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Endotracheal Stent Granulation Stenosis Resolution after Colchicine Therapy in a Dog

Authors


Corresponding author: Sara A. Brown, DVM, VCA Veterinary Referral Associates, 15021 Dufief Mill Road, North Potomac, MD 20878; e-mail: sara.brown@vcamail.com

A 6-year-old, 6.1-kg, spayed female Yorkshire Terrier presented for persistent coughing, wheezing, and productive expectoration. The patient had several previous episodes of dyspnea, stress-induced collapse, and cyanosis. Severe tracheal collapse was diagnosed based on clinical presentation, comparative inspiratory and expiratory lateral thoracic radiographs, and tracheoscopic evaluation (Fig 1). Owing to the severity of disease and clinical signs, intraluminal tracheal stent placement was recommended. Pre–stent placement CBC and serum biochemistry were within normal limits. A 12 × 77 mm woven nitinol stenta was placed under fluoroscopic guidance to span the collapsing tracheal segment from the 3rd cervical vertebra to the 4th rib. The patient recovered uneventfully from anesthesia and was discharged from the hospital 2 days after stent placement. Post–stent placement medical therapy was directed at decreasing airway inflammation and cough-induced airway injury and consisted of a tapering dose of prednisoneb (0.4 mg/kg PO q12h for 7 days, then 0.4 mg/kg PO q24h for 7 days, and then 0.4 mg/kg PO q48h), butorphanolc (0.4 mg/kg PO up to q6h), and a 2-week-course of amoxicillin-clavulinic acidd (10.25 mg/kg PO q12h).

Figure 1.

 Pre–stent placement image showing tracheal collapse.

The patient was rechecked 7 weeks after stent placement. At this time, owners reported marked improvement in the patient's quality of life with some persistent coughing but no dyspneic episodes. Routine tracheoscopic examination was performed with a 2.7 mm 30 degree visual field rigid endoscope. Anesthetic induction and maintenance were accomplished with 4 mg/kg propofole IV followed by intermittent 1 mg/kg boluses IV. Oxygen supplementation was provided at approximately 2 L/min via the endoscopic biopsy port. Tracheoscopic findings indicated appropriate stent contact cranially and epithelialization of approximately 30–40% of the stent with some mucus trapping (Fig 2). Recommendations at discharge included nebulization therapy, continuation of prednisone and butorphanol at previous dosages, and a 30-day course of doxycyclinef (7.5 mg/kg PO q24h) for bacterial infection prophylaxis because of the mucous trapping. Follow-up conversations after 2 and 4 weeks indicated intermittent dry coughing but good stamina and no observed dyspnea.

Figure 2.

 Progressive epithelialization of the proximal stent 7 weeks after placement.

Recheck evaluation and tracheoscopy were repeated 24 weeks post-stent placement. When questioned, owners reported worsening of cough, an audible wheeze, productive mucus expectoration, and intermittent episodes of dyspnea. The patient's weight had increased to 7.4 kg and she was being treated at home with prednisone (0.17 mg/kg PO q48h) and butorphanol (0.17 mg/kg PO q12h). CBC, chemistry, and urinalysis indicated mildly increased alkaline phosphatase activity (136 U/L; reference range, 5–131 U/L), thrombocytosis (589 × 103/μL; reference range, 170–400 × 103/μL), and proteinuria (3+; reference range, negative), all of which were attributed to chronic corticosteroid therapy. Tracheoscopic examination disclosed fixed granulation tissue causing stenosis at the proximal edge of the stent (Fig 3), focal granulation mass proliferation in the middle region of the stent, and progressive epithelialization throughout the stent. Periendoscopic medications included dexamethasone sodium phosphateg (0.2 mg/kg IV) and butorphanol (0.2 mg/kg IV). Supplemental oxygen therapy was provided during recovery and was gradually withdrawn over 12–24 hours. The patient was discharged with no change in its prednisone and butorphanol dosages and a 30-day course of doxycycline (6.75 mg/kg PO q24h) and oral colchicineh therapy (0.03 mg/kg PO q24h). Recommendation was made for weight loss by limiting caloric consumption by 25%.

Figure 3.

 Granulation tissue and stenosis at the proximal stent 24 weeks after placement.

Recheck evaluation and tracheoscopic examination were as performed as described previously 40 weeks after stent placement. The patient's owners reported an intermittent dry cough but no dyspnea or exercise intolerance. Patient body weight was 7.1 kg, and current medications included colchicine (0.03 mg/kg PO q24h) and butorphanol (0.17 mg/kg PO q12h). Oral prednisone had been discontinued by the owners on week 27 because of patient weight gain and polyphagia. Tracheoscopic examination revealed complete resolution of the proximal stent granulation tissue (Fig 4), diminution of the stenotic tissue in the middle section, and progressive stent epithelialization. No changes were made to the patient's medical therapy. Follow-up tracheoscopic examination was performed 64 weeks post–stent placement and showed no visible granulation tissue with continued normal epithelialization. Further phone conversations indicated no change in patient condition or respiratory characteristics.

Figure 4.

 Resolution of proximal granulation tissue 40 weeks after stent placement, 16 weeks after the patient was started on oral colchicine.

Tracheal collapse is a common syndrome seen in middle-aged toy and miniature breeds, with toy and miniature Poodles, Yorkshire Terriers, and Pomeranians being most commonly affected.1–3 Dorsoventral tracheal ring flattening with dorsal membrane laxity results in dynamic or static obstruction of the tracheal lumen.1,2 Clinical signs of tracheal collapse include cough, which can worsen with excitement, exercise, tracheal compression, eating, or drinking.1 The ultrastructure of tracheal cartilage in affected breeds is hypocellular, with decreased glycoprotein, glycosaminoglycans, chondroitin sulfate, and calcium.1–3 Medical treatment options for tracheal collapse include the use of antitussives and anti-inflammatory doses of glucocorticoids to break the cycle of cough-induced airway irritation and treat underlying inflammation and edema, respectively.1–3 Antibiotic use is recommended when indicated on tracheal wash cultures, but they also are used empirically in many cases.1 Bronchodilators have been recommended, but bronchoconstriction may not play an important role in clinical disease.1,2 When clinical signs are not well controlled with medical therapy or the severity of disease is potentially life threatening, surgical intervention may be considered. External prosthetics, intraluminal stents, corrective chondrotomy, and plication of the dorsal tracheal membrane all have been described, but no one procedure has been without complication.1–4

Self-expanding metallic stents are gaining popularity in human5–7 and veterinary medicine8,9 because of their ease of insertion and lack of invasiveness compared with other surgical techniques. The introduction of endotracheal stents has inherent risks such as tracheal perforation, stent misplacement, and bleeding.8,9 Reported postoperative complications of stent placement include stent fracture, collapse, migration, retention of secretions, coughing, pneumonia, granulation tissue formation, ulceration of the tracheal epithelium, and acute pulmonary edema.6,8–11 A well-documented complication of stent placement in human patients is eventual formation of granulation tissue and stenosis of the tracheal lumen.5,6,10

Two variations of metal, self-expanding endotracheal stents have been used in veterinary medicine. These include a woven cobalt-based alloy filament with silicon covering and uncovered metallic ends (Wallstent) and a nickel titanium alloy (nitinol) stent (Ultraflex or Vet-Stent). Nitinol stents are composed of highly flexible metal allowing close adherence to normal tracheal conformation and less tracheal erosion and migration.9 Disadvantages of metallic stents include removal difficulty once the stent has epithelialized and the propensity to develop excessive granulation tissue secondary to substantial local reaction.5,11

Histologic evaluation of tracheal tissue 4 weeks after nitinol stent placement in the trachea and bronchus of normal dogs revealed substantial tissue proliferation and fibrosis, chronic lymphocytic, eosinophillic and neutrophillic inflammation, edema, and hemorrhage. The histopathologic changes resolved 2 weeks after stent removal.11 In humans, tissue granulation is more likely to occur in patients that have tracheal inflammation or compromise at the time of stent placement.6,10 Formation of tracheal granulation tissue may lead to failure to clear secretions, atelectasis, airway obstruction, respiratory distress, and eventual stent removal in humans.6

Research into prevention and management of fibrosis after tracheal surgical intervention has been reported in the human medical literature. Rabbit research models of tracheal reconstruction with autografts showed that the use of topical vascular endothelial growth factor decreased tracheal granulation tissue formation, inflammation, and anastomotic fibrosis.12 This decrease in granulation tissue was not appreciated after intraluminal stent placement in a later model.13 Clinically, mitomycin-C, an antimetabolite that inhibits fibroblast proliferation, has been used topically with some success in human pediatric patients with tracheal scarring and stenosis after reconstruction surgery.14 Ablation with Nd-YAG or CO2 laser and dilating and coring with a rigid bronchoscope in human patients with tracheal stenosis or tumor ingrowth have been used with some success.6,7,15

The use of colchicine to prevent or manage tracheal granulation tissue has not previously been reported in human or veterinary patients. An alkaloid that binds microtubules and inhibits their polymerization, colchicine interferes with cell shape, migration, chromosomal translocation during mitosis, and the transport of extracellular macromolecules. By inhibiting microtubule assembly, colchicine inhibits proliferation of fibroblasts and other protein synthesizing cells and disturbs the synthesis and secretion of collagen.16,17 Experimentally, colchicine also stimulates production of tissue collagenase.18,19 Colchicine also has anti-inflammatory effects, which may contribute to its antifibrotic effects. Relatively high concentrations accumulate in leukocytes20 and inhibition of leukocyte chemotaxis, adhesiveness, amoeboid motility, mobilization, and degranulation of lysozymes have all been reported.16,17

Colchicine is used chiefly in the treatment of gout in humans, but it is also used for other inflammatory diseases such as familial Mediterranean fever, hepatic fibrosis, amyloidosis, and various skin diseases.16,17 Veterinary use previously has previously been limited to treatment of hepatic fibrosis19 and amyloidosis.21 Colchicine has a relatively narrow therapeutic index in human and veterinary patients.17,22 Oral dosages of <0.5 mg/kg can cause gastrointestinal upset in dogs; dosages 0.5–0.8 mg/kg have been associated with bone marrow aplasia and alopecia, and dosages greater than 0.8 mg/kg have been associated with mortality from shock, multiple organ failure, or cardiopulmonary arrest.22 The lowest lethal oral dosage reported for dogs is 0.13 mg/kg.22 Colchicine is known to be excreted by the kidneys and metabolized by the liver in rats and humans and should be used with caution in patients with hepatic or renal disease.16,17

The placement of self-expandable endotracheal stents can provide relief of the clinical signs of tracheal collapse in dogs, but the chronic inflammation present in the trachea of these dogs may predispose to tissue proliferation and life-threatening complications. The therapeutic response observed in this patient was attributed to oral colchicine administration; however, an effect of the concurrent doxycycline therapy cannot be excluded. Besides the antimicrobial activity of tetracyclines, they also have been reported to exhibit myriad anti-inflammatory properties and may be useful in the treatment of pathologic conditions in which acute or chronic inflammation is involved.23–24 Doxycycline specifically has been shown experimentally to inhibit inflammation, edema, fever, cell migration, and formation of fibrovascular tissue.25 Further investigation into the use of colchicine in these cases may prove it to be useful in long-term maintenance of intraluminal stents in dogs with tracheal collapse.

Footnotes

aNitinol Stent, Infiniti Medical LLC, West Hollywood, CA

bPrednisone, Vintage Pharmaceuticals Inc, Charlotte, NC

cButorphanol, Fort Dodge Animal Health, Fort Dodge, IA

dClavamox, Glaxo Smith Kline, Research Triangle Park, NC

ePropoflo, Abbott Laboratories, N. Chicago, IL

fDoxycycline, Mutual Pharmaceutical Co, Philadelphia, PA

gDexamethasone Sodium Phosphate, Phoenix Scientific Inc, St Joseph, MI

hColchicine, West-ward Pharmaceutical Corp Eatontown, NJ

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