Should We Be Evaluating Blood Pressure Dipping Status in Clinical Practice?

One of the unique aspects of ambulatory blood pressure (BP) monitoring is its ability to record the diurnal variation of BP. The normal pattern is a decrease of around 10%–20% during the night, which coincides with the hours of sleep, and is commonly referred to as dipping. This pattern is not universal, however, and in some people (about 25% of hypertensives), a non-dipping pattern is seen in which the normal nocturnal fall of pressure is absent. A further classification that some authors have used is to identify people who show an excessive fall of pressure (the extreme dippers whose nocturnal pressure falls more than 20%), or an actual increase (risers).1 A major question at the present time is the pathological significance of the differences in these patterns, and whether identification of them has clinical relevance. There are several potential ways by which the nondipping pattern could affect prognosis. First, if the daytime pressure is used as the reference level, nondippers by definition are exposed to a higher BP load over 24 hours than dippers, which could result in more target organ damage and a more adverse clinical outcome. So if the issue is whether the pattern of the diurnal rhythm of BP matters, comparisons should be made between dippers and non-dippers who have the same 24-hour level of BP. Second, non-dippers will have a more modest early morning surge of BP than dippers. An excessive morning rise is now thought to have pathogenic significance, so by this criterion non-dippers should be at reduced risk.2 Third, if an excessively low BP during the night is associated with ischemic damage to various organs, non-dippers are less likely to be exposed to this than dippers. The point of these considerations is that if non-dipping does have independent pathological significance, it may be limited to certain specific end points. The issue is becoming of practical importance because dipping and nighttime BP can only be assessed by 24-hour BP monitoring. In contrast, a good estimate of the average daytime pressure can be provided by self- or home-monitoring. Home monitors are cheaper and more widely available than 24-hour monitors. Another issue is how the nocturnal BP changes should be expressed. Dipping and non-dipping is a binary classification, and while this may be useful for therapeutic decision making, the chosen limits separating dippers from non-dippers are quite arbitrary. This, of course, is true of just about any definition based on BP levels. Since all definitions of dipping and non-dipping rely on some measure of the differences between daytime and nighttime pressures, it is clear that both components will influence the classification. The nocturnal BP is mainly influenced by two factors: assuming the horizontal posture, and going to sleep. Likewise, the daytime BP level will depend on posture and activity. This has been well illustrated in a 2-day study combining activity monitoring and BP monitoring, when subjects were relatively active during 1 day and inactive during the other.3 As expected, both the recorded activity levels and the daytime BPs were higher on the active day, and subjects were consequently more likely to be classified as dippers on the active day than on the inactive day. One factor that will affect the nocturnal pressure is the body position. When the patient is lying on one side, the BP recorded in the two arms will be different because of the effects of the hydrostatic pressure differences between the arm and the right atrium. These differences can be 10 mm Hg or more.4 It is possible to record body position during ambulatory BP monitoring, and it has been reported that the non-dipping status may be influenced by the body position during sleep.4 Changes of body position could thus be one reason for the relatively low reproducibility of dipping. The depth and quality of sleep may also affect dipping. Thus in subjects who are kept awake during the first part of the night, the BP remains high until they are allowed to go to sleep.5 Normally, BP is at its lowest during the first few hours of sleep when stage 4 sleep predominates. Therefore, one possible reason for non-dipping may be a diminished amount of stage 4 sleep. One study did find that non-dippers had a worse sleep profile than dippers (less stage 4 and less rapid eye movement, and more micro-arousals).6 In addition, non-dippers are likely to have some degree of sleep-disordered breathing (snoring and apnea), but the association between dipping and sleep apnea is not close.7,8 Another factor affecting the dipping pattern is the volume and electrolyte status: sodium-sensitive subjects are more likely to be non-dippers than sodium-resistant ones, and when the former are put on a low-sodium diet, their BP tends to shift to a dipper pattern.9 Several studies have reported that African Americans are more likely to be non-dippers than whites. A recent meta-analysis of 18 such studies looked at American and non-American blacks separately, and concluded that American blacks are more likely to be non-dippers than American whites, whereas this trend is not apparent in blacks studied outside the United States, raising the possibility that the difference is of psychosocial rather than genetic origin.10 If a classification such as dipping and non-dipping is to be clinically useful, it should be statistically reliable from one occasion to another. There has been considerable debate on this point, which is still unresolved. Manning et al.11 performed three ambulatory BP recordings in 79 untreated hypertensive and normotensive subjects at intervals of 6 months. Only 54% of subjects were classified as dippers on all three occasions, leading the authors to conclude that the phenomenon was not a reliable one. In the Italian Study on Ambulatory Monitoring of Pressure and Lisinopril Evaluation (SAMPLE),12 170 hypertensive patients were studied while untreated on two occasions separated by more than 1 year (but with active treatment in between). Approximately 40% of those patients changed their dipping status from one occasion to another. One of the most comprehensive studies involved 414 newly diagnosed hypertensive patients who underwent ambulatory BP monitoring twice over the period of 1 month, and were classified as dippers or non-dippers.13 Three quarters of the patients showed no change in dipping status, and two-thirds of the non-dippers identified on the first recording were classified as non-dippers on the second. These studies are thus reasonably consistent in showing that the reproducibility of dipping status is limited, which means that it would be wrong to expect very close correlations between dipping and measures of target organ damage or clinical outcomes. It has been suggested that to get an accurate estimate of a patient's dipping status, two ambulatory BP recordings should be made. This obviously is not practical for the majority of patients. Several studies have examined the relevance of dipping status as a predictor of target organ damage. The measures most commonly used are left ventricular hypertrophy (LVH), microalbuminuria, and magnetic resonance imaging of the brain. Patients with essential hypertension who have microalbuminuria are more likely to be non-dippers than those without it, independently of the daytime level of BP.14 The fact that microalbuminuria is associated with the non-dipping pattern in patients with essential hypertension and grossly normal renal function raises the possibility that the non-dipping pattern may contribute to renal damage. LVH is the most frequently measured marker of hypertensive target organ damage. Even in asymptomatic hypertensive patients, those with LVH have a worse cardiovascular prognosis than those without it.15,16 While BP is certainly one of the major determinants of LVH, there is disagreement as to whether the daytime or nighttime pressure is more important. Some studies have shown that LVH is more pronounced in non-dippers, while others have found no difference.17–20,21–24 In view of the fact that dipping has a relatively low reproducibility, the most rigorous test of the role of dipping on target organ damage is to look at the relationships in patients whose dipping status is derived by averaging the daytime and nighttime BPs measured on two separate occasions. This was done by Cuspidi et al.,25 who compared left ventricular (LV) mass in 238 dippers with 117 non-dippers, and found an insignificantly higher LV mass in the non-dippers, but a significantly higher prevalence of LVH. The overall (48-hour) average BP level was the same in the two groups, suggesting that there is, indeed, a modest effect of the non-dipping pattern on LVH. Silent lacunar infarction can be detected by brain magnetic resonance imaging in approximately 30%–50% of asymptomatic elderly hypertensives, and is a strong predictor of clinically overt stroke.26–28 Its major determinants are aging and hypertension, but an abnormal diurnal BP pattern is also a factor, and in elderly hypertensive patients, non-dippers have more frequent lacunar infarcts than dippers.26 The big question here is whether the non-dipping pattern is related to a higher risk of cardiovascular events than dipping, independently of the 24-hour BP level. Although there have been several claims for this, the evidence is mixed. Three large-scale prospective studies have found that non-dipping is associated with a higher risk than dipping. The first was the Ohasama study,29 a population-based prognostic study of 1542 Japanese who were followed for 9 years, which found that dipping and BP level were independent predictors of the risk of cardiovascular mortality compared with normotensive dippers; the relative risk in normotensive non-dippers was 2.35. In hypertensive dippers it was 2.67, and in hypertensive non-dippers it was 5.37.29 It is important to note that in both the normotensive and hypertensive groups the 24-hour average levels were the same in the dippers and non-dippers. Interestingly, the daytime BP was higher in the hypertensive dippers than the non-dippers (152 vs. 144 mm Hg), even though their risk was lower. The second study was the Italian Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study,30 in which it was found that men and women who were non-dippers (defined in this case as the highest one-third of the distribution of the nightday ratio of BP) were at approximately double the risk of events as the dippers. This was the case after controlling for the 24-hour level and diabetes. The one-third was the Systolic Hypertension in Europe trial (Syst-Eur),31 a placebo-controlled study of the treatment of isolated systolic hypertension, in which a subgroup was evaluated with 24-hour monitoring. Office BP had a weak predictive value, but the 24-hour readings gave a much broader spread of risk because there were some patients at low risk (the white coat hypertensives) and others at much higher risk than predicted from the clinic pressures. The best predictor of risk was the nightday ratio, which was independent of BP level. These three studies provide the strongest evidence for risk from the non-dipping pattern. One other study is consistent with these results. This was a 4-year follow-up study32 of 324 elderly Japanese who were residents of a community home, about one-half of whom were hypertensive and on treatment. A high nighttime BP predicted clinical events (mostly strokes), while the daytime and clinic pressure did not. These authors did not report on dipping status or the night:day ratio. Two other recent studies did not confirm these findings, however. One was a Japanese study of elderly patients which reported that an exaggerated morning surge of BP (a greater than 55 mm Hg increase of systolic pressure from the lowest sleep level to the first 2 hours after waking) predicted risk independently of the BP level.2 The people at the highest risk were those who showed a pronounced dipping pattern, and the non-dippers had a relatively small morning surge. Another study by Bjorklund et al.33 performed in 872 elderly Swedish men found that nighttime BP and dipping were no better at predicting risk than the daytime pressure. The only prospective study using intra-arterial pressure monitoring also found that including nighttime pressure was no better than 24-hour or daytime pressure.34 Another prospective study of treated hypertensives confirmed earlier reports that the ambulatory pressure was a better predictor of risk than the clinic pressure, but did not find any superior prediction of nighttime over daytime pressures.35 One explanation for this finding may be the fact that the patients were on antihypertensive treatment when first studied, and it is well recognized that drug treatment may change the dipping pattern. There are also studies performed in selected groups of patients that have suggested that non-dipping may be related to increased risk. In a study of 288 diabetics, 87 had a reversed diurnal rhythm of BP (defined as a peak BP occurring between 8 p.m. and 8 a.m.).36 Over a 3- to 4-year follow-up period, this reversed rhythm pattern was a strong predictor of mortality and non-fatal cardiovascular events. The authors did control for the presence or absence of 'hypertension, but not for the actual 24-hour level of BP, which appeared to be higher in the group with a reversed diurnal rhythm than the group with a normal rhythm. The group with the abnormal rhythm also had more renal disease, which also was not controlled for in the analysis. It has been proposed that the non-dipping pattern may be an independent risk factor for progression of renal damage. This is supported by results of a study by Timio and colleagues,37 who conducted a 3-year longitudinal study to test the hypothesis that an association exists between a reduced or absent nighttime fall in BP and a future decline of kidney function in renal hypertensive patients. After 3 years, non-dippers had a faster rate of decline in creatinine clearance compared with dippers (0.37 vs. 0.27 mL/min/mo; p=0.002). In addition, non-dippers had greater increases in proteinuria compared with dippers (993 vs. 438 mg/24 h; p=0.009). The authors recommended that proper nocturnal BP control should be an additional aim of antihypertensive therapy. In 218 patients who had experienced a first stroke, 24-hour average systolic pressure predicted mortality, but the day-night difference did not have any predictive value.38 These patients were not receiving antihypertensive treatment. Another Japanese study of patients with lacunar infarcts detected on brain magnetic resonance imaging found that non-dippers were more likely to develop recurrent strokes than dippers.39 On the grounds that hypertension is usually characterized by a sustained increase of BP throughout the day and night, it seems reasonable to propose that the goal of antihypertensive drug treatment should be to lower the BP to the same extent during the day and night. Whether treatment should be directed to convert hypertensive non-dippers to normotensive dippers with treatment is unresolved, but certainly feasible. Diuretics normalize the non-dipper pattern by lowering the nocturnal more than the daytime pressure.40 In an analysis of the effects of doxazosin on dipping status, we found that non-dippers were likely to become dippers following treatment and that the best explanation was that the effects of the drug on BP were proportional to the pretreatment level, such that the nighttime pressure is lowered more in non-dippers than dippers.1 Similarly, studies with calcium channel blockers have found that the drugs lower daytime BP in both dippers and non-dippers, but nighttime BP more in non-dippers.41 The timing of antihypertensive drug dosing may also be a factor: in patients with renal disease who were predominantly non-dippers, evening dosing of a calcium channel blocker (isradipine) lowered the nighttime pressure more than morning dosing.42 However, it must be admitted that at the present time there is no evidence that selectively lowering the nighttime BP has any impact on clinical outcome. The practical issue is whether it is worth going the extra mile to measure nighttime BP in our hypertensive patients. We can obtain a lot of information about BP levels during the day using self-monitoring at relatively low cost, but getting nighttime levels can only be done using ambulatory monitoring, which is much more expensive and less convenient. It must be admitted that the evidence that the dipping pattern increases risk independently of the 24-hour BP level, an important scientific question, is not fully resolved. From a practical point of view, however, that may not be the most relevant issue. If we have a reasonable estimate of our patient's daytime BP from self-monitoring, it may be helpful to know if the nighttime pressure is also high. Scientifically, the answer to this question would be whether the 24-hour BP level predicts risk significantly better than the daytime level, which are so far unproven. It would be reasonable to expect that it would, since the number of readings that make up the average is greater, and it captures the whole profile of the diurnal rhythm, but the prospective studies reported above have not found this. In fact, the studies fall into two categories: those that have found that the nighttime pressure or dipping pattern improves the prediction of risk, and those that have found that the risk is equally well predicted by the 24-hour level as by the daytime or nighttime levels. In all these studies, the number of nighttime readings is smaller than the number of daytime readings, so it may be that the nighttime pressure does have some special significance. This might simply be that the nighttime pressure is less subject to “noise” than the daytime pressure, which varies greatly according to mental and physical activity. Another unresolved issue concerns how we should deal with the nighttime pressure. Should we retain the binary dipper/non-dipper classification (with all the limitations of such arbitrary divisions)?; should we use the night:day ratio (more scientifically correct)?; or should we use the absolute level of nighttime pressure? These three methods of looking at the data will classify patients differently, and we do not have any good answers at the present time concerning which one is better from the point of view of predicting risk and guiding treatment. Until these questions are answered, it would seem reasonable not to recommend routine measurement of the nighttime BP.