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Why do young women (donors) faint?_2593 522..525

In humans, tolerance to orthostasis requires the suc-cessful integration of multiple elements of cardio-vascular control. Syncope or near-syncope mayoccur when there is an abnormally large postural

decrease in central blood volume, cardiac filling pressure,stroke volume, and cardiac output or inadequate (or inap-propriate) neurohumoral reflex responses to orthostasis,primarily tachycardia and vasoconstriction.1

Young women are more susceptible to orthostaticintolerance compared to similarly aged men; this sex dif-ference is especially dramatic under hypovolemic condi-tions when circulating blood volume is reduced. Forexample, postflight syncope or near-syncope is greatest inwomen astronauts,2,3 and orthostatic tolerance decreasesare greater in women than men after a period of head-down bed rest (i.e., simulated microgravity exposure)4 orafter acute dehydration.5 Additionally, postural orthostatictachycardia syndrome (also called chronic orthostaticintolerance, in which patients are unable to stand orremain upright for prolonged periods of time due to intol-erable light-headedness, weakness, and near-syncope)affects primarily young women,6 with perturbed bloodvolume regulation and reduced plasma volume in many ofthese patients.7

Circulating blood volume has a profound effect onarterial pressure during orthostasis in humans.8,9 Indi-viduals with reduced vascular volumes exhibit subnormalcardiac filling pressure and the capacity to buffer orthos-tatic reductions in central blood volume is limited.8 In thisissue of TRANSFUSION, Kamel and coworkers10 providestrong evidence of orthostatic intolerance in youngwomen after blood donation. In this large retrospectivestudy, the authors assessed 793,293 donors from 15 bloodcenters and identified risk factors for moderate or severeadverse reactions to blood donation. For the sake ofclarity, we will use the term “neurally mediated” ratherthan “vasovagal” to describe these reactions because therelative contribution of sympathetic withdrawal (leadingto vasodilation) and increased vagal tone (leading tobradycardia and reduced cardiac output) may be quitevariable among individuals who faint. They found that lowestimated blood volume, youth, and first-time donorstatus are major risk factors for both immediate anddelayed reactions, while female sex is a better predictor ofa delayed neurally mediated reaction.

What are the clinical implications of these findings?As the authors state, the identified characteristics may

shape policy and procedures intended to reduce the risksof adverse reactions to blood donation; understanding thephysiologic basis of delayed reactions may lead to thedevelopment of appropriate interventions to reduce theirlikelihood. The observations made by Kamel and cowork-ers10 are novel. However, the mechanisms underlying sexdifferences in orthostatic tolerance are not completelyunderstood. It is possible that certain sex-specific factorssuch as differences in some hormonal levels, which mayaffect the neurohumoral regulation of arterial pressure, orphysical characteristics such as a smaller and less disten-sible heart,11 may affect orthostatic blood pressurecontrol.

Sex differences in arterial pressure have been sug-gested to be associated with the sex hormones. Amongthese, estrogen is proposed to be responsible for the lowerblood pressure in premenopausal women. Meyer and col-leagues12 showed previously that estrogen replacementattenuated resistance artery adrenergic sensitivity viaendothelial vasodilators such as nitric oxide and prostag-landins in female rats. It was also found that estrogensupplementation selectively attenuated vasoconstrictorresponses in perimenopausal women.13 Conversely,recent data from healthy young women demonstratedthat the fluctuations of female sex hormones estrogen andprogesterone during the normal menstrual cycle did notalter arterial pressure and peripheral vasoconstriction inthe upright posture,14,15 suggesting that the relationshipbetween blood pressure and endogenous levels of sex hor-mones is complex and is probably affected by otherfactors.

Sympathetic neural control plays an important role inarterial pressure maintenance through peripheral vaso-constriction during orthostasis in humans.16,17 When thiscompensatory mechanism fails or is overwhelmed, bloodpressure will drop and syncope may occur.17 Sex differ-ences in orthostatic tolerance have been suggested tobe related to sympathetic neural control. One previousstudy with the microneurographic technique to directlymeasure intraneural efferent sympathetic nerve dis-charges demonstrated that healthy young men andwomen had comparable sympathetic neural responsesduring acute upright posture in normovolemic andhypovolemic conditions; in addition, vasoconstrictorresponses to tilting were similar between sexes under bothconditions.5 Recently, it was found that healthy youngmen and women had comparable sympathetic neural andvasoconstrictor responses during prolonged (i.e., 45 min)orthostasis.18 These results do not support the notion thatTRANSFUSION 2010;50:522-525.

522 TRANSFUSION Volume 50, March 2010

an impairment of sympathetic neural control contributesto the high prevalence of orthostatic intolerance in youngwomen. Orthostatic intolerance is the main circulatoryexpression of chronic failure of autonomic neural controlof cardiovascular and sympathetic responses, but can alsooccur without apparent autonomic dysfunction, forexample, in the setting of a decreased blood volume asoccurs with blood donation.19

Since the renin-angiotensin-aldosterone system is akey regulator of plasma volume, particularly in responseto sustained orthostasis and/or hypovolemia,20 it may bepossible that young women have less activation of thissystem in hypovolemic conditions than men. An earlierstudy by Vernikos and colleagues21 showed that youngwomen exhibited greater plasma renin activity and aldos-terone responses to standing before and larger aldoster-one responses to standing after 7 days of 6° head-downbed rest compared with their male counterparts; thesestudies suggest that activation of the renin-angiotensin-aldosterone system is actually greater, rather than smaller,in women than men in the face of “cardiovascular decon-ditioning” and hypovolemia.

Young women usually have lower systolic pressurebut similar diastolic pressure compared with youngmen,5,14 which is predominantly attributable to a smallerstroke volume.5,11 It has been found that cardiac sizeand/or mass is smaller in healthy young women thanmen even when normalized to body mass.22 A sex-specific smaller, and thus less distensible, left ventricle inwomen may result in a larger reduction in stroke volumefor a decrease in cardiac filling pressure as a function ofthe Frank-Starling mechanism, leading to an excessivereduction in stroke volume during orthostasis11 and ulti-mately causing intolerance. It is highly likely that thesmaller and less distensible heart in women increasestheir sensitivity to fluid shifts and/or a loss of bloodvolume.

Numerous studies have demonstrated one clear sex-specific hemodynamic difference during orthostasis,namely, stroke volume, is smaller in women comparedwith men. This sex difference can be exaggerated underhypovolemic conditions.5 Stroke volume is the key vari-able in the heart rate–stroke volume–total peripheralresistance (triple product of arterial pressure) relation thatis directly affected by gravity.23 Moreover, stroke volume isa direct, linear function of central blood volume and leftventricular end-diastolic volume.8 Results from our labo-ratory and others have provided strong evidence thatwomen and men have comparable vasoconstrictorresponses during orthostasis. Ultimately, orthostatichypotension and syncope occur more in women becausethis vasoconstrictor reserve can be overwhelmed byreduced stroke volume and impaired cardiac filling duringhypovolemic “shock.” The latter may also have con-tributed to reflex sympathetic withdrawal as the final

common pathway to neurally mediated syncope in manypatients.

In the study by Kamel and coworkers,10 women andmen donated their blood at the same “standard” amount(i.e., 525 mL). Therefore, the percentage of blood losswould have been greater in women than in men, sincewomen generally have a smaller blood volume. Indeed,this practice seems to us to be the most glaring problemand the one which places small people (who are moreoften women) at greatest risk for a delayed, hemodynami-cally mediated faint. One simple approach would be toreduce the amount of blood donated by small women.However this solution is practically quite difficult sinceblood collection sets come with fixed amounts of preser-vative and anticoagulants that must be precisely matchedto the donated volume. Even if the donations could be setto three different sizes: small, medium, or large, based onspecific estimated blood volume cut points, this proposalwould be preferable to the current “one size fits all”system, although we realize that there may be economic,procedural, and therapeutic hurdles.

Other approaches are possible that might mitigate therisk of a delayed reaction based on the informative workby Kamel and colleagues. For example, the finding thatfirst-time donors are most susceptible suggests that donoreducation may be beneficial. Development of printed,video, or electronic-based instructions that describe thesymptoms associated with cerebral hypoperfusion or aneurally mediated reaction could be provided to first-timedonors and perhaps repeat donors if they are smallwomen or have had a previous reaction. Given the factthat most of the delayed reactions occur in young donors,it might even be possible to link the education materials toa cell phone attachment or personal video/music player.Maneuvers such as leg crossing, squatting, or hand-gripexercise with a rubber ball could be demonstrated andchecked before leaving the area after blood donation toimprove orthostatic tolerance and to reduce adverse reac-tions in donors (see http://www.stars.org.uk/patient-info/treatment-options/managing-your-syncope fordetails).24 Other simple strategies like increasing dietarysalt and water intake and elevating the head of the bed atnight during sleep 1 to 2 weeks after donation to expandplasma volume and blood volume could be helpful. Itshould be emphasized that drinking before blood dona-tion, when neurohumoral volume regulatory mechanismsare operating to maintain the status quo,25 may not be ashelpful as salt and water consumption begun during thedonation and extended aggressively into the early recov-ery period. The practice of providing snacks that are pre-dominantly sweet and carbohydrate based shouldperhaps be replaced with salty snacks combined withfluid/electrolyte replacement as noted by the authors.These hypotheses could be and should be tested in pro-spectively designed trials. Results obtained from these

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trials may lead to revision of the AABB guidelines and FDArequirements.

In summary Kamel and colleagues provide importantnew data about fainting after blood donation, emphasiz-ing a problem that occurs perhaps more commonly thanpreviously recognized and with substantial morbidity.Fortunately, this informative analysis may lead the waytoward developing creative approaches to limiting theoccurrence of syncope in this setting and making theprocess of blood donation safer for all.

Qi Fu, MD, PhDBenjamin D. Levine, MD

e-mail: benjaminlevine@texashealth.orgInstitute for Exercise and Environmental Medicine

Texas Health Presbyterian Hospital Dallas andthe University of Texas Southwestern Medical Center at

DallasDallas, TX

CONFLICT OF INTEREST

None.

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