Multicenter Trials of Treatment for Empyema — After All These Years
http://www.100md.com
《新英格兰医药杂志》
It is paradoxical that Hippocrates established in ancient times the clinical importance of pleural infections, yet only a few high-quality trials have studied this common condition during the intervening 2400 years. Just five years ago, published guidelines for the management of empyema1 could identify only three relevant controlled trials, with a combined enrollment of fewer than 100 patients. This lack of evidence results partly from difficulties that are inherent in investigating pleural infections, which represent heterogeneous disorders with outcomes strongly influenced by multiple factors that include coexisting illnesses, underlying lung function, the severity of associated pneumonia, the extent of pleural inflammation, and the virulence of the causative pathogens. Controlling for these confounders requires large studies that necessitate multiple sites, selective inclusion criteria to enroll sufficiently homogeneous populations with a reasonable likelihood of having a response to a study intervention, and rigorous treatment protocols to limit the bias that results when different investigators use poorly reproducible clinical judgment both to guide therapeutic interventions and to define the outcomes.
In the absence of high-quality trials, recommendations for managing pleural infections have depended on pathophysiological observations, small studies, and expert opinion, all of which lend some credence to the value of intrapleural fibrinolytic agents.2 The rationale for these studies derives from knowledge that fibrin strands bridge pleural membranes and transform free-flowing pleural fluid in the early "exudative" stage of empyema into loculations and fibrous peels in the late "organized" stage.2,3 Patients who progress through the intermediate fibrinopurulent stage commonly do not benefit from chest-tube drainage and require surgical intervention to drain infected pleural fluid. Intrapleural fibrinolytic agents are thought to disrupt the fibrin loculations, enhance chest-tube drainage, and obviate the need for surgical drainage.
Clinical evidence of a benefit, however, remains marginal. Reviews performed by the Cochrane Collaboration describe existing studies as underpowered, with little evidence of efficacy with respect to important outcomes such as the need for surgical drainage.4,5 Moreover, advances in minimally invasive surgical techniques, such as video-assisted thoracoscopy and muscle-sparing thoracotomy, offer safe and rapidly effective methods for draining empyemas.6 Faced with marginal scientific evidence, the empyema panel of the American College of Chest Physicians concluded that fibrinolytic therapy and surgical drainage techniques represent competing options, but that appropriate patient selection and the relative timing of the procedures remain uncertain.1
In this context, the multicenter study by Maskell and colleagues, reported in this issue of the Journal,7 is greatly appreciated, despite being a couple of millennia overdue. These investigators report no benefits from the intrapleural administration of streptokinase in 427 patients with pleural infections. Clear lessons emerge from this study. First, the lack of benefit in terms of mortality at 3 and 12 months is in agreement with the findings of previous trials.5 It is also logical, considering that there are no data to establish that any deaths are solely attributable to appropriately managed pleural infections associated with pneumonia. In fact, medium-term mortality after hospitalization for pneumonia (that is, mortality more than three months after discharge) among middle-aged and older patients is more closely associated with the fact that an episode of pneumonia often identifies a fragile underlying health status than with the severity of the acute episode of pneumonia itself.8,9 We should abandon improvement in mortality as an achievable outcome of fibrinolytic therapy in broad categories of patients. The second lesson of the study is that the routine administration of fibrinolytic agents to all patients after chest-tube insertion, regardless of the stage of empyema, is unwarranted.
It is more difficult to accept the authors' conclusion that fibrinolytic therapy "should generally be avoided in pleural infection." The study's inclusion criteria led to the enrollment of heterogeneous patients at all stages of empyema formation. Some patients probably had "organized" (fibrous) pleural infections and were unlikely to benefit from fibrinolysis. The absence of computed tomographic or ultrasonographic studies at enrollment and of comprehensive information on intraoperative findings makes it impossible to evaluate this factor. Within the intervention group, the advanced age of many of the patients (mean [±SD] age 60±18 years) and the large proportion of patients with coexisting conditions (65 percent) most certainly influenced some of the study end points, such as the duration of the hospital stay, more strongly than did the potential benefits of fibrinolytic therapy. It remains possible, pending further studies, that more homogeneous subgroups of patients with fibrinopurulent empyemas may benefit from fibrinolytic therapy.
As an additional limitation, important therapeutic interventions, such as the administration of antibiotics and techniques for the insertion of chest tubes, were left to the judgment of individual clinicians, rather than specified in standardized protocols. Clinical judgment — with no assurance of reproducibility — also determined one of the primary study outcomes, referral for surgical drainage.
This study should be compared with a trial of streptokinase recently completed by Diacon and colleagues,10 who reported a less frequent need for surgical drainage among 22 patients with empyema who were randomly assigned to receive intrapleural streptokinase than among 22 patients assigned to receive saline (9 percent vs. 45 percent). Diacon et al. enrolled younger patients than did Maskell et al. (mean age, 39±13 years), with fewer coexisting conditions (in 38 percent of patients) and a low in-hospital mortality (4.5 percent), suggesting that specific patients may benefit from fibrinolytic agents. Diacon and colleagues also used structured protocols to standardize treatment interventions and definitions of outcomes and used larger chest tubes (24 or 28 French) under ultrasonographic guidance to ensure proper positioning, whereas Maskell et al. used smaller tubes (median, 12 French) that were placed without imaging. Although uncontrolled case series support the use of small catheters inserted under guidance from imaging for the drainage of empyema,11 their relative efficacy, as compared with larger tubes, has not been studied in randomized trials.
Maskell and coworkers have conducted an important trial that establishes — all these years after Hippocrates — the feasibility and value of multicenter studies of treatment for empyema. Considering the frequency of pleural infections and the high associated morbidity, funding is needed for additional trials that will enroll specific populations with the potential to benefit from fibrinolytic therapy, apply structured protocols, include a group treated by video-assisted thoracoscopy, adjust outcomes for the severity of infection, and use computed tomography to determine the stage of empyema before treatment. As more selective fibrinolytic drugs become available for study,12 they can be used in combination with agents that reduce the viscosity of pleural pus and promote its drainage. Meanwhile, the results of this study should dampen the ardor for the routine use of fibrinolytic agents in all patients with pleural infections, regardless of stage. Existing data favor early use of video-assisted thoracoscopy for patients with fibrinopurulent empyemas that cannot be managed by chest-tube drainage, with fibrinolytic therapy reserved for patients who are poor surgical candidates or for health care settings in which surgical interventions are unavailable. Hippocrates's primary recommendation remains the same: whatever the approach, drain infected pleural fluid as rapidly as possible.
Source Information
From the Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston.
References
Colice GL, Curtis A, Deslauriers J, et al. Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline. Chest 2000;118:1158-1171.
Sahn SA. Use of fibrinolytic agents in the management of complicated parapneumonic effusions and empyemas. Thorax 1998;53:Suppl 2:S65-S72.
Idell S, Girard W, Koenig KB, McLarty J, Fair DS. Abnormalities of pathways of fibrin turnover in the human pleural space. Am Rev Respir Dis 1991;144:187-194.
Coote N. Surgical versus non-surgical management of pleural empyema. Cochrane Database Syst Rev 2002;2:CD001956-CD001956.
Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of parapneumonic effusions and empyema. Cochrane Database Syst Rev 2004;2:CD002312-CD002312.
Petrakis I, Katsamouris A, Drossitis I, Bouros D, Chalkiadakis G. Usefulness of thoracoscopic surgery in the diagnosis and management of thoracic diseases. J Cardiovasc Surg (Torino) 2000;41:767-771.
Maskell NA, Davies CWH, Nunn AJ, et al. U.K. controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med 2005;352:865-874.
Mortensen EM, Kapoor WN, Chang CC, Fine MJ. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia. Clin Infect Dis 2003;37:1617-1624.
Waterer GW, Kessler LA, Wunderink RG. Medium-term survival after hospitalization with community-acquired pneumonia. Am J Respir Crit Care Med 2004;169:910-914.
Diacon AH, Theron J, Schuurmans MM, Van de Wal BW, Bolliger CT. Intrapleural streptokinase for empyema and complicated parapneumonic effusions. Am J Respir Crit Care Med 2004;170:49-53.
Ulmer JL, Choplin RH, Reed JC. Image-guided catheter drainage of the infected pleural space. J Thorac Imaging 1991;6:65-73.
Idell S, Mazar A, Cines D, et al. Single-chain urokinase alone or complexed to its receptor in tetracycline-induced pleuritis in rabbits. Am J Respir Crit Care Med 2002;166:920-926.(John E. Heffner, M.D.)
In the absence of high-quality trials, recommendations for managing pleural infections have depended on pathophysiological observations, small studies, and expert opinion, all of which lend some credence to the value of intrapleural fibrinolytic agents.2 The rationale for these studies derives from knowledge that fibrin strands bridge pleural membranes and transform free-flowing pleural fluid in the early "exudative" stage of empyema into loculations and fibrous peels in the late "organized" stage.2,3 Patients who progress through the intermediate fibrinopurulent stage commonly do not benefit from chest-tube drainage and require surgical intervention to drain infected pleural fluid. Intrapleural fibrinolytic agents are thought to disrupt the fibrin loculations, enhance chest-tube drainage, and obviate the need for surgical drainage.
Clinical evidence of a benefit, however, remains marginal. Reviews performed by the Cochrane Collaboration describe existing studies as underpowered, with little evidence of efficacy with respect to important outcomes such as the need for surgical drainage.4,5 Moreover, advances in minimally invasive surgical techniques, such as video-assisted thoracoscopy and muscle-sparing thoracotomy, offer safe and rapidly effective methods for draining empyemas.6 Faced with marginal scientific evidence, the empyema panel of the American College of Chest Physicians concluded that fibrinolytic therapy and surgical drainage techniques represent competing options, but that appropriate patient selection and the relative timing of the procedures remain uncertain.1
In this context, the multicenter study by Maskell and colleagues, reported in this issue of the Journal,7 is greatly appreciated, despite being a couple of millennia overdue. These investigators report no benefits from the intrapleural administration of streptokinase in 427 patients with pleural infections. Clear lessons emerge from this study. First, the lack of benefit in terms of mortality at 3 and 12 months is in agreement with the findings of previous trials.5 It is also logical, considering that there are no data to establish that any deaths are solely attributable to appropriately managed pleural infections associated with pneumonia. In fact, medium-term mortality after hospitalization for pneumonia (that is, mortality more than three months after discharge) among middle-aged and older patients is more closely associated with the fact that an episode of pneumonia often identifies a fragile underlying health status than with the severity of the acute episode of pneumonia itself.8,9 We should abandon improvement in mortality as an achievable outcome of fibrinolytic therapy in broad categories of patients. The second lesson of the study is that the routine administration of fibrinolytic agents to all patients after chest-tube insertion, regardless of the stage of empyema, is unwarranted.
It is more difficult to accept the authors' conclusion that fibrinolytic therapy "should generally be avoided in pleural infection." The study's inclusion criteria led to the enrollment of heterogeneous patients at all stages of empyema formation. Some patients probably had "organized" (fibrous) pleural infections and were unlikely to benefit from fibrinolysis. The absence of computed tomographic or ultrasonographic studies at enrollment and of comprehensive information on intraoperative findings makes it impossible to evaluate this factor. Within the intervention group, the advanced age of many of the patients (mean [±SD] age 60±18 years) and the large proportion of patients with coexisting conditions (65 percent) most certainly influenced some of the study end points, such as the duration of the hospital stay, more strongly than did the potential benefits of fibrinolytic therapy. It remains possible, pending further studies, that more homogeneous subgroups of patients with fibrinopurulent empyemas may benefit from fibrinolytic therapy.
As an additional limitation, important therapeutic interventions, such as the administration of antibiotics and techniques for the insertion of chest tubes, were left to the judgment of individual clinicians, rather than specified in standardized protocols. Clinical judgment — with no assurance of reproducibility — also determined one of the primary study outcomes, referral for surgical drainage.
This study should be compared with a trial of streptokinase recently completed by Diacon and colleagues,10 who reported a less frequent need for surgical drainage among 22 patients with empyema who were randomly assigned to receive intrapleural streptokinase than among 22 patients assigned to receive saline (9 percent vs. 45 percent). Diacon et al. enrolled younger patients than did Maskell et al. (mean age, 39±13 years), with fewer coexisting conditions (in 38 percent of patients) and a low in-hospital mortality (4.5 percent), suggesting that specific patients may benefit from fibrinolytic agents. Diacon and colleagues also used structured protocols to standardize treatment interventions and definitions of outcomes and used larger chest tubes (24 or 28 French) under ultrasonographic guidance to ensure proper positioning, whereas Maskell et al. used smaller tubes (median, 12 French) that were placed without imaging. Although uncontrolled case series support the use of small catheters inserted under guidance from imaging for the drainage of empyema,11 their relative efficacy, as compared with larger tubes, has not been studied in randomized trials.
Maskell and coworkers have conducted an important trial that establishes — all these years after Hippocrates — the feasibility and value of multicenter studies of treatment for empyema. Considering the frequency of pleural infections and the high associated morbidity, funding is needed for additional trials that will enroll specific populations with the potential to benefit from fibrinolytic therapy, apply structured protocols, include a group treated by video-assisted thoracoscopy, adjust outcomes for the severity of infection, and use computed tomography to determine the stage of empyema before treatment. As more selective fibrinolytic drugs become available for study,12 they can be used in combination with agents that reduce the viscosity of pleural pus and promote its drainage. Meanwhile, the results of this study should dampen the ardor for the routine use of fibrinolytic agents in all patients with pleural infections, regardless of stage. Existing data favor early use of video-assisted thoracoscopy for patients with fibrinopurulent empyemas that cannot be managed by chest-tube drainage, with fibrinolytic therapy reserved for patients who are poor surgical candidates or for health care settings in which surgical interventions are unavailable. Hippocrates's primary recommendation remains the same: whatever the approach, drain infected pleural fluid as rapidly as possible.
Source Information
From the Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston.
References
Colice GL, Curtis A, Deslauriers J, et al. Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline. Chest 2000;118:1158-1171.
Sahn SA. Use of fibrinolytic agents in the management of complicated parapneumonic effusions and empyemas. Thorax 1998;53:Suppl 2:S65-S72.
Idell S, Girard W, Koenig KB, McLarty J, Fair DS. Abnormalities of pathways of fibrin turnover in the human pleural space. Am Rev Respir Dis 1991;144:187-194.
Coote N. Surgical versus non-surgical management of pleural empyema. Cochrane Database Syst Rev 2002;2:CD001956-CD001956.
Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of parapneumonic effusions and empyema. Cochrane Database Syst Rev 2004;2:CD002312-CD002312.
Petrakis I, Katsamouris A, Drossitis I, Bouros D, Chalkiadakis G. Usefulness of thoracoscopic surgery in the diagnosis and management of thoracic diseases. J Cardiovasc Surg (Torino) 2000;41:767-771.
Maskell NA, Davies CWH, Nunn AJ, et al. U.K. controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med 2005;352:865-874.
Mortensen EM, Kapoor WN, Chang CC, Fine MJ. Assessment of mortality after long-term follow-up of patients with community-acquired pneumonia. Clin Infect Dis 2003;37:1617-1624.
Waterer GW, Kessler LA, Wunderink RG. Medium-term survival after hospitalization with community-acquired pneumonia. Am J Respir Crit Care Med 2004;169:910-914.
Diacon AH, Theron J, Schuurmans MM, Van de Wal BW, Bolliger CT. Intrapleural streptokinase for empyema and complicated parapneumonic effusions. Am J Respir Crit Care Med 2004;170:49-53.
Ulmer JL, Choplin RH, Reed JC. Image-guided catheter drainage of the infected pleural space. J Thorac Imaging 1991;6:65-73.
Idell S, Mazar A, Cines D, et al. Single-chain urokinase alone or complexed to its receptor in tetracycline-induced pleuritis in rabbits. Am J Respir Crit Care Med 2002;166:920-926.(John E. Heffner, M.D.)