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


CONCLUSIONS
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.
Miao
Chang-Hong
CH
Laboratory of Pediatric Respiratory and Intensive Care, Children's Hospital, Shanghai 200032, China.
Sun
Bo
B
Jiang
Hao
H
Xue
Zhang-Gang
ZG
Lindwall
Robert
R
D000280:Administration, Inhalation; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D018821:CD18 Antigens / Q000096:biosynthesis / Q000235:genetics; D004285:Dogs; D004731:Endotoxins; D004926:Escherichia coli; D005260:Female; D008168:Lung / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000378:metabolism*; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D039481:CD11b Antigen; D018821:CD18 Antigens; D004731:Endotoxins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide