Original Article

Pharmacodynamics and pharmacokinetics of inhaled nitric oxide in dogs with septic acute respiratory distress syndrome.

Authors: Chang-Hong MIAO, Bo SUN, Hao JIANG, Zhang-Gang XUE, Robert LINDWALL

Abstract

AIM: To evaluate pharmacodynamics and pharmacokinetics of inhaled nitric oxide
(iNO) in dogs with acute respiratory distress syndrome (ARDS).
METHODS: ARDS, induced after iv injection of endotoxin, was evidenced by
reduction of paO2/FiO2 from (62.5 +/- 2.8) to (26 +/- 4) kPa and dynamic lung
compliance (Cdyn) from (14.8 +/- 0.7) to (8.6 +/- 0.6) mL.kPa-1 . kg-1, increase
of dead space (VD/VT) from (0.14 +/- 0.06) to (0.58 +/- 0.05), intrapulmonary
shunting (Qs/Qt) from 4.7 % +/- 1.7 % to 39 % +/- 7 %, and pulmonary vascular
resistance index (PVRI) from (16 +/- 4) to (51 +/- 8) kPa.s.L-1 . m-2 (all P <
0.05), along with severe intrapulmonary neutrophil recruitment and peripheral
neutropenia. The animals were then treated as either a control or an NO group (n
= 6 each, iNO 0.4 - 3.2 micromol/L) for another 10 h.
RESULTS: More survival was found in NO group (4/6 vs 0/6, P < 0.05). iNO at 0.8,
1.6, and 3.2 micromol/L (20, 40, and 80 ppm) resulted in > 40 % increase of
paO2/FiO2 and Cdyn, a reduction of VD/VT to 0.32, Qs/Qt to < 25 %, and PVRI by >
50 % (30.8 kPa . s . L-1 . m-2) compared to the control. Optimal iNO dose was
around 0.8 micromol/L as higher methemoglobin (MetHb, > 3 %) was found at higher
NO. iNO had no adverse effects on surfactant phospholipids and lung fluid
balance, but attenuated expression of tumor necrosis factor alpha,beta2 integrin
CD11b, and interleukin-8 mRNA in the lungs by 22 %, 44 %, and 25 %, respectively
(P < 0.05).
CONCLUSION: Pharmacodynamics of iNO in this model was related to improvement in
gas exchange, Cdyn, PVRI, and suppression of proinflammatory cytokine expression
in the lungs, and its adverse effect was mainly confined to MetHb at higher NO
dose.
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