Intrapleural Instillation of Qllinacrjne for Treatment of Recurrent Spontaneous Pneumothorax

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1 Intrapleural Instillation of Qllinacrjne for Treatment of Recurrent Spontaneous Pneumothorax Alberto J. Larrieu, M.D., G. Frank. Tyers, M.D., Edward H. Williams, M.D., Martin J. O'Neill, M.D., and John R. Derrick, M.D. ABSTRACT We used intrapleural instillation of quinacrine hydrochloride in patients (Group A) with recurrent spontaneous pneumothorax (one bilateral) and compared their clinical course with 9 patients who underwent thoracotomy and scarification or pleurectomy (Group B) and 3 patients treated by tube thoracostomy alone (Group C). In Group A, there was one complication of treatment, a pneumothorax immediately following tube removal, which necessitated repeat tube thoracostomy, and there was one late ipsilateral recurrence years after treatment. These patients with recurrent spontaneous pneumothoraces treated with intrapleurally administered quinacrine have been followed for from months to more than 4 years with only one late recurrence on the treated side. Eight patients in Group B had postoperative complications: patients who had had pleurectomy required reoperation for postoperative bleeding; lobar pneumonia developed in 3; had lack of total expansion of the lung; an intrathoracic hematoma developed in ; and an ipsilateral pneumothorax necessitating tube thoracostomy developed in. In Group C, the rate of recurrence of pneumothorax was 3% during the first year following treatment. Intrapleural instillation of quinacrine is a simple, low-risk, reliable, and effective treatment for recurrent spontaneous pneumothorax, and is equally as effective as thoracotomy and scarification. Spontaneous pneumothorax is a clinical entity resulting from a sudden, nontraumatic rupture From the Divisions of Cardiovascular and Thoracic Surgery, the University of Texas Medical Branch, Galveston, 'IX, and the Pennsylvania State University, Hershey, PA. We wish to acknowledge the careful preparation of this manuscript by Ms. Valerie Martin, and the assistance of Elbert B. Whorton, Jr., Ph.D., with the statistical analysis. Presented at the Twenty-fifth Annual Meeting of the Southem Thoracic Surgical Association, Nov -4, 98, Marco Island, FL. Address reprint requests to Dr. Tyers, Division of Cardiovascular and Thoracic Surgery, The University of Texas Medical Branch, Galveston, TX 55. of the lung. It occurs most often in young adults but also is seen in patients with chronic obstructive pulmonary disease. Its cause, therefore, can be idiopathic (the great majority) or secondary to other pulmonary diseases such as cystic fibrosis and tuberculosis. The most common complication of spontaneous pneumothorax is recurrence [lo]. The aim of the treatment of recurrent spontaneous pneumothorax has been obliteration of the pleural space, and open thoracotomy with pleural scarification has been shown to be effective [3,8, 9. However, this approach is associated with the hazards of general anesthesia and major operation, which may not be insignificant in high-risk patients. Although they are well accepted in the treatment of malignant pleural effusions [4,,, chemical irritants introduced through a chest tube have been used only in isolated instances to produce pleural adhesions in patients with recurrent pneumothorax. We have used the intrapleural instillation of quinacrine hydrochloride (Atabrine) for the treatment of spontaneous recurrent pneumothorax in patients ( pneumothoraces) and have compared their clinical course with 9 patients (9 pneumothoraces) who underwent thoracotomy and scarification ( patients) or pleurectomy ( patients) and with 3 patients ( pneumothoraces) treated by tube thoracostomy alone. The results form the basis for this report and for the proposal that intrapleurally administered quinacrine be considered as a simple, low-risk, effective treatment for recurrent spontaneous pneumothorax. Materials and Methods A total of patients with incidents of spontaneous pneumothorax treated from January, 9, to December, 9, at the University of Texas Medical Branch and the Milton S. Hershey Medical Center of the Pennsylvania 4 98 by Alberto J. Larrieu

2 .I4 Larrieu et al: Quinacrine Instillation for Recurrent Pneumothorax State University were reviewed for this study. Three treatment groups were compared. Group A was comprised of the patients treated with intrapleural instillation of quinacrine; Group B, the 9 patients who underwent thoracotomy and scarification or pleurectomy; and Group C, the 3 patients who received tube thoracostomy alone. Originally, -mg vials of sterile quinacrine hydrochloride powder were purchased from Winthrop Laboratories and diluted into 5 ml of sterile solution. However, because the parenteral form of the drug was discontinued, we are currently manufacturing the solution in the pharmacy of the University of Texas Medical Branch. Quinacrine hydrochloride powder is obtained from the Sigma Chemical Company, and the injectant is prepared aseptically using a clean fill procedure as follows: Sterile 5-ml vials are placed under a laminar flow hood and stripped of their outer metal covers. The quinacrine powder is aseptically weighed under the laminar flow hood. The rubber diaphragm is removed from each vial with sterile forceps and mg of powder is added. The powder-containing vials are then placed under a glass bell through which sterile nitrogen gas is passed. This replaces the air, reducing the possibility of aerobic bacterial growth. The rubber diaphragm is replaced on each vial, a new metal seal is crimped over it, and the vials are labeled. Representative samples are taken for pyrogen and sterility testing according to the standards of the US Pharmacopeia. The remaining vials are given an arbitrary expiration date, at which time the powder is checked to assure that the physical properties of the drug have remained intact. The procedure for the intrapleural instillation of quinacrine is as follows: After the air leak has stopped, mg of quinacrine in 5 ml of either 5% glucose or normal saline solution is injected by applying gentle pressure to a bulb syringe inserted into the unclamped chest tube. Care must be taken to maintain sterility and the air seal. The chest tube is then clamped for one hour during which time the patient s position is varied to ensure the spread of the solution. This process is repeated once daily for a total of four treatments; then the chest tube is removed. Once the powder is dissolved, it is stable in solution for approximately sixty hours, after which it gradually deteriorates to acridone, which is insoluble and precipitates. Results The age distribution of the patients is depicted in Table. Recurrent spontaneous pneumothorax affected those in the third decade most frequently. The mean age for each treatment group was almost identical: 3. f 8. years in Group A, 3.5 f. years in Group B, and 35.5 f 8. years in Group C (mean f standard deviation). Male patients predominated in a :l ratio. Distribution of pneumothoraces by side of collapse in the three groups is as follows: Group A had 4 (%) on the right side and (33%) on the left, with one instance of bilateral simultaneous collapse; Group B had (53%) on the right and 9 (4%) on the left; and Group C had 4 (59%) on the right and 9 (4%) on the left. The degree of collapse is noted in Table. If the collapse was less than %, it was classified as small; if to 5oy, moderate; if greater than 5%, large. The majority fell in the to 5% range. The mean hospital stay was days for Group A, 5 days after treatment started. Group B had a mean hospital stay of 3 days, 9 days after treatment started. Group C had a mean hospital stay of days. The relative effectiveness of the three treatment modes is illustrated in the Figure. There were no major complications in Group A although patient had a small late ipsilateral Table. Age at Occurrence of Pneumothorax Treatment Groups Decade A B C Total First Second Third Fourth Fifth Sixth Seventh Eighth Ninth Total

3 48 The Annals of Thoracic Surgery Vol 8 No August 99 Table. Size of Pneumothorax Treatment Groups A B C Total Small (< %) 3 (4%) (.5%) (%) (5%) Moderate (-5%) (5%) (58%) 8 (39%) 5 (45%) Large (> 5%) (33%) (.5%) 8 (39%) 3 (33%) Not specified 4 (%) 3 (4%) (%) Total a - P I GROUP A -A GROUP B - GROUP C - YEARS Actuarial analysis of the three treatment groups depicting the high percentage of nonrecurrence in Groups A and B versus Group C []. Using the chi-square analysis and Yates's correction, the differences between Group A and Group C and between Group B and Group C are significant (p <.5) at the end of the first year of follow-up. recurrence years after treatment. He underwent a scarification and decortication procedure, which was probably not indicated and which was complicated by postoperative bleeding and reoperation. Six patients in Group A have been followed for more than years, of them for more than 4 years without any respiratory symptomatology or ipsilateral recurrence. As if to document the continued presence of the underlying disease, a contralateral pneumothorax developed in of these patients and 4 years after treatment of the opposite side. The remaining 3 patients in Group A have experienced no late recurrence months to years after treatment. This includes the patient who was seen with simultaneous bilateral pneumothoraces and who received bilateral instillation of quinacrine. One patient who had early collapse before drug-induced adhesions could be formed ( day after treatment, a 3% pneumothorax developed) required repeat tube thoracostomy. Nine months later, the patient had experienced no other sequelae. A patient on high-dose steroids for systemic lupus erythematosus received quinacrine instillation after intrapleurally administered tetracycline had failed. He was discharged from the hospital days later and has had no recurrence after a year. In Group B, 8 patients had postoperative complications, and had recurrence 9 months after operation. Following pleurectomy, patients required reoperation for bleeding. Pneumonia developed in 3 patients and necessitated antibiotics and a lengthened hospital stay. One patient had a prolonged air leak postoperatively and cannot achieve total expansion of the involved lung. In addition to pneumonia, patient also had an intrathoracic hematoma requiring thoracenteses, and patient who had undergone pleurectomy had an ipsilateral recurrence after a week, necessitating reinsertion of the chest tube. In addition, arrhythmias, segmental atelectasis, and small pleural effusions were seen in other patients. In Group C, 4 patients had or more pneumothoraces on the ipsilateral side during the first year following treatment of the first pneumothorax. This rate of recurrence is 3%. Nine patients were followed for to 3 years, with late recurrences in 3 (33%). There were hospital deaths in elderly patients in this group, due to cerebral hypoxia secondary to the pneumothorax. In 5 patients, incomplete expansion of the pneumothorax required another tube thoracostomy. Two patients had prolonged air leaks, and lobar pneumonia de-

4 I49 Larrieu et al: Quinacrine Instillation for Recurrent Pneumothorax veloped in additional patients. One patient sustained a myocardial infarction during hospitalization. The most frequently associated disease was chronic obstructive pulmonary disease. It involved 4 patients-5 in Group A, 4 in Group B, and 5 in Group C. Infrequent associations were angiosarcoma of the scalp and lupus erythematosus in patient each in Group A. In Group C, 3 patients had metastatic malignancies: with adenocarcinoma of the lung and with tumors of the female genital tract. One patient in Group C had Marfan s syndrome and 4 female patients were taking oral contraceptives. Comment Quinacrine produces a serosal inflammatory reaction, which results in adhesion of the visceral and parietal pleural surfaces [4-, 8. In 9, Gellhom and co-workers [ reported the usefulness of intrapleurally administered quinacrine for the management of intractable neoplastic effusions, and several reports have been supportive [4, 8,. Boat and associates [3 were among the first to report the use of quinacrine in pneumothorax. Their patients had cystic fibrosis. After years, patient had had no recurrence and the other had experienced only a small pneumothorax during which the pleural surfaces over the apex remained in apposition and no treatment was required. Kattwinkel and colleagues [8 discussed the use of intrapleural instillation of quinacrine in a 9-year-old patient who had successive recurrent bilateral pneumothoraces secondary to cystic fibrosis. There was no recurrence 3 months after left and months after right intrapleural instillation. The patient died of cystic fibrosis, and postmortem, both lungs were found to be closely bound to the parietal pleura. Cattaneo [5, Stowe [lll, and their co-workers also reported using intrapleurally administered quinacrine successfully in a total of 5 high-risk patients. Stowe and associates ill noted that recurrence rates after the use of pleural sclerosing agents and after open scarification were similar. In this series, instances of spontaneous recurrent pneumothorax (Group A) were treated satisfactorily with intrapleural instillation of Table 3. Quinacrine Toxicity in Patients High Dose Low Dose > 5 mg < 5 mg Symptom (39 Patients) ( Patients) Fever 39 (%) 9 (%) Pain ( 4%) 8 (3%) Nausea or ( 4%) vomiting Hallucination ( 4%) Hypotension 4 ( %) Data from reference 4. Data from present series and references 3, 5, and 8. quinacrine. Major operation was avoided, few side effects were encountered, hospital stay was short, and the recurrence rate has been minimal after follow-up of up to 4 years. These results compare favorably with the results obtained with thoracotomy, as evidenced by an equally low rate of recurrence (4.8% vs 5.%). However, an increased complication rate was associated with thoracotomy, primarily following, pleurectomy, which we no longer recommend [3], and in the subset of patients with chronic obstructive pulmonary disease. In Group A this involved 5 patients (5%) and in Group B, 4 patients (%). In Group A, the 5 patients (mean age, 5.8 f 5.years) treated with quinacrine had no recurrence of the pneumothorax and no major complication after up to months of follow-up. Their stay in the hospital after treatment was significantly lower than in Group B (. days vs days). Two of the 4 Group B patients (mean age,. f 9.8 years) with advanced chronic obstructive lung disease required wedge resection of blebs in addition to the scarification procedure. Lobar pneumonia developed in of them, arrhythmias and acute respiratory distress in another. The signs and symptoms of quinacrine toxicity are directly related to the amount of drug administered [4, 5. The amount utilized in our series was relatively small ( mg in 5 ml of sterile solution daily for 4 days) compared with that used for neoplastic effusions, and side effects were generally mild (Table 3). Transient fever and pain were seen in 9 and 8 instances, respectively; however, this is well tolerated with mild analgesics. In some patients, a small

5 5 The Annals of Thoracic Surgery Voi 8 No August 99 Table 4. Combined Results of the Use of Intrapleural Administration of Quinacrine Instances of Spontaneous Authors Pneumothorax Recurrence Boat et a [3] Cattaneo et a [5] Kattwinkel et a [8] Stowe et a [Ill 4 Present series Total 3 (%) pleural effusion developed but resolved within a few days. A potential hazard, already alluded to by Kattwinkel and colleagues [8], is the introduction of the chemical into a bronchopleural fistula that might still be present, resulting in a chemical bronchitis and pneumonitis. This potential complication has not yet been seen and can be avoided by waiting to start treatment until twenty-four hours after the chest tube has stopped bubbling. In addition to quinacrine, other pleural sclerosing agents have been used, including silver nitrate [, talc [ll, tetracycline [, and nitrogen mustard []. We have used tetracycline in 4 patients, with recurrence of the pneumothorax in 3. One of these patients later underwent quinacrine treatment without recurrence. Fifty percent glucose, which we used when quinacrine was withdrawn from the market, was similarly ineffective. Review of the literature and our experience show an effectiveness of more than 9% with intrapleurally administered quinacrine in the treatment of recurrent spontaneous pneumothorax (Table 4). This compares favorably with the late results of surgical treatment. In 9, Luck and associates [9 suggested using a sclerosing agent during the initial pneu- mothorax in patients with cystic fibrosis. We now recommend intrapleural administration of quinacrine as the initial treatment of choice in all patients with recurrent spontaneous pneumothorax, not only those who constitute an increased operative risk. References. Adler RH: A talc powder aerosol method for the prevention of recurrent spontaneous pneumothorax. Ann Thorac Surg 5:44, 98. Andersen I, Nissen H: Results of silver nitrate pleurodesis in spontaneous pneumothorax. Dis Chest 54:, Boat TF, di Sant Agnese PA, Warwick WJ, et al: Pneumothorax in cystic fibrosis. JAMA 9:498, Borja ER, Pugh RP: Single dose quinacrine (Atabrine) and thoracostomy in the control of pleural effusions in patients with neoplastic diseases. Cancer 3999, Cattaneo JM, Sirak HD, Klassen KP: Recurrent spontaneous pneumothorax in the high-risk patient. J Thorac Cardiovasc Surg :4, 93. Gellhorn A, Zaidenweber J, Ultmann J, et al: The use of Atabrine (quinacrine) in the control of recurrent neoplastic effusions: a preliminary report. Dis Chest 38:5, 9. Grunkemeier GL, Starr A: Actuarial analysis of surgical results: rationale and method. Ann Thorac Surg 4:44, 9 8. Kattwinkel J, Taussig LM, McIntosh CL, et al: Intrapleural instillation of quinacrine for recurrent pneumothorax. JAMA :55, Luck SR, Raffensperger JG, Sullivan HJ, et al: Management of pneumothorax in children with chronic pulmonary disease. J Thorac Cardiovasc Surg 4334, 9. Smith WG, Ruthwell PPG: Treatment of spontaneous pneumothorax. Thorax :34, 9. Stowe S, Boat TF, Mandelsohn H, et al: Open thoracotomy for pneumothorax in cystic fibrosis. Am Rev Respir Dis :, 95. Wallach HW: Intrapleural tetracycline for malignant pleural effusions. Chest 8:5, Youmans C, Williams RD, McMinn MR, et al: Surgical management of spontaneous pneumothorax by bleb ligation and pleural dry sponge abrasion. Am J Surg :44, 9