Proximal Duodenal Perforation in Three Dogs Following Deracoxib Administration

Introduction

The use of nonsteroidal antiinflammatory drugs (NSAIDs) to reduce discomfort and inflammation associated with elective orthopedic procedures has become ubiquitous in veterinary medicine.¹ These inflammatory mediators act by decreasing the conversion of arachidonic acid to prostaglandins and thromboxanes, and they have a myriad of other effects—both cytoprotective and potentially cytotoxic.^2–5 As a consequence, investigation into the specific functions of these mediators has been a primary aim of drug companies. Currently, a number of NSAIDs have specificity toward either or both arms of the cyclooxygenase pathway. These NSAIDs have demonstrated variable effects on different tissues and cell functions.^6–8

Typical adverse reactions seen with NSAID administration include the development of gastrointestinal ulcers and perforations, renal tubular damage, and coagulopathies. Adverse gastrointestinal events are commonly associated with all forms of NSAIDs.^5–8 These drugs exert their effects on the gastrointestinal mucosa by decreasing the levels of prostaglandin E₂ (PGE₂) and prostaglandin I₂ (PGI₂).7 These substances are important for mucosal health.^3,7

Deracoxib^a is a selective cyclooxygenase-2 (COX-2) inhibitor.^1,7 It has been associated with gastrointestinal perforation in dogs being treated for both chronic and postoperative pain when administered in conjunction with other antiinflammatory drugs or at doses higher than the approved label dosage.⁹

The purpose of the current report is to describe the clinical and gross pathological findings, treatment, and outcome of three deracoxib-treated dogs that subsequently developed proximal duodenal perforations and septic peritonitis.

Case Report

Gastrointestinal perforation was documented in three dogs following elective cranial cruciate ligament surgery at Flatiron Veterinary Specialists between October 2005 and January 2007. One dog was a 61-kg, 2.5-year-old, intact male Saint Bernard. The other two dogs were 10-year-old, castrated male Labrador retrievers—one weighing 37.8 kg and the other weighing 39.1 kg. No other dogs with NSAID-associated gastrointestinal perforation were presented during this period.

Preoperative blood work was not obtained for the Saint Bernard because of his young age and apparently healthy status. Results of complete blood counts and serum biochemical profiles were unremarkable in both Labrador retrievers. All three dogs were treated surgically with a tibial plateau-leveling osteotomy prior to development of septic peritonitis. Intravenous (IV) Normosol R^b crystalloid solution was administered at 10 mL/kg per hour during the surgical procedure. Following surgery, IV Normosol R crystalloid solution was administered at 2.5 mL/kg per hour for 12 to 24 hours.

The Saint Bernard was receiving no medications at the time of surgery. Following surgery, deracoxib (3 mg/kg per os [PO] q 24 hours for 7 days) was administered. Tramadol (3 mg/kg PO q 6 hours) and cephalexin (22 mg/kg PO q 8 hours) were also prescribed. The first Labrador retriever had been receiving deracoxib (2 mg/kg PO q 24 hours) for 21 days prior to surgery. Twenty-four hours after surgery, deracoxib (2.5 mg/kg PO q 24 hours for 7 days) therapy was reinstituted. Tramadol (3.5 mg/kg PO q 6 hours for 7 days) and cephalexin (20 mg/kg PO q 8 hours for 14 days) were also instituted after surgery. The other Labrador retriever had been receiving deracoxib (2.5 mg/kg PO q 24 hours) for 5 days prior to surgery and for 21 days after surgery. This dog developed an infection at the surgical site and consequently had been receiving the following medications at different times postoperatively: tramadol (3 mg/kg PO q 8 hours), cephalexin (15 mg/kg PO q 8 hours), amoxicillin (15 mg/kg PO q 12 hours), and enrofloxacin (10 mg/kg PO q 24 hours). No steroids or other NSAIDs were administered concurrently or perioperatively (14 days pre- or postsurgery).

In all cases, the first clinical sign seen was acute vomiting followed by anorexia and lethargy. The Saint Bernard began vomiting on the seventh day of deracoxib treatment. The first Labrador began vomiting 1 day after discontinuing deracoxib therapy. The second Labrador vomited after receiving deracoxib for 26 days.

The initial physical examination revealed dehydration, tachycardia, and abdominal discomfort in all three dogs. A fluid wave was palpable in one dog. Complete blood counts and serum biochemical profiles were obtained for both Labrador retrievers when they were presented for vomiting. Total white blood cell count was 23,000 for the first Labrador and 4100 for the second Labrador. Serum albumin concentrations were 2.8 and 2.5 g/dL, and blood glucose levels were 176 and 78 g/dL for the Labradors, respectively. Preoperative blood was pulled but not submitted, as the Saint Bernard died during surgery.

Abdominal radiographs demonstrated loss of serosal detail in the three dogs. Abdominocentesis and fluid cytology revealed degenerate neutrophils in all three dogs, with intracellular bacteria in two of the three.

Prior to anesthesia, all dogs were stabilized with IV crystalloids and colloids. Crystalloid therapy was based on the individual status of the dog. In general, 50 to 100 mL/kg was used for initial stabilization, with 20 mL/kg boluses administered as indicated by tachycardia (heart rate >140 beats per minute) and mean blood pressure (<60 to 80 mm Hg). Hetastarch^c was administered at 10 to 15 mL/kg q 24 hours. Exploratory laparotomy was performed in all dogs. Swabs of peritoneal fluid were collected for culture and sensitivity testing prior to administration of ampicillin (22 mg/kg IV q 8 hours) and enrofloxacin (10 mg/kg IV q 24 hours). Gross pathological findings in all dogs included free peritoneal fluid and discrete, proximal duodenal perforations immediately orad to the major duodenal papilla, near the mesenteric border. The edges of the ulcer were débrided and closed with simple interrupted, absorbable sutures of 4-0 polyglyconate.^d The entire abdomen was explored prior to peritoneal lavage with 200 mL/kg sterile 0.9% saline. A single Jackson-Pratt^e closed-suction drain was placed in all three dogs. During peritoneal lavage, the Saint Bernard went into cardiac arrest. Direct cardiac massage was instituted via a diaphragmatic incision, and resuscitation was successful. Just prior to abdominal closure, the dog rearrested. Cardiopulmonary resuscitation with cardiac massage was started, but we were unable to resuscitate the dog a second time.

Two of the three dogs recovered from anesthesia and surgery without complications. These two dogs were hospitalized for 7 days following surgery. Peritoneal cultures yielded Enterococcus spp. in one dog and beta-hemolytic Streptococcus spp. in the other. Postoperative serum albumin concentrations were 0.9 and 1.4 g/dL, respectively. One bottle (50 mL) of 25% human serum albumin was administered over 2 to 4 hours following surgery. The same albumin treatment was repeated 12 and 24 hours later in the first Labrador. Medications sent home for the owner to administer included famotidine (1 mg/kg PO q 24 hours), sucralfate (1 gram PO q 8 hours), amoxicillin (20 mg/kg PO q 8 hours), and enrofloxacin (10 mg/kg PO q 24 hours).

Discussion

The labeled drug dosage (1 to 2 mg/kg for chronic use, or 3 to 4 mg/kg q 24 hours for up to 7 days for postoperative analgesia) was followed appropriately in two out of three dogs receiving deracoxib in this cases series. Both of these dogs, as well as a third dog receiving a dosage higher (2.5 mg/kg for >7 days) than the approved dosage, developed duodenal perforations and septic peritonitis, just orad to the major duodenal papilla [Figure 1]. None of the dogs received another NSAID or steroid while on deracoxib. While the dogs reported here could have possibly had underlying gastrointestinal disease, which may have contributed to the development of duodenal perforation, it is unlikely given the normal preoperative clinicopathological findings and the lack of clinical signs.

Gastrointestinal perforation associated with inappropriate deracoxib administration has previously been documented.⁹ In that study, a higher incidence of duodenal perforation was seen in dogs treated for acute pain (7/14; 50%) when compared to dogs treated for chronic pain (3/15; 20%). These results suggest an increased risk for duodenal perforation in dogs being treated at higher dosages. In this case series, the first Labrador received deracoxib for 21 days at the approved dosage prior to surgery. The dosage was increased to 2.5 mg/kg q 24 hours for 7 days following surgery. This dosing regimen is interesting in that it combines a chronic dosage with a dosage just below that labeled for postsurgical pain. The current Food and Drug Administration-approved label makes no mention of dosing animals with postoperative pain that have been on deracoxib for chronic pain prior to surgery. Caution should be exercised when recommending dosages for postoperative pain in animals that have been on deracoxib prior to surgery.

It is well accepted that the use of NSAIDs at higher-than-approved dosages or in conjunction with other antiinflammatory medications such as corticosteroids can result in gastrointestinal ulceration and perforation.⁹ The exact cause of deleterious gastrointestinal effects associated with high doses of specific NSAIDs is unclear. Previous studies have demonstrated decreased levels of PGE₂ and PGI₂ at the level of the gastric mucosa.⁷ These substances are important for mucosal health and act to maintain mucosal blood flow, sodium bicarbonate, and mucous secretion.^3,7

Selective COX-2 inhibitors are designed to spare mucosal and renal protective prostaglandins while inhibiting prostaglandins associated with nociception.⁷ Many NSAIDs are considered to be COX-2 selective, such as deracoxib, carprofen, meloxicam, and etodolac. Carprofen and etodolac have been compared to nonselective NSAIDs and have been shown to induce significantly fewer gastrointestinal lesions following 4-week administration.⁶ Disparity exists among the individual effects of the COX-2-selective NSAIDs. For example, carprofen has been shown to have a lower frequency of gastrointestinal side effects when compared to other COX-2-selective NSAIDs, including meloxicam and etodolac.⁸

Previous studies have demonstrated an increased risk of gastrointestinal perforation when NSAIDs are administered with other antiinflammatory medications.^9,10 No dogs in this report received another antiinflammatory drug concurrently or during the defined perioperative period (14 days).

Vomiting is often the first clinical sign reported by owners of dogs with gastrointestinal perforation.⁹ All three dogs in the current study developed vomiting as the first clinical sign noticed by the owners. This finding is in agreement with a previous study in which vomiting was also found to be the first clinical sign in 23/29 (79%) of dogs that developed gastrointestinal perforation following NSAID usage.⁹

All three dogs developed duodenal perforation immediately orad to the major duodenal papilla. The incidence of gastrointestinal perforation in the duodenum is higher in dogs treated for acute pain compared to dogs treated for chronic pain.⁹ This study made no reference to the location of the perforation within the duodenum. In a retrospective study by Hinton et al, out of 16 dogs with spontaneous gas-troduodenal perforation, one case of proximal duodenal perforation was described.¹¹ The perforation was closely associated with the major duodenal papilla and required duodenojejunostomy (Billroth 1) and a biliary stent. None of the current cases required more than focal ulcer debridement and submucosal apposition [Figure 2].

The occurrence of biliary excretion of NSAIDs and their glucuronide products is well known.^12,13 Direct damage to the duodenal mucosa may possibly be a sequela to the use of NSAIDs. In fact, the reactive acyl glucuronides of diclofenac (an NSAID commonly used in humans) have been demonstrated to cause a significant increase in the frequency of small intestinal ulceration in rat models following bile transfer.¹⁴ The glucuronides are excreted into the bile and have electrophilic properties that allow them to disrupt enterocyte membrane proteins and potentially cause intestinal ulceration.^12–14 No studies, to our knowledge, have examined the biliary excretion fraction of deracoxib in dogs, so it is not known to what extent deracoxib is excreted in the bile.

Conclusion

This case series suggests that dogs receiving deracoxib at or above the recommended dosage should be monitored very closely for signs of duodenal ulceration, and inappropriate doses should be discontinued immediately. Any dog that develops vomiting and is receiving deracoxib should be evaluated carefully for duodenal ulceration and perforation. The finding of a duodenal perforation just orad to the major duodenal papilla in all three dogs is interesting and suggests that further studies evaluating the biliary excretion fraction and direct gastrointestinal mucosal effects of deracoxib and its metabolites are warranted.