Haemodynamic effects, safety, and tolerability of haemoglobin-based oxygen carrier-201 in patients undergoing PCI for CAD
AIMS: Haemoglobin based oxygen carriers (HBOCs) are considered in the treatment of patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). In light of their potential vasopressor and colloidal properties, their effect on coronary physiology, safety and tolerability needs to be established. METHODS AND RESULTS In this phase II pilot trial, 45 patients were randomly assigned, (1:1:1) to double blind treatment with a 30 minute intravenous (IV) infusion of either 15 or 30 g of HBOC-201, compared to an equivalent volume of non-oxygen carrier colloid control. Systemic, pulmonary, and coronary haemodynamics were studied during this infusion period. IV HBOC-201 administration produced an increase in systolic blood pressure (SBP), pulmonary capillary wedge pressure and calculated systemic vascular resistance (SVR) and a concomitant decrease in cardiac output (CO); there was a decrease in mixed venous saturation (SVO2) following IV HBOC-201. The left ventricular stroke work index (LVSWI) was not altered by HBOC-201 treatment. Of note, no coronary vasoconstriction was observed, nor were there significant changes in resting average peak velocity (APV), coronary-artery diameter, volumetric coronary blood flow, or coronary vascular resistance. The percentage of patients with adverse events did not differ between the HBOC-201 treated and control groups (76% vs. 63%, respectively, P=0.49). Seven serious adverse events (SAE) occurred in six patients in the treatment group and two in two patients in the control group. Only one SAE (hypertension) was judged HBOC-201 related. Patients in both the HBOC-201 and control group had a similar incidence of increased liver alanine transaminase (31% vs 31%, respectively, NS); 10% of the patients in the HBOC-201 group had increases greater than three times the upper limit of normal. Differential increases were noticed in some inflammatory markers (IL-6, CRP) 18-24 hours after infusion between the HBOC-201 arms and the control group. CONCLUSION No compromise in the coronary blood flow or LVSWI was observed despite HBOC-201's known vasoactive effects. One SAE was adjudicated as "drug related" and fully resolved. The clinical relevance of the differential rise in certain biochemical markers and the adverse effects of plasma haemoglobin in the context of ACS needs further investigation.
Use of perftoran emulsion to decrease allogeneic blood transfusion in cardiac surgery: clinical trial
Artificial Cells, Blood Substitutes, and Immobilization Biotechnology. 2006;34((4):):433-54.
Perflurocarbon emulsions (PFC) have the capacity of transporting oxygen through the bloodstream and may be safe and effective alternatives to allogeneic blood transfusions during surgical procedures. Perftoran was the PFC used in a randomized clinical trial conducted at Hospital de Especialidades Centro Medico La Raza, Mexico City. The clinical trial took a sample group, n = 30, of patients that were scheduled for elective cardiac valvuloplasty surgery in combination with preoperative acute normovolemic hemodilution and an inspiratory oxygen fraction (FI02) of 1. 0. The participants were randomly divided into a Control group (n = 15) and a Perftoran (PFC) group (n = 15). The PFC group had significantly higher intraoperative PaO2 levels and needed less allogeneic red blood cell packs than the Control group. There were no complications or deaths in either group. These results suggest that Perftoran is safe, efficacious, and reduces the need for allogeneic blood and blood derivatives in patients undergoing cardiac surgery.
A phase II dose-response study of hemoglobin raffimer (Hemolink) in elective coronary artery bypass surgery
The Journal of Thoracic and Cardiovascular Surgery. 2004;127((1):):79-86.
BACKGROUND We performed this study to determine the dose-response of hemoglobin raffimer administered in conjunction with intraoperative autologous donation in patients undergoing coronary artery bypass grafting surgery. A secondary objective was to evaluate hemoglobin raffimer for reducing the incidence of allogeneic red blood cell transfusions. METHODS This was a phase II, single-blind, multicenter, placebo-controlled, open-label study. Patients undergoing coronary artery bypass grafting with cardiopulmonary bypass and intraoperative autologous donation were randomized to receive a single dose of hemoglobin raffimer or control (10% pentastarch). Patients were sequentially enrolled in a dose block of 250, 500, 750, and 1000 mL. RESULTS Sixty patients received hemoglobin raffimer (n = 30) or control (n = 30). Hemoglobin raffimer was well tolerated. Most (98%) adverse events were mild or moderate in severity. There was an expected dose-dependent increase in the incidence of blood pressure increases and jaundice in hemoglobin raffimer-treated patients. In a dose-pooled analysis of hemoglobin raffimer versus control, increased blood pressure (43% vs 17%), nausea (37% vs 33%), and atrial fibrillation (37% vs 17%) were the most frequently reported adverse events. All serious adverse events were considered unrelated or unlikely to be related to study drug. No hemoglobin raffimer-treated patient required an intraoperative allogeneic red blood cell transfusion, compared with 5 (17%) pentastarch-treated patients (P =. 052). This advantage of hemoglobin raffimer was maintained at 24 hours after surgery (7% vs 37%; P =. 010) and up to 5 days after surgery (10% vs 47%; P =. 0034). CONCLUSIONS Hemoglobin raffimer was not associated with any serious adverse events in patients undergoing primary coronary artery bypass grafting with cardiopulmonary bypass and intraoperative autologous donation in a dose-response study up to 1000 mL. Hemoglobin raffimer was effective in facilitating decreased exposure or avoidance of allogeneic red blood cell transfusions when used in conjunction with intraoperative autologous donation.
A prospective trial of diaspirin cross-linked hemoglobin solution in patients after elective repair of abdominal aortic aneurysm
Military Medicine. 2004;169((7):):546-50.
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.
Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: results of a randomized, double-blind trial
Journal of Thoracic and Cardiovascular Surgery. 2002;124((1):):35-42.
BACKGROUND Blood loss leading to reduced oxygen-carrying capacity is usually treated with red blood cell transfusions. This study examined the hypothesis that a hemoglobin-based oxygen-carrying solution can serve as an initial alternative to red blood cell transfusion. METHODS In a randomized, double-blind efficacy trial of HBOC-201, a total of 98 patients undergoing cardiac surgery and requiring transfusion were randomly assigned to receive either red blood cell units or HBOC-201 (Hemopure; Biopure Corporation, Cambridge, Mass) for the first three postoperative transfusions. Patients were monitored before and after transfusion, at discharge, and at 3 to 4 weeks after the operation for subsequent red blood cell use, hemodynamics, and clinical laboratory parameters. RESULTS The use of HBOC-201 eliminated the need for red blood cell transfusions in 34% of cases (95% confidence interval 21%-49%). Patients in the HBOC group received a mean of 1.72 subsequent units of red blood cells; those who received red blood cells only received a mean of 2.19 subsequent units (P =.05). Hematocrit values were transiently lower in the HBOC group but were similar in the two groups at discharge and follow-up. Oxygen extraction was greater in the HBOC group (P =.05). Mean increases in blood pressure were greater in the HBOC group, but not significantly so. CONCLUSION HBOC-201 may be an initial alternative to red blood cell transfusions for patients with moderate anemia after cardiac surgery. In a third of cases, HBOC-201 eliminated the need for red blood cell transfusion, although substantial doses were needed to produce this modest degree of blood conservation.
Safety and preliminary efficacy of hemoglobin raffimer for patients undergoing coronary artery bypass surgery
Journal of Cardiothoracic & Vascular Anesthesia. 2002;16((6):):695-702.
OBJECTIVE To evaluate the safety and preliminary efficacy of escalating doses of hemoglobin raffimer (Hemolink) with intraoperative autologous blood donation for coronary artery bypass graft (CABG) surgery. DESIGN Randomized, controlled, single-blind phase II dose escalation trial. SETTING Multi-institutional university setting. PARTICIPANTS Adult patients (n = 60) undergoing elective CABG surgery. INTERVENTIONS After induction of anesthesia, autologous whole blood was collected to achieve a hemoglobin of 7 g/dL on cardiopulmonary bypass. Patients were randomized to receive either hemoglobin raffimer (treatment) or 6% hetastarch (control) in sequential escalating dose blocks of 250 mL, 500 mL, or 750 mL. After return of autologous blood, allogeneic red blood cells were transfused according to predetermined hemoglobin triggers. MEASUREMENTS AND MAIN RESULTS Safety parameters (vital signs, hematology, blood chemistry, coagulation, and adverse events) were monitored from randomization through week 4 postdischarge. Serious adverse events were distributed evenly between the 2 groups of patients. Elevated blood pressure was more frequent in the treatment group (16/28 mmHg v 9/32 mmHg, p = 0.036). In the group of 40 patients in the 750-mL dose block, 8 of the 18 treatment patients and 4 of the 22 control patients avoided allogeneic red blood cell transfusion (p = 0.093). Median volume of allogeneic red blood cells transfused was lower in treated subjects compared with controls (p = 0.042). CONCLUSION Hemoglobin raffimer is well tolerated and may be effective in reducing transfusion for patients undergoing CABG surgery. Although perioperative hypertension was more frequent in the treated patients, blood pressure management prevented serious adverse sequelae. Definitive evaluation of efficacy in a larger phase III trial is warranted. Copyright 2002, Elsevier Science (USA). All rights reserved.
The reduction of the allogenic transfusion requirement in aortic surgery with a hemoglobin-based solution
Journal of Vascular Surgery. 2000;31((2):):299-308.
OBJECTIVE Because of allogenic red blood cell (RBC) availability and infection problems, novel alternatives, including hemoglobin-based oxygen-carrying solutions (HBOC), are being explored to minimize the perioperative requirement of RBC transfusions. This study evaluated HBOC-201, a room-temperature stable, polymerized, bovine-HBOC, as a substitute for allogenic RBC transfusion in patients undergoing elective infrarenal aortic operations. METHODS In a single blind, multicenter trial, 72 patients were prospectively randomized two-to-one to HBOC (n = 48) or allogenic RBC (n = 24) at the time of the first transfusion decision, either during or after elective infrarenal aortic reconstruction. Patients randomized to the HBOC group received 60 g of HBOC for the initial transfusion and had the option to receive three more doses (30 g each) within 96 hours. In this group, any further blood requirement was met with allogenic RBCs. Patients randomized to the allogenic RBC group received only standard RBC transfusions. The efficacy analysis was a means of assessing the ability of HBOC to eliminate the requirement for any allogenic RBC transfusions from the time of randomization through 28 days. Safety was evaluated by means of standard clinical trial methods. RESULTS The two treatment groups were comparable for all baseline characteristics. Although all patients in the allogenic RBC group required at least one allogenic RBC transfusion, 13 of 48 patients (27%; 95% CI, 15% to 42%) in the HBOC group did not require any allogenic RBC transfusions. The only significant changes documented were a 15% increase in mean arterial pressure and a three-fold peak increase in serum urea nitrogen concentration after HBOC. The complications were similar in both groups, with no allergic reactions. There were two perioperative deaths (8%) in the allogenic RBC group and three perioperative deaths (6%) in the HBOC group (P = 1.0). CONCLUSION HBOC significantly eliminated the need for any allogenic RBC transfusion in 27% of patients undergoing infrarenal aortic reconstruction, but did not reduce the median allogenic RBC requirement. HBOC transfusion was well tolerated and did not influence morbidity or mortality rates.
Randomized trial of diaspirin cross-linked hemoglobin solution as an alternative to blood transfusion after cardiac surgery. The DCLHb Cardiac Surgery Trial Collaborative Group
BACKGROUND Risks associated with transfusion of allogeneic blood have prompted development of methods to avoid or reduce blood transfusions. New oxygen-carrying compounds such as diaspirin cross-linked hemoglobin (DCLHb) could enable more patients to avoid allogeneic blood transfusion. METHODS The efficacy, safety, hemodynamic effects, and plasma persistence of DCLHb were investigated in a randomized, active-control, single-blind, multicenter study in post-cardiac bypass surgery patients. Of 1,956 screened patients, 209 were determined to require a blood transfusion and met the inclusion criteria during the 24-h post-cardiac bypass period. These patients were randomized to receive up to three 250-ml infusions of DCLHb (n = 104) or three units of packed erythrocytes (pRBCs; n = 105). Further transfusions of pRBCs or whole blood were permitted, if indicated. Primary efficacy end points were the avoidance of blood transfusion through hospital discharge or 7 days postsurgery, whichever came first, and a reduction in the number of units of pRBCs transfused during this same time period. Various laboratory, physiologic, and hemodynamic parameters were monitored to define the safety and pharmacologic effect of DCLHb in this patient population. RESULTS During the period from the end of cardiopulmonary bypass surgery through postoperative day 7 or hospital discharge, 20 of 104 (19%) DCLHb recipients did not receive a transfusion of pRBCs compared with 100% of control patients (P < 0.05). The overall number of pRBCs administered during the 7-day postoperative period was not significantly different. Mortality was similar between the DCLHb (6 of 104 patients) and the control (8 of 105 patients) groups. Hypertension, jaundice/hyperbilirubinemia, increased serum glutamic oxalo-acetic transaminase, abnormal urine, and hematuria were reported more frequently in the DCLHb group, and there was one case of renal failure in each group. The hemodynamic effects of DCLHb included a consistent and slightly greater increase in systemic and pulmonary vascular resistance with associated increases in systemic and pulmonary arterial pressures compared with pRBC. Cardiac output values decreased more in the DCLHb group patients after the first administration than the control group patients. At 24 h postinfusion, the plasma hemoglobin level was less than one half the maximal level for any amount of DCLHb infused. CONCLUSIONS Administration of DCLHb allowed a significant number (19%) of cardiac surgery patients to avoid exposure to erythrocytes postoperatively.
Haemodynamic effects of diaspirin crosslinked haemoglobin (DCLHb) given before abdominal aortic aneurysm surgery
British Journal of Anaesthesia. 1999;83((5):):702-7.
We studied 34 patients undergoing elective repair of an abdominal aortic aneurysm under combined general anaesthesia and epidural block to evaluate the acute effects of diaspirin crosslinked haemoglobin (DCLHb) 50, 100 and 200 mg kg-1 i.v. Haemodynamic variables were measured continuously using pulmonary and radial artery catheters, and oxygen delivery and consumption were calculated at regular intervals. DCLHb was shown to be vasoactive, producing an increase in mean arterial pressure of approximately 25% with each dose, with small decreases in cardiac index and calculated oxygen delivery. These effects persisted beyond the end of infusion and provided a degree of cardiovascular stability during the operative procedure. The effects of DCLHb on oxygen consumption at these doses were minimal.
The effects of increased doses of bovine hemoglobin on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery
Anesthesia & Analgesia. 1998;87((2):):284-91.
UNLABELLED In two consecutive studies (Study A and Study B), we evaluated the effects of increasing doses of HBOC-201, a bovine hemoglobin-based oxygen carrier, on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. After the induction of anesthesia and the exchange of 1 L of blood for 1 L of lactated Ringer's solution, 24 patients (12 in each study) were randomly assigned to receive, within 30 min, a predetermined volume of either HBOC-201 or 6% hydroxyethyl starch (Study A 6.9 mL/kg; Study B 9.2 mL/kg). Monitored variables included systemic and pulmonary arterial pressures, arterial and mixed venous blood gases, and calculations of cardiac index (CI), systemic (SVRI) and pulmonary (PVRI) vascular resistance indices, oxygen delivery index (DO2I), oxygen consumption index (VO2I), and oxygen extraction ratio (O2ER). In both studies, the infusion of HBOC-201 was associated with increases in SVRI (Study A 121%; Study B 71%) and PVRI (Study A 70%; Study B 53%) and with a decrease in CI (29% both studies). Hemodilution with HBOC-201 maintained the arterial oxygen content at levels higher than hemodilution with hydroxyethyl starch, but the advantage of a greater oxygen-carrying capacity was offset by the increase in SVRI, with a resulting net decrease in both CI and DO2I (Study A 30%; Study B 28%); VO2I was maintained by increased O2ER. In terms of hemodynamics and oxygen transport, hemodilution with bovine hemoglobin in these doses provided no apparent benefit over hemodilution with hydroxyethyl starch. IMPLICATIONS Bovine hemoglobin in doses ranging between 55 and 97 g of hemoglobin increased vascular resistance and decreased cardiac output in anesthetized surgical patients. In terms of hemodynamics and oxygen transport, hemodilution with bovine hemoglobin in these doses provided no apparent benefit over hemodilution with hydroxyethyl starch.