Point: Should Fibrinolytics Be Routinely Administered Intrapleurally for Management of a Complicated Parapneumonic Effusion? Yes
2014; Elsevier BV; Volume: 145; Issue: 1 Linguagem: Inglês
10.1378/chest.13-2354
ISSN1931-3543
AutoresJohn Corcoran, Najib M. Rahman,
Tópico(s)Pneumothorax, Barotrauma, Emphysema
ResumoThe introduction of a therapeutic intervention into everyday 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.1Grijalva CG Zhu Y Nuorti JP Griffin MR Emergence of parapneumonic empyema in the USA.Thorax. 2011; 66: 663-668Crossref PubMed Scopus (191) Google Scholar, 2Farjah F Symons RG Krishnadasan B Wood DE Flum DR Management of pleural space infections: a population-based analysis.J Thorac Cardiovasc Surg. 2007; 133: 346-351Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 3Li ST Tancredi DJ Empyema hospitalizations increased in US children despite pneumococcal conjugate vaccine.Pediatrics. 2010; 125: 26-33Crossref PubMed Scopus (159) Google Scholar 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.1Grijalva CG Zhu Y Nuorti JP Griffin MR Emergence of parapneumonic empyema in the USA.Thorax. 2011; 66: 663-668Crossref PubMed Scopus (191) Google Scholar, 4Sonnappa 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: 221-227Crossref PubMed Scopus (257) Google Scholar, 5Rahman NM Maskell NA West A et al.Intrapleural use of tissue plasminogen activator and DNase in pleural infection.N Engl J Med. 2011; 365: 518-526Crossref PubMed Scopus (487) Google Scholar 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,1Grijalva CG Zhu Y Nuorti JP Griffin MR Emergence of parapneumonic empyema in the USA.Thorax. 2011; 66: 663-668Crossref PubMed Scopus (191) Google Scholar, 6Maskell NA Davies CW Nunn AJ First Multicenter Intrapleural Sepsis Trial (MIST1) Group et al.UK controlled trial of intrapleural streptokinase for pleural infection.N Engl J Med. 2005; 352: 865-874Crossref PubMed Scopus (618) Google Scholar, 7Meyer CN Rosenlund S Nielsen J Friis-Møller A Bacteriological aetiology and antimicrobial treatment of pleural empyema.Scand J Infect Dis. 2011; 43: 165-169Crossref PubMed Scopus (43) Google Scholar 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,1Grijalva CG Zhu Y Nuorti JP Griffin MR Emergence of parapneumonic empyema in the USA.Thorax. 2011; 66: 663-668Crossref PubMed Scopus (191) Google Scholar a population in whom physicians manage an ever-expanding range of medical comorbidities and where the mortality rate at 3 months from pleural infection remains steadfastly > 30%.6Maskell NA Davies CW Nunn AJ First Multicenter Intrapleural Sepsis Trial (MIST1) Group et al.UK controlled trial of intrapleural streptokinase for pleural infection.N Engl J Med. 2005; 352: 865-874Crossref PubMed Scopus (618) Google Scholar 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 children8Davies 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: ii41-ii53Crossref PubMed Scopus (423) Google Scholar, 9Colice GL Curtis A Deslauriers J et al.Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline.Chest. 2000; 118: 1158-1171Abstract Full Text Full Text PDF PubMed Scopus (526) Google Scholar, 10Balfour-Lynn IM Abrahamson E Cohen G Paediatric Pleural Diseases Subcommittee of the BTS Standards of Care Committee et al.BTS guidelines for the management of pleural infection in children.Thorax. 2005; 60: i1-i21Crossref PubMed Scopus (344) Google Scholar 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.1Grijalva CG Zhu Y Nuorti JP Griffin MR Emergence of parapneumonic empyema in the USA.Thorax. 2011; 66: 663-668Crossref PubMed Scopus (191) Google Scholar, 2Farjah F Symons RG Krishnadasan B Wood DE Flum DR Management of pleural space infections: a population-based analysis.J Thorac Cardiovasc Surg. 2007; 133: 346-351Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 7Meyer CN Rosenlund S Nielsen J Friis-Møller A Bacteriological aetiology and antimicrobial treatment of pleural empyema.Scand J Infect Dis. 2011; 43: 165-169Crossref PubMed Scopus (43) Google Scholar, 8Davies 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: ii41-ii53Crossref PubMed Scopus (423) Google Scholar 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.2Farjah F Symons RG Krishnadasan B Wood DE Flum DR Management of pleural space infections: a population-based analysis.J Thorac Cardiovasc Surg. 2007; 133: 346-351Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 11Marks DJ Fisk MD Koo CY et al.Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre.PLoS ONE. 2012; 7: e30074Crossref PubMed Scopus (76) Google Scholar, 12Suchar 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: 688-692PubMed Google Scholar 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%5Rahman NM Maskell NA West A et al.Intrapleural use of tissue plasminogen activator and DNase in pleural infection.N Engl J Med. 2011; 365: 518-526Crossref PubMed Scopus (487) Google Scholar and 11%6Maskell NA Davies CW Nunn AJ First Multicenter Intrapleural Sepsis Trial (MIST1) Group et al.UK controlled trial of intrapleural streptokinase for pleural infection.N Engl J Med. 2005; 352: 865-874Crossref PubMed Scopus (618) Google Scholar 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.2Farjah F Symons RG Krishnadasan B Wood DE Flum DR Management of pleural space infections: a population-based analysis.J Thorac Cardiovasc Surg. 2007; 133: 346-351Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 11Marks DJ Fisk MD Koo CY et al.Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre.PLoS ONE. 2012; 7: e30074Crossref PubMed Scopus (76) Google Scholar, 13Mongardon 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: 677-681Crossref PubMed Scopus (52) Google Scholar Furthermore, two large surgical case series from the United States2Farjah F Symons RG Krishnadasan B Wood DE Flum DR Management of pleural space infections: a population-based analysis.J Thorac Cardiovasc Surg. 2007; 133: 346-351Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar and United Kingdom11Marks DJ Fisk MD Koo CY et al.Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre.PLoS ONE. 2012; 7: e30074Crossref PubMed Scopus (76) Google Scholar 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.5Rahman NM Maskell NA West A et al.Intrapleural use of tissue plasminogen activator and DNase in pleural infection.N Engl J Med. 2011; 365: 518-526Crossref PubMed Scopus (487) Google Scholar, 6Maskell NA Davies CW Nunn AJ First Multicenter Intrapleural Sepsis Trial (MIST1) Group et al.UK controlled trial of intrapleural streptokinase for pleural infection.N Engl J Med. 2005; 352: 865-874Crossref PubMed Scopus (618) Google Scholar Given that the highest mortality from pleural infection is seen in elderly patients with comorbidities,6Maskell NA Davies CW Nunn AJ First Multicenter Intrapleural Sepsis Trial (MIST1) Group et al.UK controlled trial of intrapleural streptokinase for pleural infection.N Engl J Med. 2005; 352: 865-874Crossref PubMed Scopus (618) Google Scholar 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 universal frontline surgical intervention in pleural infection. Frequently cited studies in adults14Wait MA Sharma S Hohn J Dal Nogare A A randomized trial of empyema therapy.Chest. 1997; 111: 1548-1551Abstract Full Text Full Text PDF PubMed Scopus (312) Google Scholar, 15Bilgin M Akcali Y Oguzkaya F Benefits of early aggressive management of empyema thoracis.ANZ J Surg. 2006; 76: 120-122Crossref PubMed Scopus (83) Google Scholar suffer from inadequate power, unorthodox medical management in control arms, and a lack of objective decision-making criteria, whereas studies in children have shown no clinical or financial gain from a more radical front door surgical approach.4Sonnappa 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: 221-227Crossref PubMed Scopus (257) Google Scholar, 16St 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: 106-111Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar 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.17Tillett 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: 173-190Crossref Scopus (214) Google Scholar Early studies using streptokinase and urokinase in adults showed promise without ever providing conclusive data,18Cameron 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)Crossref Google Scholar ultimately leading to the first Multicenter Intrapleural Sepsis Trial (MIST1).6Maskell NA Davies CW Nunn AJ First Multicenter Intrapleural Sepsis Trial (MIST1) Group et al.UK controlled trial of intrapleural streptokinase for pleural infection.N Engl J Med. 2005; 352: 865-874Crossref PubMed Scopus (618) Google Scholar This large randomized controlled trial (N = 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.10Balfour-Lynn IM Abrahamson E Cohen G Paediatric Pleural Diseases Subcommittee of the BTS Standards of Care Committee et al.BTS guidelines for the management of pleural infection in children.Thorax. 2005; 60: i1-i21Crossref PubMed Scopus (344) Google Scholar, 19Thomson AH Hull J Kumar MR Wallis C Balfour Lynn IM Randomised trial of intrapleural urokinase in the treatment of childhood empyema.Thorax. 2002; 57: 343-347Crossref PubMed Scopus (230) Google Scholar 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.3Li ST Tancredi DJ Empyema hospitalizations increased in US children despite pneumococcal conjugate vaccine.Pediatrics. 2010; 125: 26-33Crossref PubMed Scopus (159) Google Scholar, 4Sonnappa 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: 221-227Crossref PubMed Scopus (257) Google Scholar, 7Meyer CN Rosenlund S Nielsen J Friis-Møller A Bacteriological aetiology and antimicrobial treatment of pleural empyema.Scand J Infect Dis. 2011; 43: 165-169Crossref PubMed Scopus (43) Google Scholar, 11Marks DJ Fisk MD Koo CY et al.Thoracic empyema: a 12-year study from a UK tertiary cardiothoracic referral centre.PLoS ONE. 2012; 7: e30074Crossref PubMed Scopus (76) Google Scholar 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.20Light 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: 13-18Crossref PubMed Scopus (77) Google Scholar The MIST2 study5Rahman NM Maskell NA West A et al.Intrapleural use of tissue plasminogen activator and DNase in pleural infection.N Engl J Med. 2011; 365: 518-526Crossref PubMed Scopus (487) Google Scholar 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, double-placebo, randomized controlled trial design (N = 210), MIST2 demonstrated a highly significant effect (P = .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 interventions routinely used to treat pleural infection, such as thoracic surgery. Pleural infection continues to result in significant morbidity and mortality despite current therapeutic strategies.1Grijalva CG Zhu Y Nuorti JP Griffin MR Emergence of parapneumonic empyema in the USA.Thorax. 2011; 66: 663-668Crossref PubMed Scopus (191) Google Scholar, 6Maskell NA Davies CW Nunn AJ First Multicenter Intrapleural Sepsis Trial (MIST1) Group et al.UK controlled trial of intrapleural streptokinase for pleural infection.N Engl J Med. 2005; 352: 865-874Crossref PubMed Scopus (618) Google Scholar, 7Meyer CN Rosenlund S Nielsen J Friis-Møller A Bacteriological aetiology and antimicrobial treatment of pleural empyema.Scand J Infect Dis. 2011; 43: 165-169Crossref PubMed Scopus (43) Google Scholar The routine administration of intrapleural fibrinolytics (with single-agent streptokinase or urokinase) is already firmly established and evidence based in pediatric pleural infection.4Sonnappa 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: 221-227Crossref PubMed Scopus (257) Google Scholar, 10Balfour-Lynn IM Abrahamson E Cohen G Paediatric Pleural Diseases Subcommittee of the BTS Standards of Care Committee et al.BTS guidelines for the management of pleural infection in children.Thorax. 2005; 60: i1-i21Crossref PubMed Scopus (344) Google Scholar, 19Thomson AH Hull J Kumar MR Wallis C Balfour Lynn IM Randomised trial of intrapleural urokinase in the treatment of childhood empyema.Thorax. 2002; 57: 343-347Crossref PubMed Scopus (230) Google Scholar Although this approach has been proven unsuccessful in adults, there is now compelling evidence from the MIST2 study5Rahman NM Maskell NA West A et al.Intrapleural use of tissue plasminogen activator and DNase in pleural infection.N Engl J Med. 2011; 365: 518-526Crossref PubMed Scopus (487) Google Scholar 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.
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