Normovolaemic haemodilution and hyperoxia have no effect on fractal dimension of regional myocardial perfusion in dogs.

Hypervolaemic haemodilution makes myocardial perfusion more homogenous as reflected by reduced fractal dimension of regional myocardial perfusion. The clinically more commonly performed acute normovolaemic haemodilution, however, has not yet been studied in this respect. Hyperoxic ventilation with 100% oxygen is used in conjunction with haemodilution to compensate for low oxygen content by increasing physically dissolved oxygen in plasma. Since hyperoxia is known to cause disturbance in microcirculatory regulation we studied the effects of acute normovolaemic haemodilution to haematocrit (hct) 20 +/- 1% and hyperoxia on regional myocardial perfusion heterogeneity in 22 anaesthetized dogs using fractal and correlation analysis. Regional myocardial perfusion was assessed with radioactive microspheres. The results of the study were that heart rate, blood volume and arterial pressure were unchanged during haemodilution. Cardiac index was 3.6 +/- 0.7 L min-1 m-2 before and 4.6 +/- 0.7 L min-1 m-2 after haemodilution (P < 0.05). Fractal dimension (D) of regional myocardial perfusion was 1.17 +/- 0.10 at baseline. Neither haemodilution (D = 1.19 +/- 0.10) nor hyperoxia (D = 1.17 +/- 0.10) altered fractal properties of regional myocardial perfusion. Spatial correlation of blood flow to adjacent tissue samples before haemodilution was 0.58 +/- 0.15. Haemodilution and hyperoxia did not significantly influence spatial correlation (0.57 +/- 0.12 vs. 0.60 +/- 0.09; ns). We conclude that neither acute normovolaemic haemodilution nor haemodilution in combination with hyperoxic ventilation alter physiological myocardial perfusion heterogeneity.

Effects of hyperoxic ventilation on hemodilution-induced changes in anesthetized dogs.

BACKGROUND: In subjects who have undergone acute preoperative normovolemic hemodilution (ANH), intraoperative hemorrhage is generally treated by immediate return of autologous blood collected during ANH. Simply increasing blood oxygen content by hyperoxic ventilation (HV, inspiratory fraction [FIO2] 1.0) might compensate for the acute anemia, allow further ANH, and delay onset of autologous blood return. STUDY DESIGN AND METHODS: This study 1) evaluated the effects of HV (FIO2 1.0) upon ANH to a hemoglobin (Hb) concentration of 7 g per dL in anesthetized dogs ventilated with room air and 2) compared the effects of subsequent profound ANH (Hb, 3 g/dL) with and without an intravenous perfluorocarbon emulsion (perflubron 60% wt/vol) versus those of autologous red cell transfusion. The results of the entire study are presented in two parts. Organ tissue oxygenation was assessed in skeletal muscle and liver, and systemic oxygenation status was evaluated. Myocardial contractility was deduced from left ventricular pressure-volume relationship. Seven of 22 dogs underwent further hemodilution while breathing 100-percent O2, for a determination of the Hb concentration at which HV-induced effects were abolished. RESULTS: HV completely reversed the ANH-induced increase in cardiac index (4.6 +/- 0.7 vs. 3.8 +/- 0.9 L/min/m2 before and during HV; p < 0.05) and partially reversed the decrease in systemic vascular resistance (1784 +/- 329 vs. 2087 +/- 524 dyn x cm-5 x sec x m-2; p < 0.05). Despite unchanged global O2 delivery, organ tissue oxygenation improved during HV (mixed venous partial pressure of O2: 40 +/- 3 vs. 59 +/- 7 torr; coronary venous pressure of O2: 30 +/- 4 vs. 43 +/- 6 torr; p < 0.05; liver surface: 31 +/- 11 vs. 39 +/- 13 torr; skeletal muscle surface: 30 +/- 14 vs. 41 +/- 22 torr; p < 0.05). This improvement was due to an increased contribution of physically dissolved O2 in plasma to O2 delivery (3.2 +/- 0.2% before HV vs. 14.6 +/- 1% during HV; p < 0.05) and O2 consumption (whole body: 6 +/- 1% vs. 47 +/- 8%, p < 0.05; myocardium: 4.3 +/- 0.9% vs. 31 +/- 6%, p < 0.05). The beneficial effects of HV were lost after an additional volume-compensated exchange of 19 percent of blood volume (Hb, 5.6 g/dL). CONCLUSION: In anesthetized dogs ventilated with room air and hemodiluted to a Hb of 7 g per dL, simple oxygen therapy by HV (FIO2 1.0) rapidly improves tissue oxygenation and permits extended hemodilution to Hb of 5.8 g per dL until the HV-induced effects are lost.

Hemodilution and intravenous perflubron emulsion as an alternative to blood transfusion: effects on tissue oxygenation during profound hemodilution in anesthetized dogs.

BACKGROUND: Intravenously administered perfluorocarbon (PFC) emulsions increase oxygen solubility in plasma. PFC might therefore temporarily replace red cells (RBCs) lost during intraoperative hemorrhage. In patients who have undergone hemodilution, the return of autologous blood may be delayed by the administration of PFC, and autologous RBCs may be saved for transfusion after surgical bleeding is stopped and PFC is cleared by the reticuloendothelial system. STUDY DESIGN AND METHODS: In 22 anesthetized, hemodiluted dogs (hemoglobin [Hb] 7 g/dL) breathing 100-percent O2, an intraoperative volume-compensated blood loss was simulated. The efficacy of three therapeutic regimens in maintaining tissue oxygenation was compared: 1) RBC group (n = 7): maintenance of a Hb > 7 g per dL by transfusion of autologous RBCs; 2) PFC group (n = 7): bolus application of a second-generation PFC emulsion (60% wt/vol perflubron) and further acute normovolemic hemodilution (ANH) to a Hb of 3 g per dL; and 3) control group (n = 7): further ANH alone to a Hb of 3 g per dL. Systemic and myocardial oxygenation status and tissue oxygenation were assessed. RESULTS: Autologous RBCs transfused to maintain a Hb of 7 g per dL preserved hemodynamics and tissue oxygenation during blood loss. In the PFC and control groups, heart rate and cardiac index increased significantly in response to further ANH. Tissue oxygenation was not different in the PFC and the RBC groups. Direct comparison of the PFC and control groups revealed better tissue oxygenation in the PFC group, as reflected by significantly higher mixed venous, coronary venous, and local tissue pO2 on liver and skeletal muscle. CONCLUSION: Bolus intravenous administration of 60-percent (wt/vol) perflubron emulsion and further hemodilution from a Hb of 7 g per dL to one of 3 g per dL were as effective as autologous RBC transfusion in maintaining tissue oxygenation during volume-compensated blood loss designed to mimic surgical bleeding.

Hemodilution and hyperoxia locally change distribution of regional pulmonary perfusion in dogs.

In seven anesthetized dogs, the effects of acute normovolemic hemodilution (ANH) to a hematocrit of 20 and 8% and the effects of hyperoxic ventilation (100% oxygen) on distribution of regional pulmonary blood flow (rPBF; radioactive microspheres) were investigated. Normovolemia was monitored with blood volume measurements (indocyanine green dilution kinetics). Before ANH, fractal dimension (D) of rPBF in the whole lung was 1.19 +/- 0.09 (mean +/- SD). Spatial correlation (rho) of rPBF in the whole lung was 0.6 +/- 0.08. D is a resolution-independent measure for global rPBF distribution, and rho is the averaged flow relationship of directly neighboring lung samples. With regard to the entire lung, neither ANH nor hyperoxia changed D or rho. With regard to horizontal, isogravitational planes, ANH induced opposite changes of rPBF heterogeneity depending on the vertical location of the plane and the parameter used. In ventral planes, a change in relative dispersion (SD/mean) indicated decreased homogeneity. However, rho suggested more homogeneous perfusion. Hyperoxia restored baseline rPBF distribution. Our data suggest that ANH causes different alterations of heterogeneity of rPBF depending on location within the lung.

A pilot study of the effects of a perflubron emulsion, AF 0104, on mixed venous oxygen tension in anesthetized surgical patients.

A pilot study of a perfluorochemical (PFC) emulsion was undertaken to determine whether administration of a perflubron emulsion could result in measurable changes in mixed venous oxygen tension. Seven adult surgical patients received a 0.9-g PFC/kg intravenous dose of perflubron emulsion after acute normovolemic hemodilution (ANH). Hemodynamic and oxygen transport data were collected before and after ANH, immediately after PFC infusion, and at approximate 15-min intervals throughout the surgical period. There were no clinically significant hemodynamic changes associated with the administration of the PFC emulsion. There was a significant increase in mixed venous oxygen tension (PVO2) after the PFC infusion, while cardiac output and oxygen consumption were unchanged. As surgery progressed, the hemoglobin concentration decreased with ongoing blood loss while PVO2 values remained at or above predosing levels. Peak perflubron blood levels were 0.8 g/dL immediately postinfusion, and approximately 0.3 g/dL at 1 h. This pilot study demonstrates that administration of perflubron emulsion results in measurable changes in mixed venous oxygen tension during intraoperative ANH.

Effects of a perfluorocarbon emulsion for enhanced O2 solubility on hemodynamics and O2 transport in dogs.

Perfluorocarbon emulsions raise blood O2 solubility and thus augment O2 transport, but their cardiopulmonary effects at higher doses may limit their use. We therefore examined effects of increasing doses of perfluorooctylbromide emulsion (Oxy) on 1) pulmonary gas exchange, 2) pulmonary and systemic hemodynamics, and 3) mixed venous PO2 (PVO2). After hematocrit reduction to 24-26% by exchange with 5% albumin, anesthetized ventilated dogs breathing 100% O2 were given Oxy (n = 6) or 5% albumin (n = 5) intravenously in four successive 3 ml/kg doses. After each dose, arterial and venous PO2, PCO2, and pH, [O2], hematocrit, heart rate, and systemic, pulmonary arterial, and airway pressures were measured. Ventilation-perfusion relationships and cardiac output (QT) were determined by the multiple inert gas method. Oxy at 12 ml/kg almost doubled blood O2 solubility, increasing arterial [O2] by 1.28 ml/100 ml but did not affect O2 consumption and ventilation-perfusion relationships. QT rose by 21% after 3 ml/kg, then fell with increasing doses (-18% from baseline after 12 ml/kg); O2 delivery remained constant. Oxy at > 6 ml/kg increased systemic blood pressure and systemic vascular resistance considerably. Mean pulmonary arterial pressure and pulmonary vascular resistance increased slightly. Airway pressures were unaffected. PVO2 rose from 66 to 77 Torr (6 ml/kg), then fell to 72 Torr (12 ml/kg), in accord with theoretical-predictions. In this model, Oxy 1) dose not impair pulmonary gas exchange in doses up to 12 ml/kg, 2) leads to progressively higher systemic vascular resistance and fall in QT at > 3-6 ml/kg, possibly because of increased blood viscosity, and 3) augments PVO2, as predicted from the increase in plasma O2 solubility.

Effect of supplemental perfluorocarbon administration on hypotensive resuscitation of severe uncontrolled hemorrhage.

Recent animal studies of acute hemorrhage in the presence of a vascular injury have demonstrated improved survival and decreased hemorrhage volume with hypotensive resuscitation, but this has occurred at the expense of tissue perfusion. It was hypothesized that addition of an oxygen-carrying perfusate would improve tissue oxygen delivery during hypotensive resuscitation. Hypotensive resuscitation of severe uncontrolled hemorrhage was compared with and without supplementation with Oxygent HT, an emulsion of perflubron (perfluorooctylbromide; PFOB; Alliance Pharmaceutical Corporation, San Diego, CA), an oxygen-carrying perfusate. Fifteen swine (15 to 22 kg) with 4-mm aortic tears were bled to a pulse pressure of 5 mm Hg and then resuscitated (estimated blood loss, 40 to 50 mL/kg). All animals were resuscitated with normal saline (6 mL/kg/min) infused as needed to maintain a mean arterial pressure of 40 mm Hg. One group (PFC) of animals also received an infusion of 6 mL/kg perfluorooctylbromide emulsion. Another group served as controls and received an equal volume of placebo (normal saline). Animals were observed for 120 minutes or until death. Data were compared using repeated measures analysis of variance (ANOVA) the Student's t test, and Fisher's exact. A P value < .05 was considered significant. Two-hour mortality rates were 12.5% and 43% for PFC-treated animals and controls, respectively (P > .05; 95% confidence interval [95% CI] for this difference in mortality is -13% to 74%). Oxygen content and delivery were significantly greater in the treatment group. In conclusion, administration of an oxygen-carrying perfusate significantly improves oxygen delivery in hypotensive crystalloid resuscitation of severe uncontrolled hemorrhage.

Enhanced oxygen delivery by perflubron emulsion during acute hemodilution.

A high-concentration 90% w/v perflubron (perfluorooctyl bromide [PFOB]) emulsion (Oxygent HT) is being evaluated as an oxygen carrier for use during surgery. This study was done to assess oxygen delivery by Oxygent HT during acute normovolemic hemodilution. Anesthetized mongrel dogs, instrumented with femoral and pulmonary artery catheters, were hemodiluted to a hematocrit of 25% with 3:1 (v/v) of Ringers-lactate (R-L). Dogs were then ventilated with 100% O2 and hemodiluted to a Hct approximately 11% with 1.5 (v/v) of colloid (autologous plasma and 5% albumin). Dogs then received either 3.3 mL/kg Oxygent HT (n = 5) or 3.3 mL/kg R-L (n = 4), and were monitored for 3 hours. Total oxygen delivery (DO2), blood oxygen content, cardiac output, mixed venous PO2, and mixed venous Hb saturation was higher in Oxygent HT treated dogs compared to the R-L controls. The percentage of total DO2 contributed by perflubron-dissolved oxygen was about 8-10% and accounted for 25-30% of total oxygen consumption (VO2). The percentage of VO2 contributed by Hb-carried oxygen was significantly higher in R-L controls (46 +/- 4%) than in the treated dogs (15 +/- 3%), indicating that the availability of the perflubron-dissolved oxygen allowed for a reserve of oxygen to remain available in the red blood cells.

Improvement in circulatory and oxygenation status by perflubron emulsion (Oxygent HT) in a canine model of surgical hemodilution.

To examine the effect of a low dose of Oxygent HT on hemodynamics and oxygen transport variables in a canine model of profound surgical hemodilution, two groups of adult anesthetized splenectomized beagles were hemodiluted with Ringer's solution to Hb 7 g/dL. The treated group received 1 mL/kg Oxygent HT (90% w/v perflubron emulsion [perfluorooctyl bromide], Alliance Pharmaceutical Corp.) and both groups (7 controls and 10 treated) were further hemodiluted using 6% hydroxyethyl starch until cardiorespiratory decompensation occurred. Pulmonary artery catheterization data and oxygen transport variables were recorded at Hb decrements of 1 g/dL breathing room air. There was no difference among groups during initial hemodilution. However, in the Oxygent HT group there was a statistically significant improvement in mean arterial pressure, CVP, cardiac output, PvO2, SvO2, DO2, and pulmonary venous admixture shunt during profound hemodilution to Hb levels of 6, 5, and 4 g/dL. A low dose of Oxygent HT offered benefit in improving hemodynamics and oxygen transport parameters even under air breathing conditions in a model of surgical hemodilution. This effect was most apparent at lower levels of Hb.

Mechanisms and efficacy of fluorochemical oxygen transport and delivery.

Fluorochemicals for medical use are metabolically inert liquids with a high solubility for gases, and can dissolve 50 percent or more of their own volume of oxygen (O2) at ambient pressures. The solubility is directly proportional to the oxygen tension (PO2) and transport is thus not saturable, unlike the O2 saturation of hemoglobin (Hb) which follows the well known "S" shaped relationship with PO2. Intravenously-injected emulsions of fluorocarbons transport only about one seventh as much O2 as Hb on a gram for gram basis, even when high concentrations of O2 are respired. However, because of the high O2 extraction from fluorocarbons in these circumstances, their contribution to O2 consumption is more than 65% of that of Hb. O2 delivery to the tissues depends on the product of the cardiac output and the arterial oxygen content. When red cells are transfused, blood viscosity increases and cardiac output decreases. This lessens the efficacy of blood in comparison to that of fluorocarbons, and increases the relative transport of O2 in the metabolically readily-accessible plasma compartment. This provides an interesting application for low dose fluorocarbons during surgery in combination with autologous blood use. The efficacy of fluorocarbons in this setting can be predicted by computer modelling.

Comparison of ventilatory support with intratracheal perfluorocarbon administration and conventional mechanical ventilation in animals with acute respiratory failure.

We investigated the efficacy of intratracheal perfluorocarbon (PFC) administration combined with mechanical ventilation to support gas exchange in adult animals with acute respiratory failure. These were compared with a similar group of animals treated with continuous positive-pressure ventilation (CPPV) with respect to respiratory parameters and postmortem lung histology. After lung lavage with saline, 18 adult rabbits were divided into three groups (n = 6 per group). All groups received conventional CPPV. Additionally, one group received intratracheal PFC administration at a volume of 18 ml/kg (corresponding to functional residual capacity) (PFC group); another received 18 ml/kg of saline administration (saline group), and the last had no further treatment (CPPV group). All groups were ventilated for 3 h using 100% oxygen, with the same ventilator settings of tidal volume of 12 ml/kg, respiratory frequency of 30/min, and positive end-expiratory pressure of 6 cm H2O. In the PFC group, PaO2 increased from 67.2 +/- 11.4 to 424.2 +/- 14 mm Hg and remained stable for 3 h with well-preserved PaCO2 values. Only in the PFC group were significant decreases in airway pressures and increase in respiratory system compliance seen. In the CPPV group, PaO2 stayed around 60 mm Hg and PaCO2 gradually increased. PFC treatment with conventional mechanical ventilation in acute respiratory failure proved to be a successful supportive technique to improve gas exchange at low inflation pressures.

Intratracheal perfluorocarbon administration combined with mechanical ventilation in experimental respiratory distress syndrome: dose-dependent improvement of gas exchange.

OBJECTIVES: To test the efficacy of intratracheal instillation of a perfluorocarbon, combined with conventional mechanical ventilation, as well as to establish the dose response of this application on pulmonary parameters in adult animals with acute respiratory failure. DESIGN: Prospective, randomized, placebo-controlled study. SETTING: Anesthesiology laboratory of a university. SUBJECTS: Twelve, adult male New Zealand rabbits. INTERVENTIONS: After inducing respiratory failure by repeated lung lavage with saline, one group of animals was treated with perfluorocarbon, while another group was treated with saline to serve as controls (n = 6 per group). Treatment consisted of intratracheal instillation of incremental doses of 3 mL/kg of each liquid up to a total volume of 15 mL/kg. Animals were mechanically ventilated for 15 mins after each treatment dose with volume-controlled ventilation, a tidal volume of 12 mL/kg, frequency of 30 breaths/min, FIO2 of 1.0, and a positive end-expiratory pressure of 6 cm H2O. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases and lung mechanics were determined. In the perfluorocarbon group, PaO2 increased with increases in dosage from 75 +/- 15 to 420 +/- 27 torr (10.0 +/- 2.0 to 55.9 +/- 3.6 kPa); PaCO2 decreased from 49 +/- 6 to 43 +/- 5 torr (6.5 +/- 0.8 to 5.7 +/- 0.6 kPa) after the first dose, and remained stable thereafter. Airway pressures were significantly lower after treatment compared with pretreatment values. CONCLUSION: The remarkable improvements in pulmonary parameters suggest that this type of ventilatory support offers an effective and simple method of perfluorocarbon application in acute respiratory failure.