Clinical Science (1992) 83, 1-12 (Printed i n Great Britain)

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Editorial Review

Blood pressure measurement: an epitaph for the mercury sphygmomanometer? M. J. STEWART and P. L. PADFIELD Department of Medicine, Western General Hospital, Edinburgh, U.K.

HISTORICAL BACKGROUND

The pressure exerted by the heart on the circulation was first measured in 1733 by the Reverend Stephen Hales, who cannulated the femoral artery of a horse and measured the vertical height to which blood rose in a glass tube some 9 feet in length. In 1828, this procedure was simplified by Poiseuille, who used a much shorter U-tube filled with mercury and measured arterial blood pressure (BP) in mmHg for the first time. Poiseuille was also the first to recognize that the same pressure is maintained throughout the arterial tree. However, BP measurement in man required a non-invasive technique. Vierordt was the first to attempt this, in 1854, using a scale pan attached to a lever pressed on the radial pulse to determine the weight in grams required to obliterate the radial pulse. Mahomed, working in Guy’s Hospital in London, began to apply these techniques to human disease for the first time and in 1874 described the association between high BP and acute nephritis. The potential importance of an accurate technique for the measurement of BP was thus beginning to be appreciated. The prototype of the modern mercury sphygmomanometer was devised by Riva-Rocci, who, in 1896, placed a band around the upper arm and inflated it with air until the pressure was sufficient to obliterate the pulse. By releasing the air gradually while observing the pressure on a manometer and palpating the pulse, he was able to record the systolic BP. In 1901, Janeway described the occurrence of sounds during deflation of the cuff, but it was Korotkoff, in 1905, who related these sounds to the systolic and diastolic BPs. The equipment used has since been modified to improve accuracy, but the technique is essentially unchanged.

BP MEASUREMENT AND THE MERCURY SPHYGMOMANOMETER

In 1939, in an attempt to standardize the technique for the measurement of BP, the American Heart Association (AHA) and the Cardiac Society of Great Britain and Ireland issued joint recommendations on methods of BP determination [l]. These have subsequently been updated at intervals as appropriate by the AHA in the U.S.A. [2] and the British Hypertension Society (BHS) in the U.K. [3] and, despite some vacillation over the issue of the diastolic end-point [2], these two bodies are now in broad agreement. With careful attention to detail, the mercury sphygmomanometer provides accurate, reliable and reproducible BP measurement. In clinical practice, however, errors in BP determination are common. Despite the AHA, BHS and World Health Organization all recommending the routine use of Korotkoff sound phase V, many physicians continue to record phase IV [4]. As the vast majority of epidemiological data [S] and the major therapeutic intervention trials [6, 71 have used phase V readings, and as there are greater errors in the identification of phase IV [S], the arguments in favour of the universal use of phase V (with the possible exception of readings in children and in pregnancy, when sounds may persist to zero) are overwhelming. Controversy over the appropriate cuff size continues. The AHA recommend the use of a cuff with a ratio of bladder width to upper arm circumference of 0.4 [2]. The bladder length should be at least twice the width, thus ensuring that the bladder will encircle 80% of the arm, and the centre of the bladder should be over the brachial artery. A bladder which encircles the arm completely corre-

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Key words: ambulatory, blood pressure determination, diurnal rhythm, home monitoring, hypertension, ‘whitecoat’ effect. Abbreviations: AHA, American Heart Association; BHS, British Hypertension Society; BP, blood pressure. Correspondence: D r M. J. Stewart, Department of Medicine, Western General Hospital, Edinburgh EH4 ZXU, U.K.

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M. J. Stewart and P. L. Padfield

lates better with intra-arterial recordings [9, lo], yet the standard adult cuff (12 cm by 23 cm) will encircle only 33% of adult arms. The BHS therefore recommends the use of a standard cuff measuring 12cm by 35cm, which would encircle 99% of adult arms [3]. Under-estimation of BP with larger cuffs is not a problem in practice [lo]. As many as 14% of hypertensive patients may have spurious elevation of BP related to use of a standard cuff [ll]. Pseudo-hypertension in the elderly [121 is probably an artefact related to inappropriate cuff size and is not seen when larger cuffs are used [ l l , 131. Although such cuffs are not widely available, their use should be encouraged. A newly developed cuff containing three rubber bags of different sizes, which automatically selects the appropriately sized bag in relation to arm circumference (the Tricuff), appears to give BP readings which correlate well with intra-arterial values [14] and may overcome the problems of cuff size selection. Observer bias, particularly when there is an arbitrary division between normal and high BP, is a common cause of error in BP measurement, the magnitude of which is sufficient to have important implications for both research and management [15, 161, and the reduction in bias seen with re-training of observers is short-lived [l5]. Terminal digit preference is also widespread, with as many as 84% of systolic values and 73% of diastolic values being recorded to the nearest ‘0’ [16, 171. As this tendency tends to be more common around diagnostic levels for hypertension [16], this could well affect the level of treatment in a population. The Hawksley random-zero sphygmomanometer, designed to reduce the effect of observer bias, introduces computational error and may also be subject to additional, systematic machine error [ls]. Problems with the equipment in common usage are also widespread, with as many as a half of hospital sphygmomanometers being defective [191, and regular maintenance being the exception rather than the norm. Aneroid sphygmomanometers, which are commonly used by general practitioners, are even more susceptible to failing accuracy if not regularly serviced [191.

BP VARIABILITY AND ‘WHITE-COAT HYPERTENSION’

In 1940, Ayman & Goldshine [20] first reported that the BP of hypertensive patients measured in their own home was substantially lower than that recorded in the clinic and they suggested that homemeasured BP may be a better indicator of prognosis. At around the same time Smirk and coworkers [21-231 were studying casual (clinic), basal m d supplemental BPs in essential hypertension. Basal BP was that measured after patients had

spent a night in a single room under mild sedation using a barbiturate and had been habituated to the BP-measuring procedure. Supplemental BP was defined as the difference between casual and basal BP and is the more variable part of the casual BP, representing the response of the individual to the current environment [21]. Basal BP was shown to be a strong predictor of morbidity and mortality, whereas supplemental BP had little predictive value [22, 231. However, it is only with the development of techniques for monitoring BP throughout 24 h that the extent of the variability of arterial BP has been appreciated [24, 251. Ambulatory intra-arterial recording of BP demonstrates that it is a continuous variable with considerable beat-to-beat and minuteto-minute variation [25]. Consequently, any noninvasive measure of BP can only be a rough estimate of a subject’s true BP, with repeated measurements over a period of time improving the precision of the estimate [26, 271. Conventional clinic BP measurement should be performed twice per visit for at least three visits [28], and preferably more often [29], to achieve a reasonable estimate of hypertensive status, and this process should be repeated each time a change in anti-hypertensive therapy is considered. In addition to spontaneous variability in BP, a large proportion of subjects who come to a doctor’s clinic show a transient rise in BP, seen almost immediately after the arrival of the doctor, peaking within 1-4 min and averaging 27/15mmHg in one study [30]. This response is highly variable, with the rise in systolic BP ranging from 4 to 75mmHg (see Fig. l), and is unrelated to age, sex, baseline BP or BP variability [30]. It persists with repeated visits over a short time span [31] and, as the rise is also seen when a subject measures his own BP in the presence of a doctor [32], it is clearly due to subject-doctor interaction, rather than to the measuring procedure itself. A similar but smaller rise is seen when BP is measured by a nurse [31]. As a result of this ‘white-coat hypertension’, between 20 and 50% of patients with borderline hypertension may be misclassified as hypertensive [33-351 and started on treatment, perhaps unnecessarily [36]. In both the Medical Research Council [7] and Australian National Blood Pressure [6] studies a fall in BP to normotensive levels was seen in up to 50% of placebo-treated patients and these had a similar prognosis to hypertensive patients with the same BP on anti-hypertensive therapy. This fall largely occurred in the first 3-4 months and, as no such placebo effect is seen when 24h mean ambulatory pressure is measured [37, 381, it seems likely that this fall in BP with time is due to a diminution of the ‘white-coat’ effect. ‘White-coat hypertension’ may not be an entirely benign condition. Epidemiological studies show that a single clinic BP reading is predictive of cardiovascular morbidity and mortality [5]. Furthermore,

Blood pressure measurement

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Time of day (hours) Fig. I. ‘Whit-oat hypertension’. The Figure shows a twenty-four hour ambulatory BP trace in a patient with ‘white-coat hypertension’. The clinic BP was 178/1IBmmHg, whereas day-time (08.00-23.59 hours) BP was 146/87mmHg. The rapid drop in BP is clearly seen after the patient has left the hospital environment. An increase in BP is also apparent as the patient returns t o hospital t o have the monitor removed at 10.00 hours. The broken lines represent cut-off values for day-time hypertension (135/85mmHg).

in the Tecumseh study, patients with ‘white-coat hypertension’ had a cardiovascular risk profile and haemodynamic parameters (vascular resistance and minimal forearm resistance) similar to those of patients with sustained hypertension and significantly different from those of a normotensive group [39]. In contrast with patients with borderline or mild hypertension, the clinic BP of normotensive subjects tends to be slightly lower than the day-time average ambulatory BP [40]. The ‘white-coat’ effect may, then, be one of the earliest clinical indications of the transition from a ‘normotensive’ to a ‘hypertensive’ state [41]. Thus, while such patients are probably at lower risk of hypertensive complications and may not require anti-hypertensive therapy, they should be monitored and counselled on nonpharmacological methods of BP control and the modification of other cardiovascular risk factors.

HOME (SELF) MONITORING OF BP

In addition to the diagnosis of ‘white-coat hypertension’, home monitoring of BP by a patient or a member of the family allows more frequent readings of BP over a short time period, improving diagnostic accuracy. The average home BP over a period of 3 days predicts the ultimate clinic BP of newly diagnosed hypertensive patients after 4 weeks with an accuracy of 79% [42]. Home BP is highly reproducible [43] and remains stable over a 4 week period (Fig. 2) [44]. It has also been shown to correlate better with left ventricular hypertrophy [45] and its regression [46] than clinic BP. Home-measured BP is devoid of a placebo effect [47] and should provide a better guide to changes

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Time (weeks) Fig. 2. Relationship of clinic BP (611) to home BP (a) over time. The effect of time on clinic BP and home BP in patients with mild . a prohypertension (n= 17) is shown. Values are means ~ S E M Despite gressive fall in clinic BP, from 181 +4/97+3 t o 167+5/93+2mmHg after 2 weeks and 162f5/93+2mmHg after 4 weeks, there was no change in home BP, which was significantly lower than clinic BP in all patients (153+3/89&3mmHg at the first visit, 152+4/89f3mmHg at 2 weeks and 154+3/89f3mmHg at 4 weeks).

in drug therapy [43]. It may also be of benefit when assessing the effect of new anti-hypertensive agents in clinical trials [48]. BP measurement with an electronic sphygmomanometer will abolish observer bias, which may be an advantage in clinical and epidemiological studies, and machines of proven accuracy are available [49]. Self-monitoring techniques can also improve patients’ understanding of their disease and many patients appreciate the opportunity to participate in the management of their disease [SO], which may

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M. J.Stewart and P. L. Padfield

improve patient compliance [Sl]. Conversely, other patients may become overtly conscious of minor fluctuations in BP, which could result in anxiety and possibly inappropriate self-adjustment of therapy [SO]. Inadequate instruction may lead to inaccurate readings, misleading both the patients and the physician. Detailed education on correct methodology is therefore of considerable importance [52]. At present, there is no agreed standard for the frequency or duration of self-measurement regimens, with published work ranging from BP readings taken twice daily for 1 week to six times daily for 14 days or longer [33, 42, 45, 531. We currently recommend a series of five readings a day for 3 days and have shown this to be a valid [42] and reproducible [44] regimen. As there may be a significant fall in BP on the first day, particularly on the first series [54], the average of the ten readings on day 2 and day 3 is taken as the home-monitored BP. This regimen is well tolerated by patients and allows a rapid turnover of available equipment. Home or self-measured BP recording remains under-utilized in the U.K. This may reflect concerns over the ability of patients to learn selfmeasurement techniques. In early studies, in which patients were taught to use a stethoscope and a mercury sphygmomanometer, many patients were unable to master the technique [33, 53, 551, However, techniques for self-monitoring have become simpler with the development of micro-electronics [SO] and a wide variety of semi-automated machines are now available. Virtually all use a sphygmomanometer cuff and utilize a microphone for Korotkoff sound detection, oscillometry or ultrasound. No one technique appears to be consistently more accurate, although oscillometric machines have the advantage of not requiring accurate cuff placement. Fully automatic machines, which do not require self-inflation of a sphygmomanometer cuff, are preferable, as the isometric exercise involved in self-inflation can raise BP significantly [56]. Unfortunately, the accuracy of these machines is variable, with many inaccurate and unreliable machines being marketed [57-591, and it is important that any machine is validated before use and at regular intervals thereafter, ideally after each set of home recordings is complete [35]. Despite the apparent advantages, it must be emphasized that prospective data on clinical outcome based on home-monitored BP are still lacking, and these techniques should complement rather than replace clinic BP measurement.

AMBULATORY BP MONITORING The development of devices for monitoring BP over periods of 24 h or more while patients continue their normal daily activities adds a new dimension

to the evaluation of the hypertensive patient. Early work with invasive intra-arterial monitoring systems clearly demonstrated the extent of the variability of BP throughout the day [60] and the extent of the diurnal variation in BP [61]. Although this technique has proved to be a valuable research tool [25], it is clearly not suited to general clinical use. Consequently, a variety of non-invasive, fully automatic ambulatory BP recorders have been developed, generally using oscillometric or Korotkoff sound techniques [62, 631. These devices can be programmed to inflate an arm cuff automatically at pre-set intervals, typically ranging from 6 to 120min, throughout a 24-48 h period. Data are stored on microcomputer hardware within the monitor and down-loaded directly on to a personal computer at the end of the monitoring period. Data can then be edited and analysed according to preset criteria. As with home monitors, the accuracy and reliability of ambulatory BP monitors is variable [64], but standards for the evaluation of these devices have been agreed [65, 661. At the present time, only the Spacelabs 90202 [67], Spacelabs 90207 [67a] and Medilog [68] systems have fulfilled the criteria of the Association for the Advancement of Medical Instrumentation for both systolic and diastolic BPs and can therefore be recommended for routine use ~641. Although reasonably accurate at rest, no currently available device is accurate during exercise [69] and patients must therefore be instructed to keep their arm motionless during each BP reading. Similarly, accuracy is significantly reduced in the presence of cardiac arrhythmias, such as atrial fibrillation [70], and at present this represents a serious deficiency in these devices. Nonetheless, 24 h ambulatory BP records, with BP readings every 30min or less, correspond closely to simultaneous intra-arterial recordings [71] and are highly reproducible [43]. No alerting reaction or pressor response is seen with intermittent cuff inflation [72, 731, monitoring does not affect the normal haemodynamics of sleep [74] and no placebo response is seen in clinical trials [75]. Thus non-invasive ambulatory BP recorders appear to accurately reflect an individual’s BP over 24h and will provide similar information to home BP monitoring, including the recognition of ‘white-coat hypertension’ [34]. These machines are generally well tolerated, with less than 10% of patients being unable to tolerate the equipment or refusing to wear it in public [63], and disturbance of sleep is less of a problem with newer, quieter devices [76]. Complications are exceptionally rare. Petechiae and oedema distal to the cuff [77], and ecchymoses [78] and thrombophlebitis [79] at the cuff site, may appear. Localized exfoliative dermatitis [78] and allergic reactions [63] have also been reported. These complications appear to be more common with very frequent

Blood pressure measurement

measuring intervals or when the equipment is malfunctioning, with delayed deflation of the cuff. A major disadvantage of these devices is their cost, with current machines costing over E3000 each. Computer hardware and software for analysis are also necessary, adding to the costs. As it takes around 30min to fit a device and educate a subject, personnel costs also need to be considered. However, in patients with mild hypertension, ambulatory monitoring has shown that as many as 40% of patients have BPs low enough to withhold antihypertensive treatment [80], and it has been suggested that the resultant savings would offset the cost of the investigation [SO]. By enabling the direction of treatment at those with the highest. BPs, a more effective reduction in cardiovascular morbidity could be achieved, while actually lowering the drug bill.

DATA ANALYSIS IN AMBULATORY BP MO NITORlNG

There are many different approaches to the analysis of a 24h ambulatory BP trace, designed to provide information on BP profiles over 24h, during day-time and night-time. The simplest and most widely used method is to calculate the 24h, day and night mean BP values. Some workers have excluded readings in the early morning and late evening, when rapid changes in BP may be taking place, from this calculation [40]. However, as there is an excess of cardiovascular events at these times [8 11, important prognostic or diagnostic information may be omitted. Any arbitrary definition of day-times and night-times can also affect the mean values calculated [82], and analysing wake and sleep periods may therefore be more appropriate. Smoothing procedures, including the use of spline functions and Fourier analysis, have been developed [83, 841. Although such methods overcome problems in analysis resulting from irregular spacing in time of BP measurements and smooth the spikes inherent in BP over time, they are complex to compute and assume, wrongly [85], that BP has a natural circadian rhythm. An alternative method of presenting and analysing data is to calculate the BP load, defined arbitrarily as the percentage of BP measurements exceeding 140/90 mmHg during waking hours and 120/80mmHg during sleep [86]. Although of some prognostic relevance [87], this method fails at extremes in that all normotensive subjects will have a load of 0% and all severe hypertensive patients will have a load of 100%. In routine clinical use, the arithmetic mean and median BP values for wake, sleep and 24h remain the simplest and most appropriate way to present data.

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PROGNOSTIC VALUE OF AMBULATORY BP MONITORING

Evidence that these readings are of prognostic importance and a better predictor of cardiovascular risk than clinic BP is growing [88]. Several workers have demonstrated that mean ambulatory BP is a better predictor of echocardiographically determined left ventricular mass [87, 89-93], a marker of hypertensive target organ damage. Patients whose ambulatory BP is similar to their clinic BP have a higher prevalence of target organ damage (assessed by ECG and fundal change) than those who have lower ambulatory BP [94], and latent cerebrovascular disease, assessed by n.m.r. imaging of the brain, is related to mean ambulatory BP but not to clinic BP [95]. There are also two prospective studies relating clinical events to ambulatory BP. Perloff et al. [96] have followed 1076 patients for 5 years and have shown that those whose day-time mean ambulatory BP is low relative to their clinic BP at presentation have a better prognosis, with lower mortality and lower incidence of cardiovascular events, than those whose ambulatory BP is higher. Thus, as clinic BPs were comparable in the two groups, ambulatory BP recording appeared to provide prognostic information over and above the clinic BP. This was true particularly in younger patients and those with borderline or mild hypertension, in whom the decision to treat can be the most difficult, but also applied to patients who had already developed a cardiovascular complication [97]. However, this study depended entirely on the initial ambulatory BP, with no information on the change in ambulatory BP with time, and recorded day-time BP only. Mann et al. [98] have followed 137 patients for a mean of 2 years, with 14 patients experiencing a first cardiovascular event in this time. Ambulatory BP was better than clinic BP at predicting these events. Ambulatory monitoring also provides an accurate estimate of BP variability, usually taken as the SD of the 24h BP [60, 991, provided readings are taken every 15min or more frequently [71]. The importance of this measurement is not clear. Early studies [89, 981 did not find any correlation between BP variability and target organ damage or cardiovascular damage. However, Parati et al. [loo] and Palatini et al. [loll both found that BP variability provided additional prognostic information and suggested that it may be an independent risk factor for cardiovascular disease.

DIURNAL VARIATION IN BP

Since the introduction of techniques for ambulatory BP monitoring, it has been clear that BP has a diurnal rhythm, with levels during sleep about 20% less than those during the day [61]. This rhythm is generally preserved in hypertensive patients, with an

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upward shift of the entire curve [25], but in about 20% of essential hypertensive patients [1023 this ‘dip’ in BP during sleep is reduced or absent. Although the hypertensive population has been classified into two broad groups, ‘dippers’ and ‘nondippers’ [102], we have found that the nocturnal fall in BP in a group of 93 untreated essential hypertensive patients has a Gaussian distribution (see Fig. 3). The systolic dip ranged from -4 to 28% with a mean of 12% and an SD of 7%, whereas the diastolic dip ranged from 0 to 35% with a mean of 17% and an SD of 8%. This distribution is essentially the same in normotensive subjects and treated hypertensive patients. Thus any limits used to define ‘dippers’ and ‘non-dippers’ must be completely arbitrary and at present there is no agreed standard. However, as an absent or reduced nocturnal dip appears to impart an increased cardiovascular risk, this may be of more than academic interest. OBrien et al. [lo21 have reported the frequency of stroke in a population of non-dippers to be 23.8%, compared with a frequency of only 2.9% in age-, sex- and weight-matched ‘dippers’ with similar day-time BP. Kobrin et al. [lo31 studied 21 elderly (>65 years) hypertensive patients and found a normal diurnal BP rhythm in 14, but a reduced or absent nocturnal

dip in seven. One hundred per cent of the ‘nondippers’, but only 43% of the ‘dippers’, had clinical evidence of hypertensive or atherosclerotic complications. Gosse et al. [93] have found night-time BP to be the best correlate of left ventricular mass in 24 treated hypertensive patients, and more recently Verdecchia et al. [92] have published the results of a large study comparing 24 h ambulatory BP profile and echocardiographic left ventricular hypertrophy in 137 untreated hypertensive patients and 98 healthy normotensive subjects. In the hypertensive group, left ventricular mass correlated more closely with night-time BP than with day-time BP. Of the hypertensive patients, 40% had a reduced nocturnal dip ( < l o % of systolic and diastolic BP) and this group had a greater left ventricular mass index. There was an inverse correlation between left ventricular mass index and the nocturnal dip. Thus, these data suggest that the nocturnal dip in BP prevents or delays the development of left ventricular hypertrophy. Shimada et al. [95] have also found that hypertensive cerebrovascular disease, assessed by n.m.r. imaging in the brain of 73 elderly asymptomatic subjects, correlates more closely with night-time BP than with day-time or 24h BP [95].

SECONDARY HYPERTENSION AND THE DIURNAL VARIATION IN BP

Many, but not all, causes of secondary hypertension disturb the diurnal BP rhythm [104, 1051. An absent diurnal rhythm is seen in patients with phaeochromocytoma [106, 1071, end-stage renal failure [1081, pre-eclampsia [1091, Cushing’s syndrome [1lo] and treatment with high-dose corticosteroids [l 111. Sleep apnoea syndrome, which several studies suggest is present in around 30% of treated hypertensive patients [112-1 141, also results in a ‘non-dipping’ BP profile [1151. However, the renin-angiotensin system seems to have less influence on the BP rhythm. Early reports that suggested that patients with primary aldosteronism and renovascular hypertension lost their diurnal variation involved older patients with more severe hypertension [1161. Later studies have failed to confirm these observations [104, 1171. Younger patients with fibromuscular dysplasia have a normal diurnal rhythm; and treatment with angioplasty for renovascular hypertension or excision of an adrenal adenoma in primary aldosteronism does not affect the rhythm [l05]. Complete reversal of the diurnal rhythm is also seen in patients with autonomic failure [118], and the nocturnal dip is attenuated or absent in patients with diabetic autonomic neuropathy [119, 1203 and in quadriplegic spinal cord injury patients [l2l]. Patients with cardiac failure [122] and cardiac

B l d pressure measurement

transplant patients (whose ventricles are denervated) [120, 1231 also have a disturbed rhythm.

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PATHOPHYSIOLOGY OF THE DIURNAL VARIATION IN BP

The normal dip in BP is intrinsically related to sleep. Junior hospital doctors lose their nocturnal dip when on-call [124], and shift workers reverse their diurnal rhythm when moving from night to day shift [1251. This reversal occurs immediately, without a period of adjustment, in contrast to true circadian rhythms, suggesting that there is no ‘internal clock‘ determining the diurnal variation [125]. Patients on strict bed rest also exhibit a diurnal rhythm [1261, suggesting that activity is not solely responsible. This concept is supported by the observation that many patients with secondary hypertension lose their nocturnal dip. A reduction in sympathetic nervous system activity during sleep may be an important factor controlling the nocturnal fall [127] and would explain the absent dip in autonomic neuropathy, phaeochromocytoma and after cardiac transplantation. However, urinary catecholamine excretion does not correlate with diurnal BP changes in patients with essential hypertension [1281, suggesting that other mechanisms are involved. Although the observation that patients with Cushing’s syndrome [110] or on high-dose corticosteroids [111] have no nocturnal dip in BP is intriguing, physiological doses of cortisol do not appear to influence the diurnal rhythm in patients with hypopituitarism [129], and a major role for the pituitary-adrenal axis in essential hypertension seems unlikely. Similarly, conditions affecting the renin-angiotensin system do not appear to consistently alter the nocturnal BP [104], and the diurnal variation in BP of essential hypertensive patients is not affected by treatment with an angiotensinconverting enzyme inhibitor [1301. Thus the cause of differences in the BP pattern of patients with essential hypertension remains obscure. CLINICAL RELEVANCE OF THE DIURNAL RHYTHM

Knowledge of the diurnal rhythm of BP, which can only come from ambulatory monitoring, appears to provide additional prognostic and diagnostic information. Although the effect of treatment of night-time BP on prognosis is unknown, it seems likely that, where it is high, treatment which reduces BP throughout 24 h will be beneficial. Patients with pre-eclampsia are more susceptible to crises during the night [lo91 and treatment should be given and monitored accordingly [1091. After heart transplantation, patients may initially have hypertension during the night only [123], and again the need for treatment should be assessed and therapy given accordingly.

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Conversely, ‘dippers’ may drop their BP to normal levels during sleep and, particularly in the presence of left ventricular hypertrophy and ischaemic heart disease, may be at greater risk if drug therapy induces a further significant reduction in BP [131, 1323. It has even been suggested that unrecognized nocturnal hypotension may be one reason why the reduction in the incidence of myocardial infarction with anti-hypertensive treatment has been so disappointing [1331. It is possible that drug therapy in such patients should be tailored to reduce BP during the day only, although this has yet to be tested. AMBULATORY BP MONITORING: NORMAL REFERENCE DATA

Despite the wealth of information on ambulatory BP monitoring in disease, the need to determine adequate normal reference values for 24 h ambulatory BP has only recently been addressed. Initial values for ambulatory BP normality were based on relatively small numbers, and groups studied were often pre-selected by normal clinic BP [134-1371. A meta-analysis of studies on non-invasive ambulatory monitoring in normal subjects determined the mean day-time BP to be 122/77mmHg, the mean nighttime BP to be 106/64mmHg and the 24h mean ambulatory BP to be 117/72mmHg [138]. In a large epidemiological study OBrien et al. [40] have recorded ambulatory BP in 815 employees of the Allied Irish Bank, aged 17-79 years. This group was not pre-selected, although subjects on antihypertensive drugs were excluded, and should therefore be reasonably representative of the population. The results [40] were similar to those of the large meta-analysis [138]: mean day-time BP was 124/ 78 mmHg, mean night-time BP was 106/61mmHg and 24h mean ambulatory BP was 118/72mmHg. Significant differences in relation to age and sex were observed and means for different age groups and sex were provided. Baumgart et al. [1391, performing linear regression analysis on ambulatory BP records of 1039 subjects to relate ambulatory BP to their clinic BP, calculated that a mean day-time BP value of 135/ 85mmHg was equivalent to a clinic BP of 140/ 90 mmHg. Data such as these provide reference values for non-invasive ambulatory BP monitoring, but the relevance of such data to morbidity and mortality is still not proven. However, at present, a day-time mean BP of >135/85mmHg has been suggested as representing a hypertensive condition [140]. AMBULATORY BP MONITORING IN CLINICAL STUDIES

Ambulatory BP monitoring, by identifying and excluding ‘white-coat hypertensives’ [34] and by

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improving the reproducibility of the BP measurement [141], can assist in clinical trials and reduce the sample size necessary to show a significant BPlowering effect [75]. A sample size of only 16 should be sufficient to detect a reduction of 8/5mmHg [75]. In addition, as ambulatory BP monitoring appears to be devoid of a significant placebo effect [38, 751, clinical studies without a placebo limb are possible and could simplify the design and conduct of clinical studies of anti-hypertensive drugs [1421. A further advantage of ambulatory BP monitoring is the ability to indicate the duration of drug effect and the influence of drugs on nocturnal BP [1431. In a clinical trial comparing once-daily lisinopril (a long-acting angiotensin-converting enzyme inhibitor) with twice-daily captopril (a short-acting angiotensin-converting enzyme inhibitor) [1441, BP control was maintained for 9-10 h after each dose of captopril but then began to return towards baseline. As a result, BP reduction over 24 h was greater with lisinopril. Similarly, in a comparison of the antihypertensive effect of P-adrenoreceptor blockers [145], atenolol is shown to reduce BP throughout 24 h, whereas the anti-hypertensive effect of pindolol lasts only 15h and that of metoprolol lasts only 12 h. Information such as this is only available from clinical trials involving ambulatory BP monitoring and its routine use in the evaluation of drug efficacy has been advocated [143].

CLINICAL APPLICATIONS OF AMBULATORY BP MONITOR1NG

Whilst ambulatory BP monitoring may not be necessary in patients with moderate to severe hypertension or with evidence of target organ damage, in whom the benefits of treatment are clear, it is a valuable technique in the assessment of borderline hypertension [1461, to help exclude ‘white-coat hypertensives’ and to target those who will benefit most from treatment C34). It should also be regarded as an initial investigation in the evaluation of apparently resistant hypertension when there is no evidence of target organ damage [147, 1481, both to document the size of the ‘white-coat’ response and to demonstrate the degree and duration of anti-hypertensive drug action. Symptoms suggestive of hypotension due to antihypertensive medication can also be investigated when symptomatic marked reductions in BP in response to taking medication may be identified [149]. Episodic hypertension may cause concern, as it may indicate adrenergic excess. If phaeochromocytoma is suspected, ambulatory BP monitoring may document episodic hypertension, which could otherwise be missed by clinical evaluation [1501. Episodic hypertension may also be associated with

anxiety syndromes, and such patients can present with a variety of cardiovascular symptoms. Ambulatory BP monitoring may help in the identification of such patients [l5l]. Ambulatory BP monitoring may help in the evaluation of patients with type 1 [152] and type 2 [153] diabetes mellitus, when early intervention with BP-lowering drugs may be of benefit. It has also been recommended for the diagnosis of hypertensive disease in pregnancy [154] and particularly in pre-eclampsia [l09]. However, the lack of normative data in these populations must hamper the interpretation of ambulatory BP results. More widespread use of ambulatory BP monitoring techniques as part of the routine evaluation of hypertensive patients cannot be recommended until more information about the relationship of data derived from ambulatory BP monitoring to morbidity and mortality is available. On-going prospective studies should provide this information in the next few years [l55].

NEW METHODS OF BP MEASUREMENT

Application of the plethysomographic method first described by Penaz has provided a non-invasive means of measuring BP continuously (the Finapres system) [156]. Arterial pulsation in a finger is detected by a pbotoplethysmograph under a pressure cuff. The size of the artery is measured when its internal pressure (i.e. arterial pressure) equals the external cuff pressure. This point, when transmural pressure equals zero, is maintained by continuous automatic adjustments of the external cuff pressure. These adjustments parallel intra-arterial pressure variations and algorithms determine the systolic, diastolic and mean arterial BPs [156]. The BPs so determined appear to reflect intra-arterial pressure [1571, although they under-estimate indirect brachial artery BP [l58]. This device appears to accurately follow BP changes over time and as such has been of particular interest to anaesthetists [159, 1601 and obstetricians [161, 1621. It is also of use in clinical research studies monitoring BP changes over short time intervals [163]. However, its accuracy in routine clinical use remains unproven and there is evidence that digital BP is influenced by the severity of hypertension and anti-hypertensive drugs [1581, when peripheral circulation may be impaired, and by diseases affecting the peripheral circulation [164]. A technique for indirect BP measurement based on wave-form analysis of the Korotkoff signal has also been described, the K2 technique [165]. The potential advantage of this system is its dependence on pattern recognition, rather than the absolute level of sound, which varies widely from one individual to another [85]. This technique is, however, still in the developmental stage.

Blood pressure measurement

CO NCLUSlONS

Although careful measurement of BP with a stethoscope and a mercury sphygmomanometer is a valid and accurate technique, there are many potential sources of error, due to both equipment and methodology. More importantly, the inherent variability of BP itself, and its tendency to increase in the presence of medical and nursing staff, means that clinic measurement cannot reliably reflect the BP load affecting the individual patient. With the development of reliable electronic sphygmomanometers which have a reasonable standard of accuracy, patients can be taught how to measure their own BP in their normal environment over several days. In addition to providing information on an individual’s BP profile, home measurement is a valuable opportunity to educate patients and can improve compliance. By reducing observer bias, electronic sphygmomanometers are also of use in clinical and epidemiological studies. Unfortunately, many of the electronic devices marketed to date are unreliable and no machine should be purchased unless supported by data on its accuracy from a reliable and independent source. Newer techniques for the non-invasive measurement of ambulatory BP now allow us to obtain a large number of measurements over 24 h, including during sleep. This technique is safe, can be repeated and is reproducible. Information on the variability, and particularly the diurnal variation, of BP is also obtained. The evidence that these measurements provide prognostic information over and above the clinic BP is growing and on-going prospective clinical trials should help delineate the place of ambulatory BP monitoring in the diagnosis and management of essential hypertension. Again, it is imperative that these devices are validated before use and the publication of guidelines on methodology for their evaluation is a great advance in this regard. ‘White-coat hypertension’ appears to be a common phenomenon and, while not synonymous with normotension, may indicate a substantially lower cardiovascular risk. It may, therefore, be possible to target anti-hypertensive therapy at those who will benefit most. Although this equipment is expensive, this may well be offset by the financial, therapeutic and social advantages of not treating thousands of individuals unnecessarily. Ambulatory or home monitoring of BP should also be an integral part of the evaluation of apparently resistant hypertension, and can be valuable in the differential diagnosis of episodic hypertension. Ambulatory BP monitoring has proved to be a valuable research tool. Clinical trials of new antihypertensive agents should be possible with small numbers and without a placebo limb. Information on the action of such agents over the whole 24h is available, and may become of increasing importance if preliminary data on the prognostic importance of

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an absent nocturnal ‘dip’ in BP are borne out in prospective studies. New methods of BP measurements being developed may improve the diagnostic accuracy of such devices further, and allow continuous non-invasive ambulatory monitoring. Critics of the use of electronic monitoring of BP in the evaluation of hypertensive patients proclaim that our understanding of the benefits of therapy has come from studies involving clinic measurements of BP and hence anything else remains invalid. While this argument may be rationally applied to groups of patients, the wide range of individual risk seen in studies of mild hypertension [6, 71 reminds us that we may need more than clinic BP to identify those individuals most in need of long-term anti-hypertensive therapy. There is little doubt that the use of such electronic home monitoring is increasing and may yet replace the mercury sphygmomanometer. If and when that day comes, then the last bastion in the fight against SI units, the mmHg, may finally be replaced by the kPa!

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