A randomized, single-blind, increasing dose safety trial of an oxygen-carrying plasma expander (Hemospan) administered to orthopaedic surgery patients with spinal anaesthesia.

The objective of this study was to further explore the safety of Hemospan (Sangart Inc., San Diego, CA, USA), an oxygen-carrying plasma expander. The aim of this study was to determine if Hemospan is well tolerated in orthopaedic surgery patients with spinal anaesthesia in doses up to 1 L. Hemospan was previously found to be well tolerated in normal volunteers and orthopaedic surgery patients with spinal anaesthesia in doses up to 500 mL. Five cohorts of six orthopaedic surgery patients, American Society of Anesthesiologists (ASA) I and II, were studied. In each cohort, four patients received Hemospan in doses ranging from 200 to 1000 mL, and two received Ringer's lactate immediately prior to induction of spinal anaesthesia. There were no serious adverse events (SAEs). Iohexol clearance measured before and 24 h after dosing was unaffected. There were 14 adverse events (AEs) in the 10 control patients (1.4 per patient) and 30 in the 20 patients receiving Hemospan (1.5 per patient). One patient in the group receiving 200 mL Hemospan had elevated mean arterial pressure after dosing, but there were no elevations in any of the other patients. The peak plasma Hemospan concentration in the 1000 mL group was 1.3 g dL(-1), with a dose-dependent clearance (T(1/2)) ranging from 14.1 to 23.0 h. Plasma methaemoglobin levels were independent of dose, reaching a maximum at 40 h after dosing and never exceeded 0.125 g dL(-1). Troponin T was transiently elevated in two patients receiving Hemospan without symptoms or electrocardiographic abnormalities or elevation of myocardial creatinine kinase isoenzyme. Hemospan was well tolerated in this group of patients at doses up to 1000 mL.

Randomized safety studies of intravenous perflubron emulsion. I. Effects on coagulation function in healthy volunteers.

Previous perfluorocarbon (PFC) emulsions have been associated with transient adverse events (i.e., platelet activation, decreased platelet count, febrile responses, changes in hemodynamic function). The Phase I studies described in this report were parallel, randomized, double-blinded, placebo-controlled studies conducted in 48 healthy volunteers (n = 24 per study) with perflubron emulsion (Oxygent; Alliance Pharmaceutical Corp., San Diego, CA). Because of the decreased platelet counts observed with previous PFC emulsions and the intended use of perflubron emulsion in surgical patients, these studies assessed postdosing coagulation responses and hemostasis. PFC pharmacokinetic variables were also evaluated. The primary endpoint for examination of coagulation effects was prospectively defined as bleeding time. Subjects received either saline (3 mL/kg) control, or perflubron emulsion at 1.2 g PFC/kg or 1.8 g PFC/kg, and were evaluated for a 14-day period. No postinfusion changes in bleeding time or differences in ex vivo agonist-induced platelet aggregation were observed. A 17% reduction in platelet count was observed 3 days after dosing in the 1.8-g PFC/kg group; levels recovered to baseline by Day 7. The intravascular half-life of perflubron for the first 24 h was dose dependent: 9.4+/-2.2 h and 6.1+/-1.9 h in the 1.8- and 1.2-g PFC/kg groups, respectively. Results indicate that this perflubron emulsion did not affect coagulation function in healthy volunteers.

Randomized safety studies of intravenous perflubron emulsion. II. Effects on immune function in healthy volunteers.

Particle size distribution is a major determinant of particle clearance by the mononuclear phagocytic system and the potential for concomitant activation of resident macrophages. To test the safety of a second-generation perflubron-based emulsion (60% perfluorocarbon [PFC] wt/vol; Oxygent [Alliance Pharmaceutical Corp., San Diego, CA]) with a small mean particle size, two parallel, randomized, double-blinded, placebo-controlled studies were conducted in 48 healthy volunteers (n = 24 per study). The study described herein focuses on safety concerning immune function. The primary endpoint was defined prospectively as delayed hypersensitivity skin test responses with lymphocyte proliferative responses to mitogenic stimulation providing a secondary measure for changes in cell-mediated immunity. Subjects received either perflubron emulsion IV (1.2 g PFC/kg or 1.8 g PFC/kg) or saline (3 mL/kg) control. Perflubron emulsion had no effect on delayed hypersensitivity skin reactions, lymphocyte proliferative potential, circulating immunoglobulins, complement activation, or plasma levels of the inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha, and interleukin-1 beta. Perflubron emulsion was generally well tolerated, although there was a dose-dependent increase in minor flu-like symptoms in the perflubron treatment groups at 24 h after dosing. Increased serum levels of interleukin-6 were observed in those subjects exhibiting febrile responses. The clinical safety profile of perflubron emulsion supports its continued investigation as a temporary oxygen carrier in surgical patients to reduce exposure to allogeneic blood transfusion.

Perflubron emulsion delays blood transfusions in orthopedic surgery. European Perflubron Emulsion Study Group.

BACKGROUND: Fluorocarbon emulsions have been proposed as temporary artificial oxygen carriers. The aim of the present study is to compare the effectiveness of perflubron emulsion with the effectiveness of autologous blood or colloid infusion for reversal of physiologic transfusion triggers. METHODS: A multinational, multicenter, randomized, controlled, single-blind, parallel group study was performed in 147 orthopedic patients. Patients underwent acute normovolemic hemodilution with colloid to a target hemoglobin of 9 g/dl with an inspiratory oxygen fraction (FIO2) of 0.40. Patients were then randomized into one of four treatment groups after having reached any of the protocol-defined transfusion triggers including tachycardia (heart rate > 125% of posthemodilution rate or > 110 bpm), hypotension (mean arterial pressure < 75% of posthemodilution level or < or = 60 mmHg), elevated cardiac output (> 150% of posthemodilution level) or decreased mixed venous oxygen partial pressure (PVO2; < 38 mmHg). Treatments in the four groups were 450 ml autologous blood harvested during acute normovolemic hemodilution given at FO2 = 0.40; 450 ml colloid at FIO2 = 1.0; 0.9 g/kg perflubron emulsion with colloid (total = 450 ml) at FIO2 = 1.0; and 1.8 g/kg perflubron emulsion with colloid (total = 450 ml) at FIO2 = 1.0. The primary endpoint was duration of transfusion-trigger reversal. A secondary end-point was percentage of transfusion-trigger reversal. RESULTS: Perflubron emulsion was well tolerated with no serious adverse event attributed to drug treatment. Duration of reversal was longest in the 1.8 g/kg perflubron group (median, 80 min; 95% confidence interval, 60-100 min; P = 0.014 vs. autologous blood, P < 0.001 vs. colloid) followed by the 0.9 g/kg perflubron group (median, 59 min; 95% confidence interval, 40-90 min), the autologous blood group (median, 55 min; 95% confidence interval, 30-70 min) and the colloid group (median, 30 min; 95% confidence interval, 27-60 min). Percentage of reversal was also highest in the 1.8 g/kg perflubron group (97%; P < 0.001 vs. autologous blood; P = 0.014 vs. colloid), followed by 0.9 g/kg perflubron (82%), colloid (76%), and autologous blood (60%). CONCLUSIONS: Perflubron emulsion (1.8 g/kg) combined with 100% oxygen ventilation is more effective than autologous blood or colloid infusion in reversing physiologic transfusion triggers.

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.

Effect of hemoglobin- and Perflubron-based oxygen carriers on common clinical laboratory tests.

Polymerized hemoglobin solutions (Hb-based oxygen carriers; HBOCs) and a second-generation perfluorocarbon (PFC) emulsion (Perflubron) are in clinical trials as temporary oxygen carriers ("blood substitutes"). Plasma and serum samples from patients receiving HBOCs look markedly red, whereas those from patients receiving PFC appear to be lipemic. Because hemolysis and lipemia are well-known interferents in many assays, we examined the effects of these substances on clinical chemistry, immunoassay, therapeutic drug, and coagulation tests. HBOC concentrations up to 50 g/L caused essentially no interference for Na, K, Cl, urea, total CO2, P, uric acid, Mg, creatinine, and glucose values determined by the Hitachi 747 or Vitros 750 analyzers (or both) or for immunoassays of lidocaine, N-acetylprocainamide, procainamide, digoxin, phenytoin, quinidine, or theophylline performed on the Abbott AxSym or TDx. Gentamycin and vancomycin assays on the AxSym exhibited a significant positive and negative interference, respectively. Immunoassays for TSH on the Abbott IMx and for troponin I on the Dade Stratus were unaffected by HBOC at this concentration. Tests for total protein, albumin, LDH, AST, ALT, GGT, amylase, lipase, and cholesterol were significantly affected to various extents at different HBOC concentrations on the Hitachi 747 and Vitros 750. The CK-MB assay on the Stratus exhibited a negative interference at 5 g/L HBOC. HBOC interference in coagulation tests was method-dependent-fibrometer-based methods on the BBL Fibro System were free from interference, but optical-based methods on the MLA 1000C exhibited interferences at 20 g/L HBOC. A 1:20 dilution of the PFC-based oxygen carrier (600 g/L) caused no interference on any of these chemistry or immunoassay tests except for amylase and ammonia on the Vitros 750 and plasma iron on the Hitachi 747.

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.

Use of Oxygent, a perfluorochemical-based oxygen carrier, as an alternative to intraoperative blood transfusion.

Oxygent is a stable concentrated perfluorochemical (PFC) emulsion being developed for use as a temporary oxygen carrier. In this application, PFC emulsions can be used to augment oxygen delivery during acute blood loss and thereby provide a margin of safety during hemodilution and surgical anemia. PFCs simply dissolve oxygen in direct proportion to its partial pressure. The oxygen transported by a PFC emulsion is present in the plasma compartment and is therefore easily extracted and consumed by the tissues. Preclinical and clinical studies have demonstrated that a relatively low dose (1.35 g PFC/kg) of Oxygent can support oxygen delivery despite ongoing blood loss. Clinical safety studies in 57 healthy, conscious volunteers and in 30 anesthetized surgical patients have been completed. In these studies, there were no hemodynamic changes or vasoconstriction and cardiac output increased normally in response to hemodilution. Two transient side effects were observed, but only in the high dose (1.8 g PFC/kg) group: a 1-1.5 degrees C increase in body temperature (at 4-6 hours), and a moderate decrease in platelet count (mean nadir approximately 130,000/microL by 2-3 days) without any bleeding complications. Oxygent is presently being evaluated as an alternative to allogeneic blood transfusion in patients undergoing medium- to high-blood-loss surgical procedures.

Diaspirin cross-linked hemoglobin: tissue distribution and long-term excretion after exchange transfusion.

This report describes the tissue distribution and long-term (14-day) excretion of hemoglobin cross-linked between the alpha-chains (alpha alpha Hb) with carbon 14-labeled bis(3,5-dibromosalicyl)fumarate. Fully conscious, chronically cannulated rats (n = 40) were treated with a 50% isovolemic exchange transfusion (ET) with solutions of 14C-labeled alpha alpha Hb (8.0 gm/dl) and were then monitored for as long as 14 days. Thirteen tissue types were analyzed for radioactivity by liquid scintillation counting. The highest concentration of label was found in the kidney and in tissues of the reticuloendothelial system (i.e., spleen, bone marrow, and liver). The 14C-labeled alpha alpha Hb did not appear to cross the blood-brain barrier, because radioactivity in the brain was barely detectable. The dose of 14C-labeled alpha alpha Hb (2.4 gm Hb/kg) produced an initial plasma Hb level of 4.6 gm/dl, with a half-life in the plasma of 5.0 hours. The peak concentration in kidney, spleen, and liver occurred at 24 hours after ET, when at least 92% of the 14C-labeled alpha alpha Hb in plasma had been cleared. At 48 hours, red casts were seen in a tiny number of renal tubules in some rats. By 14 days, up to 64% of the injected radioactivity had been recovered in urine and about 10% was recovered in feces. Most excretion occurred 24 to 48 hours after ET. This study demonstrated that 2 weeks were required for the metabolic degradation and elimination of a large dose of alpha alpha Hb in rats.

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.

Influence of perflubron emulsion particle size on blood half-life and febrile response in rats.

Perfluorochemical (PFC) emulsions are particulate in nature and, as such, can cause delayed febrile reactions when injected intravenously. This study investigated the influence of emulsion particle size on intravascular retention and on body temperature changes in unrestrained conscious rats. Concentrated (60% to 90% w/v) emulsions based on perflubron (perfluorooctyl bromide [PFOB]) with mean particle sizes ranging from 0.05 microns to 0.63 microns were tested. Rats were fitted with a chronic jugular catheter and an abdominal body temperature telemetry unit. Fully recovered, conscious rats were monitored for 24 hours after infusion (dose = 2.7 g PFC/kg). Emulsion blood half-life (T1/2) was determined from blood perflubron levels measured by gas chromatography. Emulsions with a particle size of 0.2-0.3 microns caused fevers (6 to 8 hour duration) which peaked at 1-1.5 degrees C above normal (approximately 37.5 degrees C). Fevers could be blocked by i.v. treatment with either cyclooxygenase inhibitors (ibuprofen) or corticosteroids (dexamethasone). Both intensity and duration of the temperature response, quantified by area under the temperature curve, was decreased significantly for emulsions with a particle size < or = 0.12 micron. Blood T1/2 varied inversely with particle size, and was 3 to 4 fold longer for emulsions with a mean particle size < or = 0.2 micron. Thus, smaller emulsion particles more effectively evaded the reticuloendothelial system, which resulted in longer intravascular retention, less macrophage activity, and reduced febrile responses.