Autologous Blood Pleurodesis in a Great Dane with a Persistent Spontaneous Pneumothorax Margaret F Winter Clinical advisor: Dr. Jill DiFazio Basic science advisor: Dr. James Flanders Senior Seminar Paper Cornell University College of Veterinary Medicine April 23, 2014 Spontaneous pneumothorax—Persistent pneumothorax—Pleurodesis—Pleural port—Blood pleurodesis—Sclerosing agents Abstract A spontaneous pneumothorax is the accumulation of air in the pleural space without an inciting iatrogenic or traumatic event1. In the last decade there has been a shift from managing canine spontaneous pneumothorax medically to managing it surgically, due to evidence that there is recurrence in 53% of medically managed cases and only 12% of surgically managed cases2. The need for a second-line treatment if surgery fails or is not an option has resulted in several novel alternatives such as modified vascular access ports known as pleural ports, autologous blood pleurodesis, and chemical pleurodesis using sclerosing agents. Case History A 7 year old, spayed female, Great Dane was referred to Cornell University’s Hospital for Animals’ emergency service for further work-up and treatment of a spontaneous pneumothorax. The patient had been boarding at a kennel when, 3 days prior to presentation, she started to become tachypneic with increased respiratory effort. She was sent to a referral hospital, where radiographs revealed a bilateral pneumothorax and diffuse interstitial pattern. After thoracocentesis yielded greater than 1 liter of air from each hemithorax, the patient had bilateral Mila chest tubes placed, was put on continuous suction, had bilateral intranasal cannulas placed for oxygen supplementation, was maintained on IV antibiotics and analgesia over night, and was referred to Cornell the following day. The patient’s past medical history included a GDV with gastropexy, a left cruciate repair, severe pododermatitis, self mutilation of her left hind foot, a suspected tachyarrhythmia, a suspected chylothorax, chronic gastrointestinal signs and a 2.5 year history of significant weight loss. 2 Clinical Findings On presentation at Cornell, the patient was tachycardic and tachypneic with decreased bronchovesicular lung sounds dorsally. She was under-conditioned (BCS of 3/9) with moderate, diffuse muscle atrophy, severe medial buttress bilaterally, was short strided in all four limbs, had all of her claws scuffed down to distal P3, and pododermatitis in all four paws. Point of care blood work was unremarkable, her SpO2 was 97% on room air, and her tachycardia improved after receiving 0.1mg/kg methadone IV and removing a total of 2.7 liters of air and 20 mL of pleural effusion. In-house cytology of the effusion revealed non-degenerate neutrophils, lymphocytes, and mesothelial cells. No further initial blood work was performed because the prior day’s results were normal at the referring veterinarian. The patient’s problem list included 1) bilateral spontaneous pneumothorax, 2) diffuse pulmonary interstitial pattern on thoracic radiographs, 3) mild, sterile, suppurative pleural effusion 4) severe generalized muscle atrophy, 5) abnormal gait, and 6) pododermatitis. Differential Diagnoses The differential diagnoses for canine spontaneous pneumothorax can be prioritized somewhat by signalment. With an older, large breed patient, bullous emphysema (ruptured bullae) and neoplasia would be the greatest concerns, with migrating foreign bodies and infectious processes such as D. immitis, Paragonimus pulmonary cysts, and pneumonia being possibilities as well. This patient’s diffuse pulmonary interstitial pattern was likely a result of atelectasis, but further diagnostic tests are necessary to rule out pneumonia, hemorrhage, and immune mediated disease. The last major thoracic problem, pleural effusion, has a large list of differential diagnoses that requires basic fluid analysis (total protein and cell composition) to 3 narrow it down. Only cytology to identify cells and bacteria was initially performed on this patient, therefore further test results are required. The remaining problems (severe generalized muscle atrophy, abnormal gait, and pododermatitis) were considered secondary problems that were not explored further due to the owner’s wishes. Diagnostic and Therapeutic Plan After a night of stabilization and supportive care, which included fluid therapy, continuous suction, analgesia, gastroprotectants, and anti-microbial therapy, the patient had left stifle radiographs performed to rule out a neoplastic cause for such profound medial buttress. The radiographs revealed osteoarthritis, so the patient was put under general anesthesia for advanced imaging to assess the pneumothorax. Thoracic CT revealed a small amount of air in each hemithorax, 5-6 small gas filled bullae in the right caudal lung lobe, and a narrow vertebral canal with mild spinal cord compression at C5-6 and C6-7. Based on these results, an exploratory thoracotomy with partial right cranial and accessory lung lobectomies was performed and the Mila chest tubes were replaced with bilateral thoracostomy tubes. Histopathology of the lung tissue confirmed the presence of pulmonary emphysema and multifocal bullae- changes consistent with spontaneous pneumothorax. Postoperative Complications- Treatment and Outcome Postoperatively, the patient’s thoracostomy tubes were checked every 2 hours. The patient produced a moderate amount of serosanguinous effusion and a small amount of air intermittently. After 3 days, the patient became tachypneic again and several hundred milliliters of air were removed from her chest. No leaks in the tubes could be found and the pleural fluid 4 was submitted for analysis and culture, revealing a sterile, non-chylous, exudate with many nondegenerate neutrophils. After four days of hospitalization, the patient’s owner wanted to treat palliatively at home, so a pleural port was placed under general anesthesia in the left 8th intercostal space. The following day, several hours prior to being discharged from the hospital, autologous blood pleurodesis was performed as a final attempt to stop the persistent pneumothorax. A closed system was created between an 18 gauge jugular catheter and a thoracostomy tube using 2 extension sets, 2 three-way stopcocks, and a 30mL syringe. 4.2mL/kg (250mL) of blood was instilled into the right thoracostomy tube and the patient was rolled several times to distribute the blood throughout the thoracic cavity. After this procedure, the patient’s remaining thoracostomy tube was removed from the right chest wall, her temperature was monitored frequently, and several hours later, without any post-procedural complications, she was discharged to the care of her owner. The following month after discharge from the hospital, the patient exhibited no respiratory problems or difficulties and no need for tapping her pleural port. However, she returned to her local veterinarian for hyperthermia (103°F), progressive weight loss, anorexia, lethargy, and a urinary tract infection refractory to antimicrobial therapy. Initial diagnostic tests revealed a mature neutrophilia and scant pleural effusion. Beyond this, no other information could be ascertained and the patient was lost to follow up. Discussion In both human and veterinary medicine, spontaneous pneumothorax is often a recurrent problem that lacks reliable and definitive treatment options1-3. As a result, numerous treatments 5 have been utilized in varying ways and dosages, but without randomized, prospective studies validating or refining their usage. For many years, canine spontaneous pneumothorax had been treated according to human guidelines, which describe thoracocentesis and rest as the standard of care2,3. However, recent studies have shown that dogs with spontaneous pneumothorax respond to various treatment modalities differently from humans2. This is exemplified by the Puerto et al. study, which showed that, unlike humans, dogs have a much higher rate of recurrence when spontaneous pneumothorax is treated medically instead of surgically2. Similarly, many studies suggest that humans are more responsive to pleurodesis than dogs and other animals based on the much lower recurrence rates observed in humans3-6. Despite the variable efficacy seen in dogs, several promising procedures and treatments have been adapted from human medicine, including the pleural port, autologous blood pleurodesis, and chemical pleurodesis with sclerosing agents. The use of pleural ports to manage persistent cases of spontaneous pneumothorax has been described in several dogs after surgery failed7. A pleural port is similar to a vascular access port used for chemotherapy, but it has a long, fenestrated catheter that sits in the pleural cavity. The port is placed subcutaneously in the 7th or 8th intercostal space and is accessed with a sterile 22 gauge Huber needle through surgically scrubbed skin. This device is intended to be used as a second line treatment if surgery has failed or is not an option. In one case report, two dogs refractory to surgical treatment had pleural ports placed 5 days after their unsuccessful surgeries. One of the dogs was tapped on an outpatient basis for 3 weeks, until the owner was able to acquire the money necessary for a second surgery. Following the second surgery, the dog survived another 17 months before recurrence of the spontaneous pneumothorax and subsequent euthanasia. The other reported dog was tapped on an outpatient basis via the pleural port until resolution of the pneumothorax, which occurred within two weeks. The dog continued to do well 6 for at least another 23 months before being lost to follow up. In both cases, the dogs’ lives were extended substantially as a result of using a pleural port for palliative care when surgery was unsuccessful7. The Great Dane discussed in this case report was also, to some extent, successfully managed with a pleural port. While it was not needed for removing air or fluid, the port enabled the dog to go home for whatever remaining time she had left. Autologous blood pleurodesis is another treatment alternative for persistent spontaneous pneumothorax6,8. It is a simple and inexpensive treatment that involves taking the patient’s own blood and putting it into the pleural space. The mechanism of action is believed to be multifactorial and includes pleurodesis- an induced inflammatory reaction that creates adhesions between the visceral and parietal plurae so that the pleural space is obliterated, leaving no room for air to accumulate. However, some patients see results within minutes to hours of the procedure, so in addition to promoting adhesion formation, it is thought that the blood acts as a Bandaid™ and clots over the leaking bullae/blebs in the lungs8. There have been several case reports and studies in both humans and animals that have documented the successful use of autologous blood pleurodesis, but there are still many knowledge gaps in the technique, dose of blood, adverse reactions, and so forth. In general, most literature suggests using 2-5mL/kg of autologous blood for successful results3,5,8,9. A study performed on rats determined that 23mL/kg of autologous blood reliably produced adhesions, and that unsuccessful studies likely used an insufficient volume of blood9. One such study used rabbits as the test subjects, and found autologous blood pleurodesis to not be a successful treatment modality; however, this study used a low dose of 1mL/kg of blood6. A case report of a dog with persistent pneumothorax was treated successfully using 5mL/kg of blood without any adverse reactions8. Human literature cites fever as the most common adverse reaction to autologous blood pleurodesis, but this has not been 7 reported in dogs8. Despite not being reported, since it occurs with some frequency in humans, it would be a wise practice to monitor the temperature of dogs for a few hours after the procedure. The patient in this case report was sedated with a low dose of butorphanol, treated with 4.2mL/kg of autologous blood, rolled a few times to distribute the blood evenly, and monitored closely for hyperthermia afterwards. She responded well to the procedure with no adverse side effects, and her pneumothorax resolved clinically for at least a month. One of the most common methods of pleurodesis in human medicine is chemical pleurodesis. Sclerosing agents are put into the pleural cavity to elicit an inflammatory response, like with blood pleurodesis. Historically, tetracycline was used most frequently, but it is no longer available in a form conducive to pleurodesis, so other antibiotics such as doxycycline or minocycline have been used3. Several human and animal studies have reported successful pleurodesis with these two agents, however they are associated with more systemic effects, severe pain, and prolonged hospitalization when compared with other pleurodesing agents such as autologous blood and talcum powder3,6. Silver nitrate has also shown some promise based on a rabbit study, but there were serious side effects such as hemothorax and atelectasis, so further studies need to be conducted with this agent3. The most effective and inexpensive sclerosing agent in humans is talcum powder3. Talc can be instilled into the pleural space either as a slurry through a thoracostomy tube or as a poudrage during a thoracotomy or thoracoscopy- a human prospective study comparing these two methods found no difference in recurrence rates4. While the success of talc pleurodesis in humans is about 87%, animals have a much more variable and unreliable response3. Studies across several species including dogs, pigs, rabbits, and humans have found highly variable results and ideal dose to use, suggesting that the dose of talc for pleurodesis may be species 8 specific and vary from 70mg/kg up to 400mg/kg4,6. Even though it is considered the superior agent for pleurodesis, talc is associated with greater adverse effects than blood. Chest pain and fever are the most reported side effects, but acquired respiratory distress syndrome (ARDS) and acute respiratory failure were reported in 0.15% of patients treated with talc poudrage3. Conclusion The treatment of choice for canine spontaneous pneumothorax is surgery, but if surgery fails or is not an option pleural ports, autologous blood pleurodesis, and chemical pleurodesis are all viable treatment options. To further elucidate which of these alternatives is best and how to maximize their therapeutic success, more randomized prospective studies need to be conducted. 9 References 1) Smith S, Byers C. Spontaneous Pneumothorax Compendium 2009; 11.3:5-11. 2) Puerto D, Brockman D, Lindquist C, et al. Surgical and non-surgical management of and selected risk factors for spontaneous pneumothorax in dogs: 64 cases (1986-1999). J Am Vet Med Assoc 2002; 220:1670–1674. 3) Tschopp J, Rami-Porta R, Noppen M, Astoul P. Management of Spontaneous Pneumothorax: State of the Art. Eur Respir J 2006; 28.3:637-650. 4) Jerram R, Fossum T, Berridge B, Steinheimer D, Slater M. The Efficacy of Mechanical Abrasion and Talc Slurry as Methods of Pleurodesis in Normal Dogs. Vet Surg 1999; 28.5:322-332. 5) Oliveira, Frederico H, Cataneo D, Ruiz R, Cataneo A. Persistent Pleuropulmonary Air Leak Treated with Autologous Blood: Results from a University Hospital and Review of Literature. Respiration (2010); 79.4:302-306. 6) Mitchem R, Herndon B, Fiorella R, et al. Pleurodesis by Autologous Blood, Doxycycline, and Talc in a Rabbit Model. Ann Thorac Surg 1999; 67:917-921. 7) Cahalane, Kosanovich A, Flanders J. Use of Pleural Access Ports for Treatment of Recurrent Pneumothorax in Two Dogs. J Am Vet Med Assoc 2012; 241.4:467-471. 8) Merbl Y, Kelmer E, Shipov A, et al. Resolution of persistent pneumothorax by use of blood pleurodesis in a dog after surgical correction of a diaphragmatic hernia. J Am Vet Med Assoc 2010; 237:299–303. 9) Ozpolat B, Gazyagci S, Gozubuyuk A, et al. Autologous Blood Pleurodesis in Rats to Elucidate the Amounts of Blood Required for Reliable and Reproducible Results. J Surg Res 2010; 161:228-232. 10