Secondary Logo

Journal Logo

Original Clinical Report

Sex Differences in Orthostatic Tolerance Are Mainly Explained by Blood Volume and Oxygen Carrying Capacity

Diaz-Canestro, Candela PhD1; Pentz, Brandon MSc2; Sehgal, Arshia BSc2; Montero, David PhD1–3

Author Information
doi: 10.1097/CCE.0000000000000608

Abstract

The capacity to withstand the upright posture is remarkably diverse among healthy individuals (1,2). Increasing gravitational stress on the cardiovascular system inexorably leads to syncope in humans, yet some individuals reach their limit of orthostatic tolerance (OT) well in advance than others (3). A consistent gap between sexes is long known to exist, with women commonly presenting lower OT compared with men (4). Far from irrelevant, impaired OT may contribute to the increased risk of falls (up to 50% increment) in women relative to men throughout the adult lifespan (5–8). Outstanding research efforts have identified a plethora of anthropometrical, autonomic, cardiovascular and hematological factors potentially underpinning sex differences in OT (9,10). A number of potentially contributing factors cannot be safely manipulated in humans, yet certain phenotypic variables may be experimentally modified in order to assess their influence in OT (11). Notably, fluid-related factors such as blood volume (BV), which is generally lower in women versus men even when adjusted by anthropometrical differences (12,13), can be carefully manipulated (14). BV is a fundamental circulatory variable that primarily determines venous return, cardiac filling, and output (15), thus possibly holding a major contributing role in OT (11). Likewise, another key hematological variable determining oxygen delivery, that is, blood oxygen carrying capacity, can be experimentally modulated and matched between sexes (16). The extent to which major sex-specific blood variables, that is, BV and oxygen carrying capacity, explain sex differences in OT can thus be addressed.

Accordingly, the aim of the present study was to experimentally determine the role of sex differences in BV and oxygen carrying capacity in OT, cardiac volumetric and functional responses in healthy women and men throughout the adult lifespan.

METHODS

Detailed experimental methods are included in the Supplemental Material File (https://links.lww.com/CCX/A883).

Participants

Ninety healthy women and men throughout the adult lifespan (20–89 yr) were recruited via electronic/printed advertisements on community notice boards in the city of Calgary. Moderate-to-vigorous physical activity levels were determined from established questionnaires as previously described (17). Inclusion criteria comprised healthy status, absence of current medical symptoms, and no history of cardiac, pulmonary, or neuromuscular diseases. Individuals fulfilling the above criteria but having donated blood within 3 months prior to the study were excluded. The study was approved by the Conjoint Health Research Ethics Board (REB18-1654) of the University of Calgary and conducted in accordance with the declaration of Helsinki. Prior to the start of the experiments, informed oral and written consents were obtained from all participants.

Experimental Design

Participants were required to report to our laboratory at least once, depending on sex and a voluntary familiarization visit. Each man was assessed twice, prior to and after blood uniformization relative to a previously assessed woman with similar age and physical activity level (one-to-one matching). Time of day of testing sessions was kept consistent for each men and women-men matched pair with a minimum of 48 hours and a maximum of 7 days between the first (baseline) and second (blood uniformization) sessions. All individuals were instructed to avoid strenuous exercise, alcohol and caffeine from 24 hr prior to testing, as well as to maintain their usual baseline activity and daily dietary habits throughout the study. All measurements were performed in fasting conditions (≥ 4 hr) in a quiet room with controlled temperature between 22°C and 23°C. Prior to testing, the participants completed demographic and clinical questionnaires and rested in supine position for 20 minutes in order to stabilize cardiovascular, hemodynamic, and hematological variables.

Measurements

Hemoglobin mass and BV were determined via the carbon monoxide (CO) rebreathing technique. Transthoracic echocardiography and central hemodynamics were noninvasively assessed using high-resolution ultrasound (Mindray Medical M9, Mahwah, NJ) and the volume-clamped method (Finapres Medical Systems, Enschede, The Netherlands). The OT test was performed in a lower body negative pressure (LBNP) chamber designed to facilitate echocardiography via left lateral tilting. The negative pressure inside the chamber was increased every 10 minutes by –10 mm Hg, from 0 to –50 mm Hg. The test was terminated immediately after completion of the last 10 minutes LBNP (–50 mm Hg) level or in the presence of presyncope.

RESULTS

Baseline Characteristics

Main general characteristics of the study participants are presented in Table 1. All individuals were nonsmokers and nonobese (body mass index < 30 kg/m2). Age and physical activity levels were matched between women and men. As expected, women presented smaller anthropometric indices (height, weight, body surface area [BSA]) compared with men (p < 0.001). Likewise, hematological variables fell within normal age- and sex-related levels, with women presenting lower hemoglobin concentration, hematocrit, and BV than men (p < 0.001). BV per unit body weight was positively associated with body mass index in women (r = 0.63; p < 0.001) and men (r = 0.58; p < 0.001). Age was not significantly associated with OT time or BV per unit of body weight in women and men (p ≥ 0.115). With respect to resting cardiac variables, smaller left ventricular (LV) volumes, stroke volume (SV), and cardiac output adjusted by BSA were noted in women compared with men (p ≤ 0.022). Resting central blood pressures did not differ between sexes, whereas systemic vascular resistance (SVR) was elevated in women compared with men (p = 0.001).

TABLE 1. - Baseline Characteristics of Study Subjects
Variable Women Men
n 45 45
Age (yr) 54.4 ± 16.0 53.5 ± 18.9
Height (cm) 164.8 ± 7.2 178.3 ± 7.6a
Weight (kg) 62.5 ± 9.1 79.5 ± 10.8a
Body surface area (m2) 1.68 ± 0.14 1.97 ± 0.15a
Mean arterial pressure (mm Hg) 96.9 ± 16.6 97.4 ± 15.4
Moderate-to-vigorous physical activity (hr/wk) 5.8 ± 2.9 6.8 ± 4.0
Smoking (%) 0 0
Blood
 Hemoglobin concentration (g/dL) 13.3 ± 0.7 15.0 ± 1.0a
 Carboxyhemoglobin (%) 0.8 ± 0.3 0.9 ± 0.2
 Effective hemoglobin concentration (g/dL) 12.0 ± 0.6 13.5 ± 0.9a
 Hematocrit (%) 41 ± 2 46 ± 3a
 Plasma volume (mL/kg) 49 ± 6 48 ± 6
 RBC volume (mL/kg) 34 ± 5 41 ± 5a
 Blood volume (mL/kg) 83 ± 10 88 ± 10a
Resting echocardiography
 Heart rate (beats/min) 58.7 ± 8.1 57.3 ± 7.2
 Right atrial (mL/m2) 18.4 ± 7.1 20.4 ± 6.2
 Right ventricle end-diastolic area (cm2/m2) 10.8 ± 2.3 11.2 ± 2.1
 Right ventricle end-systolic area (cm2/m2) 5.0 ± 1.6 5.0 ± 1.8
 Left atrial (mL/m2) 22.5 ± 9.7 22.4 ± 8.6
 Left ventricular end-diastolic volume (mL/m2) 46.4 ± 9.3 54.9 ± 13.8a
 Left ventricular end-systolic volume (mL/m2) 13.5 ± 4.7 16.9 ± 6.6a
 Left ventricular ejection fraction (%) 71.1 ± 7.9 69.6 ± 6.7
 Stroke volume (mL/m2) 32.9 ± 7.3 38.0 ± 9.3a
 Cardiac output (L/min/m2) 2.0 ± 0.6 2.2 ± 0.6a
ap < 0.05, men vs women.
Data are presented as mean ± sd.

Blood Uniformization

The manipulation of blood oxygen carrying capacity in men resulted in a precise match of effective hemoglobin between sexes (12.0 ± 0.6 vs 12.0 ± 0.8 g/dL; p = 0.598). Likewise, no differences in BV per kg of body weight were present between women and men after blood withdrawal (83 ± 10 vs 83 ± 9 mL/kg; p = 0.743). It should be noted that BV per kg of body weight measured via CO-rebreathing yields higher values compared with dye dilution methods (e.g., indocyanine green) (18). The average absolute BV removed from men was 510.6 ± 191.1 mL, approximately equivalent to a standard blood donation (19). Blood withdrawal in men did not alter hemoglobin concentration (15.0 ± 1.0 vs 15.0 ± 0.9 g/dL; p = 0.598) nor hematocrit (46.0 ± 2.9 vs 45.8 ± 2.5 g/dL; p = 0.598), which remained elevated relative to women (p < 0.001).

Orthostatic Tolerance

Figure 1 illustrates the frequency distribution of women and men (prior to and after blood uniformization) throughout the orthostatic test as well as the OT time. Before blood uniformization, all women and men reached moderate LBNP levels (–20 mm Hg). From –30 to –50 mm Hg, a decreasing number of women and men completed each LBNP stage, with women being outnumbered by men at all levels (p ≤ 0.043) (Fig. 1A). Approximately a third of women (14/45) and two thirds of men (31/45) (p-for-sex < 0.001) completed the entire orthostatic test without signs and symptoms of presyncope. After blood uniformization, men did not outnumber women at any LBNP level. Indeed, only seven out of 45 men completed the test after blood uniformization (p-for-sex = 0.081). The average OT time was shorter in women compared with men before blood uniformization (51.3 ± 8.9 vs 57.4 ± 4.7 min; p < 0.001), whereas women’s time was longer relative to men after blood uniformization (51.3 ± 8.9 vs 45.7 ± 11.9 min; p = 0.014) (Fig. 1B).

F1
Figure 1.:
Frequency distribution of women and men prior to and after blood uniformization at each completed lower body negative pressure (LBNP) level (A) and orthostatic tolerance (OT) time (B). *p < 0.05 between women and men prior to blood uniformization. †p < 0.05 between women and men after blood uniformization. Data are expressed as n or mean ± sem.

Cardiac Structure, Function, and Hemodynamics During Orthostatic Stress

Right and left cardiac volumes and output at each completed LBNP level are presented in Figure 2. Right and left cardiac volumes were substantially decreased along with increasing LBNP levels in both women and men before blood uniformization (p < 0.001). Furthermore, right atrial and LV volumes (left ventricular end-diastolic volume [LVEDV], left ventricular end-systolic volume [LVESV]) were lower in women compared with men during the orthostatic test (p ≤ 0.003). Similarly, SV and cardiac output were markedly lower in women compared with men prior to blood uniformization (p < 0.001). After blood uniformization, main LV volumes and output (LVEDV, SV, and cardiac output) remained elevated in men compared with women (p ≤ 0.047). Likewise, SVR was augmented in women relative to men prior to and after blood uniformization (p ≤ 0.002) (Fig. 3). Between-sex comparisons in individuals reaching presyncope revealed that sex differences in right atrial volume, LVESV and SVR are abolished after blood uniformization in men at the individual-specific LBNP level closer to presyncope (p ≥ 0.199) (Fig. 4).

F2
Figure 2.:
Cardiac volumes and function during progressive lower body negative pressure (LBNP) in women and men prior to and after blood uniformization. *p < 0.05 between women and men prior to blood uniformization. †p < 0.05 between women and men after blood uniformization. Data are expressed as mean ± sem. LVEDV = left ventricular end-diastolic volume, LVESV = left ventricular end-systolic volume, Q = cardiac output, RA = right atrial, SV = stroke volume.
F3
Figure 3.:
Central blood pressures and peripheral resistance during progressive lower body negative pressure (LBNP) in women and men prior to and after blood uniformization. *p < 0.05 between women and men prior to blood uniformization. †p < 0.05 between women and men after blood uniformization. Data are expressed as mean ± sem. DBP = diastolic blood pressure, HR = heart rate, SBP = systolic blood pressure, SVR = systemic vascular resistance.
F4
Figure 4.:
Main cardiac and hemodynamic variables prior to presyncope in women and men prior to and after blood uniformization. *p < 0.05 between women and men prior to blood uniformization. †p < 0.05 between women and men after blood uniformization. Data are expressed as mean ± sem. LVEDV = left ventricular end-diastolic volume, LVESV = left ventricular end-systolic volume, Q = cardiac output, RA = right atrial, SV = stroke volume, SVR = systemic vascular resistance.

DISCUSSION

This main purpose of the present study was to experimentally assess the role of BV and oxygen carrying capacity on sex differences in OT. The main findings are: 1) the match of BV and oxygen carrying capacity between women and men abolishes sex differences in OT; 2) sex differences in LV filling and output remain after blood uniformization; 3) prior to presyncope, SVR is augmented in women compared with men prior to, but not after blood uniformization.

The growing emphasis on understanding biomedical sciences in a sex-specific manner is warranted by the recognition of quantitative as well as qualitative sex divergences in clinically relevant phenotypic variables (20–23). In this respect, the strong relationship between low OT in women and increasing risk of falls, plausibly entailing adverse consequences for hard clinical outcomes, merits further research (8,24). Consistent with prevalent findings in the literature (9,10), we found markedly lower OT in women compared with men matched by age and physical activity levels. Specifically, ~50% less women reach the highest level of LBNP relative to men. Such a pronounced gap in OT may be explained by differences in fundamental phenotypic variables. Herein, a precise match of key blood variables, BV and oxygen carrying capacity, between women and men eliminated sex differences in OT. Indeed, after blood uniformization, a substantially reduced number of men (n = 7) were able to finish the orthostatic test, while their OT time was shorter compared with women. Of note, differences OT time between sexes prior to and after blood uniformization (± 6 min) approximately correspond with the effects of interventions involving the ingestion of a volume of fluid (500 mL) similar to the BV removed in the present study (11). BV seems to play a prominent, albeit not exclusive, role in determining increases and decreases in OT. The positive prospect is that BV is amenable to modification, for example, via exercise training or specific physical maneuvers such as head-up sleep, and thus plausibly translated into effective targets to improve or preserve hemodynamic stability in the general population (25–29).

The potential mechanisms underlying the effects of blood uniformization on OT require examination. Conforming to well established physiologic principles, blood plays a primary role as a hemodynamic “driver” of the circulatory system. The more blood fills the system, particularly the heart, the greater the myocardial capacity to increase SV until a plateau is reached, conforming to the Frank-Starling mechanism (30,31). A sex-specific ventricular filling and SV has been suggested as a key mechanical divergence underlying sex differences in OT (32). Namely, similar sex differences in LVEDV and SV at presyncope to those identified in the present study (20–30% decrements in women vs men) have been previously associated with corresponding differences in OT time (–5 min in women vs men) (32). Unexpectedly, LV volumes (LVEDV, SV, cardiac output) remained elevated prior to presyncope in men after blood uniformization (Fig. 2). In this respect, the matching of blood oxygen carrying capacity between women and men generally involves a ~10% reduction of effective hemoglobin concentration in the latter (33,34), which entails a relative state of hypoxia and compensatory vasodilation (16,35). Accordingly, reduced oxygen carrying capacity may have facilitated peripheral blood flow in men after blood uniformization, concurring with previous studies combining hypoxia and orthostatic stimuli (36). Yet, in those men that could not complete the orthostatic test due to presyncope, blood uniformization induced an increase in SVR reaching the values observed in women (Fig. 4). This was accompanied by a decrease in LVESV also matching women’s level, plausibly reflecting augmented ventricular contractibility (37). Hence, certain peripheral and central responses under autonomic control were comparable between sexes after blood uniformization in individuals experiencing presyncope. These findings suggest that hematological determinants of OT interact with central and peripheral sympathetic activation, both being generally lower in women compared with men presenting with intact hematological variables (38,39). In addition, sex differences in intrinsic peripheral vascular functions (e.g., vascular capacitance, compliance) to a given LBNP stimuli have been previously identified and could contribute to central hemodynamic responses (40–42). Further experimental research is needed to elucidate the independent role of sex differences in the sympathetic reserve and vascular function during orthostatic challenges.

Consideration shall be given to the administration of CO in the present study. The use of CO to experimentally manipulate blood oxygen carrying capacity has deep roots in human physiology (16,43–45). CO rebreathing resulting in up to 18% decrements in oxygen carrying capacity does not alter hematological (blood pH, bicarbonate, electrolytes, hemoglobin concentration) and biophysical (temperature) characteristics of blood (16). As predicted, proportional reductions in oxygen carrying capacity and aerobic capacity are found after CO rebreathing in healthy individuals (45,46). The CO administered essentially remains in the circulation and even in the presence of large hemodynamic alterations, there is no diffusion into the tissue (16). In this line, the hemodynamic (vasodilatory- and perfusion-related) effects of reduced blood oxygen content induced by low oxygen breathing (hypoxic hypoxia) are similar to those elicited by CO-mediated hypoxia (16). In fact, hypoxia, per se, do not substantially alter blood pressure responses to high LBNP (–30 to –50 mm Hg) or head-up tilt in normobaric conditions in healthy women and men (47,48). Collectively considered, the reduction of oxygen carrying capacity via CO is not deemed to compound the intrinsic consequences of hypoxia in men (49). Molecular investigations will be needed to unravel sex-specific signaling pathways linking oxygen carrying capacity with hemodynamic regulation and OT (23).

Healthy individuals were included in order to limit the influence of disease-related confounding factors. Whether the present findings can be extrapolated to particular pathologic conditions will need to be determined by further experimental and clinical investigations. Second, the investigators that performed the analyses, but not the study participants, were blinded to the experimental condition. Provided that a blinded intervention for phlebotomy and CO rebreathing could be successfully implemented, the main outcomes of the study are not thought to be altered by an hypothetical nocebo effect when standard signs and symptoms of presyncope are strictly observed (50). Finally, the potential effects of blood withdrawal on neurohormonal compensating mechanisms were not assessed in the present study.

CONCLUSIONS

The present study indicates that blood uniformization between men and women largely eliminate differences in OT. The match of BV and oxygen carrying capacity between sexes was not paralleled by that of main cardiac outcomes. In contrast, prior to presyncope, a similar SVR level was detected in both sexes after blood uniformization, suggesting the interplay of blood with autonomic responses determining OT. Further studies are needed to unravel the blood-dependent signaling pathways determining sex differences in OT throughout the lifespan.

ACKNOWLEDGMENTS

We thank the study participants for their willingness, time, and effort devoted to this study.

REFERENCES

1. Weiss A, Grossman E, Beloosesky Y, et al.: Orthostatic hypotension in acute geriatric ward: Is it a consistent finding? Arch Intern Med 2002; 162:2369–2374
2. Goswami N, Lackner HK, Grasser EK, et al.: Individual stability of orthostatic tolerance response. Acta Physiol Hung 2009; 96:157–166
3. Schroeder C, Tank J, Heusser K, et al.: Orthostatic tolerance is difficult to predict in recurrent syncope patients. Clin Auton Res 2011; 21:37–45
4. Montgomery LD, Kirk PJ, Payne PA, et al.: Cardiovascular responses of men and women to lower body negative pressure. Aviat Space Environ Med 1977; 48:138–145
5. Johansson J, Nordström A, Nordström P: Greater fall risk in elderly women than in men is associated with increased gait variability during multitasking. J Am Med Dir Assoc 2016; 17:535–540
6. Talbot LA, Musiol RJ, Witham EK, et al.: Falls in young, middle-aged and older community dwelling adults: Perceived cause, environmental factors and injury. BMC Public Health 2005; 5:86
7. Timsina LR, Willetts JL, Brennan MJ, et al.: Circumstances of fall-related injuries by age and gender among community-dwelling adults in the United States. PLoS One 2017; 12:e0176561
8. Mol A, Bui Hoang PTS, Sharmin S, et al.: Orthostatic hypotension and falls in older adults: A systematic review and meta-analysis. J Am Med Dir Assoc 2019; 20:589–597.e5
9. Goswami N, Blaber AP, Hinghofer-Szalkay H, et al.: Lower body negative pressure: Physiological effects, applications, and implementation. Physiol Rev 2019; 99:807–851
10. Cheng YC, Vyas A, Hymen E, et al.: Gender differences in orthostatic hypotension. Am J Med Sci 2011; 342:221–225
11. Schroeder C, Bush VE, Norcliffe LJ, et al.: Water drinking acutely improves orthostatic tolerance in healthy subjects. Circulation 2002; 106:2806–2811
12. Diaz-Canestro C, Montero D: Unveiling women’s powerhouse. Exp Physiol 2020; 105:1060–1062
13. Lundby C, Robach P: Performance enhancement: What are the physiological limits? Physiology (Bethesda) 2015; 30:282–292
14. Montero D, Cathomen A, Jacobs RA, et al.: Haematological rather than skeletal muscle adaptations contribute to the increase in peak oxygen uptake induced by moderate endurance training. J Physiol 2015; 593:4677–4688
15. Montero D, Diaz-Canestro C, Oberholzer L, et al.: The role of blood volume in cardiac dysfunction and reduced exercise tolerance in patients with diabetes. Lancet Diabetes Endocrinol 2019; 7:807–816
16. Gonzalez-Alonso J, Richardson RS, Saltin B: Exercising skeletal muscle blood flow in humans responds to reduction in arterial oxyhaemoglobin, but not to altered free oxygen. J Physiol 2001; 530:331–341
17. Montero D, Houben AJ, Koster A, et al.: Physical activity is associated with glucose tolerance independent of microvascular function: The Maastricht study. J Clin Endocrinol Metab 2016; 101:3324–3332
18. Keiser S, Meinild-Lundby AK, Steiner T, et al.: Detection of blood volumes and haemoglobin mass by means of CO re-breathing and indocyanine green and sodium fluorescein injections. Scand J Clin Lab Invest 2017; 77:164–174
19. Mayoclinic: Blood Donation: What to Expect. Available at: https://www.mayoclinic.org/tests-procedures/blood-donation/about/pac-20385144. Accessed December 13, 2019
20. Diaz-Canestro C, Montero D: Sex dimorphism of VO2max trainability: A systematic review and meta-analysis. Sports Med 2019; 49:1949–1956
21. Diaz-Canestro C, Montero D: The impact of sex on left ventricular cardiac adaptations to endurance training: A systematic review and meta-analysis. Sports Med 2020; 50:1501–1513
22. Diaz-Canestro C, Montero D: Female sex-specific curtailment of left ventricular volume and mass in HFpEF patients with high end-diastolic filling pressure. J Hum Hypertens 2021; 35:296–299
23. Regitz-Zagrosek V, Kararigas G: Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev 2017; 97:1–37
24. Xin W, Lin Z, Mi S: Orthostatic hypotension and mortality risk: A meta-analysis of cohort studies. Heart 2014; 100:406–413
25. Montero D, Breenfeldt-Andersen A, Oberholzer L, et al.: Erythropoiesis with endurance training: Dynamics and mechanisms. Am J Physiol Regul Integr Comp Physiol 2017; 312:R894–R902
26. Montero D, Diaz-Cañestro C, Flammer A, et al.: Unexplained anemia in the elderly: Potential role of arterial stiffness. Front Physiol 2016; 7:485
27. Montero D, Diaz-Cañestro C, Keiser S, et al.: Arterial stiffness is strongly and negatively associated with the total volume of red blood cells. Int J Cardiol 2016; 221:77–80
28. Montero D, Lundby C: Regulation of red blood cell volume with exercise training. Compr Physiol 2018; 9:149–164
29. Montero D, Rauber S, Goetze JP, et al.: Reduction in central venous pressure enhances erythropoietin synthesis: Role of volume-regulating hormones. Acta Physiol (Oxf) 2016; 218:89–97
30. Pezza F: The law of the heart. Lancet 1974; 2:1972
31. Maestrini D: Sulla genesi dell’automatismo cardiaco. Arch Di Farmacologia Sperimentale E Scienze Affini 1915:467–480
32. Fu Q, Arbab-Zadeh A, Perhonen MA, et al.: Hemodynamics of orthostatic intolerance: Implications for gender differences. Am J Physiol Heart Circ Physiol 2004; 286:H449–H457
33. Murphy WG, Tong E, Murphy C: Why do women have similar erythropoietin levels to men but lower hemoglobin levels? Blood 2010; 116:2861–2862
34. Niittymäki P, Arvas M, Larjo A, et al.: Retrospective analysis of capillary hemoglobin recovery in nearly 1 200 000 blood donor returns. Blood Adv 2017; 1:961–967
35. Malo J, Goldberg H, Graham R, et al.: Effect of hypoxic hypoxia on systemic vasculature. J Appl Physiol Respir Environ Exerc Physiol 1984; 56:1403–1410
36. Halliwill JR, Minson CT: Cardiovagal regulation during combined hypoxic and orthostatic stress: Fainters vs. nonfainters. J Appl Physiol (1985) 2005; 98:1050–1056
37. McManus DD, Shah SJ, Fabi MR, et al.: Prognostic value of left ventricular end-systolic volume index as a predictor of heart failure hospitalization in stable coronary artery disease: Data from the Heart and Soul Study. J Am Soc Echocardiogr 2009; 22:190–197
38. Hogarth AJ, Mackintosh AF, Mary DA: Gender-related differences in the sympathetic vasoconstrictor drive of normal subjects. Clin Sci (Lond) 2007; 112:353–361
39. Momen A, Gao Z, Cohen A, et al.: Coronary vasoconstrictor responses are attenuated in young women as compared with age-matched men. J Physiol 2010; 588:4007–4016
40. Lindenberger M, Länne T: Sex-related effects on venous compliance and capillary filtration in the lower limb. Am J Physiol Regul Integr Comp Physiol 2007; 292:R852–R859
41. Lindenberger M, Olsen H, Länne T: Lower capacitance response and capillary fluid absorption in women to defend central blood volume in response to acute hypovolemic circulatory stress. Am J Physiol Heart Circ Physiol 2008; 295:H867–H873
42. Olsen H, Vernersson E, Länne T: Cardiovascular response to acute hypovolemia in relation to age. Implications for orthostasis and hemorrhage. Am J Physiol Heart Circ Physiol 2000; 278:H222–H232
43. Asmussen E, Nielsen M: The cardiac output in rest and work at low and high oxygen pressures. Acta Physiol Scand 1955; 35:73–83
44. Chiodi H, Dill DB, Consolazio F, et al.: Respiratory and circulatory responses to acute carbon monoxide poisoning. Am J Physiol 1941; 134:683–693
45. Vogel JA, Gleser MA: Effect of carbon monoxide on oxygen transport during exercise. J Appl Physiol 1972; 32:234–239
46. Ekblom B, Huot R: Response to submaximal and maximal exercise at different levels of carboxyhemoglobin. Acta Physiol Scand 1972; 86:474–482
47. Fox WC, Watson R, Lockette W: Acute hypoxemia increases cardiovascular baroreceptor sensitivity in humans. Am J Hypertens 2006; 19:958–963
48. Rickards CA, Newman DG: The effect of low-level normobaric hypoxia on orthostatic responses. Aviat Space Environ Med 2002; 73:460–465
49. Siebenmann C, Lundby C: Regulation of cardiac output in hypoxia. Scand J Med Sci Sports 2015; 25(Suppl 4):53–59
50. Arnold AC, Ng J, Lei L, et al.: Autonomic dysfunction in cardiology: Pathophysiology, investigation, and management. Can J Cardiol 2017; 33:1524–1534
Keywords:

blood volume; female sex; older age; orthostatic tolerance; oxygen carrying capacity

Supplemental Digital Content

Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.