the indications for biliary stenting have

expanded. A vast array of stents are available.

Although

expandable stents have become the standard in interventional radiology and

cardiology, plastic stents continue to dominate in biliary endoscopy

for 2 reasons: lower cost and the ease of stent exchange if clogging occurs. However, plastic stents continue to be limited by clogging

and migration. Expandable metal stents are less prone

to clogging, but stent-ingrowth and overgrowth limit patency. Migration of expandable

stents is uncommon, but at the trade-off of permanency.

The

new challenges in biliary stenting include the

development of removable expandable stents and biodegradable stents. The development of stents that deliver therapeutic agents

presents further challenges. We can learn from our

interventional colleagues in cardiology, who are already using a spectrum of

novel expandable stents.

Plastic

stents are affordable, but clog after 3 to 4 months. The

mechanisms that lead to clogging are still not understood. The

initial event is thought to be the adherence of a biofilm

of bacteria along the inner surface of the stent. Subsequently,

glycocalix formation by the bacteria forms a gel-like

biofilm protecting them from antibiotics, the immune

system, and shearing effects of bile flow.

Additionally,

Escherichia coli, the most

commonly found microorganism in sludge, can produce beta-glucuronidase,

which can deconjugate bilirubin-glucuronide,

which results in the precipitation of calcium bilirubinate. An increase in biofilm with

trapping of insoluble crystals, cellular debris, and refluxed duodenal debris

ultimately leads to stent occlusion.

There

have been numerous strategies developed to retard or prevent stent clogging

which include increasing stent diameter, prophylactic administration of

antibiotics, stent impregnation with antibiotics, administration of drugs that

alter bile (e.g., ursodeoxycholic acid), stent

placement entirely within the bile duct with an intact sphincter of Oddi and modifications of stent design. The

only strategy proven to increase stent patency is the

use of larger-diameter stents.

Several

randomized trials comparing Teflon stents without side holes (Tannenbaum stent) with standard polyethylene stents with

side holes have not shown improved patency rates. A recent multicenter US study

showed similar implantation success and complication rates for both stents.

Proximal

or distal stent migration, described in 5 to 7% of patients after placement of

a plastic biliary stent, can result in various complications, including cholangitis, ulceration, bleeding, and perforation.

Duodenal

wall ulceration and perforation resulting from pressure necrosis may occur

following placement of straight prostheses with a long distal intraduodenal part. Impaction and

perforation of the gut in sites distant from duodenum (especially at the level

of sigmoid diverticula) have been reported.

With

proximal migration, distal perforation of the common bile duct by the distal

tip can occur. Bile duct fistulas have been reported

secondary to proximal stent migration.

Pigtail

stents, the standard in other disciplines where plastic stents are used

(urology, interventional radiology) fell out of favor after studies showed

higher rates of clogging compared with straight stents. However,

pigtail stents afford superior anchorage and rarely cause the tissue injury

seen with migration of straight stents.

Other

complications from plastic stent insertion include post-ERCP pancreatitis and cholecystitis. Placement of a large diameter biliary stent without

previous sphincterotomy may cause relative

obstruction of the pancreatic orifice at the papilla, causing pancreatitis. This has been an

argument for performing a sphincterotomy with stent

placement, especially when placing intrahepatic stents. Cholecystitis is a rare complication after plastic stent

placement.

The

observation that an increase in stent diameter produces increased patency rates led to the development of expandable metal

stents. Randomized controlled trials comparing

expandable metallic stents with plastic stents have demonstrated significantly

lower rates of stent obstruction and cholangitis.

Nonetheless,

expandable stents will occlude after a period of time, mainly due to tumor ingrowth and/or overgrowth, mucosal hyperplasia induced by

a chronic inflammatory reaction to the stent mesh, biliary sludge, and food

impaction at the duodenal end of the stent.

Stent

integration into the wall of the bile duct plays an important role in

prevention of stent migration. However, the trade-off

is permanency. This has resulted in the restriction of

expandable stents to unresectable malignant

strictures.

Manufacturers

have developed and marketed a variety of expandable stents. They

differ in the physical properties by virtue of wire material, gauge,

configuration, and their delivery systems. The stents

shorten to varying degrees.

Despite

the proliferation of stent types over the past decade, the classic open mesh

stainless steel Wallstent remains the predominant

stent used. Most of the published literature has also

utilized this stent.

In

a Korean multicenter study the cumulative rates of Wallstent patency after 3, 6, and

12 months were 84%, 56%, and 44%, respectively. The

stent patency rate was found to be linked to the

severity of the stricture, gauged by the difficulty passing different caliber

instruments through the stricture before stent placement. Easy

passage of larger-diameter catheter before stent placement was predictive of

long-term relief of obstruction. The time course of

stent expansion was also a key factor for the prediction of stent patency. regression analysis

showed a significantly longer patency for stents with

rapid (<24 hour) expansion.

The

use of covered expandable stents has been proposed to inhibit tumor ingrowth. Anecdotal experience

supports this, but published data are scant.

Using

the covered Wallstent - currently the only

commercially available covered expandable stent in the United

States - Isayama et al

reported an occlusion rate of 14% due to tumor overgrowth above or below the

edges of stent, but no tumor ingrowth .

Sludge

accumulation was observed, but did not result in stent occlusion. Stent migration was not observed. There

were 2 cases of cholecystitis and 1 case of pancreatitis that occurred within 7 days of stent

insertion.

Randomized

data comparing covered and uncovered stents are needed.

Future

research will focus on the development of removable expandable stents and

biodegradable stents.

Both

strategies will enable the use of expandable stents in benign disease. For malignant strictures, the development of stents that

deliver therapeutic agents may further enhance the palliative efficacy.

The

permanency of expandable metal stents has limited their application to patients

with malignant strictures who are deemed unfit for surgery, whether due to

inoperability or unresectability. A

removable expandable stent would broaden the indication to include benign

strictures. Furthermore, removability

will allow for error in deployment.

Expandable

stents made of plastic should be easy to remove. The

implantation of the first prototype expandable Teflon stent was reported by Huibregste in 1998. The stent was

made of Teflon with an acrylic resin that was dilated up to 18 Fr with a

balloon, then polymerized by the application of UV light. Although

successfully deployed in 3 patients, removability was

not evaluated and no further reports using this stent have followed.

A

biodegradable stent that disintegrates over a defined period of time in the

bile duct addresses the limitations of the permanency and long-term

complications associated with expandable metal stents. Specifically,

biofilm accumulation and proliferative

changes should be reduced.

A

biodegradable stent also relieves the patient of an additional procedure for

stent removal. In an editorial on biodegradable

coronary stents, Colombo and Karvouni elegantly summarized the biodegradable stent as

“fulfilling the missing and stepping away”.

Biodegradable

materials have been in use for 2 decades (sutures and orthopedics devices), yet

biodegradable stents have been slow to develop. Inadequate

radial strength, stent fracturing, and inflammatory responses to the

biodegradable material have been the major barriers.

In

1997, Fry and Fleisher implanted a coil spring expandable esophageal stent made

of a single wire of polyglycolide. The

stent lost expansile strength prematurely and

fractured proximally, occluding the esophageal lumen. The

fragments required endoscopic removal with an overtube.

A

report from Japan

describes the first experience using a poly-L-lactic

acid (PLLA) in coronary arteries. The stent is a

self-expanding coil made of a monofilament in a zigzag helical design that is

deployed using a balloon inflated with heated dye. The

stents were found to maintain good scaffolding strength for more than 6 months.

There

is work in progress on biodegradable biliary stents. A

PLLA stent (Microvasive) made of polymer strands

woven in a tubular mesh incorporates tantalum strands for radioopacity. Results in 50 patients were reported in a multicenter trial reported in abstract form (DDW 2001). The compression force of the stent was rated to good, but

the radial force was suboptimal, necessitating balloon dilation for expansion. Lumen obstruction was common due to stent fragmentation

and residue.

Another

biodegradable PLLA stent (BioStent, Bionx Implants) uses elastomeric

axial runners to provide radial force to the braided structure, eliminating the

need for balloon expansion. Abstract data suggested

excellent biotolerance without bile duct integration

or proliferative change in the porcine bile duct (DDW

2002).

As

a result of their scaffolding action, stents are an attractive platform for

delivering drugs locally. The

“therapeutic” effect may be the prevention of tumor-ingrowth in malignant strictures, mucosal proliferation in

benign strictures, and tumor ablation of ductal

malignancies.

Our

colleagues in interventional cardiology have a considered lead in the

development of drug-coated stents. In an animal model,

coronary stents coated with a polylactic acid polymer

releasing antithrombotic analogues with antiproliferative effects (hirudin

and the prostacyclin analogue iloprost)

were found to reduce coronary restenosis.

Preliminary

data in human subjects have shown impressive reduction of coronary restenosis with a stent coated with sirolimus

- a potent immunosuppressive agent that induces cell-cycle arrest (developed

for the prophylaxis of renal transplant rejection). Follow-up

studies have shown a sustained effect.

Trials

with stents releasing other cell cycle inhibitors such as actinomycin

D or metalloproteinase inhibitors are in the pilot stages. The

first studies exploring the use of drug-coated stents in the biliary tract are

emerging. In the porcine model Lee et al found that Paclitaxel

was effectively released in a buffer for more than 6 weeks after insertion of a

paclitaxel coated metal stent in the pig biliary

epithelium (DDW 2002).

A

further area of research in cardiology is focused on the development of

coronary artery stents with a special polymer coating that releases genetic

material into the stented arterial wall that inhibits

cell growth. Similar genes could be identified to

inhibit biliary mucosal hyperplasia or tumor proliferation.

Radioactive

stents for intravascular implantation were used as far back as 1995. Preliminary animal and clinical data suggest that

short-term, low-dose ionizing irradiation, delivered by a stent embedded with a

beta-particle emitter (half-life of 14 days) reduces neointimal

formation and stenosis by impairing smooth muscle cell proliferation.

In

a German study, Palmaz-Schatz stents were made

radioactive in a cyclotron (mostly beta particles). A

dose-dependent inhibition of neointimal formation and

smooth-muscle cell proliferation was observed. Radioactive

stents may impede mucosal hyperplasia in the biliary tract.

The

problem of stent clogging has driven research in biliary stent technology over

the past 2 decades. Expandable metal stents have

improved patency rates, but we are still in search of

the holy grail. Permanency, occlusion due to tumor ingrowth, and high cost have limited the application

of expandable metal stents to a minor subset of patients with malignant biliary

strictures.

Covered

expandable stents appear to improve patency rates,

but their application is restricted to distal CBD strictures.

Removable plastic expandable stents may expand the application of

expandable stents to benign strictures.

Biodegradable

stents offer the greatest hope for real progress. The

use of biodegradable materials with different degradation times can be tailored

to different indications.

Stent-coating

with pharmacologic agents and radioactive stents may further improve stent

function, and provide additional therapeutic benefits.