TITLE: EFFECTS OF INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITION ON PULMONARY EDEMA FORMATION AFTER BURN AND SMOKE INHALTION COMBINED INJURY IN SHEEP

AUTHORS: Kazutaka Soejima, MD¹, Csaba Czabo, MD, PhD², Andrew Salzman, MD², Lillian D. Traber, RN¹, Daniel L. Traber, PhD¹
AFFILIATION: ¹Univ. of Texas Medical Branch, Galveston, TX; ²Inotek Corporation, Beverly, MA.

INTRODUCTION: Patients with severe cutaneous burn and/or smoke inhalation injury suffer pulmonary microvascular hyperpermeability. It leads to a lung edema, an important determinant of mortality of these patients¹. We hypothesized that inducible nitric oxide synthase (iNOS) is responsible for the pulmonary vasculature hyperpermeability which is seen with acute lung injury and multiple trauma. To test this hypothesis, conscious sheep subjected to combined injury of 40% TBSA, 3_ burn, and smoke inhalation were treated with mercaptoethylguanidine (MEG), a selective inhibitor of iNOS.
METHODS: Sheep (n=12) were surgically prepared for chronic study with lung lymph fistula². After recovery period, the sheep received 40% 3° burn and were insufflated with 48 breaths of cotton smoke. A MEG group [30mg/kg MEG was given 1 h after injury and every 8 h for 41 h, n=6] and control group (0.9% NaCl, n=6) were studied. All sheep were resuscitated with Ringer's lactate solution following the Parkland formula (4ml/kg/%burn). NO₂/NO₃ (NOx) concentration in plasma and lymph was measured with NO chemiluminescence technique. Colloid oncotic pressure in plasma (p_P) and lymph (p_L) was measured and lung lymph permeability index (l-PI) was calculated according to the following equation: l-PI = l-Q_L X p_L/p_P, (l-Q_L: lung lymph flow). After sacrifice, the entire right lung was harvested for measurement of blood free wet weight-to-dry weight (wet/dry) ratio, an index of pulmonary edema. Values are means ± the standard error of the mean. Statistical analysis was performed by ANOVA with post hoc Fisher's LSD. Significance was set at p<0.05.
RESULTS: In the control group, plasma and lymph NOx concentration was significantly increased from baseline value at 24 h after injury. In the MEG group, the NOx did not increase significantly (Plasma NOx: 3.25±0.4 µmol/l at baseline, 6.56±0.8 µmol/l at 24 h in the control group, [p<0.05], 2.61±0.3 µmol/l at baseline, 3.1±0.9 µmol/l at 24h in the MEG group, Lymph NOx: 4.06±0.8 µmol/l at baseline, 8.44±1.5 µmol/l at 24 h in the control group, [p<0.05], 4.41±1.2 µmol/l at baseline, 4.03±0.9 µmol/l at 24 h in the MEG group). Lung lymph flow was significantly attenuated in the MEG group (Figure). Lung permeability index was also significantly lower in the MEG group (32.1±5.8 in the control group, 14.5±3.4 in the MEG group at 36 h after injury, p<0.05). Lung wet/dry ratio was significantly lower in the MEG group than in the control group (Figure).
DISCUSSION: These data suggest that iNOS plays an important role in the pulmonary microvascular changes following extensive cutaneous burn and smoke inhalation injury. The selective inhibition of iNOS has beneficial therapeutic effect on pulmonary edema formation after this combined injury.
REFERENCES:

1) J. Burn Care Rehabil. 6, 490-494, 1985.

2) J. Surg. Res. 19, 315-320, 1975.