Treatment Of Pleural Infection Research Articles

Effects of Concurrent Dosing on the Efficacy of Tissue Plasminogen Activator and Deoxyribonuclease in the Treatment of Pleural Infection.

The goal of this study was to evaluate how the administration of concurrent tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) therapy with variable dosing for complicated parapneumonic effusions and empyema affects patient outcomes in an inner-city community hospital. This retrospective analysis was performed at an inner-city hospital located in Raleigh, North Carolina. A list of all patients treated with tPA and DNase between July 1, 2015, and December 31, 2017, was generated and screened. Data were collected through a review of past medical records, including demographics, past medical history, and details about their hospital course. A total of 38 patients were found to have been treated with concurrent tPA and DNase for complicated parapneumonic effusion or empyema. Twenty (52.6%) patients received the full six doses of combined concurrent tPA/DNase. Of the 18 (47.4%) patients who did not receive the full six doses, 11 did not require the full six doses for effusion resolution, and seven had to discontinue therapy due to tube blockage or pain. Only seven (18.4%) patients had complications related to tPA/DNase administration, most commonly pain. Nineteen (50%) patients had complete radiological clearance of effusion, with 13 (34.2%) having partial clearance, and six (15.8%) having no change or worsening of their effusion. Eight (21.1%) patients needed further surgical management of their effusion. The current most common dosing pattern for combined tPA and DNase therapy of twice daily for three days may not be optimal for all patients. The dosing regimen should be individualized depending on clinical response.Concurrent dosing is safe.

Intrathoracic vacuum therapy for the therapy of pleural empyema-a systematic review and analysis of the literature.

Pleural empyema is a serious and potentially deadly disease leading to a significant burden on health care systems. Conservative and surgical treatment results remain poor, with high morbidity and mortality rates. Patients with pleural empyema are often multimorbid and poor candidates for surgery. Therefore, it appears sensible to explore alternative, less invasive treatment options. Recently, the well-established vacuum sponge therapy has been adopted in the treatment of pleural infections. The goal of this systematic review was to identify the existing literature and reported results of vacuum therapy for pleural empyema. A systematic search of MEDLINE and the Cochrane Database was performed independently by two reviewers using predefined criteria according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. In addition, abstracts from selected conference proceedings were screened and reference scanning of the search results was performed. Single case reports were excluded. Fourteen studies met the selection criteria and were reviewed. A total of 165 patients were treated with vacuum therapy in the studies reviewed. 61.2% of the patients had pleural empyema secondary to thoracic surgery. In 71.5% of the patients, vacuum therapy was applied following open window thoracostomy (OWT). Mortality rates of 0-33% were reported for vacuum therapy after OWT and 0-9.3% for vacuum therapy without OWT. Length of hospital stay (LOHS) ranged from 44-217 days for patients after OWT and could not be analysed for vacuum therapy without OWT due to lacking data. Median treatment time was 7-14 days. Treatment related complications were rare overall. Success rates defined as infection resolution were high irrespective of previous treatment and cause of empyema. The current literature shows that pleural vacuum therapy is a promising, safe, and feasible treatment alternative to existing treatment modalities for pleural empyema. However, the evidence for vacuum therapy without OWT is poor, and further data, optimally prospective or randomised control trials comparing the conventional surgical approach of video-assisted thoracoscopic surgery (VATS) decortication and minimally invasive vacuum therapy, are needed.

Saline lavage for the management of severe pleural empyema: A cohort study.

Despite advances in the treatment of pleural infection, up to 20% of patients die. So far, studies assessing the role of intrapleural saline lavage for the management of all stage pleural infections are very scarce, usually excluding patients with cancer. The method used was a retrospective cohort study including pleural empyema managed with a pleural lavage of saline solution through a small-bore chest tube. The primary outcome was the rate of failure at 3months (surgical referral or additional pleural manoeuver due to recurrent infection or all-cause mortality). Secondary outcomes were hospital stay, the change of the chest radiograph and inflammatory biomarkers, and complications. Thirty patients with pleural empyema were included, 11 (36.7%) with an active cancer. The overall rate of failure at 3months was 13.3% (surgical referral = 0; additional pleural manoeuver = 3; mortality = 1). Median length of pleural lavage and hospital stay were, respectively, 14 days (7-28) and 17 days (11-42). Inflammatory markers and size of the effusion on chest radiograph significantly decreased for Day 0 to Day 14. No chest tube blockade was reported, but seven (23.3%) accidentally withdrew. No other side effects were reported. Intrapleural saline lavage is efficient and safe for the management of pleural empyema, even in severe status patients with cancer, at the cost of a prolonged hospitalization.

Use of fibrinolytics and deoxyribonuclease in patients with pleural infection

Just over a decade ago, it was widely accepted that intrapleural instillation of fibrinolytics was ineffective in treatment of pleural infection. Due to the accumulation of clinical study evidence, an expert team from several countries developed an international consensus and recommended that tissue plasminogen activator and deoxyribonuclease should be instilled intrapleurally at the same time as the initial treatment, or as a follow-up treatment after surgery for pleural infection. The recommended dosages are as follows: tissue plasminogen activator 10 mg, twice a day, deoxyribonuclease 5 mg, twice a day. The future researches should focus on optimizing the tissue plasminogen activator and deoxyribonuclease schemes and developing more effective fibrinolytics.

Role of medical thoracoscopy in the treatment of complicated parapneumonic effusions.

Objective:The role of medical thoracoscopy in the treatment of pleural infections is increasingly being recognized. This study was done to assess the role of medical thoracoscopy in the management of carefully selected subset of patients with complicated parapneumonic effusions (PPEs).Materials and Methods:We analyzed retrospective data of 164 thoracoscopic procedures performed at our center on patients with complicated PPE in the past 10 years. Patients were subjected to medical thoracoscopy based on ultrasonographic stratification and a computed tomography (CT) thorax. Medical thoracoscopy was performed after an intercostal block under conscious sedation with midazolam (2 mg) and fentanyl (50 mcg) and local anesthesia with lignocaine 2% (10–15 ml), through a single port 10 mm diameter thoracoscope.Results:A total of 164 patients (119 males and 45 females) underwent medical thoracoscopy during the study period. The mean age was 47.4 ± 15.9 (median, 50; range, 16–86). The final diagnosis by thoracoscopy was bacterial empyema in 93 patients and tuberculosis in 71 patients. Medical thoracoscopy was successful without subsequent intervention in 160 (97.5%) patients, two patients underwent a second procedure, in the form of decortication, and two patients died due to sepsis. There were no major procedure-related complications that required intervention.Conclusion:Early adhesiolysis and drainage of fluid using medical thoracoscopy should be considered in patients with multiloculated complicated PPE after careful radiological (ultrasonography and CT) stratification, as a more cost-effective and safe method of management.

High Occurrence of Thrombo-Embolic Complications During Long-Term Follow-up After Pleural Infections\u2014A Single-Center Experience with 536 Consecutive Patients Over 17 Years

PurposePleural infections are associated with significant inflammation, long hospitalizations, frequent comorbidities, and are often treated operatively—all of which are consequential risk factors for thrombo-embolic complications. However, their occurrence following the treatment of pleural infection is still unknown. The aim of the study was to ascertain the early and long-term occurrence of thrombo-embolic events in patients treated for pleural infections.MethodsThe study included all patients that were treated for pleural infections in Tampere University Hospital between January 2000 and December 2016. Data regarding later treatment episodes due to pulmonary embolisms and/or deep vein thromboses as well as survival data were requested from national registries. The rates were also compared to a demographically matched reference population adjusted for age, sex, and the location of residence.ResultsThe final study population comprised 536 patients and 5318 controls (median age 60, 78% men). The most common etiology for pleural infection was pneumonia (73%) and 85% underwent surgical treatment for pleural infection. The occurrence of thrombo-embolic complications in patients and controls was 3.8% vs 0.1% at three months, 5.0% vs 0.4% at one year, 8.8% vs 1.0% at three years, and 12.4% vs 1.8% at five years, respectively, p < 0.001 each. Female sex, advanced age, chronic lung disease, immunosuppression, video-assisted surgery, and non-pneumonic etiology were associated with a higher incidence of thrombo-embolism.ConclusionsThe occurrence of thrombo-embolic events—particularly pulmonary embolism but also deep vein thrombosis—was significant in patients treated for pleural infections, both initially and during long-term follow-up.

Recent developments in the management of pleural infection: A comprehensive review.

Pleural infection is a condition commonly encountered by the respiratory physician. This review aims to provide the reader with an update on the most recent data regarding the epidemiology, microbiology, and the management of pleural infection. Medline was searched for articles related to pleural infection using the terms "pleural infection," "empyema," and "parapneumonic." The search was limited to the years 1997-2017. Only human studies and reports in English were included. A rise in the incidence of pleural infection is seen worldwide. Despite the improvement in healthcare practices, the mortality from pleural infection remains high. The role of oral microflora in the etiology of pleural infection is firmly established. A concise review of the recent insights on the pathogenesis of pleural infections is presented. A particular focus is made on the role of tPA, DNAse and similar substances and their interaction with inflammatory cells and how this affects the pathogenesis and treatment of pleural infection. Pleural infection is a common disease with significant morbidity and mortality, as well as a considerable economic burden. The role of medical management is expanding thanks to the widespread use of newer treatments.

Concurrent Versus Sequential Intrapleural Instillation of Tissue Plasminogen Activator and Deoxyribonuclease for Pleural Infection.

Treatment of pleural infection with instillation of sequential intrapleural tissue plasminogen activator (tPA) and human recombinant deoxyribonuclease (DNase) twice daily for a total of 6 doses has been shown to decrease surgical referral and improve radiographic imaging. This labor-intensive regimen was empirically chosen. Thus, it remains unclear whether the 2 drugs can be administered immediately one after the other (concurrent administration) instead of instilling them separately with a 1-hour to 2-hour interval in between (sequential administration). The aim of this study was to compare the efficacy and safety of sequential versus concurrent tPA/DNase therapy in patients with pleural infection. This was a prospective observational study. Consecutive patients with pleural infection who received concurrent and sequential tPA/DNase were included. The initiation and number of doses of tPA/DNase therapy were based on the amount of pleural fluid drainage, clinical response and radiographic findings. A total of 38 patients with pleural infection received tPA/DNase treatment: 18 in the sequential group and 20 in the concurrent group. Treatment was successful in 77.7% in the sequential group and 75% in concurrent group (P=0.57). There was no statistically significant difference between the 2 treatment groups (sequential and concurrent) in median pleural fluid drainage (P=0.45), median volume of pleural effusion estimated on chest computed tomography scan (P=0.4) or median hemithorax occupied by effusion on chest radiography (P=0.83) following intrapleural therapy. One patient required a blood transfusion for gradual pleural blood loss in each treatment group. Pain needing escalation of analgesia affected 3 patients in each arm but none required cessation of therapy. A simpler regimen of concurrent administration of intrapleural tPA/DNase as compared with sequential intrapleural therapy is safe, effective, and represents a viable option for the management of pleural infection.

Advances in pleuroscopy.

To describe the technique of pleuroscopy, its clinical uses such as diagnosis of exudative pleural effusion, treatment of pleural infection, treatment of pneumothorax, and diagnosis and pleurodesis of malignant pleural mesothelioma. Also to describe the newer techniques developed such as minothoracoscopy, semirigid thoracoscopy, narrow band imaging pleuroscopy, infrared pleuroscopy, autofluorescence pleuroscopy. We searched the pubmed the last decade for publications with the keywords pleuroscopy, medical thoracoscopy, pneumothorax and pleuroscopy, malignant pleural mesothelioma, minothoracoscopy, semirigid thoracoscopy, autofluorescence pleuroscopy. Medical thoracoscopy is the method of choice for investigation of the undiagnosed exudative pleural effusions. Newer techniques, such as narrow band imaging thoracoscopy, infrared thoracoscopy, autofluorescence thoracoscopy are offering a promising future for medical thoracoscopy.

Concurrent Intrapleural Instillation of Tissue Plasminogen Activator and DNase for Pleural Infection. A Single-Center Experience.

Treatment of pleural infection with instillation of intrapleural tissue plasminogen activator (tPA) and human recombinant DNase (DNase) has been proven to decrease the length of hospital stay, decrease surgical referral, and improve drainage. The optimal dosage, administration, timing, and frequency of the regimen remain unclear. It is unknown if the two drugs can be administered immediately one after the other (referred to as concurrent) instead of instilling them separately with a 1- to -2-hour interval in between. To assess the safety and efficacy of concurrent instillation of intrapleural tPA/DNase guided by radiographic and clinical response in patients with pleural infection. We conducted a retrospective cohort study. Consecutive patients with pleural infection who received concurrent tPA/DNase were included. The initiation and number of doses of tPA/DNase therapy were based on pleural fluid drainage, clinical response, and radiographic findings. Seventy-three patients received concurrent tPA/DNase therapy. Treatment was successful in 90.4% of them; 80.8% were effectively treated with fewer than six doses of therapy (median, 2; interquartile range [IQR], 1-3.5); and 71.2% received their first dose of tPA/DNase within 24 hours after chest tube insertion. The median hospital stay from the first dose of tPA/DNase to discharge was 7 days (IQR, 5-11 d). The volume of pleural fluid drained increased from a median of 295 ml (IQR, 97.5-520 ml) 24 hours before treatment to a median of 1,102 ml (IQR, 627-2,200 ml) 72 hours following therapy (P < 0.001). Nonfatal pleural bleeding occurred in 5.4%, 15.1% had chest pain, and 2.7% died as a result of pleural infection. This cohort study shows that early administration of concurrent tPA/DNase in patients with pleural infection is relatively safe and effective. Given the high cost of therapy, it is feasible to guide therapy on the basis of clinical and radiographic response.

Pleural effusion adenosine deaminase: a candidate biomarker to discriminate between Gram-negative and Gram-positive bacterial infections of the pleural space

OBJECTIVES:Delay in the treatment of pleural infection may contribute to its high mortality. In this retrospective study, we aimed to evaluate the diagnostic accuracy of pleural adenosine deaminase in discrimination between Gram-negative and Gram-positive bacterial infections of the pleural space prior to selecting antibiotics.METHODS:A total of 76 patients were enrolled and grouped into subgroups according to Gram staining: 1) patients with Gram-negative bacterial infections, aged 53.2±18.6 years old, of whom 44.7% had empyemas and 2) patients with Gram-positive bacterial infections, aged 53.5±21.5 years old, of whom 63.1% had empyemas. The pleural effusion was sampled by thoracocentesis and then sent for adenosine deaminase testing, biochemical testing and microbiological culture. The Mann-Whitney U test was used to examine the differences in adenosine deaminase levels between the groups. Correlations between adenosine deaminase and specified variables were also quantified using Spearman’s correlation coefficient. Moreover, receiver operator characteristic analysis was performed to evaluate the diagnostic accuracy of pleural effusion adenosine deaminase.RESULTS:Mean pleural adenosine deaminase levels differed significantly between Gram-negative and Gram-positive bacterial infections of the pleural space (191.8±32.1 U/L vs 81.0±16.9 U/L, p<0.01). The area under the receiver operator characteristic curve was 0.689 (95% confidence interval: 0.570, 0.792, p<0.01) at the cutoff value of 86 U/L. Additionally, pleural adenosine deaminase had a sensitivity of 63.2% (46.0-78.2%); a specificity of 73.7% (56.9-86.6%); positive and negative likelihood ratios of 2.18 and 0.50, respectively; and positive and negative predictive values of 70.6% and 66.7%, respectively.CONCLUSIONS:Pleural effusion adenosine deaminase is a helpful alternative biomarker for early and quick discrimination of Gram-negative from Gram-positive bacterial infections of the pleural space, which is useful for the selection of antibiotics.

S12 Experience with Intrapleural Tissue Plasminogen Activator and DNase in the Treatment of Pleural Infection

IntroductionIntrapleural infection remains a significant cause of morbidity and mortality. In many patients medical management with chest tube drainage and antibiotics fails and surgical intervention is required. The MIST2 trial...

The most common isolates from pleural infections

Isolation and identification of the pathogens are important for appropriate treatment of pleural infections. Distribution of the most frequent causative agents varies throughout the world and may change in time.The objective of the study is to analyze the bacteriological isolates of pleural fluids in order to identify the most frequent infectious agents and assess their variability in time.The retrospective study included 272 patients with positive pleural fluid samples analyzed in 5-year period. The samples were examined using the conventional microbiological technique.Of 315 bacterial isolates the most common were streptococcal species, 105 (33%), of which 55 (17.3%) represented the Streptococcus milleri group. Gram-positive anaerobic cocci were detected in 56 (17.6%) isolates. Enterobacteriaceae family included 27 (8.5%) isolates and Pseudomonas aeruginosa was registered in 13 (4.1%). No statistically significant difference was registered in pathogen distribution in the examined period (p = 0.288).The most common agents of community-acquired pleural infections are the Streptococcus milleri group and anaerobic Gram-positive cocci. They differ from the most common pathogens of pneumonia. Among the hospital-acquired pleural infections, Pseudomonas species, Staphylococcus aureus and enterobacteria prevail. The distribution of bacterial agents isolated in the 5-year period exhibits no significant differences.

Intrapleural agents for pleural infection

Pleural infection is a common, increasing clinical problem with a high morbidity and mortality. Medical management of pleural infection often fails, requiring invasive thoracic surgery to drain infected pleural collections, and for many years intrapleural agents have been assessed to reduce the need for surgical drainage and improve clinical outcomes. Randomized trials assessing intrapleural fibrinolytic agents have given conflicting results, and recent evidence provides important information on the role of intrapleural agents in the treatment of pleural infection, and the possible biology associated with infection progression in these patients. Pleural infection is increasing in both the adult and paediatric populations. The combined previous evidence assessing intrapleural fibrinolytics alone in pleural infection suggests lack of efficacy for clinically important outcomes. The Multi-Centre Intrapleural Sepsis Trial 2 (MIST2) study provides the first evidence of a novel treatment combination [intrapleural tissue plasminogen activator (tPA) combined with intrapleural deoxyribonuclease (DNase)], which significantly improves the chest radiograph compared with either agent alone or placebo, and has potentially important benefits to important clinical outcomes (need for surgery and hospital stay). The precise mechanism of action of combination fibrinolytic and DNase in pleural infection is speculative. Fibrinolytic therapy alone has not been proven to be of use in the treatment of pleural infection. The MIST2 study provides clear-cut evidence demonstrating improved chest radiographs, and highly suggestive secondary outcomes suggesting improved clinically important outcomes, using a combination of intrapleural tPA and DNase. This novel treatment combination may represent an important step in our understanding and treatment of pleural infection; however, larger clinical studies specifically addressing important clinical outcomes and further laboratory research describing the potential mechanisms of action are now required.

Advances in the investigation and treatment of pleural effusions

Pleural effusions present a challenge for both diagnosis and treatment. They are a commonly presenting problem of a wide range of local and systemic potentially life threatening diseases and cause significant breathlessness. Significant advances have been made in the last 5 years in the diagnostic pathway and management options. This article reviews recent developments in the investigation of pleural effusions, particularly in pleural fluid analysis, biomarkers, imaging and pleural biopsy, and in the treatment of pleural infection and both malignant and benign effusions, including the use of indwelling pleural catheters. Although significant recent advances have been made in the management of pleural effusions, there the need still remains for further research if we are to reduce the morbidity and mortality caused by pleural effusions.

Recombinant tissue plasminogen activator in the treatment of pleural infections in adults

Intrapleural recombinant tissue plasminogen activator (r-TPA) has been successfully evaluated in pediatric patients with complicated parapneumonic pleural effusion (CPE) and pleural empyema (PE). Yet, there is no data concerning r-TPA in adults with CPE/PE. The aim of our study was to investigate the efficacy and complications of r-TPA in adult patients with CPE/PE. Twenty consecutive patients (mean age 50+/-18.9 years) with pleural infection (14 CPE and 6 PE) were included. Chest tube was inserted under guidance of chest ultrasound and/or computed tomography. After failure of pleural fluid drainage, 25mg of r-TPA was administered intrapleurally in a single daily dose. The evaluation was made according to imaging and clinical status. The mean volume of fluid increased significantly after r-TPA administration (p<0.0001). White blood cells count (WBC) and C-reactive protein (CRP) were significantly improved after r-TPA instillations (both p<0.0001). Significant clinical and imaging improvement was noted in all but one patient after r-TPA administration (overall p<0.0001). Complications observed were mild: pain in 4 (25%) and local bleeding in 3 (15%) patients. The median number of r-TPA instillations was 3 (range 2-5). Intrapleural instillation of r-TPA at a dose of 25 mg is a well-tolerated and effective treatment in 95% of our adult patients with CPE/PE.

Diagnosis and Management of Infectious Pleural Effusion

Pleural infection remains a common illness, with a high morbidity and mortality. The development of frank empyema from a simple exudative pleural effusion is a result of biochemical changes within the pleural space in response to bacterial invasion. These changes can be used in the diagnosis of pleural infection and used to predict which patients will require intercostal drainage for resolution of infection. Recent large trials in empyema have further advanced our knowledge of microbiologic patterns, informing important decisions about empiric antibacterial therapy. Diagnosis of pleural infection relies on high clinical suspicion in association with clinical features, radiology, and pleural fluid characteristics. Treatment of pleural infection is based upon accurate and often empiric choice of antibacterial agents, intercostal drainage in certain contexts, and appropriate surgical referral. Intrapleural thrombolytic therapy is not currently recommended for the treatment of pleural infection, on the basis of evidence from the largest randomized trial in empyema to date.

Recent advances in parapneumonic effusion and empyema.

Complicated parapneumonic effusion and empyema continue to account for significant morbidity and mortality, and uncertainties remain regarding their optimal management. This review describes recent advances in this field, as well as areas for future research. Recent advances have addressed the pathogenesis, bacteriology, and treatment of pleural infection. Key areas for research in the development of empyema include the interplay between inflammatory and coagulation cascades and development of fibrosis within the pleural space. The varied bacteriology of empyema has been more clearly defined, and in particular the differences between community- and hospital-acquired infection highlighted. Studies of treatment have focused particularly on the roles of intrapleural fibrinolytics and surgery. Increased understanding of the pathogenesis of empyema may ultimately yield novel therapeutic targets. Comprehensive descriptions of the bacteriology of empyema aids antibiotic choice, and the use of intrapleural DNase shows promise in facilitating drainage of infected pleural fluid. Uncertainties remain, such as the role of intrapleural fibrinolytics and the optimal timing of surgical intervention.

The management of pleural space infections.

Pleural infection is responsible for significant morbidity and mortality worldwide, and its clinical management is challenging. The diagnosis of empyema and tuberculous pleurisy may be difficult, and these conditions may be confused with other causes of exudative pleural effusions. Complicated parapneumonic effusion or empyema may present with 'atypical' clinical features; delays in diagnosis are common and may contribute to the high mortality of these infections. Pleural aspiration is the key diagnostic step; pleural fluid that is purulent or that has a pH < 7.2, or organisms on Gram stain or culture, is an indication for formal intercostal drainage. In order to achieve a definitive diagnosis of tuberculous pleurisy, Mycobacterium tuberculosis must be isolated in the culture of pleural fluid, pleural tissue or sputum; demonstration of granulomas in pleural tissue is also suggestive of tuberculosis. The use of pleural fluid biochemical markers, such as adenosine deaminase, in the diagnosis of tuberculous pleurisy varies among clinicians; the diagnostic value of such markers is affected by the background prevalence of tuberculosis and the likelihood of an alternative diagnosis. Uncertainties also remain regarding the treatment of pleural infection. Treatment of complicated parapneumonic effusion and empyema involves prolonged courses of antibiotics and attention to the patient's nutritional state. The role of intrapleural fibrinolytics and the optimal timing of surgical intervention are unknown. The lack of clear predictors of clinical outcome in empyema contributes to the difficulty in treating this condition. The pharmacological treatment of tuberculous pleurisy is the same as for pulmonary tuberculosis; the precise role of steroids in the treatment of tuberculous pleurisy remains uncertain.

The Preparation of Partially Purified Plasmin, and an Account of Its Intrathecal Use in Patients

The treatment of tuberculous meningitis is frequently hindered by the formation of exudate within the cerebrospinal spaces. This exudate may obstruct the cerebrospinal circulation and give rise to the complications of subtentorial, basal cistern, and spinal block. Furthermore, the presence of exudate predisposes to the occurrence of tuberculous arteritis, which is responsible for the cerebral and spinal cord softenings frequently found in this disease (1-4). Cathie (5) introduced the use of intrathecal streptokinase to prevent the formation of, and to remove exudate. It was hoped that the use of this agent would reduce the incidence of complications, render chemotherapy more effective, and lessen the likelihood of relapse. Clinical trials in tuberculous meningitis with streptokinase have yielded contradictory results (6-9). The majority of investigators believe that its value remains unproven. Streptokinase has no intrinsic proteolytic properties, but activates a precurser plasminogen to form a proteolytic enzyme plasmin, the action of whichmay be inhibited bybody fluids (10). Streptokinase was used in the treatment of pleural infections by Tillett and Sherry (11), who showed that clinical response was dependent upon the demonstration of adequate fibrinolytic activity in these fluids. Investigators interested in intrathecal treatment have relied upon clinical response to assess the adequacy of the dose, and have for the most part employed a dose of 100 Christensen units (600 Cathie units) of streptokinase for intrathecal use. The development of methods for the measurement of the various components of the plasminogen-plasmin system in biological fluids (12) led Fletcher (13) to determine the composition of the cerebrospinal fluid with respect to these compo