PYRIDOXALATED HEMOGLOBIN POLYOXYETHYLENE CONJUGATE DOES NOT RESTORE HYPOXIC PULMONARY VASOCONSTRICTION IN-OVINE SEPSIS

Objectives: Hypoxic pulmonary vasoconstriction, a protective mechanism , minimizes perfusion of underventilated lung areas to reduce ventilat ion-perfusion mismatching. We studied the effects of sepsis on hypoxic pulmonary vasoconstriction and attempted to determine whether hypoxic pulmonary vasoconstriction is influenced by pyridoxalated hemoglobin polyoxyethylene conjugate, a nitric oxide scavenger. Design: Prospecti ve, randomized, controlled experimental study with repeated measures. Setting: Investigational intensive care unit at a university medical c enter. Subjects: Nineteen female merino sheep, divided into three grou ps: group 1, controls (n = 5); group 2, sheep with sepsis (n = 6); and group 3, septic sheep treated with pyridoxalated hemoglobin polyoxyet hylene conjugate (n = 8). Interventions: All sheep were instrumented f or chronic study. An ultrasonic flow probe was placed around the left pulmonary artery. After a 5 day recovery, a tracheostomy was performed and a double lumen endotracheal tube was placed. Animals in groups 2 and 3 received a 48-hr infusion of live Pseudomonas aeruginosa (6 x 10 (6) colony-forming units/kg/hr). After 24 hrs, sheep in group 3 receiv ed pyridoxalated hemoglobin polyoxyethylene conjugate (20 mg/kg/hr) fo r 16 hrs; sheep in groups 1 and 2 received only the vehicle. Hypoxic p ulmonary vasoconstriction was repeatedly tested by unilateral hypoxia of the left lung with 100% nitrogen. Hypoxic pulmonary vasoconstrictio n was assessed as the change in left pulmonary blood flow. Measurement s and Main Results: In the animals in group 1, left pulmonary blood fl ow decreased by 62 +/- 8 (SEM) % during left lung hypoxia and remained stable during repeated hypoxic challenges throughout the study period . After 24 hrs of sepsis, left pulmonary blood flow decreased from 56 +/- 10% to 26 +/- 2% (group 2) and from 50 +/- 8% to 23 +/- 6% (group 3). In the sheep in group 2, there was no adaptation over time. Pulmon ary shunt fraction increased. Pyridoxalated hemoglobin polyoxyethylene conjugate had no effect on hypoxic pulmonary vasoconstriction or pulm onary shunt. The animals receiving the bacterial infusion developed a hyperdynamic circulatory state with hypotension, decreased systemic va scular resistance, and increased cardiac output. Pyridoxalated hemoglo bin polyoxyethylene conjugate increased mean arterial pressure and sys temic vascular resistance but did not influence cardiac index. Pulmona ry arterial pressure was increased during sepsis and increased even fu rther after pyridoxalated hemoglobin polyoxyethylene conjugate adminis tration. Oxygenation and oxy gen delivery and uptake were not affected by pyridoxalated hemoglobin polyoxyethylene conjugate. Conclusions: H ypoxic pulmonary vasoconstriction is blunted during sepsis and there i s no adaptation over time. It is not influenced by pyridoxalated hemog lobin polyoxyethylene conjugate. Pyridoxalated hemoglobin polyoxyethyl ene conjugate reversed hypotension and, with the exception of an incre ase in pulmonary arterial pressure, had no adverse effects on hemodyna mics or oxygenation.