Response

To the Editor:

We thank Dr Thommi and colleagues for their comments regarding our point/counterpoint debate^1-4 on the use of fibrinolytics in managing complicated parapneumonic effusions. There are two points raised in this letter that should be considered. First, the effective dosing regimen for intrapleural administration of tissue plasminogen activator (tPA) in managing complicated parapneumonic effusions has not been confirmed by appropriate phase 1/2 dose escalation and phase 2 dose-response studies. While determination of the dosing regimen for any drug can be challenging, it is especially important when using intrapleural tPA to manage complicated parapneumonic effusions. This is because both dose and dosing interval must be considered; dosing efficacy requires precise definition, and tPA inhibitors, including plasminogen activator inhibitor-1 that is typically increased in these effusions, may affect outcomes.² Unfortunately, studies in this area have not adequately addressed these issues.

The second Multicenter Intrapleural Sepsis Trial (MIST2) studied only a single dosing regimen of tPA: 10 mg bid administered intrapleurally for 3 days.⁵ A justification for this dose and dosing interval was not provided. Dr Thommi and colleagues should be applauded for exploring the effect of higher doses of tPA. They administered intrapleural tPA doses ranging from 10 mg to 100 mg once daily for 3 days.⁶ We are perplexed, though, by the approach used to determine the dosing regimen. Apparently, doses of tPA were adjusted upward for more turbid pleural effusions and downward for complicated malignant effusions. Also, tPA dosing could have been continued for > 3 days based on clinical response. Using objective measures to determine dosing adjustments in these studies would have been preferred. In a later study, Thommi et al⁷ administered 25 mg of tPA once daily for 3 days, but did not explain why this dose was chosen.⁷ Further studies of fibrinolysins for managing complicated parapneumonic effusions in adults are reasonable, particularly if an appropriate dosing regimen is validated.

Second, the risk/benefit balance for intrapleural tPA should be carefully evaluated. There are safety concerns with intrapleural administration of tPA related to bleeding risk. In a retrospective review, four of 57 patients (7%) treated with intrapleural tPA for a parapneumonic effusion (PPE) or empyema suffered a bleeding complication, some of which were serious.⁵ Although in their letter Dr Thommi and colleagues advise against use of tPA in patients with coagulopathy, thrombocytopenia, and/or platelet dysfunction, in their own experience and despite using these exclusion criteria, they reported that two of 68 patients (3%) had clinically meaningful bleeding after intrapleural tPA.⁷ Balanced against the bleeding risk with tPA, Rahman et al⁵ concluded in the well-performed MIST2 that intrapleural administration of “tPA alone was ineffective.” With possible risk but no consistent benefit, we do not favor routine administration of intrapleural tPA for adults with a PPE requiring drainage.

Our recommended approach is straightforward. Evaluate patients with pneumonia for a PPE. If a PPE is present, determine whether drainage is recommended. If drainage would provide benefit, perform tube thoracostomy and consult thoracic surgery. If there is clear, rapid clinical improvement in the PPE with tube thoracostomy and antibiotics, no further steps may be needed. If, however, tube thoracostomy does not provide adequate pleural drainage and the clinical picture does not improve, the next step should be video-assisted thoracoscopic surgery to effectively break down loculations and drain the pleural space under direct vision. In patients with limiting comorbid conditions or in whom surgery is not an option, administration of intrapleural tPA/DNase should be considered.