BLOOD PRODUCTS ADVISORY COMMITTEE 96 th Meeting, November 16-17, 2009 Bethesda Marriott Hotel 5151 Pooks Hill Road, Bethesda, MD

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1 BLOOD PRODUCTS ADVISORY COMMITTEE 96 th Meeting, November 16-17, 2009 Bethesda Marriott Hotel 5151 Pooks Hill Road, Bethesda, MD Issue Summary Topic III: Blood Pressure and Pulse as Blood Donor Eligibility Criteria Issue: FDA seeks the advice of the Committee on using blood pressure and pulse as part of the donor physical assessment to determine donor eligibility. Introduction: FDA seeks the Committee s advice on appropriate standards for assessing and ensuring the health of blood donors. In particular, FDA seeks advice on the use of blood pressure and pulse in the blood donor setting as indicators of donor health and to prevent donation-related adverse events. Executive Summary: More than 9.5 million individuals donate blood each year with relatively few suffering adverse health events. However, there have been a number of publications about adverse events in blood donors including vasovagal reactions, delayed reactions, and death. In the United States, measurement of blood pressure has been a part of the assessment of donor health prior to blood donation for many decades. In 1987, AABB set upper limits for donor systolic and diastolic blood pressure at 180 mm Hg and 100mm Hg respectively. In 2009, AABB dropped the requirement for measuring blood pressure and pulse from its standards. There is currently a lack of consensus regarding the possible association between blood pressure, pre-donation bradycardia and pre-donation tachycardia and the risk of adverse events during and after donation. As a measure to ensure the donor is in good health and to ensure the safety of the donation process to the donor, FDA s current regulations for Whole Blood (21 CFR 640.3)(b) and Source Plasma (2) donation require demonstration that systolic and diastolic blood pressure are within normal limits, unless the examining physician is satisfied that an individual with blood pressures outside these limits is an otherwise qualified donor under the provisions of the section. These regulations do not explicitly define what should be regarded as a normal systolic or diastolic blood pressure range for the purposes of Whole Blood or Source Plasma donation. The current Source Plasma regulations further require that the donor have a normal pulse rate. These measures are intended to ensure that the donor is in good health and that the donation process will be safe for the donor. On November 8, 2007, FDA published in the Federal Register (Volume 72, pages ) proposed requirements for Human Blood and Blood Components Intended for 1

2 Transfusion or for Further Manufacturing Use. In of this proposed rule, FDA would require a collecting establishment to perform certain prescribed steps or assessments to determine if the donation may adversely affect either the health of the donor or the safety, purity, or potency of blood or blood components. To ensure consistency of requirements, these general provisions would apply equally to any establishment that collects Whole Blood, blood components, or Source Plasma, and would apply to all uses, whether for autologous use, further manufacturing, or use as a component of a medical device. In this rule, FDA proposed to specify parameters for systolic and diastolic blood pressure for Whole Blood and Source Plasma donors (systolic not to exceed 180 mm Hg or fall below 90 mm Hg, diastolic blood pressure not to exceed 100 mm Hg or fall below 50 mm Hg). For Whole Blood donors, FDA also proposed to require that a donor s pulse be regular and in the range of bpm. Although the proposed rule, once finalized, would have made FDA s regulations on donor blood pressure and pulse consistent with previous industry standards, AABB has since changed these standards. Comments on the proposed rule have questioned both the need and the scientific rationale for the proposed measurement of pulse rate and blood pressure and the proposed ranges or limits for pulse, blood pressure and temperature. However, none of the comments submitted to FDA provided affirmative scientific support for dropping blood pressure or pulse screening requirements, or proposed alternative measures for physically assessing good health as it relates to maintaining the health of the donor during and after the donation process. Acute cardiovascular events including vasovagal reactions and clinically significant hypotension (with or without loss of consciousness, with or without injury, with or without seizure), cardiac events (arrhythmia, angina, myocardial infarction or arrest), CNS events (cerebrovascular accident), and death are potentially related to baseline blood pressure values. The term neurocardiogenic syncope has been used to describe both vasovagal reactions (sympathetic withdrawal and increased vagal activity with bradycardia) and vasodepressor reactions (sympathetic withdrawal alone). It is generally thought that approximately 3% of blood donors experience post-donation adverse reactions, 0.3% have a moderate reaction such as complete loss of consciousness, 0.03% experience more severe reactions such as seizure, and % have a life-threatening complication necessitating medical intervention. Assessments that help distinguish between donors who experience adverse events and those who do not would permit collection facilities to focus more attention on those donors at higher risk. The literature highlights the difficulties in assessing complications associated with blood donation. On the one hand, young age and first time donor status have been associated with a higher frequency of post-donation adverse events, generally classified as vasovagal in nature and generally mild. Low blood volume appears to be related to the occurrence of both immediate and late reactions, while female gender appears to relate more to delayed reactions. Hypotheses about differences in tolerance to orthostatic stress between men and women have been formulated to account for the findings that low weight, low volume female donors are more likely to react, particularly late. On the other hand, more severe complications of donation, also predominantly vasovagal but 2

3 potentially including significant cardiovascular events, have been linked to older age, though this is not a uniform finding. Whether blood donation in the elderly is as safe as that among younger donors is not yet clear and the contribution to adverse events of underlying cardiovascular risk factors and co-morbidities in elderly donors also is not known. Appendix 2 contains a tabular summary of the recent literature that addresses adverse events in whole blood donors, and a review of the literature on adverse events in apheresis donors. Papers were initially obtained through PubMed search and other search engines. Additional references were obtained from the references cited in the papers obtained through the initial searches. Additionally, presentations were made at the NHLBI sponsored State of the Science symposium held at NIH on September 15, AABB has published a compendium of abstracts to be presented at the upcoming annual meeting in New Orleans, October 24-28, The committee today will hear presentations on adverse events in blood donors, possible causes and possible interventions. We seek input from the committee on donor assessments for blood pressure and pulse as they relate to the donation process itself and as predictors of donation-related adverse reactions. 3

4 Background: In the United States, measurement of blood pressure has been a part of the assessment of donor health prior to blood donation for many decades. In 1987 AABB set upper limits (180 mm Hg and 100mm Hg) for donor systolic and diastolic blood pressure, respectively. In 2009, AABB has dropped the requirement for these measurements from their standards. There has been a lack of consensus on whether blood pressure, particularly low blood pressure, as well as pre-donation bradycardia or pre-donation tachycardia, influence the risk of adverse events during and after donation. Data on the safety of donation when blood pressure measurements are outside established ranges are sparse. On November 8, 2007, FDA published in the Federal Register (Volume 72, pages ) proposed requirements for Human Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use. These proposed regulations distinguish between eligibility of the donor and suitability of the donation for transfusion or for further manufacturing use. To accomplish both goals, FDA proposed in 21 CFR which would require a collecting establishment to perform certain prescribed steps or assessments to determine if the donation may adversely affect either the health of the donor or the safety, purity, or potency of blood or blood components. To ensure consistency of requirements, these general provisions would apply to any establishment that collects Whole Blood, blood components, or Source Plasma, and to all uses, including autologous use, use in further manufacturing or use as a component of a medical device. As proposed, the determination of eligibility of the donor to donate would consist of four parts: 1. assessing donor deferral status; 2. assuring that the donation interval is appropriate, taking into account whether the donor is participating simultaneously in other blood or blood component collection programs; 3. assessing the donor s medical history; and 4. assessing the donor s health by performing a physical assessment of the donor. Under current Whole Blood regulations at 21 CFR 640.3, FDA mandates that the suitability of the donor be determined on the day of collection and that good health be indicated by: 1. normal temperature 2. demonstration that systolic and diastolic blood pressure are within normal limits unless the examining physician is satisfied that an individual with blood pressures outside these limits is an otherwise qualified donor under the provisions of the section 3. certain specifications for blood hemoglobin levels. Under current Source Plasma regulations at 21 CFR , FDA also requires that: 4

5 1. the donor s pulse be normal, 2. the donor s protein levels be no less than 6 gm per 100 milliliters, and 3. the donor weight be more than 110 lbs. Additional protections exist for Source Plasma donors. In the proposed rule at 21 CFR (a), FDA combined the Whole Blood and Source Plasma regulations into a single section in which FDA specified that blood and blood components must not be collected unless the donor is eligible to donate as reflected by their overall good health and the absence of any factors that may adversely affect the health of the donor or the safety, purity, and potency of the blood or blood components collected from the donor. To the items listed above, FDA: added specific parameters for temperature (not to exceed 37.5ºC when taken orally), systolic blood pressure (not to exceed 180 mm Hg or fall below 90 mm Hg), diastolic blood pressure (not to exceed 100 mm Hg or fall below 50 mm Hg); made changes to the permitted hemoglobin ranges for women blood donors (and questioned the use of the copper sulfate method as an appropriate method for hemoglobin determination); added a requirement that whole blood donors must have a pulse rate that is regular and in the range of beats per minute, and added requirements for minimum weight (already measured for donors of source plasma- see 21 CFR (b)(2)) of 110 lbs (50 kg) with no unexpected loss >10% body weight within the past 6 months. The intent of the proposed rule was to make the FDA s regulations consistent with industry standards in effect in 2007 when the proposed rule was published, to enhance donor safety and to resolve potential compliance issues related to interpretation of normal limits (particularly for blood pressure). Comments received in response to the proposed rule have questioned the need and the scientific rationale for the proposed measures (as in the case of pulse rate and even blood pressure) and the proposed ranges or limits (for pulse, blood pressure, temperature). None of the comments proposed alternative measures other than the donor questionnaire for determining a donor s good health at the time of donation, nor did any of the comments propose alternative measures for physically assessing good health as it relates to maintaining the health of the donor during and after the donation process. If in a final rule the requirements for blood pressure (and blood pressure ranges), temperature maximum, and pulse (with range) are removed from the proposed rule, the remaining donor health assessments would be hemoglobin concentration and weight restriction. The discussion today focuses on donor assessments as they relate to donor health and as predictors of adverse reactions related to whole blood or apheresis donation. 5

6 Discussion: A. General Considerations According to the 2007 National Blood Collection and Utilization Survey Report published by DHHS, in 2006 there were 9.53 million allogeneic donors, of whom million (28.5%) were first-time donors and million (71.5%) were repeat donors (The 2007 National Blood Collection and Utilization Survey Report, AABB). These repeat donors provided 11.7 million donations for an average of 1.7 donations per donor per year. Total collections were million units. There were approximately 11,000 severe adverse donor reactions, a rate of approximately 0.07%. Donor screening and collection practices vary worldwide (Appendix 1). In the United States, blood pressure is measured pre-donation and although not an AABB standard, donors may have their blood pressure or pulse measured by blood center personnel as many as 2 or 3 times before they are deferred for readings outside accepted limits. In the United Kingdom, the requirement to measure blood pressure has been dropped. In other countries, blood pressure is measured if indicated by the medical history. In the United States, donors taking antihypertensive medications are permitted to donate. Other countries vary in their deferral practices related to antihypertensive medications. The meaning of a unit or pint of blood has not been standardized worldwide. U.S. regulations at 21 CFR define unit as the volume of blood or one of its components in a suitable volume of anticoagulant obtained from a single collection of blood from one donor, while specifying at 21 CFR 640.4(c) for blood containers that the volume of anticoagulant required for the quantity of blood to be collected shall be in the blood container at the time of sterilization These provisions permit the collection of ml +10%, giving a range of unit volumes from mL. Boulton et al. (2008) noted that in the United States, a pint is equivalent to 473 ml which, according to one widely used formula for calculating blood volume (estimated blood volume = 70 ml/kg), would result in the removal of approximately 13.5% of the blood volume from a donor weighing 50 kg (110 lbs). By the late 1990s, however, many blood centers in the United States had increased the standard collection to 500 ml plus up to 25 ml for test samples. In 1999, the Standards of the American Association of Blood Banks (AABB) allowed up to 15% of estimated blood volume to be collected, while blood centers in the United States have maintained the minimum donor weight at 50 kg or 110 lbs. AABB recorded this recommendation as removal of up to 10.5 ml/kg for a donor weighing the minimum 50 kg. These limits were endorsed by speakers and participants at a workshop on Blood Donor Suitability sponsored by FDA in 1999 after substantial discussion about estimated blood volume, its relationship to volume of a unit of blood and the risk of syncopal reactions. Eder et al. (2009) (Appendix 1) surveyed donor screening practices in the United States, Canada, Australia, the United Kingdom, and France, and summarized existing literature on what is known about donor deferral criteria based on history and certain physical characteristics. Based on this review, Eder commented that the published data provide 6

7 little guidance in setting a safe lower weight limit, minimum age limit, or acceptable blood volume for donors. In a 2005 editorial Gillespie noted that for more than 40 years, there has been a paucity of studies about blood donors and the blood donation decision and that AABB and its scientific funding arm, the National Blood Foundation, had categorized work involving blood donation as administrative rather than scientific (Gillespie 2005). In a 2008 review article Boulton et al. also noted the paucity of data on donors, the decision to donate, the donation procedure and its outcomes; and recommended that more study was needed. The paucity of data with regard to blood donors, their decision to donate, and assessments of health as they relate to the donation procedure hinders evidence-based decisionmaking about both currently employed and proposed assessments of donor health. To date in the United States, there has been no comprehensive data collection system for reporting of adverse blood donor reactions. The need for national standards for donor and recipient adverse event reporting has been recognized. Internationally, in 2004, the International Society of Blood Transfusion (ISBT) and the European Hemovigilance Network (EHN) established a Common Working Group on complications Related to Blood Donation. This group has worked to establish standard definitions of adverse events, including severity and imputability grades, to facilitate international benchmarking. Based in part on this work, AABB and the Department of Health & Human Services (DHHS) have been developing a component of the Biovigilance effort related to donor safety ( etwork/). Simultaneously, FDA has worked on revising its regulations on Safety Reporting Requirements for Serious Adverse Events including adding rules to capture donor safety events ( Information from these sources would be helpful in establishing recommendations/ mandates for donor eligibility determination. Another consideration relates to action in the face of uncertainty. In the case of the various elements of the physical examination for volunteer blood donors, as noted above, scientific data are limited and there is no consensus among governmental regulators, medical experts or industry about appropriate standards for blood pressure or pulse. Some would argue that donation blood pressure or pulse requirements should remain unless there is convincing evidence that removing these requirements will do no harm to blood donors. Others may argue that the risk to donors, if any, is minimal and unclear while such changes will help to significantly expand the nation s supply of blood and blood products. Independent of its value in the determination of donor eligibility, an issue also arises whether taking blood pressure and pulse on donors is important as a public health measure. Davey reported on his experience in using the blood center as a community health resource (2006). He noted the number of donor encounters per day and that the 7

8 required screening procedures, even if not predictive of outcome for donation, might be used to generate valuable health information for the donor. Blood pressure might be considered to fall into the category of useful health information irrespective of its predictive capability for post-donation adverse events. Of 5432 donors evaluated, 374 (6.9%) were found to have at least stage 1 hypertension ( /90-99). Of these, 105 were found to have stage 2 hypertension ( 160/ 100 mm Hg). All were given health information and the option for referral to a clinical. 316 of the affected donors were contacted, of whom 85 (27%) responded. Fifty-three responded that they had seen their own personal physician and 12 more indicated that they would do so within the next 2 months. Two donors arranged clinical visits. Based on this information, NY Blood Center has implemented hypertension education and counseling as part of its program for all blood donors. Outcomes from the donation procedure were not reported. B. Risk Factors for Adverse Events in Blood Donors Certain limited physical measurements are performed on the day of donation to assess donor health as it relates to donation and to ensure that the donation process does not pose undue risk to the donor. In order to frame the issue of the need for blood pressure and pulse determination prior to blood donation and for ranges for systolic and diastolic blood pressure and for pulse, it is important to evaluate: the types of adverse events that occur among blood donors, whether whole blood or apheresis donors; what is known about the causes of adverse events among blood donors; and donor eligibility criteria as they relate to assessing and maintaining donor health, and preventing injury to the donor. Types of adverse events: Blood donation is extremely safe (9.5 million individuals donate each year). Over the years, however, there have been a number of publications about adverse events in blood donors. By regulation (21 CFR ), only fatalities associated with the collection or administration of blood are reported to FDA; donor fatalities have been reported. Information about less severe donor reactions is more limited. A review of adverse reactions associated with whole blood donation and plasmapheresis was published by Grindon (1982). Reported donor adverse reaction types and categories included allergic reactions, reactions related to apheresis procedures, local injury related to needle use, prefaint and faint reactions classified as vasovagal reactions, and other (such as cardiac and CNS). Among apheresis donors, adverse reactions include hematoma formation, citrate toxicity, vasovagal reactions, syncope, and hypotension. Severe adverse events in all donors include arterial puncture, loss of consciousness for a minute or more and loss of consciousness with injury. Causes: The term neurocardiogenic syncope has been applied to both vasovagal and vasodepressor syncope. Recently it has been hypothesized that some donor reactions, previously categorized as probably vasovagal, might instead be due to intolerance to orthostatic stress. It has come to be appreciated that the mechanisms underlying early and 8

9 late presyncopal and syncopal reactions might differ, meaning that different predonation assessments and different interventions might be needed to prevent these reactions or to mitigate them if they do occur. Donor eligibility criteria: Physical examination: In general, assessments of health in the medical setting require integration of medical history, physical examination, and the results of routine laboratory tests and other diagnostic procedures. Accurate assessment of blood pressure requires trained personnel performing the procedure using correct techniques including proper cuff selection and patient/donor positioning. Obtained properly, there are three measures of blood pressure that might contribute to the adverse effects of hypertension. These include the average blood pressure level, the diurnal variation, and short-term variability. It is believed that the measure most closely related to long-term adverse events is the average blood pressure level, although accumulating data suggest that people whose pressures remain high at night are also at greater risk for cardiovascular events than those whose blood pressure drops at night (Pickering et al., 2005; Chobanian et al., 2003). It is not clear whether blood pressure and pulse alone can discriminate whether a donor of allogeneic whole blood or apheresis products is/is not healthy enough to donate on any particular day. Further, blood pressure readings in the acute setting may not be representative of readings taken outside that setting. Whether donation of blood reduces the risk of myocardial infarction among those at risk is not known. It is generally agreed that adverse events or deferral discourage donors from future donations, resulting in a loss to the donor pool (Custer et. al. 2009). France et al. (2005) reported for a single center that moderate and severe vasovagal reactions reduced the likelihood of repeat donation by as much as 50% and that less severe adverse events reduced return rates by as much as 20% for first-time donors and 33% for experienced donors. Among randomly selected donors, experiencing a vasovagal reaction reduced return rates from 59% to 47% (Newman et al. 2004). It is also generally agreed that there is a higher rate of adverse events in young donors. Among teenage donors, experiencing a vasovagal reaction reduced the repeat donation rate from 47% to 33% (Gorlin and Petersen 2004). Assessments that help distinguish between donors who experience adverse events and those who do not would permit collection facilities to focus more attention on donors at higher risk and remove barriers to donation. A report by Eder et al. (2008) documenting efforts by the American Red Cross (ARC) to track all complications of blood donation reported during 2006 highlights some of the difficulties in assessing the contribution of the various identified potential risk factors, particularly to the occurrence of vasovagal and syncopal events. Eder noted regional center variation in addition to donor age, gender, and donation status as an independent risk factor for adverse events, but identified imprecise coding of adverse events and overlapping definitions of donor complications as limitations of hemovigilance efforts. Eder et al. reported that excluding large hematomas, adverse reactions occurred at a rate of 7.4, 5.2, and 3.3 per 10,000 collections for whole blood, apheresis platelet, and automated red cell collections, and the need for donors to seek outside medical care was recorded at a similar rate for both whole blood and automated procedures (3.2 and 2.9 per 9

10 10,000 donations respectively). Forty-six percent of all reactions associated with seeking further medical care were accounted for by major syncopal-type reactions (long loss of consciousness, loss of consciousness or presyncope with injury, and prolonged recovery). The number of donation events that led to hospitalization was not noted, and reasons for 54% of cases in which outside care was obtained after donation also were not recorded. Some caveats about the literature should be noted. First, most of the studies were performed at a time when AABB had in place its previous standard for blood pressure. With the exception of the study by Tomasulo et al. (1980), no information about donors with blood pressure outside the previously applied AABB ranges are available. Second, data on adverse events from foreign sources where blood pressure is not routinely measured are not available from the literature. For whole blood collections, these data would also be confounded by differences in volume of whole blood removed during each donation cycle. It has been suggested that vasovagal reactions occur less frequently among apheresis donors than among whole blood donors, and it has been hypothesized that hemodynamic shifts may be more moderate due to concomitant fluid replacement and the slower donation process. Hypotension during apheresis procedures may be related to intravascular volume depletion, vasovagal reactions, citrate reactions, allergic reactions, and air embolism, and may be multifactorial. As with the literature on whole blood donation, disparate results have been reported for apheresis procedures. 1. Risk Factors for Vasovagal Reactions Vasovagal reactions are the most commonly reported adverse events in blood donors and have been reported to occur in 2-5% of blood donations, with syncope occurring in % of blood donors. Tetany or seizure activity has been reported to occur in 25% of syncopal reactions. The pathophysiology and mechanism of vasovagal reactions and the transition from presyncope to syncope are incompletely understood. Mechanistically, vasovagal syncope is thought to occur in two phases: 1) presyncopal, with an increase in cardiac output and peripheral vascular resistance with increased blood pressure in response to stress and blood loss, and 2) syncopal, characterized by a sudden decrease in peripheral vascular sympathetic activity resulting in peripheral vascular dilatation, blood pooling, and hypotension. In addition, increased cardiac parasympathetic activity results in bradycardia. Syncope results when brain perfusion is reduced. Vasovagal syncope is thought to depend on the donor s peripheral baroreceptor sensitivity which, in turn, is influenced by age, gender, race/ethnicity, emotional stress, and the presence of hypertension. The magnitude of the baroreceptor response is directly related to the volume of blood that is removed. Over the years, this uncertainty about the pathophysiology and mechanism of vasovagal reactions has led to different conclusions about who is at risk for such events. Since the s it has generally but not universally been thought that adverse reactions are more likely to occur among young, female, first-time, low-weight donors, and among those with a prior history of fainting or a history of nervousness. 10

11 Occupation, hunger, fatigue, degree of anemia, rate of blood withdrawal, and environmental conditions at the collection facility have generally not been found to be risk factors. The roles of low pre-donation blood pressure and pre-donation tachycardia have been controversial. In a number of reviews of mass donation campaigns during World War II, early researchers hypothesized that youth, weight less than 110 lbs, and relative hypotension before donation were the best predictors of adverse cardiovascular effects of donation. Boynton and Taylor (1945) noted that fainting appeared to be a multifactorial process. More recently, a number of analyses have been performed in an attempt to identify better those most at risk of vasovagal reactions and syncope, and those biometric and psychological characteristics most predictive of adverse reactions. As noted, these various efforts have yielded sometimes contradictory data regarding physical or psychological factors thought to be predictive of adverse donor reactions. The following factors have been considered to be correlated with vasovagal reactions: a. Donation status- first time vs. repeat b. Age of donor c. Gender d. Volume of blood removed e. Pulse and blood pressure f. Psychological profile g. Environment a. Donation Status- first time vs. repeat In virtually all studies in which this variable was assessed, donation status has been found to be a strong independent predictor of vasovagal reactions among whole blood donors (Boynton and Taylor (1945; Ogata et al. (1980); Tomasulo et al. (1980); Kasprisin et al. (1992); Eder et al. (2008b, 2009); Trouern-Trend, et al.( 1999); Wiltbank, et al.( 2008); Newman, B. (2002); Newman, B. et al.( 2003); Rios, et al. (2008), although this finding is not universal (Graham 1961)). First-time donors are more likely to experience adverse reactions, particularly vasovagal and syncopal reactions, to blood donation than more experienced donors. Vasovagal reactions are generally reported to occur less frequently among apheresis donors, possibly because collection times are longer to allow for better control of fluid balance (McLeod et al. (1998); Despotis et al. (1999); Wiltbank, (2002); Yuan et al. (2008)), and most adverse events associated with apheresis procedures relate to local effects from the venipuncture or to the effects of citrate anticoagulation rather than to vasovagal responses (McLeod et al. (1998), Despotis et al. (1999)). For red blood cell apheresis, the administration of saline may help mitigate procedure-related adverse events. Nevertheless, the finding regarding vasovagal reaction rate is not universal. Tomita et al. (2002), for example, reported a higher (2-3x) rate of adverse reactions to donations among female apheresis donors than among female whole blood donors. The relationship of donation status to vasovagal events is less clear for apheresis donors than for whole blood donors, possibly because apheresis donors are identified from the 11

12 population of experienced whole blood donors. However, some authors have noted that first-time apheresis donors are more likely to experience a vasovagal reaction than experienced apheresis donors in a pattern similar to that found for whole blood donors (McLeod et al. (1998), Despotis et al. (1999). Tomita et al. (2002), however, reported a higher rate of vasovagal reactions with repeated cycles of apheresis among older female donors. b. Age of Donor Younger donors are more likely to experience vasovagal symptoms and fainting than older donors, and age is a strong, independent, inverse predictor of risk of vasovagal reaction after whole blood donation, even after controlling for other factors such as weight or blood volume. The relationship between age and risk of reaction to donation has been recognized since the 1940s and is well described in the literature ((Poles, et al. (1942); Greenbury (1942); Boynton and Taylor (1945), Graham (1961), Callahan et al. (1963), Tomasulo et al. (1980), Kasprisin et al. (1992), Trouen-Trend, et al. (1999), Wiltbank et al. (2008), Newman, et al. (2001), Newman, B. (2003), Newman and Roth (2005); Rios et al.( 2008); Newman B. et al. (2008; Eder A., et al. (2008b, 2009)). As reported by Eder et al., international deferral policies based on age for whole blood donors vary considerably; in the United States, there are no age requirements for donation specified either in regulation or in guidance, and state laws vary in their requirements for parental consent for teen-age donors under 18 years of age (15-18 year-olds). Nevertheless, regardless of age specification, the youngest individuals accepted as donors in a collection facility are at the greatest risk of reactions related to the donation process. For apheresis donors, the relationship between age and reaction rate is less clear. Tomita et al. (2002) reported fewer vasovagal reactions with increasing age among male donors but a more complicated relationship between age and reaction rates for female donors. Among female apheresis donors, the incidence of vasovagal reactions was lowest among women years old and higher for younger women, and for older women following repeated apheresis cycles. No explanation for this finding was provided. Reiss et al. (2009) reported that among platelet apheresis donors, there was little correlation between age and incidence of reactions for either males or females, but that among male double red cell collection donors, there was a statistically insignificant trend toward increasing adverse reaction rate for younger donors. c. Gender Since the 1940s, many researchers have related gender to adverse blood donation reaction rates ((Poles et al. (1942); Greenbury (1942); Boynton and Taylor (1945; Tomasulo et al. (1980); Wiltbank et al. (2008); Newman et al. (2001); Newman et al. (2006); Newman et al. (2003); Kamel et al. (2008); Rios et al. (2008); Newman et al. (2008); Eder et al. (2008b);. Newman et al. ((2001, 2006, 2008)) found that within 20 lb weight categories, females had higher reaction rates than males, in all weight categories. Many other authors, however, have failed to confirm the relationship ((Graham (1961); Ogata et al. (1980); Kaspirsin et al. (1992);, Trouen-Trend et al. (1999)). The relationship 12

13 between gender and donor reaction rates is confounded by the influence of donor weight (body mass index) and blood volume. Among apheresis donors, Despotis et al (1999) noted the independent contribution of gender to the development of adverse events in a multivariate analysis performed to identify risk factors. Tomita et al. ( 2002) also reported that female donors in general, including apheresis donors, experienced more vasovagal events than male donors, and that female apheresis donors experienced 2-3 times more vasovagal events than did female whole blood donors, a finding they did not explain. d. Donor weight and volume of blood removed Higher reaction rates found among female donors are confounded by the influence of donor weight and blood volume. In recent studies, researchers have attempted to elucidate further the independent roles of gender, body mass index, and blood volume on the risk of adverse reactions to whole blood donation. Tomasulo et al. (1980) showed that: a) donor weight played a role in reaction rates for first time female donors but not for experienced female donors; b) percent blood volume removed from female donors was higher than for male donors; and c) more blood volume was removed from female reactors than from female non-reactors (statistically significant). For male donors, however, except for a few donors who reacted early during the course of the phlebotomy, the volume of blood removed was equivalent between male reactors and non-reactors. Other authors have also found that weight (or in some instances, body mass index) is an independent predictor of increased reaction rates ((Trouen-Trend et al. (1999);, Wiltbank et al. (2008); Newman, B., (2002, 2003); Newman and Roth, (2005), Kamel et al. (2008), Rios et al. (2008)). However, Rios et al. (2008) also found that after controlling for age, gender, race/ethnicity, and donation status, body mass index, while a significant predictor of vasovagal reactions, was not as strong a predictor as age, gender, and donation status. As noted, collection practices, including the definition and volume of a unit of blood have not been standardized worldwide. Although current eligibility requirements in the United States include a minimum weight of 50 kg (110 lbs) to ensure that collection of 525 ml translates to an estimated maximum 10.5 ml/kg or 15% blood volume, findings from a number of studies highlight the difficulty in estimating blood volume in an individual donor using standard formulas that relate volume to height and weight. Thus, Wiltbank et al. (2008) found that donors with estimated blood volume <4,000 ml were much more likely to experience an adverse reaction when compared with donors with estimated blood volume >4,500 ml. These authors found that 5% of donors in the study had blood volume <3,500 ml (calculated from self-reported height and weight using standard gender-specific formulas from Nadler et al. (1962) despite meeting donor eligibility criteria for weight. Newman et al. (2006) found by modeling using logistic regression from observed reaction rates that an increase in volume of a whole blood unit from 450 to 525 ml would likely increase reaction rates by a relative 18% in both male and female donors and that conversely, a reduction in the volume of a unit of whole blood from 500 ml to 400mL would likely decrease donor reaction rates by 29% and 27% for female and male donors, respectively. 13

14 Rios et al. (2009) reported research into the role of estimated blood volume in the occurrence of adverse reactions to donation. Blood volume was estimated from selfreported height and weight using a formula published by Nadler et al. (see above). Donor reactions were classified as prefaint without injury or faint. Faint reactions were further classified as short loss of consciousness, long loss of consciousness ( 60 seconds), reactions with injury, and reactions with prolonged recovery ( 30 minutes). Data from were analyzed according to gender. Nine percent of female donors had an estimated blood volume < 3.5 L. 16% of female donors experiencing prefaint reactions and 19% of female donors experiencing faint reactions had estimated blood volume < 3.5L. Almost none of the male donors had estimated blood volume <3.5L and almost 66% had estimated blood volume >5.0L. The authors concluded that avoiding whole blood donation from donors with estimated blood volume <3.5L might reduce the incidence of prefaint and faint reactions in females, but would not prevent these adverse reactions among male donors. Hypotension during apheresis procedures may be related to intravascular volume depletion, vasovagal reactions, citrate reactions, allergic reactions, and air embolism, and may be multifactorial. It has been suggested that vasovagal reactions occur less frequently among apheresis donors than among whole blood donors, and it has been hypothesized that hemodynamic shifts may be more moderate due to concomitant fluid replacement and the slower donation process. As with the literature on whole blood donation, disparate results have been reported for apheresis procedures. e. Blood pressure and pulse Currently acceptable ranges for blood pressure among donors in the United States and other countries include readings that would otherwise be classified as Stage I or Stage II hypertension ( /90-99 mm Hg and 160/100 mm Hg respectively) or hypotension. The relationship between high or low blood pressure and risk for adverse events has been evaluated since the 1930s. Early studies provided conflicting data about the relationship of low blood pressure, particularly low diastolic blood pressure to the rate of vasovagal reactions during or following donation. Thus, Poles et al. (1942) reported no relationship between low initial blood pressure and fainting, while Boynton and Taylor (1945) noted that although pre-donation pulse appeared to correlate poorly with the risk of vasovagal reaction, low pre-donation blood pressure did appear to correlate. Callahan et al. (1963) suggested that donors who reacted tended to have a higher pulse rate and pulse pressure together with a lower diastolic blood pressure before donation. More recently, Ogata et al. (1980) have reported that while reaction rates did not differ between men and women, there was a statistically significant relationship between lower diastolic blood pressure and the incidence of vasovagal reactions. Tomasulo et al. (1980) reported the results of a prospective evaluation of criteria for blood donor deferral at a single blood center. When considering factors thought to be associated with high risk for reaction, reaction rates in donors with low blood pressure, systolic blood pressure between 180 and 200 mm Hg, bradycardia (heart rate < 50 bpm), or hunger were found to be slightly higher than in the 14

15 overall donor population but were less than for female first-time donors less than 30 years of age and in individuals weighing between lbs. In recent studies, researchers have evaluated the independent associations between predonation blood pressure (systolic or diastolic) and/or pulse, and vasovagal reactions. Wiltbank et al. (2008) found that although pre-donation blood pressure was an important variable in univariate analysis, this relationship was not maintained in a multivariate analysis with adjustment of the Odds Ratio for covariates of age, gender, donation history, race/ethnicity, estimated blood volume, pulse, systolic blood pressure, and blood center. These authors did not report on whether there was a statistical association between blood pressure and vasovagal reactions for young females in particular. Systolic blood pressure over 140 mm Hg and pulse < 65 appeared to be protective while pulse >90 bpm appeared to be associated with higher risk of reaction. Trouen-Trend et al (1999) also found that after adjustment for other variables by regression analysis, predonation blood pressure and pre-donation pulse were not significant independent predictors for reactions but that systolic blood pressure > 150 mm Hg appeared to be protective. ARC researchers have also evaluated the contribution of blood pressure and pulse to risk of adverse reactions to donation. Eder et al. (2009) reported that prior to 2004, ARC had not defined an acceptable lower limit for blood pressure to qualify donors. An unpublished multivariate analysis of 1,778 adverse reactions from 8 ARC regions after 72,059 whole blood donations showed that there was no statistical association between adverse events and systolic or diastolic blood pressure. Newman et al. (2008) reported the analysis of retrospective data collected for a previous study. Among 72, 171 whole blood collections (450 ±50 ml), these authors noted that systolic and diastolic blood pressure and type of collection site (fixed vs. mobile) were not significant contributors to adverse reactions among donors. At the time of the collection of these data in 1999, ARC used 110 bpm as the upper limit for pulse. ARC noted a statistically significant but relatively small difference in reaction rates for donors with pulse of 100 bpm or less when compared with donors with pulse bpm. Re-analysis of these data for the abstract demonstrated that the contribution of pulse to overall risk of reactions was small, but the actual results were not presented. Kamel et al. (2008) reported in a retrospective review of 2,994 moderate to severe reactions occurring after completion of the donation procedure, that 77.3% of reactions occurred immediately ( 15 minutes after needle removal) and 22.7% were delayed (> 15 minutes after needle removal). Two percent of immediate reactions and 32% of delayed reactions occurred off-site. These authors noted that delayed reactions were significantly more likely to occur in females, donors with lower blood volume, donors with predonation pulse >90 bpm, and after whole blood collection; and suggested that additional analyses, including multivariate analyses, were needed to control for potential confounding. Hanson et al. (2004), performed a single center, randomized controlled study 15

16 powered to detect differences in Blood Donation Reactions Inventory after 500 ml water loading or no water-loading 30 minutes before donation. Among 83 novice blood donors (43 male and 40 female), he found that water loading resulted in fewer donation-related symptoms and that males and females had similar effects. There was no significant difference in total number of phlebotomist interventions between groups. A hierarchical regression analysis confirmed that acute water ingestion was associated with significantly lower scores on the donation inventory, but predonation total body water was not predictive of reactions. Alaman et al. ( 2009) reported that vasovagal reactions among 16-year old donors were reduced when donation was accompanied by consumption of a 12 oz bottle of water 0-15 minutes before phlebotomy and a nutrition bar following donation if the donor had not eaten within 2 hours prior to donation. f. Psychological profile and environment In addition to biophysical predictors of vasovagal syncope, a number of authors have highlighted the role that psychosocial characteristics play in affecting the incidence of vasovagal events in volunteer blood donors. As with analyses based on donor biophysical characteristics, findings for psychological predictors may also be contradictory. Brown and McCormack (1942) reported that blood donors who experienced vasovagal symptoms often had a prior history of fainting, either with or independent of phlebotomy, and that both high blood pressure and high pulse rate were often seen in the predonation period among donors who fainted. They related these characteristics to nervousness on the part of the donor. Kaloupek et al. (1985) evaluated characteristics associated with vasovagal reactions in donors. They sought to assess the potential roles of physical and health variables (food intake, body weight, chronic or acute medical conditions) and coping strategies that might be related to the second phase of vasovagal reactions (bradycardia and hypotension). These studies generally confirmed that donors who experienced reactions had given fewer prior donations and were more likely to have a prior history of syncope. Coping mechanisms such as suppression (which has been associated with decrease in heart rate) and rational cognition (not thinking about the situation or imagining oneself elsewhere, and attempts at self relaxation) were higher in the group that reacted to donation than in the group that did not, and inexperienced donors resorted to ineffective coping strategies more often than did experienced donors. In these studies, physical characteristics of age, time since last meal, and acute and chronic physical conditions did not correlate with incidence of vasovagal reactions. Meade et al. (1996) highlighted that one significant limitation of prior studies of adverse reactions in donors was that syncope was evaluated as a dichotomous event (fainting present or absent) and that less extreme reactions had not been captured adequately. They further noted that although anticipatory anxiety had been identified as a predictor of 16

17 donor outcome and that findings from a number of studies had suggested that existing psychological measures of anxiety might be useful in predicting donors at risk of vasovagal reactions, little attention had been paid to evaluating the relative importance of psychosocial as opposed to biophysical predictors to syncopal reactions. Using a prospective design to assess psychological measures of blood and injury fear, pain sensitivity, and anxiety in volunteer blood donors, Meade found that among 215 collegeage donors, the Blood and Injury Fears Subscale of the Fear Survey Schedule best predicted reactions among first-time donors. Among experienced donors, the Mutilation Questionnaire was the best predictor. Symptoms of reactions were captured in a Blood Donation Reactions Inventory (France et. al. 2008) that required respondents to rate 11 subjective physiological reactions including fainting, dizziness, weakness, facial flushing, visual disturbances, difficulty hearing, lightheadedness, rapid or pounding heartbeat, sweating, rapid or difficult breathing, and nausea. Each reaction was rated on a scale of 0 (none) to 5 (most), and a total score was derived by summing all individual scores. This scoring system had been found to have both a high level of internal consistency and significant correlation with the phlebotomist rating of donor reactions. Another finding of this study was that it failed to confirm a relationship between donor characteristics of age, body mass index, donation status, or caffeine intake and subsequent reactions. The authors hypothesized that this discrepancy might be attributed to the small sample size and to the relatively homogeneous donor population studied. The authors concluded that use of the scales might prove useful in identifying donors most at risk of adverse reactions to donation. Ditto and France (2006) reported their findings from a study of 671 inexperienced blood donors participating in a trial to assess the effects of applied muscle tension on blood donation-related symptoms. In a prior publication, the authors had demonstrated that for each point increase in the Blood Donation Reactions Inventory (see above), there was a 4% reduction in the donor s likelihood to donate blood again within one year. In this publication, there was a linear relationship between predonation anxiety as measured on the Spielberger State Anxiety Scale and scores on the Blood Donation Reactions Inventory, and a positive relationship to frequency of chair reclining by the nurse responding to donor symptoms. Anxious inexperienced female donors were more likely to experience donation-related symptoms and were less likely to return to donate subsequently, independent of age or body mass index. The authors noted that while the results show a correlation among predonation anxiety, donation-related events short of syncope, and subsequent likelihood of donation, they do not prove that predonation anxiety is causally related to adverse symptoms, and they do not imply that strategies aimed at reducing predonation anxiety will result in fewer symptoms. Sauer and France (1999), in a randomized, double-blind study of 62 female undergraduate first-time donors, documented that administration of 250 mg caffeine resulted in lower scores on the Blood Donation Reactions Inventory and fewer phlebotomist interventions to counter adverse reactions. The authors suggested that administration of a moderate dose of caffeine to first-time female donors might increase the likelihood of repeat donations. 17

18 2. Risk Factors for Cardiovascular Adverse Events High blood pressure is a risk factor for cardiovascular disease (CVD). High blood pressure increases the risk of myocardial infarction, heart failure, stroke, and renal disease. High blood pressure can be modified by behavior or medication. Favorable blood pressure levels are associated with a greater probability of survival to age 85 as well as increased longevity without major co-morbidities. Based on Centers for Disease Control and Prevention surveys in , 29% of all U.S. adults 18 years of age were hypertensive (systolic BP 140 mm Hg or diastolic BP 90 mm Hg or taking medications for hypertension). The prevalence of hypertension was nearly equal between men and women. Seven percent of the total U.S. adult population had a systolic BP 140 mm Hg or diastolic BP 90 mm Hg, but had never been told by a health care provider that they were hypertensive. Among hypertensive adults, 78% were aware of their condition. Overall, 68% of adults with hypertension were using anti-hypertensive medication. Over 64% of adults who were taking antihypertensive medication achieved BP less than 140/90 mm Hg (Ostchega et. al. 2008). Bravo et al. (2009) reported on the prevalence of selected markers of cardiovascular risk among blood donors from four generations (Y [ ], X [ ], baby boomers [ ], and veterans [ ]) who donated blood during a 21 month period. Data were extracted from donor records. High cholesterol levels and obesity were more prevalent among baby boomers and generation X than the other two groups. Hypertension increased with increasing age, with approximately 40% of all groups in the range of prehypertension, 7.6%-22.4% with stage 1 hypertension, and % with stage 2 hypertension. The literature regarding adverse outcomes for hypertensive blood donors is sparse. Pisciotto et al. (1982) reported the results of a study of adverse events in donors taking antihypertensive agents other than beta blocking agents. These authors sought to assess whether such donors were at increased risk of vasovagal reactions during or following donation. Among 16,424 donors observed over a 3-month period, 546 experienced a vasovagal reaction. As reported in other studies, first-time donors had a higher rate of reaction than repeat donors (9.1% vs 2.4%, p<0.001). Eighty-five percent of all donors were experienced donors. Two hundred twelve donors were on chronic antihypertensive medications, of whom 96% were repeat donors. Only 8 donors taking antihypertensive medication were first-time donors. The reaction rate in repeat donors was not significantly different between those on antihypertensive medications and those not being treated (1.5% vs 2.4% respectively, NS). Popovsky et al. (1995) evaluated severe outcomes of allogeneic and autologous blood donation during the period of July 1993 to March Very severe complications of donation were defined as donation-related incidents for which the donor was hospitalized. This study was undertaken because the incidence of events such as tetany, seizures, arterial puncture, myocardial infarction, and death, although reported, was not known. Popovsky et. al. recorded a total of 33 very serious outcomes among 4.1 million donations. The incidence was % (20 events in 3.89 million donations) in 18

19 allogeneic donors, and 0.006% (13 in 218,190 donations) among autologous donors, a rate that was more than 12 times that for allogeneic blood donors and probably related to underlying pathologic conditions such as cardiac, vascular, and respiratory disease among autologous blood donors. First time donors were three times more likely to experience a very serious outcome. Donors > 40 years old experienced approximately 88% of the reactions, and donors >60 years old had 48.5% of the very serious reactions. The most frequent complications were vasovagal (66.7%, 22/33) and anginal (12.1%, 4/33). 66.7% of the very severe reactions occurred at the blood collection site. The mean hospital stay was 1.9 days. Whether these results are due to bias by blood center personnel related to donor age could not be determined by the authors. Blood pressures were not recorded. Despite the higher incidence of cardiovascular and other co-morbidities with increasing age, other reports, however, have not documented increased risk of donation among older donors. Pindyck et al. (1987) found that moderate and severe reactions occurred among elderly donors at approximately the same rate as for donors less than 50 years old. In fact, the highest rates of severe reactions consisting of seizures, incontinence, chest pain, cyanosis, and cardiac arrest, occurred among donors less than 25 years old. Simon et al. (1991) made similar observations. In a randomized study of 244 healthy elderly donors randomized to donation or no donation, only 2 persons were disqualified for conditions not detected by the usual blood center screening protocols. Although this group of donors reported more co-morbid conditions and current medications, Simon noted only 10 moderate reactions consisting of vasomotor symptoms that persisted for more than 30 minutes. There were no serious reactions after 900 donations among donors >65 years of age. Blood pressures among older donors in general, and in donors experiencing adverse events were not reported. C. Current Research and Future Directions Research is ongoing to evaluate the impact of enhanced donor education on willingness to donate and on adverse reactions to donation. Kowalsky et al. (2009) reported in an abstract that donors randomized to read a new donor brochure that addresses common donor concerns and suggests specific coping strategies, or a standard blood collection brochure were less likely to exhibit anxiety and had more positive attitudes toward donation than were donors randomized to read a brochure on healthy eating and exercise. These authors reported that readers of the new brochure were more willing to sign up to donate and had a higher proportion of appointments made than were readers of the two other types of brochure. Shaz et al. (2009) reported in an abstract on efforts to enhance educational outreach to members of minority churches who may lack trust in the healthcare system. Steele et al. (2009) reported that among minorities in particular, fear of contracting HIV still remains a significant barrier to donating. The authors suggested that enhanced outreach and education regarding the donation process and adverse reactions might help in recruitment efforts. Sinclair et al. (2009) examined use of a postdonation motivational interview on post-donation attitudes and actual repeat donation behavior. They found that novice and repeat donors who were followed up with a postdonation adapted motivational interview had more positive attitudes toward subsequent 19

20 donation and that among novice donors, there was a significantly higher rate of subsequent donation within one year. As noted above, it has come to be appreciated that some donor reactions previously categorized as probably vasovagal might instead be due to intolerance to orthostatic stress. Research is ongoing regarding validation of prognostic scores for immediate and delayed adverse reactions in whole blood donors. James et al. (2009a, 2009b) reported the development and validation of prognostic scores for immediate adverse events (generally vasovagal) and delayed adverse events. Immediate adverse events were defined as syncope or other serious events that occur within 15 minutes of needle removal, while delayed events were defined as those events occurring more than 15 minutes after needle removal. Among 546,937 whole blood donations, there were 2,113 immediate adverse events noted, 1,049 among 274,123 donations in the training portion, and 1,064 events among 272,814 in the validation portion. Statistically significant variables in the logistic regression model included donation status, age, race, estimated blood volume, location of the clinic, and pulse group (not defined in the abstract). Parameter estimates were translated into integer scores and tested in the validation subset. Increasing scores were associated with increasing rate of adverse donation reactions. Receiver-operator characteristics of the validation set were reported to have an areaunder the curve of 0.79 (95% CI ) suggesting that the score was an improvement over chance alone. For delayed reactions, the same authors reported that there were 705 delayed reactions overall, 364/273,404 observations for the training dataset, and 341/272,175 observations in the validation dataset. Significant covariates in the logistic regression model of the training dataset included donation experience, age group, race, estimated blood volume, location of clinic, pulse group, and female gender. Increasing integer scores were associated with increasing rates of reactions. The receiveroperator estimate of the area under the curve was 0.79 (95% CI ). On September 15, 2009, at a Symposium on the State of the Science sponsored by the National Heart, Lung and Blood Institute (NHLBI), ARC presented proposals for two studies, the first intended to evaluate the effect of reducing the volume of whole blood collected from young donors on the incidence and severity of donor reactions and the second intended to evaluate the effect of enhanced pre-donation education on donor recruitment and retention (State of Science Symposium 2009). ARC estimates that approximately 10% of donor reactions occur during the phlebotomy itself, 25% occur within 15 minutes after needle removal, and almost all occur within two hours of needle removal. Despite mathematical modeling to suggest that reducing the volume of whole blood collected might reduce the incidence of vasovagal reactions (see Newman et al., 2006), particularly among young, first-time donors, ARC noted that the benefit of reducing the volume is not known and cannot be determined easily from currently available hemovigilance data. The primary hypothesis of this study is that reduced volume (460 ml) from young donors will reduce the incidence of vasovagal reactions (prefaint) relative to conventional 525 ml collection by more than 20%. The proposed primary outcome measure is the rate of self-reported donor adverse experiences within 7 days 20