Hypoxic pulmonary vasoconstriction (HPV) is inhibited by inhaled nitric oxide (NO) in healthy animals and is blunted in endotoxemia. We investigated whether the loss of HPV during sepsis could be reversed by NO synthase (NOS) inhibition. Hypoxic challenges were induced in intubated, awake sheep breathing 100% nitrogen to the left lung and 100% oxygen to the right lung. HPV was assessed as the decrease in left pulmonary blood flow during hypoxia, measured with an ultrasonic flow probe around the left pulmonary artery. Group I (n = 5) received carrier solutions and Groups II (n = 6) and III (n = 8) received an infusion containing Pseudomonas aeruginosa. After 24 h, Group III also received an infusion of 6.6 mg.kg.h-1 N omega-monomethyl-L-arginine (L-NMMA). After 24 h of sepsis, HPV decreased from 60 +/- 9% in Group II and 56 +/- 4% in Group III to 27 +/- 2% and 26 +/- 4%, respectively. Group I showed no change in HPV. During infusion of L-NMMA, HPV increased to 38 +/- 4%. Pulmonary shunt during hypoxia increased in Group III to 161 +/- 10% of its baseline value, and decreased to 121 +/- 11% during infusion of L-NMMA. We conclude that L-NMMA improves but does not restore HPV, indicating that other vasodilatory mediators besides NO also influence HPV in sepsis.

We investigated the effects of modified hemoglobin on regional blood flow and function of different organs during hyperdynamic sepsis. Fourteen sheep were surgically prepared for the study. After a 5-day recovery period, a continuous infusion of live Pseudomonas aeruginosa bacteria was begun and maintained for 48 h. At 24 h, after a hyperdynamic circulation had developed, the animals were randomly assigned to two groups: 1) a treatment group (n = 7) that received an infusion with 100 mg/kg pyridoxalated hemoglobin polyoxyethylene conjugate (PHP) over 30 min and 2) a control group (n = 7) that received only the vehicle. PHP infusion increased mean arterial pressure from 86 +/- 2.8 to 101.8 +/- 3.5 mmHg (P < 0.05) and systemic vascular resistance index from 769 +/- 42.1 to 1,087 +/- 56.8 dyn . s . m2 . cm-5 (P < 0.05). PHP infusion did not decrease regional blood flow, measured with fluorescent microspheres, below the baseline values in any of the analyzed tissues. None of the investigated blood chemistry variables showed any changes indicative of impaired organ function after PHP infusion. In our model of ovine sepsis we found no side effects after PHP infusion that would limit the use of PHP as a nitric oxide scavenger in sepsis.

We have measured plasma volume expansion (Evans blue and hematocrit changes) and hemodynamic responses in conscious hemorrhaged and normovolemic splenectomized sheep after a 30-min infusion of either 20 ml/kg of diaspirin cross-linked hemoglobin (DCLHb), 20 ml/kg of human albumin (Alb), or 60 ml/kg of a solution of Ringer lactate (RL). All regimens expanded blood volume and increased blood pressure and cardiac output after hemorrhage. However, only 15 ± 3% of the infused volume of RL was evident as intravascular expansion 10-min postinfusion, compared with 67 ± 16% and 139 ± 139% for Alb and DCLHb, respectively. DCLHb infusions were associated with higher blood pressures and lower cardiac outputs compared with RL and Alb infusions, but the increased oxygen content of blood with DCLHb resulted in systemic delivery of oxygen similar to that of the other infusions. These differences in hemodynamics and vascular volume continued for 6 h, and at 24 h vascular volume and all hemodynamics were similar in all three groups. The better volume expansion with DCLHb may be due to greater mobilization of endogenous interstitial protein or reduced transcapillary loss as total intravascular endogenous plasma protein increased after infusion of DCLHb, whereas there was an apparent loss of endogenous intravascular protein after infusions of Alb and RL. Vasoconstriction by DCLHb is one mechanism that could lower blood-to-tissue transport of fluid and protein. In addition to its oxygen-carrying capacity and vasoactivity, DCLHb is associated with volume expansion properties out of proportion to its colloid osmotic pressure.

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