Dose De-escalation of Intrapleural Tissue Plasminogen Activator Therapy for Pleural Infection. The Alteplase Dose Assessment for Pleural Infection Therapy Project.
BACKGROUND
Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10 mg and DNase 5 mg administered twice daily has been shown in randomized and open-label studies to successfully manage over 90% of patients with pleural infection without surgery. Potential bleeding risks associated with intrapleural tPA and its costs remain important concerns. The aim of the ongoing Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) project is to investigate the efficacy and safety of dose de-escalation for intrapleural tPA. The first of several planned studies is presented here.


OBJECTIVE
To evaluate the efficacy and safety of a reduced starting dose regimen of 5 mg of tPA with 5 mg of DNase administered intrapleurally for pleural infection.


METHODS
Consecutive patients with pleural infection at four participating centers in Australia, the United Kingdom, and New Zealand were included in this observational, open-label study. Treatment was initiated with tPA 5 mg and DNase 5 mg twice daily. Subsequent dose escalation was permitted at the discretion of the attending physician. Data relating to treatment success, radiological and systemic inflammatory changes (blood C-reactive protein), volume of fluid drained, length of hospital stay, and treatment complications were extracted retrospectively from the medical records.


RESULTS
We evaluated 61 patients (41 males; age, 57 ± 16 yr). Most patients (n = 58 [93.4%]) were successfully treated without requiring surgery for pleural infection. Treatment success was corroborated by clearance of pleural opacities visualized by chest radiography (from 42% [interquartile range, 22-58] to 16% [8-31] of hemithorax; P < 0.001), increase in pleural fluid drainage (from 175 ml in the 24 h preceding treatment to 2,025 ml [interquartile range, 1,247-2,984] over 72 h of therapy; P <  0.05) and a reduction in blood C-reactive protein (P < 0.05). Seven patients (11.5%) had dose escalation of tPA to 10 mg. Three patients underwent surgery. Three patients (4.9%) received blood transfusions for gradual pleural blood loss; none were hemodynamically compromised. Pain requiring escalation of analgesia affected 36% of patients; none required cessation of therapy.


CONCLUSIONS
These pilot data suggest that a starting dose of 5 mg of tPA administered intrapleurally twice daily in combination with 5 mg of DNase for the treatment of pleural infection is safe and effective. This regimen should be tested in future randomized controlled trials.
1 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.|2 Institute for Respiratory Health, Nedlands, Western Australia, Australia.|3 Pharmacy Department, and.|4 Respiratory Medicine Department, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Natalia
http://orcid.org/0000-0003-0200-1819
N
Popowicz
5 Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
Oliver
O
Bintcliffe
5 Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
Duneesha
D
De Fonseka
6 Queen Elizabeth University Hospital, Glasgow, United Kingdom.
Kevin G
KG
Blyth
7 Respiratory Department, Wellington Regional Hospital, Wellington, New Zealand.
Nicola A
NA
Smith
8 Respiratory Medicine Department, St. John of God Midland, Midland, Western Australia, Australia; and.
Francesco
F
Piccolo
6 Queen Elizabeth University Hospital, Glasgow, United Kingdom.
Geoffrey
G
Martin
4 Respiratory Medicine Department, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Donny
D
Wong
9 Department of Radiology, North Bristol NHS Trust, Bristol, United Kingdom.
Anthony
A
Edey
5 Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
Nick
N
Maskell
1 School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.|2 Institute for Respiratory Health, Nedlands, Western Australia, Australia.|4 Respiratory Medicine Department, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Y C Gary
http://orcid.org/0000-0002-0036-511X
YCG
Lee
D000328:Adult; D000368:Aged; D001315:Australia; D002097:C-Reactive Protein / Q000032:analysis; D003851:Deoxyribonucleases / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004322:Drainage / Q000009:adverse effects; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D010996:Pleural Effusion / Q000628:therapy*; D010998:Pleurisy / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D013902:Radiography, Thoracic; D012189:Retrospective Studies; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*; D016896:Treatment Outcome; D006113:United Kingdom
D005343:Fibrinolytic Agents; D002097:C-Reactive Protein; D003851:Deoxyribonucleases; D010959:Tissue Plasminogen Activator
deoxyribonuclease; empyema; intrapleural; pleural infection; tissue plasminogen activator