Intrapleural Alteplase-Tyloxapol vs Intrapleural Alteplase-DNase in Pleural Infection

Official title

Comparative Analysis of Intrapleural Alteplase-Tyloxapol vs Intrapleural Alteplase-DNase in Pleural Infection (ALTON-PI)

Overview

Pneumonia, thought to be the chief aetiological process in the development of pleural space infection, is defined as an infection of the lung parenchyma with an estimated annual incidence rate of 5-11 cases per 1000 population, with around 50,000 hospital admissions in the U.K. per year. Parapneumonic effusions caused by an infection of the pleural membranes occur in 40-57% of cases of pneumonia. A variable percentage (10-20%) of parapneumonic effusions progresses to empyema (pus) and/or abscess formation (encapsulation). Pleural infection is associated with significant morbidity and mortality, which may be as high as 20-35% in immunocompromised patients. Standard treatment of these collections in adults involves antibiotic therapy, adequate drainage of infected fluid, and surgical intervention if conservative management fails. Appropriate treatment is adequate drainage via an intercostal catheter (ICC) with antibiotic therapy for parapneumonic effusions requiring clearance. Frequently, simple ICC drainage is ineffective due to the presence of loculations, formed predominantly by fibrinous material deposited in the fibrinopurulent phase of empyema, preventing free drainage of infected pleural fluid. The presence of fibrinous septae in the pleural space, known as loculations, may result in inadequate drainage of effusions and, therefore, nonresolution of infection and systemic sepsis. Surgical intervention (VATS or open) is usually required to clear loculations and resolve infection without adequate intercostal catheter drainage. Although the success rate of surgical intervention remains high, the morbidity and mortality of both VATS and open thoracotomy are of concern, particularly in a cohort of patients who may be older and with significant comorbidity. Less invasive therapies, which promote pleural space drainage and effective resolution of pleural infection, are therefore likely to be of considerable clinical utility. The MIST 2 trial has established intrapleural therapy as the mainstay of CPEE treatment, hence avoiding surgery and decreasing the length of hospitalization; however, little is known about the correct dosage needed for tPA and Dornase Alfa/Deoxyribonuclease (DNase). Dose and duration of intrapleural therapy based on MIST 2 involve multiple dosing and can be time-consuming for health care providers. Nevertheless, treatment of pleural infection with fibrinolytic therapy has been incorporated in the British Thoracic Society guideline 2023. Another study in 2022 by Cheong et al. used a modified regimen of intrapleural alteplase 16 mg t-PA with 5 mg DNase for three doses administered sequentially within 24 h. In this study, a modified regimen of t-PA and DNase offers an alternative therapeutic option for patients who are unfit or refuse surgical intervention but have persistent pleural infection. They have demonstrated similar treatment success comparable to other studies, as evidenced by improved pleural fluid drainage and reduced pleural opacity on day 7 chest x-ray, approximately 50% from the baseline. The mechanism of action of t-PA and DNase in the pleural cavity remains unclear. Studies suggested that IPFT may trigger the monocyte chemoattractant protein 1 (MCP-1) pathway, which promotes pleural fluid formation and subsequently causes a therapeutic lavage effect that increases pleural fluid drainage.

Detailed description

Research Questions:

• Is there a difference in efficacy and safety between a combination of intrapleural alteplase (5 mg + tacholiquin, with intrapleural alteplase 5mg and DNase (Pulmozyme) 5mg in managing pleural infection?

Primary Objective:

• To compare the reduction of pleural opacity (in percentage) on chest radiograph from baseline (0-24 hours pre-intervention) to day 7 post-intervention between group A (alteplase + DNase) and group B (alteplase + tacholiquin)

Secondary Objectives:

* To compare the absolute and percentage change in inflammatory markers (WBC/CRP) from baseline (0-24 hours pre-intervention) to day 7 between the two groups * To compare the volume of pleural effusion drainage (in mL) 72 hours following post-intervention between the two groups * To compare the outcome between the two groups:

* Length of hospital stay (in days) after the intervention for each group * The need for surgical intervention within 30 days * Adverse effects following alteplase/DNase and talteplase +Tacholiquin * Mortality rate at 30 days

Study Hypothesis

* The mean reduction in pleural opacity (%) from baseline (0-24 h pre-intervention) to day 7 is the same in both groups. * The mean change in WBC/CRP from baseline to day 7 is the same in both groups. * The mean pleural effusion drainage volume in both groups over the first 72 hours post-intervention is the same. * The mean length of hospital stay (days) post-intervention is the same in both groups. * The proportion requiring surgical intervention within 30 days is the same in both groups. * The proportion experiencing adverse effects is the same in both groups. * The 30-day mortality proportion is the same in both groups.

Study Design Retrospective, observational cohort; on patients with pleural infection exposure defined by intrapleural regimen received (Alteplase+DNase vs Alteplase+Tyloxapol) DNase from June 2023 to June 2025 in HCTM UKM and University Malaya Medical Centre.

Study Population Adult patients with pleural infection (complex pleural effusion or empyema) with poor outflow (≤ 150 cc) from chest drain after 24 Hours of insertion in medical and non-medical wards, HCTM UKM, and UMMC from June 2023 to June 2025.

Sample Size and Power of Study Following the guidance of the UH Bristol and Weston Clinical Audit Team (Version 5), a pragmatic snapshot sample of 40 cases for each arm was deemed sufficient to measure current practice against the pre-defined standard, prioritizing feasibility over formal statistical representativeness.

Interventions

• Drug Intrapleural t-PA/Dnase arm
  t-PA (Alteplase) 5-10mg and DNase (Pulmozyme)5mg t-PA (Alteplase) that is available in our pharmacy is 50mg ampoule and DNase (Pulmozyme) is 2.5mg per ampoule The number of installation of intrapleural t-PA/DNase depends on the discretion of the treating physician (at least 6 hours apart between each dose). 5-10mg of Alteplase (t-PA) and 5mg DNase are diluted in each 50ml of 0.9% sodium. Both medication are administered sequentially which t-PA is first instilled intrapleurally and the chest tub
• Drug t-PA (Alteplase) 5-10mg and Tyloxapol 200mg
  t-PA (Alteplase) that is available in our pharmacy is 50mg ampoule and Tyloxapol 200mg. The number of installation of intrapleural t-PA/Tyloxapol depends on the discretion of the treating physician (at least 6 hours apart between each dose). 5-10mg of Alteplase (t-PA) and 200mg Tyloxapol are diluted in each 50ml of 0.9% sodium. Both medication are administered sequentially which t-PA is first instilled intrapleurally and the chest tube is then clamped for 45 minutes, then unclamped to allow fre

Primary outcome measures

• To measure the change in the area of pleural opacity in chest x-ray compared to baseline [Time frame: Day 7]

Secondary outcome measures (6)

• Reduction in the level of serum C-reactive protein (CRP) from Day 1 to Day7 measured in mg/dL [Time frame: Day 7]
• Reduction in the level of stotal white cell count from Day 1 to Day7 measured in 10x9/L [Time frame: Day 7]
• to evaluate the volume of pleural effusion drainage (in mls) 72 hours following randomization [Time frame: 72 hours]
• Length of hospitalization [Time frame: throughout admission (up to 30 days)]
• the need for surgical referral [Time frame: throughout admission (up to 30 days)]
• to compare of the adverse effects between t-PA/Dnase and t-PA/Tyloxapol and intrapleural saline irrigation. [Time frame: Day 7]

Eligibility criteria

Inclusion criteria

Inclusion criteria

• Adult patient aged ≥ 18 years old
• Patients with pleural infection (complex parapneumonic effusion or empyema) with poor pleural fluid drainage of ≤ 150 ml after 24 hours of chest drain insertion received either t-PA-DNAse or t-PA/Tyloxapol.
• Clinical features consistent with pleural infection; fulfilling ≥ 2 of the following characteristics:

i) Clinical evidence of infection, such as fever and or elevated C-reactive protein (CRP) or total white blood count (TWBC) ii) Complex pleural effusion proven by thoracic ultrasound is defined as the presence of fibrin strands or septations within the pleural cavity iii) Pleural fluid that fulfils at least one of the characteristics:

• Frank Pus,
• Exudative type of pleural effusion (according to light's criteria)
• Gram stain or culture positive
• Lactate dehydrogenase (LDH) > 900U/L
• Acidic with pH < 7.2
• Glucose level < 3.3 mmol/L

Exclusion criteria

• Incomplete data.
• Medical records that cannot be retrieved.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Other

Study locations

Malaysia · 1 center

• National University of Malaysia, Faculty of Medicine — Cheras

Publications

• Mohamad Jailaini MF, Saini NA, Che Rahim MJ, Abdul Hamid MF. A potential prospect: The novel treatment of intrapleural saline irrigation with intrapleural tyloxapol in treating thoracic empyema. Respirol Case Rep. 2024 Aug 10;12(8):e70000. doi: 10.1002/rcr2.70000. eCollection 2024 Aug. PMID 39130089
• Scarci M, Abah U, Solli P, Page A, Waller D, van Schil P, Melfi F, Schmid RA, Athanassiadi K, Sousa Uva M, Cardillo G. EACTS expert consensus statement for surgical management of pleural empyema. Eur J Cardiothorac Surg. 2015 Nov;48(5):642-53. doi: 10.1093/ejcts/ezv272. Epub 2015 Aug 7. PMID 26254467
• Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, Bentley A, Kahan BC, Wrightson JM, Davies HE, Hooper CE, Lee YC, Hedley EL, Crosthwaite N, Choo L, Helm EJ, Gleeson FV, Nunn AJ, Davies RJ. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med. 2011 Aug 11;365(6):518-26. doi: 10.1056/NEJMoa1012740. PMID 21830966
• 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 May;106(5):716-23. doi: 10.1016/j.rmed.2012.02.005. Epub 2012 Mar 6. PMID 22398159
• Walker CA, Shirk MB, Tschampel MM, Visconti JA. Intrapleural alteplase in a patient with complicated pleural effusion. Ann Pharmacother. 2003 Mar;37(3):376-9. doi: 10.1345/aph.1C248. PMID 12639166
• Majid A, Kheir F, Folch A, Fernandez-Bussy S, Chatterji S, Maskey A, Fashjian M, Cheng G, Ochoa S, Alape D, Folch E. Concurrent Intrapleural Instillation of Tissue Plasminogen Activator and DNase for Pleural Infection. A Single-Center Experience. Ann Am Thorac Soc. 2016 Sep;13(9):1512-8. doi: 10.1513/AnnalsATS.201602-127OC. PMID 27333122
• Cheong XK, Ban AY, Ng BH, Nik Abeed NN, Nik Ismail NA, Nik Fuad NF, Syed Zakaria SZ, Ghan SL, Abdul Hamid MF. Modified regimen intrapleural alteplase with pulmozyme in pleural infection management: a tertiary teaching hospital experience. BMC Pulm Med. 2022 May 17;22(1):199. doi: 10.1186/s12890-022-01995-z. PMID 35581627
• Provan JL. The management of postpneumonectomy empyema. J Thorac Cardiovasc Surg. 1971 Jan;61(1):107-9. No abstract available. PMID 5540449

Identifiers

NCT: NCT07432373 · FF-2026-033

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗