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John P. Corcoran, MD; Najib M. Rahman, DPhil
Author and Funding Information

From the Oxford Centre for Respiratory Medicine (Drs Corcoran and Rahman), Oxford University Hospitals; Oxford Respiratory Trials Unit (Drs Corcoran and Rahman), University of Oxford; and NIHR Oxford Biomedical Research Centre (Dr Rahman).

CORRESPONDENCE TO: Najib M. Rahman, DPhil, Oxford Respiratory Trials Unit, Oxford University Hospitals, Old Rd, Oxford, OX3 7LE, England; e-mail: najib.rahman@ndm.ox.ac.uk


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following conflicts of interest: Dr Rahman is the first and corresponding author of the MIST2 trial. Dr Corcoran has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(3):e105-e106. doi:10.1378/chest.14-1173
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Published online
To the Editor:

We would like to thank Dr Thommi and colleagues for their letter regarding our point/counterpoint debate1-4 on fibrinolytic treatment in pleural infection, in which they discuss the use of intrapleural tissue plasminogen activator (tPA) in the treatment of adult and pediatric pleural infection. We agree that the risks of intrapleural bleeding with intrapleural therapy is small, and this has also been demonstrated in the first Multicenter Intrapleural Sepsis Trial (MIST1)5 and subsequent MIST26 trial, in which there was no statistically significant increase in bleeding events compared with placebo with either fibrinolytics alone or tPA plus deoxyribonuclease (DNase).

The authors suggest that failure to drain viscous effusions may be related to chest tube size. We do not agree that there is strong evidence to support this statement; the largest study to directly address this issue, although not a randomized dataset, analyzed clinically important outcomes from the MIST1 trial by initial chest tube size used and demonstrated that there was no difference in outcome comparing chest tubes of varying sizes.7 Indeed, this study demonstrated a statistically significant improvement in outcome with the use of smaller chest tubes in the purulent (and, therefore, more viscous) subgroup.7 As this was nonrandomized data, we do not take this as evidence of smaller tubes being more effective in the treatment of purulent fluid. However, this does provide compelling evidence that larger tube sizes are not likely to be more effective in the treatment of pleural infection. In addition, our analysis of factors predictive of outcome in pleural infection8 did not demonstrate a significant effect of chest tube type.

We disagree with the authors that chest radiograph outcomes are a flaw in the MIST1 and MIST2 trials. Chest radiographs are the most common clinical surrogate used in decision-making in pleural infection, although we agree that they cannot differentiate consolidation from pleural effusion. However, the MIST15 trial primary and secondary outcomes were not radiologic (death, surgery, lung function, and hospital stay). In the MIST2 trial6 and in acceptance of the previous point, the digital chest radiograph measurement system used was shown to have very high correlation with the amount of pleural fluid change as measured by CT scan. The quoted article from the authors describing a randomized, crossover trial using tPA9 also uses a radiologic outcome (CT scan), and we do not believe that a crossover trial is the correct design for addressing the efficacy of intrapleural agents in pleural infection.

The authors suggest that if surgical outcome was the primary outcome measure in the MIST2 trial, there would be no difference between the tPA and tPA plus DNase groups. However, there was a statistically significant improvement in surgical referral in the tPA plus DNase group (OR, 0.17; P = .03) and not in the tPA group (OR, 0.29; P = .1) compared with placebo. The differences were small (down to one patient); however, these were secondary outcomes, and any treatment effect should be treated with caution. If all data from the trial are taken together, it is clear that the tPA plus DNase group demonstrates consistent improvement in several outcomes (chest radiograph, surgical referral, hospital stay, and reduction of fever) compared with placebo, whereas tPA only shows a modest effect in surgical referral that is statistically nonsignificant. This, in parallel to the MIST1 trial result, suggests that fibrinolytics alone are not effective in the treatment of pleural infection. Our view remains that the published data suggest that combination tPA and DNase has been shown to be superior to placebo and the agents individually and that further large trials are required to provide precise data on the treatment effect on surgical, hospital stay, and mortality outcomes.

References

Corcoran JP, Rahman NM. Point: should fibrinolytics be routinely administered intrapleurally for management of a complicated parapneumonic effusion? Yes. Chest. 2014;145(1):14-17. [CrossRef] [PubMed]
 
Colice GL, Idell S. Counterpoint: should fibrinolytics be routinely administered intrapleurally for management of a complicated parapneumonic effusion? No. Chest. 2014;145(1):17-20. [CrossRef] [PubMed]
 
Corcoran JP, Rahman NM. Rebuttal from Drs Corcoran and Rahman. Chest. 2014;145(1):20-21. [CrossRef] [PubMed]
 
Colice GL, Idell S. Rebuttal from Drs Colice and Idell. Chest. 2014;145(1):21-23. [CrossRef] [PubMed]
 
Maskell NA, Davies CW, Nunn AJ, et al; First Multicenter Intrapleural Sepsis Trial (MIST1) Group. UK Controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med. 2005;352(9):865-874. [CrossRef] [PubMed]
 
Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365(6):518-526. [CrossRef] [PubMed]
 
Rahman NM, Maskell NA, Davies CW, et al. The relationship between chest tube size and clinical outcome in pleural infection. Chest. 2010;137(3):536-543. [CrossRef] [PubMed]
 
Rahman NM, Kahan BC, Miller RF, Gleeson FV, Nunn AJ, Maskell NA. A clinical score (RAPID) to identify those at risk for poor outcome at presentation in patients with pleural infection. Chest. 2014;145(4):848-855. [CrossRef] [PubMed]
 
Thommi G, Shehan JC, Robison KL, Christensen M, Backemeyer LA, McLeay MT. A double blind randomized cross over trial comparing rate of decortication and efficacy of intrapleural instillation of alteplase vs placebo in patients with empyemas and complicated parapneumonic effusions. Respir Med. 2012;106(5):716-723. [CrossRef] [PubMed]
 

Figures

Tables

References

Corcoran JP, Rahman NM. Point: should fibrinolytics be routinely administered intrapleurally for management of a complicated parapneumonic effusion? Yes. Chest. 2014;145(1):14-17. [CrossRef] [PubMed]
 
Colice GL, Idell S. Counterpoint: should fibrinolytics be routinely administered intrapleurally for management of a complicated parapneumonic effusion? No. Chest. 2014;145(1):17-20. [CrossRef] [PubMed]
 
Corcoran JP, Rahman NM. Rebuttal from Drs Corcoran and Rahman. Chest. 2014;145(1):20-21. [CrossRef] [PubMed]
 
Colice GL, Idell S. Rebuttal from Drs Colice and Idell. Chest. 2014;145(1):21-23. [CrossRef] [PubMed]
 
Maskell NA, Davies CW, Nunn AJ, et al; First Multicenter Intrapleural Sepsis Trial (MIST1) Group. UK Controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med. 2005;352(9):865-874. [CrossRef] [PubMed]
 
Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011;365(6):518-526. [CrossRef] [PubMed]
 
Rahman NM, Maskell NA, Davies CW, et al. The relationship between chest tube size and clinical outcome in pleural infection. Chest. 2010;137(3):536-543. [CrossRef] [PubMed]
 
Rahman NM, Kahan BC, Miller RF, Gleeson FV, Nunn AJ, Maskell NA. A clinical score (RAPID) to identify those at risk for poor outcome at presentation in patients with pleural infection. Chest. 2014;145(4):848-855. [CrossRef] [PubMed]
 
Thommi G, Shehan JC, Robison KL, Christensen M, Backemeyer LA, McLeay MT. A double blind randomized cross over trial comparing rate of decortication and efficacy of intrapleural instillation of alteplase vs placebo in patients with empyemas and complicated parapneumonic effusions. Respir Med. 2012;106(5):716-723. [CrossRef] [PubMed]
 
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