Pretreatment with N-nitro-L-arginine methyl ester improved oxygenation after inhalation of nitric oxide in newborn piglets with Escherichia coli pneumonia and sepsis

Abstract

We evaluated the effects of a combined therapy of pre-blockade endogenous nitric oxide synthase (NOS) with N-nitro-L-arginine methyl ester (L-NAME) and continuous inhaled NO (iNO) on the gas exchange and hemodynamics of Escherichia coli pneumonia and sepsis in newborn piglets. Seven to ten day old ventilated newborn piglets were randomized into 5 groups: control, E. coli pneumonia control, pneumonia with iNO 10 ppm, pneumonia pre-treated with L-NAME 10 mg/kg, and pneumonia with the combined therapy of L-NAME pretreatment and iNO. E. coli pneumonia was induced via intratracheal instillation of Escherichia coli, which resulted in progressively decreased cardiac index and oxygen tension; increased pulmonary vascular resistance index (PVRI), intrapulmonary shunting, and developed septicemia at the end of 6 hr experiment. iNO ameliorated the progressive hypoxemia and intrapulmonary shunting without affecting the PVRI. Only two of 8 animals with L-NAME pretreated pneumonia survived. Whereas when iNO was added to infected animals with L-NAME pretreatment, the progressive hypoxemia was abolished as a result of a decrease in intrapulmonary shunting without reverse of the high PVRI and systemic vascular resistance index induced by the L-NAME injection. This result suggests that a NOS blockade may be a possible supportive option for oxygenation by iNO treatment in neonatal Gram-negative bacterial pneumonia and sepsis.

Fig. 1

Scheme of the experimental protocol. L-NAME, administration of N-nitro-L-arginine methyl ester; E.coli/Saline, intratracheal instillation of Escherichia coli or Saline; iNO, administration of inhaled nitric oxide; Ventilator re-adjustment, Ventilator settings were changed to peak inspiratory pressure (PIP) 30 cmH₂O, rate 25/min, peak end expiratory pressure (PEEP) 4 cmH₂O, inspiratory time (IT) 0.6 sec. Animals in PNA were not included for the results because only two of eight survived. Measurement of variables was recorded hourly.

Fig. 2

Mean systemic arterial pressure (MAP), mean pulmonary arterial pressure (PAP), mean systemic vascular resistance index (SVRI), mean pulmonary vascular resistance index (PVRI) and cardiac index in the newborn piglets of 4 groups at -1, 0, 3, and 6 hr of experiment. CON: control group; PCON: E. coli pneumonia control; PNO: E. coli pneumonia with 10 ppm nitric oxide inhalation; PNANO: E. coli pneumonia with added nitric oxide inhalation to L-NAME pretreatment (10 mg/kg). Data represent mean±standard deviation. ^*p<0.05 compared to CON, ^†p<0.05 compared to PCON.

Fig. 3

Arterial oxygen tension, carbon dioxide tension, intrapulmonary shunt fraction (venous admixture %) and Vd/Vt (dead space to tidal volume ratio) in the newborn piglets of 4 groups at 0, 3, and 6 hr of experiment. CON: control group; PCON: E. coli pneumonia control; PNO: E. coli pneumonia with 10 ppm nitric oxide inhalation; PNANO: E. coli pneumonia with added nitric oxide inhalation to L-NAME pretreatment (10 mg/kg). Data represent mean±standard deviation. ^*p<0.05 compared to CON, ^†p<0.05 compared to PCON, ^‡p<0.05 compared to PNO.