Cardiovascular responses to orthostatic stress in healthy altitude dwellers, and altitude residents with chronic mountain sickness

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1 Exp Physiol 9.1 pp Experimental Physiology Cardiovascular responses to orthostatic stress in healthy altitude dwellers, and altitude residents with chronic mountain sickness V. E. Claydon 1,L.J.Norcliffe 1,J.P.Moore 1,M.Rivera 2,F.Leon-Velarde 2,O.Appenzeller 3 and R. Hainsworth 2 1 Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, UK 2 Laboratorio de Transporte de Oxigeno, Departamento de Ciencias Biologicas y Fisiologicas, Universidad Peruana Cayetano Heredia, Apartado 4314, Lima 1, Peru, 3 3 New Mexico Health Enhancement and Marathon Clinics Research Foundation, 361 Big Horn Ridge NE, Alberquerque, NM 87122, USA High altitude (HA) dwellers have an exceptionally high tolerance to orthostatic stress, and this may partly be related to their high packed cell and blood volumes. However, it is not known whether their orthostatic tolerance would be changed after relief of the altitude-related hypoxia. Furthermore, orthostatic tolerance is known also to be influenced by the efficiency of the control of peripheral vascular resistance and by the effectiveness of cerebral autoregulation and these have not been reported in HA dwellers. In this study we examined plasma volume, orthostatic tolerance and peripheral vascular and cerebrovascular responses to orthostatic stress in HA dwellers, including some with chronic mountain sickness () in whom packed cell and blood volumes are particularly large. Eleven HA control subjects and 11 patients underwent orthostatic stress testing, comprising head-up tilting with lower body suction, at their resident altitude (4338 m) and at sea level. Blood pressure (Portapres), heart rate (ECG), brachial and middle cerebral artery blood velocities (Doppler) were recorded during the test. Plasma volumes were found to be similar in both groups and at both locations. Packed cell and blood volumes were higher in patients than controls. All subjects had very good orthostatic tolerances at both locations, compared to previously published data in lowland dwellers. In patients responses of forearm vascular resistance to the orthostatic stress, at sea level, were smaller than controls (P <.5). Cerebral blood velocity was less in than in controls (P <.1) and, at sea level, it decreased more than the controls in response to head-up tilting (P <.2). Cerebral autoregulation, assessed from the relationship between cerebral pressure and velocity, was also impaired in patients compared to HA controls, when examined at sea level (P <.2). These results have shown that the good orthostatic tolerance seen in high altitude dwellers at altitude is also seen at sea level. There was no difference in orthostatic tolerance between patients, with their exceptionally large blood volumes, and the HA controls. This may be because peripheral vascular and cerebrovascular responses (at least at sea level) are impaired in the patients relative to HA controls. Thus, the advantage of the large blood volume may be offset by the smaller vascular responses. (Received 3 June 24; accepted after revision 23 September 24; first published online 4 October 24) Corresponding author V. E. Claydon: Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, UK. claydon@icord.org Orthostatic tolerance is a measure of a person s ability to maintain a normal level of arterial blood pressure and normal consciousness in spite of the venous pooling and plasma transudation which occurs during standing or other simulated orthostatic stress (Hainsworth, 1985). Orthostatic tolerance has been shown to be correlated with plasma volume (El-Sayed & Hainsworth, 1995, 1996; Mtinangi & Hainsworth, 1998, 1999). Recently, we have DOI: /expphysiol

2 14 V. E. Claydon and others Exp Physiol 9.1 pp reported that Andean altitude dwellers have an extremely good tolerance to orthostatic stress and we suggested that this might be related to their exceptionally large packed cell and blood volumes (Claydon et al. 24). However, that study included a group of highland dwellers with chronic mountain sickness () in whom packed cell and blood volumes were even larger than those in the healthy altitude residents (HA), and we observed little difference between their orthostatic tolerance and that of the healthy highlanders. It is known that plasma or blood volume is not the only factor influencing an individual s orthostatic tolerance. Other factors include the strength of vasoconstriction in the peripheral circulation (Brown & Hainsworth, 2; Bush et al. 2; Claydon & Hainsworth, 24) and the effectiveness of autoregulation in the cerebral circulation (Claydon & Hainsworth, 23). It is not known whether high altitude residents vasoconstrict more or less than lowland dwellers, or whether their cerebrovascular control is more or less effective. A further possibility is that the hypoxia at high altitude might have induced vasoconstriction and this also could have affected orthostatic tolerance. The present report is of an extension to the study recently reported (Claydon et al. 24). We now report vascular responses in a forearm and in the cerebral circulation in the same altitude dwellers and during the same orthostatic stress as previously reported. We also transported all our subjects to a sea-level location and repeated all the tests. We hoped that this would provide an insight into the mechanisms responsible for the good orthostatic tolerance in these subjects. By repeating all tests at sea level, we should see whether the hypoxia at altitude had any effect on orthostatic tolerance. Studies of responses of forearm vascular resistance would indicate the likely importance of this in contributing to their good orthostatic tolerance. We were interested to see whether the patients with chronic mountain sickness, in whom blood and packed cell volumes were exceptionally large, would have smaller reflex responses to explain the fact that their orthostatic tolerance was not greater. Finally, we wished to see whether the cerebrovascular control was affected by either the altitude induced hypoxia or the high haematocrit values. Methods Subjects Studies were performed on 22 male high altitude residents from Cerro de Pasco (altitude, 4338 m) in the Peruvian Andes. Of these, 11 were healthy control volunteers (mean age, 39.3 ± 2years) and 11 were diagnosed with (mean age, 43.1 ± 1.7 years) on the basis of haematocrit levels consistently in excess of 6%, and clinical histories compatible with the disorder (Monge, 1953). All subjects were free from any other known medical disorder. No subject was taking any prescribed medication and none had worked in a mine. Written informed consent was obtained from all subjects. The research was approved by the local ethics committee of the Universidad Peruana Cayetano Heredia, and was performed in accordance with the Declaration of Helsinki (1989) of the World Medical Association. Procedure Subjects were studied first in Cerro de Pasco (4338 m). They were asked to eat only a light breakfast on the day of testing, avoiding caffeine. They were also asked to abstain from caffeine and alcohol for the 24 h preceding the study. Orthostatic stress testing was performed as described below. One week later subjects descended to Lima (sea level) and were re-assessed on the morning after arrival under the same experimental conditions. The repeat test was completed within 24 h of descent. Plasma and blood volumes Plasma and blood volumes were determined from Evans Blue dilution and haematocrit as previously described in detail (Claydon et al. 24). All subjects rested for 3 min before the dye injection. Plasma volume was estimated from serial venous samples taken 1 25 min after injection and compared with known dilutions made in the subject s own plasma. Orthostatic tolerance test A graded orthostatic stress test of combined head-upright tilting and lower body suction was used to determine orthostatic tolerance (El-Bedawi & Hainsworth, 1994). After a2-min period of supine rest, subjects were tilted head-up to 6 deg for 2 min. After this, while still tilted, negative pressure (lower body negative pressure, LBNP) was applied to the body below the level of the iliac crest at 2, 4 and 6 mmhg for 1 min each, or until onset of presyncope. Presyncope was recognized, the test terminated and the subject returned to supine, when systolic blood pressure fell below 8 mmhg associated with signs and symptoms of presyncope (such as dizziness, pallor, light-headedness or visual disturbances). Orthostatic tolerance was taken as the time from head-up tilt to presyncope in minutes. Throughout the testing procedure recordings were made

3 Exp Physiol 9.1 pp Effects of altitude on cardiovascular responses to orthostatic stress 15 Table 1. Oxygen saturation (S O2 ), end-tidal P CO2 (P ET,CO2 ) and respiratory frequency (RF) in high altitude controls (HA) and chronic mountain sickness () patients at 4338 m and at sea level 4338 m Sea level HA HA S O2 (%) 86 ± ± ±.7 94 ±.7 P ET,CO2 (mmhg) 27.3 ± ± ± ± 1.4 RF (Hz).32 ±.3.32 ±.2.29 ±.2.28 ±.1 Values are of means ± S.E.M. and significant differences (P <.5 and P <.2, respectively) between subject groups; significant difference between locations in some subjects. of heart rate using a standard three-lead ECG (Hewlett Packard, 78352C Boeblingen, Germany) and beat-to-beat blood pressure using the Portapres (Portapres Model 2, TNO-TPD Biomedical Instrumentation, Amsterdam, the Netherlands), which was calibrated at regular intervals against an autoinflating sphygmomanometer (Hewlett Packard, 78352C Boeblingen, Germany) on the opposite arm. The Portapres was positioned on the right arm, which was supported at heart level. Forearm blood flow velocity and cerebral blood flow velocity were determined as described below. In addition, we continuously monitored peripheral oxygen saturation using finger pulse oximetry (Hewlett Packard, 78352C, Boeblingen, Germany) and end-tidal carbon dioxide levels via paired nasal cannulae using an infra red analyser (Binos-1, Leybold-Heraeus Limited, Köln, Germany). Assessment of forearm and cerebral blood flow velocity Blood flow velocities were determined using Doppler ultrasound. An 8 MHz pulsed wave ultrasound probe was positioned over the brachial artery (forearm blood flow velocity) and a 2 MHz pulsed wave ultrasound probe was positioned over the middle cerebral artery (cerebral blood flow velocity). Both probes were securely clamped into position with the angle of insonation fixed and as close to zero degrees relative to the insonated artery as possible. The depth and gain of the signals were adjusted as appropriate. Mean blood flow velocity was calculated off-line using a dedicated recording device (T2-Dop, DWL Elektronische System GmbH, Sipplingen, Germany). It was assumed that the diameter of these vessels, and the angle of insonation, did not change during the test procedure and hence that the blood velocity calculated would be proportional to flow. Forearm vascular resistance was calculated as mean arterial blood pressure divided by brachial blood flow velocity. Cerebrovascular resistance was calculated as mean cerebral arterial blood pressure divided by cerebral blood flow velocity. Cerebral arterial pressure was calculated from the pressure recorded at heart level, corrected for the height difference between head and heart upon tilting. Statistical analysis Data were tested for normality and parametric or nonparametric tests were used as appropriate. Within group comparisons ( or control) were performed using paired Student t tests. Comparisons between groups were performed using unpaired Student t tests. Correlations between variables were examined using the Spearman ranked correlation coefficient. A value of P <.5 was taken to represent statistical significance. Unless otherwise stated, all data are expressed as mean ± standard error of the mean. Results Respiratory gases Estimated oxygen saturations were lower in the group at both locations compared to the healthy altitude dwellers (HA) and, as expected, values at sea level were higher than those at altitude (Table 1). Values of end-tidal P CO2 (P ET,CO2 )were not significantly different between the groups or at the different locations. Respiratory frequency (RF) also was not different between groups and tended to be lower (significantly in ) at sea level. Plasma and blood volumes Values obtained from subjects studied at altitude have already been reported (Claydon et al. 24). Plasma volumes in the and HA subjects at sea level were 36.2 ± 2.5 and 43.4 ± 4.8 ml kg 1,respectively. These were not significantly different from the values obtained at altitude, and not significantly different from each other. Blood volumes at sea level were significantly greater in patients than HA (97.4 ± 6.3 and 83.8 ± 8.3 ml kg 1,

4 16 V. E. Claydon and others Exp Physiol 9.1 pp Table 2. Values of systolic (SAP) and diastolic (DAP) arterial blood pressures and heart rate in HA controls and chronic mountain sickness patients () at 4338 m and sea level 4338 m Sea level HA HA SAP (mmhg) Supine ± ± ± ± 3.6 Tilt ± ± ± ± 3.3 DAP (mmhg) Supine 73.1 ± ± ± ± 2.5 Tilt 76.4 ± ± ± ± 3. Heart rate (beats min 1 ) Supine 58.9 ± ± ± ± 1.4 Tilt 7.6 ± ± ± ± 2.8 Values are means ± S.E.M. Tilt indicates values at the end of the 2 min phase of head-up tilt. Systolic pressure was not different between groups at any time, but was lower in both groups during tilt than supine at sea level (P <.5). Supine diastolic pressure was significantly lower in at sea level than at altitude (P <.5). Tilted diastolic pressure was lower in control than at sea level (P <.5). Supine heart rates were significantly slower in HA than at altitude (P <.5). At sea level, supine heart rates were not significantly different between groups, but tilted heart rates were significantly slower in HA than in (P <.5). Heart rates in both groups were slower at all stages of testing at sea level compared to altitude (P <.1). Significant difference between locations; significant difference between HA and ; significant differences between supine and tilt. respectively; P <.5). The values of blood volume in patients were a little less than those previously reported at altitude (16.5 ± 8.3; P <.1) although, when corrected for blood previously withdrawn, there was no significant change. Responses to orthostatic stress Orthostatic tolerance (time to termination of the test) in the two groups at altitude has previously been reported (Claydon et al. 24). All subjects had exceptionally good orthostatic tolerance as indicated by the ability of all to tolerate the test to the end of the head-up tilt and lower body suction at 4 mmhg phase. At 4338 m, four of the 11 HA controls and five of the tolerated the entire procedure (to the end of LBNP at 6 mmhg). Orthostatic tolerance was even better at sea level, with nine HA controls and eight patients tolerating the entire test. The mean time to presyncope in controls increased from 46.1 ± 1.2 to 48.8 ±.9 min, and in patients from 47.3 ± 1.2 to 48.2 ± 1. min. Effects on blood pressure and heart rate Supine heart rate was higher at altitude in the patients than in the HA controls (Table 2). During head-up tilting, heart rate increased in both groups. At the high altitude study, the maximum increase in heart rate achieved during the test was greater in controls than in (+53.9 ± 4.1 and ± 3.8 beats min 1, P <.1). The stage of the test at which heart rate peaked was similar in both groups (HA, 43.8 ± 1.1 min;, 44.2 ± 1.5 min). The maximum heart rates in HA and were ± 3.9 and 12.3 ± 4.1 beats min 1,respectively (NS). At sea level, heart rate was lower in both groups than at altitude (Table 2). However, the change in heart rate during the orthostatic stress was now similar in both groups. The maximum heart rates during the stress test in HA and were 91.5 ± 4.8 and 14.3 ± 5.7 beats min 1,respectively (NS). There was no significant difference in supine systolic blood pressure between the groups, or the locations. Diastolic pressure tended to be lower at sea level, significantly so for patients (Table 2). During headup tilting, systolic pressure was lower at sea level than at altitude in both groups. At sea level diastolic pressure increased during tilting, but this did not occur at altitude. Effects on forearm vascular resistance Forearm vascular resistance increased progressively during the orthostatic stress. At altitude the maximum responses were not significantly different between the two groups

5 Exp Physiol 9.1 pp Effects of altitude on cardiovascular responses to orthostatic stress 17 (Fig. 1). In HA controls it increased by ± 19.8% and in by 88.2 ± 13.6%. The maximum change occurred at similar times; HA after 22.7 ± 3.2 min and after 21. ± 5.3 min. At sea level the response of the HA controls tended to increase and the to decrease such that the patients had a smaller response than that of the HA controls (HA, ± 21.6;, ± 11.9%, P <.5). A CBFV (cm.sec -1 ) P<.1 P<.5 Cerebrovascular responses Middle cerebral artery blood flow velocity was significantly less in patients than controls whilst supine. This was seen both at altitude and at sea level (Fig. 2). During head-up tilt blood flow velocity decreased. The decrease was similar in the two groups at altitude, although at sea level the change in the group increased, and was significantly greater than that in the HA controls (Fig. 2). Cerebrovascular resistance decreased in both groups similarly at altitude. At sea level it tended to be greater in HA controls and less in patients so that the decrease in resistance became significantly greater in HA controls than in subjects (Fig. 3). The efficiency of cerebral autoregulation was assessed from the correlation between middle cerebral artery blood flow velocity and pressure, whereby good autoregulation was indicated by the lack of a significant correlation and a low correlation coefficient. At altitude, five HA controls and four patients had significant correlations and there was no significant difference between the correlation coefficients of the groups. At sea level, the HA controls showed evidence of good autoregulation; Max FVR (% change from supine) m Sea level P<.5 Figure 1. Maximum forearm vascular resistance (FVR) responses to orthostatic stress in the two groups studied Responses are expressed as percentage changes from the supine value. Forearm vascular resistance responses tended to be smaller in than control at 4338 m (NS) and were significantly so when tested at sea level. B CBFV (% change from supine) m Sea level 4338m Sea level P<.2 Figure 2. Cerebral blood flow velocity (CBFV) whilst supine (A), and the change in CBFV upon tilting (B) inthe two groups Supine cerebral blood flow velocity was significantly lower in than control at both locations. Upon head-up tilting, CBFV was reduced in both groups compared to supine levels. The initial percentage reduction in CBFV at was similar in both groups, but at sea level the reduction was greater in than control. five still had significant correlations and the mean correlation coefficient was unchanged. However in patients, nine had significant correlations and the mean correlation coefficient was greater than that in the HA Mean decrease in CVR (% from supine) m Sea level P<.1 Figure 3. Cerebrovascular resistance (CVR) responses to tilting in control and at 4338 m and at sea level Both groups showed a reduction in CVR upon tilting, which was similar between groups at 4338 m but was significantly (P <.1) smaller in at sea level.

6 18 V. E. Claydon and others Exp Physiol 9.1 pp controls (,.68 ±.5; HA,.43 ±.8; P <.2, Fig. 4). Discussion The main findings of this study were, firstly, that the very high tolerance to orthostatic stress seen in high altitude residents when studied in their natural environment was, if anything, even greater following descent to sea level. Secondly, at least when studied at sea level, the patients with chronic mountain sickness had less effective control of peripheral vascular resistance and of cerebral blood flow than the healthy altitude dwellers. Orthostatic tolerance has previously been found to be related to plasma volume, in that subjects who have a large plasma volume are likely also to have a high orthostatic tolerance (El-Sayed & Hainsworth, 1995) and procedures, including salt loading (El-Sayed & Hainsworth, 1996; Mtinangi & Hainsworth, 1998) and exercise training (Mtinangi & & Hainsworth, 1999), which increase plasma volume, also increase orthostatic tolerance. However, this study and that recently reported (Claydon et al. 24; conducted on the same individuals) have shown that high altitude residents do not have particularly high plasma volumes but that their orthostatic tolerance is exceptional. We suggest that it is probable that the large packed cell volumes or blood volumes, seen in these individuals, could be an important contributing factor. However, there are other factors that could contribute to the good orthostatic tolerance of high altitude dwellers. Also, we need to consider why, if blood volume is the major factor, orthostatic tolerance is not greater in the subjects in whom packed cell and blood volumes are much greater than in the HA controls. The factors to consider are the possible effects of altitude-related hypoxia Correlation coefficient m Sea level P<.2 Figure 4. The correlation coefficient (R) describing the relationship between cerebral mean arterial pressure and cerebral blood flow velocity in control and At 4438 m the correlation coefficient was similar in both groups. However, at sea level it was significantly stronger in (P <.2). itself, the responses of peripheral vascular resistance, and the efficiency of cerebral autoregulation. Altitude-related hypoxia High altitude residents are not only subjected to hypoxia but are also hypocapnic due to the increased respiratory drive (Leon-Velarde et al. 23). Our subjects had low oxygen saturations and these, as expected (Sun et al. 1996; Keyl et al. 23; Leon-Velarde et al. 23) were even lower in the group. However, end-tidal CO 2 values were similar. Descent to sea level relieved the hypoxia but the CO 2 levels were little changed. This is expected and is due to the altitude adaptation (Leon-Velarde et al. 23). Hypoxia is associated with an increased sympathetic drive (Rowell et al. 1989). This is seen in response to acute hypoxia both in animals and in humans and is attributed to peripheral chemoreceptor stimulation (Halliwell & Minson, 22; Halliwell et al. 23). It is likely that the level of sympathetic activity in our subjects was less at sea level. This is reflected in the lower heart rates and the lower diastolic blood pressures in the supine condition. What effect the lower supine sympathetic activity would have on orthostatic tolerance is uncertain. It might be thought that if the supine level of sympathetic activity was less, there would be a greater capacity for an increase. However, it seems that levels of heart rate at least remained lower at all stages of the test, suggesting that, at least cardiac sympathetic drive did not increase by a greater amount. Forearm vascular responses There was little difference in the maximum change in vasoconstriction in the forearm between the groups of subjects when studied at altitude, and the responses were quantitatively similar to those previously reported in lowland dwellers (average change approximately +1%; Brown & Hainsworth, 2; Bush et al. 2). However, it is interesting that when the test was repeated at sea level the maximum change in vascular resistance was significantly smaller in than controls. It seems surprising that this difference was apparent only in the sea level study, and we can only speculate as to the possible reasons. We have already suggested that the supine level of sympathetic activity is likely to be lower at sea level and, if this were true, the capacity to increase vascular resistance would be greater. There was a tendency in the controls for the response to be enhanced, but in the patients the trend was for the response to be less. The reasons for this are uncertain although it is known that patients do have some neural deficiency (Thomas et al. 2; Keyl et al. 23) and this may limit the extent to which sympathetic activity could increase.

7 Exp Physiol 9.1 pp Effects of altitude on cardiovascular responses to orthostatic stress 19 The smaller response of vascular resistance in the patients may be part of the reason that, despite their very high blood volumes, their orthostatic tolerances were not different from those in the healthy high altitude subjects. However, if this was the only reason, we should have expected to see a similar difference in the responses of vascular resistance in the high altitude study. Cerebrovascular responses In keeping with a previous report, we have shown that cerebral blood flow velocity was significantly lower in patients than in controls (Wood et al. 1988), and this difference was seen both in the high altitude and in the sea level studies. The difference is likely to be due to the difference in blood viscosities (Rebel et al. 23). However, despite the reduction in blood flow velocity, the rate of oxygen delivery to the brain would not be very different due to the difference in the haematocrit levels. Cerebral autoregulation was studied in two ways. Firstly we examined the effects of the tilt-induced decrease in cerebral arterial pressure on velocity and resistance to flow in the middle cerebral artery. Secondly, we examined the relationship between velocity and pressure. This was studied over the course of the orthostatic stress test, from head-up tilt until blood pressure at the level of the head fell to 5 mmhg. This is the range over which autoregulation would be expected to occur (Lassen, 1959). The correlation coefficient (R value) provides a measure of the effectiveness of autoregulation, whereby good autoregulation is associated with the absence of a significant correlation and a low value of R.This measure has been used in previous investigations and is able to show changes in response to interventions such as salt or water ingestion (Schroeder et al. 22; Claydon & Hainsworth, 24). In the present study we found that cerebral autoregulation, assessed by both methods, was similar in both groups when determined at altitude, and the values were also similar to those reported previously in sea-level residents (Schroeder et al. 22; Claydon & Hainsworth, 23). However, when the study was repeated on our high altitude subjects at sea level, autoregulation in the patients was significantly worse. They had a larger fall in cerebral velocity on tilting with a smaller change in resistance. Also a greater proportion had significant correlations, and the correlation coefficient was significantly greater. The good autoregulation when studied at altitude is a new finding and differs from some previous reports which have claimed that autoregulation is impaired at altitude (Jensen et al. 1996; Jansen et al. 1999, 2). However, the previous studies have been more concerned with the acute changes in autoregulation on ascent to altitude, rather than the effects in lifelong altitude dwellers. We did show that, although autoregulation was similar in patients as in controls, their values of blood velocity were reset to lower levels. Although autoregulation was effective when studied at altitude, when the patients descended to sea level their autoregulation was markedly impaired. The obvious difference in the arterial blood is that the oxygen saturation was much higher. However end-tidal CO 2 levels changed very little in either group, and it is this that is known to have an effect on autoregulation (Levick, 2). It seems that in these patients efficient autoregulation is dependent on hypoxia. We did find, in the same patients, that their sensitivities to acute changes in oxygen and CO 2 were different at sea level from those at altitude (Norcliffe et al. 23). However, they do not adequately explain the changes in autoregulation seen in the patients. Furthermore, in that study, the acute changes in reactivity occurred equally in both groups of subjects. Some animal studies have indicated that chronic hypoxia induces changes in noradrenergic second messenger coupling (Ueno et al. 1997; Bucholz & Duckles, 21), and it is conceivable that the patients in some way have adapted to the chronic hypoxia. It would be of interest to examine whether, at sea level, re-introduction of hypoxia equivalent to that at altitude would restore autoregulation. Conclusion This study has shown for the first time that the high orthostatic tolerance of Andean high altitude residents is also seen when studied within 24 h of descent to sea level. The good tolerance is not therefore dependent on continuing hypoxia. Relief of hypoxia caused heart rate and blood pressure changes indicative of lower levels of sympathetic activity, so this does not seem to be a major factor. The main reason for the high orthostatic tolerance in these subjects remains likely to be their high packed cell and blood volumes. However, tolerance was not greater in the patients than the HA controls, and this may be explained by the finding that, at least at sea level, their reflex vasoconstriction and their cerebral autoregulation were less effective. This may be due to the neurological deficit that is known to be associated with this condition. However, the study does leave some unanswered questions. The principal of these are why, in the patients, is their control of peripheral vascular resistance and the effectiveness of cerebral autoregulation impaired when studied at sea level, at a time when they were no longer hypoxic.

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