Point: Should Fibrinolytics Be Routinely Administered Intrapleurally for Management of a Complicated Parapneumonic Effusion? Yes

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Point: Should Fibrinolytics Be Routinely Administered Intrapleurally for Management of a Complicated Parapneumonic Effusion? Yes Abbreviations: DNase 5 deoxyribonuclease; MIST 5 Multicenter Intrapleural Sepsis Trial; PPE 5 parapneumonic effusion; tPA 5 tissue plasminogen activator; VATS 5 video-assisted thoracoscopic surgery

introduction of a therapeutic intervention into Theeveryday clinical practice must always be given

careful consideration by physicians regarding the risks and benefits the intervention poses to patients. Factors to be taken into account are the incidence of the condition being targeted, the morbidity and mortality associated with the condition, the adequacy of preexisting therapeutic approaches, the side-effect profile of the proposed intervention, and the additional financial cost incurred during the care of the patient. In this regard, one can make a strong and valid argument for the routine administration of intrapleural fibrinolytics for pleural infection (complicated parapneumonic effusion or empyema thoracis) in adults. Infection of the pleural space is a serious respiratory disease for which the case incidence is rising in adult and pediatric populations without a clearly identifiable cause.1-3 Current data predict . 80,000 new cases per year of adult pleural infection in the United Kingdom and United States alone at a financial cost of . $500 million in health-care services.1,4,5 Furthermore, despite apparent improvements in the diagnostic and therapeutic tools available to physicians over the past 3 decades, there has been little or no impact on the morbidity and mortality associated with pleural infection,1,6,7 a poor return compared with such conditions as coronary vascular disease where mortality has been significantly reduced over the same time frame. The greatest increase in caseload has been in patients aged . 65 years,1 a population in whom phy14

sicians manage an ever-expanding range of medical comorbidities and where the mortality rate at 3 months from pleural infection remains steadfastly . 30%.6 These facts highlight the need to consider and develop new therapeutic strategies in adult pleural infection given the apparent inadequacy of those we already possess. Current and widely accepted guideline statements for the management of pleural infection in adults and children8-10 advocate the combination of early drainage of the infected pleural space with appropriate antibiotic therapy as critical. Failure to adhere to this advice (eg, through a delay in diagnosis or intervention) is directly associated with a poorer outcome for the patient.1,2,7,8 This has led some to advocate early thoracic surgical intervention as the best means by which to ensure both adequate clearance of infected material and a better clinical outcome.2,11,12 However, this argument has several fundamental flaws. Although surgery is vital and lifesaving in selected patients, the majority of adult patients with pleural infection can be successfully managed medically, with this approach failing in only 18%5 and 11%6 of patients in two large prospective randomized studies. Adopting an unselected approach to surgical drainage would consequently impose an unnecessary procedure on the majority of patients alongside the perioperative and anesthetic risks of this intervention, which include a 28-day mortality of around 5%, complication rates of up to 20%, and chronic pain in up to 50% of patients at 1 year.2,11,13 Furthermore, two large surgical case series from the United States2 and United Kingdom11 showed that patients undergoing surgery for pleural infection are younger (aged approximately 50 vs 60 years) and have fewer comorbidities than an unselected patient population.5,6 Given that the highest mortality from pleural infection is seen in elderly patients with comorbidities,6 the possibility is raised that selection bias is augmenting the apparent survival advantage claimed for surgical intervention and that patients being selected for thoracic surgery would have a better outcome regardless. Most critical, however, is the absence of any robust prospective trial data to support a role for Point/Counterpoint Editorials

universal frontline surgical intervention in pleural infection. Frequently cited studies in adults14,15 suffer from inadequate power, unorthodox medical management in control arms, and a lack of objective decisionmaking criteria, whereas studies in children have shown no clinical or financial gain from a more radical front door surgical approach.4,16 Accepting that medical management is, therefore, most appropriate for the majority of patients with pleural infection, finding a means to ensure that clearance of the infected collection through an intercostal drain is as swift and complete as possible should be a priority to minimize both hospital stay and long-term morbidity. Targeting the fibrinolysis pathway to enhance drainage and prevent progression of pleural infection from exudative to fibrinopurulent and fibrotic stages represents one potential option that has been pursued by chest physicians for more than half a century.17 Early studies using streptokinase and urokinase in adults showed promise without ever providing conclusive data,18 ultimately leading to the first Multicenter Intrapleural Sepsis Trial (MIST1).6 This large randomized controlled trial (N 5 454) in adults surprised many clinicians by failing to show any benefit between streptokinase and placebo for a number of key clinical outcomes, including mortality, surgical referral rate, and hospital stay. This result was in direct contrast to results for pleural infection in children, where the role of intrapleural fibrinolytics was already well established and remains so even now.10,19 Pediatric empyema is predominantly community acquired (notably from Streptococcus pneumoniae), whereas adult cases have a higher proportion of nosocomial or mixed infections, including anaerobes, staphylococci, and gram-negative organisms.3,4,7,11 This variation in etiology and microbiology may explain the differing results in adult and pediatric studies of intrapleural streptokinase in pleural infection. Adequate clearance of an infected pleural collection requires not only the breakdown of septations that might otherwise obstruct drainage but also a reduction in fluid viscosity and biofilm formation. In this regard, streptokinase (or urokinase) may be the wrong fibrinolytic agent for adults with pleural infection given its inability to influence these factors in an in vitro setting.20 The MIST2 study5 used a novel combination of a direct tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) to address this. tPA exerts a direct fibrinolytic effect to break down septations, bypassing the need for streptokinase to combine with plasminogen in vivo and rendering the former vulnerable to depleted levels of the latter in the pleural space. DNase targets uncoiled DNA to reduce both fluid viscosity and biofilm formation that might otherwise encourage retention of infected material in the pleural space and relapsing sepsis. Through a double-dummy, doublejournal.publications.chestnet.org

placebo, randomized controlled trial design (N 5 210), MIST2 demonstrated a highly significant effect (P 5 .005) of combination tPA-DNase therapy vs placebo for the primary outcome of relative change in chest radiograph pleural opacity (Fig 1), as validated against CT scan as a measure of successful drainage of pleural collections. Among the secondary outcomes, both surgical referral rate and hospital stay were also significantly reduced in the combination therapy arm, whereas no increase in adverse events compared with the placebo arm were found. The combination of intrapleural tPA and DNase in pleural infection clearly improves chest radiographic appearance compared with placebo and may reduce hospital stay and the requirement for surgery, all of which are clinically significant outcomes important to both physicians and patients. This benefit (accepting the sample size limitations of MIST2) was realized in the absence of any increase in adverse events and was independent of purulence of pleural fluid (as demonstrated in the balanced subgroup analysis). Given this evidence demonstrating potential treatment benefit, and when no other treatment has been demonstrated against placebo to have such benefit, the routine use of intrapleural tPA and DNase can be considered rational and has more of an evidence base than other

Figure 1. Relative change in chest radiograph pleural opacity by treatment arm in the Multicenter Intrapleural Sepsis Trial 2 study on d 7 vs d 1 and expressed as a percentage of hemithorax occupied. DNase 5 deoxyribonuclease; t-PA 5 tissue plasminogen activator. (Reprinted with permission from Rahman et al.5) CHEST / 145 / 1 / JANUARY 2014

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interventions routinely used to treat pleural infection, such as thoracic surgery.

© 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-2354

Conclusions

References

Pleural infection continues to result in significant morbidity and mortality despite current therapeutic strategies.1,6,7 The routine administration of intrapleural fibrinolytics (with single-agent streptokinase or urokinase) is already firmly established and evidence based in pediatric pleural infection.4,10,19 Although this approach has been proven unsuccessful in adults, there is now compelling evidence from the MIST2 study5 that the combination of a directly acting fibrinolytic (ie, tPA) with DNase offers a viable alternative, enhancing successful drainage and, thereby, clearance of infected material from the pleural space. Although further clinical and laboratory-based studies may build a more precise understanding of how these therapies work or allow individualized selection of patients most likely to benefit from intrapleural fibrinolytics, the results already available represent a significant step forward in the treatment of this debilitating and previously resistant disease. Evidence supports the use of this combination therapy in patients who require rapid clearance of infected pleural material due to ventilatory compromise (eg, in critical care settings) or who experience a failure in conventional medical therapy and are not fit for an alternative surgical approach. However, in the absence of realistic alternatives that offer either greater therapeutic efficacy or a lower risk to patients, there is a clear rationale for the universal administration of combination intrapleural tPA-DNase in all cases of pleural infection to try and improve clinical outcomes in a condition that chest physicians have not, up until now, significantly affected. John P. Corcoran, MD Najib M. Rahman, DPhil Oxford, England Affiliations: 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). Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Rahman was the corresponding author for the Multicenter Intrapleural Sepsis Trial 2 (MIST2) study and is the current clinical director of the Oxford Respiratory Trials Unit, which received an unrestricted educational grant from Roche UK to the University of Oxford for the conduct of the MIST2 study. 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. Correspondence to: Najib M. Rahman, DPhil, Oxford Respiratory Trials Unit, Oxford University Hospitals, Old Rd, Oxford, OX3 7LE, England; e-mail: [email protected]

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1. Grijalva CG, Zhu Y, Nuorti JP, Griffin MR. Emergence of parapneumonic empyema in the USA. Thorax. 2011;66(8): 663-668. 2. Farjah F, Symons RG, Krishnadasan B, Wood DE, Flum DR. Management of pleural space infections: a population-based analysis. J Thorac Cardiovasc Surg. 2007;133(2):346-351. 3. Li ST, Tancredi DJ. Empyema hospitalizations increased in US children despite pneumococcal conjugate vaccine. Pediatrics. 2010;125(1):26-33. 4. Sonnappa S, Cohen G, Owens CM, et al. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema. Am J Respir Crit Care Med. 2006; 174(2):221-227. 5. 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. 6. 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. 7. Meyer CN, Rosenlund S, Nielsen J, Friis-Møller A. Bacteriological aetiology and antimicrobial treatment of pleural empyema. Scand J Infect Dis. 2011;43(3):165-169. 8. Davies HE, Davies RJ, Davies CW; BTS Pleural Disease Guideline Group. Management of pleural infection in adults: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010; 65(suppl 2):ii41-ii53. 9. Colice GL, Curtis A, Deslauriers J, et al. Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline. Chest. 2000;118(4):1158-1171. 10. Balfour-Lynn IM, Abrahamson E, Cohen G, et al; Paediatric Pleural Diseases Subcommittee of the BTS Standards of Care Committee. BTS guidelines for the management of pleural infection in children. Thorax. 2005;60(suppl 1):i1-i21. 11. Marks DJ, Fisk MD, Koo CY, et al. Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre. PLoS ONE. 2012;7(1):e30074. 12. Suchar AM, Zureikat AH, Glynn L, Statter MB, Lee J, Liu DC. Ready for the frontline: is early thoracoscopic decortication the new standard of care for advanced pneumonia with empyema? Am Surg. 2006;72(8):688-692. 13. Mongardon N, Pinton-Gonnet C, Szekely B, Michel-Cherqui M, Dreyfus JF, Fischler M. Assessment of chronic pain after thoracotomy: a 1-year prevalence study. Clin J Pain. 2011;27(8): 677-681. 14. Wait MA, Sharma S, Hohn J, Dal Nogare A. A randomized trial of empyema therapy. Chest. 1997;111(6):1548-1551. 15. Bilgin M, Akcali Y, Oguzkaya F. Benefits of early aggressive management of empyema thoracis. ANZ J Surg. 2006;76(3):120-122. 16. St Peter SD, Tsao K, Spilde TL, et al. Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: a prospective, randomized trial [published correction appears in J Pediatr Surg. 2009;44(9):1865]. J Pediatr Surg. 2009;44(1):106-111. 17. Tillett WS, Sherry S. The effect in patients of streptococcal fibrinolysin (streptokinase) and streptococcal deoxyribonuclease on fibrinous, purulent and sanguinous pleural exudations. J Clin Invest. 1949;28(1):173-190. 18. Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of parapneumonic

Point/Counterpoint Editorials

effusions and empyema. Cochrane Database Syst Rev. 2004; 2(2):CD002312. 19. Thomson AH, Hull J, Kumar MR, Wallis C, Balfour Lynn IM. Randomised trial of intrapleural urokinase in the treatment of childhood empyema. Thorax. 2002;57(4):343-347. 20. Light RW, Nguyen T, Mulligan ME, Sasse SA. The in vitro efficacy of varidase versus streptokinase or urokinase for liquefying thick purulent exudative material from loculated empyema. Lung. 2000;178(1):13-18.

Counterpoint: Should Fibrinolytics Be Routinely Administered Intrapleurally for Management of a Complicated Parapneumonic Effusion? No this debate, the question involves three key terms: Infibrinolytics, routine administration intrapleurally,

and complicated parapneumonic effusion (PPE). Fibrinolytics promote lysis of fibrin by generating plasmin. The only currently available fibrinolytic in the United States is tissue plasminogen activator (tPA). Routine use implies that administration of intrapleural fibrinolytic therapy represents a standard approach. Complicated PPE is a term introduced by Light1 to describe a PPE that evolved into the fibropurulent stage with a higher pleural fluid lactate dehydrogenase level, a lower pleural fluid glucose level, and a higher likelihood of a positive pleural fluid Gram stain. Light1 suggested that complicated PPE would not resolve with antibiotic treatment but would require drainage. Instead of the term complicated PPE, we prefer the approach adopted by the American College of Chest Physicians consensus panel for the management of PPE for identifying those PPEs in need of effective drainage.2 This consensus panel divided PPE into four different groups with varying risks for poor outcomes based on pleural space anatomy, pleural fluid bacteriology, and pleural fluid chemistry criteria (Table 1). The groups at increased risk for poor outcomes, such as those with large or loculated effusions, empyema, or a pleural fluid pH , 7.20, would benefit from drainage. With the question defined, there are three reasons why fibrinolytics should not be administered intrapleurally as part of standard procedure for managing PPEs at increased risk for poor outcomes. Dosing regimens for fibrinolytics do not ensure effective intrapleural fibrinolysis. Clinical trials in adults have failed to demonstrate consistent clinical benefit with administration of intrapleural fibrinolytics. An alternative approach, surgical drainage by video-assisted thoracoscopic surgery (VATS), provides effective drainage of the pleural space with improved clinical outcomes. journal.publications.chestnet.org

Developing any agent for human use requires determining the effective dose and dosing interval. The dose and dosing interval of intrapleural fibrinolytic agents has been and remains empirical. tPA usually is administered intrapleurally at a 10-mg dose once or twice daily for several days.3 However, tPA is subject to rapid inhibition by plasminogen activator inhibitor 1, the levels of which may be markedly increased in the pleural fluid of patients with pleural infection, as previously reviewed.4 We are not aware of evidence-based indicators to guide clinicians about how much more fibrinolysin to give if adequate pleural drainage is not initially achieved. To our knowledge, no US Food and Drug Administration-approved fibrinolytic agents for intrapleural use are currently available. In addition, no formal toxicology studies have been done to identify the optimal and safest dosing in animals as the basis for determining a safe starting dose for clinical safety trials, nor have dose escalation phase 1 and 2 safety trials of fibrinolytic agents in patients with PPE been conducted prior to broad clinical application. These considerations likely underlie the wide variability in patient outcomes in trials of intrapleural fibrinolytic therapy. Small case series in the 1990s suggested that intrapleural administration of streptokinase provide clinical benefit in managing PPE requiring drainage.2,5 The first Multicenter Intrapleural Sepsis Trial (MIST1), published in 2005, was an important step forward because it included a large number of well-characterized patients with PPE requiring drainage randomized to either intrapleural streptokinase or placebo.6 The results disagreed with previous work and showed no clinical benefit with intrapleural fibrinolytics compared with placebo (Table 2). A Cochrane review of intrapleural fibrinolytic therapy in 2008, largely based on the results of MIST1, did not find consistent benefit for these agents.7 The subsequent MIST2 trial was smaller and included four possible treatment options, one of which was intrapleural administration of tPA.3 Again, the results demonstrated no clinical benefit with the use of intrapleural fibrinolytics vs placebo (Table 3). A systematic review and meta-analysis evaluated outcomes with intrapleural fibrinolytic therapy for managing PPE in 801 patients from seven placebocontrolled trials.8 Although the authors concluded that there was a potential benefit with intrapleural fibrinolytics in reducing treatment failures (surgical intervention and death), concerns exist about this analysis. There were no differences in treatment failures between intrapleural fibrinolytics and placebo in the two largest trials included in the analysis: MIST1 and MIST2. In the next largest trial, calculations of treatment failures might have been affected by a critical methodological flaw.9 Of the 65 patients randomized to streptokinase, eight (12%) were lost to follow-up because the protocol was not followed. None of the 70 patients managed CHEST / 145 / 1 / JANUARY 2014

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