A Prospective Trial of Diaspirin Cross-Linked Hemoglobin Solution in Patients after Elective Repair of Abdominal Aortic Aneurysm

Military Medicine, Jul 2004 by Bloomfield, Eric L, Rady, Mohamed Y, Esfandiari, Shahpour

We evaluated the safety, pharmacokinetics, and pharmacodynamics of diaspirin cross-linked hemoglobin (DCLHb) solution in patients after repair of abdominal aortic aneurysm. We performed a randomized, single-blind controlled study with 10 patients in the surgical intensive care unit of a tertiary care facility. Within 24 hours after repair of an abdominal aortic aneurysm, each patient received an infusion of DCLHb (50 mg/kg or 35 mL for a 70-kg patient) or an equal volume of hetastarch. Variables were measured before infusion, at 15 and 30 minutes postinfusion, and at hourly intervals up to 72 hours. Compared with controls, the experimental group had significantly greater mean pulmonary artery pressure at 30 minutes (mean � SD, 26.4 � 3.18 vs. 22.8 � 2.86 mm Hg), greater mean arterial pressure through 30 minutes (100.8 � 8.67 vs. 81.6 � 13.8 mm Hg), and greater plasma hemoglobin through 2 hours (69.3 � 6.08 vs. 1.8 � 0 g/dL). Cardiac output was significantly less in the DCLHb group at 2 hours (5.34 � 7.92 vs. 6.18 � 0.54 L/minute), levels of serum bilirubin were significantly less at 24 and 48 hours (94 � 0.26 vs. 1.56 � 0.73 mg/dL), and platelet counts were significantly greater at 24 hours (128 � 35.8 vs. 101 � 55.7 mg/dL). The two groups did not differ in oxygen delivery or consumption. One patient treated with DCLHb had a myocardial infarction 36 hours postinfusion. No patient had antibodies to DCLHb. At this dosage, DCLHb was well tolerated without severe organ dysfunction or toxicity. However, its use may lead to decreases in cardiac output because of increases in afterload, which may pose serious problems with left ventricular function.

Introduction

Hemoglobin-based, oxygen-carrying solutions have been studied for more than 50 years. However, because of the adverse side effects of early hemoglobin solutions, their clinical development fell into disfavor until the 1990s. Diaspirin crosslinked hemoglobin (DCLHb) solution (Baxter Health Care, Deerfield, IL) is a purified, heat-treated solution of stabilized human hemoglobin tetrameters that has an oxygen pressure at 50% saturation of 32 mm Hg compared with approximately 28 mm Hg in normal blood. Therefore, DCLHb has a lower affinity for oxygen than does native hemoglobin.12 Animal studies have shown that DCLHb is similar to whole blood in oxygen transport and delivery properties. 3-5

The pharmacologie activity of DCLHb includes a presser effect with evidence of increased tissue perfusion in animal studies.6"10 Infusion of 100 to 500 mL of DCLHb is efficacious in weaning patients in intensive care units from vasopressor therapy.11 Models of hemorrhagic shock suggest that administration of DCLHb may provide potential benefits comparable with those from administration of autologous blood.12 However, recent data from Sloan et al.13 have shown that patients being treated for trauma have increased mortality when administered DCLHb. In a Phase I safety study, Przybelski et al.14 observed the pressor effect in a group of healthy volunteers; minimal side effects occurred.

Clinically, blood substitutes may help seriously ill patients; therefore, it is important to study their safety and effects in such patients. Therefore, we conducted a randomized, single-blinded controlled trial to study the safety and pharmacodynamics of DCLHb in critically ill patients recovering from elective abdominal aortic aneurysm repair.

Materials and Methods

We performed a randomized, single-blind controlled trial of five patients receiving an infusion of DCLHb (50 mg/kg; DCLHb group) and five patients receiving an equal volume of hetastarch (Hespan; DuPont Pharmaceuticals, Wilmington, DE; control group) in the surgical intensive care unit after repair of an abdominal aortic aneurysm. The protocol was approved by the Cleveland Clinic Foundation Institutional Review Board, and preoperatively all patients gave written informed consent as required by the board.

To be eligible, patients had to undergo elective repair of an abdominal aortic aneurysm; be monitored with an arterial line, a Swan-Ganz catheter (Baxter Edwards Critical Care, Irvine, CA) and a gastric tonometer; and have a Foley catheter. Inclusion criteria included age older than 18 years, mean pulmonary artery wedge pressure less than 20 mm Hg, cardiac index less than 4.5 L/minute per m^sup 2^, left ventricular stroke work index less than 55 g � m per m^sup 2^, and hemoglobin of 9 g/dL or more. Patients were excluded if they were pregnant or had a history of renal disease, liver disease, coagulopathy, hypertension (blood pressure > 160/1OO mm Hg), or cardiac arrest, or were enrolled in any drug or device study in the previous 30 days.

All invasive monitors were brought to the operating room so that patients could be monitored continuously during the procedure. In the surgical intensive care unit, patients were connected to a DeltaTrac Metabolic Monitor (SensorMedics, Yorba Linda, CA) for measurement of oxygen delivery and consumption. If these measurements met the inclusion criteria, the patient was enrolled and randomly assigned to receive DCLHb at 50 mg/kg (35 mL for a 70-kg patient) or an equal volume of hetastarch through assignment by envelopes. The randomization scheme was determined by Baxter Healthcare. all test and control solutions were infused for more than 30 minutes through a 20-�m blood filter. Patients received additional treatment deemed necessary for their well-being. All patients were intubated and mechanically ventilated during the infusion.

The test solution of DCLHb, prepared by Baxter Healthcare, was pasteurized and free of viruses. It was mixed with a balanced electrolyte solution to yield a hemoglobin concentration of 10 g/dL as described by several authors.L2�14'15