The non-intubated, spontaneously breathing, continuous positive airway pressure (CPAP) ventilated pre-term lamb: a unique animal model.
Neonatologists prefer non-invasive ventilation methods for pre-term neonates, who often require surfactant treatment. Therefore, a technology for non-invasive surfactant administration would be highly appreciated. We have developed a Continuous Powder Aerosolization (CPA) system for the generation of a humidified recombinant surfactant protein-C (rSP-C) surfactant aerosol for non-invasive administration to pre-term neonates via bi-nasal prongs. Before conducting clinical trials, safety testing in an adequate pre-clinical animal model is necessary. In contrast to existing pre-term lamb models, this model should use non-intubated animals to include upper airways for safety testing. Pre-term animals should have already a sufficient respiratory drive to breathe spontaneously on non-invasive continuous positive airway pressure (CPAP) support, but their lungs should still be pre-mature to be comparable with the clinical situation for the treatment of pre-term infants. The aim of this feasibility study was therefore to establish a CPAP-stable, non-intubated pre-term lamb model for the investigation of safety, efficacy, and pulmonary deposition of a humidified rSP-C surfactant aerosol. For this purpose, 19 pre-term lambs with a gestational age of 135-137 days (term: about 144 days) were delivered via Caesarean section. Four animals died before start of treatment, while the remaining animals were treated via customized bi-nasal prongs with rSP-C surfactant aerosol or humidified air as vehicle control. To determine pulmonary deposition, selected animals received rSP-C surfactant labelled with samarium oxide as non-radioactive tracer. Treatment was started at 30 min of age and was continued for 1 or 2.5 h. Investigations during the in-life phase included observation of clinical signs, haematology, blood gas analysis, and determination of minute volume. At 3 h of age, animals were euthanized and organs removed for histopathology investigation or for determination of pulmonary deposition. Administration of humidified, aerosolized rSP-C surfactant was well tolerated, and histopathology investigation of upper airways and lungs revealed no aerosol-related changes. Mean body weight-corrected pulmonary deposition of rSP-C surfactant ranged from 1.7 to 7.7 mg/kg depending on the duration of treatment and aerosolization parameters used. A trend towards reduced spontaneous minute volumes indicating reduced breathing efforts and towards reduced lung weights indicating less fluid in the lungs of surfactant-treated animals compared to animals of the vehicle control group could be seen. Taken together, a CPAP-stable, non-intubated pre-term lamb model was successfully established and the parameters for the investigation of safety, efficacy, and pulmonary deposition of aerosolized rSP-C surfactant for the subsequent main study were identified.
Institute for Pharmacology and Preclinical Drug Safety, Nycomed GmbH, Barsbüttel, Germany. daniela.rahmel@takeda.com
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DK
Rahmel
G
G
Pohlmann
P
P
Iwatschenko
J
J
Volland
S
S
Liebisch
H
H
Kock
L
L
Mecklenburg
C
C
Maurer
J
J
Kemkowski
F J H
FJ
Taut
D000336:Aerosols; D000818:Animals; D045422:Continuous Positive Airway Pressure; D004947:Esophagus / Q000187:drug effects / Q000473:pathology; D005260:Female; D005333:Fetus; D006403:Hematologic Tests; D008297:Male; D023421:Models, Animal; D063087:Noninvasive Ventilation; D010743:Phospholipids / Q000008:administration & dosage; D012137:Respiratory System / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D012756:Sheep; D013501:Surface-Active Agents / Q000008:administration & dosage; D018675:Toxicity Tests / Q000379:methods
D000336:Aerosols; D010743:Phospholipids; D013501:Surface-Active Agents