Intrapleural Fibrinolytic Therapy in Complicated Parapneumonic Effusion and Empyema: Present Status

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1 Review Article Intrapleural Fibrinolytic Therapy in Complicated Parapneumonic Effusion and Empyema: Present Status Col (Dr) M.S. Barthwal Department of Pulmonary Medicine, Military Hospital, Namkum, Ranchi, India ABSTRACT Pneumonia remains one of the commonest community- and hospital-acquired infection despite the advent of potent antimicrobial agents. A significant number of patients with pneumonia develop parapneumonic effusions. The parapneumonic effusion may be simple consisting of free-flowing, clear exudative fluid which almost resolves completely with antibiotics alone. In case of delayed or inappropriate treatment, some of these simple effusions progress to complicated parapneumonic effusions and empyema. The management of these types of effusions with intercostal tube drainage and antibiotics fails most of the time due to the presence of thick viscous fluid and multiple pleural space loculations. The various therapeutic options available at this stage include intrapleural instillation of fibrinolytic agents, breaking down of loculations or decortication either by video-assisted thoracosopic surgery (VATS) or thoracotomy and open drainage procedures. Videoassisted thoracic surgery is a better option but it is neither easily available nor affordable by majority of patients in developing countries, like India. Intrapleural instillation of fibrinolytic agents has been found to be a useful adjunctive therapy in various small uncontrolled and randomised trials. After a recent and first large multicentre trial which showed that this therapy does not have any significant effect in reducing mortality and need for surgery in patients with pleural infection, the role of intrapleural fibrinolytics has become more controversial. In view of this, there is a need to re-define its role especially in the developing countries. [Indian J Chest Dis Allied Sci 2008; 50: ] Key words: Intrapleural fibrinolysis, Pneumonia, Empyema, Effusion, VATS, Treatment. INTRODUCTION Pneumonia remains one of the most commonest community- and hospital-acquired infection and as many as 36% to 57% of bacterial pneumonia develop parapneumonic effusion. 1, 2 To start with, parameumonic effusion consists of clear, sterile fluid which resolves with antibiotics alone. In case of inappropriate and delayed initiation of antibiotics, the fluid becomes more viscous with development of loculations and in presence of continuing uncontrolled infection and noninitiation of pleural space drainage, frank empyema with thick loculations and significant pleural thickening develops. The presence of loculations and thick viscous fluid leads to failed pleural space drainage in spite of tube being patent and correctly positioned. The management options in such cases consist of either use of minimally invasive video-assisted thoracoscopic surgery (VATS) or the more invasive conventional thoracotomy. In spite of being effective, VATS is not easily accessible and affordable in developing countries like India. The use of intrapleural fibrinolytics is a safer, easier and cost-effective option and various uncontrolled and small randomised studies have shown it to be a useful alternative. However, a recent large multicentre randomised trial 3 using intrapleural streptokinase in cases of pleural infection and using mortality and need for surgery as primary outcomes, found no significant difference between patients receiving streptokinase or placebo. This study 3 met with serious criticism with regard to the selection of primary outcomes and methodology. The present review discusses the rationale of this therapy, its indications, various treatment protocols that are used and the present status of this therapy, especially in the developing countries. PATHOPHYSIOLOGY OF PARAPNEUMONIC EFFUSION Exudative Stage The pleural fluid at this stage is free flowing, non-turbid and sterile. Pleural fluid analysis shows ph greater than 7.2, glucose greater than 60 mg/dl and pleural fluid lactic acid dehydrogenase (LDH) levels less than three times the upper limit of serum LDH. 4 [Received: May 16, 2007; accepted after revision: November 15, 2007] Correspondence and reprint requests: Col (Dr) M.S. Barthwal, Senior Advisor (Med. & Pulmonary Med.), Military Hospital, Namkum, Ranchi ; Phone: (Mobile) , ; msbarthwal@rediffmail.com.

2 278 Intrapleural Fibrinolytic Therapy M.S. Barthwal Fibrinopurulent Stage In the absence of early diagnosis or appropriate therapy, the fibrinopurulent stage ensues. The pleural fluid becomes clottable due to leakage of plasma proteins, increased formation of procoagulants and loss of fibrinolytic activity in pleural space resulting in the formation of a thick layer of fibrin over the parietal and visceral pleura and loculations within the fluid. The pleural fluid at this stage is invariably turbid but may be clear. The pleural fluid ph is less than 7.2, glucose level is less than 60 mg/dl, and LDH levels are more than three times the upper limit of serum LDH. 4 Empyema Stage In the absence of inadequate or delayed pleural space drainage and inappropriate antibiotics, the stage of empyema ensuses over a period of two to several weeks. There is a proliferation of fibroblasts leading to formation of soild fibrous peel, preventing the reexpansion of lung and creating a persistent pleural space with continuing potential for infection. The empyema is either in the form of single loculus or can be multiloculated. CLASSIFICATION OF PARAPNEUMONIC EFFUSION It is important to know the various stages of parapneumonic effusions since the management differ for each stage. A new classification has been proposed by an expert panel from the American College of Chest Physicians (ACCP) 5 and is based on anatomic characteristics of the fluid, bacteriology and the chemistry of pleural fluid. This classification 5 is not practical in resource limited settings, since it requires the measurement of pleural fluid ph, which is not widely available. A more practical classification as suggested by British Thoracic Society (BTS) 6 is described below. Empyema Empyema is a condition of frank pus with single or multiple loculations. The mamagement of empyema is always by chest tube drainage with or without fibrinolytic agents or by surgical drainage. Diagnosing Parapneumonic Effusions The diagnosis of simple parapneumonic effusion and empyema is quite straightforward. The diagnosis of CPE is not so straightforward, especially in the presence of clear pleural fluid and, it is very essential to diagnose CPE at the earliest so that timely pleural space drainage can be initiated. Furthermore, in case intercostal tube drainage fails due to the presence of loculations, intrapleural instillation of fibrinolytic agents may be helpful. If tube drainage is delayed, the CPE progresses to empyema stage. In a multicentre trial 3 no attempt was made to indentify this important subset of patients with CPE and this may be one of the reasons why intrapleural streptokinase was found to be ineffective in this trial. There are no definite clinical, radiological or biochemical parameters, which suggest CPE. However, following parameters suggest the development of CPE. Clinical Long duration of symptoms prior to presentation, combination of leucocytosis, anaemia and hypoalbuminaemia and failure of clinical response to antibiotics may suggest CPE. 7 Radiological The presence of D-shaped opacity or absence of typical sickle-shaped opacity in postero-anterior and lateral chest radiographs is suggestive of CPE or empyema which is loculated (Figure 1). Ultrasonography of chest is a useful and easily accessible test for detecting the Simple Parapneumonic Effusion Simple parapneumonic effusion corresponds to exudative stage of parapneumonic effusion and it almost always resolves with antibiotics alone. Complicated Parapneumonic Effusion Complicated parapneumonic effusion (CPE) corresponds to late fibrinopurulent stage. The pleural fluid is usually clear or turbid, but is non-purulent. Fibrin strands with or without loculations may be evident on ultrasonography (USG) or computed tomography (CT). This stage requires pleural space drainage along with either instillations of intrapleural fibrinolytic agents or VATS apart from appropriate antibiotics. Figure 1. Chest radiograph (PA view) showing D-shaped opacity suggestive of loculated effusion on the right side.

3 2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 279 presence of fibrin strands, septations or necrotic debris, the presence of which suggest the development of CPE. Contrast enhanced computed tomography (CECT) of chest can reliably detect loculations, their number, sizes, and pleural thickening (Figure 2). Figure 2. CECT showing loculated pleural collection on the left side. Pleural Fluid Characteristics The pleural fluid may be clear, cloudy or turbid. In case of clear or slightly turbid fluid, ph can be measured using blood gas analyser and a heparinised sample. The biochemical analysis, apart from routinely done protein estimation, must include sugar and LDH estimation. Pleural fluid ph less than 7.2; glucose less than 60mg/ dl and LDH levels more than three times the upper limit of serum LDH suggest the diagnosis of CPE. A positive Gram's stain or bacterial culture further confirms CPE. If ph testing is not possible because of lack of facility or turbid nature of the pleural fluid, then, finding of low glucose and high LDH levels in the pleural fuid along with presence of fibrin strands or septations on ultrasonography of the chest practically confirms the presence of CPE and is an indication for intercostal tube drainage. INTRAPLEURAL FIBRINOLYTIC THERAPY When the chest tube is correctly positioned (as evidenced by postero-anterior and lateral chest radiographs) and there is a significant amount of pleural fluid, the major reasons for failed drainage are multiple pleural space loculations or tube obstruction by thick and viscous fluid. 8 The various modalities of treatment available at this stage are: saline flushes, placing one or more catheters in loculi under image guidance, thoracosocpic debridement, standard thoracotomy, drainage of empyema and decortication. The first two modalities are not so effective in improving drainage. The last two surgical modalities are more invasive, not easily available and, if available, are not affordable by majority of patients in the developing countries like India. The fibrinolytic agents, if used early in the CPE, break loculations and early pleural peel thereby facilitating pleural space drainage. These agents possibly do not have significant liquefying effect on pus and hence may not be effective in empyema stage. 9,10 Sherry and Tillet were the first ones to use fibrinolytic agents in 1949 in 23 patients who had loculated empyema or haemothorax. Their patients received intrapleural instillation of both streptokinase and streptodornase, which was extracted from concentrated filtrates of streptococci of Lancefield group C. There was significant improvement in drainage of fluid. However, the initial enthusiasm waned because of significant systemic adverse effects in the form of fever, leucocytosis and general malaise. These side effects were due to immunological reaction caused by impurities in the preparation of agents. There was not much of use of this therapy until Bergh and colleagues 14 in 1977 used purified streptokinase and reported significant improvement in 10 of 12 patients with empyema without the need for any major surgical intervention and without any significant adverse effects. In the last 25 years, there have been numerous case series 15 and randomised controlled trials using streptokinase (STK) and urokinase (UK) in CPE and empyema with encouraging results. There are about 25 published uncontrolled case series 15 using intrapleural fibrinolytic (STK/UK) agents. The number of patients in these case series varied from 3 to 30 and the indication for initiating fibrinolytic therapy was failed chest tube drainage in presence of patent and adequately positioned tube or catheter. Streptokinase dose used was 250,000 IU in 50 to 100 ml of saline daily and the tube was clamped for two to four hours. The dosage of UK used in these studies has ranged from 50, ,000 IU. The number of instillations ranged from 2 to 10. Treatment success criteria included increased volume of fluid drainage and clinical and radiological resolution of CPE or empyema. Success rate was 67% to 100% in these studies. The majority (>90%) of patients had no complications but 5% to 10% had transient fever, pleuritic chest pain and chest wall erythema. Both STK and UK have been found to be equally effective but UK has the advantage of being non-antigenic. Till date, there are five small randomised trials on the use of fibrinolytic agents. In the first trial, 16 three doses of intrapleural STK (250,000 lu/day) were compared with saline flushes in 24 patients (13 with empyema and 11 with CPE). The STK group had significantly greater drainage of pleural fluid and radiological resolution. The second study 17 compared UK (n=15 patients; 11 with CPE and 4 with empyema) with normal saline (n=16 patients; 13 with CPE and 3 with empyema) with pleural infection resulting in significantly more fluid drainage in UK group. In another study 18, which was not a formal randomised trial but a sequential trial in

4 280 Intrapleural Fibrinolytic Therapy M.S. Barthwal which only chest tube drainage was used during first half of the study and intrapleural STK was administered during the later half of the study. The study 18 included 52 patients with empyema (n=40) and CPE (n=12) who were treated with chest tube drainage (n=29) and intrapeural STK (n=23). A significantly larger volume of pleural fluid drained in STK group but there was no difference in the need for surgery or in the mortality rate. In the fourth study, patients with parapneumonic empyema were randomly assigned to receive either intrapleural UK or normal saline for five consecutive days. The UK group had shorter time for defervescence, shorter need for hospitalisation and a lower need for decortication. In another randomised controlled trial, patients were randomised to receive either STK or normal saline. The primary outcome measures were taken as need for surgery, response to treatment and mortality. The significant beneficial effect of STK was seen between fourth and seventh day after initiation of treatment and there was reduced need for surgical referral in STK group. Most of these studies may be criticised for using the pleural fluid drainage and radiological improvement as primary outcome measures, since it has been shown that radiological improvement does not reliably predict outcome 21 and STK can increase pleural fluid drainage due to mechanisms independent of fibrinolysis. 22 At the same time using other primary outcome measures like need for surgery, mortality, hospital stay, also may not be appropriate end points for assessing the effect of fibrinolytic therapy. During last five years or so, the intrapleural STK has been used with encouraging results in our country, as reflected in various case reports, 23, 24 and non-randomised trials 25 and randomised 26, 27 trials. However, the results of the most recent and long awaited study on the utility of intrapleural STK have been disappointing. In this multicentre randomised, double-blind study 3 in which 427 patients with pleural infection were randomised to receive either intrapleural STK or placebo. There were no significant differences between the two groups in terms of mortality, need for surgery, radiographic outcome or length of hospital stay and, the authors 3 concluded that intrapleural STK should generally be avoided in pleural infection. Although this was a large multicentre trial, it had some significant flaws in selection of primary outcomes and methodology. Mortality in patients with parapneumonic effusions depends more on the extent of underlying pneumonia, other co-morbid conditions and age rather than facilitation of pleural space drainage with intrapleural fibrinolytic agents and it has been suggested that extent of pleural fluid drainage should not be considered as primary outcome measure. 28 Moreover significant number of patients in this trial were more than 60 years of age and majority of them had co-morbid diseases, which could have contributed in increasing mortality and hospital stay. The patient population was heterogeneous in this study and radiological investigations like USG or CT were not used to select patients with CPE or empyema with loculations without any significant pleural thickening. This subgroup of patients is most likely to benefit from fibrinolytic therapy which breaks the loculations but possibly does not have any significant effect in liquefying pus. 9,10,28 Although in this trial, subgroup analysis of the outcome measures in patients with and without septations/loculations was carried out, yet it is difficult to select such patients only on the basis of chest radiography. 29,30 A recent meta-analysis 31 of all randomised trials comparing intrapleural fibrinolytic agents with placebo in adult patients with empyema and CPE did not not support the routine use of fibrinolytic therapy for all patients who require chest tube drainage. However, there was significant heterogeneity of the treatment effects among the trials and it was suggested that the selected patients might benefit from the treatment. Hence, better designed trials are required with emphasis on proper selection of 27, 32 patients before we abandon this therapy. The above-mentioned randomised, controlled trials, except for the multicentre trial, 3 have nevertheless shown that intrapleural fibrinolytic therapy with either STK or UK does facilitate the drainage of pleural fluid by breaking the loculations without any significant adverse effects. The most important prerequisite for initiating this therapy is early diagnosis of CPE and empyema with loculations by means of USG or CT. The usefulness of VATS in such effusions has been brought out by the multicentre trial, 3 but in resource limited setting where VATS is inaccessible and a costlier option, the use of intrapleural fibrinolytics appears to be a cheaper, safer and effective option. The ACCP evidencebased guidelines 5 have also recommended fibrinolytic agents and VATS as acceptable options in CPE and empyema. The BTS guidelines 6 have also recommended intrapleural fibrinolytic agents in failed drainage in CPE and empyema. There has been a problem in using the daily dosage schedule of intrapleural STK or UK advocated in the ACCP 5 and BTS 6 guidelines in India due to nonavailability of STK or UK in the prescribed dosage. The minimum strength of STK freely available in India is 750,000 IU per vial. Once the vial is reconstituted, the solution can be stored only for eight hours at 2 to 8 C. By using intrapleural STK in the dosage of 250,000 IU, eight hourly, two doses can be utilised thereby minimising the wastage and at the same time maintaining its potency. The same dosing regimen have 23, 24 been used in cases reported earlier from this country and in an uncontrolled study. 25 Urokinase is available as 250,000 IU per vial in India and has been used in the dosage of 100,000 IU eight hourly for similar reasons. However, Strange et al 22 in an experimental study demonstrated that increasing dosing interval might in fact increase the efficacy of fibrinolytic therapy. The

5 2008; Vol. 50 The Indian Journal of Chest Diseases & Allied Sciences 281 possible explanation for this could be that due to various protease inhibitors in the inflammed pleural space, the half-life and therefore, the proteolytic activity of STK is shortened. Increasing the dosing frequency appears to prolong the half-life as well as proteolytic activity of STK. These issues need to be further evaluated by randomised, controlled clinical trials. The intrapleural fibrinolytic therapy has been used successfully in paediatric patients as reflected by various case reports 33, 34 and a randomised, control trial. 35 Apart from STK or UK other fibrinolytic agent like tissue plasminogen activator (tpa), has also been used with positive results in uncontrolled studies A wide range of dosing schedules have been used in these studies but 10 mg appears to be the most favoured. 4 There has been no consensus on standardised protocol for using intrapleural fibrinolytic agents and a suggested protocol is as shown in figure 3. Adverse Effects of Fibrinolytic Agents Fever and chest pain have been reported in less than 10% of patients. Major haemorrhage was reported in a single case report after 500,000 IU of STK and dwell time of six hours. 39 There have been isolated case reports of ventricular fibrillation following UK. 40 It is recommended that a single dose should not exceed 250,000 for STK and 100,000 for UK and dwell time should not be more than four hours. There is no significant activation of systemic fibrinolytic system even when a total dose of 1,500,000 IU given in a dose of 250,000 IU, 12 hourly and no monitoring of coagulation parameters is required. 41 Contraindications of Using Fibrinolytic Therapy A history of bleeding diathesis, stroke or significant haemorrhage in the preceding six months and use of fibrinolytic agents by any route in the previous two years are contraindications for using fibrinolytic therapy. FUTURE PROSPECTS A multicentre trial is underway in the United Kingdom in which patients with CPE are randomised to receive saline, 10 mg tpa, 1 mg recombinant streptodornase (Dnase) or the combination of tpa and Dnase twice a day. Further, well-designed trials are also required in Tube/Catheter drainage of CPE/empyema Daily drainage < 50 ml/day (tube being patent and correctly positioned) + significant loculated fluid or fluid with fibrin strands and necrotic debris as assessed by USG chest/cect Instill two doses of intrapleural STK 250,000/UK 100,000 in 50mL normal saline at eight hourly interval followed by flushing with 20 ml saline. Clamp the tube for two hours after each dose Monitor clinical response daily and cumulative drainage Repeat chest radiograph + USG chest after 48 hours Significant drainage and radiological resolution Insignificant drainage and no radiological (> 50% reduction in size of effusion) resolution Continue STK/UK for 2-3 more doses as per the reponse and assess as before Further, fibrinolytic therapy may not work. Consider VATS or other surgical options Figure 3. Suggested protocol for intrapleural fibrinolytic therapy [CPE = complicated parapneumoni effusion, USG = ultrasonography, CECT = contrast enhanced computed tomography, STK = streptokinase, UK = urokinase]

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