Orthostatic Hypertension
R. P. SAPRU, M.D., Ph.D., M.A.M.S. Chandigarh, India P. SLEIGHT, M.D., D.M., F.R.C.P. Oxford, England I. S. ANAND, D.Phil. M.R.C.P.
A 40 year old man was found to have marked hypertension when he was in the upright position with normal pressures when he was supine. Investigations disclosed normal catecholamine and renin levels. The haroreceptor reflex was somewhat depressed. The mechanism of this orthostatic hypertension is not known. The condition has not been reported previously.
Chandigarh, India M. P. SAMBHI, M.D., M.Sc., Ph.D. Sepulveda, California R. LOPEZ, B.Sc.. M.D. (V) Oxford, England P. N. CHHUTTANI,
M.D.. F.A.M.S.
Chandigarh, India
Physiologic mechanisms that ensure fairly small oscillations in blood pressure, around a central mean point, with changes in posture are well known [l-4]. Failure of adequate reflex adaptation from disease, drugs or other causes often results in postural hypotension [5-81. The opposite phenomenon, that of hypertension on standing, is less well documented. Frohlich et al. [9] described a moderate increase in mean arterial pressure [average + 16 mm Hg) on 50 degree head-up tilt in approximately 35 per cent of patients with mild hypertension but not in subjects with normal blood pressure. We describe a patient who shows a consistent and dramatic postural hypertension; the arterial pressure is normal when he is supine but markedly increased when he is erect. We are unable to provide a definite answer to the mechanism of this phenomenonal, though some possibilities are suggested. CASE REPORT
From the Department of Medicine of the Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India: the Cardiology Department, the Radcliffe Infirmary, Oxford, England; and the Department of Medicine, Sepulveda VA Hospital, UCLA, Sepulveda, California. Requests for reprints should be addressed to Dr. R. P. Sapru. Department of Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Manuscript accepted June 13.1978.
A 40 year old civil servant noticed weakness and easy fatiguability starting in May 1972. Physical examination at the time disclosed no abnormalities, but two months later the blood pressure level was found to be elevated. A total of three neurofibromas over the arms and abdomen were noted. The optic fundi were within normal limits. The patient was 5 feet 61/Z inches tall and weighed 65 kg. A detailed functional enquiry was unhelpful. Effort tolerance was good, and his daily routine included a 45 minute nonstop swim. Married with two children, he worked long hours in a highly responsible executive position. He was a teetotaller, and there was no history of drug abuse. Except for an occasional dysentery, there had been no significant previous illnesses. His father, aged 61. and one of three brothers, suffered from mild hypertension. Both had multiple neurofibromas. His father had suffered a myocardial infarction three years earlier. The patient’s symptoms and physical signs since July 1972 have progressed but marginally; a grade 2 hypertensive retinopathy has been present for the past four years.
SPECIAL STUDIES
AND RESULTS
Blood Pressure Response. The blood pressure changes (both direct intra-arterial and sphygmomanometric) have been documented repeatedly at various centers in India, UK, USA, USSR and Poland. A typical intra-arterial blood pressure response to orthostasis is illustrated in Figure 1. The supine blood pressure has been normal around 120180
January 1979
The American Journal of Medicine
Volume 66
177
ORTHOSTATIC HYPERTENSION-SAPRU
ET AL.
lant blood pressure monitoring over 10 hours revealed systolic, diastolic and mean pressures of 117.4 (k 13.1 SD), 91.0 (& 21.8 SD] and 104.5 (& 25.2 SD] mm Hg, respectively. The pulse interval during this time averaged 660.5 (& 112.9 SD] msec. The computer print out of a part of the 24 hour recording is shown in Figure 2. The patient has consistently denied any symptoms during change of posture, and no flushing or sweating have ever been noted. Mathematical Calculations. Simple mental arithmetic in the supine position raised the blood pressure from 122/79 mm Hg to a maximum of 147/103 mm Hg and the heart rate from 63/min to 80/min within 10 to 15 cardiac cycles. Cold Pressor Test. Immersion of one hand in cold water at 4% resulted in a dramatic increase in blood pressure from 123/87 mm Hg to a maximum of 249/166
mm Hg, although on a few occasions low figures of 80/50 mm Hg have been recorded. On sitting or standing, the blood pressure initially decreases by 20 to 40 mm Hg over 10 to 15cardiac cycles and then gradually increases to reach a plateau in about 2 minutes at which level it persists so long as the posture is maintained. Blood pressure is highest in the standing position with intermediate values in the sitting position, The standing blood pressure has usually ranged between 15CV11O and 170/140 mm Hg, but the highest recorded figure has been 210/160 mm Hg. The hypertensive response is generally accompanied by an increase of about 20 beats/min in the heart rate, which always precedes the change in blood pressure and is complete within 10 seconds. On regaining the supine position the heart rate, as well as the blood pressure, fall promptly [within 10 seconds) to normal levels. On another occasion ambuSKM - 1218172
1
STANDING
I
SUPINE
1
IF&
u 170-
i$ la9 l5@
c”lLO2% l-j@
_k 3
120-
if
IIO-
n 3
mo-
Figure 1. Changes in systolic blood pressure (intraarterial) and heart rate with change of posture. The arrows point to the onset of change in posture. MA = motion artefact.
m LX8o-
Figure 2. Computer print out of a part of a 24 hour blood pressure record from 1200 to 1900 hours showing striking variability in arterial pressure. The top panel shows the systolic, mean and diastolic pressures in millimeters of mercury (mm Hg) averaged every 2 minutes. The bottom panel is the heart rate per minute. The low pressures occur when the patient is supine and the higher pressures when standing.
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ORTHOSTATIC HYPERTENSION-SAPRU
mm Hg within 1 minute. Heart rate increased from 65/min to a maximum of llO/min. Graded Tilt. During graded tilt the blood pressure response, determined by sphygmomanometry, was related to the grade of tilt (Figure 3). Venous tourniquets (40 mm Hg) and venous splints (40 mm Hg pressure in an inflatable splint from ankles to mid-thighs] did not materially alter the changes in blood pressure. Static Exercise. Sustained handgrip at approximately 30 per cent of maximum voluntary contraction increased the blood pressure from 126/82 mm Hg to a maximum of 198/135 mm Hg with a corresponding increase in heart rate from 75/min to llO/min. Dynamic Exercise. During the treadmill exercise test (Bruce protocol), following the initial increase on standing (from 120 to 150 mm Hg], the systolic blood pressure decreased to about 100mm Hg during exercise
ET AL.
and never rose above 115 mm Hg despite a heart rate of 155/min. On stopping the exercise, the heart rate decreased to lOO/min and the systolic blood pressure increased immediately to 135 mm Hg, settling later to a normal pressure of 110 mm Hg. There were no ischemic changes in the electrocardiogram during the treadmill exercise. During supine leg exercise for 4 minutes, the blood pressure increased from 110/70 to 120/75 mm Hg whereas the pulse rate increased from 60 to lOO/min. Baroreflex Function. Following bolus injections of phenylephrine to raise the systolic blood pressure there was only moderate cardiac slowing. The slope of the baroreceptor sensitivity curve at 4 msec/mm Hg was only about half of the normal value for a man of this patient’s age [lo]. Valsalva Maneuver. The Valsalva manuever was WITH VENOUS TOURNIQUET
CONTROL
WITH VENOUS SRINT
lrnlso-
Figure 3. Blood pressure and heart rate changes during graded tilt. Systolic pressure O-O, diastolic pressure 0-O and heart rate A-A. Venous tourniquets or venous splints make little difference to the gradient of change.
80
160 :::.::11.::I:I:::!: o 30
15
60
75
0
30 L5 60 GRADE OF TILT
75
0
30
A_ L5
60
75
AFTER PROPRANOLOL ,,, 100 SKM - 1218172 -z+ ‘E $ 90 @- 80 a, 0 3 I 70 60 PINE1
STANDING
SUPINE fi
Figure 4. Heart and biocd pressure with change in posture after P-adrenergic block. The hypertension on standing is no longer present.
tV January
1979
The American
Journal of Medicine
Volume 66
179
ORTHOSTATIC HYPERTENSION-SAPRU
TABLE I
ET AL.
Renin and Angiotensin Levels Measured as Angiotension I (Al) Actlvity Plasma Renln Plasma Renin (ngAllmll3 hr)
Condition
Dale
Substrate (ngAllmll3 hr)
Blood Anglotension Wml)
At UCLA, Callfornla 6/16/74 6/21/74
8123174
Normal values Random on oral propranolol Off propranolol for 5 days Unrestricted diet Morning before rising 4 hours after standing After 2 days of diuretic and low sodium diet
O-10 1.53
.. ..
2.33 9.26 20.2
1,107 964 1.422
41.1 (Al) 20.2 (All) . .
.. . . . . . . . .
. . . .. . .. ..
... ...
At Oxford, England 12/10/75
Supine On tilt After Saralasin infusion 3aralasin + tilt
NOTE: Al = angiotensin
I; All = angiotensin
5.4,6.3 11.3, 10.5 10.5 9.9 II.
abnormal in that the reduction of pulse pressure during phase II (during strain) was accompanied by a marked increase in mean arterial pressure. Further, the reflex cardiac slowing during phase IV was minimal. Effect of Pharmacologic Autonomic Blockade. Following the intravenous injection of propranolol(10 mg intravenously] the resting supine blood pressure and heart rate were unaltered. However, on standing after /3-adrenergic block the blood pressure did not increase beyond control levels although the initial decrease was still present. The heart rate increased as before (Figure 41.
After the administration of propranolol(l0 mg intravenously] and atropine (1.2 mg intravenously, the heart rate was fixed at lOO/min and the hypertensive Gsponse on standing was absent. Further Investigations. Plasma renin activity, together with plasma and urinary catecholamine studies at UCLA in August 1974 and at Oxford in January 1976 were all within normal limits (Tables I and II). Blood angiotensin I and II levels, measured with the patient in the recumbent posture, were in the high normal range at 41.1 pg/ml and 20.2 pg/ml, respectively. Urinary sodium excretion during a normal salt diet was 135 and 125 meq/24 hours, during reduced salt intake (2 g/24 hours) 110 and 120 meq/24 hours, and during increased salt intake (5 g/24 hours) 245 meq/24 hours. Urinary vanillyl mandelic acid levels were 2.88, 2.52 and 3.4 mg in 24 hours on three different occasions. No porphobilinogens could be detected in the urine, and 5-hydroxyindole acetic acid (&HIAA) measured 5.2 and 1.5 mg/24 hours. Routine investigations, performed on a number of occasions in different laboratories, were all within normal limits and included the blood count, erythrocyte sedimentation rate (10 to 15 mm first hour), urinalysis, serum electrolytes, blood urea (25 to 40 mg/lOO ml), 180
January
1979
serum creatinine (1.2 to 2.9 mg/lOO ml), creatinine clearance (87 to 102 ml/min), plasma proteins, albumin and globulin ratios, serum calcium, inorganic phosphate, alkaline phosphatase and oral glucose tolerance test. Repeated urine cultures were sterile. Fasting blood lipid levels were raised with a serum cholesterol of 348 mg/lOO ml, phospholipid 340 mg/lOO ml, triglycerides 142 to 217 mg/lOO ml, cY-lipoprotein 8 per cent and @lipoprotein 92 per cent. Serum cholesterol was reduced to 200 to 225 mg/lOO ml with clofibrate therapy. The electrocardiogram was within normal limits, as were films of the chest and abdomen. Rapid sequence intravenous pyelography repeated twice showed normal-sized kidneys with normal excretion. The kidneys did not show undue mobility with change in posture. Selective renal angiograms were also within normal limits. Management. Methyl dopa, clonidine, metalazone and thiazides were tried singly and in various combinations with varying degrees of success but without optimal blood pressure control. Propranolol in a total daily dose of 160 mg was found to be the most effective. Currently, the patient is receiving chlorthiazide and clofibrate in addition. COMMENTS During orthostasis, the venous return diminishes despite peripheral venoconstriction so that the diastolic ventricular volume and stroke volume decrease. Partial compensation by a modest tachycardia prevents a drastic decrease in cardiac output. The blood pressure is maintained by systemic vasoconstriction. Precise adjustments in regional circulations are not as well known as during exercise, but cutaneous and skeletal muscle blood flow is reduced [l,ll-161. The baroreflex probably plays an active role in promoting these adjustments. The net result of these adjustments is that the blood pressure remains largely unchanged, although a
The American Journal of Medicine Volume 66
ORTHOSTATICHYPERTENSION-SAPRUETAL.
TABLE II
Date
3/21/74
12lll175
Plasma and Urinary Catecholamines (Epinephrine [E] and Norepinephrine [NE]) in Different Postures
Condttkta
Supine (AM) Standing (PM)
PlasmaNE (nglltter) At UCLA, California 102 564 At Oxford, England
Lower inferior vena cava Supine Erect Upper inferior vena cava Supine Erect Left renal vein Supine Erect Right renal vein Supine Erect
10 to 15 mm Hg rise or fall in the systolic arterial pressure is probably not an uncommon experience [17-201. A precise distribution of the normal response of blood pressure during orthostasis has not been worked out. However, there can be little doubt that the hypertensive response on standing in this patient (+40 to + 90 mm Hg systolic blood pressure) is distinctly abnormal. A careful search of the literature has failed to turn up a similar previous experience. Investigations so far have failed to reveal an identifiable cause for the postural hypertension of this patient. There is no evidence of a phaeochromocytoma or of a renin-secreting tumor, and the kidneys are not unduly mobile. The renin-angiotensin responses, although somewhat brisk, are within the normal range. The possibility of some other chemical mediator, although unlikely, remains unresolved. The blood pressure changes during graded tilt were not affected by venous splints or tourniquets applied to the lower limbs. Although the blood pressure and heart rate responses to mental arithmetic were normal [21,22], an overactive adrenergic reaction is suggested by the exaggerated response to the cold pressor test [23,24]and phase II of the Valsalva’s maneuver. There are, however, no other features described for the “hyperdynamic fi-adrenergic circulatory state” [25]. The poor bradycardia during phase IV of the Valsalva maneuver is compatible with poor baroreflex function which was also confirmed by the phenylephrine test. The normal blood pressure responses during supine static and dynamic exercises are perhaps understandable insofar as the supine blood pressures have always been normal. However, the response during treadmill exercise is of considerable interest. The hypertension disappeared during this form of exercise, suggesting that the chief functional abnormality in this patient is in the vascular responses rather than changes in cardiac output. The muscle vasodilatation in response to the metabolic needs of the exercising muscles may, by over-
PlasmaE (ng/ltter)
Urinary Excretion Rate
99 251
1.2(E% = 2) 2.1 (E% = 16)
40 60
600 720
120 130
840 790
110 100
640 630
120 130
620 680
(Whour)
.
...
coming the erstwhile vasoconstriction, be responsible for the normal blood pressure during treadmill exercise despite an (presumed] increase in the cardiac output. The favorable response to ,f3-adrenergic block with propranolol was obtained within 15 minutes after administration of the drug. A modest increase in diastolic (and mean) blood pressure on head up tilt has been reported in 18 of the 50 patients with mild hypertension studied by Frohlich et al. [9], but not in 17 normal control subjects. Such a response is particularly seen in the younger, nonobese patients with a recent onset of hypertension and in patients with “hyperdynamic &adrenergic disease.” These patients also show increased catecholamines in their urine [26]. Our patient has been entirely normotensive in the supine position during the past five years of observation, although it is possible that his condition may yet progress to sustained hypertension. He does not have features of “hyperdynamic p-adrenergic disease” and showed normal catecholamine responses during postural changes. The exaggerated normal blood pressure response to standing in our patient would seem, therefore, to be due to an excessive peripheral vasoconstriction causing an increase in the total systemic vascular resistance far in excess of the needs arising from a decrease in cardiac output. There is some evidence favoring the participation of low pressure baroreceptors in the heart in modulating cardiovascular reflexes, either without [27] or with the participation of aortic and carotid baroreceptors [28]. The state of these low pressure baroreceptors has not been examined in our patient. ACKNOWLEDGMENT
We are grateful to Dr. Claude Benedict for some of the catecholamine estimations, to Dr. J.G.G. Ledingham and Dr. B. McGrath for some of the renin studies, and to other colleagues who have helped with the investigations.
January 1979 The American Journal of Medicine
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ORTHOSTATIC HYPERTENSION-SAPRU
ET AL.
REFERENCES 1. Gauer OH, Thron HL: Postural changes in the circulation. Handbook of Physiology Circulation, Sect. 2 III, Washington D.C., Am Physiological Society, 1965, p 2409. 2. Korner PI: Integrative neural cardiovascular control. Physiol Rev 51: 312,1971. 3. Kirchheim HR: Systemic arterial baroreceptor reflexes. Physiol Rev 56: 100, 1976. 4. iiberg B: Overall cardiovascular regulation. Ann Rev Physiol 38: 537, 1976. 5. Chakroverty S, Barron KD, Katz FH, et al.: The syndrome of primary orthostatic hypotension. Brain 92: 743, 1969. 6. Johnson RH, Spalding JMK: Disorders of the Autonomic Nervous System. Oxford, Blackwell, 1974. 7. Ibrahim MM, Tarazi RC, Dustan HP: Orthostatic hypotension: mechanisms and management. Am Heart J 90: 513, 1975. 8. Thulesius 0: Pathophysiological classification and diagnosis of orthostatic hypotension. Cardiology 61 (suppl 1): 180, 1976. 9. Frohlic ED, Tarazi RC, Ulrych M. et al.: Tilt test for investieation of a neural comnonent in hvoertension. Circulation I. :S: 387,1967. . 10. Bristow JD, Honour AJ, Pickering GW, et al.: Diminished baroreflex sensitivity in high blood pressure. Circulation 39: 48, 1969. 11. McMichael J. Sharpey-Schafer EP: Cardiac output in man by a direct Fick method. Effects of posture, venous pressure change, atropine and adrenaline Br Heart J 6: 33,1944. 12. Brigden W, Howarth S, Sharpey-Schafer EP: Postural changes in the peripheral blood-flow of normal subjects with observations on vasovagal fainting reactions as a result of tilting, the lordotic posture, pregnancy and spinal anaesthesia. Clin Sci 9: 79.1950. 13. Rushmer RF: Postural effects on the baselines of ventricular performance. Circulation 20: 897, 1959. 14. Bevegard S, Holmgren A, Jonsson B: The effect of body position on the circulation at rest and during exercise with special reference to the influence on the stroke volume. Acta Physiol Stand 49: 279, 1960. 15. Wang Y, Marshall RJ, Shepherd JT: The effect of changes in
182
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1979
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Journal of Medicine
posture and of graded exercise on stroke volume in man.
1Clin Invest 39: 1051,196O. 16. Reeves JT, Grover RF, Blount SG Jr, et al.: Cardiac output response to standing and treadmill walking.____ 1Ann1 Phvsiol . 16:~283,1961. 17. Schneider EC, Truesdell D: A statistical study of the pulse rate and the arterial blood pressures in recumbency, standing and after standard exercise. Am J Physiol61: 429.1922. 18. Wald H, Guernsey M, Scott FH: Some effects of alteration of posture on arterial blood pressure. Am Heart J 14: 319, 1937. 19. Currens JH: A comparison of the blood pressure in the lying and standine nositions. A studv of five hundred men and five hundred -women. Am Heart J 35: 646,1948. 20. Green RS. Ielauer A. McGuire 1: Alterations of radial or brachial intraarterial blood pressure and of the electrocardiogram induced by tilting. J Lab Clin Med 33: 951, 1948. 21. Brod J, Fencl V, Hejl Z, et al.: Circulatory changes underlying blood pressure elevation during acute emotional stress (mental arithmeticl in normotensive and hypertensive subjects. Clin Sci 18: 269, 1959. 22. Marshall RJ, Shepherd JT: Cardiac Function in Health and Disease, Philadelphia, W.B. Saunders, 1968. 23. Hines EA, Jr, Brown GE: A standard stimulus for measuring vasomotor reactions. Its application in the study of hypertension. Proc Staff Meet Mayo Clinic 7: 332.1932. 24. Wolf S, Hardy JD Studies on pain. Observations on pain due to local cooling and on factors involved in the “cold pressor” effect. J Clin Invest 20: 521.1941. 25. Frohlich ED, Tarazi RC, Dustan HP: Hyperdynamic &adrenergic circulatorv state. Arch Intern Med 123: 1.1969. 26. Esler Mb, Nestel PJ: Sympathetic responsiveness to iead-up tilt in essential hvnertension. Clin Sci 44: 213. 1973. 27. Zoller RP, Mark AL: -Abboud FM, et al.: Role of low-pressure baroreceptors in reflex vasoconstrictor responses in man. J Clin Invest 51: 2967,1972. 28. Eckberg DL, Abboud FM, Mark AL: Modulation of carotid baroreflex responsiveness in man: effects of posture and propranolol. J Appl Physiol41: 383,1976.
Volume 66
R. P. SAPRU, M.D., Ph.D., M.A.M.S. Chandigarh, India P. SLEIGHT, M.D., D.M., F.R.C.P. Oxford, England I. S. ANAND, D.Phil. M.R.C.P.
A 40 year old man was found to have marked hypertension when he was in the upright position with normal pressures when he was supine. Investigations disclosed normal catecholamine and renin levels. The haroreceptor reflex was somewhat depressed. The mechanism of this orthostatic hypertension is not known. The condition has not been reported previously.
Chandigarh, India M. P. SAMBHI, M.D., M.Sc., Ph.D. Sepulveda, California R. LOPEZ, B.Sc.. M.D. (V) Oxford, England P. N. CHHUTTANI,
M.D.. F.A.M.S.
Chandigarh, India
Physiologic mechanisms that ensure fairly small oscillations in blood pressure, around a central mean point, with changes in posture are well known [l-4]. Failure of adequate reflex adaptation from disease, drugs or other causes often results in postural hypotension [5-81. The opposite phenomenon, that of hypertension on standing, is less well documented. Frohlich et al. [9] described a moderate increase in mean arterial pressure [average + 16 mm Hg) on 50 degree head-up tilt in approximately 35 per cent of patients with mild hypertension but not in subjects with normal blood pressure. We describe a patient who shows a consistent and dramatic postural hypertension; the arterial pressure is normal when he is supine but markedly increased when he is erect. We are unable to provide a definite answer to the mechanism of this phenomenonal, though some possibilities are suggested. CASE REPORT
From the Department of Medicine of the Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India: the Cardiology Department, the Radcliffe Infirmary, Oxford, England; and the Department of Medicine, Sepulveda VA Hospital, UCLA, Sepulveda, California. Requests for reprints should be addressed to Dr. R. P. Sapru. Department of Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Manuscript accepted June 13.1978.
A 40 year old civil servant noticed weakness and easy fatiguability starting in May 1972. Physical examination at the time disclosed no abnormalities, but two months later the blood pressure level was found to be elevated. A total of three neurofibromas over the arms and abdomen were noted. The optic fundi were within normal limits. The patient was 5 feet 61/Z inches tall and weighed 65 kg. A detailed functional enquiry was unhelpful. Effort tolerance was good, and his daily routine included a 45 minute nonstop swim. Married with two children, he worked long hours in a highly responsible executive position. He was a teetotaller, and there was no history of drug abuse. Except for an occasional dysentery, there had been no significant previous illnesses. His father, aged 61. and one of three brothers, suffered from mild hypertension. Both had multiple neurofibromas. His father had suffered a myocardial infarction three years earlier. The patient’s symptoms and physical signs since July 1972 have progressed but marginally; a grade 2 hypertensive retinopathy has been present for the past four years.
SPECIAL STUDIES
AND RESULTS
Blood Pressure Response. The blood pressure changes (both direct intra-arterial and sphygmomanometric) have been documented repeatedly at various centers in India, UK, USA, USSR and Poland. A typical intra-arterial blood pressure response to orthostasis is illustrated in Figure 1. The supine blood pressure has been normal around 120180
January 1979
The American Journal of Medicine
Volume 66
177
ORTHOSTATIC HYPERTENSION-SAPRU
ET AL.
lant blood pressure monitoring over 10 hours revealed systolic, diastolic and mean pressures of 117.4 (k 13.1 SD), 91.0 (& 21.8 SD] and 104.5 (& 25.2 SD] mm Hg, respectively. The pulse interval during this time averaged 660.5 (& 112.9 SD] msec. The computer print out of a part of the 24 hour recording is shown in Figure 2. The patient has consistently denied any symptoms during change of posture, and no flushing or sweating have ever been noted. Mathematical Calculations. Simple mental arithmetic in the supine position raised the blood pressure from 122/79 mm Hg to a maximum of 147/103 mm Hg and the heart rate from 63/min to 80/min within 10 to 15 cardiac cycles. Cold Pressor Test. Immersion of one hand in cold water at 4% resulted in a dramatic increase in blood pressure from 123/87 mm Hg to a maximum of 249/166
mm Hg, although on a few occasions low figures of 80/50 mm Hg have been recorded. On sitting or standing, the blood pressure initially decreases by 20 to 40 mm Hg over 10 to 15cardiac cycles and then gradually increases to reach a plateau in about 2 minutes at which level it persists so long as the posture is maintained. Blood pressure is highest in the standing position with intermediate values in the sitting position, The standing blood pressure has usually ranged between 15CV11O and 170/140 mm Hg, but the highest recorded figure has been 210/160 mm Hg. The hypertensive response is generally accompanied by an increase of about 20 beats/min in the heart rate, which always precedes the change in blood pressure and is complete within 10 seconds. On regaining the supine position the heart rate, as well as the blood pressure, fall promptly [within 10 seconds) to normal levels. On another occasion ambuSKM - 1218172
1
STANDING
I
SUPINE
1
IF&
u 170-
i$ la9 l5@
c”lLO2% l-j@
_k 3
120-
if
IIO-
n 3
mo-
Figure 1. Changes in systolic blood pressure (intraarterial) and heart rate with change of posture. The arrows point to the onset of change in posture. MA = motion artefact.
m LX8o-
Figure 2. Computer print out of a part of a 24 hour blood pressure record from 1200 to 1900 hours showing striking variability in arterial pressure. The top panel shows the systolic, mean and diastolic pressures in millimeters of mercury (mm Hg) averaged every 2 minutes. The bottom panel is the heart rate per minute. The low pressures occur when the patient is supine and the higher pressures when standing.
178
January 1979
The American Journal of Medicine
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ORTHOSTATIC HYPERTENSION-SAPRU
mm Hg within 1 minute. Heart rate increased from 65/min to a maximum of llO/min. Graded Tilt. During graded tilt the blood pressure response, determined by sphygmomanometry, was related to the grade of tilt (Figure 3). Venous tourniquets (40 mm Hg) and venous splints (40 mm Hg pressure in an inflatable splint from ankles to mid-thighs] did not materially alter the changes in blood pressure. Static Exercise. Sustained handgrip at approximately 30 per cent of maximum voluntary contraction increased the blood pressure from 126/82 mm Hg to a maximum of 198/135 mm Hg with a corresponding increase in heart rate from 75/min to llO/min. Dynamic Exercise. During the treadmill exercise test (Bruce protocol), following the initial increase on standing (from 120 to 150 mm Hg], the systolic blood pressure decreased to about 100mm Hg during exercise
ET AL.
and never rose above 115 mm Hg despite a heart rate of 155/min. On stopping the exercise, the heart rate decreased to lOO/min and the systolic blood pressure increased immediately to 135 mm Hg, settling later to a normal pressure of 110 mm Hg. There were no ischemic changes in the electrocardiogram during the treadmill exercise. During supine leg exercise for 4 minutes, the blood pressure increased from 110/70 to 120/75 mm Hg whereas the pulse rate increased from 60 to lOO/min. Baroreflex Function. Following bolus injections of phenylephrine to raise the systolic blood pressure there was only moderate cardiac slowing. The slope of the baroreceptor sensitivity curve at 4 msec/mm Hg was only about half of the normal value for a man of this patient’s age [lo]. Valsalva Maneuver. The Valsalva manuever was WITH VENOUS TOURNIQUET
CONTROL
WITH VENOUS SRINT
lrnlso-
Figure 3. Blood pressure and heart rate changes during graded tilt. Systolic pressure O-O, diastolic pressure 0-O and heart rate A-A. Venous tourniquets or venous splints make little difference to the gradient of change.
80
160 :::.::11.::I:I:::!: o 30
15
60
75
0
30 L5 60 GRADE OF TILT
75
0
30
A_ L5
60
75
AFTER PROPRANOLOL ,,, 100 SKM - 1218172 -z+ ‘E $ 90 @- 80 a, 0 3 I 70 60 PINE1
STANDING
SUPINE fi
Figure 4. Heart and biocd pressure with change in posture after P-adrenergic block. The hypertension on standing is no longer present.
tV January
1979
The American
Journal of Medicine
Volume 66
179
ORTHOSTATIC HYPERTENSION-SAPRU
TABLE I
ET AL.
Renin and Angiotensin Levels Measured as Angiotension I (Al) Actlvity Plasma Renln Plasma Renin (ngAllmll3 hr)
Condition
Dale
Substrate (ngAllmll3 hr)
Blood Anglotension Wml)
At UCLA, Callfornla 6/16/74 6/21/74
8123174
Normal values Random on oral propranolol Off propranolol for 5 days Unrestricted diet Morning before rising 4 hours after standing After 2 days of diuretic and low sodium diet
O-10 1.53
.. ..
2.33 9.26 20.2
1,107 964 1.422
41.1 (Al) 20.2 (All) . .
.. . . . . . . . .
. . . .. . .. ..
... ...
At Oxford, England 12/10/75
Supine On tilt After Saralasin infusion 3aralasin + tilt
NOTE: Al = angiotensin
I; All = angiotensin
5.4,6.3 11.3, 10.5 10.5 9.9 II.
abnormal in that the reduction of pulse pressure during phase II (during strain) was accompanied by a marked increase in mean arterial pressure. Further, the reflex cardiac slowing during phase IV was minimal. Effect of Pharmacologic Autonomic Blockade. Following the intravenous injection of propranolol(10 mg intravenously] the resting supine blood pressure and heart rate were unaltered. However, on standing after /3-adrenergic block the blood pressure did not increase beyond control levels although the initial decrease was still present. The heart rate increased as before (Figure 41.
After the administration of propranolol(l0 mg intravenously] and atropine (1.2 mg intravenously, the heart rate was fixed at lOO/min and the hypertensive Gsponse on standing was absent. Further Investigations. Plasma renin activity, together with plasma and urinary catecholamine studies at UCLA in August 1974 and at Oxford in January 1976 were all within normal limits (Tables I and II). Blood angiotensin I and II levels, measured with the patient in the recumbent posture, were in the high normal range at 41.1 pg/ml and 20.2 pg/ml, respectively. Urinary sodium excretion during a normal salt diet was 135 and 125 meq/24 hours, during reduced salt intake (2 g/24 hours) 110 and 120 meq/24 hours, and during increased salt intake (5 g/24 hours) 245 meq/24 hours. Urinary vanillyl mandelic acid levels were 2.88, 2.52 and 3.4 mg in 24 hours on three different occasions. No porphobilinogens could be detected in the urine, and 5-hydroxyindole acetic acid (&HIAA) measured 5.2 and 1.5 mg/24 hours. Routine investigations, performed on a number of occasions in different laboratories, were all within normal limits and included the blood count, erythrocyte sedimentation rate (10 to 15 mm first hour), urinalysis, serum electrolytes, blood urea (25 to 40 mg/lOO ml), 180
January
1979
serum creatinine (1.2 to 2.9 mg/lOO ml), creatinine clearance (87 to 102 ml/min), plasma proteins, albumin and globulin ratios, serum calcium, inorganic phosphate, alkaline phosphatase and oral glucose tolerance test. Repeated urine cultures were sterile. Fasting blood lipid levels were raised with a serum cholesterol of 348 mg/lOO ml, phospholipid 340 mg/lOO ml, triglycerides 142 to 217 mg/lOO ml, cY-lipoprotein 8 per cent and @lipoprotein 92 per cent. Serum cholesterol was reduced to 200 to 225 mg/lOO ml with clofibrate therapy. The electrocardiogram was within normal limits, as were films of the chest and abdomen. Rapid sequence intravenous pyelography repeated twice showed normal-sized kidneys with normal excretion. The kidneys did not show undue mobility with change in posture. Selective renal angiograms were also within normal limits. Management. Methyl dopa, clonidine, metalazone and thiazides were tried singly and in various combinations with varying degrees of success but without optimal blood pressure control. Propranolol in a total daily dose of 160 mg was found to be the most effective. Currently, the patient is receiving chlorthiazide and clofibrate in addition. COMMENTS During orthostasis, the venous return diminishes despite peripheral venoconstriction so that the diastolic ventricular volume and stroke volume decrease. Partial compensation by a modest tachycardia prevents a drastic decrease in cardiac output. The blood pressure is maintained by systemic vasoconstriction. Precise adjustments in regional circulations are not as well known as during exercise, but cutaneous and skeletal muscle blood flow is reduced [l,ll-161. The baroreflex probably plays an active role in promoting these adjustments. The net result of these adjustments is that the blood pressure remains largely unchanged, although a
The American Journal of Medicine Volume 66
ORTHOSTATICHYPERTENSION-SAPRUETAL.
TABLE II
Date
3/21/74
12lll175
Plasma and Urinary Catecholamines (Epinephrine [E] and Norepinephrine [NE]) in Different Postures
Condttkta
Supine (AM) Standing (PM)
PlasmaNE (nglltter) At UCLA, California 102 564 At Oxford, England
Lower inferior vena cava Supine Erect Upper inferior vena cava Supine Erect Left renal vein Supine Erect Right renal vein Supine Erect
10 to 15 mm Hg rise or fall in the systolic arterial pressure is probably not an uncommon experience [17-201. A precise distribution of the normal response of blood pressure during orthostasis has not been worked out. However, there can be little doubt that the hypertensive response on standing in this patient (+40 to + 90 mm Hg systolic blood pressure) is distinctly abnormal. A careful search of the literature has failed to turn up a similar previous experience. Investigations so far have failed to reveal an identifiable cause for the postural hypertension of this patient. There is no evidence of a phaeochromocytoma or of a renin-secreting tumor, and the kidneys are not unduly mobile. The renin-angiotensin responses, although somewhat brisk, are within the normal range. The possibility of some other chemical mediator, although unlikely, remains unresolved. The blood pressure changes during graded tilt were not affected by venous splints or tourniquets applied to the lower limbs. Although the blood pressure and heart rate responses to mental arithmetic were normal [21,22], an overactive adrenergic reaction is suggested by the exaggerated response to the cold pressor test [23,24]and phase II of the Valsalva’s maneuver. There are, however, no other features described for the “hyperdynamic fi-adrenergic circulatory state” [25]. The poor bradycardia during phase IV of the Valsalva maneuver is compatible with poor baroreflex function which was also confirmed by the phenylephrine test. The normal blood pressure responses during supine static and dynamic exercises are perhaps understandable insofar as the supine blood pressures have always been normal. However, the response during treadmill exercise is of considerable interest. The hypertension disappeared during this form of exercise, suggesting that the chief functional abnormality in this patient is in the vascular responses rather than changes in cardiac output. The muscle vasodilatation in response to the metabolic needs of the exercising muscles may, by over-
PlasmaE (ng/ltter)
Urinary Excretion Rate
99 251
1.2(E% = 2) 2.1 (E% = 16)
40 60
600 720
120 130
840 790
110 100
640 630
120 130
620 680
(Whour)
.
...
coming the erstwhile vasoconstriction, be responsible for the normal blood pressure during treadmill exercise despite an (presumed] increase in the cardiac output. The favorable response to ,f3-adrenergic block with propranolol was obtained within 15 minutes after administration of the drug. A modest increase in diastolic (and mean) blood pressure on head up tilt has been reported in 18 of the 50 patients with mild hypertension studied by Frohlich et al. [9], but not in 17 normal control subjects. Such a response is particularly seen in the younger, nonobese patients with a recent onset of hypertension and in patients with “hyperdynamic &adrenergic disease.” These patients also show increased catecholamines in their urine [26]. Our patient has been entirely normotensive in the supine position during the past five years of observation, although it is possible that his condition may yet progress to sustained hypertension. He does not have features of “hyperdynamic p-adrenergic disease” and showed normal catecholamine responses during postural changes. The exaggerated normal blood pressure response to standing in our patient would seem, therefore, to be due to an excessive peripheral vasoconstriction causing an increase in the total systemic vascular resistance far in excess of the needs arising from a decrease in cardiac output. There is some evidence favoring the participation of low pressure baroreceptors in the heart in modulating cardiovascular reflexes, either without [27] or with the participation of aortic and carotid baroreceptors [28]. The state of these low pressure baroreceptors has not been examined in our patient. ACKNOWLEDGMENT
We are grateful to Dr. Claude Benedict for some of the catecholamine estimations, to Dr. J.G.G. Ledingham and Dr. B. McGrath for some of the renin studies, and to other colleagues who have helped with the investigations.
January 1979 The American Journal of Medicine
Volume 66
181
ORTHOSTATIC HYPERTENSION-SAPRU
ET AL.
REFERENCES 1. Gauer OH, Thron HL: Postural changes in the circulation. Handbook of Physiology Circulation, Sect. 2 III, Washington D.C., Am Physiological Society, 1965, p 2409. 2. Korner PI: Integrative neural cardiovascular control. Physiol Rev 51: 312,1971. 3. Kirchheim HR: Systemic arterial baroreceptor reflexes. Physiol Rev 56: 100, 1976. 4. iiberg B: Overall cardiovascular regulation. Ann Rev Physiol 38: 537, 1976. 5. Chakroverty S, Barron KD, Katz FH, et al.: The syndrome of primary orthostatic hypotension. Brain 92: 743, 1969. 6. Johnson RH, Spalding JMK: Disorders of the Autonomic Nervous System. Oxford, Blackwell, 1974. 7. Ibrahim MM, Tarazi RC, Dustan HP: Orthostatic hypotension: mechanisms and management. Am Heart J 90: 513, 1975. 8. Thulesius 0: Pathophysiological classification and diagnosis of orthostatic hypotension. Cardiology 61 (suppl 1): 180, 1976. 9. Frohlic ED, Tarazi RC, Ulrych M. et al.: Tilt test for investieation of a neural comnonent in hvoertension. Circulation I. :S: 387,1967. . 10. Bristow JD, Honour AJ, Pickering GW, et al.: Diminished baroreflex sensitivity in high blood pressure. Circulation 39: 48, 1969. 11. McMichael J. Sharpey-Schafer EP: Cardiac output in man by a direct Fick method. Effects of posture, venous pressure change, atropine and adrenaline Br Heart J 6: 33,1944. 12. Brigden W, Howarth S, Sharpey-Schafer EP: Postural changes in the peripheral blood-flow of normal subjects with observations on vasovagal fainting reactions as a result of tilting, the lordotic posture, pregnancy and spinal anaesthesia. Clin Sci 9: 79.1950. 13. Rushmer RF: Postural effects on the baselines of ventricular performance. Circulation 20: 897, 1959. 14. Bevegard S, Holmgren A, Jonsson B: The effect of body position on the circulation at rest and during exercise with special reference to the influence on the stroke volume. Acta Physiol Stand 49: 279, 1960. 15. Wang Y, Marshall RJ, Shepherd JT: The effect of changes in
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posture and of graded exercise on stroke volume in man.
1Clin Invest 39: 1051,196O. 16. Reeves JT, Grover RF, Blount SG Jr, et al.: Cardiac output response to standing and treadmill walking.____ 1Ann1 Phvsiol . 16:~283,1961. 17. Schneider EC, Truesdell D: A statistical study of the pulse rate and the arterial blood pressures in recumbency, standing and after standard exercise. Am J Physiol61: 429.1922. 18. Wald H, Guernsey M, Scott FH: Some effects of alteration of posture on arterial blood pressure. Am Heart J 14: 319, 1937. 19. Currens JH: A comparison of the blood pressure in the lying and standine nositions. A studv of five hundred men and five hundred -women. Am Heart J 35: 646,1948. 20. Green RS. Ielauer A. McGuire 1: Alterations of radial or brachial intraarterial blood pressure and of the electrocardiogram induced by tilting. J Lab Clin Med 33: 951, 1948. 21. Brod J, Fencl V, Hejl Z, et al.: Circulatory changes underlying blood pressure elevation during acute emotional stress (mental arithmeticl in normotensive and hypertensive subjects. Clin Sci 18: 269, 1959. 22. Marshall RJ, Shepherd JT: Cardiac Function in Health and Disease, Philadelphia, W.B. Saunders, 1968. 23. Hines EA, Jr, Brown GE: A standard stimulus for measuring vasomotor reactions. Its application in the study of hypertension. Proc Staff Meet Mayo Clinic 7: 332.1932. 24. Wolf S, Hardy JD Studies on pain. Observations on pain due to local cooling and on factors involved in the “cold pressor” effect. J Clin Invest 20: 521.1941. 25. Frohlich ED, Tarazi RC, Dustan HP: Hyperdynamic &adrenergic circulatorv state. Arch Intern Med 123: 1.1969. 26. Esler Mb, Nestel PJ: Sympathetic responsiveness to iead-up tilt in essential hvnertension. Clin Sci 44: 213. 1973. 27. Zoller RP, Mark AL: -Abboud FM, et al.: Role of low-pressure baroreceptors in reflex vasoconstrictor responses in man. J Clin Invest 51: 2967,1972. 28. Eckberg DL, Abboud FM, Mark AL: Modulation of carotid baroreflex responsiveness in man: effects of posture and propranolol. J Appl Physiol41: 383,1976.
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