Abstract

HBOC-201, Hemoglobin glutamer-250 (bovine), (Biopure Corp. , Cambridge, MA) has been studied in an international, multicenter, pivotal Phase III trial. A subset analysis of use of blood products indicated that the HBOC-201 group required no more than the packed red blood cell (PRBC) group and was limited to less than 6% in both treatment groups. In a subset analysis from one site, platelet function using PFA-100 was assessed before and after transfusion, and compared those receiving HBOC-201 versus PRBC. After initial IRB approval, patient consent for the Phase III trial and blood draws for PFA-100, an additional IRB exemption for retrospective chart review was obtained. cEPI and cADP means were compared at seven time periods: true baseline(before starting surgery and anesthesia), before transfusion, after transfusion, 1 day, 2 days, 3 to 9 days and 21 or more days after transfusion. Twenty-seven (HBOC: n = 12, PRBC n = 15) subjects were studied. Comparing data from before transfusion and baseline did not show statistically significant differences in any of cEPI or cADP measurements. cEPI means for the HBOC-201 group increased after transfusion compared to the true baseline (P = 0. 01), before transfusion (P = 0. 0004) and day 1 after transfusion (P = 0. 002). cADP means for the HBOC-201 group were greater after transfusion compared to the true baseline (P = 0. 05) and before transfusion (P = 0. 005). In the PRBC group there were no significant difference in cEPI and cADP means between all of the time periods. Our study shows that HBOC-201 causes mild platelet dysfunction. Although there were significant changes after HBOC infusion and cEPI and cADP mean values were above the upper normal limit, they did not reach the non-closure time. Further controlled studies are needed to establish definitively the effects that HBOC-201 has on platelet function in patients.

Abstract

BACKGROUND Vasoactivity has hampered progress of hemoglobin-based oxygen carriers (HBOCs) due to concern for adverse blood pressure responses and secondary complications. A recent formulation, highly polymerized HBOC-201 (Biopure, Cambridge, MA), has been found to be less vasoactive than prior less polymerized formulations, and to improve outcome in animal models of hemorrhagic shock (HS) compared with standard resuscitation fluids. HBOCs are envisioned to have life- saving potential for severe trauma patients for whom death due to HS is common despite transport to level I trauma centers. As part of a benefit:risk analysis for a proposed clinical trial of HBOC-201 in patients with traumatic HS, we analyzed data from a previous phase III clinical trial of this HBOC that involved orthopedic surgery patients, for vasoactivity and related effects, with focus on patients more representative of the trauma population. STUDY DESIGN In a previous phase III study involving orthopedic surgery patients, HEM-0115, consented/stabilized patients were randomized to receive HBOC-201 (N = 350) (up to ten 30 g Hb units) or red blood cells (RBC) (N = 338) (up to 9 units) at the first transfusion decision. Systolic blood pressure (SBP) responses, key system and individual adverse events (AEs) and serious adverse events, and cardiac biomarker elevation incidences, were compared in the overall population and subpopulations with stable trauma, hypotension, and with age stratification (Student's t and Fisher's exact tests, significance p < 0. 05). RESULTS Mild to moderate peak SBP responses were common in HBOC-201 subjects and more common than with RBC in the overall population (mean, 60. 8 years old), but less frequent in HBOC-201 subjects with stable trauma, younger age (<50 years old), and hypotension, in whom group differences were narrowed. SBP Delta responses were more common with HBOC-201 than RBC in the overall population, but not in subjects with stable trauma and <50 year olds, in whom response rates were lower. In the overall population, AEs were more common than with RBC in most systems (also, hypertension and stroke); only cardiac system serious adverse events were more common with HBOC-201. In contrast, there were few significant group differences in stable trauma, hypotensive, and <70 and especially <50-year-old subjects, in whom AE incidences were generally lower. A disproportionate number of key AEs occurred in elderly subjects. Troponin (but not CK-MB) elevation was more frequent with HBOC-201 than RBC in the overall population but not in <50 year olds, and was not associated with acute coronary syndrome (ACS) or death. CONCLUSIONS Our limited HEM-0115 safety analysis shows that key potentially vasoactivity-related adverse safety signals were more frequent with HBOC-201 than RBC in older patients undergoing orthopedic surgery with rapid access to safe blood transfusions. That incidences of these safety signals were generally lower and group differences narrowed in subpopulations with stable trauma, hypotension, and younger age, suggests an acceptable safety profile in younger acute trauma populations, especially in settings where rapid access to safe blood transfusions is unavailable; confirmation in controlled clinical trials is urgently warranted.

Abstract

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.

Abstract

BACKGROUND The ability of hemoglobin based oxygen carrier-201 (HBOC-201) to safely reduce and/or eliminate perioperative transfusion was studied in orthopedic surgery patients. METHODS A randomized, single-blind, packed red blood cell (PRBC)-controlled, parallel-group multicenter study was conducted. Six hundred eighty-eight patients were randomized to treatment with HBOC-201 (H, n = 350) or PRBC (R, n = 338) at the first transfusion decision. Primary endpoints were transfusion avoidance and blinded assessment [Mann-Whitney estimator (MW)] of safety noninferiority. Groups were compared directly and by paired/matching group analyses predicated on a prospectively defined dichotomy [treatment success (HH) vs. failure (HR)] in the H arm and an equivalently defined dichotomy [≤3 (R3-) vs. >3 (R3+) units PRBC] in the R arm, based on need (moderate vs. high) for additional oxygen carrying capacity. RESULTS A total of 59. 4% of patients in the H arm avoided PRBC transfusion. Adverse events (8. 47 vs. 5. 88), and serious adverse events (SAEs) (0. 35 vs. 0. 25) per patient were higher in the H versus R arms (p < 0. 001 and p < 0. 01) with MW = 0. 561 (95 CI 0. 528-0. 594). HH versus R3- had identical (0. 14) serious adverse events/patient and a MW = 0. 519 (95% confidence limit 0. 481-0. 558), whereas the incidence was higher (0. 63 vs. 0. 47) for HR versus R3+ with a MW = 0. 605 (95% confidence limit 0. 550-0. 662). Age (>80 years), volume overload and undertreatment contributed to this imbalance. CONCLUSION HBOC-201 eliminated transfusion in the majority of subjects. The between arms (H vs. R) safety analysis was unfavorable and likely related to patient age, volume overload, and undertreatment and was isolated to patients that could not be managed by HBOC-201 alone. However, patients <80 years old with moderate clinical need may safely avoid transfusion when treated with up to 10 units of HBOC-201.

Abstract

BACKGROUND Hemospan (Sangart Inc. , San Diego, CA), a polyethylene glycol-modified hemoglobin with unique oxygen transport properties, has successfully completed a phase I trial in healthy volunteers. Because adverse events are expected to increase with age, the authors conducted a phase II safety study of Hemospan in elderly patients undergoing elective hip arthroplasty during spinal anesthesia. METHODS Ninety male and female patients, American Society of Anesthesiologists physical status I-III, aged 50-89 yr, in six Swedish academic hospitals were randomly assigned to receive either 250 or 500 ml Hemospan or Ringer's acetate (30 patients/group) before induction of spinal anesthesia. Safety assessment included vital signs and Holter monitoring from infusion to 24 h, evaluation of laboratory values, and fluid balance. The hypothesis to be tested was that the incidence of adverse events would be no more frequent in patients who received Hemospan compared with standard of care (Ringer's acetate). RESULTS Three serious adverse events were noted, none of which was deemed related to study treatment. Liver enzymes, amylase, and lipase increased transiently in patients in all three groups. There were no significant differences in electrocardiogram or Holter parameters, but there was a suggestion of more bradycardic events in the treated groups. Hypotension was less frequent in the treated patients compared with controls. CONCLUSIONS In comparison with Ringer's acetate, Hemospan mildly elevates hepatic enzymes and lipase and is associated with less hypotension and more bradycardic events. The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken.

Abstract

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.