A Pilot Study of the Effects of a Perflubron Emulsion, AF 0104, on Mixed Venous Oxygen Tension in Anesthetized Surgical Patients

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1 GENERAL ARTICLES A Pilot Study of the Effects of a Perflubron Emulsion, AF 0104, on Mixed Venous Oxygen Tension in Anesthetized Surgical Patients Joyce A. Wahr, MD*, Adrianus Trouwborst, MD, rhdt, Richard K. Spence, MD*, Christian P. Henny, MDt, Aurel C. Cernaianu, MD$, Gregory I?. Graziano, MD*, Kevin K. Tremper, MD, PhD*, Kathryn E. Flaim, PhD, Peter E. Keipert, PhD, N. Simon Faithfull, MD, PhD, and Janice J. Clymer, PhD Departments of Anesthesiology, *University of Michigan, Ann Arbor, Michigan, tuniversity of Amsterdam Medical Center, The Netherlands, and the SDepartment of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Camden, New Jersey, and SAlliance Pharmaceutical Corporation, San Diego, California 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 (Pvo,) after the PFC infusion, while cardiac output and oxygen consumption were unchanged. As surgery progressed, the hemoglobin concentration decreased with ongoing blood loss while Pvo, 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. (Anesth Analg 1996;82:103-7) T here are significant concerns associated with the use of allogeneic blood transfusions, despite the fact that the blood supply in the United States is thought to be safer at present than at any time in history. These concerns include the rare but serious morbidity associated with blood-borne infections (e.g., hepatitis and acquired immunodeficiency syndrome [AIDS]), availability during episodic shortages, and problems associated with the requirement for cold storage, typing, and cross-matching which limit the usefulness of allogeneic blood during battlefield or mass casualty situations (1,2). Perfluorochemicals (PFC) are inert substances with a high solubility for all gases, including oxygen and carbon dioxide (3,4). The first commercially available, biocompatible PFC emulsion (FluosoP; Green Cross Corp., Osaka, Japan) had three serious disadvantages-low concentration Accepted for publication September 15, Address correspondence and reprint requests to Joyce A. Wahr, MD, Department of Anesthesiology, University of Michigan Hospitals, lg ,150o E. Medical Center Dr., Ann Arbor, MI of PFC, short intravascular half-life, and instability of the emulsion. Although FluosoP was found to supplement oxygen transport in severely anemic surgical patients who refused blood transfusion on religious grounds (5), the contribution was not clinically significant, due to the low dose which could be given and the short intravascular half-life (5,6). More problematic was the fact that the emulsifying agent used in Fluosol@, Pluronic F-68, was associated with complement-mediated adverse reactions (7,8). A concentrated, stable PFC emulsion has been developed which contains 90% wt/vol perflubron (CsFi,), 45% by volume, uses egg yolk phospholipids as the emulsifying agent, and is stable at room temperature (AF0104; Alliance Pharmaceutical Corp., San Diego, CA). Like any of the synthetic oxygen-carrying solutions which are cleared by the reticuloendothelial system (PFC emulsions and hemoglobin solutions), the intravascular half-life of AF0104 is less than 24 h. For this reason, the most appropriate applications for this solution are in settings where the requirement for increased oxygen transport is temporary. One such application may be by the International Anesthesia Research Society /96/$5.00 Anesth Analg 1996;82:

2 104 WAHR ET AL. PERFLUBRON EMULSION AND MIXED VENOUS PO, ANESTH ANALG 1996;82:103-7 during intraoperative acute normovolemic as has been demonstrated with a perflubron emulsion in a canine model of profound ANH (9). The purpose of this current pilot study was to test whether administration of a perflubron emulsion could result in measurable changes in mixed venous oxygen tension. In addition, we sought to assess the effect of this perflubron emulsion on hemodynamic and oxygen transport variables in patients undergoing ANH. Methods With the approval of the individual institutional review boards and ethics committees, seven patients who met entry criteria and gave informed consent were enrolled in this open-label, multicenter trial. Patients were screened prior to the day of their scheduled surgery. Male or female patients scheduled to undergo elective surgery under general anesthesia during which significant blood loss (i.e., 23 U) was anticipated were considered. Patients with extensive cardiac or renal disease, those undergoing cardiac surgery, and those receiving platelet affecting medications within 7 days of surgery were excluded. All patients were able to undergo perioperative ANH and the placement of pulmonary artery catheters. All medications were continued throughout the morning of surgery as per standard therapy. Complete blood chemistry, hematology, coagulation, and urinalysis were performed within 48 h prior to surgery. On the day of surgery, an arterial catheter and a pulmonary artery catheter were placed prior to initiation of surgery. Induction of anesthesia and intubation were performed as per standard of care. After induction of anesthesia, ANH was performed with a colloid plasma expander to an expected hemoglobin of 9 g/dl. This procedure consisted of withdrawing the patient s blood and concomitant administration of an equal volume of a colloid plasma expander. The whole blood units were stored at room temperature to preserve the function of the platelets and coagulation factors were reinfused as required. After completion of ANH, at the point that the investigators judged that it was appropriate to transfuse the first unit of blood, the perflubron emulsion was administered instead of blood. All patients were ventilated with a high concentration of inspired oxygen (FIo, = 1.0) prior to infusion of perflubron emulsion, and throughout the intraoperative study period. The decision to transfuse was based on clinical judgment and included assessment of hemoglobin concentration, mixed venous oxygen tension (Pvo,), amount of blood loss, subject condition and age, and cardiovascular performance. Each patient received one intravenous dose of perflubron emulsion (0.9 g PFC/kg) over approximately 10 min. The hemodynamic data collected with each data set were heart rate, systolic and diastolic blood pressure, systolic and diastolic pulmonary artery pressure, cardiac output (performed in triplicate at each recording period), and body temperature. These data were recorded prior to induction of anesthesia, after induction, prior to ANH, at the end of ANH, prior to infusion of perflubron emulsion, and at 15-min intervals or at every 500 ml of blood loss after conclusion of infusion. Blood samples for hemoglobin concentration and hematocrit, arterial and mixed venous blood gases, and oxyhemoglobin saturation were withdrawn prior to ANH, at the end of ANH, prior to infusion of AF0104, and at 15-min intervals or at every 500 ml of blood loss after dosing. Blood was also withdrawn for determination of perflubron concentration after completion of ANH (prior to administration of study drug), and at 15-min intervals after completion of study drug infusion. These samples were frozen and analyzed by gas chromatography to determine plasma perflubron concentrations. At 2 h postdosing, data collection and blood sampling were reduced to every 30 min until the end of surgery. In the postoperative period, vital signs and blood samples were taken at 1, 2, 6, 12, and 18 h after surgery. Those measurements dependent on the pulmonary artery catheter or the arterial line were collected until 18 h after surgery or the time the catheters were removed, whichever came first. The volume, time, and nature of all transfusion of fluids, blood, or blood products were recorded. Data were analyzed with two-sided paired t-test for analysis of change from baseline; significance was set at the P < 0.05 level. Results Demographic and patient characteristics of the seven patients who entered the study are shown in Table 1. All patients were ASA class I or II. All patients completed ANH and drug infusion without incident. An average (median) of 2 U were withdrawn from each patient, resulting in a mean hemoglobin of 9.5 g/dl at the end of ANH. Peak plasma perflubron concentrations were 0.8 g/dl immediately postinfusion, and approximately 0.3 g/dl at 60 min. Hemodynamic and oxygen transport data are shown in Table 2 and Figure 1. Oxygen transport data are presented only until the time of first blood transfusion. There were no clinically significant hemodynamic changes associated with administration of perflubron. There was an apparent increase in cardiac output and in pulmonary capillary wedge pressure associated with the performance of ANH, with no change associated with perflubron emulsion infusion. There were no serious adverse events which were attributed to perflubron administration.

3 ANESTH ANALG WAHR ET AL ;82:103-7 PERF LUBRON EMULSION AND MIXED VENOUS PO, Table 1. Demographic Data Gender Age (yr) Weight (kg) Male Female Male Female Male Male Male Height (cm) Surgery 176 Laparotomy, liver biopsy 160 Anterior spinal fusion L Anterior spinal fusion TlO-L4 157 Posterior osteotomy TlO-12; spinal fusion T5-Sl 177 Gastrojejunostomy; choledochojejunostomy 185 Total radical prostatectomy 167 Total radical prostatectomy Table 2. Hemodynamic Changes with Perflubron Administration n Baseline n 10 min n 30 min n 45 min n 60 min Heart rate (bpm) 7 74t ? i 7 Systolic blood pressure (mm Hg) 7 128? ? * 5 128? ? 5 Pulmonary capillary wedge c t ? 1.5 pressure (mm Hg) Cardiac index (L. mini. m - ) ? t t t t 0.46 Data are mean -t SEM. Baseline is the last value before perflubron emulsion administration. * P compared to baseline. After administration of PFC, there was an increase in Pvo, (Figure 1B) with no alteration seen in cardiac index (Figure 1C) or in total oxygen consumption. There was a significant decrease in hemoglobin at 30 min, while Pvo, remained above baseline value. Although the calculated percent of oxygen delivery due to perflubron was limited at this low dose (1.06%), perflubron contributed 5.1% of the oxygen consumed (see Appendix 1 for equations). Discussion Increases in Pvo,, such as those seen in this study, reflect either an increase in oxygen transport or a decrease in oxygen consumption (see equations, Appendix 1). Oxygen delivery to the tissues is the product of the arterial oxygen content and the cardiac output. An increase in hemoglobin or perflubron concentration will increase oxygen content. Although oxygen content was not measured directly in this clinical study, it has been demonstrated in earlier trials that the measured and calculated content are not significantly different in the presence of PFCs (5). Alternatively, this increase in Pvo, could reflect an increase in cardiac output or a decrease in oxygen consumption. We found no such evidence that either cause could have been responsible for the increase in Pvo,. These data are consistent with those of the earlier animal study which found a Pvo, increase directly related to perflubron emulsion administration (10). Finally, it is possible that the PFC could have produced a type of peripheral shunt which resulted in an increase in Pvo,. This would most likely have been associated with a decrease in oxygen consumption and a progressive metabolic acidosis. Neither of these was seen. This pilot study was undertaken at a low dose of perflubron emulsion to determine if there were any measurable changes in oxygen transport in the clinical setting. We found a significant increase in Pvo, after administration of perflubron emulsion, even at this low dose. Perflubron emulsions, like plasma, carry oxygen via direct solubility, resulting in a linear dissociation curve rather than the familiar sigmoidal curve of hemoglobin (Figure 2). At high Pao, values, therefore, both plasma and perflubron emulsions contribute to oxygen delivery, and contribute even more to oxygen consumption. Since oxygen leaves the soluble phases (plasma and perflubron) in direct proportion to the partial pressure, at a Pao, of 500 mm Hg, 80% of the oxygen from the soluble phases will be released to the tissues prior to any oxygen being released from the hemoglobin phase. In this way, relatively small contributions to oxygen transport result in more substantial contributions to the oxygen consumption. It would be anticipated that a likely clinical dose of 1.8 g PFC/kg, at a Pao, of mm Hg, could supply between lo%-15% of the total oxygen consumption, i.e., be equivalent to the contribution from 2-3 U of packed red blood cells (see Appendix 1 for calculations). These calculations have been validated in animal models. Keipert et al. (9) found that administration of perflubron emulsion at a dose of 2.7 g PFC/kg significantly increased total oxygen transport in a canine model of profound hemodilution (hematocrit of 12%). The perflubron-dissolved oxygen accounted for only 8%-10% of the total oxygen delivery, but, because of

4 106 WAHR ET AL. ANESTH ANALG PERFLUBRON EMULSION AND MIXED VENOUS PO, 1996;82:103-7 (4 whole Blood (Hct = 45%) H 4 xt ANH 0 T PW- I f c oy(i,,, /,,,,,,,,,, 0 4f (Psooz) Arterial Blood POn Level (mm Hg) Figure 2. Total oxygen-carrying capacity of 90% wt/vol perflubron emulsion compared to whole blood. The arterial PO, required to deliver 5 ~01% oxygen is indicated by the arrows. Note that the solubility of oxygen in perflubron emulsions obeys Henry s law and depends only on the PO, present in the blood. Hct = hematocrit; Hb = hemoglobin; PFC = perfluorochemicals. [Adapted with permission from Keipert et al. (9).] z 65 0 Z s 60 B.x 45 z 1 0, I Post ANH PR- 62 Post ANH pre- Figure 1. Temporal changes in physiologic variables during the study period. Post-ANH data point is the mean of the first values recorded after completion of ANH (n = 7). Time 0 values are those recorded immediately preceding perflubron emulsion administration; time O-60 denotes times from the start of perflubron infusion. Only data recorded prior to start of first blood transfusion are the high oxygen extraction coefficient for perflubron, accounted for 25%-30% of the total oxygen consumed. This study was a pilot efficacy trial intended to determine whether perflubron emulsion, at a dose of 0.9 g PFC/kg, could result in measurable changes in oxygen transport. The findings of this study are lim- ited by a small sample size and by the fact that each patient s pretreatment data served as the control, rather than a randomized control group. Because of the limited sample size, significant changes may have occurred which could not be detected because of the limited power of this study. In addition, although no serious adverse events were ascribed to the use of this emulsion, the limited sample size and lack of a control group preclude any conclusions regarding safety. Despite these limitations, treatment with perflubron emulsion in this study was associated with an increase in Pvo~, while oxygen consumption and cardiac output remained unchanged. These clinical findings are consistent with data from animal models. The potential clinical utility of a perflubron emulsion as a supplemental oxygen-carrying solution during ANH will be the reduction of allogeneic blood use and/or an improvement in overall patient outcome. A larger, controlled clinical study will be required to evaluate these clinical efficacy end-points. included here. For n values at each time point, see Table 2. Pretransfusion data point is the last value before blood was transfused (n = 5, as only five patients were transfused intraoperatively). ANH = acute normovolemic hemodilution. * = P ; statistical analysis performed comparing only data recorded at 10 min to that recorded at baseline. A, Hemoglobin concentration; B, Mixed venous oxygen tension (mm Hg), C, Cardiac index (L. min-. m- ).

5 ANESTH ANALG 1996;82:103-7 WAHR ET AL. 107 PERFLUBRON EMULSION AND MIXED VENOUS PO, Appendix 1: Equations Oxygen Con tent Arterial 0, content = hemoglobin 0, content + plasma 0, content + perflubron 0, content Cao, = (1.34 * [Hbl * Sao,/100)+(0.003 * Pao,) Venous + ( [PFBl/1.92 * PaoJ760 mm Hg) cvo, = (1.34. [Hbl * sv0,/100) + (0.003 * Pvo,) + (0.53 * [PFB]/1.92 * PvoJ760 mm Hg) where Sao, and Svo, are expressed as percents, Pao, and Pvo, are expressed in millimeters of mercury, [Hb] and [PFBI are concentrations (in g/dl) of hemoglobin and perflubron, respectively, 1.34 is the oxygen-carrying capacity in milliliters of O2 of 1 g of hemoglobin, is the solubility of oxygen in the plasma (ml 0, of a dl of whole blood per mm Hg), 0.53 is the solubility of oxygen (ml 0,) in 1 ml of perflubron at 1 atm and 37 C, and 1.92 is the density of perflubron in grams per milliliter. Oxygen Consumption (in ml/min) Vo, = (Cao, - Cvo,) * cardiac output * 100 Percent of Oxygen Consumption to Perflubvon %Vo2cpBFj = (CacbFj Due - CV~,~~,,,) /(Cao, - Cvo,) * 100 Delivery of Oxygen by PerjIubron Versus Whole Blood Emulsion Oxygen delivery of 1 dl of the 90% emulsion is equivalent to approximately the oxygen delivery of 3 dl of whole blood. Hemoglobin (1.34 ml 0,/g Hb) * (15 g Hb/dL) - (Sao, - Svo,) = 4.5 ml O,/dL Plasma (0.003 ml O,/dL whole blood) - Pao, - Pvo,) = 1.35 ml O,/dL where Sao, = 97.5%, Svo, = 75%, Pao, = 500 mm Hg, and Pvo, = 50 mm Hg. Whole Blood Perflubron (Hb) + (plasma) = 5.9 ml OJdL (PFB) Emulsion (90% wtlvol) (53 ml O,/dL PFB) * [(Pao, - Pvo,)/760 mm Hgl * (1 dl PFB/192 g) * (90 g PFCIdL) = 14.7 ml OJdL (90%) emulsion where Pao, = 500 mm Hg, and Pvo, = 50 mm Hg. These equations apply to stable conditions. If oxygen requirements per minute remain relatively constant, as cardiac output increases, the proportion of total oxygen utilized from the plasma/pfc compartment will increase, and the hemoglobin-bound oxygen will be spared. References Nicholls MD. : morbidity and mortality. Anaesth Intensive Care 1993;21:15-9. Biro GP. Perfluorocarbon-based red blood cell substitutes. Transfus Med Rev 1993;7: Geyer RI, Monroe RG, Taylor K. Survival of rats having red cells totally replaced with emulsified fluorocarbon. Fed Proc 1968;27:384. Clark LC, Gollan F. Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure. Science 1966;152: Tremper KK, Freedman AE, Levine EM. The preoperative treatment of severely anemic patients with perfluorochemical emulsion oxygen transporting fluid; Fluosol-DA. N Engl J Med 1982; 307~277. Gould SA, Rosen AL, Sehgal LR, et al. Fluosol-DA as a red-cell substitute in acute anemia. N Engl J Med 1986;314: Vercellotti GM, Hammerschmidt DE, Craddock PR, Iacob HS. Activation of plasma complement by perfluorocarbon artificial blood: probable mechanism of adverse pulmonary reactions in treated patients and rationale for corticosteroids prophylaxis. Blood 1982;59: Tremper KK, Vercellotti GM, Hammerschmidt DE. Hemodynamic profile of adverse clinical reactions to Fluosol-DA 20%. Crit Care Med 1984;12: Keipert PE, Faithful1 NS, Bradley JD, et al. Oxygen delivery augmentation by low-dose perfluorochemical emulsion during profound normovolemic hemodilution. Adv Exp Med Biol1994; 345: