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1 Institute for Cardiovascular Research, University of Leeds, Leeds, LS 9JT, UK,2 Laboratorio de Transporte de Oxigeno, Departamento de Ciencias Biologicas y Fisiologicas, Universidad Peruana Cayetano Heredia, Apartado 4314, Lima 100, Peru3 NMHEMC Research Foundation, 361 Big Horn Ridge NE, Alberquerque, NM 87122, USA
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Abstract |
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(Received 16 March 2004;
accepted after revision 3 June 2004; first published online 7 June 2004)
Corresponding author V. E. Claydon: Institute for Cardiovascular Research, University of Leeds, Leeds, LS2 9JT, UK. Email: v.e.claydon{at}leeds.ac.uk
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Introduction |
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Orthostatic tolerance has been shown to correlate with plasma volume (El-Sayed & Hainsworth, 1995), and various interventions which have increased plasma volume have also increased orthostatic tolerance (El-Sayed & Hainsworth, 1996; Mtinangi & Hainsworth, 1999). Another factor which has been shown to influence orthostatic tolerance is the magnitude of the reflex vasoconstriction that is achieved during orthostatic stress (Brown & Hainsworth, 1999; Bush et al. 2000). A further possibility is that orthostatic tolerance may be influenced by the quantity of red cells, and there have been reports that increasing haemopoiesis by administration of erythropoietin may be of help to some patients with poor orthostatic tolerance (Hoeldt & Streeton, 1993; Perera et al. 1995; Nair et al. 1996).
Prolonged exposure to high altitude, and the resulting hypobaric hypoxia, leads to a variety of adaptive changes. The main features are increases in haematocrit and haemoglobin, increased pulmonary gas exchange, a shift to the right of the haemoglobin–oxygen dissociation curve due to an increase in the enzyme 2,3-diphosphoglyceride and improved oxygen extraction in the tissues (Ward et al. 2000). These changes are seen in Andean high altitude dwellers, who have high packed cell volumes as a reaction to the chronic hypoxia (Ou et al. 1998), although the extent to which the haematocrit is increased varies between individuals (Beall et al. 2002). A proportion of them have a disorder known as chronic mountain sickness (CMS), which is characterized by exceptionally large haematocrits and high haemoglobin levels (Ou et al. 1998). CMS was first described by Carlos Monge in (1928) and is associated with an inadequate respiratory drive, exaggerated hypoxia, excessive polycythaemia, cyanosis, and a spectrum of symptoms related to the hypoxia such as sleep disorder, confusion and fatigue. Particularly serious complications are pulmonary hypertension and right heart failure.
The aims of this study were, firstly, to determine whether these Andean subjects, who had high haematocrits and probably large packed cell volumes, would also have large blood volumes, or whether their plasma volumes would be affected in a reciprocal way. Secondly, we were interested to know whether their large packed cell volumes and/or blood volumes would be associated with an exceptionally good orthostatic tolerance.
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Methods |
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Studies were performed on 22 male high altitude residents from Cerro de Pasco in the Peruvian Andes (altitude 4338 m, barometric pressure 
450 mmHg). Of these subjects, 11 were healthy control volunteers (mean age 39.3 ± 2.0 years) and 11 suffered with chronic mountain sickness (CMS, aged 43.1 ± 1.7 years) characterized by haematocrit levels above 60%. All subjects were male and free from any medical disorder (except for CMS). None was taking any prescribed medication. Further details of the subjects are listed in Table 1.
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The study was approved by the local ethics committee of the Universidad Peruana Cayetano Heredia, Peru and the United Leeds Teaching Hospitals NHS Trust, and was performed in accordance with the Declaration of Helsinki (2000) of the World Medical Association. All subjects gave informed written consent.
Subjects were instructed to eat nothing from the previous evening and to avoid drinks containing fat (including milk), caffeine or alcohol. No restriction was imposed upon water drinking. Avoidance of fatty food on the day before the study was also important, since high levels of lipid in the plasma interfere with the spectrophotometric assay of Evans Blue dye. Plasma volume estimates were carried out first, in the mornings. Following this, subjects were allowed a light snack and the orthostatic stress test was carried out at least 2 h later.
Plasma volume assessment
Plasma volume was determined by Evans Blue dye dilution (El-Sayed et al. 1995). Plasma volume assessment was performed in the supine position, following at least 30 min of supine rest to allow for stabilization of plasma volume and brachial venous haematocrit. The arm to be catheterized was supported at heart level, and room temperature was controlled at 20–22°C. A sterile catheter (20 G) with sterile plastic tap was inserted into an antecubital vein. After 5 min, 18 ml of blood (baseline sample) was withdrawn via the cannula to provide plasma for construction of a standard Evans Blue calibration curve, and determination of haematocrit. Exactly 2 ml of Evans Blue dye (The New World Trading Corporation, Debarry, FL, USA) was injected through the catheter, using tuberculin syringes, and thoroughly washed into the vein using sterile saline. Then, 3 ml blood samples were taken 10, 15, 20 and 25 min after injection. Care was taken to minimize the risk of haemolysis by withdrawing blood samples very slowly. Each blood sample was introduced into a sterile tube containing heparinized glass beads to prevent clotting, and then centrifuged and the plasma extracted.
Standard curves were constructed for each study, using the subject's own plasma, and Evans Blue dye from the same ampoule used in the study, to make concentrations of 5 and 10 µg l–1. The absorbencies of these samples were determined and the blank absorbency from the subject's plasma subtracted. Using the standard curve, plots were derived of log10 concentration of dye in plasma against time following injection. Values of absorbency from the four samples taken following injection of the dye were used to construct a decay curve whereby reverse-extrapolated linear regression analysis gave the theoretical concentration of dye at time zero (the point of injection). This concentration was used to determine the dilution, and hence plasma volume. Haematocrit was calculated from the packed cell ratio, in quadruplicate. Blood volume and packed cell volume were calculated using the haematocrit from the peripheral venous blood and plasma volume.
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). Subjects initially rested supine for 20 min and then were head-up tilted to 60 deg for 20 min. Following this, while still tilted, a subatmospheric pressure (lower body negative pressure, LBNP) was applied to the body below the level of the iliac crest at –20, –40 and –60 mmHg for 10 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 80 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. If an end-point was not reached after LBNP at –60 mmHg, orthostatic tolerance was taken as 50 min. Throughout the testing procedure, recordings were made of blood pressure with an autoinflating sphygmomanometer, and heart rate using a standard three-lead ECG (Hewlett Packard, 78352C Boebringen, Germany). Beat-to-beat blood pressures were determined using finger plethysmography (Portapres Model 2, TNO-TPD Biomedical Instrumentation, Amsterdam, Netherlands) of the right middle finger, supported at heart level.
Statistical analysis
Data were tested for normality and parametric or non-parametric tests were used as appropriate. Comparisons between groups were performed using Studentis unpaired t test. Correlations between variables were examined using the Spearman ranked correlation coefficient. A value of P < 0.05 was taken to represent statistical significance. Unless otherwise stated, all data are expressed as means ±S.E.M.
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Results |
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Blood and plasma volumes
Blood and plasma volume data are expressed per kilogram body weight. Plasma volumes in high altitude normal subjects (HA) and CMS subjects were 39.3 ± 1.9 and 34.8 ± 1.6 ml kg–1, respectively, and were not significantly different (Fig. 1). Haematocrit values (by selection) were significantly higher in the CMS patients (67.8 ± 2.0%) than in HA (53.6 ± 1.2%), P < 0.001 (Fig. 2). Packed cell volume was greater in the CMS patients than in HA (71.7 ± 7.3 and 45.3 ± 2.6 ml kg–1, respectively, P < 0.01). There was no significant correlation between plasma volume and packed cell volume (r= 0.144, P= 0.57). Blood volume was also greater in CMS than in the normal high altitude dwellers (106.5 ± 8.3 and 83.6 ± 4.0 ml kg–1, respectively, P < 0.05).
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All of the high altitude dwellers tolerated the test beyond the second level of suction, i.e. into the –60 mmHg phase, indicating unusually good orthostatic tolerance. Four of the 11 healthy high altitude dwellers and five of the patients with CMS were able to tolerate the entire procedure to the end of the test, i.e. the end of 10 min at –60 mmHg lower body suction. There was no significant difference between the orthostatic tolerance of the two groups of high altitude residents (Table 1).
Heart rates and blood pressures
Resting supine values of heart rate and mean arterial pressures can be seen in Fig. 3. Resting blood pressures were not significantly different between the two groups. Resting heart rates were significantly slower in HA than CMS (58.9 ± 2.0 and 65.0 ± 2.9 beats min–1, respectively, P < 0.05). There was no difference in the maximum heart rate attained during the orthostatic stress in HA and CMS, although it tended to be greater in HA normal subjects than in CMS. Maximum heart rates were: HA 112.8 ± 3.97 and CMS 102.3 ± 4.1 beats min–1 (P= 0.08). This reflects a greater rise in heart rate from the resting levels in HA than in CMS (HA +53.9 ± 4.1 and CMS +37.2 ± 3.8 beats min–1, P < 0.05).
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Discussion |
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Polycythaemia in high altitude dwellers is well documented. However, the extent to which the haematocrit is increased varies between individuals (Ou et al. 1998) and different altitude populations (Beall et al. 2002). In the Andean altitude dwellers investigated in this study, there was a subpopulation with even higher haematocrits than those normally seen. In this study, we have demonstrated that in the normally adapted high altitude residents, the polycythaemia and high packed cell volumes associated with lifelong hypoxia were not associated with reduced plasma volumes. In fact, the plasma volumes in these individuals were almost identical to those obtained from previous studies, using the same technique, of lowland dwellers with much lower haematocrit levels (El-Sayed & Hainsworth, 1995, 1996; El-Sayed et al. 1995; Mtinangi & Hainsworth, 1999). Even in the patients with CMS and very high haematocrits, plasma volumes were not significantly lower than those reported previously, although there was a tendency for it to be less. Since, in both groups of high altitude dwellers, the plasma volumes were similar to lowland dwellers, despite the large packed cell volumes, it follows that the blood volumes of the high altitude individuals were also large. This was particularly marked in those individuals with CMS.
The extremely large blood volumes of this group of high altitude dwellers might be expected to be associated with good orthostatic tolerance, and this was found to be the case. This is the first assessment of orthostatic tolerance in permanent high altitude dwellers using a test which has previously been shown to be sensitive, specific and highly reproducible (El-Bedawi & Hainsworth, 1994). All of the subjects had orthostatic tolerances greater than the average predicted values obtained from previous studies of control volunteers resident at sea level performed both in our laboratory (El-Bedawi & Hainsworth, 1994; Bush et al. 2000; Cooper & Hainsworth, 2002; Schroeder et al. 2002) and in those of others (Stevens, 1966; Fitzpatrick et al. 1991; Kapoor & Brant, 1992; Jellema et al. 1996). The exceptionally high orthostatic tolerance in the high altitude subjects compared to lowland residents may be related to their high packed cell volume. However, it is important to note that most data reported from lowland dwelling subjects are from individuals who were clearly genetically distinct from the Andean subjects, and they also would have been subjected to different environmental influences such as diet, exercise and working environments.
We determined correlations between orthostatic tolerance and other variables using data from all subjects. Because many of the high altitude subjects (9 out of 22) were able to tolerate the orthostatic stress for the maximum that could be applied, we took their tolerance to be 50 min. Despite this limitation, significant correlations were obtained between orthostatic tolerance and: haematocrit (r= 0.57; P < 0.01, Fig. 4); packed cell volume (r= 0.54; P < 0.01); and blood volume (r= 0.48; P < 0.05). Although previous studies have shown that orthostatic tolerance is significantly dependent upon plasma volume (El-Sayed et al. 1995; El-Sayed & Hainsworth, 1996; Mtinangi & Hainsworth, 1999), we have now demonstrated that there may be a link between packed cell volume or blood volume and orthostatic tolerance. Other possible evidence in support of this is that administration of recombinant erythropoietin to some patients with autonomic failure improves orthostatic hypotension (Hoeldt & Streeton, 1993; Perera et al. 1995; Nair et al. 1996). However, although these results are compatible with the view that packed cell volume or blood volume is a major determinant of orthostatic tolerance, these experiments do not prove cause and effect.
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One limitation of this study is that all the high altitude dwelling subjects had such exceptional orthostatic tolerance that for many individuals the entire test was tolerated without presyncope. In this case their orthostatic tolerance was defined as 50 min. However, their actual tolerance, had we been able to measure it, must have been higher than this. Had we been able to continue the test further (perhaps with an additional phase of –80 mmHg lower body suction), we might have found an even stronger relationship between packed cell volume and orthostatic tolerance. Such extreme levels of lower body suction can become uncomfortable, and in an effort to avoid alterations in cardiovascular control due to discomfort the test was terminated after 10 min at –60 mmHg (50 min of stress in total).
The other limitation of this study is the lack of a low altitude dwelling control group. Comparisons with lowland dwellers from the UK (as mentioned previously) are confounded by different genetic profiles and environmental alterations. Had it been possible, it would have been preferable to study a control group of Andean men who had been living at low altitude since birth, but were genetically similar to the volunteers in the present study. It would be of interest to study other high altitude populations, such as in Tibet or Ethiopia, in whom the adaptive mechanisms to high altitude living may be different to the Andean altitude dwellers (Beall et al. 2002).
Conclusions
This study has shown that high altitude dwellers have similar plasma volumes to lowland residents, but higher packed cell and blood volumes, and this was particularly apparent in those with chronic mountain sickness. In addition, the high altitude dwellers had exceptional orthostatic tolerance. These results are not incompatible with the view that, in addition to plasma volume, packed cell or blood volume is also a determinant of the ability to tolerate orthostatic stress.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Beall
CM, Decker
MJ, Brittenham
GM, Kushner
I, Gebremedhin
A
&
Strohl
KP (2002). An Ethiopian pattern of human adaptation to high-altitude hypoxia. Proc Natl Acad Sci
99, 17215–17218.
Brown CM & Hainsworth R (1999). Assessment of capillary fluid shifts during orthostatic stress in normal subjects and subjects with orthostatic intolerance. Clin Auton Res 9, 69–73.[CrossRef][Medline]
Brown CM & Hainsworth R (2000). Forearm vascular responses during orthostatic stress in control subjects and patients with posturally related syncope. Clin Auton Res 10, 57–61.[CrossRef][Medline]
Bush VE, Wight VL, Brown CM & Hainsworth R (2000). Vascular responses to orthostatic stress in patients with postural tachycardia syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls. Clin Auton Res 10, 279–284.[CrossRef][Medline]
Cooper VL & Hainsworth R (2002). Effects of head-up tilting on baroreceptor control in subjects with different tolerances to orthostatic stress. Clin Sci 103, 221–226.[Medline]
El-Bedawi KM & Hainsworth R (1994). Combined head-up tilt and lower body suction – a test of orthostatic tolerance. Clin Auton Res 4, 41–47.[CrossRef][Medline]
El-Sayed H, Goodau SR & Hainsworth R (1995). Re-evaluation of Evans blue dye dilution method of plasma volume measurement. Clin Laboratory Hematol 17, 189–194.
El-Sayed H & Hainsworth R (1995). Relationship between plasma volume, carotid baroreceptor sensitivity and orthostatic tolerance. Clin Sci 88, 463–470.[Medline]
El-Sayed
H
&
Hainsworth
R (1996). Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope. Heart
75, 134–140.
Fitzpatrick A, Theodorakis G, Vardas P & Sutton R (1991). Methodology of head-up tilt testing in patients with unexplained syncope. J Am Coll Cardiol 17, 125–130.[Abstract]
Hainsworth R (1985). Arterial blood pressure. In Hypotensive Anaesthesia, ed. Enderby, GEH, pp. 3–29. Churchill Livingstone, London.
Hoeldt
RD
&
Streeton
DH (1993). Treatment of orthostatic hypotension with erythropoietin. N Engl J Med
329, 611–615.
Jellema WT, Imholz BPM, Van Goudoever J, Wesseling KH & Van Lieshout JJ (1996). Finger arterial versus intrabrachial pressure and continuous cardiac output during head-up tilt testing in healthy subjects. Clin Sci 91, 193–200.[Medline]
Kapoor WN & Brant N (1992). Evaluation of syncope by upright tilt testing with isoproterenol. Ann Intern Med 116, 358–363.
Kwaan HC & Wang J (2003). Hyperviscosity in polycythemia vera and other red cell abnormalities. Semin Thromb Hemost 29, 451–458.[CrossRef][Medline]
Monge MC (1953). Chronic mountain sickness in America. An Fac Med Lima 36, 544–562.[Medline]
Mtinangi BL & Hainsworth R (1999). Effects of moderate exercise training on plasma volume, baroreceptor sensitivity, and orthostatic tolerance in healthy subjects. Exp Physiol 84, 121–130.[Abstract]
Nair B, Leitch J & Black A (1996). Erythropoietin treatment for postural hypotension from autonomic dysfunction. Aust N Z J M 26, 859–860.
Ou
LC, Salceda
S, Schuster
SJ, Dunnack
LM, Brink-Johnsen
T, Chen
J
&
Leiter
JC (1998). Polycythemic responses to hypoxia: molecular and genetic mechanisms of chronic mountain sickness. J Appl Physiol
84, 1242–1251.
Perera R, Isola L & Kaufman H (1995). Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure. Clin Auton Res 5, 211–213.[CrossRef][Medline]
Schroeder
C, Bush
VE, Norcliffe
LJ, Luft
FC, Tank
J, Jordan
J
&
Hainsworth
R (2002). Water drinking acutely improves orthostatic tolerance in healthy subjects. Circulation
106, 2806–2811.
Stevens PM (1966). Cardiovascular dynamics during orthostasis and the influence of intravascular instrumentation. Am J Cardiol 17, 211–218.[CrossRef][Medline]
Ward MP, Milledge JS & West JB (2000). Subacute and chronic mountain sickness. In High Altitude Medicine and Physiology, pp. 252–258. Edward Arnold publishing, London.
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, HA; 
, CMS. There was no significant difference in plasma volume between the two groups. There was a trend (not significant) for plasma volumes to be smaller in CMS.
, HA normal subjects; •, CMS patients. Subjects who tolerated the entire test were designated as having an OT of 50 min.