Intrapleural Fibrinolytic Treatment of Traumatic Clotted Hemothorax

Intrapleural Fibrinolytic Treatment of Traumatic Clotted Hemothorax* Ilhan lnci, MD; Cemal Ozr;elik, MD; Refik Ulkii, MD; Adnan Tuna, MD; and Nesimi Eren, MD

Study objective: To evaluate the role of intrapleural fibrinolytic treatment (IPFT) in traumatic clotted hemothorax. Design and patients: Between August 1995 and February 1997, 24 patients with traumatic dotted hemothorax were included. Streptokinase (SK), 250,000 IU, or urokinase (UK), 100,000 IU, diluted in 100 mL of saline solution was given daily. We administered 5.0±1.8 (range, 2 to 9) doses of SK or 6.25±5.97 (range, 2 to 15) doses of UK. Setting: Dicle University School of Medicine, Thoracic and Cardiovascular Surgery Department. Results: Complete response, which was defined as resolution of symptoms with complete drainage of fluid and no residual space radiographically, occurred in 15 (62.5%) patients. Partial response, which was defined as resolution of symptoms with a small pleural cavity, occurred in seven (29.2%) patients. Two patients (8.3%) required decortication; they were defined as nonresponders. The mean period of time between the diagnosis and fibrinolytic treatment (FT) was 11.65±6.38 (range, 4 to 25) days. There were no complications related to IPFT. There was no mortality during the course of IPFT. Conclusion: The use of intrapleural fibrinolytic agents has resulted in resolution of dotted hemothorax with an overall success rate of91.7%. We recommend that IPFT should be added to the algorithm for management of clotted hemothorax before proceeding with minithoracotomy or pleural decortication. (CHEST 1998; 114:160-165) Key words: dotted hemothorax; intrapleural fibrinolysis; streptokinase; trauma; urokinase Abbreviations: CR=complete response; FT= fibrinolytic treatment; IPFT = intrapleural fibrinolytic treatment; NR=nonresponder; PR=partial response; SK=streptokinase; UK = urokinase

H emothorax may occur as a result of thoracic

trauma or following diagnostic and therapeutic pleural aspiration. The traditional initial treatment of all patients with acute traumatic hemothorax is closed tube thoracostomy drainage. Early removal of blood from the pleural cavity is essential to prevent coagulation and fibrin deposition within the pleural cavity. Controversy still exists, however, regarding the approach to residual clotted hemothorax after trauma. 1 Both aggressive and conservative types of treatment of residual traumatic hemothorax have been advocated.1 -3 The administration of streptokinase (SK) for enzymatic debridement of the pleural cavity for empyema and hemothorax was advocated in 1949 by Tillet and Sherry 4 Although there were no hemorrhagic complications, allergic reactions were common . In 1977, Bergh et al5 used more purified SK to decrease

*From the Department of Thoracic and Cardiovascular Surgery, Dicle University School of Medicin e, Diyarbakir, Turkey. Manuscript received June 11, 1997; revision accepted D ecember 31 , 1997. 160

immunologic reactions. Over the years, many others have described the use of intrapleural SK to facilitate treatment of loculated hemothorax and empyema.s-12 In 1987, Vogelzang et all 3 reported the first use of urokinase (UK), the other major fibrinolytic agent that is nonantigenic and nonpyrogenic, in the treatment of infected extravascular hematomas. However, UK was later used by many others to facilitate drainage of proteinaceous pleural space collections, whether hemorrhagic or purulent.9.ll .l4-l7 Herein, we report our experience with 24 consecutive patients with traumatic clotted hemothorax in whom intrapleural fibrinolytic agents, SK and UK, were used as an adjunct to chest tube drainage. MATERIALS AND METHODS

Patient Population

To evaluate the role of intrapleural fibrinolysis in clotted hemothorax, a prospective trial in 24 consecutive patients from August 28, 1995, to F ebmary 28, 1997, was carried out in our clinic. Clinical Investigations

Inclusion and Exclusion Criteria Patients were included if they had clotted or loculated hemothorax that did not resolve after ple ural drainage with a chest tube. Loculation or coagulation of hemothorax was considered when a chest tube fai led to drain ple ural flui d, and opacities on chest radiography persisted ancl/or were demonstrated through ches t CT. Multiloculations of pleural fluid were defin ed as septations seen on chest CT scan orair-fluid levels in the effusion on the c hest radiograph. Patients were also incl uded if they had delayed hemothorax that developed within 30 days following hospital discharge with an un eventful obse1vation period. Pati ents wi th hemothorax after pulmonary resection , decmiication , or who were in th e first 48 h following trauma were not included. Also excluded were patients with coagulation abnormalities and prior reaction to SK or UK. Fibrinolytic Agent Instillation SK, 250,000 IU, or UK, 100,000 IU, was diluted in 100 mL of saline solution and administered throu gh th e chest tube with a sterile injection . The chest tube was clamped for 4 h and the patients were mobili zed during th is period to allow a better the clamp was removed and distribution. After the 4 h eriod, p placed back on negative 20 em H 2 0 suction. The dai ly drainage was recorded. Net output was calculated by su btracting the

volume of SK or UK injected from total output. This procedu re was repeated eve1y clay until radiographic im provement was achieved. The numbe r of consecutive days the agents were used depended on th e clinical and radiographic response and pleural fluid drainage. The chest tube was removed when pleural drainage was <50 mL in 24 h. Assessment of Response Complete response (C R) was defined as resolution of symptoms with complete drainage of fluid and no residual space radiographically (Fig 1). Partial response (PR) was defin ed as resolution of symptoms with a small pleural cavity (Fig 2). Nonresponders (N Rs ) were patients who unde1went decortication. Standard posteroanterior and late ral chest radiographs were obtained daily. Chest CT scans were perfo rmed prior to, during (in some of th em), and after fibrinolytic treatment (FT). Prothrombin tim e, partial thromboplastin time, and plate let counts were measured prior to initiating therapy and during the period of fibrinolytic agent instillation. Figu re 3 shows th e algorithm used in our study. Patients were assessed carefully for evidence of drug complications, including pain, allergic reactions, bleeding, or he modynamic changes.

FrcuRE l. CR: chest radi ograph and CT prior to IPFT (top); chest radiograph and CT following completion of IPFT (bottom). CHEST I 114 I 1 I JULY, 1998

161

FIGURE 2. PR: CT prior to IPFT (top ) and CT following completion of IPFT (bottom).

RES U LTS

From August 1995 to February 1997, 24 consecutive patients were included for this study. Mean age was 36.8± 16.03 (range, 7 to 62) years . Twenty patients were male (83.3%) and 4 were female (16.7%). Nineteen patients were treated with SK and five were treated with UK. The cause of thoracic trauma was traffic accident in 16, fall in 2, stab wound in 5, and gunshot wound in 1 patient. Right hemithorax was involved in 17, and left hemithorax in 7 patients . Of 24 patients, 4 had infected h emothoraces. Pleural fluid cultures revealed Pseudomonas aeruginosa in two patients. In the remaining two patients , the causative agent was not identified. Delayed hemothorax occurred in four patients. In these patients , delayed h emothorax occurred 20, 21 , 22, and 25 days following the chest injury. The mean period of tim e between the diagnosis and FT was 11.65±6.38 (range, 4 to 25) days . We administered 5.0± 1.8 (range, 2 to 9) 250,000-IU doses of SK and 6.25±5.97 (range, 2 to 15) 100,000-IU doses of UK. Mean postintrapleural FT drainage in the flrst day after administration was 334.8± 1.52.6 (range, 100 to 162

600) mU24 h. Total drainage at the end of intrapleural FT was 1,105±922 (range, 250 to 3,700) mL. The mean hospital stay for all patients was 16.9±8.05 (range, 5 to 37) days. The mean pretreatment prothrombin time was 11.49 ± 0.76 s; posttreatment it was 12.33 ± 0.65 s. The partial thromboplastin time pretreatment was 29.29±0.8 s; posttreatm ent it was 29.88±0.65 s. The platelet count pretreatment was 291.7±36.46 cells/ mm 3 . Posttreatment it was 313.9±34.4 cells/mm 3 . No patients had significant changes in renal or liver function test results after intrapleural fibrinolytic treatment (IPFT). In this study, the CR rate was 62.5% (15/24), the PR rate was 29 .2% (7/24), and the NR rate was 8.3% (2/24). Thus, the overall success rate was 91.7%. CR cases received 5.38±3.3 (range, 2 to 15) doses of fibrinolytic agent. PR cases received 5.0±2.38 (range, 2 to 9) doses of fibrinolytic agent. In PR patients, as the pleural cavities were small, we did not use an additional chest tube. There were no statistical differences among CR, PR, and NR patients in the fibrinolytic agent used, duration of hemothorax prior to IPFT, volume of drainage, duration of IPFT, and presence of infection (Table 1). There were no complications related to the IPFT. No systemic bleeding complication occurred during IPFT. Vital signs and hematocrit levels were monitored routinely and were stable throughout the course of drainage in all patients. There was no mortality during the course of IPFT. Unsuccessful fibrinolysis occurred in two patients. In one of them, we started UK therapy for 5 days . In the first day of UK administration, 500 mL net drainage occurred. The total net output was 1,200 mL after 5 days. Control CT revealed collapsed right lower lobe and multiloculations. Thus, he undetwent thoracotomy with a successful decortication. The second patient had started intrapleural SK treatment for 7 days. A total of 750 mL drainage occurred at the end of 7 days . Control CT showed hematoma and collapsed right lower lobe. She underwent a successful decortication. In these two failed cases, the time period between the diagnosis of hemothorax and IPFT was 20 and 5 days, respectively. Follow-up

All patients had chest radiographs at the end of 2 weeks following hospital discharge. After this period, follow-up could be done in 18 of 24 patients. The mean follow-up period was 6 (range, 1 to 10) months. During follow-up of PR patients, no complications such as recurrence or empyema occurred. Clinical Investigations

Traumatic hemothorax ,[, Chest tube

Clotted hemothorax - loculations on chest x-ray or CT ,[, IPFT ,[, Daily chest x-ray or chest CT during IPFT(optional) ,[, Daily measurement of pleural fluid drainage ,[, Pleural fluid drainage < SO ml/24 hr ,[, Remove chest tube ,[, ,[, Clinical condition Control CT ,[, ,[, A) No symptom with complete drainage A) No residual space ---> CR ,[, B) Small pleural cavity ---> PR Complete Response (CR) ,[, Observe weekly by chest x-ray B) Resolution of symptoms ,[, ,[, ,[, Enlarging cavity, No change Partial response(PR) pleural peel

tcr

Decortication C)No Response(NR)

FIGURE 3. Algorithm for IPFT.

DISCUSSION

Hemothorax and hemopneumothorax commonly occur following both blunt and penetrating thoracic trauma. There is general agreement that the initial treatment of patients with traumatic hemothorax includes chest tube drainage. 2 ·3 · 18 Chest tube drainage is enough in about 60 to 90% of the patients.l9 A hemothorax that is not adequately managed by initial chest tube drainage or thoracentesis may simply coagulate and not be accessible to tube

Table !-Comparison of CR, PR, and NR Patients

SK* UK* Duration of hemothorax prior to IPFT, d Total volume of drainage, mL Duration of IPFT, d Presence of infection* *Number of patients.

CR

PR

NR

12 3 11.2

6 1 13.8

1 12.5

1,058 5.1 2

1,050 5.4 2

975 6

drainage. 20 Burford et al2 1 recognized that intrapleural blood almost universally clots in the early postinjury period. They observed that a thin covering of the pleural surface by fibrin and cellular elements occurs. This covering develops into a progressively thicker membrane that coats the visceral and parietal surface and forms a saclike structure containing the hemothorax. In its early development, this thin membrane has little substance and is attached very loosely to the underlying pleural surface. By the seventh day, there is an angioblastic and fibroblastic proliferation. The membrane continues to thicken by progressive deposition and organization of the coagulum within the cavity. An understanding of the pathologic features of a clotted hemothorax makes it clear that, if possible, the clotted hemothorax should be evacuated within 7 to 10 days of injury.22 If, however, the hemothorax is not evacuated by the lOth day, the clotted blood cannot be easily removed and the decortication will be required at a later day (4 or 5 weeks).22 When extensive opacifications are found on chest CHEST/114/1 /JULY, 1998

163

radiograph, proper placement and patency of the chest tube should be evaluated. If the tube is blocked or positioned improperly, the tube should be replaced or repositioned. 22 If proper placement and patency of the tube is confirmed, a CT scan of the chest should be obtained to differentiate a hemothorax from consolidation of the lung parenchyma. There is no agreement, however, considering the approach to residual clotted hemothorax after trauma. Both aggressive and conservative modes of management of residual traumatic hemothorax have been advocated. The experimental observation that pleural blood is spontaneously absorbed 23 has led some investigators to recommend a conservative approach with expectant management of residual clotted hemothorax after trauma. 2·3·24 Wilson et aF reported that an early operative intervention to remove residual blood was not necessary with traumatic hemothorax. However, several studies have stated the adverse sequelae of incomplete evacuation of hemothorax in trauma victims 1·25 ·26 and they have advocated early thoracotomy in such cases. The use of intrapleural fibrinolytic agent instillation is another alternative to facilitate drainage and lung expansion in traumatic hemothorax inadequately treated by tube thoracostomy. Complications of the the rapeutic use of intrapleural fibrinolytic agents are infrequent. Berglin et al 27 reported that the use of intrapleural SK has caused no evidence of coagulation effects. However, Rosen et al 28 reported a single case of a major hemorrhage following intrapleural SK instillation. This has been attributed to systemic absorption of the agent. Other systemic side effects with intrapleural SK are fever as high as 40°C and pleural pain .28.29 Toxic responses such as arthralgias, nausea, malaise, and headache were also reported earlier with this agent, 30 although they appear to be less frequent with a purified form of SK .s Anaphylaxis and acute hypoxemic respiratory failure, although very uncommon, have also been reported. 31·32 UK has the major advantage of being nonantigenic and nonpyrogenic. 11 · 14 -17 However, Frye et aP 2 described a patient who developed acute hypoxemic respiratory failure following the intrapleural instillation of both SK and UK 24 h apart. Hypoxemia results, most likely, from a direct effect of the products of fibrinolysis on the pulmonary circulation. To our knowledge, instillation of UK to loculated pleural effusions was first reported in 1989 by Moulton et al. 16 They treated five patients with infected hemothoraces and eight patients with empyema. They reported 92% success rate without any complications. Jerges-Sanchez et al,10 in a multicenter trial, 164

reported 23 hemothoraces (11 infected, 12 sterile) from 48 cases. Only 1 of 23 patients underwent decortication. Moulton et al 14 described l18 patients with complicated pleural fluid collection treated with intracavitmy UK. There were 16 traumatic hemothoraces from 23 clotted hemothorax cases. Decortication was performed in only one of these patients who had a chronic sterile hemothorax. Their overall success rate was 94% (ll1/118) without any complication. Pollak and Passik 15 described eight patients with nine loculated pleural effusions treated with UK. In one of their patients, there was infected, loculated hemothorax; successful resolution occurred in this patient. Aye et al8 used purified SK in both empyema and hemothorax. In their series, there were four pure hemothoraces and all patients were cured with this type of treatment. They stated that the output was greater in hemothorax than in empyema cases (282% increase vs 128% increase). Bergh et al5 described 10 patients with traumatic hemothorax treated with SK out of 38 cases with other diagnosis. Of the 10 patients, 7 had radiologic improvement. There was no need for thoracotomy or decortication. In this series, we treated 24 patients with clotted traumatic hemothorax with IPFT. Our CR rate was 62.5% and the PR rate was 29.2% with an overall response rate of 91.7%. No complications occurred due to the application of either SK or UK in our series. This response rate should not be overlooked. If this alternative treatment had not been applied, they would have been treated with thoracotomy which, we think, is an aggressive mode of treatment. This type of treatment has been largely overlooked by thoracic surgeons in the last several decades. 9 One reason for this lack of enthusiasm is the variable results and side effects of the fibrinolytic agent SK used exclusively in the earlier studies, and the only drug meriting even a cursory mention in the major surgical and trauma textbooksY We hope that this type of treatment is going to take place in major thoracic surgery and trauma textbooks as trials with these agents continue to show the effectiveness and safety in treating patients with loculated traumatic hemothorax. Although there is not a consensus on the frequency and duration of instillation, duration of FT, instillation amount, and assessment of response, the results that have been published are encouraging. Every center uses these agents according to its own experience. In conclusion, intrapleural fibrinolytic agent instillation should be added to the algorithm for management of clotted hemothorax20 before proceeding with minithoracotomy or pleural decortication. Clinical Investigations

REFERENCES

1 Caselli JS , Mattox KL, Beall AC. Reevaluation of early evacuation of clotted he mothorax. Am J Surg 1984; 148: 786-90 2 Wilson JM, Bore n CH, Peterson SR, et al. Traumatic hemothorax: is decortication necessary? J Thorac Cardiovasc Surg 1979; 77:489-95 3 Maloney JV. The conservative manage me nt of traumatic hemothorax. Am J Surg 1957; 93:533-39 4 Tillett WS , Sherry S. The effect in patients of streptococcal fibrinolysin (streptokinase) and streptococcal deoxyribonuclease on fibrinous , purulent, and sanguinous pleural exudations. J Clin Invest 1949; 23:173-79 5 Be rgh NP , Ekroth R, Larsson S, eta!. Intrapleural streptokinase in the treatme nt of hae mothorax and empye ma. Scand J Thorac Cardiovasc Surg 1977; 11:265-68 6 Mitchell ME, Alberts WM , Chandler KW, et al. Intraple ural streptokinase in manage ment of parapne umonic effusions: report of series and review of lite rature . J Fla Med Assoc 1989; 76:1019-22 7 Lysy Y, Gavish A, Lieberson A, et al. Intraple ural instillation of streptokinase in the treatme nt of organizing empyema. Isr J Med Sci 1989; 25:284-87 8 Aye RW, Froese DP, Hill LD. Use of puriHed streptokinase in e mpyema and hemothorax. Am J Surg 1991; 161:560-62 9 Robinson LA, Moulton AL, Fleming WH , e t la. Intrapleural fibrinolytic treatm ent of multiloculated thoracic e mpyemas. Ann Thorac Surg 1994; 57:803-14 10 Je rges-Sanchez C, Ramirez- Rive ra A, E lizalde JJ, e t a!. Intrapleural fibrinolysis with streptokinase as an adjunctive treatment in he mothorax and e mpye ma: a multicenter trial. Chest 1996; 109:1.514-19 11 Temes RT, Follis F, Kessler RM , et al. Intraple ural fibrinolytics in management of e mpyema thoracis. Chest 1996; 110:102-06 12 Fraedrich G, Hofmann D , Effenhauser P, et al. Instillation of fibrinolytic e nzymes in the treatm ent of ple ural e mpyema. Thorac Cardiovasc Surg 1982; 30:36-38 13 Vogelzang RL, Tobin RS , Burstein S, e t al. Transcathe te r intracavitary fibrinolysis of infected extravascular hematomas. AJR 1987; 148:378-80 14 Moulton JS , Benkert RE , Weis iger KH , e t al. Treatment of complicated pleural fluid collections with image-guided drainage and intracavitary urokinase. Chest 199.5; 108:12.52-59 1.5 Pollak JS , Passik CS. Intraple ural urokinase in the treatment

of loculated ple ural effusions. Chest 1994; 105:868-73 16 Moulton JS , Moore PT, Mencini RA. Treatment of loculated pleural effusions with transcathete r intracavitary urokinase. AJR 1989; 153:941-45 17 Cohen ML, Finch IJ. Transcatheter intrapleural urokinase for loculated pleural effusion. Chest 1994; 105:1874-76 18 Griffith GL, Todd EP, McMillian RD , e t al . Acute traumatic he mothorax. Ann Thorac Surg 1978; 26:204-07 19 Ozgen G, Duygulu I, Solak H. Chest injuries in civilian life and their treatm ent. Chest 1984; 85:89-92 20 Hood RM. Pulmonmy and pleural complications of trauma. In: Hood RM , Boyd AD , Gulliford AT, eds. Thoracic trauma. Philadelphia: WB Saunders, 1989; 359-82 21 Burford TH, Parker EF, Samson PC. Early pulmonary decortication in the treatm ent of posttraumatic empyema. Ann Surg 1945; 122:163-67 22 Boyd AD. Pneumothorax and he mothorax. In: Hood RM , Boyd AD , Culliford AT, eds. Thoracic trauma. Philadelphia: WB Saunde rs , 1989; 133-48 23 Condon RE. Spontaneous resolution of experimental clotted hemothorax. Surg Gynecol Obstet 1968; 126:505-51 24 Cordice J'W, Cabezon J. Chest trauma with pneumothorax and hemothorax. J Thorac Cardiovasc Surg 1965; 50:316-38 25 Eddy AC, Luna GK, Copass M. Empye ma thoracis in patients undergoing emergent closed tube thoracostomy for thoracic trauma. Am J Surg 1989; 157:494-97 26 Milfeld DJ, Mattox KL, Beall AC Jr. Early evacuation of clotted hemothorax. Am J Surg 1978; 136:686-92 27 Be rglin E , Ekroth R, Teger-Nilsson AC, et al. Intrapleural instillation of streptokinase : effects on syste mic fibrinolysis. Tborac Cardiovasc Surg 1981; 29:124-26 28 Rosen H , Nadkarni V, Theroux M, et al. Intrapleural streptokinase as adjunctive treatment for pe rsistent empyema in pediatric patients. Chest 1993; 103:1190-93 29 Geha AS. Pleural empyema: changing e tiologic, bacte1iologic, and the rapeutic aspects. J Thorac Cardiovasc Surg 1971; 61 :626-35 30 Hubbard WN. The systemic toxic responses of patients to treatme nt with streptokinase-streptodornase. J Clin Invest 1951; 30:1171-74 31 Goehring \NO, Grant JJ. Alle rgic reaction to streptokinasestreptodornase solution given intrapleurally. JAMA 1953; 152:1429-30 32 Frye MD, Jarratt M, Sahn SA. Acute hypoxemic respirat01y filllure following intrapleural thrombolytic therapy for hemothorax. Chest 1994; 10.5:1595-96

CHEST I 114 I 1 I JULY, 1998

165