Pulmonary administration of vasoactive substances by perfluorochemical ventilation.
OBJECTIVE
Therapeutic management of respiratory distress syndrome, pneumonia, and pulmonary hypertension includes delivery of biologically active agents to the neonatal lung. However, mechanical abnormalities of the lung, intrapulmonary shunting, ventilation-perfusion mismatching, and elevated surface tension impede effective systemic or intratracheal delivery of agents to the lung during conventional gas ventilation. The objective of this study was to test the hypothesis that perfluorochemical (PFC) liquid ventilation can be used for pulmonary administration of vasoactive drugs (PAD) and to compare these responses to those elicited with intravascular (IV) administration during tidal liquid ventilation.


METHODS
Cardiovascular responses of 16 preterm and neonatal lambs to randomized doses of acetylcholine, epinephrine, and priscoline were studied. Physiologic gas exchanged and acid-base balance were maintained using previously described tidal liquid ventilation techniques. In subgroups of animals, the distribution pattern of carbon 1- and choline 14-labeled dipalmitoylphosphatidylcholine (14C-DPPC) in saline and the responses to priscoline after hypoxia-induced pulmonary hypertension and hypoxemia administered during liquid ventilation were studied.


RESULTS
Dose-response curves for PAD and IV administration demonstrated progressive, dose-dependent, cholinergic responses to acetylcholine (decreased mean systemic arterial pressure [MAP] and heart rate), sympathomimetic responses to epinephrine (increased MAP and heart rate), and alpha-adrenergic blockade responses to priscoline (decreased MAP and mean pulmonary arterial pressure). Compared with IV administration, PAD of priscoline resulted in a significantly greater decrease in pulmonary relative to systemic arterial pressure; this response was potentiated by hypoxia, reduced pulmonary pressures to near normal values, and improved oxygenation. The 14C-DPPC in saline was distributed relatively homogeneously throughout the lung by PAD, with 80% of the lung pieces receiving amounts of 14C-DPPC with +/-20% of the mean value.


CONCLUSIONS
This study demonstrates that vasoactive agents can be delivered to the lung directly by PAD during PFC liquid ventilation. The inherent advantages of this method relate to the physical properties of PFC liquid ventilation as a vehicle (respiratory gas solubility, low surface tension-enhancing distribution, and inertness precluding interaction) and physiological properties of the lung as an exchanger.
Wolfson
M R
MR
Department of Physiology and Pediatrics, Temple University School of Medicine, Philadelphia, Pennsylvania 19149, USA.
Greenspan
J S
JS
Shaffer
T H
TH
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000493:pharmacokinetics; D000109:Acetylcholine / Q000008:administration & dosage*; D000136:Acid-Base Equilibrium; D000280:Administration, Inhalation; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage*; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000008:administration & dosage*; D005466:Fluorocarbons / Q000008:administration & dosage*; D006339:Heart Rate / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D000860:Hypoxia / Q000188:drug therapy; D007275:Injections, Intravenous; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D011659:Pulmonary Gas Exchange; D012121:Respiration, Artificial; D012756:Sheep; D014043:Tolazoline / Q000008:administration & dosage*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*; D014665:Vasodilator Agents / Q000008:administration & dosage*
D000317:Adrenergic alpha-Antagonists; D005466:Fluorocarbons; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D015060:1,2-Dipalmitoylphosphatidylcholine; D014043:Tolazoline; D000109:Acetylcholine; D004837:Epinephrine