F-cell shift and protein loss strongly affect validity of PV reductions indicated by Hb/Hct and plasma proteins.

Numerous studies have focused on alterations in plasma volume (PV) on interventions like quiet standing, exercise, or heat stress. However, no method seems capable of truly estimating the PV alteration. Therefore, an attempt was made to validate commonly used indexes of PV changes. Quiet standing was used to cause graded PV reductions estimated from hemoglobin and hematocrit (Hb/Hct) and from serum concentrations of total protein, albumin, and "large proteins" (LP; total protein minus albumin). Results indicated the following. 1) Hb/Hct, with the merit that the marker (erythrocyte) stays within the circulation, reflect accurately a small-to-moderate PV loss (/=15-20% of control), however, F-cell shift can cause Hb/Hct to underestimate the response by up to 25-30%. 2) Albumin and total protein underrate PV loss due to protein escape (mainly albumin) from the circulation. 3) LP also underestimate the PV decline due to protein escape but can often predict large PV reductions clearly better than Hb/Hct. 4) Prolonged standing can lead to pronounced 25% PV decline.

Pronounced 25-30% plasma volume reduction induced by gravitational stress.

NASA: The authors report a study of the validation of the commonly used indexes of plasma volume changes in response to quiet standing and lower body negative pressure. Plasma volume reductions were estimated from hemoglobin/hematocrit and serum concentrations of total protein, albumin, large proteins, and IgG.^ieng

Rapid plasma volume decline upon quiet standing reflects large filtration capacity in dependent limbs.

The plasma volume (PV) decline upon 1.5, 3, 5, 8, 10, 15 and 35 min periods of quiet standing was studied (Hb/Hct) in male volunteers (n = 7). This approach permitted detailed definition of the time-course of the volume change. PV decreased by as much as 8.5 +/- 0.4% (328 +/- 15 mL) after 3 min standing and by no less than 11.7 +/- 0.4% (466 +/- 22 mL) after 5 min. The reduction was 14.3 +/- 0.7, 16.8 +/- 0.8, 17.7 +/- 0.8 and 17.4 +/- 0.9% after 8, 10, 15 and 35 min, or 568 +/- 30, 671 +/- 39, 707 +/- 41 and 691 +/- 44 mL. These data, in conjunction with the 1.5 min experiments, indicated a very rapid approximately 125 mL min-1 fluid loss initially on standing. However, the PV loss showed marked decline with time and was virtually completed within 10 min. Finally, the observation was made that the rate of PV recovery after standing was inversely related to the duration of standing. It is suggested that (a) the transcapillary hydraulic conductivity in the dependent limbs, the predominant targets for fluid filtration on standing, is about 0.010 mL min-1 100 mL-1 mmHg-1 and much greater than indicated previously. However, protective mechanisms restrict rapid fluid loss to early phases of standing. (b) Decrease in PV may contribute importantly to haemodynamic stress and to orthostatic, fainting reactions during short quiet standing. Apparently, PV loss may be equally important as pooling of blood, traditionally regarded as a dominant cause of adverse orthostatic reactions. (c) The duration of standing, as such, may be critical for the rate of PV recovery after standing.

Protein loss and capillary protein permeability in dependent regions upon quiet standing.

Seven healthy males were exposed to quiet standing (15 min) after supine rest. Alterations in the total mass of plasma proteins were analysed from changes in plasma volume (PV; determination of control PV and subsequently of induced per cent PV changes using Hb/Hct) and protein concentration as revealed in arterial blood collected after standing. This approach adopted the concept that valid data on overall circulatory haemoconcentrations prevailing on standing can only be reached when blood is sampled on resumption of the recumbent posture, whereas conventional sampling from the standing subject provides erroneous information. The PV reduction on standing averaged 649 +/- 65 mL (16.9 +/- 1.0%). There were very similar net decreases in plasma (serum) total protein (7.6 +/- 0.8 g) and albumin (7.8 +/- 0.9 g). These findings permitted the following main conclusions of physiological and methodological pertinence: (1) Quiet standing leads to a clear-cut net decrease in the plasma protein content predominantly confined to albumin, in all probability via convection secondary to PV loss by filtration in dependent regions. (2) It is suggested that the albumin loss reflects a quite high capillary macromolecular permeability in the dependent limbs on standing preferentially confined to skin/subcutaneous tissues. (3) The albumin loss implies that plasma concentration changes of neither albumin nor of total protein can be used to describe the PV loss on standing. However, concentration changes of the plasma globulin fraction as a whole, expressed by the difference (total protein-albumin), seem to reflect PV alterations approximately.

Pronounced and rapid plasma volume reduction upon quiet standing as revealed by a novel approach to the determination of the intravascular volume change.

Plasma volume (PV) changes to 15 min quiet standing were analysed (Hb/Hct-alterations) in two studies (nine and 11 healthy males). Data confirmed and extended our findings that blood, arterial or venous, sampled on standing fails to reveal the induced overall haemoconcentration (PV loss). First, standing led to markedly incomplete mixing of blood between circulatory compartments. Secondly, with sampling of antecubital venous blood, haemoconcentration was strongly affected by regional plasma loss and, apparently equally important, by regional blood flow. These difficulties were circumvented, however, by the finding that the PV restitution (haemoconcentration) in the recumbent subject after standing fitted invariably a monoexponential function with striking precision. It allowed, by extrapolation, a seemingly superior definition of the PV reduction at the very end of standing as supported by the fact that PV changes from Hb/Hct and from IgM protein concentration changes were similar, refuting that Fcell-changes contributed to the pronounced Hb/Hct changes. The described novel approach revealed a nicely reproducible PV loss of no less than 692 +/- 46 mL (18.1 +/- 0.6%, Study I; 18.4 +/- 0.5%, Study II), or approximately 11% reduction of blood volume, showing that quiet standing leads to a much more rapid and haemodynamically important decrease in PV than reported previously. Yet, PV was virtually restored within 20 min of recumbency after standing, with 50% recovery within 6 min and regain of as much as 70 mL in the very first min. The latter data indicate that the body possesses a surprising capacity for rapid fluid transfer from the extra- to the intravascular space.

Transcapillary fluid transfer and plasma volume changes in response to quiet standing and LBNP.

Quiet standing is one of the conditions of daily life. Still, it may lead to acute circulatory failure even in normal man, a phenomenon ascribed mainly to the early large pooling of blood and secondary decrease in central blood volume. Reduction of plasma volume (PV) by filtration in dependent regions apparently contributes, but there is no indication that this process is of major importance during short periods of standing still in normal life. Hence, studies have indicated that the plasma fluid loss occurs at relatively slow rate due to the presence of protective mechanisms that prevent rapid fluid loss.

Failure of hemoconcentration during standing to reveal plasma volume decline induced in the erect posture.

The hypothesis was tested that the hemoconcentration observed during standing provides erroneous information about the induced plasma volume (PV) decline. Male volunteers (n = 10) stood quietly for 15 min after supine rest. On standing arterial hemoglobin (Hb) rose slowly to reach an increase of 5.9 +/- 0.3% (SE) after 15 min. Early after resuming the supine position, Hb increased further to 9.2 +/- 0.5% above control level and then declined gradually. Venous antecubital blood from the left arm supported horizontally at heart level in both the supine and standing positions (no hydrostatic load) showed very similar changes. However, Hb in venous blood collected during standing from the right arm held in the natural dependent position rose much more markedly than that in arterial blood and in venous blood from the horizontal arm (470 +/- 122, 105 +/- 24, and 55 +/- 7% greater increase at 5, 10, and 15 min, respectively). Taken together, these observations indicated that 1) analyses of arterial blood sampled from the standing subject grossly underestimated the prevailing "overall" hemoconcentration and PV decline, a phenomenon ascribed to incomplete mixing of blood between dependent and nondependent regions; 2) arterial blood sampled from the recumbent subject early (60 s) after completion of standing reflected the "true" overall intravascular hemoconcentration, with a calculated PV decline of no less than 511 +/- 27 ml, because the supine position facilitated proper mixing of blood between circulatory compartments; 3) data from common venous sampling from the dependent arm during standing primarily reflected a regional hemoconcentration (fluid loss) in the arm rather than PV decline; and 4) short-term quiet standing caused a more prominent and hemodynamically important decrease in PV than usually believed.

Skeletal muscle and skin as targets for powerful homeostatic vasomotor baroreflexes in humans during prolonged circulatory stress: a study on the innervated and nerve blocked forearm.

Flow (vascular resistance) was followed in the innervated and axillary nerve blocked arm during prolonged low to high and barely tolerated circulatory stress [15-85 mmHg LBNP (lower body negative pressure) for 10 min; room temperature 24.8-25.7 degrees C]. With intact innervation LBNP caused initial graded and potent forearm vasoconstriction. At low LBNP, however, there was soon significant and maintained partial (50%) abolition of the early response. At high LBNP, the initial striking vasoconstriction remained constant throughout 10 min of pronounced circulatory stress [marked tachycardia; fall in systolic pressure but mean arterial pressure (MAP) normal]. Flow decreased in steady state by 15 +/- 4, 38 +/- 5, 63 +/- 2 and by pronounced 78 +/- 3% at 15, 40, 70, and 85 mmHg LBNP (resistance raised 27 +/- 7, 78 +/- 16, 192 +/- 18, and 387 +/- 55% above control), alterations ascribed to constriction in both muscle and skin. Comparison of LBNP responses with intact and blocked innervation revealed that the vasoconstriction was neurogenic with little or no humoral contribution. The overall observations show that under normal comfortable (thermoneutral) conditions the resistance vessels in muscle and skin, with haemodynamically important large tissue mass and great tolerance to even drastic and prolonged ischaemia, indeed are important targets in the homeostatic sympathetic control, especially when cardiovascular homeostasis is challenged by marked stress with urgent need for strong, maintained compensatory vasoconstriction. The study also demonstrated > three-fold (4.1 +/- 0.5 to 13.1 +/- 1.9 ml min-1 100 ml-1) forearm flow increases upon blockade of resting nervous vasoconstrictor tone. It thus appears that the sympathetic nerves not only can elicit prominent and maintained baroreflex limb vasoconstriction but also that, in humans, reflex inhibition of resting tone might allow surprisingly large resistance decline.

Very large range of baroreflex sympathetic control of vascular resistance in human skeletal muscle and skin.

We analyzed in the forearm of "comfortably warm" male volunteers 1) reflex sympathetic vascular resistance changes evoked by short-term graded [1.5-min exposure to 15, 40, 55, and 70 mmHg and high and barely tolerated (77-95 mmHg)] lower body negative pressure (LBNP) and 2) resistance changes evoked by abolition of control sympathetic vasoconstrictor tone (anesthetic axillary nerve block). Graded LBNP caused graded neurogenic vasoconstriction with pronounced average flow decline at high LBNP from 3.7 to 0.8 ml.min-1 x 100 ml-1 (77 +/- 2% decrease), corresponding to a drastic resistance increase from 25.4 to 127 mmHg.ml-1 x min x 100 ml (352 +/- 27% rise above control). Axillary nerve block caused marked increases in forearm blood flow from 4.3 +/- 0.4 to 15.7 +/- 1.4 ml.min-1 x 100 ml-1 [> 3-fold flow increase equivalent to an average resistance decline from 19.7 to 6.3 mmHg.ml-1 x min x 100 ml (72 +/- 5%)], reflecting a surprisingly high resting constrictor fiber vascular tone. The overall results indicate that the sympathetic skeletal muscle and skin resistance vessel control in men allows very large (almost 20-fold) alterations in blood flow and vascular resistance from complete inhibition of neurogenic vascular tone to maximal reflex nerve activation. This range of sympathetic control was clearly greater than that revealed in comparative experiments on the cat lower leg.

Sympathetic baroreflex control of vascular resistance in comfortably warm man. Analyses of neurogenic constrictor responses in the resting forearm and in its separate skeletal muscle and skin tissue compartments.

Resting forearm vascular resistance changes elicited in male volunteers by graded reflex sympathetic activation evoked by graded lower body negative pressure (LBNP) were studied at room temperatures of 24-25 and 20-21 degrees C. The latter condition caused strong suppression of skin flow and permitted preferential analysis of muscle responses and, by comparison with responses at 24-25 degrees C, secondary estimation of circulatory reactions in the skin. Short-lasting LBNP-bouts (1.5 min) allowed analyses of reflex vascular reactions to high and barely tolerated LBNP (85 mmHg) and thereby to high levels of circulatory stress and sympathetic nerve discharge, yet without risks for the subjects under study. Both muscle and skin reacted intensely and in a graded manner to graded sympathetic activation with very pronounced resistance change (74-77% flow decline; 350-400% resistance rise above control level) at high LBNP. Therefore, the sympathetic vasomotor fibres can exert a very potent control of vascular resistance both in skeletal muscle and in skin under thermoneutral conditions, and both tissues apparently can serve as major targets for powerful sympathetic homeostatic baroreflexes. Evidence indicated that this control is exerted from both low-pressure cardiopulmonary and high-pressure arterial baroreceptor areas. These conclusions deviate from previous literature, in which baroreflex sympathetic vasoconstriction in the human limb has been proposed to be more or less selectively mediated from cardiopulmonary receptors and, further, muscle to respond fully already at mild circulatory stress without further constriction if the stimulus is increased.

Dynamics of transcapillary fluid transfer and plasma volume during lower body negative pressure.

Lower body negative pressure (LBNP) is a stimulus frequently used to study reflex circulatory responses in humans. Studies have provided data on LBNP-induced blood pooling; however, the possibility that LBNP also might be associated with an important loss of plasma fluid has attracted little attention. Therefore this problem was analysed in male volunteers exposed to prolonged (10 min) high (70-75 mmHg) LBNP. Data on LBNP-induced blood pooling that were more reliable than in previous literature were also provided. LBNP caused early pooling of more than 870 ml of blood. Rapid filtration of plasma into the exposed tissues occurred throughout LBNP. The cumulative oedema in the legs and buttocks averaged as much as 460 ml, and additional quite large volumes of plasma apparently accumulated in other parts of the lower body. Concomitantly, there was compensatory absorption of extravascular fluid in the upper body. The net decrease in plasma volume (PV) was still large and averaged 491 +/- 29(SE) ml. Two aspects of the demonstrated process of transcapillary fluid fluxes and PV decline may be emphasized. Firstly, in conjunction with the primary large redistribution of intravascular volume, it certainly implies that LBNP is a potent stimulus as also indicated by a progressive increase in heart rate (HR) and a progressive decline in systolic pressure throughout experimental intervention. In fact, LBNP-induced circulatory stress clearly has bearings on the extreme hypovolaemic situation provided by the pressure-bottle haemorrhage technique used in animals. Secondly, it not only offers an interesting example of the dynamics of PV but appears to have more general validity with regard to states characterized by gravitational shifts of blood (hydrostatic load), like upright exercise and quiet standing.

Much more potent baroreflex sympathetic control of vascular resistance in the resting human limb than previously believed.

The concept that, in man, the sympathetic control of the resting limb vascular resistance is truly limited and thus strikingly different from animal species, was challenged in the present study. Analyses were performed in healthy male volunteers of reflex forearm vascular resistance changes evoked by lower body negative pressure (LBNP) ranging from low (15 mmHg) to high and barely tolerated (85 mmHg) levels. Graded LBNP was associated with graded increases in resistance. At high 85 mmHg LBNP the responses were pronounced with a rise in forearm resistance to no less than 120 mmHg ml-1 min 100 + ml soft tissue, on average, corresponding to a 377% increase above control. This drastic response seemed entirely neurogenic in origin and calculations, based on the likely assumption that a similar response occurred in all skeletal muscle and skin/(subcutaneous fat), showed that it permitted a marked increment in total systemic vascular resistance because of the fact that these tissues constitute so large a proportion of the body mass. The conclusion was reached that the studied tissues may serve as main targets for powerful homeostatic reflexes. It is also suggested, in contrast to current views, that the high-pressure arterial rather than the low-pressure cardio-pulmonary baroreceptors may be the main mediators of haemodynamically important vasoconstrictor responses.

Mechanisms in man for rapid refill of the circulatory system in hypovolaemia.

Compensatory, net fluid transfer across the capillaries was studied in the arm of man with plethysmographic technique during experimental hypovolaemia induced by lower body negative pressure (LBNP). Thirty, 60, and 110 cmH2O LBNP evoked rapid transfer of fluid from tissue to blood at average rates of 0.053, 0.088 and 0.147 ml min-1 100 ml-1 soft tissue, i.e. graded responses typical for a true homeostatic regulation. Other experiments demonstrated a net fluid absorption not only from the arm but also from a wide range of skeletal muscle and skin regions in the body during experimental hypovolaemia, i.e. the more or less generalized response required if the absorption process is to contribute importantly to plasma volume regulation. In a third series of experiments it was shown that gradually applied LBNP was a much less efficient stimulus for fluid gain into the circulation than rapidly instituted LBNP, tentatively explaining the fairly slow plasma volume refill in main in previous literature after experimental, true and necessarily slow blood loss. Taken together, the findings described warrant the conclusion that the described process of fluid gain into the circulation may be a very important component in the overall homeostatic circulatory regulation in states of hypovolaemia. The data in fact suggest that the process might be capable of increasing plasma volume by as much as 600 ml within only 10 min, suggesting that such plasma volume control might be much more potent than previously believed.

Large capillary fluid permeability in skeletal muscle and skin of man as a basis for rapid beneficial fluid transfer between tissue and blood.

Our previous studies strongly indicate that the capillary filtration coefficient (CFC) in skeletal muscle and skin of man is much larger than previously believed, or about 0.050 ml min-1 100 ml-1 mmHg-1. The hypothesis that this large capillary fluid permeability is a factor of primary importance for plasma volume control was approached. Experimental hypovolaemia induced by lower body negative pressure (LBNP of 70-95 cmH2O) was associated with a rapid net fluid gain from the studied upper arm into the circulation of 0.17 ml min-1 100 ml-1 tissue. The transcapillary driving force for this fluid transfer, probably caused by adrenergic adjustment of vascular resistance, with a decline of capillary pressure, was relatively small, or 1.7 mmHg on average. CFC was instead very high during LBNP, increasing from a control value of 0.054 +/- 0.004 (SE) to no less than 0.097 +/- 0.007 ml min-1 100 ml-1 mmHg-1, probably reflecting an increased number of effectively perfused capillaries. It is suggested that the large capillary fluid permeability in skeletal muscle and skin of man, with large tissue mass and fluid reservoir, may be of great functional importance for plasma volume control after blood loss and also in other (patho)physiological situations. As demonstrated, it can thus permit rapid transfer of large fluid volumes into the circulation and, perhaps of special importance, with only small transcapillary driving force (capillary pressure decline).(ABSTRACT TRUNCATED AT 250 WORDS)

Large capacity in man for effective plasma volume control in hypovolaemia via fluid transfer from tissue to blood.

Compensatory absorption of extravascular fluid from skeletal muscle and skin into the circulation in response to experimental hypovolaemia was studied by plethysmographic technique in the upper arm of man. Lower body negative pressure (LBNP) of 90 cmH2O, applied for 10 min, served to produce rapid and prominent hypovolaemic stress as indicated by prompt decrease in central blood volume (external recording of [99Tcm]erythrocyte activity) followed by marked tachycardia. The arm concomitantly showed an initial mobilization of regional blood, an increased vascular resistance, and a continuous net transcapillary fluid absorption, i.e. similar responses as reported in animals upon haemorrhage. The absorption of extravascular fluid, validated by simultaneous analyses of changes in tissue volume and in regional blood volume [99Tcm]erythrocyte activity), was rapid and averaged 0.13 ml min-1 100 ml-1 soft tissue during the 10 min of LBNP exposure. In some subjects with symptoms and signs of pronounced circulatory stress fluid was transferred twice as fast. Separate experiments indicated that the rapid fluid flux was causally linked to the existence in the studied tissue of a large transcapillary hydraulic conductance. It is concluded that man possesses a surprisingly great capacity for compensatory circulatory refill via fluid transfer from tissue to blood. The data in fact suggest that in true states of hypovolaemia as much as 500 ml might be gained into the circulation in only 10 min.

Microvascular effects and oedema formation of felodipine in man.

The microvascular mechanisms responsible for oedema formation following the administration of calcium antagonists were studied in 10 healthy volunteers given intravenous felodipine and vehicle in a double-blind crossover trial. Plethysmography and laser Doppler flowmetry were used to measure microvascular parameters. Felodipine increased both skin and forearm blood flow. Due to a more pronounced inhibition of vascular tone in pre- than in postcapillary resistance vessels, capillary hydrostatic pressure increased and caused a net fluid filtration from blood to tissue. No evidence for increased vascular permeability was found. Under control conditions, a hydrostatic load led to fluid filtration despite constriction of resistance vessels and precapillary sphincters. Felodipine increased this fluid filtration and impaired the local vasoconstrictor responses. It is concluded that oedema formation induced by felodipine and other calcium antagonists can partly be ascribed to the vasodilatory effect of the drug (increased capillary pressure) and partly to interference with the local vascular control (probably the myogenic component) that protects dependent vascular regions from enhanced fluid filtration.