Effects of hemoglobin-based blood substitutes on vasoactivity of rat aortic rings.

Our objective is to characterize the vasoactive properties of a 10% alphaalpha diaspirin cross-linked human hemoglobin (alphaalphaHb) and to test the hypothesis that sodium nitroprusside (SNP)-induced relaxation is inhibited in the presence of alphaalphaHb. Experiments were performed on aortic rings from 18 Wistar rats; the rings were suspended in aerated Krebs solution. Changes in isometric tension were measured to increasing concentrations of alphaalphaHb (1.8 x 10(-9) to 10(-4) M) on phenylephrine (PE)-induced contraction (3 x 10(-7) M), on acetylcholine (ACh)-induced relaxation (10(-8) to 10(-6) M), on SNP-induced relaxation (10(-9) and 10(-8) M), and on PE-induced contraction with an endothelin-1 (ET1) receptor antagonist, BQ123 (10(-5) M). Control rings received no alphaalphaHb. A concentration-dependent increase of the PE-precontraction (1.3%, 6.8%, 17.4%, and 34%, respectively) as well as the inhibition and reversal of ACh-induced relaxation was observed after alphaalphaHb. The presence of alphaalphaHb decreased the SNP-induced relaxation in the presence or absence of endothelium. The relaxation induced by SNP was reduced with time in the presence, but not in the absence, of alphaalphaHb. In conclusion, although pharmacological modulation of the vasoconstriction is possible with nitric oxide donors, our findings suggest that in the clinical setting, large sustained donor doses may be required.

Pulmonary hypertension and systemic vasoconstriction may offset the benefits of acellular hemoglobin blood substitutes.

OBJECTIVE: We tested the hypothesis that the pharmacologic properties of a small volume of alpha alpha-cross-linked hemoglobin (alpha alpha Hb) could effectively resuscitate pigs subjected to hemorrhage. METHODS: Fourteen pigs hemorrhaged to a mean arterial pressure (MAP) of 40 mm Hg for 60 minutes were treated with a 4-mL/kg 2-minute infusion of 10 g/dL alpha alpha Hb or 7 g/dL human serum albumin, an oncotically matched control solution. RESULTS: The removal of blood (17 +/- 1.5 mL/kg) caused the typical physiologic responses to hemorrhagic hypovolemia. Infusion of alpha alpha Hb restored mean arterial pressure and coronary perfusion pressure, but cardiac output and mixed venous O2 saturation did not improve significantly. Pulmonary arterial pressure and pulmonary vascular resistance increased markedly and were higher than baseline levels after alpha alpha Hb. Infusion of human serum albumin produced only minor hemodynamic changes. Brain blood flow did improve to baseline values after alpha alpha Hb, but was the only tissue to do so. In the human serum albumin group, superior mesenteric artery blood flow recovered to baseline values, whereas brain blood flow did not. Blood flows to other tissues were similar in both groups. CONCLUSION: Small-volume infusion of alpha alpha Hb restored mean arterial pressure and brain blood flow, but pulmonary hypertension and low peripheral perfusion may offset benefits for trauma patients.

Comparison of hypertonic saline/dextran versus hypertonic saline/hetastarch for resuscitation of hypovolemia.

In the present study, we compare resuscitation of bled sheep with hypertonic saline/dextran or hypertonic saline/hetastarch. Unanesthetized sheep were subjected to 2 h of hemorrhagic hypotension and then resuscitated with 200 ml of 7.5% NaCl solution made up to include either 6% dextran 70 (Macrodex) or 6% hetastarch (Hespan). Both solutions provided an immediate and sustained improvement in arterial pressure and cardiac output. The hypertonic saline/dextran provided a slightly better overall response as mean arterial pressure, cardiac output and central venous pressure were higher in the dextran group at all times post resuscitation. However, only the differences in arterial pressure and initial plasma volume expansion were statistically significant. The somewhat better response to hypertonic saline/dextran may be explained by the higher oncotic pressures generated by dextran compared to equal concentrations of hetastarch.

Resuscitation of hemorrhage with intraosseous infusion of hypertonic saline/dextran.

We resuscitated unanesthetized bled sheep (bled volume = 1.2-1.7 liters) with 200 ml of hypertonic saline/dextran 70 infused either through a peripheral vein (n = 6) or directly into the red marrow of the sternum (n = 6). Intraosseous infusion of the viscous 7.5% NaCl/6% dextran solution required 2-4 min. Plasma sodium was rapidly increased to the same level in both groups demonstrating equally rapid entry into the vascular space. Both regimens provide rapid and sustained normalization of arterial pressure and cardiac output. No significant differences between the two groups were apparent for any measured variable. Intraosseous infusion of hypertonic resuscitation fluids merits further research to evaluate the safety and efficacy for prehospital treatment of hypovolemia and trauma.

Perspectives on clinical trials for hypertonic saline/dextran solutions for the treatment of traumatic shock.

Animal studies with hypertonic solutions suggest that they can achieve resuscitation of hypovolemic shock with extremely small volumes. Such small volume resuscitation might be ideal in the field treatment of injured patients. Our studies to date, with 60 patients entered into a prospective, randomized, placebo-controlled, and double-blind clinical trial, suggest that the use of a 7.5% NaCl/Dextran 70 solution increases blood pressures during transport. The solutions have been safe, and we have encountered no adverse side effects from their use. Survival rates to date favor use of the solutions, but we do not have convincing statistical significance yet in that regard.

Cardiac performance following hypertonic saline.

The present study was undertaken to examine cardiovascular function before and after either intravenous or intra-arterial infusion of hypertonic saline (7.5% NaCl) in halothane-anesthetized dogs. A high-fidelity micromanometer and ultrasonic dimension transducers were implanted to measure pressure and wall motion of the left ventricle (LV). Cardiac output (CO) was measured using an electromagnetic flowmeter and thermodilution. The slope (Ees) of the linear regression of the LV pressure-diameter relationship was used as an index of cardiac contractility. Intravenous infusion of hypertonic saline (3 ml/kg) increased mean arterial pressure (MAP, 104 +/- 6 to 116 +/- 6 mmHg), heart rate (HR, 124 +/- 21 to 140 +/- 13 bpm), CO (3.2 +/- 0.9 to 4.2 +/- 0.5 l/m) and Ees (11.6 +/- 2.1 to 14.8 +/- 1.9 mmHg/mm). Systemic vascular resistance (SVR) fell by 18%. The above responses were similar whether infusion was intravenous or intra-arterial into innervated or denervated hind limbs. While nerve blockade at T-4 (xylocaine) attenuated the changes in CO and SVR and completely prevented the tachycardia, the inotropic response remained intact. These studies suggest that the cardiac effects of hypertonic saline infusion are not mediated by pulmonary or peripheral osmoreceptors and the increased contractility may result from a direct myocardial effect of increased osmolality.

Comparison of hypertonic saline/dextran versus hypertonic saline/hetastarch for resuscitation of hypovolemia

In the present study, we compare resuscitation of bled sheep with hypertonic saline/dextran or hypertonic saline/hetastarch. Unanestherized sheep were subjected to 2h of hemorrhagic hypotension and then resuscitated with 200 ml of 7.5% NaCl solution made up to include either 6% dextran 70 (Macrodex) or 6% hetastarch (Hespan). Both solutions provided an immediate and sustained improvement in arterial pressure and cardiac output. The hypertonic saline/dextran provided a slightly better overall response as mean arterial pressure, cardiac output and central venous pressure were higher in the dextran group at all times post resuscitation. However, only the ddifferences in arterial pressure and initial plasma volume expansion were statistically significant. The somewhat better response to hypertonic saline/dextran may be explained by the higher oncotic pressures generated by dextran compared to equal concentrations of hetastarch

Resuscitation of hemorrhage with intraosseous infusion of hypertonic saline/dextran

We resuscitated unanesthetized bled sheep (bled volume = 1.2-1.7 liters) with 200 ml of hypetonic saline/dextran 70 infused either through a peripheral vein (n=6) or directly into the red marrow of the sternum (n = 6). Intraosseous infusion of the viscous 7.5% NaCl/6% dextran solution required 2-4 min. Plasma sodium was rapidly increased to the same level n both groups demonstrating equally rapid entry into the vascular space. Both regimens provide rapid and sustained normalization of arterial pressure and cardiac output. No significant differences between the two groups were apparent for any measured variable. Intraosseous infusion of hypertonic resuscitation fluids merits further research to evaluate the safety and efficacy for prehspital treatment of hypovolemia and trauma

Perspectives on clinical trials for hypertonic saline/dextran solutions for the treatment of traumatic shock

Animal studies with hypertonic solutins suggest that they can achieve resuscitation of hypovolemic shock with extremely small volumes. Such small volume ressuscitation might be ideal in the field treatment of injured patients. Our studies to date, with 60 patients enterd into a prospective, randomized, placebo-controlled, and double-blind clinical trial, suggest that the use of a 7.5% NaCl/Dextran 70 solution increases blood pressures during transport. The solutions have been safe, and we have encoutered no adverse side effects from their use. Survival rates to date favor use of the solutions, but we do not have convincing statistical significance yet in that regard

Cardiac performance following hypertonic saline

The present study was undertaken to examine cardiovascular function before and after either intravenous or intra-arterial infusion of hypertonic saline (7.5% NaCl) in halothane-anesthetized dogs. A high-fidelity micromanometer and ultrasonic dimension transducers were implanted to measure pressure and wall motion of the left ventricle (LV). Cardiac output (CO) was measured using an elelctromagnetic flowmeter and thermodidlution. The slop (Ees) of the linear regression of the LV pressure-diameter relationship was used as an index of cardiac contractility. Intravenous infusion of hypertonic saline (3 ml/Kg) increased mean arterial pressure (MAP, 104 ñ 6 to 116 ñ 6 mmHg), heart rate (HR, 124 ñ 21 to 140 ñ 13 bpm), CO(3.2 ñ 0.9 to 4.2 ñ 0.5 l/,) and Ees (11.6 ñ 2.1 to 14.8 ñ 1.9 mmHg/mm). Systemic vascular resistance (SVR) fell by 18%. The above responses were similar whether infusion was intravenous or intra-arterial into innervated or denervated hind limbs. While nerve blockade at T-4 (xylocaine) attenuated the changes in CO and SVR and completely prevented the tachicardia, the inotropic response remained intact. These studies suggest tht the cardiac effect of hypertonic saline infusion are not mediated by pulmonary or peripheral osmoreceptors and the increased contractility may results form a direct myocardial effect of increased osmolatity