Alex West

Intrapleural Use of Tissue Plasminogen Activator and DNase in Pleural Infection

BACKGROUND More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial. METHODS We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. RESULTS The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P=0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P=0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P=0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P=0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. CONCLUSIONS Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.).

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial.

IMPORTANCE For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. OBJECTIVE To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. DESIGN, SETTING, AND PARTICIPANTS A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. INTERVENTIONS Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). MAIN OUTCOMES AND MEASURES Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). RESULTS Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). CONCLUSIONS AND RELEVANCE Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN33288337.

Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion

BACKGROUND Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single‐blind basis. Follow‐up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between‐group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012–000599–40.)

S129 Does inflammation predict successful pleurodesis? a post hoc analysis from the time 1 trial

Introduction Malignant pleural effusions are a common complication of advanced malignancy, have a poor prognosis and have a significant impact on quality of life. Treatment strategies include chest drain and pleurodesis, or insertion of an indwelling pleural catheter. Successful pleurodesis is thought to be due to the body’s inflammatory response resulting in pleural symphysis. This post hoc analysis of data from the TIME 1 was conducted to address assess whether there is a correlation between the pleurodesis and a systemic inflammatory response. Methods A total of 282 patients from the TIME 1 trial had data on pleurodesis success, which was defined as no further pleural procedures for up to 3 months after pleurodesis. Patients who had undergone thoracosopy and poudrage as well as those who had undergone chest drain with pleurodesis were included. Sterile talc was used in all patients. The difference in the white cell count (WCC) and C-reactive protein (CRP) levels was calculated between the day of pleurodesis (Day 0) and Day 1. The data are normally distributed thus independent t test was used for analysis. The CRP Day 0 and 1 data were not normally distributed, and therefore were log transformed to produce a normal distribution. Results Two hundred and eighty two patients were included in the analysis with a mean age of 71 in both groups. 229 had a successful pleurodesis and 53 patients required a further pleural procedure on the ipsilateral side signifying failed pleurodesis. 193 patients had CRP levels and 220 patients had WCC levels recorded on both Day 0 and Day 1. Patients who had a successful pleurodesis had a significantly greater rise in CRP than those who failed pleurodesis. There was no significant difference in the change in WCC between the groups. There was also no significant difference in Day 0 and Day 1 WCC or CRP levels between the two groups. Conclusions This analysis demonstrates that systemic rise in CRP as an indicator of inflammation is a better predictor of pleurodesis success than the WCC. These data support the hypothesis that higher levels of inflammation are associated with pleurodesis success. Abstract S129 Table 1 Pleurodesis Success Pleurodesis Failure Significance WCC Day 0 8.84 (SD 4.00, n=213) 9.12 (SD – 3.14, n=46) p=0.582 WCC Day 1 11.14 (SD 3.78, n=191) 10.71 (SD 4.01, n=42) p=0.525 WCC Change 2.30 (SD 3.07, n=180) 1.55 (SD 2.82, n=40) p=0.140 CRP Day 0 (log) 1.46 (SD 0.58, n=181) 1.45 (SD 0.58, n=42) p=0.900 CRP Day 1 (log) 1.92 (SD 0.34, n=179) 1.83 (SD 0.33, n=41) p=0.123 CRP Change 47.81 (SD 52.08, n=154) 27.05 (SD 32.47, n=39) p=0.003 SD=Standard Deviation and n=number of patients

Providing safe and effective pleural medicine services in the UK: an aspirational statement from UK pleural physicians

Physicians face considerable challenges in ensuring safe and effective care for patients admitted to hospital with pleural disease. While subspecialty development has driven up standards of care, this has been tempered by the resulting loss of procedural experience in general medical teams tasked with managing acute pleural disease. This review aims to define a framework though which a minimum standard of care might be implemented. This review has been written by pleural clinicians from across the UK representing all types of secondary care hospital. Its content has been formed on the basis of literature review, national guidelines, National Health Service England policy and consensus opinion following a round table discussion. Recommendations have been provided in the broad themes of procedural training, out-of-hours management and pleural service specification. Procedural competences have been defined into descriptive categories: emergency, basic, intermediate and advanced. Provision of emergency level operators at all times in all trusts is the cornerstone of out-of-hours recommendations, alongside readily available escalation pathways. A proposal for minimum standards to ensure the safe delivery of pleural medicine have been described with the aim of driving local conversations and providing a framework for service development, review and risk assessment.

P7 Clinicians’ perspectives of health related quality of life and priorities in deciding management for malignant pleural effusion

Introduction Malignant pleural effusion (MPE) management has dramatically changed in the last decade with the increasing use of indwelling pleural catheters (IPC) and thoracoscopy. Although treatment is aimed at improving health related quality of life (HRQOL), data on outcomes are limited, with management guided by clinician perspectives and experiences. Aims We sought clinician perspectives of HRQOL for patients with MPE and its impact on decision making worldwide. We present the UK data. Methods We invited all respiratory doctors in the UK to complete an online survey advertised in the British Thoracic Society newsletter and by e-mail. Responses to questions with ranked options were assigned consecutive integers with lower values indicating a more favoured or higher prioritised response. Responses to best answer questions are presented as frequencies and percentages. Results 121 UK-based doctors (104 consultants, 1 associate specialist, 16 respiratory registrars) completed the survey. Factors determining HRQOL (rank 1–9): shortness of breath and chest pain (mean rank 1.48) and functional status (mean rank 2.57) were ranked the most important. Social set up – mean rank 5.16, depression/anxiety – mean rank 5.22, tumour type and stage – mean rank 5.78, distance to travel for medical care – mean rank 5.86, age – mean rank 6.59, financial difficulties from treatment – mean rank 8.27. Factors in the decision to offer intervention for MPE (rank 1–6): breathlessness ranked highest (mean rank 1.83) followed by the risk of significant harm from procedure vs chance of benefit (mean rank 2.73). Perspectives on which interventions most improve HRQOL are presented in Figure 1. Abstract P7 Figure 1 Which intervention most improves quality of life in malignant pleural effusion? (n = 108) Conclusion Shortness of breath and chest pain ranked highly in the perspective of HRQOL with shortness of breath a key factor in offering intervention. There is a lack of consensus on the ideal treatment to maximise HRQOL, which may reflect the paucity of data. Robust clinical trial evidence on HRQOL outcomes is therefore required to guide management decisions of patients with MPE. This should be complemented by a patient survey to ascertain differences in clinician and patient perspectives of quality of life and care.

PRIMARY RESULT OF THE 1ST THERAPEUTIC INTERVENTIONS IN MALIGNANT EFFUSION (TIME1) TRIAL: A 2 x 2 FACTORIAL, RANDOMISED TRIAL OF CHEST TUBE SIZE AND ANALGESIC STRATEGY FOR PLEURODESIS IN MALIGNANT PLEURAL EFFUSION

Background Optimal management of pleurodesis for malignant pleural effusion (MPE) has not been defined either in terms of optimal analgesia or chest tube size. Non-steroidal anti-inflammatory drugs (NSAID) are highly effective analgesics, but are avoided in pleurodesis as they may reduce pleurodesis efficacy. Smaller (<14 French) chest tubes may be less painful compared to larger chest tubes, but their efficacy in MPE pleurodesis has not been proven. This study investigated chest tube size (large versus small) and analgesia (NSAID versus opiate) in this setting. Methods A 2 × 2 factorial, phase 3 randomised controlled trial in 320 patients with MPE undergoing pleurodesis. Patients were randomised to opiate/NSAID and 24 French drain/12 French drain. Co-primary outcomes were; pain while tube in situ, measured on 100 mm visual analogue scale (VAS) over 5 days (superiority comparison) and pleurodesis efficacy at 3 months (non-inferiority comparison, margin of non-inferiority 15%). Secondary outcomes included use of rescue analgesia, pleurodesis success to 6 months, adverse events and mortality. Results 320 patients were randomised (63% male, mean age 71.8 years), with similar baseline characteristics. Mean VAS scores in opiate and NSAID groups were similar (adjusted mean difference, -1.5 mm (95% confidence interval [CI], -5.0 to 2.0; p = 0.40). Patients receiving NSAID required more rescue analgesia (38% vs. 26%). Pleurodesis failure occurred in 33/144 (23%) NSAID patients compared with 30/150 (20%) of participants receiving opiate, meeting criteria (15%) for non-inferiority (difference 3%; (90% CI -5% to 10%)). Smaller chest tubes were modestly less painful than larger tubes (adjusted mean difference, -6.0 mm (95% CI, -11.7 to -0.2; p = 0.04)) and were associated with a higher pleurodesis failure rate which failed to meet non-inferiority criteria (pleurodesis failure 15/50 (30%) and 12/50 (24%) respectively, difference 6% (90% CI, -9% to 20%)). Adverse events did not differ between analgesic groups, but complications during insertion occurred more commonly with smaller drains (adjusted odds ratio, 1.91; 95% CI 0.71 to 5.13, p = 0.20). Conclusion NSAID and opiate analgesia were not significantly different in treatment of post-pleurodesis pain and neither was associated with impaired efficacy of pleurodesis. Smaller chest tubes were associated with less pain, but may be associated with reduced pleurodesis success compared with larger tubes. These results challenge current guidelines for pleurodesis of MPE, which advocate avoidance of NSAID and use of small chest tubes.