National standard for measurement of resting and ambulatory blood pressures with automated sphygmomanometers.

The Association for the Advancement of Medical Instrumentation develops voluntary standards for medical devices so that manufacturers might provide information on their product and basic safety and performance criteria that should be considered in qualifying the instrument for clinical use. American national standards are generated through a consensus process by committees consisting of experts in research, development, and design from user, industry, and government communities. Draft standards are made available for public review and may become American national standards after review by the American National Standards Institute. The first American national standard for electronic and automated sphygmomanometers was published in monograph form in 1987. The objective of the revised 1992 standard for electronic and automated sphygmomanometers is to provide updated labeling, safety, and performance requirements that help ensure that consumers and health care professionals are supplied with safe, accurate devices for the indirect measurement of blood pressure, including ambulatory blood pressure recorders. This standard permits validation of the automatic or electronic device by comparison with either direct, intra-arterial blood pressure measurements or the noninvasive cuff/stethoscope technique, based on Korotkoff sounds identified by individuals trained in auscultation. This summary report of the 1992 American national standard for automatic sphygmomanometers provides recommendations for the methods of comparison, statistical analysis of the data, presentation of the results, and criteria for acceptability. Users, researchers, and instrument designers should refer to the American national standard monograph for detailed requirements.

Determination of alpha-adrenergic blocking potency.

Determination of the alpha-adrenergic blocking potency of drugs in humans is usually done by measuring the shift in the blood pressure versus logarithm of intravenous phenylephrine dose-response relationship. Change in blood pressure activates homeostatic reflexes that may change this relationship. This study examines the effect of autonomic (beta 1- and beta 2-adrenergic, parasympathetic, and alpha-adrenergic) blockade on the dose versus blood pressure response relationship to sequential doses of phenylephrine in humans. Phenylephrine dose responses were conducted under controlled conditions, during propranolol and atropine infusion, during prazosin-induced alpha 1-adrenergic blockade, and during prazosin, propranolol, and atropine administration. Propranolol-atropine infusion decreased the threshold dose of phenylephrine required to increase mean blood pressure (p less than 0.00001), increased the slope of the phenylephrine dose versus increase in mean blood pressure relationship (p = 0.019), and and decreased the dose of phenylephrine required to increase mean blood pressure by 20 mm Hg (p less than 0.00001). Determination of the alpha-adrenergic blocking potency of prazosin was not affected by autonomic blockade with propranolol and atropine (dose ratio 5.2 before and 5.0 after autonomic blockade; p = 0.465). We conclude that beta 1- and beta 2-adrenergic and muscarinic blockade increase sensitivity to phenylephrine by increasing the slope and decreasing the threshold dose of the phenylephrine dose-response curve, and that alpha-adrenergic-blocking potency of prazosin may be determined with or without blocking homeostatic blood pressure regulatory mechanisms in humans.

An evaluation of the A&D UA-751 semi-automated cuff-oscillometric sphygmomanometer.

We compared blood pressure recordings made with the A&D UA-751 semi-automated cuff-oscillometric sphygmomanometer (A&D Co. Ltd, Tokyo, Japan) and with a conventional Hawksley random-zero mercury sphygmomanometer (Hawksley and Sons Ltd, Lancing, UK). Simultaneous single-arm recordings were obtained in duplicate with both devices in 200 subjects having blood pressure in the ranges 92-221/51-121 mmHg. The measurements obtained by three observers using the Hawksley sphygmomanometer were compared with recordings from two A&D UA-751 devices. In most cases, there was an acceptable level of agreement between the results, according to the criteria suggested by the Association for the Advancement of Medical Instrumentation (range of differences systolic: mean - 0.9 to 1.4 mmHg, s.d. 4.6-9.8 mmHg; diastolic: mean - 0.6 to 1.3 mmHg, s.d. 2.9-5.1 mmHg), although there were sizeable discrepancies in individual subjects. Thus the A&D UA-751 device appears to be an acceptable alternative to a conventional sphygmomanometer; it should be suitable for routine clinical and limited research use, including intermittent home blood pressure recording.

Bench and ambulatory field evaluation of the A & D TM-2420 automated sphygmomanometer.

Adequate evaluation of automated sphygmomanometers, in terms of safety, accuracy, mechanical reliability, patient acceptability and ability to record ambulatory blood pressure is essential before these devices are used in clinical practice and in clinical trials. We have evaluated the accuracy and performance of the A & D TM-2420 automated sphygmomanometer, an auscultatory device designed for ambulatory blood pressure recording. Four devices were tested for accuracy by simultaneous comparison against two experienced observers using standard mercury column sphygmomanometers. Two of these devices developed faults that precluded complete evaluation. One of the remaining devices met and one failed to meet the somewhat liberal criteria for accuracy recommended by the American Association for the Advancement of Medical Instrumentation, the current standard for evaluation (mean difference of less than or equal to 5 mmHg and standard deviation of differences less than or equal to 8 mmHg). The mean differences (standard deviation of differences) between observers for simultaneous triplicate observations of systolic/diastolic pressure in 50 subjects, including 35 hypertensives, were 0.8 (3.0)/-0.6 (2.4) mmHg. In comparison, the differences between each device and each observer were: device 11, observer 1, -6.4 (5.4)/-6.3 (9.9); device 11, observer 2, -5.6 (4.7)/-7.0 (10.4); device 12, observer 1, -4.9 (5.2)/-4.0 (7.5); device 12, observer 2, -4.1 (4.9)/- -4.5 (7.7) mmHg. Ambulatory trials were carried out with a further 10 devices. Of these, seven developed faults requiring their return to the supplier. Numerous additional problems were encountered with microphones, cuffs, leads and connections, the processing unit, error algorithms and data-handling software. The device was not capable of making truly ambulatory recordings. We do not confirm the previously favourable, but limited, evaluation of this device. We stress the vital importance of subjecting a number of devices to benchtesting for accuracy, and the need to undertake extensive 'field' testing before any devices can be considered suitable for ambulatory recording. Exercise testing under laboratory conditions is not an adequate substitue for true ambulatory evaluation.

The measurement of blood pressure: sitting or supine, once or twice?

In 166 patients attending a hypertension review clinic, we compared supine and sitting blood pressure measurements and first and second measurements (1 min apart) in each position to determine whether any differences seen might have implications for the routine measurement of blood pressure in these patients, as a group or as individuals. Measurements were made with the Copal UA-251 semi-automated sphygmomanometer. In the group there was no significant difference between the first and the second diastolic measurements. The first systolic measurement was on average 3-4 mmHg higher than the second in both positions. Mean supine systolic pressures were 2-3 mmHg higher and diastolic pressures 2-3 mmHg lower than the corresponding sitting pressures. In individual subjects there were substantial disagreements between successive measurements in both positions and between positions. However, these differences would not have influenced blood pressure management in more than a few instances. We suggest that two measurements should routinely be taken, and the average recorded, particularly when the average exceeds 155/90 mmHg.

Evaluation of the IITC tail cuff blood pressure recorder in the rat against intraarterial pressure according to criteria for human devices.

National standards govern the manufacture and marketing of medical devices in the United States, including those for indirect blood pressure measurement in man. There are no comparable standards for devices for recording in laboratory animals. Noninvasive tail cuff blood pressure (BP) recording in the rat is widely accepted, but beset by methodologic difficulties. Intraarterial recording is regarded as the "gold standard" but is invasive and also susceptible to methodologic error. We compared the IITC Mark 12 photoelectric/oscillometric tail cuff system (IITC Life Sciences, Woodland Hills, CA) versus simultaneous femoral intraarterial recordings in spontaneously hypertensive rats, during anesthesia and 1 to 2 days after recover (150 recordings under each condition), according to the guidelines for human data collection and analysis suggested the American National Standard for automated sphygmomanometers. Within- and between-observer disagreements in estimates made by two observers from 40 anesthetized recordings were less for intraarterial measurements than for the tail cuff method. Within-observer differences (mean +/- SD of differences [SDD]) for systolic, diastolic, and mean pressure were 0 +/- 1, 0 +/- 1, and 0 +/- 1 mm Hg for intraarterial versus -1 +/- 3, 0 +/- 8, and 0 +/- 5 mm Hg for tail cuff. Between-observer differences were 0 +/- 2, 0 +/- 1, and 6 +/- 2 mm Hg versus 5 +/- 4, 13 +/- 7, and 0 +/- 5 mm Hg, respectively. Differences between tail cuff and intraarterial methods were 16 +/- 13, -5 +/- 11, and 2 +/- 8 mm Hg in anesthetized animals and 8 +/- 14, -5 +/- 9, and 0 +/- 9 mm Hg in conscious animals (39% to 82% of differences exceeded 5 mm Hg). The upper limits of clinically acceptable disagreement in the American National Standard are: mean of 5 mm Hg, SDD of 8 mm Hg. The disagreement between tail cuff and intraarterial recordings cannot be ascribed to either method with certainty. These findings do not support the manufacturer's guarantee of tail-cuff readings within "5 mm Hg of intraarterial." Inaccuracy and unreliability of devices intended for laboratory animal use have considerable scientific, fiscal, and ethical implications. Marketing of these devices should also be governed by rigorous standards.

Ambulatory blood pressure in heart failure.

Ambulatory blood-pressure monitoring (ABPM) is accepted in the evaluation and management of hypertension. The use of ABPM in heart failure has received considerably less attention. Many patients with advanced heart failure experience disabling fatigue, orthostatic dizziness and symptoms of coronary and cerebrovascular insufficiency that may relate to periods of hypotension. These may be exacerbated by vasodilator drug therapy and may be difficult to evaluate by casual clinic recordings. ABPM in heart failure may help in the following: (i) evaluating time-dependent pharmacodynamic drug effects, such as peak and end-of-dose phenomena, tolerance and rebound; (ii) titrating ACE inhibitors and other drugs to highest-tolerated doses; and (iii) correlating circadian blood-pressure profiles with symptoms, quality of life, severity of heart failure, progression of ventricular and renal dysfunction, risks of stroke and myocardial infarction, and life expectancy. Devices for ABPM have been beset by problems of inaccuracy and unreliability. Standards for their manufacture and sale (including bench tests of accuracy against sphygmomanometry and intra-arterial recordings, and field tests of reliability) have been devised independently by several agencies, including the British Hypertension Society (BHS) and US Association for the Advancement of Medical Instrumentation (AAMI). A joint BHS/AAMI set of guidelines is in preparation. These guidelines emphasize the suitability of ABPM devices for hypertensive patients and those under general anesthesia, and may not be applicable to ambulant individuals with heart failure and blood pressures at or below the lower end of the evaluated ranges. Prospective studies of the accuracy and reliability of ABPM devices, their clinical utility and research potential should be undertaken in patients with heart failure before their informal and uncontrolled use in this population becomes widespread.

Effects of digoxin and digitoxin on circadian blood pressure profile in healthy volunteers.

BACKGROUND: The aim of the study was to investigate the potential effects of chronic digoxin or digitoxin treatment or circadian blood pressure profile in normotensive subjects. METHODS: In two randomized double-blind, placebo-controlled cross-over protocols, 22 healthy normotensive subjects were enrolled, 12 subjects in either study. After adequate loading doses, digoxin 0.25 mg twice daily or digitoxin 0.1 mg daily was given for a total of 10 days. Automatic 24-h ambulatory blood pressure measurements were carried out at days 4 and 10 of either glycoside or placebo. RESULTS: Digoxin treatment significantly decreased heart rate (HR) and diastolic blood pressure (DBP) during the overnight sleeping phase of day 10 compared with placebo (HR, 4 beats min-1; DBP, 8 mmHg; P < 0.05). Digitoxin treatment significantly decreased heart rate and diastolic blood pressure during the overnight sleeping phase of day 4 (HR, 8 beats min-1; DBP, 7 mmHg) and day 10 (HR, 7 beats min-1; DBP, 5 mmHg) compared with placebo (P < 0.05). Neither digoxin nor digitoxin significantly affected systolic blood pressure. CONCLUSIONS: Both digoxin and digitoxin, within therapeutic steady-state plasma concentrations, reduced diastolic blood pressure and heart rate during overnight sleep, presumably because of increased parasympathetic activity or decreased sympathetic activity.

Histamine response and local cooling in the human skin: involvement of H1- and H2-receptors.

AIMS: Histamine may contribute locally to cutaneous blood flow control under normal and pathologic conditions. The objective of this study was to observe the influence of skin temperature on histamine vasodilation, and the roles of H1-and H2-receptors using novel noninvasive methods. METHODS: Eleven healthy subjects received, double-blind, single doses of the H1-receptor antagonist cetirizine (10 mg), cetirizine (10 mg) plus the H2-receptor antagonist cimetidine (400 mg), or placebo on separate occasions. Histamine was dosed cumulatively by iontophoresis to the forearm skin at 34 degrees C and 14 degrees C. Laser-Doppler flux (LDF) was measured at the same sites using customised probeholder/iontophoretic chambers with Peltier cooling elements. Finger mean arterial pressure (MAP) was measured and cutaneous vascular conductance calculated as LDF/MAP. RESULTS: Histamine vasodilation was reduced in cold skin. Cetirizine shifted the histamine dose-response at both temperatures: statistically significantly at 14 degrees C only. Combined H1- and H2-receptor antagonism shifted the response significantly at both temperatures. CONCLUSIONS: H1- and H2-receptors mediate histamine-induced skin vasodilation. The sensitivity of these receptors, particularly the H1- receptor, is attenuated at low skin temperature. Whether the reduced effect in cold skin represents specific receptor or postreceptor desensitization, or nonspecific attenuation of cutaneous vasodilation remains to be elucidated.

The local effects of systemic digoxin on the cutaneous microcirculation.

OBJECTIVE: The present study was designed to explore whether digoxin modifies cutaneous vascular responses to an endothelium-dependent vasodilator (acetylcholine) or to the vasoconstrictor norepinephrine. METHODS: In a double-blind cross-over study 12 healthy subjects received digoxin 0.25 mg twice daily (after adequate loading doses) or placebo for a total of 11 days. Dose-response curves to iontophoresis of acetylcholine or norepinephrine were constructed at day 11. Laser Doppler flux (LDF) was measured at the same sites. Mean arterial pressure (MAP) was measured non-invasively and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/MAP). RESULTS: Serum concentrations of digoxin were within the therapeutic range [1.3 (0.5) ng x ml(-1); mean with (SD)]. Blood pressure and heart rate were significantly lower during supine rest under digoxin treatment [mean with (SD); minute 10 to 70 of supine rest; systolic blood pressure: 121 (11) mmHg (placebo) vs 116 (11) mmHg (digoxin); P = 0.001; diastolic blood pressure: 63 (6) mmHg vs 58 (8) mmHg; P = 0.007; heart rate: 60 (10) beats x min(-1) vs 54 (8) beats x min(-1); P = 0.001]. Digoxin also caused significantly higher baseline CVC [169 (25) Perfusion Units (PU) x mmHg(-1) (digoxin) vs 109 (14) PU x mmHg(-1)(placebo); P = 0.013] and significantly increased the vasoconstriction to norepinephrine iontophoresis. Acetylcholine iontophoresis was unaltered by digoxin treatment. CONCLUSIONS: Digoxin does not modify the cutaneous vascular response to an administered endothelium-dependent vasodilator. It reduces resting heart rate, blood pressure and baseline cutaneous blood flow and augments the vasoconstrictive effect of exogenous norepinephrine. The findings do not support the hypothesis that digoxin lowers diastolic blood pressure through a direct action on blood vessels.

The analysis of dose-response curves--a practical approach.

The rationale for the objective assessment of dose-response curves (DRCs) is presented. Using data derived from isoprenaline/heart rate responses studies, two new statistical methods of objectively defining the terminal linear segment of an incomplete DRC are presented. Using data derived from phenylephrine/diastolic blood pressure response studies, the parallel shift quadratic model of Sumner et al. (1982) has been extended to include a measure of the suitability of the quadratic model for each individual data set using the Akaike information criterion. A parallel shift Emax model is proposed for complete DRCs.

Alpha adrenergic blocking activity of urapidil in man.

Urapidil is a new antihypertensive vasodilator agent whose pharmacologic action in man has not yet been fully defined. We have assessed the alpha adrenergic blocking activity of urapidil 15 and 30 mg given intravenously in a single blind study in 8 healthy volunteers. Urapidil produced dose-dependent parallel shift of the phenylephrine log dose/blood pressure response curve, consistent with significant competitive peripheral alpha 1 antagonism. Mean dose ratios were 2.99 and 5.48 for the 15 mg and 30 mg doses respectively. The pA2 for alpha 1 blockade is 7.3. Given these data, the major mechanism of antihypertensive effect of urapidil may be alpha 1 antagonism in the peripheral vasculature.

A comparison of the chronic effects of oral xamoterol and enalapril on blood pressure and renal function in mild to moderate heart failure.

1. We compared the effects, after 3 weeks oral therapy, of xamoterol 200 mg twice daily and enalapril 2.5, 5 or 10 mg twice daily on home and clinic blood pressure, glomerular filtration rate (GFR) and renal plasma flow, stroke and minute distances, linear resistance and on plasma renin activity in 19 patients with mild to moderate heart failure in a single-blind randomised crossover study. 2. Enalapril reduced mean home blood pressure by 17/7 mm Hg compared with xamoterol (P less than 0.0001) and by 19/7 mm Hg compared with placebo. Compared with placebo xamoterol had no effect. Enalapril reduced predose blood pressure, compared with xamoterol, on average by 15/5 mm Hg (P = 0.02 systolic, 0.09 diastolic) and by 20/7 mm Hg compared with placebo. At 4 h post-dose the mean differences were: xamoterol-enalapril 13/10 mm Hg (P = 0.01 systolic, 0.0007 diastolic) and placebo-enalapril 23/9 mm Hg. 3. Stroke and minute distances were marginally less 4 h following xamoterol than following enalapril: mean (s.e. mean) values were 9.4 (0.7) vs 10.4 (0.8) cm (P = 0.23) and 699 (51.7) vs 767 (62.1) cm (P = 0.04) respectively. Linear resistance was reduced by enalapril, from the placebo value of 13.2 (1.2) to 11.0 (0.9) mm Hg m-1 and marginally increased by xamoterol, to 14.2 (1.2) mm Hg m-1, the difference between active treatments being statistically significant (P = 0.03). 4. Renal plasma flow, GFR and filtration fraction were not influenced by enalapril or xamoterol therapy. There were no significant correlations between glomerular filtration rate and either blood pressure or stroke distance.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemical image fusion. The synergy of FT-NIR and Raman mapping microscopy to enable a more complete visualization of pharmaceutical formulations.

The pharmaceutical industry uses successfully both FT-NIR and Raman microscopy to produce chemical images of solid dosage forms, typically in troubleshooting roles. However, due to the chemical composition of the formulations, it is not always possible to describe the entire chemical formulation by using a single spectroscopic method. As Raman and NIR spectroscopies are complementary in nature, their combined usage offers the opportunity to describe heterogeneous mixtures in more detail. A novel sample referencing approach has been developed that allows data to be acquired from exactly the same area of the sample using both Raman and FT-NIR microscopies. The optimum images for the components are then overlaid, which gives rise to a combined chemical image that visually describes the entire formulation. We have named this approach chemical image fusion (CIF). CIF has been applied to two examples. The first shows how a simple formulation was used to validate the CIF approach. In the second, CIF allowed an entire formulation to be visualized and the cause of tabletting problems determined. CIF provides increased confidence in the results generated by each individual technique and offers a more powerful method for the evaluation of pharmaceutical formulations.

The assessment of the beta-blocking activity of urapidil: a new method.

Urapidil is an antihypertensive vasodilator agent whose pharmacological action in man has not yet been fully defined. We have assessed the beta blocking activity of urapidil 15 mg and 30 mg i.v. in a single blind study of 10 healthy male volunteers. Urapidil at plasma concentrations in the same range as those shown to have antihypertensive affect did not significantly attenuate the chronotropic effect of isoproterenol. Propranolol 5 mg iv, the positive control, significantly shifted the isoproterenol dose-response curve to the right. We describe a new method of analyzing incomplete dose response curves whereby a linear terminal segment can be reproducibly defined.

The effect of iontophoresis on the cutaneous vasculature: evidence for current-induced hyperemia.

Combining laser-Doppler blood flux measurements of the skin microcirculation with iontophoresis of vasoactive agents is a promising noninvasive tool for pharmacological studies. However, preliminary observations in our laboratories suggested significant current-associated vasodilation when an expected vasoconstrictor (NG-monomethyl-L-arginine acetate) was iontophoresed. The present study was designed to define nonspecific current-related versus specific pharmacological effects of iontophoretically administered ions on the cutaneous vasculature. Dose-response studies to a series of anions (nitrite, chloride, acetate, and bicarbonate) and cations (sodium, lithium, and acetylcholine) were carried out in six healthy volunteers (three male) by iontophoresis to the forearm skin on separate days. Laser-Doppler flux was measured at the same sites. All ions caused dose-dependent vasodilation. There was no difference in the response between chloride, bicarbonate, or acetate and nitrite, the nitric oxide donor. The acetylcholine dose response was shifted rightward after atropine pretreatment. Cutaneous vascular responses to iontophoresis comprise nonspecific, current-induced hyperemia and specific effects of the administered agent. Acetylcholine appears to cause muscarinic and current-induced dilatation. Nitrite may cause current-induced hyperemia alone. Current-induced hyperemia should be considered in interpreting the acute cutaneous vascular responses to iontophoretically administered agents in humans.

Effect of food on oral availability of apresoline and controlled release hydralazine in hypertensive patients.

Hydralazine is a vasodilator antihypertensive drug that has been in use for many years. Efficacy after oral administration correlates well with the levels of the drug in blood. Factors such as food ingestion that affect blood levels of hydralazine may therefore be of importance. There is dispute regarding the effect of food intake on blood levels of hydralazine and on the antihypertensive response. This randomized cross-over study examined the effect of food (642 K calories, 25 g protein, 43 g fat, 40 g carbohydrates, 32 mEq sodium, 17 mEq potassium) ingested immediately before hydralazine (taken as Apresoline, Ciba Geigy, or as slow-release hydralazine, SRH, Pennwalt Corporation) on the blood levels of hydralazine in 16 essential hypertensive patients who were slow acetylators currently taking at least 100 mg Apresoline daily. Peak blood hydralazine levels were reduced by food after both Apresoline and SRH, by 69 and 66%, respectively. Time to peak blood hydralazine concentration was delayed significantly with SRH. We could detect a statistically significant food-related reduction of area under blood hydralazine concentration versus time curves (AUC) only with Apresoline (by 44%). The AUC for SRH was decreased only 29% by food. Hydralazine should be taken at a consistent time with respect to meals.