Fall In Supine Blood Pressure Research Articles

OP.3C.04] PREDICTING POSTURAL HYPOTENSION, FALLS, AND COGNITIVE IMPAIRMENT

Objective: Over three million people aged over 65 fall each year in the UK. Postural hypotension (PH) is a risk factor for falls. It is associated with excess mortality, and may affect cognition. PH is not routinely checked for in UK clinical practice. We studied the InCHIANTI dataset to derive and validate a simple prediction tool designed to facilitate identification of subjects to be checked for PH. Design and method: InCHIANTI is a population-based study of ageing. It recruited subjects from population registries in Chianti, Italy in 1998 and they were followed up triennially. Blood pressure (BP) at recruitment was measured after resting supine, and one and three minutes after standing, using a mercury sphygmomanometer. Systolic PH was defined as a > = 20 mmHg fall in supine BP on standing. Subjects were randomised to derivation or validation cohorts; allocation was undertaken blinded to PH status and medical history. Candidate predictor variables identified from literature searches were tested for univariable cross sectional associations with PH using χ2 tests. Those with significant associations were entered into multivariable linear regression models, and used to derive simple and weighted prediction scores (DROP scores). DROP scores were tested in the validation cohort for prediction of PH, future falls, cognitive decline and mortality rates. Results: PH was present in 56/726 (7.7%) of the derivation cohort and 45/727 (6.2%) of the validation cohort (p = 0.25). PH was associated with age > = 65, falls in the preceding year, diabetes, previous stroke, hypertension and Parkinson's disease. A simple score summing numbers of these variables performed equally well as weighted scores (AUROC 0.67 (0.59 to 0.74); p < 0.001). Rising DROP scores were incrementally predictive of future falls (χ2 for trend p < 0.01), increasing rates of decline in mini mental state examination (ANOVA p < 0.001) and mortality (HR 1.8 (1.6 to 2.0) per unit increment in DROP score; p < 0.001; figure).Conclusions: The DROP score can predict presence of PH, future falls, and increased rates of mortality and cognitive decline. Application of the score could facilitate detection and management of PH. External validation of the DROP score is underway.

LB02.09

Objective: Postural hypotension (PH) is a risk factor for falls, and associated with excess mortality. Recommendations on testing for PH vary: NICE (2011) advises checking in the presence of falls or symptoms whilst ESH/ESC (2013) advises checking in elderly and diabetics. It is recommended that blood pressure (BP) is measured both 1 and 3 minutes after standing; this is seldom done in clinical practice. We studied the InChianti dataset to identify associations of PH that could inform clinical practice. Design and method: The InCHIANTI study is a population-based study established to understand causes of walking difficulties in older persons. Subjects were randomly selected from population registries in the Chianti area of Italy in 1998; they underwent extensive baseline interviews and examinations, and are being followed up triennially. BP at recruitment was measured supine and after one and three minutes standing with a mercury sphygmomanometer. Systolic PH was defined as a >=20mmHg fall in supine BP on standing. Survival with or without PH was analysed and Cox proportional hazard ratios (HRs) calculated. Univariable cross sectional associations for PH were analysed using χ2 tests. Potentially significant associations (P<0.1) were included in multivariable linear regression models. Significant multivariable associations were used to derive a simple prediction score (DROP score). Results: At recruitment 101/1352 (7.5%) and 89/1352 (6.6%) participants had PH after 1 and 3 minutes standing respectively. PH was associated with increased all-cause mortality over 10 years (HR 2.0 (95%CI 1.5 to 2.7) for both 1 and 3 minutes). On multivariable regression PH was associated with age >=65 years, any fall in the previous year, and previous diagnoses of hypertension, stroke or angina. A simple scoring system of 0 to 5 according to the presence of each of these variables suggested numbers needed to screen of 11 for a score of 2 and 8 for a score of 3 (figure). Conclusions: The likelihood of PH can be predicted from existing medical history. Presence of diabetes is not a predictor of PH in this cohort. Further work is underway to refine and validate the DROP score.

Comparison of the blood pressure response to food in two clinical subgroups of multiple system atrophy (Shy–Drager syndrome)

Multiple system atrophy (MSA) is a progressive disorder in which autonomic features vary at different stages. Abnormal cardiovascular responses are common and it is now recognized that factors in daily life, such as exercise or food ingestion, can lower blood pressure (BP) substantially. The BP response to exercise differs in the cerebellar (MSA-C) and parkinsonian (MSA-P) forms of MSA. Whether this also occurs after food ingestion has not been addressed. We, therefore, compared the BP response following a liquid meal in MSA-C (n=10) and MSA-P (n=7) subjects. In both forms, after head-up tilt while fasted, there was a similar fall in mean arterial blood pressure (MAP) in MSA-C (23+/-4mmHg) and MSA-P (23+/-4mmHg). After the liquid meal there was a fall in supine BP in both forms, but the fall in MAP was greater in MSA-C (19+/-5mmHg) than in MSA-P (8+/-2mmHg, p<0.05). On re-tilt, 45min after the meal, BP fell to a lower level in both subgroups, with a similar MAP fall in MSA-C (20+/-5mmHg) and MSA-P (23+/-7mmHg). The larger supine BP fall in response to a liquid meal in MSA-C than in MSA-P was similar to the responses found with exercise and suggests that cerebellar and/or brain stem autonomic pathways are impaired to a greater extent in MSA-C than in MSA-P. Pooling MSA subgroups, therefore, may obscure patho-physiological differences to certain stimuli. The response to upright posture in MSA-C and MSA-P was similar post meal as it was after exercise. Clinically, therefore, when postural hypotension is being assessed, separation of the subgroups may not be essential.

Cardiovascular and hormonal responses to liquid food challenge in idiopathic Parkinson's disease, multiple system atrophy, and pure autonomic failure

We investigated the effect of a balanced liquid meal on blood pressure (BP) and heart rate (with patients supine and during head-up tilt), and on levels of plasma catecholamines, glucose, and insulin, in patients with idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA), pure autonomic failure (PAF), and in healthy subjects (controls). After food, supine BP fell in IPD, but to a greater extent in MSA and PAF. In controls, BP was unchanged. Head-up tilt did not lower BP in IPD and controls, but there was a postprandial fall to lower levels in both MSA and PAF. Plasma norepinephrine levels rose in IPD pre- and postprandially during tilt, but were unchanged in MSA and PAF. These data suggest that in IPD, food causes a smaller fall in supine BP than in MSA and PAF. In IPD, as in controls, food does not induce or unmask postural hypotension, unlike in MSA and PAF, in which BP falls to even lower levels. There are therefore differences in the responses to food ingestion between these groups. This may be of value in separation of these disorders at an early stage.

Alcohol ingestion lowers supine blood pressure, causes splanchnic vasodilatation and worsens postural hypotension in primary autonomic failure.

Patients with pure autonomic failure (PAF) and multiple system atrophy (MSA) may complain of feeling light-headed after alcohol ingestion particularly on assumption of the upright posture. The reasons for this have not been investigated. We therefore studied the effects of oral alcohol (40% vodka in sugar-free orange juice) and placebo (juice only) on the systemic and regional (including superior mesenteric artery, SMA) blood flow in nine patients with PAF and six patients with MSA. After alcohol, there was a fall in supine blood pressure (BP) and vasodilatation in the SMA but no change in cardiac output, or forearm muscle and cutaneous blood flow in either PAF or MSA; BP fell further during head-up tilt with no changes in levels of plasma catecholamines. After placebo, there were no changes while supine. We conclude that alcohol lowers supine BP and dilates the SMA with no change in muscle or cutaneous blood flow. Alcohol also enhances the fall in BP during head-up tilt. This may explain the symptoms experienced by PAF and MSA patients after alcohol.

Candoxatril, a neutral endopeptidase inhibitor

To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension. Double-blind, placebo-controlled, parallel-group study of 28 days' duration. Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK). Forty patients with essential hypertension with diastolic blood pressure 95-114 mmHg after a 2-4 week placebo run-in period. Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules. Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment. When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin-aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentration of candoxatril at (UK 73,967--the active metabolite of candoxatril) reached a peak of 1010 +/- 437 ng/ml after acute dosing, and 1328 +/- 405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo. Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.

Assessment of Antihypertensive Efficacy of Perindopril

Perindopril (4 mg) was compared to atenolol (50 mg), captopril (25 mg b.i.d.), or a diuretic (hydrochlorothiazide 50 mg and amiloride 5 mg) in three studies involving a total of 503 hypertensive patients with diastolic blood pressure (DBP) of 95-125 mm Hg. A 4-week single-blind placebo period preceded 12 weeks of active treatment. Dose titration was at weeks 4 and 8 if the supine DBP was greater than 90 mm Hg. The dose was doubled and, if necessary, a diuretic was added in atenolol or captopril comparison and atenolol added in the diuretic study. The fall in supine blood pressure (BP) was 27/17 mm Hg with perindopril and 21/16 mm Hg for atenolol. Fifty-five percent on perindopril and 48% on atenolol were controlled on monotherapy, increasing to 78 and 58% with addition of hydrochlorothiazide. Captopril caused a BP fall of 19/12 mm Hg compared to 27/18 mm Hg for perindopril with 49% of both groups being controlled on monotherapy. Diuretic addition produced a greater antihypertensive effect with perindopril 75% compared to 57% of the captopril patients achieving control. Perindopril caused a comparable fall in supine BP to the diuretic combination 27/19 mm Hg and 31/18 mm Hg but the fall in erect systolic BP was significantly greater for the diuretic. At 3 months, 84% of the diuretic and 78% of the perindopril group achieved the target BP. There were no adverse effects on the blood count or blood chemistry with a low incidence of side effects and withdrawals from treatment. These studies show that perindopril compares favorably with the standard antihypertensive drugs.

Effects of clonidine on central and peripheral nerve tone in primary hypertension.

To define the mechanisms whereby clonidine lowers blood pressure, we measured cerebrospinal fluid and plasma levels of norepinephrine, normetanephrine, epinephrine, dopamine, and the dopamine metabolite homovanillic acid in 10 primary hypertensive subjects before and after 3 months of clonidine treatment (mean dose, 0.68 mg/day). Catecholamines were measured by radioenzymatic methods. Cerebrospinal fluid and plasma sampling was performed after subjects had fasted and remained supine overnight, and plasma sampling was repeated 2 hours later, after subjects had ambulated. Supine and upright blood pressure fell, as might be expected. Cerebrospinal fluid levels of norepinephrine and normetanephrine fell significantly, but dopamine and homovanillic acid levels were unchanged. Plasma norepinephrine, normetanephrine, and epinephrine levels decreased 30 to 50%, and supine dopamine levels also fell. The percent fall in supine blood pressure was related to the fall of cerebrospinal fluid and plasma norepinephrine. There were also positive relationships between the decreases of plasma norepinephrine and of normetanephrine and dopamine. The cerebrospinal fluid/plasma norepinephrine ratio was unaffected by clonidine, suggesting that the drug lowered both pools equally. Our findings indicate that clonidine decreases both central and peripheral norepinephrine activity. The dopaminergic activity of cerebrospinal fluid was unaffected by clonidine, and though plasma dopamine levels tended to be lower after treatment, mean plasma prolactin level, an index of dopaminergic activity, was also unchanged. The fall in plasma epinephrine level is probably related to diminished sympathetic adrenomedullary stimulation and is unlikely to contribute to clonidine's antihypertensive action. These results also suggest that measurement of normetanephrine in cerebrospinal fluid and plasma provides a good index of norepinephrine activity.

The effects of organic nitrates on prostacyclin biosynthesis and platelet function in humans.

The results of prior studies indicate that nitroglycerin stimulates prostacyclin release by cultured endothelium and by the coronary vasculature in vivo. However, the accuracy of these findings in coronary vasculature relies on plasma samples obtained from the circulation via cardiac catheters, a procedure we have shown to stimulate prostacyclin release, thereby confounding interpretation of drug action. We studied the effects of short-acting (nitroglycerin) and long-acting (isosorbide dinitrate) nitrates on a noninvasive index of prostacyclin synthesis, excretion of urinary 2,3-dinor-6-keto-PGF1 alpha. Nitroglycerin was infused into six subjects to either a maximum of 480 micrograms/min or until mean arterial pressure fell by 20 mm Hg. Urine was collected for negative ion chemical ionization gas chromatographic, mass spectrometric analysis before and during the nitroglycerin infusion and for two 2 hr periods after nitroglycerin. The peak nitroglycerin infusion rate was 387 +/- 67 micrograms/min, which caused a fall in supine blood pressure (systolic/diastolic) of 11 +/- 5/14 +/- 4 mm Hg and a 12 +/- 3 beats/min increase in heart rate. Excretion of 2,3-dinor-6-keto-PGF1 alpha (pg/mg creatinine) was unchanged from control infusion values (106 +/- 19.5) either during (123 +/- 21) or after (134 +/- 14.6; 139 +/- 36) nitroglycerin infusion. Platelet aggregation to arachidonic acid (0.33 to 1.33 microM) and epinephrine (1 to 10 microM) ex vivo was inhibited in only one subject in whom excretion of 2,3-dinor-6-keto-PGF1 alpha was unaltered. Serum thromboxane B2 was not changed by nitroglycerin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of phenoxybenzamine on cardiovascular and plasma catecholamine responses to clonidine.

To determine whether the alpha-adrenergic antagonist phenoxybenzamine would alter cardiovascular or plasma catecholamine response to the alpha-adrenergic agonist clonidine, six patients with pheochromocytomas and eight with labile hypertension were studied. Clonidine, 0.3 mg, was given with and without 48 hr pretreatment with 30 mg/day phenoxybenzamine. The response to 10 mg diazepam was also observed in seven of the subjects who had labile hypertension. In the hypertensive patients, clonidine alone induced a fall in supine blood pressure from 137 +/- 21/91 +/- 14 to 109 +/- 18/76 +/- 17 mm Hg and, with phenoxybenzamine, clonidine reduced blood pressure from 141 +/- 22/89 +/- 10 to 107 +/- 21/72 +/- 11 mm Hg. Plasma norepinephrine fell from 179 +/- 60 to 107 +/- 79 pg/ml without phenoxybenzamine and from 229 +/- 159 to 95 +/- 46 pg/ml with phenoxybenzamine in hypertensive subjects. Responses with phenoxybenzamine did not differ from those without phenoxybenzamine and diazepam induced no cardiovascular or plasma catecholamine changes. Clonidine did not lower plasma catecholamines in patients with a pheochromocytoma in the presence or in the absence of phenoxybenzamine. Blood pressure tended to decline after clonidine in pheochromocytoma patients not taking phenoxybenzamine, but it was not reduced by clonidine when these patients were taking phenoxybenzamine. Phenoxybenzamine does not inhibit reduction in blood pressure and plasma catecholamines induced by clonidine in patients with essential hypertension or interfere with the clonidine suppression test in patients with pheochromocytomas.

Acute effects of captopril on blood pressure and circulating hormone levels in salt-replete and depleted normal subjects and essential hypertensive patients.

1. The acute effects of a single oral dose of captopril on blood pressure, pulse rate and circulating levels of angiotensin I (ANG I), angiotensin II (ANG II), renin, bradykinin and catecholamines were studied in three groups: eight normal subjects, six salt-depleted normal subjects and 16 patients with essential hypertension. 2. Captopril treatment did not cause any significant fall in supine blood pressure in salt-replete normal subjects or patients with untreated essential hypertension but was associated with a fall in mean blood pressure from 85 +/- 2 to 75 +/- 2 mmHg in salt-depleted normal subjects and from 131 +/- 7 to 117 +/- 5 mmHg in patients with essential hypertension treated with diuretics. There was no change in pulse rate in any group. 3. Hormonal responses to captopril were qualitatively similar in the three groups and consisted of significant falls in ANG II with corresponding increases in ANG I and plasma renin concentration. The changes in plasma renin concentration and ANG I were greater in salt-depleted normal subjects (mean values at 90 min were 1140% and 990% of basal levels respectively) than in salt-replete normal subjects (410%, 190%) and were blunted in patients with essential hypertension (140%, 120%). Blood bradykinin, noradrenaline and adrenaline concentrations did not change after captopril in any group. 4. The parallel fall in blood pressure and ANG II levels in salt-depleted normal subjects is consistent with maintenance of blood pressure by increased levels of ANG II in sodium depletion. 5. The failure of captopril to reduce acutely blood pressure in patients with essential hypertension despite suppression of plasma ANG II and without change in circulating bradykinin confirms that the renin-angiotensin system does not play a primary role in essential hypertension.

Influence of hospitalization and placebo therapy on blood pressure and sympathetic function in essential hypertension.

The decline in blood pressure (BP) in essential hypertensives following hospitalization may result from: 1) regression toward the mean; 2) reduction of anxiety as patients habituate to a new environment; 3) the placebo effect of medication; and 4) an independent effect of hospitalization itself. A randomized crossover study of 12 essential hypertensives demonstrated a fall in supine blood pressure from 165.0/97.9 +/- 2.3/1.1 mm Hg to 154.3/89.6 +/- 2.7/1.1 mm Hg (p less than 0.005) due to hospitalization. A similar reduction in BP from 164.9/99.5 +/- 8.4/4.1 mm Hg to 151.9/93.4 +/- 4.5/1.9 mm Hg (p less than 0.005) resulted from regression toward the mean and habituation during the study period. Urinary catecholamines fell from 68.7 +/- 5.0 to 55.1 +/- 4.3 micrograms/g creatinine/24 hours (p less than 0.05) due to hospitalization and from 56.1 +/- 5.4 to 49.7 +/- 4.3 micrograms/g creatinine/24 hours (p less than 0.05) with time. Although placebo therapy tended to reduce BP, it failed to do so significantly. When expressed as a percentage of the individual's overall mean, urinary catecholamine excretion fell from 110.5% +/- 3.7% to 89.5% +/- 3.7% (p less than 0.001) during hospitalization and from 105.8% +/- 3.9% to 94.2% +/- 3.9% (p less than 0.05) during the outpatient period. Blood pressure and sympathetic activity rapidly returned to prehospitalization values on discharge. These factors may confound the analysis of drug effects on BP and sympathetic activity in essential hypertensives following admission to hospital.

Use of minoxidil in the azotemic patient.

Twenty-seven azotemic patients with severe hypertension resistant to the usually employed antihypertensive drugs received from 5 to 60 mg of minoxidil daily in combination with other antihypertensive drugs for 3 days to 144 weeks. At the time minoxidil treatment began, the mean age of the 27 was 44 (range, 16–65) years; 18 were black, and 18 were men. Their serum creatinine levels averaged 6.4 mg/dl (range, 1.7–17.1). Fifteen had hemorrhages and/or exudates in their ocular fundi, and 6 were being hemodialyzed. After 1 month of minoxidil treatment the average fall in supine blood pressure was 27/23 mm Hg. From the last value before minoxidil to the last value during minoxidil, an average of 40 weeks, the serum creatinine concentration rose an average of 0.8 mg/dl. For the 19 patients who were never dialyzed, the increase averaged 1.1 mg/dl, and for the 8 patients who were dialyzed, there was a decrease of 0.2 mg/dl. Eleven patients discontinued minoxidil after 3 days to 35 weeks: 3 because their hypertension was controlled with other drugs during dialysis: 2 after nephrectomies because their blood pressure could not be controlled; 1 following renal transplantation; 1 each because of hirsuitism, massive congestive heart failure, and hypotension; and 2 because of refusal to continue the regimen or moving out of the area. Four patients died on minoxidil: 2 from end-stage renal disease after 4 and 17 weeks, 1 from bronchopneumonia after 3 days, and 1 with a previous history of myocardial infarction from acute cardiorespiratory arrest after 3 weeks.

Atenolol and chlorthalidone in combination for hypertension.

1 The hypotensive effect of single daily dosing with atenolol 100 mg and chlorthalidone 25 mg given alone or in combination has been assessed in a double-blind, crossover, placebo controlled trial in fifteen hypertensive patients. 2 Average lying blood pressures were: Placebo 155.4/103.9 mm Hg, atenolol 134.6/85.8 mm Hg, chlorthalidone 139.5/90.1 mm Hg, combination 127.7/82.5 mm Hg. 3 The effect of the combination therapy in reducing lying diastolic pressure compared with placebo (a fall of 21.4 mm Hg) was significantly less than the 31.9 mm Hg fall predicted from the sum of the individual effects (P = 0.01). 4 Observations on blood pressure at rest and under mental, isometric and bicycle ergometer stress were made pre-dose and post-dose for a 12 h period at the end of the last treatment period. 5 Lying blood pressure declined from the zero hour (pre-dose) reading on all treatments to a low at 15.00--18.00 h and then rose again. 6 The rise in systolic blood pressure after isometric exercise and mental stress was of a similar magnitude with all four treatment regimes. 7 Atenolol, alone and in combination with chlorthalidone, reduced the blood pressure and the pulse rate increase on exercise 2 h post-dose when compared with readings 24 h post-dose. 8 Once daily dosing with a combination of atenolol and chlorthalidone produced a fall in supine blood pressure over a 24 h period but the effect on exercise induced changes was not uniform over this period.