Background: The safety of the hemoglobin based oxygen carrier diaspirin crosslinked hemoglobin (DCLHb) has been reported only in the low (50-200 mg/kg) dose range [Przybelski. R.J.; Daily, E.K.; Kisicki, J.C.; Mattia-Goldberg, C.; Bounds, M.J.; Colburn, W.A. Phase I study of the safety and pharmacologic effects of diaspirin crosslinked hemoglobin solution. Crit. Care Med. 1996, 24 (12), 1993-2000, Bloomfield, E.; Rady, M.; Popovich, M.; Esfandiari, S.; Bedocs, N. The use of diaspirin crosslinked hemoglobin (DCLHb 1996, 95, (3A), A220.]. We conducted a randomized prospective open-label trial of DCLHb and packed red blood cells (PRBCs) in high-blood loss surgical patients to show the effect of 750 ml DCLHb (approximately 1000 mg/kg) on selected indices of organ function.
Method: After institutional approval, 24 patients scheduled to undergo elective orthopedic or abdominal surgery, were randomized to receive either PRBCs or 10% DCLHb within 12 hours after the start of surgery. Patients with renal insufficiency, abnormal liver function, severe coronary artery disease (CAD) and ASA physical status > or = IV were excluded. The anesthetic technique was left to the judgment of the anesthesiologist. Autologous predonation and intraoperative blood conservation techniques were utilized as appropriate. The indications for blood transfusion were individualized on disease state, stage of surgery, and plasma Hb concentration. Laboratory studies were obtained preoperatively and up to 28 days postoperatively. Patients were observed daily for development of jaundice, hematuria, nausea, vomiting, gastrointestinal discomfort, cardiac, respiratory, and infectious complications. Organ effects were assessed with urinalysis, creatinine clearance, electrocardiogram (ECG), and a panel of blood and serum laboratory tests.
Results: The dose of DCLHb administered ranged from 680-1500 mg/kg (mean = 999 mg/kg). Estimated blood loss was 27 +/- 13 ml/kg and 31 +/- 15 ml/kg in the control and DCLHb groups, respectively. Fewer PRBCs (1.9 +/- 1.2 vs. 3.4 +/- 2.4 units. P = 0.06) were transfused to DCLHb patients on the operative day although this difference was no longer apparent later on. In the DCLHb group, 4/12 patients avoided any allogeneic PRBC transfusion vs. none in the control group (P = 0.09). Systolic, diastolic and mean blood pressure increased moderately after DCLHb for a period of 24-30 hours. There were no occurrences of cardiac ischemia. myocardial infarction, stroke, or pulmonary edema, by clinical or laboratory parameters up to the 28th postoperative day (POD). Seven of 12 (58%) DCLHb patients had yellow skin discoloration vs. none in the PRBC group (P < 0.01). Two of four non-urologic surgery patients developed asymptomatic postoperative hemoglobinuria after DCLHb. Creatinine clearance was unchanged postoperatively. Because of hemoglobin interference, bilirubin, gamma-glutamyl transferase (GGT), and amylase could not be measured reliably on POD1; on POD2. amylase was transiently elevated to 3 times ULN along with mild elevations of bilirubin, transaminases and BUN. Mean total creatine phoshokinase (CPK) peaked at 8 times the upper limit of normal (ULN) in the DCLHb group, compared with less than twice ULN for controls. Three DCLHb patients had prolonged ileus. Two of these patients had postoperative hyperamylasemia, one of whom developed mild pancreatitis. DCLHb did not affect white blood cell count or coagulation tests.
Conclusion: Administration of approximately 1000 mg/kg DCLHb was associated with transient arterial hypertension, gastrointestinal side effects, laboratory abnormalities, yellow skin discoloration, and hemoglobinuria. These observations point to opportunities for improvement in future synthetic hemoglobin design.