The 3 most frequently reported nonserious AEs were an increase in blood pressure (systolic blood pressure >160 mm Hg), an increase in liver enzymes (outside normal range), and the development of metHb (outside normal range). Systolic blood pressure increased in 10 of 16 survivors (63%) and 9 of 23 nonsurvivors (39%). Of these 19 patients with increased systolic blood pressure, 3 of the 10 survivors and 5 of the 9 nonsurvivors required treatment with antihypertensive drugs. Liver enzymes, measured in only 22 patients, were outside the normal range in 12 of 16 nonsurvivors (75%) and 6 of 6 survivors and were considered transient effects of HBOC-201; none of the patients developed clinical signs of hepatic dysfunction or required medical treatment. Increases in [metHb] were reported in 6 nonsurvivors (12.2% [4.2%–22.3%]) and 7 survivors (6.0% [2.6%–13.6%]). In 7 cases, methylene blue was used to treat the metHb. There was no correlation between units of HBOC-201 given and the maximal [metHb] measured (P = 0.328). No attending physicians reported unexpected difficulty in product use to the Biopure or consultant physicians.
This case series is unusual, representing a group of acutely anemic patients untreated with blood transfusion. Many clinicians use 8 g/dL as the [Hb] below which blood transfusion is begun in critically ill patients. All current guidelines for red blood cell transfusions recommend that transfusion is indicated when [Hb] is <6 g/dL39,40 because the mortality of groups not treated with blood or an HBOC was significantly increased at <5 g/dL.41,42
There is no published case series of this size involving the use of HBOC-201 in life-threatening situations, but there have been several individual cases reported.43–46 Reports on the association between decreased [Hb] and increased risk of morbidity and mortality are available from large retrospective studies and systematic reviews.41,42 Reports including Jehovah's Witnesses as historical controls collected between 1969 and 2000 generally support the relationship between decreasing [Hb] and increasing morbidity and mortality.47–52 The more recent reanalysis by Carson et al.,42 used as historical control data by Gould48 identified the association of [Hb] <5–6 g/dL with high morbidity and mortality. However, these retrospective data are not an appropriate control group; because they are a more uniform population, these patient data would need to be interpolated and broken into discrete historical intervals (which we are unable to do) to be comparable and used as a control for the patients in this series.
Data are available describing HBOC efficacy in transfusion-sparing and oxygen-carrying capabilities.30,32,33 A recent phase 3 clinical trial of human polymerized Hb (PolyHeme®, Northfield Laboratories, Evanston, IL) showed more AEs and MIs, but no mortality difference when blood was needed but was not available.53 Both trauma and large blood loss surgery trials have described cardiovascular, cerebral, and other complications of HBOCs,24 although the meta-analysis data, methods, and conclusions can be criticized.25–28 Further analysis of these AEs, observed with HBOC-201, the product used in these cases, suggests that they are related to a subpopulation of patients with advanced age and multiple comorbidities.30 Despite the risk of complications and AEs, HBOCs may prove lifesaving under specific circumstances, especially where blood is not an option or available. It becomes important to establish the point at which the benefit overshadows the risk.
In the heterogeneous patient population reported, the common denominator was anemia with historical data suggesting increases in patient mortality when augmentation of oxygen-carrying capacity is not provided.41,42,47 Although 82% of patients in this series received erythropoietin, drugs of this type have no known benefit during acute anemia. Sampling, testing, and abnormal values were insufficient for statistical analysis of hepatic enzymes, renal markers, coagulation, and cardiac enzymes.
An important observation in this case series is that at low [Hb] (<8 g/dL), mortality increased proportional to duration from onset of anemia until administration of HBOC-201. Early treatment often gave good results in terms of subjective statements made about feeling better, relatives commenting about the patients being more alert, and patients stating they had more energy. Delay between identifying need for additional oxygen-carrying capacity and administration of HBOC-201 would prolong the period of impaired perfusion, allowing further accumulation of oxygen debt, and increase the risk of ischemia-related events. Efficient and timely delivery of HBOC-201 to the patient bedside was compromised by various delays including obtaining informed consent, IRB (or administrative surrogate) approval, FDA review and approval to issue a unique IND for each individual patient, shipment of the product, and ultimate arrival and processing of it in the hospital pharmacy (or other dispensing unit).
Patients with rapid blood loss who died waited on average 3.6 days before receiving HBOC-201, a wait not significantly different from the 1.8 days for surviving patients (P = 0.178). The delay before treatment of medical anemia among nonsurvivors was longer than that of survivors (10.6 vs 4.4 days; P = 0.016).
Patients were aware of their high risk of nonsurvival without HBOC-201 infusion and gave informed consent and accepted the potential benefit, knowing there were risks associated with the use of HBOC-201. Risks explicitly noted included arterial blood pressure increase affecting cardiac or brain tissue perfusion. There was no correlation between blood pressure increases or the use of antihypertensives and survival in this series of patients.
Patients with abnormal vascular endothelial function (e.g., history of cardiovascular disease or diabetes) might be at higher risk to develop an adverse blood pressure response to HBOC-201, but none of the 7 diabetic patients and 5 of the 22 patients with cardiovascular disease had blood pressure increases compared with 6 of 33 patients without these comorbidities. Four of 5 patients with cardiovascular comorbidities survived. Although some patients had abnormal liver enzymes, there have been no cases of hepatic failure-related demise reported with HBOC-201 use.
The metHb increase observed with the use of HBOCs is likely due to the lack of sufficient reductase enzyme activity in the plasma. Increases in [metHb] did not affect survival, were independent of HBOC-201 dose, and, when treatment was necessary, generally were responsive to methylene blue infusion. A sufficient quantity of red blood cells containing metHb reductase seems necessary to minimize increases in total [metHb], and a low hematocrit may decrease the effectiveness of methylene blue in these patients. Increases in [metHb], as a percentage of total Hb, decrease the functional oxygen available to tissues, adding to the impact of low [Hb]. Although [metHb] <10% is well tolerated at normal or mild levels of anemia, 10% of an [Hb] <5 g/dL significantly impairs oxygen-carrying capacity and functional oxygen delivery.
Adequate [Hb] is not the only factor necessary to prevent mortality from acute anemia because the survivors had average [Hb] values of 4.5 g/dL compared with 3.8 g/dL in nonsurvivors with considerable overlap in their range of [Hb]. Other factors influencing survival included the duration of the anemia, the rapidity of onset of anemia, cardiopulmonary conditions that affect oxygen delivery, the patient's underlying pathologies and prior physical status, side effects of all medical treatments including HBOC-201, and the intensity of the medical, nursing, and family support to continue treating the patient. Underlying illnesses leading to the low [Hb] may be responsible for mortality, not the failure to reverse dying by increasing [Hb]. Carson et al.48 speculated that transfusion would improve postoperative outcome in patients with [Hb] <5 g/dL, because mortality remains extremely high with [Hb] <5 g/dL. Among the 24 patients with known outcomes for whom an IND was approved but HBOC-201 was not administered, 5 did not survive, leading to an apparent mortality rate of 20.8%. It should be noted, however, that in many of these patients, IND was applied for in anticipation of a severe anemia or blood loss that never happened, or the patient was eventually transfused. Exclusion of these cases (n = 14) would yield a new mortality rate of 50% among the remaining 10 anemic patients for whom an IND was issued, but HBOC-201 was not administered. Although this mortality rate is slightly higher compared with patients who received HBOC, the difference is not statistically significant (P = 0.734).
The limitations of this series of CU patients include the absence of a concurrent comparison control group, detailed systematic collection of markers of organ dysfunction (e.g., cardiac enzymes) at preset intervals, and rigorous assessment of severity of injury or illness. Because limits were placed on blood sampling, only incidences of abnormal laboratory tests were sometimes available, but there were few data on the duration of abnormalities. A control group was not available. Historical data on patients who cannot receive blood are distinctly different from the current population because the literature generally reports on homogeneous patient populations often in a single operative setting.48,49 The in-hospital postoperative ≤30-day mortality rates related to anemia, in Jehovah's Witness patients refusing Hb infusion or transfusion, in a multi-institutional study were [Hb] ≤5 g/dL, 34.4% (n = 32); ≤4 g/dL, 25% (n = 28); ≤3 g/dL, 54.2% (n = 24); and ≤2 g/dL, 100% (n = 7).48
In this report, only patients who were anemic for a variety of medical, surgical, and other reasons (Table 3) received HBOC-201 because blood was not an option. The 25 patients who did not receive HBOC-201, despite issuance of an IND number, are an inadequate control because of the wide variety of reasons for not receiving HBOC-201, as described above. Going forward, an FDA-approved single IND CU protocol, with standardized criteria for HBOC-201 release, data collection, and an independent data safety monitoring board, would minimize delays, potentially improve outcome, and improve the quality of data for analysis. One can speculate that survival in this series of patients, who were perceived to be dying, would potentially have been greater if patients enduring low [Hb] for extended periods resulting in irreversible fatal damage were excluded or, ideally, treated sooner. The Biopure manufacturing facility, name, and operation have been sold to OPK Biotech which will continue to manufacture, pursue United States registration with existing and future collaborations, and evaluate the product HBOC-201 described in this article.
In conclusion, this study adds evidence to the literature that, regardless of the organ system studied or surgical procedure evaluated, “anemia” is an independent risk factor for adverse outcome. This series of patients shows that, when used selectively and earlier in the course of acute anemia in patients when red blood cells are not readily available or for whom red blood cell transfusion is not an option, HBOC-201 administered by first-time users provides physicians with an additional, but unapproved, treatment.
Drs. Shander, Mackenzie, and Greenburg form the team of consulting physicians who advised the attending physicians on the compassionate use of HBOC-201 described in this case series. Ms. Melissa Zafirelis, Director, Clinical Operations at Biopure Corporation is acknowledged for acquisition of the data presented in this article.Ms. June Clark, Senior Project Administrator at Biopure Corporation, is acknowledged for administrative support.
Supported by Biopure Corporation. Hemopure (HBOC-201) was supplied at no charge to the participant institutions.
Both Drs. Moon-Massat and Greenburg were previously full-time employees of Biopure Corporation. Drs. Shander and Mackenzie were paid consultants to Biopure Corporation. Dr. Shander also has been/is a consultant for Bayer, Hemo Concepts, NovoNordisk, OrthoBiotech, and Zymogenetics, has received grants/research support from Abbott, AstraZeneca, OrthoBiotech, and Zymogenetics and speaking honorariums from Baxter, Bayer, Pfizer, Hemo Concepts, NovoNordisk, OrthoBiotech, and Zymogentics. Dr. Mackenzie was also a paid site principal investigator in a clinical trial with HBOC-201 (Trial HEM-0115). No authors held equity interests in Biopure Corporation.
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