Correspondence
A Trial of Intrapleural Streptokinase
N Engl J Med 2005; 352:2243-2245May 26, 2005
- Article
To the Editor:
The design and execution of the First Multicenter Intrapleural Sepsis Trial (MIST1), reported by Maskell et al. (March 3 issue),1 are discordant with the contemporary management of pleural-space infections. The anatomical features of complicated pleural-space infections are better characterized by thoracic ultrasound and computed tomographic scanning.2 Frontal radiography used as the sole imaging method is grossly inadequate for this purpose. Knowing the extent of pleural septation and spatial separation of infected locules is essential for the management of thoracostomy drains, use of thrombolytic agents, and decisions about surgical management. Even when used in conjunction with clinical and laboratory markers of inflammation, frontal radiographs are deficient in differentiating unresolved pneumonia and retrocardiac lesions from pleural infection.3
For these reasons, the radiologic criteria for enrollment and the basis for surgical referral in the MIST1 trial were subjective. Similarly, the finding from the post hoc subgroup analysis — that loculation does not affect mortality — is misleading because of the limitations of chest radiography in defining septation. It is our perception that international variations in the standards of management confound the outcomes of this study and limit its generalizability.
3 ReferencesChandra K. Katikireddy, M.D.
Daniel S. Dube, M.D.
Stanford University, Palo Alto, CA 94305-5236
ddube@stanford.edu 1
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
Full Text | Web of Science | Medline2
Moulton JS . Image-guided management of complicated pleural fluid collections. Radiol Clin North Am 2000;38:345-374
CrossRef | Web of Science | Medline3
Stark DD ,Federle MP ,Goodman PC ,Podrasky AE ,Webb WR . Differentiating lung abscess and empyema: radiography and computed tomography. AJR Am J Roentgenol 1983;141:163-167
Web of Science | Medline
To the Editor:
Several studies1-3 have shown that fibrinolysis increases the volume of fluid drained from infected pleura. Maskell et al. provide no information on the volume of fluid drained. This omission, together with their use of small-bore chest tubes, casts doubt on the efficacy of their chest-tube drainage. Notwithstanding the impressive numbers of cases Maskell et al. studied, we believe that further standardized trials (with patients stratified according to the stage of empyema) are needed before fibrinolysis is discarded as a viable treatment, especially in patients who are not good candidates for surgery.
3 ReferencesAndreas H. Diacon, M.D.
Coenraad F.N. Koegelenberg, M.R.C.P.
Chris T. Bolliger, M.D., Ph.D.
University of Stellenbosch, Tygerberg, Cape Town 7505, South Africa
coeniefn@sun.ac. za 1
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
CrossRef | Web of Science | Medline2
Sahn SA . Use of fibrinolytic agents in the management of complicated parapneumonic effusions and empyemas. Thorax 1998;53:Suppl 2:S65-S72
CrossRef | Web of Science | Medline3
Chin NK ,Lim TK . Controlled trial of intrapleural streptokinase in the treatment of pleural empyema and complicated parapneumonic effusions. Chest 1997;111:275-279
CrossRef | Web of Science | Medline
To the Editor:
The study by Maskell et al. did not restrict enrollment to patients with acute, loculated empyema. Streptokinase acts by lysing fibrin strands, thus opening pockets to drainage. It does not treat infection or drain pus; antibiotics and pleural drainage accomplish those goals. Thus, the design of the trial appears off target and should not be expected to show a difference between the study groups.
Diacon et al.1 recently demonstrated that patients with loculated empyema who received intrapleural streptokinase had faster resolution of infection and less need for surgery than those who received saline. It appears likely that the inconsistency between the results of their study and those of the study by Maskell et al. is related to different enrollment criteria: Diacon et al. restricted enrollment to patients with loculated empyema, whereas Maskell et al. allowed indiscriminate enrollment of patients with pleural infection. Furthermore, if one postulates that both chemical lysis and surgical lysis are effective treatments for breaking down loculations, then mortality and late outcome may not be useful end points for discriminating between these treatments.
1 ReferencesUte W. Rosa, M.D.
Long Island College Hospital, Brooklyn, NY 112011
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
CrossRef | Web of Science | Medline
To the Editor:
Maskell et al. conclude that fibrinolytic therapy “should generally be avoided in pleural infection.” Although their randomized, controlled trial on the role of fibrinolytics in pleural infection is very large, the design of the study does not address many issues relevant to this conclusion. The authors do not take into account the various stages of evolution of parapneumonic pleural effusions. Patients with parapneumonic pleural effusions who have a single loculus or patients with thick, purulent effusions, such as those in the study, are not expected to benefit from fibrinolytic agents. Proper chest-tube positioning guided by imaging and proper chest-tube size play more crucial roles. In contrast, the use of fibrinolytic agents in multiloculated parapneumonic pleural effusions has been shown to be associated with a reduced need for surgical procedures.1-3
Because many issues remain — among them the roles of thoracoscopy, ultrasonography, newer fibrinolytic agents, and catheter size — additional well-designed controlled trials are needed. Hippocrates emphasized the need to use surgery only in those patients whom “pharmaka” does not cure.4
4 ReferencesDemosthenes Bouros, M.D.
University of Thrace, 68100 Alexandroupolis, Greece
bouros@med.duth. gr 1
Bouros D ,Schiza S ,Tzanakis N ,Chalkiadakis G ,Drositis J ,Siafakas N . Intrapleural urokinase versus normal saline in the treatment of complicated parapneumonic effusions and empyema: a randomized, double-blind study. Am J Respir Crit Care Med 1999;159:317-3422
Bouros D ,Schiza S ,Patsourakis G ,Chalkiadakis G ,Panagou P ,Siafakas NM . Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study. Am J Respir Crit Care Med 1997;155:291-295
Web of Science | Medline3
Bouros D ,Antoniou KM ,Chalkiadakis G ,Drositis J ,Petrakis I ,Siafakas N . The role of video-assisted thoracoscopic surgery in the treatment of parapneumonic empyema after the failure of fibrinolytics. Surg Endosc 2002;16:151-154
CrossRef | Web of Science | Medline4
Hippocrates. Aphorisms. Vol. 4. In: Loeb classical library. Series no. 149. Jones WHS, trans. Cambridge, Mass.: Harvard University Press, 1979:160-1.
Author/Editor Response
The correspondents suggest that streptokinase may have a therapeutic effect in a subgroup of patients not identified by our analyses — perhaps those with a loculated empyema or empyema at a particular stage. These hypotheses have not been examined in appropriately powered trials, and we agree that such work may identify a subgroup with a response to streptokinase. However, the overall result of our trial was that placebo offered a slight but not statistically significant advantage over streptokinase; thus, benefits in one subgroup will probably be associated with larger disadvantages in others. For this reason, definitive identification of treatment-responsive subgroups is essential before any patients are exposed to a potentially disadvantageous treatment. Until trials to achieve this are completed, we believe it is appropriate to conclude that intrapleural streptokinase “should generally be avoided” in pleural infection.
The data reported by Diacon et al.1 have been assessed elsewhere.2 Diacon et al. found a 9 percent rate of surgery in the streptokinase group.1 Allowing for the small size of their trial, this rate is not significantly different from the rate in both the streptokinase group (15 percent) and the placebo group (14 percent) in MIST1. The positive result in the trial by Diacon et al.1 is of borderline significance and is due to the high rate of surgery in the control group (45 percent). Why this rate was so high is unclear, although it may be because a poor radiographic outcome in the absence of uncontrolled infection was an indication for surgical drainage. With this approach, surgery can become a surrogate for the radiographic outcome.2 In MIST1, surgery was used only in patients in whom uncontrolled infection, together with residual pleural fluid, persisted. If surgery rates are to be used as an outcome in future trials, care should be taken not to make the decision to proceed to surgical drainage on the basis of radiographic progress alone.
The production of pleural fluid that follows the administration of intrapleural streptokinase is unlikely to explain our results, since this effect was seen in the small trials that preceded the current study (e.g., our own pilot study3), and yet these trials appeared to be positive. We have performed a subgroup analysis of patients in whom chest tubes of different sizes were used, and it yielded the same result as the overall analysis: a small, nonsignificant advantage with placebo.
MIST1 has shown that it is possible to conduct adequately powered trials of treatment in patients with pleural infection, and its results are thought-provoking. We strongly support the call from Dr. Bouros for additional, well-designed trials to help define optimal care for these seriously ill patients.
3 ReferencesRobert J.O. Davies, D.M.
Nicholas A. Maskell, M.R.C.P.
Oxford Centre for Respiratory Medicine, Oxford OX3 7LJ, United Kingdom
robert.davies@ndm. ox. ac. uk Andrew J. Nunn, M.Sc.
Medical Research Council, London NW1 2DA, United Kingdom1
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
CrossRef | Web of Science | Medline2
Lee YCG . Ongoing search for effective intrapleural therapy for empyema: is streptokinase the answer? Am J Respir Crit Care Med 2004;170:1-2
CrossRef | Web of Science | Medline3
Davies RJO ,Traill ZC ,Gleeson FV . Randomised controlled trial of intrapleural streptokinase in community acquired pleural infection. Thorax 1997;52:416-421
CrossRef | Web of Science | Medline
- Citing Articles (6)
Citing Articles
1
Rahman, Najib M., Maskell, Nicholas A., West, Alex, Teoh, Richard, Arnold, Anthony, Mackinlay, Carolyn, Peckham, Daniel, Davies, Chris W.H., Ali, Nabeel, Kinnear, William, Bentley, Andrew, Kahan, Brennan C., Wrightson, John M., Davies, Helen E., Hooper, Clare E., Lee, Y.C. Gary, Hedley, Emma L.Crosthwaite, Nicky, Choo, Louise, Helm, Emma J., Gleeson, Fergus V., Nunn, Andrew J., Davies, Robert J.O., . (2011) Intrapleural Use of Tissue Plasminogen Activator and DNase in Pleural Infection. New England Journal of Medicine 365:6, 518-526
Full Text2
Jannie Nielsen, Christian N. Meyer, Signe Rosenlund. (2011) Outcome and clinical characteristics in pleural empyema: A retrospective study. Scandinavian Journal of Infectious Diseases 43:6-7, 430-435
CrossRef3
Marios E. Froudarakis, George Kouliatsis, Paschalis Steiropoulos, Stavros Anevlavis, Athanasia Pataka, Maria Popidou, Demitrios Mikroulis, Ioannis Pneumatikos, Demosthenes Bouros. (2008) Recombinant tissue plasminogen activator in the treatment of pleural infections in adults. Respiratory Medicine 102:12, 1694-1700
CrossRef4
Coenraad F.N. Koegelenberg, Andreas H. Diaconi, Chris T. Bolligeri. (2008) Parapneumonic Pleural Effusion and Empyema. Respiration 75:3, 241-250
CrossRef5
Demosthenes Bouros, Argyris Tzouvelekis, Katerina M. Antoniou, John E. Heffner. (2007) Intrapleural fibrinolytic therapy for pleural infection. Pulmonary Pharmacology & Therapeutics 20:6, 616-626
CrossRef6
Demosthenes Bouros, Argyris Tzouvelekis, Katerina M Antoniou. (2006) Current medical management of pleural infection. Therapy 3:1, 163-174
CrossRef
