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||June 14, 2001 |
||Harvey G. Klein, MD President |
Karen Shoos Lipton, JD Chief Executive Officer
||Noninfectious Serious Hazards of Transfusion |
At its July 2000 meeting, the American Association of Blood Banks’ (AABB) Board of Directors requested that the Transfusion Practices Program Committee (TPPC) review and report back to the Board regarding noninfectious serious hazards of transfusion (NISHOT). In January 2001, the TPPC presented a detailed report to the Board on this important issue, outlining the most serious noninfectious threats to patients receiving transfusions and recommending steps to be taken to reduce such risks. Drawing from the report, this Association Bulletin summarizes information regarding several noninfectious transfusion risks and AABB’s recommendations and actions to protect patients from these risks.
Summary – The Issue
Safe and effective transfusion depends on a series of linked processes:
Although there has been a 10,000-fold reduction in the risk to patients from transfusion-transmitted infectious diseases in recent decades, there has been little progress in reducing the risk of noninfectious hazards of transfusion. As a result, patients today are harmed from noninfectious serious hazards of transfusion at a rate that exceeds infectious hazards by 100-fold to 1000-fold. The most common NISHOT include:
- Mistransfusion and ABO/Rh incompatible transfusion
- Cardiopulmonary toxicity
- Transfusion-related acute lung injury (TRALI)
- Transfusion-associated graft-vs-host disease (TA-GVHD)
- Metabolic derangements in pediatric and massive transfusion
In order to protect patients requiring transfusions, greater attention should be paid to reducing the incidence and severity of noninfectious transfusion risks. While the blood banking and transfusion medicine community, along with government policy makers, should continue to invest in research and improved technologies and procedures to prevent the transmission of infectious diseases through transfusions, comparable investments in research and improved patient care should be directed at noninfectious risks of transfusion. By emphasizing the entire process of transfusion therapy, patients will be better served.
Incidence of NISHOT
Hemovigilance programs from many countries, including the United Kingdom, France and Canada, have documented that patients still suffer significant transfusion-related morbidity and mortality. Furthermore, these adverse events result principally from noninfectious hazards of transfusion.1
Recent progress in the reduction of transfusion-transmitted disease (TTD) risk has not been matched by commensurate reduction in the risk of noninfectious hazards. From 1960 to 2000, the risk of contracting hepatitis from blood dramatically decreased from a rate of approximately 1:10 to a rate of less than 1:100,000 – representing a 10,000-fold risk reduction. In the last two decades, the risk of HIV infection from transfusion has undergone a similar 10,000-fold risk reduction.
In contrast, during the past four decades there has been little, if any, change in the risk to patients from NISHOT. The speed with which transfusion-transmitted viruses were understood and contained has been due, in no small measure, to substantial research efforts supported by both government and industry, especially after the recognition that HIV is blood-borne. By contrast, little support has been directed toward reducing noninfectious transfusion risks.
It is widely believed that current data underestimate the magnitude of noninfectious risks of transfusion. These underestimates are due in part to the fact that current data on noninfectious hazards are derived from passive reporting systems rather than the prospective, active investigation of blood components given to patients. Underestimation is found for both minor reactions (such as febrile nonhemolytic [FNH] events) and for major mishaps. For example, studies of FNH transfusion reactions to platelets consistently find that 10-30 percent of transfusions result in FNH reactions – a value many times higher than that reported to transfusion services.2 In the case of serious errors of mistransfusion, three major teaching hospitals in Belgium documented that prospective, active tracking of transfusions identified substantial underreporting of bedside errors.3 That study reported that the rate at which whole blood or red blood cells were transfused to unintended recipients was 1 in 400 units – a frequency substantially higher than current estimates based upon passive reporting. This study concluded that current, passive reporting systems underestimate the true frequency of serious hazard by 30-fold. Even fatal transfusion mishaps are subject to “significant underreporting.” Despite the established occurrence of fatal TA-GVHD, there were no TA-GVHD fatalities reported to the FDA from 1976-1985.4
Additional indirect evidence for underreporting lies in the finding that whenever nonpunitive reporting is encouraged, the number of reported adverse events increases dramatically. For example, when the province of Quebec recently established a hemovigilance program, the number of reported events increased significantly in the first few months of the program.5
Because serious “near miss events” signaling hazardous processes are not reported, accurate estimates of their frequency do not exist. However, near miss events are likely to be quite common.6,7 One measurable near miss event is the collection of a pretransfusion sample whose ABO result fails to agree with the result on record in the blood bank.
The problem of increasing medical errors continues to affect the entire health-care system, including transfusion practice. In the US, medical errors are estimated to cause 1,000,000 serious injuries and 100,000 deaths per year.8 The pressure to treat patients during shorter lengths of stay, higher patient volumes in fewer hospitals, increasingly complex systems of health-care delivery and complicated treatment protocols and higher patient expectations all contribute to increasing error rates. In the field of transfusion medicine, a recent study from the University of Michigan documented a dramatic increase in errors during the period from 1993 to 1999.9 The total number of documented occurrences rose from 1238 to 2052 per year during this period. Alarmingly, patient sample errors quadrupled from 112 (10% of errors in 1993) to 434 (20% of errors in 1999). Although transfusion errors may comprise only a small fraction of all medical errors believed to be occurring annually in this country, they stand out in stark contrast to the virologic safety of transfusion that has been achieved.
NISHOT now represent the most common risk factors in blood transfusion. Without correcting for underrecognition and underreporting of bedside mishaps, the Food and Drug Administration (FDA) reported transfusion-related death rate due to hemolytic reactions alone was more than two times higher than that due to all infectious hazards combined.10 The UK surveillance system reported that the rate of adverse events attributed to mistransfusion of the wrong blood to patients was 10 times higher than the rate attributed to infectious disease transmission.1
The following summary outlines the six most prevalent NISHOT along with estimates of their reported frequencies.
Mistransfusion Leading to Serious Morbidity or Mortality
Transfusion of incompatible blood or mistransfusion of blood is the most common cause of serious morbidity and mortality related to transfusion. Serious errors are made at the time of sample collection, within the laboratory, at the moment of blood issue from the laboratory, as well as at the bedside. ABO-incompatible transfusions due to the misidentification of type-and-crossmatch samples, errors made in the laboratory or misidentification of recipients at the time of transfusion are the reported cause of fatality for as many as two dozen patients each year in the US.11 The reported incidence of these fatal reactions has not decreased significantly in decades, as indicated by reviews of data reported to the FDA or the New York State Department of Health concerning the years 1976-1978, 1976-1985, and 1990-1999.12,4,10,13 As stated above, it is widely believed that these reported numbers significantly underestimate the actual number of these serious errors.
Circulatory Overload and Cardiopulmonary Toxicity
Published evidence also suggests that circulatory overload may be a significant problem associated with transfusions. A 7-year retrospective study from a single medical center found an incidence of circulatory overload of 1 in 3168 patients transfused with RBCs.14 This figure underestimated the true incidence, because after initiation of a bedside consultation service at the medical center, the rate of transfusion-related circulatory overload was 1 in 708 patients receiving RBCs. In 20 percent of cases, a single unit was sufficient to precipitate acute respiratory distress. One study indicated that one percent of blood transfusion recipients developed circulatory overload, at times necessitating transfer to an intensive care unit and prolonged hospital length of stay.15 Extrapolating these data to a national level suggests that perhaps 30,000-40,000 patients annually might suffer this avoidable complication.
In a 1999 prospective, multi-center, randomized trial reported in the New England Journal of Medicine, patients admitted to critical care units were randomized to receive a liberal or a conservative use of blood products. Patients given more conservative treatment had improved survival. When the two groups were compared for complications, patients who had been randomly assigned to a more liberal transfusion strategy had a significantly higher incidence of cardiac and pulmonary morbidity.16
Transfusion-Related Acute Lung Injury
TRALI is a life-threatening complication that in its classic and fulminant presentation is indistinguishable from adult respiratory distress syndrome (ARDS) secondary to other causes (eg, toxin inhalation, sepsis, or aspiration). TRALI is characterized by acute respiratory distress, severe bilateral pulmonary edema, severe hypoxia, tachycardia, fever, hypotension and cyanosis, which arise within 1-6 (and usually within 1-2) hours of transfusion of a plasma-containing blood component.
Mild to moderate cases of TRALI result in lung injury and prolonged ventilator time, and may predispose patients to lung infection. In a minority of severe cases, the outcome is fatal. In an analysis of reports to the FDA of transfusion-associated deaths, 31 (9%) were attributed to acute pulmonary problems.7 This was the third most common reported cause of transfusion-related death.
The actual incidence of TRALI remains unknown, although the number of cases reported in the literature has increased dramatically. From 1951, when the syndrome was first described, until 1985, there were fewer than 40 case reports in the English language literature. Since then, descriptions of at least 130 cases have been reported and 70 additional cases noted.17 One study found that 46 of 2430 platelet transfusions (2%) were associated with severe respiratory reactions over a 2-year period in a general hospital.18
There is ample reason to believe that TRALI may be significantly underdiagnosed. In a series of 40 patients with pulmonary edema in the operative setting, one study found that 50 percent of cases were attributed to circulatory overload or an unknown cause.19A recent study found that FFP donated by women with a history of 3 or more pregnancies resulted in significantly lower oxygen extraction compared with control FFP. In 4 of 100 patients a clinical pulmonary transfusion reaction was noted.20
Transfusion-Associated Graft-vs-Host Disease
There are also inadequate data to measure accurately the incidence of TA-GVHD. A prospective study of the development of TA-GVHD has never been undertaken and would be very difficult to perform. Estimates of the incidence and identification of patient groups at risk are subject to the limitations of retrospective data. Many cases go unreported because definitive diagnostic studies and DNA evidence are not obtained.21 Nevertheless, over 200 cases of TA-GVHD have been reported or referenced in the Japanese and English literature.22,23,24 Of great significance is the fact that TA-GVHD is approximately 90 percent fatal. Although irradiating cellular blood components will prevent TA-GVHD, irradiation has detrimental effects on erythrocytes and there is currently no agreement regarding the extent of the blood supply that should be irradiated. Further studies of the incidence of TA-GVHD among recipients who do not receive irradiated blood products would provide important information on which to base such a decision.
Metabolic Abnormalities in Pediatric Patients
Transfusions are very likely to increase the existing risk of metabolic derangement to premature infants with very low birthweights. It has been suggested that hypoglycemia during routine neonatal transfusions may go unrecognized.25 Hypoglycemia in association with simple replacement transfusion in very premature infants occurs as a result of a decrease in the rate of glucose infusion during the transfusion of the component due to limited venous access. When dextrose infusions are discontinued during a 3- to 4-hour transfusion of small volumes of CPDA-1 or AS-1 red cells, glucose infusion rates drop to 0.2 to 0.5 mg/kg/min, which is far below the normal glucose requirement.26 In a study of small-volume transfusions among 16 premature infants, 64 percent of infants receiving RBCs at 17 mL/kg required supplemental glucose within the first two hours of the transfusion.27 Supplemental glucose was given when the blood glucose decreased to < 40 mg/dL or when clinical hypoglycemia was observed. The long-term effects of neonatal hypoglycemia on brain growth and development are not known.
Among pediatric recipients of massive transfusion, the risks of hyperkalemia and hypocalcemia are well-recognized, although the true incidence of these complications and the frequency with which they contribute to cardiac arrest is not well-documented. A review of 140 exchange transfusions among 106 neonates found that hypocalcemia was a common serious morbidity: more than 34 percent of infants had documented hypocalcemia during exchange. One in 20 infants demonstrated EKG changes and one had a cardiac arrest. Among a subset of 25 ill neonates, 12 percent experienced severe complications (including 2 deaths) attributed to transfusion.28
Guidelines for the indications for transfusion are not refined. Most published guidelines attempt to establish triggers that are not adjusted for specific clinical diagnoses nor for the extent of coronary disease or vascular disease in the recipient. Thus, there is potential for undertransfusion of a portion of transfusion recipients.
Several studies have indicated that transfusions to patients with hemoglobins between 8 and 10 g/dL did not improve mortality even when adjusting for cardiovascular disease.29One study demonstrated that mortality was lower in a group of patients managed with a restrictive transfusion policy (transfusion if hemoglobin <7.0 g/dL) compared with patients transfused using a liberal strategy (transfusion if hemoglobin <10 g/dL). These and similar studies have been inappropriately interpreted to indicate that undertransfusion is not a potential clinical problem.
Although the above studies generally concluded that a hemoglobin level of 7.0 g/dL was a reasonable and safe guideline as a transfusion trigger, this has not been a uniform finding. One study involving 190 patients undergoing radical prostatectomy found that myocardial ischemic episodes occurred in 61 (34%) of 181 evaluable patients.30 After adjusting for other risk factors, the authors concluded that a hematocrit level <28 percent is independently associated with risk for myocardial ischemia during and after noncardiac surgery. They suggested that avoidance of cardiac complications may require higher transfusion thresholds.
Another report studied 27 patients having coronary artery bypass graft surgery who were randomly assigned to receive either blood and colloid solutions or crystalloid fluids.31 The patients treated only with crystalloid had delayed myocardial metabolic recovery and a decrease in myocardial lactate extraction over normal controls, suggesting that the higher grade anemia in these patients had a potentially deleterious effect on the heart.
In a study of high-risk patients undergoing infra-inguinal arterial bypass procedures, 13 of the 27 patients had a hematocrit <28 percent and, of these 13 patients, 10 demonstrated postoperative myocardial ischemia and 6 sustained a morbid cardiac event.32 Thus, the overall incidence of cardiac ischemia was 37 percent (10 of 27 patients) in this population of elderly individuals with vascular disease. A hematocrit of <28 percent was significantly associated with myocardial ischemia (p=0.001) and morbid cardiac events (p=0.0058). The authors suggested that postoperative anemia may play a role in postoperative myocardial ischemia and cardiac morbidity.
Several other reports have documented the dangers of allowing the hemoglobin level to fall to even lower levels. In a study of 2738 sequential isolated coronary artery surgery patients, after adjusting for other risk factors, the authors concluded that there was a significantly increased risk of mortality for hematocrit levels of < 14 percent.33 Also, for high-risk patients, there was a significantly increased risk of mortality for hematocrit levels <17 percent.
A meta-analysis of several studies on Jehovah’s Witnesses found that, of 50 reported deaths, 23 were primarily due to anemia.34 Except for 3 patients who died after cardiac surgery, all patients whose deaths were attributed to anemia died with hemoglobin concentrations <5 g/dL. The authors concluded that mortality with an unknown incidence is encountered at hemoglobin concentrations below 5 g/dL.
Studies that have examined actual transfusion for specific conditions document a large variability among institutions in transfusion practice.35 This variability highlights the fact that proper indications for transfusion are not agreed upon and underscores the need for clinical studies that define safe and appropriate transfusion practice.
Means of Addressing the NISHOT Problem
The AABB is committed to reducing NISHOT and thereby improving patient care. The Association believes that the incidence of NISHOT can be reduced by an increased focus of both health-care providers and policy makers on the following key areas.
Nonpunitive National Transfusion-Related Error Reporting System
In order to better understand and, in turn, reduce transfusion-related error incidence, the AABB advocates the establishment of a nonpunitive national reporting system for transfusion-related errors. Such a system should be streamlined and provide meaningful data. The error reporting system established in the airline industry may serve as a valuable model.
A Medical Event Reporting System for Transfusion Medicine (MERS-TM) is currently being tested in a limited number of facilities throughout the country. This system is designed to establish a standard method for event reporting in transfusion medicine. Currently, there is no uniformity among various systems used in individual facilities and regions. The AABB has urged the Department of Health and Human Services (DHHS) and Congress to support the establishment of such a nationwide program.
Standards to Ensure Proper Sample Collection, Patient Identification and Blood Administration
The AABB is committed to reducing errors in sample collection, patient identification and component administration. To this end, the Association will place renewed emphasis in the AABB assessment process on the enforcement of existing standards, which, when implemented appropriately, can reduce errors. Current AABB standards place the responsibility for reducing errors and accidents in the transfusion service on the executive management of the transfusion service. In order to support reducing overall errors related to transfusion medicine outside of the transfusion service, AABB standards also require that a facility have in place a functioning peer review program to monitor transfusion practices for all categories of blood and components. The peer review program is charged specifically with monitoring ordering practices, sample collection, usage, appropriateness of use, blood administration policies, the ability of transfusion services to meet patients’ needs and compliance with peer review recommendations. It is apparent that under existing standards, all errors, including those relating to proper sample collection, patient identification and blood administration, must be appropriately identified, tracked and corrected. In addition, the AABB believes that the medical community should explore the possibility of appointing a specific individual or group to monitor and address transfusion-related errors. This entity could be in the form of the peer review program required by AABB standards or an individual transfusion safety officer.
The AABB standards, in conjunction with the AABB accreditation program, are intended to address and prevent transfusion-related risks, both infectious and noninfectious, to patients. The Association believes it is critical that our accreditation program, as well as our institutions that are being assessed, place appropriate emphasis on preventing noninfectious risks of transfusion. To further this objective, the Association will be developing technical guidance for its members to strengthen the role of the peer review program in preventing noninfectious hazards of transfusion. In addition, the AABB assessment program, through its assessors, will place increased emphasis on functioning of the peer review program in our member hospitals to verify its effectiveness in reducing error.
The AABB will also formally request that the Joint Commission on the Accreditation of Healthcare Organizations place renewed focus in its accreditation process on the effectiveness of the peer review program in reducing transfusion errors and complications.
Finally, the AABB Board will ask the Standards Committee of the AABB to explore the possibility of developing requirements for performance standards in areas such as patient sample identification, accurate blood issue and correct bedside administration of blood. Implementation of such standards could encourage the adoption of electronic wristbands, a computerized blood utilization review system or other mechanisms that are designed to assist a facility in attaining certain performance goals.
Although the AABB does not endorse one specific technology over another, it does encourage research into means of reducing errors and improving care for transfusion recipients. In addition, the AABB supports the development and application of all new technologies, such as the use of bar code technology to reduce errors and the continued development of appropriately sophisticated computerized blood utilization review programs to ensure that all transfusions are medically appropriate. There has been only limited application of existing technology such as bar code technology and information systems to reduce mistransfusion, overtransfusion and undertransfusion. This inadequate use of existing technologies in the US is most likely the result of the existing reimbursement system which operates as a disincentive to the development and application of new technologies in blood transfusion. The AABB believes that this problem must be addressed if patients are to have access to and obtain the benefits of new technology.
Enhanced Clinical Research
The AABB strongly supports increased clinical research in transfusion medicine. Effective clinical transfusion therapy recognizes that the indications for blood components must be refined as new advances are made in other fields of clinical care. Refined indications are needed to avoid both overtransfusion and undertransfusion. Cooperative clinical trials have been widely used in other areas, such as cardiovascular medicine, to evaluate new interventions, determine best practice of care and evaluate new drug regimens. Within the transfusion medicine field, clinical trials are urgently needed to address the question of the appropriate triggers for transfusion, the proper “dose” and “duration” of blood therapy, ways of evaluating the efficacy of transfusion therapy and new biotechnologies related to transfusion care.
The Association continues to advocate before Congress and the DHHS the establishment of a national clinical trials network in transfusion medicine funded by the National Heart, Lung, and Blood Institute. Research should be directed at reducing noninfectious risks of transfusion and improving care for the diverse patient populations requiring blood transfusion.
Specifically, the AABB supports the establishment of two federally funded trials designed to reduce the risk of TRALI. First, the Association believes that the federal government should support an epidemiologic study regarding the incidence of TRALI. In addition, the National Institutes of Health should support a multi-center clinical study of plasma infusion. Utilizing controlled trials methodology, clinical researchers should establish the importance of leukocyte antibodies, neutral lipid generation and other potential causative mechanisms. Such studies should provide the scientific basis for therapeutic or preventive measures to reduce the incidents of TRALI.
The US has made dramatic improvements in reducing transfusion risks associated with infectious diseases. Equal and appropriate attention must also be paid to noninfectious risks of blood transfusion that now represent a greater risk to transfusion recipients. More information is needed about the true incidence of various NISHOT. In addition, the blood community and public health system should invest in research and quality measures to protect patients from potentially life-threatening risks of transfusion. Because mistransfusion of incompatible blood is the most common cause of serious morbidity and mortality to transfusion, significant attention should be paid to reducing the incidence of such errors and promoting a culture of safety within hospitals.
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