Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) Study-2: Use of 2.5 mg alteplase as a starting intrapleural dose.

BACKGROUND AND OBJECTIVE: Intrapleural tissue plasminogen activator/deoxyribonuclease (tPA/DNase) therapy is increasingly used in pleural infection. Bleeding risks and costs associated with tPA remain the clinical concerns. Our dose de-escalation series aims to establish the lowest effective dosing regimen for tPA/DNase. This study assesses the intrapleural use of 2.5 mg tPA/5 mg DNase for pleural infection. METHODS: Consecutive patients with pleural infection treated with a starting regime of 2.5 mg tPA/5 mg DNase were included from two centres in Australia and UK. Escalation of tPA dose was permitted if clinical response was inadequate. RESULTS: Sixty-nine patients (mean age 61.0 years) received intrapleural 2.5 mg tPA/5 mg DNase. Most (88.4%) were treated successfully and discharged from hospital without surgery by 90 days. Patients received a median of 5 [interquartile range [IQR] = 3-6] doses of tPA/DNase. Total amount of tPA used per patient was 12.5 mg [median, IQR = 7.5-15.0]. Seventeen patients required dose escalation of tPA; most (n = 12) for attempted drainage of distant non-communicating locule(s). Treatment success was corroborated by clearance of pleural opacities on radiographs (from median 27.0% [IQR = 17.1-44.5] to 11.0% [IQR = 6.4-23.3] of hemithorax, p < 0.0001), increased pleural fluid drainage (1.98 L [median, IQR = 1.38-2.68] over 72 h following commencement of tPA/DNase) and reduction of serum C-reactive protein level (by 45.0% [IQR = 39.3-77.0] from baseline at day 5, p < 0.0001). Two patients required surgery. Six patients with significant comorbidities (e.g., advanced cancer) had ongoing infection when palliated and died. Two patients experienced self-limiting pleural bleeding and received blood transfusion. CONCLUSION: A starting intrapleural regime of 2.5 mg tPA/5 mg DNase, with up-titration if needed, can be effective and deserves further exploration.

Effectiveness of Intrapleural Tissue Plasminogen Activator and Dornase Alfa vs Tissue Plasminogen Activator Alone in Children with Pleural Empyema: A Randomized Clinical Trial.

Importance: Clinical guidelines recommend that children with pleural empyema be treated with chest tube insertion and intrapleural fibrinolytics. The addition of dornase alfa (DNase) has been reported to improve outcomes in adults but remains unproven in children. Objective: To determine if intrapleural tissue plasminogen activator (tPA) and DNase is more effective than tPA and placebo at reducing hospital length of stay in children with pleural empyema. Design, Setting, and Participants: This multicenter, parallel-group, placebo-controlled, superiority randomized clinical trial included children diagnosed as having pleural empyema requiring drainage aged 6 months to 18 years treated at 6 tertiary Canadian children's hospitals. A total of 379 children were assessed for eligibility; 281 were excluded and 98 were randomized. One child was excluded after randomization for not meeting the inclusion criteria. Data were collected from March 4, 2013, to December 13, 2017. Interventions: Participants underwent chest tube insertion and 3 daily administrations of intrapleural tPA, 4 mg, followed by DNase, 5 mg (intervention group), or 5 mL of normal saline (placebo; control group). Participants, families, clinical staff, and members of the study team were blinded to allocation. Main Outcomes and Measures: The primary outcome was hospital length of stay from chest tube insertion to discharge. Secondary outcomes included time to meeting discharge criteria, time to chest tube removal, mean fever duration, additional pleural drainage procedures, hospital readmissions, and total health care cost. Results: Of the 97 analyzed children with pleural empyema, 52 (54%) were male, and the mean (SD) age was 5.1 (3.6) years. A total of 49 children were randomized to tPA and DNase and 48 were randomized to tPA and placebo. Treatment with tPA and DNase was not associated with decreased hospital length of stay compared with tPA and placebo (mean [SD] length of stay, 9.0 [4.9] vs 9.1 [5.3] days; mean difference, -0.1 days; 95% CI, -2.0 to 2.1; P = .96). Similarly, no significant differences were observed for any of the secondary outcomes. Of the 14 adverse events in the tPA and DNase group, 6 (43%) were serious; of the 21 adverse events in the tPA and placebo group, 8 (38%) were serious. There were no deaths. Conclusions and Relevance: The addition of DNase to intrapleural tPA for children with pleural empyema had no effect on hospital length of stay or other outcomes compared with tPA with placebo. Clinical practice guidelines should continue to support the use of chest tube insertion and intrapleural fibrinolytics alone as first-line treatment for pediatric empyema. Trial Registration: ClinicalTrials.gov identifier: NCT01717742.

Role of Intrapleural Urokinase in Empyema Thoracis.

OBJECTIVE: To study the role of fibrinolytic therapy in pediatric empyema in relation to duration of hospital stay, need for surgical intervention and survival to discharge. METHODS: Retrospective analysis of case records of children <16 y of age admitted in a tertiary care hospital during January 2013 - December 2017 with diagnosis as empyema thoracis was done. Clinico-laboratory characteristics and the primary and secondary outcomes between the group which received intrapleural urokinase (IPU) and the group which did not (non IPU), were compared. RESULTS: Of the 84 cases, 40 children received IPU. Mean duration of hospital stay in IPU group (17.51 + 4.57 d) was significantly less than non IPU group (24.32 + 10.18 d, CI -10.19 to -3.64, p < 0.001), so was the duration of intercostal drain (ICD) insertion (9.08 + 3.12 d - IPU group vs. 11.20 + 3.95 d - non IPU group, CI -3.68 to -0.50, p < 0.01). No statistically significant difference was found between the groups with regard to need for surgical intervention [IPU - 4 (10%), non IPU - 9 (20.4%), p = 0.23]. There was no mortality or adverse reaction to urokinase in either group. CONCLUSIONS: IPU holds promising results in terms of reduction of hospital stay and duration of ICD insertion. It may be the initial choice of treatment in septated empyema where surgical options are not easily available or cost-effective especially in resource limited settings.

Intrapleural Dornase and Tissue Plasminogen Activator in pediatric empyema (DTPA): a study protocol for a randomized controlled trial.

BACKGROUND: A randomized controlled trial of adults with empyema recently demonstrated decreased length of stay in hospital in patients treated with intrapleurally administered dornase alfa and fibrinolytics compared to fibrinolytics alone. Whether this treatment strategy is safe and effective in children remains unknown. METHODS/DESIGN: This study protocol is for a superiority, placebo-controlled, parallel-design, multicenter randomized controlled trial. The participants are previously well children admitted to a children's hospital with a diagnosis of empyema requiring chest tube insertion and fibrinolytics administered intrapleurally. Children will be randomized after the treating physician has decided that pleural drainage is required but prior to chest tube insertion. After chest tube insertion, participants in the treatment group will receive intrapleurally administered tissue plasminogen activator (tPA) 4 mg followed by dornase alfa 5 mg. Participants in the placebo group will receive tPA 4 mg followed by normal saline. Study treatments will be administered once daily for 3 days. All participants, parents or caregivers, clinicians, and research personnel will remain blinded. The primary outcome is length of stay from chest tube insertion to discharge from hospital. Secondary outcomes include time to meeting discharge criteria, chest tube duration, fever duration, need for additional procedures, adverse events, hospital readmission, cost of hospitalization, and mortality. DISCUSSION: This multicenter randomized controlled trial will assess the safety, effectiveness, and cost-effectiveness of combined treatment with dornase alfa and fibrinolytics compared to fibrinolytics alone for the treatment of empyema in children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01717742 . Registered on 8 October 2012.

[ANALYSIS OF MICROFLORA OF PLEURAL CAVITY IN PLEURAL EMPYEMA].

In the pleural empyema (PE) treatment, not depending on introduction of multiple operative procedures and the medicinal preparations application, some issues remain unsolved, including the infection agents verification, the most rapid bronchial fistula elimination and the lung volume restoration. The EP infection agents spectrum, their sensitivity to preparations were revealed, as well as the enhanced rate of the methicillin-resistant stamms (MRSA) and the microorganisms associations verification. A reduction of the infection agents sensitivity towards "simple" antibacterial preparations was established, so the physicians, treating PE, must prescribe "hard" antibiotics, what enhances its cost.

[Medical-and-economic substantiation of rational antibacterial therapy for patients with pleural empyema in the conditions of military medical institutions].

We have performed a post-hoc analysis of the results of using antibacterial therapy in patients with pleural empyema. The cost-effectiveness analysis of rational and empiric antibacterial therapies was performed. The cost-effectiveness ratio for rational antibacterial therapy was lower than for empiric one (2889 and 4480 rubles for 1 treated patient correspondingly). The use of the rules of rational antibacterial therapy in practice leads to proved saving of economic costs.

Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema.

BACKGROUND: Despite increasing incidence and morbidity, little evidence exists to inform the best management approach in childhood empyema. AIM: To compare chest drain with intrapleural urokinase and primary video-assisted thoracoscopic surgery (VATS) for the treatment of childhood empyema. METHODS: Children were prospectively randomized to receive either percutaneous chest drain with intrapleural urokinase or primary VATS. The primary outcome was the number of hospital days after intervention. Secondary end points were number of chest drain days, total hospital stay, failure rate, radiologic outcome at 6 mo, and total treatment costs. RESULTS: Sixty children were recruited. The two groups were well matched for demographics; baseline characteristics; and hematologic, biochemical, and bacteriologic parameters. No significant difference was found in length of hospital stay after intervention between the two groups: VATS (median [range], 6 [3-16] d) versus urokinase (6 [4-25] d) (p = 0.311; 95% confidence interval, -2 to 1). No difference was demonstrated in total hospital stay: VATS versus urokinase (8 [4-17] d and 7 [4-25] d) (p = 0.645); failure rate: 5 (16.6%); and radiologic outcome at 6 mo after intervention in both groups. The mean (median) treatment costs of patients in the urokinase arm US dollars 9,127 (US dollars 6,914) were significantly lower than those for the VATS arm US dollars 11,379 (US dollars 10,146) (p < 0.001). CONCLUSIONS: There is no difference in clinical outcome between intrapleural urokinase and VATS for the treatment of childhood empyema. Urokinase is a more economic treatment option compared with VATS and should be the primary treatment of choice. This study provides an evidence base to guide the management of childhood empyema.

Tissue plasminogen activator as an adjuvant therapy for pleural empyema in pediatric patients.

The authors retrospectively review the clinical course and outcome of 6 pediatric patients, ranging in age from 2 to 13 years, who were treated with TPA for complex empyema. Efficacy was assessed by evaluating pleural fluid drainage for 6 hours prior to and subsequent to each dose of TPA, as well as by resolution of fever and length of hospital stay. The average volume drained for 6 hours before infusion of TPA was 22.5 mL +/- 18.4 mL, and the average volume 6 hours after TPA therapy was 141.7 mL +/- 28.3 mL, P <.0001. After initiation of TPA therapy, 5 out of 6 patients became afebrile within 48 hours. The median length of stay after initiation of TPA therapy was 6 days, with a range from 4 days to 12 days. A discussion of other current therapies for empyema, along with a comparison of these therapies to TPA regarding the costs of therapies and risk-benefit ratios, is also included.

Use of urokinase in childhood pleural empyema.

Urokinase is an enzyme with a fibrinolytic effect that facilitates pleural empyema drainage through a chest tube. The aim of this study was to assess the risk of pneumothorax, the need for pleural debridement surgery, the persistence of fever, and the number of days in hospital in a group of children with parapneumonic pleural empyema treated with urokinase. This was an uncontrolled retrospective study on children suffering from parapneumonic empyema. Data collected on 17 children treated with urokinase were compared with 11 children treated prior to the advent of urokinase (the "historic" group). The urokinase was instilled in the pleural cavity over a period ranging from 2-8 days, amounting to a median total dose per kilogram of body weight of 18,556 IU (range, 7,105-40,299). Surgical treatment of the empyema involved drainage tube placement and/or debridement of the pleural cavity. Three children developed pneumothorax during their hospital stay, and one more case occurred 6 months after the child had recovered from his empyema; there were 3 cases of pneumothorax during the acute phase in the "historic" group (P = 0.54). Five children in the urokinase group were debrided and 12 were only drained, as opposed to 9 and 2, respectively, in the "historic" group (P = 0.02). The overall hospital stay was 17 days for the urokinase group, and 24 for the "historic" group (P = 0.02). No bleeding or other major complications were reported in the group treated with urokinase. In conclusion, urokinase treatment does not carry a risk of pneumothorax, while it does reduce hospital stay and the need for pleural debridement.

Rational treatment of empyema in children.

HYPOTHESIS: Efficacious and cost-effective treatment of pediatric empyema can be accomplished following a protocol based on its radiographic appearance. Therapeutic modalities include thoracostomy tube drainage (TTD) with or without fibrinolytic therapy (FT) and video-assisted thoracoscopic debridement (VATD). DESIGN: Retrospective case series. SETTING: Tertiary referral center. RESULTS: From 1995 through 1999, 31 children were treated ranging in age from 11 months to 18 years (mean age, 5.1 years). Twenty-seven (87.1%) underwent TTD; of these, 22 (81.5%) received FT with urokinase. The TTD failed in 4 children (14.8%) who required salvage VATD. Primary VATD was performed in another 4 children (12.9%). The mean length of stay was 14.6 days (TTD, 14.1 days; salvage VATD, 20. 0 days; primary VATD, 11.5 days), ranging from 8.0 to 30.0 days. Complications included readmission for fever (2 patients [6.5%]) and gastrointestinal bleeding (1 patient [3.2%]). There were no anaphylactic reactions or bleeding episodes due to urokinase. Two patients (7.4%) treated with TTD and FT developed an air leak that resolved spontaneously. The mean hospital charges were $78,832 (TTD with or without FT, $75,450; salvage VATD, $107,476; primary VATD, $69,634). The procedural charges were highest for salvage VATD. CONCLUSIONS: Most cases of pediatric empyema can be treated by TTD with or without FT. This therapy is safe and effective for children with nascent disease. Primary VATD is preferred in children with advanced disease. Cost-effectiveness could be further improved through better prediction of those patients likely to fail TTD and require salvage VATD. An algorithmic approach based on findings from computed tomography or (better) ultrasonography of the chest may be the best way to make this distinction and rationalize care.

Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study.

Intrapleural administration of fibrinolytics has been shown in small numbers of patients with complicated parapneumonic effusions (CPE) and pleural empyema to be effective and relatively safe. Although streptokinase (SK) is recommended as the fibrinolytic of choice, there are no comparative studies among fibrinolytics. We therefore compared the efficacy, safety, and the cost of treatment two of the most used thrombolytics, SK and urokinase (UK). Fifty consecutive patients with CPE or empyema were randomly allocated to receive either SK (25 patients) or UK, in a double-blind fashion. All patients had inadequate drainage through chest tube (< 70 ml/24 h). Both drugs were diluted in 100 ml normal saline and were infused intrapleurally through the chest tube in a daily dose of 250,000 IU of SK or 100,000 IU of UK. The chest tube was clamped for 3 h after instillation. Response was assessed by clinical outcome, fluid drainage, chest radiography, pleural ultrasound, and/or computed tomography. Clinical and radiologic improvement was noted in all but two patients in each group, who required surgical intervention. The mean volume drained during the first 24 h after instillation was significantly increased; 380 +/- 99 ml for the SK group (p < 0.001) and 420.8 +/- 110 ml for the UK group (p < 0.001). The total volume (mean +/- SD) of fluid drained after treatment was 1,596 +/- 68 ml for the SK group, and 1,510 +/- 55 ml for the UK group (p > 0.05). The SK instillations (mean +/- SD) were 6 +/- 2.16 (range, 3 to 10) and those of UK 5.92 +/- 2.05 (range, 3 to 8). High fever as adverse reaction to SK was observed in two patients. The total cost of the drug in the UK group was two times higher than that of SK ($180 +/- 47 for SK and $320 +/- 123 for UK). The mean total hospital stay after beginning fibrinolytic therapy was 11.28 +/- 2.44 d (range, 7 to 15) for the SK group and 10.48 +/- 2.53 d (range, 6 to 18) for the UK group (p = 0.32). We conclude that intrapleural SK or UK is an effective adjunct in the management of parapneumonic effusions and may reduce the need for surgery. UK could be the thrombolytic of choice given the potentially dangerous allergic reactions to SK and relatively little higher cost of UK.

Intrapleural fibrinolytic treatment of multiloculated thoracic empyemas.

Acute multiloculated thoracic empyemas incompletely drained by tube thoracostomy alone usually require operation. To avoid a thoracotomy yet treat this difficult problem, intrapleural fibrinolytic agents were employed. Between April 1, 1990, and April 1, 1993, 13 consecutive patients presenting with a fibrinopurulent empyema were demonstrated to have incomplete drainage. To facilitate drainage, streptokinase, 250,000 units in 100 mL 0.9% saline solution (3 patients), or urokinase, 100,000 units in 100 mL 0.9% saline solution (10 patients), was instilled daily into the chest tube, and the tube was clamped for 6 to 12 hours followed by suction. This routine was continued daily for a mean of 6.8 +/- 3.7 days (range, 1 to 14 days) until resolution of the pleural fluid collection was demonstrated by computed chest tomography and clinical indications. This regimen was completely successful in 10 of 13 patients (77%), who had resolution of the empyema, eventual withdrawal of chest tubes, and no recurrence. Two patients, both pediatric liver transplant patients, had an initial good response but eventually required decortication. One patient with a good radiographic response became increasingly febrile during streptokinase therapy and underwent a thoracotomy, but no significant undrained fluid was found. This patient's continued fever was believed to be a streptokinase reaction. Urokinase was used subsequently. No treatment-related mortalities or complications occurred. Intrapleural fibrinolytic agents, especially urokinase, are safe, cost-effective means of facilitating complete chest tube drainage, thereby avoiding the morbidity of a major thoracotomy for 77% of a group of multiloculated empyema patients who traditionally would have required open surgical therapy.