Acute effects of postural changes and lower body positive and negative pressure on the eye.

Introduction: Entry into weightlessness results in a fluid shift and a loss of hydrostatic gradients. These factors are believed to affect the eye and contribute to the ocular changes that occur in space. We measured eye parameters during fluid shifts produced by lower body negative pressure (LBNP) and lower body positive pressure (LBPP) and changes in hydrostatic gradient direction (supine-prone) in normal subjects to assess the relative effects of fluid shifts and hydrostatic gradient changes on the eye. Methods: Ocular parameters (intraocular pressure (IOP), ocular geometry, and optical coherence tomography measures) were measured in the seated, supine, and prone positions. To create a fluid shift in the supine and prone positions, the lower body chamber pressure ranged from -40 mmHg to +40 mmHg. Subjects maintained each posture and LBNP/LBPP combination for 15 min prior to data collection. A linear mixed-effects model was used to determine the effects of fluid shifts (as reflected by LBNP/LBPP) and hydrostatic gradient changes (as reflected by the change from seated to supine and from seated to prone) on eye parameters. Results: Chamber pressure was positively correlated with both increased choroidal thickness (ß = 0.11 , p = 0.01) and IOP (ß = 0.06 p < 0.001). The change in posture increased IOP compared to seated IOP (supine ß = 2.1, p = 0.01, prone ß = 9.5, p < 0.001 prone) but not choroidal thickness. IOP changes correlated with axial length (R = 0.72, p < 0.001). Discussion: The effects of hydrostatic gradients and fluids shifts on the eye were investigated by inducing a fluid shift in both the supine and prone postures. Both hydrostatic gradients (posture) and fluid shifts (chamber pressure) affected IOP, but only hydrostatic gradients affected axial length and aqueous depth. Changes in choroidal thickness were only significant for the fluid shifts. Changes in hydrostatic gradients can produce significant changes in both IOP and axial length. Fluid shifts are often cited as important factors in the pathophysiology of SANS, but the local loss of hydrostatic gradients in the head may also play an important role in these ocular findings.

Detecting changes in distortion product otoacoustic emission maps using statistical parametric mapping and random field theory.

Distortion product otoacoustic emission (DPOAE) maps collect DPOAE emissions over a broad range of frequencies and ratios. One application of DPOAE mapping could be monitoring changes in intracranial pressure (ICP) in space, where non-invasive measures of ICP are an area of interest. Data were collected in two experiments to statistically assess changes in DPOAE maps. A repeatability study where four maps per subject were collected across four weeks to establish "normal" variability in DPOAE data, and a posture study where subjects were measured supine and prone with lower body negative pressure, lower body positive pressure (LBPP), and at atmospheric pressure. DPOAE amplitude maps were analyzed using statistical parametric mapping and random field theory. Postural changes produced regional changes in the maps, specifically in the range of 5-7.5 kHz and between primary tone ratios of 1.13-1.24. These regional changes were most pronounced in the prone LBPP condition, where amplitudes were lower from baseline for the Postural Cohort than the Repeatability Cohort. Statistical parametric mapping provided a sensitive measure of regional DPOAE map changes, which may be useful clinically to monitor ICP noninvasively in individuals or for research to identify differences within in cohorts of people.

Systematic review: The safety and efficacy of hyperbaric oxygen therapy for inflammatory bowel disease.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) provides 100% oxygen under pressure, which increases tissue oxygen levels, relieves hypoxia and alters inflammatory pathways. Although there is experience using HBOT in Crohn's disease and ulcerative colitis, the safety and overall efficacy of HBOT in inflammatory bowel disease (IBD) is unknown. AIM: To quantify the safety and efficacy of HBOT for Crohn's disease (CD) and ulcerative colitis (UC). The rate of adverse events with HBOT for IBD was compared to the expected rate of adverse events with HBOT. METHODS: MEDLINE, EMBASE, Cochrane Collaboration and Web of Knowledge were systematically searched using the PRISMA standards for systematic reviews. Seventeen studies involving 613 patients (286 CD, 327 UC) were included. RESULTS: The overall response rate was 86% (85% CD, 88% UC). The overall response rate for perineal CD was 88% (18/40 complete healing, 17/40 partial healing). Of the 40 UC patients with endoscopic follow-up reported, the overall response rate to HBOT was 100%. During the 8924 treatments, there were a total of nine adverse events, six of which were serious. The rate of adverse events with HBOT in IBD is lower than that seen when utilising HBOT for other indications (P < 0.01). The risk of bias across studies was high. CONCLUSIONS: Hyperbaric oxygen therapy is a relatively safe and potentially efficacious treatment option for IBD patients. To understand the true benefit of HBOT in IBD, well-controlled, blinded, randomised trials are needed for both Crohn's disease and ulcerative colitis.

Microbubbles are detected prior to larger bubbles following decompression.

Using dual-frequency ultrasound (DFU), microbubbles (<10 µm diameter) have been detected in tissue following decompression. It is not known if these microbubbles are the precursors for B-mode ultrasound-detectable venous gas emboli (bmdVGE). The purpose of this study was to determine if microbubbles could be detected intravascularly postdecompression and to investigate the temporal relationship between microbubbles and larger bmdVGE. Anesthetized swine (n = 15) were exposed to 4.0-4.5 ATA for 2 h, followed by decompression to 0.98 ATA. Microbubble presence and VGE grade were measured using DFU and B-mode ultrasound, respectively, before and for 1 h postdecompression, approximately every 4-5 min. Microbubbles appeared in the bloodstream postdecompression, both in the presence and absence of bmdVGE. In swine without bmdVGE, microbubbles remained elevated for the entire 60-min postdecompression period. In swine with bmdVGE, microbubble signals were detected initially but then returned to baseline. Microbubbles were not detected with the sham dive. Mean bmdVGE grade increased over the length of the postdecompression data collection period. Comparison of the two response curves revealed significant differences at 5 and 10 min postdecompression, indicating that microbubbles preceded bmdVGE. These findings indicate that decompression-induced microbubbles can 1) be detected intravascularly at multiple sites, 2) appear in the presence and absence of bmdVGE, and 3) occur before bmdVGE. This supports the hypothesis that microbubbles precede larger VGE bubbles. Microbubble presence may be an early marker of decompression stress. Since DFU is a low-power ultrasonic method, it may be useful for operational diving applications.

Human baroreflex rhythms persist during handgrip and muscle ischaemia.

AIM: To determine whether physiological, rhythmic fluctuations of vagal baroreflex gain persist during exercise, post-exercise ischaemia and recovery. METHODS: We studied responses of six supine healthy men and one woman to a stereotyped protocol comprising rest, handgrip exercise at 40% maximum capacity to exhaustion, post-exercise forearm ischaemia and recovery. We measured electrocardiographic R-R intervals, photoplethysmographic finger arterial pressures and peroneal nerve muscle sympathetic activity. We derived vagal baroreflex gains from a sliding (25-s window moved by 2-s steps) systolic pressure-R-R interval transfer function at 0.04-0.15 Hz. RESULTS: Vagal baroreflex gain oscillated at low, nearly constant frequencies throughout the protocol (at approx. 0.06 Hz - a period of about 18 s); however, during exercise, most oscillations were at low-gain levels, and during ischaemia and recovery, most oscillations were at high-gain levels. CONCLUSIONS: Vagal baroreflex rhythms are not abolished by exercise, and they are not overwhelmed after exercise during ischaemia and recovery.

Hearing loss and heavy metal toxicity in a Nicaraguan mining community: audiological results and case reports.

We measured fingernail metal levels, Békésy-type pure-tone thresholds and distortion product otoacoustic emission (DPOAE) levels in 59 subjects residing in the gold mining community of Bonanza, Nicaragua. Auditory testing revealed widespread hearing loss in the cohort. Nail metal concentrations (mercury, lead, aluminum, manganese and arsenic) far exceeded reference levels. No relationship was found between metal levels and auditory test results for the group as a whole. Statistically significant relationships were found between DPOAE response amplitudes and metal concentrations in a subgroup with less than 40 h per week of significant noise exposure; however, conclusions regarding these relationships should be tempered by the large number of analyses performed. Several young individuals with high metal levels reported neurological symptoms and had poor hearing. The data suggest that metal levels in artisanal mining communities present a significant public health problem and may affect hearing.

Microbubble detection following hyperbaric chamber dives using dual-frequency ultrasound.

Venous gas emboli (VGE) can be readily detected in the bloodstream using existing ultrasound methods. No method currently exists to detect decompression-induced microbubbles in tissue. We hypothesized that dual-frequency ultrasound (DFU) could detect these microbubbles. With DFU, microbubbles are driven with two frequencies: a lower "pump" (set to the resonant frequency of the desired bubble size) and a higher "image" frequency. A bubble of the resonant size emits the sum and difference of the two transmitted frequencies. For this study we used a pump frequency of 2.25 MHz and an image frequency of 5.0 MHz, which detects bubbles of roughly 1-10 µm in diameter in a water tank. Four anesthetized swine were pressurized at 4.5 ATA for 2 h and decompressed over 5 min, inducing moderate to very severe VGE scores. Four sites on the thigh of each swine were monitored with DFU before and after the dives. A single mock dive was also performed. The number of sites returning signals consistent with microbubbles increased dramatically after the chamber dive (P < 0.01), but did not change with the mock dive. The increase in DFU signal after the chamber dive was sustained and present at multiple sites in multiple swine. This research shows for the first time that decompression-induced tissue microbubbles can be detected using DFU and that DFU could be used to monitor decompression-induced microbubbles at multiple sites on the body. Additionally, DFU could be used to track the time course of microbubble formation and growth during decompression stress.

Signals consistent with microbubbles detected in legs of normal human subjects after exercise.

Exercise may produce micronuclei (presumably gas-filled bubbles) in tissue, which could serve as nucleation sites for bubbles during subsequent decompression stress. These micronuclei have never been directly detected in humans. Dual-frequency ultrasound (DFU) is a resonance-based, ultrasound technique capable of detecting and sizing small stationary bubbles. We surveyed for bubbles in the legs of six normal human subjects (ages 28-52 yr) after exercise using DFU. Eleven marked sites on the left thigh and calf were imaged using standard imaging ultrasound. Subjects then rested in a reclining chair for 2 h before exercise. For the hour before exercise, a series of baseline measurements was taken at each site using DFU. At least six baseline measurements were taken at each site. Subjects exercised at 80% of their age-adjusted maximal heart rate for 30 min on an upright bicycle ergometer. After exercise, the subjects returned to the chair, and multiple postexercise measurements were taken at the marked sites. Measurements continued until no further signals consistent with bubbles were returned or 1 h had elapsed. All subjects showed signals consistent with bubbles after exercise at at least one site. The percentage of sites in a given subject showing signals significantly greater than baseline (P < 0.01) at first measurement ranged from 9.1 to 100%. Overall, 58% of sites showed signals consistent with bubbles at the first postexercise measurement. Signals decreased over time after exercise. These data strongly suggest that exercise produces bubbles detectable using DFU.

Dual-frequency ultrasound detection of stationary microbubbles in tissue.

Indirect evidence suggests that microbubbles that exist normally in tissue may play a key role in decompression sickness (DCS). Their sizes and locations are unknown. Dual-frequency ultrasound (DFU) exploits bubble resonance to detect bubbles over a wide size range and could potentially detect stationary tissue microbubbles. To test this capability, DFU was used to detect stationary microbubbles of known size (2-3 microm mean diameter) over a range of ultrasound pressures and microbubble concentrations. In gelatin phantoms doped with microbubbles and in ex vivo porcine tissue, signals indicative of bubbles were detected for microbubble concentrations of 5x10(5) per mL and greater. Signals were not returned from solid particle microspheres of similar size to the microbubbles or from saline controls. In the thigh of an anesthetized swine, signals were detected for concentrations of 5x10(7) per mL and greater. Because of its ability to detect bubbles over a wide range of sizes, this technique could potentially detect naturally-existing microbubbles in tissue and lead to (a) an improved understanding of the mechanics of bubble formation during decompression and (b) a new metric for evaluating DCS.

Cardiac atrophy after bed rest and spaceflight.

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.

Effects of spaceflight on human calf hemodynamics.

Chronic microgravity may modify adaptations of the leg circulation to gravitational pressures. We measured resting calf compliance and blood flow with venous occlusion plethysmography, and arterial blood pressure with sphygmomanometry, in seven subjects before, during, and after spaceflight. Calf vascular resistance equaled mean arterial pressure divided by calf flow. Compliance equaled the slope of the calf volume change and venous occlusion pressure relationship for thigh cuff pressures of 20, 40, 60, and 80 mmHg held for 1, 2, 3, and 4 min, respectively, with 1-min breaks between occlusions. Calf blood flow decreased 41% in microgravity (to 1.15 +/- 0.16 ml x 100 ml(-1) x min(-1)) relative to 1-G supine conditions (1.94 +/- 0.19 ml x 100 ml(-1) x min(-1), P = 0.01), and arterial pressure tended to increase (P = 0.05), such that calf vascular resistance doubled in microgravity (preflight: 43 +/- 4 units; in-flight: 83 +/- 13 units; P < 0.001) yet returned to preflight levels after flight. Calf compliance remained unchanged in microgravity but tended to increase during the first week postflight (P > 0.2). Calf vasoconstriction in microgravity qualitatively agrees with the "upright set-point" hypothesis: the circulation seeks conditions approximating upright posture on Earth. No calf hemodynamic result exhibited obvious mechanistic implications for postflight orthostatic intolerance.

Hearing loss in space.

BACKGROUND: Temporary and, in some cases, permanent hearing loss has been documented after long-duration spaceflights. METHODS: We examined all existing published data on hearing loss after space missions to characterize the losses. RESULTS: Data from Russian missions suggest that the hearing loss, when it occurs, affects mainly mid to high frequencies and that using hearing protection often might prevent the loss. Several significant questions remain about hearing loss in space. While the hearing loss has been presumed to be noise-induced, no clear link has been established between noise exposure and hearing loss during spaceflight. In one documented case of temporary hearing loss from the Shuttle-Mir program, the pattern of loss was atypical for a noise-induced loss. Continuous noise levels that have been measured on the Mir and previous space stations, while above engineering standards, are not at levels usually associated with hearing loss in ground-based studies (which have usually been limited to 8-10 h exposure periods). Attempts to measure hearing in space using threshold-based audiograms have been unsuccessful in both the American and Russian programs due to noise interference with the measurements. CONCLUSIONS: The existing data highlight the need for reliable monitoring of both hearing and noise in long-duration spaceflight.

Preparing for Mars: the physiologic and medical challenges.

As the twentieth century closes, retrospectives cite the Apollo moon missions as one of the important events of the past 100 years. A trip to Mars, however, would be even more challenging and significant. A round-trip Mars journey would require nearly three years away from Earth, a significant leap in complexity compared to the two week long Moon trips or the record-breaking fourteen-month flight on Mir. What would be the physiologic and medical challenges of a Mars flight? Two key areas of physiology present the greatest potential problems--calcium metabolism and radiation exposure. Data from Mir missions show that bone loss continues in space despite an aggressive countermeasure program. Average losses were 0.35% per month, but some load bearing areas lost >1% per month. A 1% loss rate, if it continued unabated for 30 months, could produce osteoporosis. Smaller losses could still increase fracture risk. Some bone loss can be well tolerated, particularly if the bone can be regained after the mission. But the effectiveness of post-flight rehabilitation to restore the density and quality of bone after spaceflight is not well known. Bone loss estimates are based on continuous weightlessness exposure, but this is not a requirement for a Mars trip. Most of the time on a Mars trip will be spent in the 1/3 Earth's gravity environment on Mars, and either intermittent or continuous artificial gravity can be provided for the transit between planets (although at an engineering cost). The dosing of the gravity exposure (e.g. the level and duration), however, has not been established. Radiation protection also requires a balance between engineering cost and human health. Excessive shielding could add billions of dollars to the cost of a mission. Trips in interplanetary space, however, expose the crew to heavy high-energy particles from cosmic rays (HZE particles), which have a high linear energy transfer. This high energy leads to significant biological damage (e.g. chromosomal aberrations, cancer induction). A recent report from the Committee on Space Biology and Medicine notes that only one systematic study of cancer induction from high-energy particles has been conducted (using the mouse Harderian gland). Predictions of cancer risk and acceptable radiation exposure in space are extrapolated from minimal data. Other areas of physiology also present problems, such as muscle loss, cardiovascular deconditioning, and vestibular adaptation. Despite all the issues, however, a focussed, aggressive research program that uses the resources of the International Space Station should pave the way for mankind's greatest adventure--a trip to Mars.

Maximal exercise performance after adaptation to microgravity.

The cardiovascular system appears to adapt well to microgravity but is compromised on reestablishment of gravitational forces leading to orthostatic intolerance and a reduction in work capacity. However, maximal systemic oxygen uptake (Vo2) and transport, which may be viewed as a measure of the functional integrity of the cardiovascular system and its regulatory mechanisms, has not been systematically measured in space or immediately after return to Earth after spaceflight. We studied six astronauts (4 men and 2 women, age 35-50 yr) before, during, and immediately after 9 or 14 days of microgravity on two Spacelab Life Sciences flights (SLS-1 and SLS-2). Peak Vo2 (Vo2peak) was measured with an incremental protocol on a cycle ergometer after prolonged submaximal exercise at 30 and 60% of Vo2peak. We measured gas fractions by mass spectrometer and ventilation via turbine flowmeter for the calculation of breath-by-breath Vo2, heart rate via electrocardiogram, and cardiac output (Qc) via carbon dioxide rebreathing. Peak power and Vo2 were well maintained during spaceflight and not significantly different compared with 2 wk preflight. Vo2peak was reduced by 22% immediately postflight (P < 0.05), entirely because of a decrease in peak stroke volume and Qc. Peak heart rate, blood pressure, and systemic arteriovenous oxygen difference were unchanged. We conclude that systemic Vo2peak is well maintained in the absence of gravity for 9-14 days but is significantly reduced immediately on return to Earth, most likely because of reduced intravascular blood volume, stroke volume, and Qc.

Central venous pressure in space.

Gravity affects cardiac filling pressure and intravascular fluid distribution significantly. A major central fluid shift occurs when all hydrostatic gradients are abolished on entry into microgravity (microG). Understanding the dynamics of this shift requires continuous monitoring of cardiac filling pressure; central venous pressure (CVP) measurement is the only feasible means of accomplishing this. We directly measured CVP in three subjects: one aboard the Spacelab Life Sciences-1 space shuttle flight and two aboard the Spacelab Life Sciences-2 space shuttle flight. Continuous CVP measurements, with a 4-Fr catheter, began 4 h before launch and continued into microG. Mean CVP was 8.4 cmH2O seated before flight, 15.0 cmH2O in the supine legs-elevated posture in the shuttle, and 2.5 cmH2O after 10 min in microG. Although CVP decreased, the left ventricular end-diastolic dimension measured by echocardiography increased from a mean of 4.60 cm supine preflight to 4.97 cm within 48 h in microG. These data are consistent with increased cardiac filling early in microG despite a fall in CVP, suggesting that the relationship between CVP and actual transmural left ventricular filling pressure is altered in microG.

Orthostatic intolerance after spaceflight.

Orthostatic intolerance occurs commonly after spaceflight, and important aspects of the underlying mechanisms remain unclear. We studied 14 individuals supine and standing before and after three space shuttle missions of 9-14 days. After spaceflight, 9 of the 14 (64%) crew members could not complete a 10-min stand test that all completed preflight. Pre- and postflight supine hemodynamics were similar in both groups except for slightly higher systolic and mean arterial pressures preflight in the finishers [15 +/- 3.7 and 8 +/- 1.2 (SE) mmHg, respectively; P < 0.05]. Postflight, finishers and nonfinishers had equally large postural reductions in stroke volume (-47 +/- 3.7 and -48 +/- 3.3 ml, respectively) and increases in heart rate (35 +/- 6.6 and 51 +/- 5.2 beats/min, respectively). Cardiac output during standing was also similar (3.6 +/- 0.4 and 4.1 +/- 0.3 l/min, respectively). However, the finishers had a greater postflight vasoconstrictor response with higher total peripheral resistance during standing (22.3 +/- 1.2 units preflight and 29.4 +/- 2.3 units postflight) than did the nonfinishers (20.1 +/- 1.1 units preflight and 19.9 +/- 1.4 units postflight). We conclude that 1) the primary systemic hemodynamic event, i.e., the postural decrease in stroke volume, was similar in finishers and nonfinishers and 2) the heart rate response and cardiac output during standing were not significantly different, but 3) the postural vasoconstrictor response was significantly greater among the finishers (P < 0.01).

Pharmacologic atrial natriuretic peptide reduces human leg capillary filtration.

Atrial natriuretic peptide (ANP) is produced and secreted by atrial cells. We measured calf capillary filtration rate with prolonged venous-occlusion plethysmography of supine healthy male subjects during pharmacologic infusion of ANP (48 pmol/kg/min for 15 min; n = 6) and during placebo infusion (n = 7). Results during infusions were compared to prior control measurements. ANP infusion increased plasma [ANP] from 30 +/- 4 to 2,568 +/- 595 pmol/l. Systemic hemoconcentration occurred during ANP infusion: mean hematocrit and plasma colloid osmotic pressure increased 4.6 and 11.3%, respectively, relative to preinfusion baseline values (p < 0.05). Mean calf filtration, however, was significantly reduced from 0.15 to 0.08 ml/100 ml/min with ANP. Heart rate increased 20% with ANP infusion, whereas blood pressure was unchanged. Calf conductance (blood flow/arterial pressure) and venous compliance were unaffected by ANP infusion. Placebo infusion had no effect relative to prior baseline control measurements. Although ANP induced systemic capillary filtration, in the calf, filtration was reduced with ANP. Therefore, pharmacologic ANP infusion enhances capillary filtration from the systemic circulation, perhaps at upper body or splanchnic sites or both, while having the opposite effect in the leg.

Cerebral versus systemic hemodynamics during graded orthostatic stress in humans.

BACKGROUND: Orthostatic syncope is usually attributed to cerebral hypoperfusion secondary to systemic hemodynamic collapse. Recent research in patients with neurocardiogenic syncope has suggested that cerebral vasoconstriction may occur during orthostatic hypotension, compromising cerebral autoregulation and possibly contributing to the loss of consciousness. However, the regulation of cerebral blood flow (CBF) in such patients may be quite different from that of healthy individuals, particularly when assessed during the rapidly changing hemodynamic conditions associated with neurocardiogenic syncope. To be able to interpret the pathophysiological significance of these observations, a clear understanding of the normal responses of the cerebral circulation to orthostatic stress must be obtained, particularly in the context of the known changes in systemic and regional distributions of blood flow and vascular resistance during orthostasis. Therefore, the specific aim of this study was to examine the changes that occur in the cerebral circulation during graded reductions in central blood volume in the absence of systemic hypotension in healthy humans. We hypothesized that cerebral vasoconstriction would occur and CBF would decrease due to activation of the sympathetic nervous system. We further hypothesized, however, that the magnitude of this change would be small compared with changes in systemic or skeletal muscle vascular resistance in healthy subjects with intact autoregulation and would be unlikely to cause syncope without concomitant hypotension. METHODS AND RESULTS: To test this hypothesis, we studied 13 healthy men (age, 27 +/- 7 years) during progressive lower body negative pressure (LBNP). We measured systemic flow (Qc is cardiac output; C2H2 rebreathing), regional forearm flow (FBF; venous occlusion plethysmography), and blood pressure (BP; Finapres) and calculated systemic (SVR) and forearm (FVR) vascular resistances. Changes in brain blood flow were estimated from changes in the blood flow velocity in the middle cerebral artery (VMCA) using transcranial Doppler. Pulsatility (systolic minus diastolic/mean velocity) normalized for systemic arterial pressure pulsatility was used as an index of distal cerebral vascular resistance. End-tidal PACO2 was closely monitored during LBNP. From rest to maximal LBNP before the onset of symptoms or systemic hypotension, Qc and FBF decreased by 29.9% and 34.4%, respectively. VMCA decreased less, by 15.5% consistent with a smaller decrease in CBF. Similarly, SVR and FVR increased by 62.8% and 69.8%, respectively, whereas pulsatility increased by 17.2%, suggestive of a mild degree of small-vessel cerebral vasoconstriction. Seven of 13 subjects had presyncope during LBNP, all associated with a sudden drop in BP (29 +/- 9%). By comparison, hyperventilation alone caused greater changes in VMCA (42 +/- 2%) and pulsatility but never caused presyncope. In a separate group of 3 subjects, superimposition of hyperventilation during highlevel LBNP caused a further decrease in VMCA (31 +/- 7%) but no change in BP or level of consciousness. CONCLUSIONS: We conclude that cerebral vasoconstriction occurs in healthy humans during graded reductions in central blood volume caused by LBNP. However, the magnitude of this response is small compared with changes in SVR or FVR during LBNP or other stimuli known to induce cerebral vasoconstriction (hypocapnia). We speculate that this degree of cerebral vasoconstriction is not by itself sufficient to cause syncope during orthostatic stress. However, it may exacerbate the decrease in CBF associated with hypotension if hemodynamic instability develops.