Gravitational effects on carotid and jugular characteristics in graded head-up and head-down tilt

Abstract

Altered gravity affects hemodynamics and blood flow in the neck. At least one incidence of jugular venous thrombosis has been reported in an astronaut on the International Space Station. This investigation explores the impact of changes in the direction of the gravitational vector on the characteristics of the neck arteries and veins. Twelve subjects underwent graded tilt from 45° head-up to 45° head-down in 15° increments in both supine and prone positions. At each angle, the cross-sectional area of the left and right common carotid arteries (A_CCA) and internal jugular veins (A_IJV) were measured by ultrasound. Internal jugular venous pressure (IJVP) was also measured by compression sonography. Gravitational dose-response curves were generated from experimental data. A_CCA did not show any gravitational dependence. Conversely, both A_IJV and IJVP increased in a nonlinear fashion with head-down tilt. A_IJV was significantly larger on the right side than the left side at all tilt angles. In addition, IJVP was significantly elevated in the prone position compared with the supine position, most likely because of raised intrathoracic pressure while prone. Dose-response curves were compared with existing experimental data from parabolic flight and spaceflight studies, showing good agreement on an acute timescale. The quantification of jugular hemodynamics as a function of changes in the gravitational vector presented here provides a terrestrial model to reference spaceflight-induced changes, contributes to the assessment of the pathogenesis of spaceflight venous thromboembolism events, and informs the development of countermeasures.

NEW & NOTEWORTHY Flow stasis and thrombosis have been identified in the jugular vein during spaceflight. We measured the area and pressure of the internal jugular vein and the area of the common carotid artery in graded head-up and head-down tilt. Experimental data are used to generate gravitational dose-response curves for the measured variables, demonstrating that jugular vein area and pressure exhibit a nonlinear response to altered gravity. Gravitational dose-response curves show good agreement with spaceflight and parabolic flight studies.

INTRODUCTION

Initial entry to microgravity induces an acute cephalad fluid shift in the human cardiovascular system. This leads to a range of systemic and autonomic effects including decreased heart rate, elevated stroke volume and cardiac output, and decreased total peripheral resistance (1–3). Furthermore, increased pressure in the carotid sinus promotes vagal activity via the arterial baroreflex while simultaneously withdrawing sympathetic nervous stimulation (4). A decreased central venous pressure (CVP) has also been reported, hypothesized as a result of the removal of hydrostatic pressure gradients, the decrease in intrathoracic pressure, and the reduced external pressure on the vascular system caused by the absence of tissue weight (5–7). Chronically, this fluid shift also leads to an endocrine-mediated reduction in circulating blood volume (8, 9). More recently, studies have reported alterations in jugular venous return, including flow stasis and, in some cases, flow reversal (10, 11). The spaceflight environment also increases hypercoagulability and endothelial dysfunction in the vascular system (12, 13). In combination with flow stasis, these factors increase the thrombotic risk of spaceflight (14). Significantly, at least one case study has reported the clinical manifestation of venous thrombosis occurring in an astronaut onboard the International Space Station (ISS) (15). Flow stasis and venous thrombosis in the upper body present a previously unidentified and potentially serious medical risk to both professional and recreational astronauts (16). Increased thrombogenicity could lead to embolic events on return to a gravitational environment if preformed thrombi are dislodged during reentry and landing (14). With the growth of commercial spaceflight, recreational astronauts are likely to be particularly at risk because of the possibly reduced medical standards and the possibility for participants with multiple preexisting comorbidities and/or undiagnosed asymptomatic cardiovascular pathologies to travel to space (17–19). Furthermore, the cephalad fluid shift is likely related to a series of ocular manifestations occurring in both short- and long-duration spaceflight, collectively known as spaceflight-associated neuro-ocular syndrome (SANS) (20–22). The exact pathoetiology of SANS is currently unknown. However, in previous publications we have hypothesized a possible relationship between SANS and chronically elevated ocular perfusion pressure (OPP) as a result of the greater gravitational dependence of mean arterial pressure at eye level (MAP_eye) than intraocular pressure (IOP) (23). Removal of tissue weight has also been posited to be part of the etiology of SANS (6). On Earth, humans experience fluid shifts daily due to natural postural changes (for example standing up vs. lying down to sleep). However, in microgravity conditions, the fluid shift is sustained continuously and over long periods of time.

Limited studies have measured jugular characteristics in altered-gravity environments (10, 24, 25). However, at present there exist no predictive models for the expected hemodynamic response to any given dose of gravity (including partial gravities). Thus, it is important to quantify jugular hemodynamics as a function of changes in the gravitational vector to inform the assessment of the pathogenesis of both spaceflight venous thromboembolism events and SANS.

Outside of the spaceflight environment, we can simulate altered gravity with a tilt paradigm, where the magnitude of the gravitational vector resolved along the cranio-caudal axis changes with the tilt angle. Six degrees head-down tilt (HDT) has been frequently used as an analog to simulate the fluid shift induced by microgravity in both acute and long-duration studies (23, 26–31). There exists some controversy over the representativeness of 6° HDT as a spaceflight analog, because of differences in the physiological response compared with microgravity (32–34). One example is the response of central venous pressure, which is observed to increase in HDT yet decrease in microgravity (5, 35). Quantifying hemodynamics in a tilt paradigm is also informative for surgical applications on Earth, where HDT is used in a clinical setting. For example, Trendelenburg positioning is used to increase surgical access for a number of surgeries including abdominal and gynecological procedures (36–38). Internal jugular vein cannulation is frequently used, in both routine surgery and Trendelenburg positioning, for hemodynamic monitoring and central venous access (39, 40). During venous cannulation, the size of the vein is important to minimize complications (41), and differences between the relative sizes of right- and left-side veins have previously been reported (42–44).

Cerebral venous drainage via the internal jugular veins is critical for regulation of intracranial pressure (ICP). In the upright position the jugular vein collapses, acting as a Starling resistor to protect the cerebral and central venous systems from severe negative pressure due to their anatomical position above the hydrostatic indifference point (10). On Earth, diurnal variation and postural changes act as part of the regulatory system for ICP. Previous terrestrial head-down tilt bed rest (HDTBR) and spaceflight studies (10, 45) have suggested that the acute increase in internal jugular venous pressure (IJVP) due to weightlessness, and the removal of daily variation patterns caused by postural changes in a gravitational field, are related to the increase in ICP and transmural central venous pressure (with respect to the upright position) found during microgravity exposure (46, 47). These changes in cerebral pressures are likely part of the etiology of SANS (23). Furthermore, the engorgement of the jugular veins could suggest an increase in passive blood pooling in the upper body venous system (48). Blood pooling, as an indicator of flow alterations, is related, via Virchow’s triad, to increased thromboembolic risk (49). Our study aims to fully characterize the evolution of the carotid and jugular vessel pressure and area when systematically exposed to increasing HDT angles. We aim to generate terrestrial models that serve as a reference for spaceflight and that can be used to compare the magnitude of microgravity (or partial gravity) response. Our work expands on previous work by Marshall-Goebel et al. (10) by capturing variation on both the left and right sides of the vascular system as well as in both supine and prone positions. We also consider a greater range of tilt angles.

In this study, we aimed to quantify acute changes in carotid and jugular venous characteristics caused by altering the gravitational environment with a graded tilt paradigm with a wide range of “gravitational conditions” (i.e., tilt angles), covering both head-up tilt (HUT) and HDT. Subsequently, we generated gravitational dose-response curves quantifying how the carotid artery area, the internal jugular vein area, and the internal jugular vein pressure respond to a given “dose” of altered gravity. Furthermore, by placing subjects in both supine (face up) and prone (face down) positions, we can reverse the direction of the gravitational vector, gaining additional insight into the role of extravascular pressures on hemodynamic response.

METHODS

Subjects and Study Approval

Twelve healthy, recreationally active male subjects between 23 and 33 yr old were recruited to participate in the study. Subject characteristics (means ± SD) are shown in Table 1. Specific subjects were selected to limit the age range as much as possible, to avoid additional confounding factors related to aging. Exclusion criteria included current use of any cardiac, blood pressure, muscle relaxant, anticoagulant, or stimulant medications, thyroid disease, chronic cardiovascular pathologies, extreme obesity, and history of hypertension. One subject was unable to complete one single condition (45° HDT, supine position) because of discomfort. However, he was returned to a head-up tilt position and experienced no lasting symptoms. The remainder of his data are included in the results. All other subjects completed the full protocol and experienced no adverse effects. Each subject received written and verbal explanations of the study protocols and gave written informed consent to participate in the experiment. All procedures performed in the study were in accordance with the 1964 Helsinki Declaration and its later amendments. The study protocol was approved by the Texas A&M Human Research Protection Program with Institutional Review Board number IRB2020-0724F.

Table 1.

Characteristics of 12 recreationally active male subjects who participated in the study

Characteristic	Value
n	12
Race	W (8), B (1), A (3)
Age, yr	26.8 ± 2.9
Height, cm	179.0 ± 8.3
Weight, kg	84.7 ± 18.7
BMI, kg/m2	26.3 ± 4.9
SBP, mmHg	129.5 ± 14.5
DBP, mmHg	82.3 ± 6.5

Data are reported as means ± SD where appropriate. Characteristics were recorded during the baseline session (seated upright) before testing sessions. Race categories: W, White; B, Black or African American; A, Asian. BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure.

Experimental Design and Testing Protocol

The complete experimental design has been fully described in a previous publication (4). In brief, all subjects took part in two separate sessions within a 2-wk period during which they were tilted from 45° HUT to 45° HDT in 15° increments with a tilt table (World Triathlon Corporation, Tampa Bay, FL). One session was in the supine (face up) position and one session was in the prone (face down) position, with the order counterbalanced between subjects. In the prone position, subjects rested with their forehead on a thin cushion 1) to support the weight of the head and prevent excessive stress on neck musculature, 2) to keep the cervical spine in a position anatomically similar to when supine, and 3) to facilitate normal ventilation, with the mouth and nose slightly displaced from the tilt table. At each tilt angle, subjects rested for ∼12 min while a range of continuous and discrete hemodynamic and autonomic measurements were collected (a 5-min rest period followed by ∼7 min of data collection). The data collection procedure was repeated at all tilt angles and also in a seated baseline during an orientation session before the first testing session. The gravitational dose responses of the systemic and autonomic hemodynamics are described in a previous publication (4). However, for completeness, data on the heart rate (HR) and blood pressure responses [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] are also presented below. This article analyzes measurements of carotid and jugular hemodynamics collected during the experiment by ultrasound (US) and compression sonography.

Instrumentation and Data Collection

The dependent variables are the following metrics related to cephalad blood circulation: 1) common carotid artery cross-sectional area (A_CCA, mm², right and left sides); 2) internal jugular vein cross-sectional area (A_IJV, mm², right and left sides); and 3) internal jugular vein pressure (IJVP, mmHg, right and left sides). Areas A_CCA and A_IJV were obtained with ultrasound (US) imagery (Vscan Extend; GE Healthcare, Chicago, IL). Pressure measurements were collected with a noninvasive peripheral venous pressure measuring device (VeinPress; VeinPress GmbH, Münsingen, Switzerland) attached to the probe head of the ultrasound.

Measurements of A_CCA were obtained from two 4-s, 15 Hz US videos recorded in each experimental condition (i.e., angle-position-side combination), capturing a transverse view of the CCA. Measurements were collected ∼30 mm inferior to the CCA bifurcation point (around the C3 vertebral level). These two video files were separated into 120 individual images (60 images per video). The images were processed by cell segmentation techniques: images were thresholded (50) and subsequently segmented with a watershed algorithm (51). Each image was manually inspected, and segmentation failures were discarded. The CCA was identified in each of the successfully segmented images based on pixel count. Finally, the A_CCA for each angle-position-side combination was calculated as the 20% trimmed mean of all the CCAs previously identified. Figure 1A shows a flow diagram of the A_CCA calculation algorithm.

Figure 1.

A: flow diagram for the common carotid artery (CCA) area (A_CCA) calculation algorithm. Individual frames of two 4-s, 15 Hz videos (60 frames per video, a total of 120 frames) are filtered and segmented to identify the CCA area based on pixel count. This process is repeated for all 120 available frames. Finally, the A_CCA at each experimental condition (i.e., angle-position-side combination) is calculated as the 20% trimmed mean of all the CCAs previously identified. B and C: internal jugular vein (IJV) area (A_IJV) shown for the same subject in 2 conditions: 45° head-up tilt (B) and 45° head-down tilt (C).

In each experimental condition, ultrasound images of the IJV were collected using a transverse view at the same level as the CCA (i.e., C3 vertebra). All images were collected at end-expiration. Because of its irregular shape and varying size, A_IJV could not be obtained with the previously described segmentation methods that were used to calculate A_CCA. Instead, two trained operators, acting independently, manually identified and circumscribed the IJV on each image to calculate A_IJV based on pixel count. If the two measured areas from the different operators differed by <10%, the final A_IJV in that condition was calculated as the average of the two independently measured areas. However, if the measured area differed by >10%, a third operator repeated the circumscription and the final A_IJV in that condition was calculated as the average of the three independently measured areas (Fig. 1, B and C).

Internal jugular vein pressure (IJVP) was obtained by manually compressing the IJV with the VeinPress manometer attached to the head of the US. The VeinPress device was zeroed before each measurement. Pressure was recorded at the point at which the walls of the IJV vessel were just about to touch each other. When this occurred, the pressure reading was allowed to stabilize for 2 s to counter any inertial effects. Two IJVP measurements were collected at each angle-position-side combination, and the final IJVP in that condition was calculated as the average of the two measurements.

Statistical Analysis

Data are reported as means ± SE unless otherwise stated. Data from all measurements were distributed approximately normally at each tilt angle, side (left or right), and position (supine or prone) combination, assessed by Shapiro–Wilk tests.

Because of the observed nonlinearity between tilt angle and some dependent variables, gravitational dose-response curves were constructed with generalized additive mixed-effects models (GAMMs). GAMMs were used to assess the effects of position (supine or prone), side (left or right), and tilt angle on measurements within subjects. Position (supine or prone) and Side (left or right) were included as parametric terms, and the sine of the tilt angle was included as a smoothed term (the seated baseline was not included in GAMMs). Sine of the angle was chosen to represent the resolved craniocaudal component of gravitational vector acting in the vertical direction. The smoothed term was fit using shrinkage cubic splines, with individual splines fit to each factor (Position or Side) where those factors were significant. Subjects were included as a random intercept. GAMMs were fit with restricted maximum likelihood. Diagnostic plots for all models were examined visually to confirm normality and homoscedasticity of residuals. Since ultrasonography images were two dimensional, the variance of measurements of A_CCA and A_IJV increased with the size of the measurement. Thus, a square-root transformation was performed on A_CCA and A_IJV before fitting the model, avoiding issues with heteroscedasticity. We elected to use $\sqrt{\mathrm{area}}$ (as opposed to a diameter) since, whereas CCAs were approximately circular in all subjects, the transverse IJV section was highly irregular and greatly varied in shape. The GAMM function used is shown in Eq. 1:

$$y_{ijk}={\beta }_0+{\beta }_1\left(\mathrm{Position}\right)+{\beta }_2\left(\mathrm{Side}\right)+f_{jk}\left[\sin \left(\mathrm{Angle}\right)\right]+{\gamma }_i+{\epsilon }_{ijk}$$ (1)

where, for each dependent variable, the measurement y_ijk for subject i (i = 1:12) in position j (j = 1:2, supine and prone, respectively) on side k (k = 1:2, left and right, respectively) is described by the tilt angle (from 45° HUT to 45° HDT), the parametric coefficients β (where β₀ represents the intercept), the smoothed splines f_jk(·), the random intercept γ_i (associated with each subject and the within-subject design), and the residual error ε_ijk. GAMMs are shown as means ± 95% confidence interval, and only significant effects are included.

All statistical analyses were completed with R version 4.1.0 (52), with GAMMs fit with the mgcv package (53). Plots of the smoothed terms are included in the appendix (Fig. A1), and the fitted GAMM objects are provided in the public data repository alongside the data sets. Significance level was set at α = 0.05 (2 sided).

RESULTS

Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) responses to graded HUT and HDT are presented in Table 2 (means ± SE). The complete data analysis, including the gravitational dose-response curves for these variables, is reported in Whittle et al. (4). In summary, HR decreased in a linear fashion from 82.2 ± 2.3 beats/min at 45° HUT to 64.0 ± 3.5 beats/min at 45° HDT in the supine position and from 86.8 ± 3.1 beats/min at 45° HUT to 70.8 ± 2.3 beats/min at 45° HDT in the prone position. Linear dose-response curves also fit the SBP and DBP data, with both variables decreasing with increasing HDT. However, there were no significant differences in blood pressure (SBP or DBP) between the supine and prone positions. Both pressure numerics were well controlled, with variation of <15 mmHg across the tilt angle range considered.

Table 2.

Heart rate and systolic and diastolic blood pressure response of 12 recreationally active male subjects to graded head-up tilt and head-down tilt in supine and prone postures

	HR, beats/min (73.6 ± 2.9 seated)		SBP, mmHg (129.5 ± 4.2 seated)		DBP, mmHg (82.3 ± 1.9 seated)
Tilt Angle	Supine	Prone	Supine	Prone	Supine	Prone
45° HUT	82.2 ± 2.3	86.8 ± 3.1	127.7 ± 2.8	129.4 ± 2.6	82.5 ± 1.4	84.3 ± 1.9
30° HUT	78.3 ± 2.4	84.3 ± 2.4	125.4 ± 3.1	128.3 ± 2.0	81.9 ± 2.2	83.1 ± 1.9
15° HUT	71.8 ± 2.4	80.5 ± 1.9	121.3 ± 4.0	123.3 ± 2.5	76.2 ± 2.4	77.5 ± 2.0
0°	68.8 ± 2.1	74.5 ± 2.1	130.1 ± 7.3	121.7 ± 3.8	74.0 ± 2.1	75.5 ± 2.5
15° HDT	67.9 ± 2.3	73.2 ± 1.9	127.4 ± 3.4	122.6 ± 2.7	73.5 ± 1.8	74.7 ± 2.0
30° HDT	66.3 ± 2.6	69.6 ± 1.6	120.3 ± 4.0	121.1 ± 6.5	69.5 ± 2.5	72.3 ± 2.7
45° HDT	64.0 ± 3.5	70.8 ± 2.3	125.8 ± 3.5	123.1 ± 3.2	75.1 ± 2.2	74.8 ± 2.6

Data are reported as means ± SE. Dose-response curves for these variables and additional cardiovascular parameters are reported in Whittle et al. (4). DBP, diastolic blood pressure; HDT, head-down tilt; HR, heart rate; HUT, head-up tilt; SBP, systolic blood pressure.

Figure 2A shows the A_CCA as a function of tilt angle (including the seated baseline). Table 3 reports the results of the GAMM analysis. There was no significant effect of Position (P = 0.341), Side (P = 0.849), or sin(Angle) (P =0.262). In the supine posture, A_CCA increased from 34.3 ± 1.9 mm² in 45° HUT to 46.0 ± 3.1 mm² in 45° HDT (averaged left and right sides). However, this change was not statistically significant when all factors were considered. In the prone posture, there was no noticeable trend of A_CCA: 36.9 ± 1.6 mm² in 45° HUT and 34.0 ± 3.5 mm² in 45° HDT (averaged left and right sides). The lack of significance of any factors was captured by the dose-response curve constructed via GAMM in Fig. 2B, which appears as a horizontal line. Because of the observable fluctuations in measured A_CCA, a gravitational dose-response curve constructed in this fashion was only able to explain 22.6% of the observed deviance.

Figure 2.

A: right (blue) and left (red) common carotid artery cross-sectional area (A_CCA) as a function of tilt angle in supine (solid line, ●) and prone (dashed line, ○) positions, collected in 12 male subjects. Measurements were taken at a seated baseline, 45° head-up tilt (HUT), 30° HUT, 15° HUT, 0°, 15° head-down tilt (HDT), 30° HDT, and 45° HDT. Data are presented as means ± SE at each tilt angle. B: gravitational dose-response curve (mean and 95% confidence interval) fitted from experimental data with generalized additive mixed-effects models (see text for methodology).

Table 3.

Details of generalized additive mixed-effects models analyses for three dependent variables: common carotid artery cross-sectional area, internal jugular vein cross-sectional area, and internal jugular vein pressure

	Parametric Terms				Smooth Termsc Sin(Angle)d				Subject SDf (σ)	Deviance Explained,g %
	Positiona		Sideb
	t	P	t	P	Curve	EDFe	F	P
$\sqrt{{\mathbf{A}}_{\mathbf{C}\mathbf{C}\mathbf{A}}}$, mmh	–0.954	0.341	–0.190	0.849		0.23	0.048	0.262	0.49	22.6
$\sqrt{{\mathbf{A}}_{\mathbf{I}\mathbf{J}\mathbf{V}}}$, mmh	0.439	0.663	–3.923	<0.001	Right	4.18	84.874	<0.001	1.10	78.0
					Left	3.41	58.191	<0.001
IJVP, mmHg	3.521	<0.001	–0.287	0.775	Supine	3.43	67.334	<0.001	5.92	76.2
					Prone	3.34	72.441	<0.001

Significance of parametric and smoothed terms, effective degrees of freedom of smoothers, size of subject random effect, and model goodness of fit (deviance explained). See text for model details.$\sqrt{{\mathrm{A}}_{\mathrm{CCA}}}$, common carotid artery cross-sectional area; ($\sqrt{{\mathrm{A}}_{\mathrm{IJV}}}$), internal jugular vein cross-sectional area; GAMM, generalized additive mixed-effects model; IJVP, internal jugular vein pressure. ^aPosition: supine or prone; t reports effect size of prone compared with supine. ^bSide: right or left; t reports effect size of left compared with right. ^cShrinkage-penalized cubic regression splines fit to each Position and Side combination; plots of the smoothers are included as Fig. A1. ^dSine of the tilt angle in radians; positive values indicate head-up tilt (HUT); F reports effect size. ^eEffective degrees of freedom. ^fRandom effect γ ∼ N(0,σ²). ^gGoodness of fit, equivalent to the unadjusted R². ^hSee text; measurements of CCA and IJV size were homoscedastic in diameter, and thus a square-root transformation was used on the cross-sectional area response.

Figure 3A shows the A_IJV as a function of tilt angle (including the seated baseline). Table 3 reports the results of the GAMM analysis. There was no significant effect of Position (P = 0.663). However, the factor Side was statistically significant (P < 0.001) as well as the smoothed term sin(Angle) for both the left and right sides (P < 0.001 for both sides). The IJV markedly expanded from 45° HUT (right side: 18.6 ± 2.6 mm², left side: 15.1 ± 2.2 mm², average of supine and prone positions) to 45° HDT (right side: 196 ± 15.8 mm², left side: 161 ± 14.1 mm², average of supine and prone positions). On both sides, the expansion was nonlinear. Given the significant differences found between the right and left sides, we constructed two gravitational dose-response curves, shown in Fig. 3B, one for each side. Together, they fit the experimental data set well, explaining 78.0% of the observed deviance in the data.

Figure 3.

A: right (blue) and left (red) internal jugular vein cross-sectional area (A_IJV) as a function of tilt angle in supine (solid line, ●) and prone (dashed line, ○) positions, collected in 12 male subjects. Measurements were taken at a seated baseline, 45° head-up tilt (HUT), 30° HUT, 15° HUT, 0°, 15° head-down tilt (HDT), 30° HDT, and 45° HDT. Data are presented as means ± SE at each tilt angle. B: gravitational dose-response curves (mean and 95% confidence interval) fitted from experimental data with generalized additive mixed-effects models (see text for methodology); separate curves created for right and left sides.

Figure 4A shows the IJVP as a function of tilt angle (including the seated baseline). Table 3 reports the results of the GAMM analysis. There was no significant effect of Side (P = 0.775). However, the factor Position was statistically significant (P < 0.001) as well as the smoothed term sin(Angle) for both the supine and prone postures (P < 0.001 for both postures). IJVP increased from 45° HUT (supine: 10.4 ± 2.0 mmHg, prone: 11.6 ± 2.0 mmHg, average of left and right sides) to 45° HDT (supine: 56.0 ± 2.1 mmHg, prone: 59.4 ± 2.2 mmHg, average of left and right sides). On average, IJVP was 4.3 ± 1.2 mmHg higher in the prone posture than in the supine posture. Similarly to A_IJV, the increase in pressure was nonlinear. Given the significant differences found between the supine and prone postures, we constructed two gravitational dose-response curves, shown in Fig. 4B, one for each posture. Together, they explain 76.2% of the observed deviance in the data.

Figure 4.

A: right (blue) and left (red) internal jugular vein pressure (IJVP) as a function of tilt angle in supine (solid line, ●) and prone (dashed line, ○) positions, collected in 12 male subjects. Measurements were taken at a seated baseline, 45° head-up tilt (HUT), 30° HUT, 15° HUT, 0°, 15° head-down tilt (HDT), 30° HDT, and 45° HDT. Data are presented as means ± SE at each tilt angle. B: gravitational dose-response curves (mean and 95% confidence interval) fitted from experimental data with generalized additive mixed-effects models (see text for methodology); separate curves created for supine and prone positions.

DISCUSSION

This study quantified CCA and IJV characteristics in graded head-up and head-down tilt. In addition, gravitational dose-response curves were constructed from the experimental data. Our main findings show the following: 1) A_CCA is not gravitationally dependent. In addition, there is no significant difference between the left and right sides. 2) In contrast, IJV characteristics show a high gravitational dependence, exhibiting a marked nonlinear behavior. 3) A_IJV is larger on the right side and expands more than on the left side. 4) IJVP is higher in the prone position than in the supine position.

In the 0° supine posture, we measure A_CCA as 34.1 ± 1.6 mm² (average of supine and prone, left and right sides), equivalent to a vascular diameter of 6.6 ± 0.5 mm. These results are congruent with reference values found in the literature, including Scheel et al. (54) (6.0 ± 0.7 mm) and Krejza et al. (55) (6.5 ± 1.0 mm). Furthermore, existing studies have found no significant difference between the left and right CCA geometries (56). Multiple studies have considered measurements of carotid arteries during tilt interventions, often in the context of investigating cerebral blood flow (57–59). Many of these studies measure the geometry of the internal carotid arteries (ICAs) and/or the vertebral arteries (VAs). It is likely that the same trends seen in ICA during tilt would be followed by CCA because of the similar characteristics of the two sections of the vessel (60). During an acute HUT maneuver (from supine to 70° HUT), van Campen et al. (57) noted no change in the diameter of the VA or right ICA and only a minor decrease in the diameter of the left ICA from 4.63 ± 0.46 mm to 4.49 ± 0.50 mm (P < 0.05). These results are similar to data from Sato et al. (59), who reported a slight decrease in ICA diameter (4.9 ± 0.1 mm to 4.7 ± 0.1 mm; P < 0.05) between 0° and 60° HUT, along with no significant change in VA diameter. Our measurements do not include HUT conditions over 45° HUT; however, we do not find any significant difference between A_CCA at 45° HUT and at a seated baseline. In contrast, Hannerz et al. (61) noted a slight significant increase in CCA diameter of 0.3 mm shortly after entering 15° HDT from 0° supine in subjects with chronic tension-type headaches, although the authors also noted that this increase was reversed 30 min after a placebo injection. We can hypothesize that any transient change in CCA geometry due to a sudden fluid shift is likely to be very short lived, on the order of minutes. Even a long period in mild altered gravity does not appear to alter the size of the CCA. For example, Palombo et al. (58) noted no change in CCA geometry or stiffness after 5 wk of head-down tilt bed rest (HDTBR). Similarly, Ogoh et al. (62) found no significant change in CCA compliance after 57 days of HDTBR.

In contrast to CCA results, our findings show that the A_IJV is highly dependent on tilt and that there is a difference between the geometries of the left and right IJVs. Lorchirachoonkul et al. (42) measured a larger IJV diameter on the right side compared to the left side (right: 13.4 ± 4.5 mm, left: 11.0 ± 4.4 mm; P < 0.05) in a moderate Trendelenburg position (15° HDT). Our results are consistent with Lobato et al. (43), who also noted the larger size of the right IJV with respect to the left IJV. Furthermore, Lobato and colleagues compared the increase in size of the left and right IJVs between the 0° supine and the 10° HDT Trendelenburg positions, noting an ∼20 mm² increase in the left IJV compared with a 35 mm² increase in the right IJV. The differences in size between the left and right IJVs are likely explained by a combination of anatomy (63) and embryologic origins (64, 65). Variation in the expansion of the left and right IJVs shown in Fig. 3B suggests that there could be a difference in compliance between the two IJVs. A paucity of data exists on left IJV compliance. However, further analysis of data from Tarnoki et al. (66) would suggest values for specific compliance (i.e., compliance per unit length) of 3.9 ± 0.2 mL/mmHg/mm for the right IJV and 2.5 ± 0.2 mL/mmHg/mm for the left IJV in a study of 169 subjects.

Anatomically, blood drains into the IJVs from the cranial sinuses via the left and right transverse sinuses (TSs) (67). Saiki et al. (63) demonstrated different drainage patterns between individuals. They noted that in 73.6% of 91 subjects the superior sagittal sinus drained principally (either perfectly or imperfectly: 100% or the vast majority) into the right TS (and hence the right IJV), whereas in 72.6% of subjects the smaller straight sinus drained equivalently into both the left and right TSs or favored the left TS (63). Thus, in the majority of people, the blood flow through the right IJV originates principally from the larger sagittal sinus and the blood flow through the left IJV originates from the smaller straight sinus. In addition, Saiki et al. hypothesized that the difference in jugular vein size is related to embryonic development, specifically the anastomosis of the left and right anterior cardinal veins leading to the disappearance of the left superior vena cava. This leads to a lower vascular resistance in the right-side path, leading to a shift of superior sagittal sinus drainage toward the right TS. We hypothesize that increased venous compliance in the right IJV is also related to this early development, with the increased blood flow in the right IJV leading to increased compliance as a result of previously identified mechanotransduction pathways during embryonic development (68).

Conversely, we found no significant differences between the left and right IJVP. The venous system splits at the confluence of sinuses before rejoining at the superior vena cava (69). Across the anatomical distance where the left and right sides are separated, the largest pressure drop occurs between the distal sigmoid and jugular bulb (70) such that, by the section where we took our measurements, proximal to the jugular bulb, IJVP on both sides is only slightly elevated above central venous pressure (71, 72). Thus, we do not expect pressures on either side to be much elevated above CVP, and hence we do not expect to see a difference between the left and right sides at the measured point. However, we note a significant difference in IJVP between the prone and supine positions. Specifically, in the prone position IJVP was, on average, 4.3 ± 1.2 mmHg higher than in the supine position. To our knowledge, this is the first study comparing the effect of posture (supine vs. prone) on IJVP. Moreover, our results are congruent with broader hemodynamic measures collected during the same study (4). We previously hypothesized that thorax compression in the prone position leads to a decreased stroke volume and cardiac output, along with increased total peripheral resistance. We further hypothesize here that this thorax compression elevates intrathoracic pressure (73) and hence central venous pressure in the prone position (74). This is reflected in our measurements as an increase in IJVP. This is supported by studies demonstrating elevated central venous pressure during a Valsalva maneuver (75, 76).

Comparison with Spaceflight Studies

A preliminary assessment of the gravitational dose-response curves can be made by comparing our results with a variety of studies that have measured A_IJV and IJVP in altered-gravity conditions. Figure 5 presents experimental data from studies by Marshall-Goebel et al. (10), Lee et al. (24), and David et al. (25), superimposed on our A_IJV and IJVP gravitational dose-response curves. Marshall-Goebel et al. conducted a cohort study with 11 astronauts to investigate the left IJV on Earth (in seated, supine, and 15° HDT positions) and during long-duration spaceflight, with data collected in flight on day 50 (FD50) and day 150 (FD150). Lee et al. conducted a parabolic flight study in which investigators collected experimental data from the right IJV (right A_IJV in 9 subjects, right IJVP in 6 subjects) in different gravitational conditions: 1 g seated, 0.75 g, 0.50 g, 0.25 g, and microgravity. David et al. conducted a study in a single Russian astronaut in which the right A_IJV was measured preflight across a range of tilt angles. Partial gravity data collected during parabolic flight [Lee et al. (24)] are depicted in Fig. 5 as the equivalent tilt position obtained by projecting the gravitational vector along the craniocaudal axis for tilt [e.g., 0.50 g is placed at 30° HUT since sin⁻¹(30°) = 0.5]. Data obtained in microgravity conditions [Lee et al. (24) and Marshall-Goebel et al. (10)] are superimposed at 6° HDT, since this is the most commonly used analog for microgravity (23, 26–28).

Figure 5.

A and B: comparison of the internal jugular vein area (A_IJV; A) and the internal jugular vein pressure (IJVP; B) gravitational dose-response curves with spaceflight-related studies that include relevant data during tilt [Marshall-Goebel et al. (10), David et al. (25)], parabolic flight [Lee et al. (24)), and in flight [Marshall-Goebel (10)]. Data collected in a weightless condition are placed at 6° head-down tilt (HDT), data at partial gravity from parabolic flight are placed at a tilt angle representative of the equivalent gravitational vector resolved along the craniocaudal axis. FD, flight day; μg, Microgravity.

Data for A_IJV demonstrates good agreement with the dose-response curves for both parabolic flight and tilt data. Data for IJVP in the same conditions is more difficult to interpret because of the low number of points and reduced number of subjects. Data from Marshall-Goebel et al. indicate that, although A_IJV in flight is elevated with respect to the seated position, it is actually reduced with respect to the supine position. This decrease seems to be exacerbated with more prolonged time in microgravity. IJVP is elevated from the (preflight) supine position after 50 days in microgravity, then reduced when remeasured after 150 days in microgravity. Based on a 6° HDT model for microgravity, we would expect A_IJV and IJVP to be elevated compared with 0° supine. There are multiple potential reasons for this difference. First, the dose-response curves generated represent an acute rather than chronic response. Entry to microgravity conditions precipitates a number of chronic changes in the hemodynamic system (9). Principal among these changes is the neurally mediated reduction in circulating blood volume by the renin-angiotensin-aldosterone (RAAS) endocrine system (77). This reduction in blood volume, which occurs over the first few hours in space, lowers fluid pressures throughout the systemic circulation, leading to decreased distension after a prolonged period (10, 78). Second, measurement of the IJVP with the noninvasive VeinPress device is dependent on the tissue surrounding the vein. Measurements of IJVP with the VeinPress are likely slightly elevated compared with the true venous pressure, because of compression of the tissue surrounding the IJV. Changes in fluid compartmentalization (79–81), including fluid shift to extravascular spaces as well as potential changes in the neck tissue due to chronic muscular deconditioning over long-duration spaceflight, may result in both a reduced venous pressure as well as an underestimation of that measurement (82). Third, there are fundamental differences in the vascular response to tilt compared with true microgravity. One key difference refers to the central venous pressure (CVP) response. On Earth, in a tilt paradigm, central venous pressure has been demonstrated to increase in HDT (37, 83) with respect to the supine position. However, data from spaceflight indicate that CVP actually decreases in microgravity (with respect to the same supine reference position). Buckey et al. (6) hypothesize that the reason for this disparity is driven by the removal of external pressures on the vascular system when exposed to true microgravity, because of the absence of tissue weight. Computational models of systemic circulation accounting for this removal of tissue weight support this hypothesis, demonstrating the anticipated reduction, rather than rise, in CVP (84). Given that IJVP is only minimally elevated above CVP, we further hypothesize that this decrease in CVP in microgravity also leads to a decreased IJVP and A_IJV with respect to the anticipated response from the dose-response curves generated in 1 g conditions with a tilt paradigm. These differences suggest that, in cases where fluid shift and hemodynamic pressures in the head and neck are important, for example when considering the pathoetiology of SANS or venous thromboembolic events, the standard 6° HDT model of microgravity may require reevaluation.

Overall, our results are congruent with studies supporting an increase in both jugular vein engorgement and jugular venous pressure in space (10, 45, 47, 48, 85). These data serve as a reference terrestrial model that can be used to compare the magnitude of A_CCA, A_IJV, and IJVP changes occurring on entry to microgravity (and, in the future, partial gravity) conditions. In addition, these dose-response models can be an invaluable resource to support the development of spaceflight countermeasures focused on counteracting the headward fluid shift and the associated hydrostatic changes [e.g., artificial gravity (86, 87)]. Such countermeasures could be used to reduce incidence of SANS and decrease venous thromboembolic risk (88).

We acknowledge several limitations of this study. First, the study population included only male subjects. Diagnoses of SANS during spaceflight have been predominantly among males, although the low number of female astronauts to date suggests that this difference may not be statistically significant (21). Furthermore, there are undoubtedly hemodynamic differences between male and female physiology. Studies by Scheel et al. (54) and Krejza et al. (55) have demonstrated that the CCA is significantly smaller in women than in men. Similarly, Choudhry et al. (56) found that men presented a larger CCA at the bifurcation point than women. To reduce variability in the dose-response curves, it was determined that males and females should be considered separately. This is supported by recent work by Patterson et al. (88) suggesting significant differences in the attenuation of the jugular vein in response to orthostatic stress between men and women. Patterson et al. conclude that data should be interpreted in a sex-dependent manner. Future work will consider the effect of sex on the dose-response curves. Second, the dose-response curves only consider the acute response to altered gravity. From the discussion of Fig. 5 it was determined that chronic effects play a role in jugular vein hemodynamics, particularly in spaceflight studies. Consideration should be given to the chronic trends in the terrestrial dose-response curves [for example through head-down tilt bed rest (89) or computational models (90)], to determine whether they follow the same pattern of deconditioning/adaptation seen in flight studies (10). Furthermore, to minimize the transient effects of large fluid shifts, we elected to progress, as opposed to randomize, the tilt angle in our methodology. It is established that there exists some amount of hysteresis in the venous vascular system. However, there are conflicting data as to whether this leads to significant creep (91, 92). Although our data undoubtedly contain some component of vascular creep, we do not believe it to be significant in the context of the magnitude of the area and pressure changes shown. Third, the data collected were limited to noninvasive measures, in particular for IJVP. The VeinPress device used in the study was chosen for its heritage of use in previous spaceflight and parabolic flight investigations (10, 24, 82), thus facilitating direct comparison between studies. It is acknowledged that invasive measures, such as venous catheterization, may provide more accurate measurements of IJVP. However, noninvasive measurements using ultrasonography are well established in a clinical environment (93–95). Fourth, in this study we attempted to capture the mean response of the common carotid artery, as opposed to pulsatility. The data analysis workflow involved measuring and averaging A_CCA at 15 Hz across a number of heartbeats in a 4-s window. Thus, the data represent an arithmetic mean (similar to mean arterial pressure) used to determine whether there are larger systemic changes outside of the pulsatility. Future work should investigate the role of pulsatility of the carotid artery at different degrees of headward fluid shift. Ideally, this would be supplemented with flow measurements (i.e., peak systolic and end-diastolic flow) to capture a more complete hemodynamic response. Finally, pressure and area measurements are only two parts of the very complex picture of vascular hemodynamics. Although the pressure and area data are useful and informative on their own, future studies should also include flow measurements to provide a more complete understanding of jugular venous flow. In particular, an assessment of the characteristics of jugular vein flow as performed by Marshall-Goebel et al. may prove insightful. However, it is noted that they did not find any flow stagnation in a terrestrial setting in seated, supine, or 15° HDT positions (10).

Conclusions

In this article, common carotid artery area and internal jugular vein area and pressure are investigated in graded head-up and head-down tilt in both supine and prone postures. Our data reveal gravitational dependence of jugular vein characteristics, whereas the common carotid artery area remains constant across tilt angles. Based on the experimental data collected, we constructed gravitational dose-response curves based on additive mixed-effects models. Results show that the right IJV distends more than the left IJV. Pressure is not statistically different between the left and right internal jugular veins. However, pressure is significantly elevated in the prone position with respect to the supine position, hypothesized as a result of thorax compression raising central venous pressure. Comparison of the dose-response curves with external studies reveals good agreement in tilt. However, differences between tilt and true microgravity are also revealed, likely as a result of reduced compressive forces on the venous system in weightless conditions due to a combination of a reduction of intrathoracic pressure and the removal of tissue weight.

DATA AVAILABILITY

The data sets analyzed for this study are publicly available; a repository can be found on GitHub: https://github.com/BHP-Lab/carotid-jugular-characteristics. The fitted generalized additive mixed-effects models (GAMMs) are available with the data on GitHub.

GRANTS

This work was supported by the National Aeronautics and Space Administration (NASA) Human Research Program (HRP), Grant 80NSSC20K1521.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

R.S.W. and A.D.-A. conceived and designed research; performed experiments; analyzed data; interpreted results of experiments; prepared figures; drafted manuscript; edited and revised manuscript; and approved final version of manuscript.

ENDNOTE

At the request of the authors, readers are herein alerted to the fact that additional materials related to this manuscript may be found at https://github.com/BHP-Lab/carotid-jugular-characteristics. These materials are not a part of this manuscript and have not undergone peer review by the American Physiological Society (APS). APS and the journal editors take no responsibility for these materials, for the website address, or for any links to or from it.

APPENDIX

Figure A1 presents the fitted smoothed terms for the generalized additive mixed-effects models (GAMMs) fit to common carotid artery cross-sectional area, internal jugular vein cross-sectional area, and internal jugular vein pressure.

Figure A1.

Fitted smoothed terms for generalized additive mixed-effects models (GAMMs). The fitted models [R .rds files containing the models fitted via mgcv::gam()] have been made publicly available online along with the data sets analyzed for this study. A_CCA, common carotid artery cross-sectional area; A_IJV, internal jugular vein cross-sectional area; IJVP, internal jugular vein pressure.