Improved Classification of Dippers by Individualized Analysis or Ambulatory Blood Pressure Profiles

Transcription

1 AJH 1995; 8: Improved Classification of Dippers by Individualized Analysis or Ambulatory Blood Pressure Profiles Christoph D. Gatzka and Roland E. Schmieder A decrease (dip) in blood pressure during sleep occurs in normal people and in patients with uncomplicated essential hypertension. Failure to identify such a dip suggests additional pathology, which makes the identification of "nondippers" important. Rigid definitions of nocturnal time periods (eg, night is defined as lasting from 22:01 to 06:00) to identify dippers and nondippers has been used for over a decade. However, these definitions may not correspond to actual sleep patterns, and thus may lead to faulty interpretations. We investigated whether or not an analysis of ambulatory blood pressure (BP) profiles according to the patients' individual reported awake/sleep pattern would result in an improved categorization of dippers and nondippers. Four groups of patients were investigated: normotensive volunteers, borderline hypertensive patients, essential hypertensive patients, and renal transplant recipients. In all four groups, blood pressure (systolic and diastolic) de- creased to a greater degree when the individual reports were employed, compared to the fixed patterns. For systolic BP this difference (individualized v fixed 06:01 to 22:00 day and 22:01 to 06:00 night) amounted to v mm Hg for normotensive subjects, v mm Hg for borderline hypertensive subjects, v 12.9 ± 10.4 mm Hg for essential hypertensive patients, and 8.6 ± 11.3 v mm Hg in renal transplant patients (all P ~.05). Individualized awake/sleep reports resulted in a better classification of dippers and nondippers, since misclassifications due to divergent sleep patterns (mainly going to bed late) were avoided. Am J Hypertens 1995;8: KEY WORDS: Blood pressure, hypertension diagnosis, circadian rhythm, ambulatory blood pressure monitoring. A mbulatory blood pressure monitoring (ABPM) has become a useful tool for the diagnosis and classification of arterioal hypertension.l'2 Normotensive volunteers and patients with mild to moderate hypertension usually exhibit a 15% to 20% average reduction in BP during sleep. Lack of an appropriate nocturnal decrease in BP has been found in patients with second- Received January 25, Accepted February 28, From the Department of Internal Medicine IV--Nephrology, University of Erlangen-Nfirnberg, Germany. Address correspondence and reprint requests to Christoph D. Gatzka, Department of Internal Medicine IV, University of Erlangen-Nfirnberg, Breslauer Strat~e 201, Nfirnberg, Germany. ary hypertension, 3~s such as chronic renal disease, 6-9 renal vascular hypertension, 6-9 hemodialysis patients, 7'1 renal transplant recipients, 7 toxemia of pregnancy, 3'11'12 pheochromocytoma, 3'7'13'14 Cushing's syndrome, 3"6"9"15 and primary aldosteronism. 6'7"9 Failure to decrease blood pressure during sleep has also been observed in cardiac transplant recipients, ~6'~7 patients with malignant hypertension, is and in patients with sleep-apnea syndrome. 19 Finally, an absent or diminished decrease in BP has been associated with left ventricular hypertrophy 3'14'2-24 and stroke. 25"26 Thus, the identification of "nondippers" may have both diagnostic and therapeutic ramifications by the American Journal of Hypertension, Ltd /95/$ (95)

2 AJH-JULY 1995-VOL. 8, NO. 7 AMBULATORY BP PROFILES IN DIPPERS 667 During the last decade, fixed day/night patterns have been applied in the analysis of 24-h ambulatory BP profiles. Time periods used to define day and night are arbitrary and different definitions have been used throughout the literature. Two different concepts have evolved: wide time spans for day and night, ie, day 06:01 to 22:00 and night 22:01 to 06:00, and narrow time spans, ie, day 10:00 to 22:59 and night 01:00 to 06:59. The former approach has the advantage of using all available BP measurements taken during 24 h and this mode of analysis has been endorsed by the WHO, the ISH, and national standardization bodies. 3'27 The latter concept, on the contrary, intentionally disregards the BP measurements taken during the transition periods between night and day and will therefore use fewer BP determinations for averaging in order to obtain a more meaningful average for the population as a whole. This approach was used in some population-based studies, 28'29 Both these rigid approaches offer the advantage of simplicity and this, indeed, seems to be appropriate for large, population-based studies. However, the choice of time periods used in any particular study remains open to discussion. In addition, the analysis does not necessarily reflect blood pressure during sleep as sleep and night may differ, in particular if results are to be considered for individual patients. Therefore, a more rational basis is needed than arbitrarily fixed day and night periods. To test the notion that "sleep" and "nocturnal" blood pressures may differ, whichever rigid time definition is applied to define night, we examined four distinct groups of subjects: normal volunteers, borderline hypertensives, essential hypertensives, and renal transplant patients. The decrease in BP obtained by using two commonly used fixed day v night schemes (wide: day 06:01 to 22:00/night 22:01 to 06:00 and narrow: day 10:00 to 22:59 and night 01:00 to 06:59) was compared with the decrease obtained by using the patients' own awake v sleep pattern (individual scheme). METHODS Study Populations Normotensive male volunteers and male patients with borderline essential hypertension were recruited as dippers. Patients with essential hypertension and renal transplant patients were recruited to provide a positive control of putative lesser or nondippers. Subjects were recruited by advertisement or by personal contact in our clinic. BP was measured according to WHO guidelines 3 four times on two occasions by trained, qualified personnel. Pressure below 140 mm Hg systolic and 90 mm Hg diastolic was considered normotensive. If either systolic or diastolic pressure exceeded 140 or 90 mm Hg, respectively, patients were considered borderline hy- pertensive. Patients with a blood pressure above 160 mm Hg systolic or 95 mm Hg diastolic were classified as essential hypertensives. Secondary causes of hypertension and coexisting diseases were excluded in all patients except the renal transplant group by history, physical examination, fundoscopy, serum electrolytes, serum creatinine, complete blood count, urinalysis, metanephrine excretion, electrocardiogram, echocardiogram, and ultrasound of the kidneys, including duplex ultrasound of the renal arteries. Patients were excluded from the present study if secondary hypertension was proven, if they had been previously diagnosed as being hypertensive or had received treatment. Adult patients who had received a renal transplant within the last 3 to 24 months were enrolled in the present study if they fulfilled the following criteria: stable renal function, lack of stenosis of the transplant artery (as assessed by duplex ultrasound or angiograms), or recurrent renal disease in the graft. Exclusion criteria were a history of myocardial infarction during the last 18 months, stroke, diabetes mellitus, or other serious disorders (including infections). All patients received triple drug therapy (cyclosporine A, azathioprine, and methylprednisone) and antihypertensive medication as indicated based on clinic BP measurements. The study was approved by the institutional committee on human subjects and informed consent was obtained. Ambulatory BP Monitoring Ambulatory BP was recorded using a SpaceLabs blood pressure monitor (SpaceLabs, Redmond, WA) on a routine working day. Mean arterial pressure (MAP) as used in this study is the point of maximum cuff oscillations as determined by the monitor. BP readings taken by the monitor were compared to readings obtained simultaneously with a binaural stethoscope and a standard mercury sphygmomanometer connected to the monitor cuff with a Y-piece. The cuff was repositioned on the contralateral extremity until differences were less than 10/5 mm Hg. This requirement was achieved in all the study patients. Recordings were made every 15 min from 06:01 to 22:00, and every 30 min from 22:01 to 06:00. When subjects returned the monitor they were asked what time they fell asleep and when they woke up. It was decided that subjects who did not sleep would have to be excluded from the study; however, none of the study subjects reported that he did not sleep. The built-in error correction was used (excluding 1.0% of readings successfully completed) and profiles were edited manually (excluding an additional 0.5% of readings successfully completed) to exclude erroneous readings. Statistical Analysis To calculate the average BP, the average of the readings in the respective period was

3 668 GATZKA AND SCHMIEDER AJH-JULY 1995-VOL. 8, NO. 7 used. To allow comparisons with other investigations, we followed previous suggestions31: dippers were defined as subjects with a reduction of mean arterial pressure (MAP) during the night (sleep) of 10% or more of the daytime (awake) mean value. All data are expressed as mean --- standard deviation except were indicated otherwise. Statistical comparisons were made using a pairedsamples t test for the comparison of the fall in respective BP values and a X 2 test (Cochran's Q) for the comparison of the percentage of dippers. No comparisons were made between both fixed (narrow and wide) schemes, as this was not the objective of this study. Two-tailed probabilities (P) are given and were considered significant if P <.05. All computations were done using the SPSS for Windows program (SPSS Inc., Chicago, IL), version RESULTS Characteristics of the Participants and Office Measurements A total of 45 male normotensive volunteers, 20 male patients with borderline hypertension, 56 patients (12 women, 44 men) with essential hypertension, and 45 renal transplant recipients (16 women, 29 men) completed the study protocol. Baseline data for these four groups are summarized in Table 1. Ambulatory Blood Pressure Data The results of ambulatory blood pressure monitoring are summarized in Table 2. All profiles were analyzed with the individualized scheme and also with both popular fixed time schemes (wide and narrow). The differences between the fixed and individualized scheme as far as the fall of BP during sleep (night) is concerned are shown in Table 3. The decrease in systolic and diastolic BP obtained using the wide fixed versus the individualized approach was significantly different, with a greater decrease observed using the individualized scheme. This observation was consistent throughout all four groups of patients and also for systolic and diastolic BP. With the narrow fixed scheme this difference was observed consistently as well in all four groups, but was not as prominent as with the wide fixed scheme. Therefore, it may be concluded that the individualized scheme of analysis is better in its congruence with the patients' diurnal and nocturnal blood pressure pattern than the fixed scheme. Classification into Dippers and Nondippers Patients who exhibited a fall in MAP during sleep (nighttime) of 10% or more of awake (daytime) averages were classified as dippers, the others as nondippets (Figure 1). Normotensives and borderline hypertensives are all expected to be dippers. And indeed, all the normotensives and borderline hypertensives were correctly identified as dippers using the individualized scheme, whereas both the wide and narrow fixed time schemes misclassified 31% and 4% of normotensives and 20% and 20% of borderline hypertensives, respectively, as nondippers. In addition, significant differences for the percentage of dippers were found in the hypertensive and renal transplant group. Those normotensives misclassified as nondippers using the fixed wide scheme fell asleep at 00: :43, which is more than 1 h later than dippers, who fell asleep at 23: :56 (P <.001). Wake-up times and duration of sleep as well as weight, height, age, or body mass index were not significantly different. If we take the individualized scheme as the standard, the sensitivity and specificity to correctly identify nondippers are 100% and 77%, respectively, for the wide and 94% and 86% for the narrow fixed scheme. DISCUSSION In the present study we investigated whether or not the classification of dippers and nondippers can be improved by applying the patients' own awake/sleep pattern instead of fixed time schemes, thereby avoiding the current, arbitrary time definitions. The individualized scheme used requires only minimal additional effort, as it is only necessary to ask the patients what time they fell asleep and what time they woke up. We found that a sizeable proportion of normoten- TABLE 1. PATIENT CHARACTERISTICS OF THE FOUR DISTINCT GROUPS INVESTIGATED: NORMOTENSIVE VOLUNTEERS (NT), BORDERLINE HYPERTENSIVES (BH), ESSENTIAL HYPERTENSIVES (EH), AND RENAL TRANSPLANT RECIPIENTS (RT) Age (range) (years) Height (cm) Weight (kg) Body mass index (kg/m 2) Causal SBP average (mm Hg) Casual DBP average (mm Hg) NT BH EH RT 26 (21-32) 24 (21-29) 44 (23-65) 46 (19-65)

4 AJH-JULY 1995-VOL. 8, NO. 7 AMBULATORY BP PROFILES IN DIPPERS 669 TABLE 2. AMBULATORY BLOOD PRESSURE MEASUREMENTS OF THE FOUR DISTINCT GROUPS INVESTIGATED: NORMOTENSIVE VOLUNTEERS (NT), BORDERLINE HYPERTENSIVES (BH), ESSENTIAL HYPERTENSIVES (EH), AND RENAL TRANSPLANT RECIPIENTS (RT)* NT BH EH RT 24-h systolic BP (mm Hg) 24-h diastolic BP (mm Hg) Time falling asleep (h) Time waking up (h) Wide fixed time spans Daytime systolic BP (ram Hg) Daytime diastolic BP (mm Hg) Nighttime systolic BP (ram Hg) Nighttime diastolic BP (mm Hg) Narrow fixed time spans Daytime systolic BP (ram Hg) Daytime diastolic BP (ram Hg) Nighttime systolic BP (mm Hg) Nighttime diastolic BP (mm Hg) Individualized approach Awake systolic BP (ram Hg) Awake diastolic BP (mm Hg) Asleep systolic BP (ram Hg) Asleep diastolic BP (ram Hg) 121 ± ± ± ± ± 5 75 ± 5 88 ± ± ± ± ± ± ± ± ± ± ± ± ± 6 80 ± 7 92 ± ± ± ± ± ~ ± 6 67± 5 80 ± ± ± ± ± ± 14 77± 6 82 ± 6 93 ± ± ± ± ± ± ± 5 65 ± 6 80 ± ± ± ± ± ± ± 6 81 ± 6 93 ± ± ± ± ± ± ±4 64 ± 5 78 ± ± 12 *Wide time spans are defined as day 06:01 to 22:00, night 22:01 to 06:00, narrow time spans as day 10:00 to 22:59, night 01:00 to 06:59, the individualized approach considers each patients" sleep pattern individually sive and borderline hypertensive individuals would have been misclassified as nondippers using a fixed approach. These misclassifications observed with the fixed approach were due to patients' divergent sleep patterns, ie, they were going to bed later than the other patients, but did not differ in their duration of sleep or in any other factor, ie, sex, age, height, weight, or body mass index. This misclassification due to divergent sleep patterns was completely avoided using the individualized scheme. Any fixed time scheme is fallible when patient populations exhibit nonuniform sleep patterns. In this study we have considered both the current consensus definition (wide fixed time spans) as well as the alternative approach with narrow fixed time spans that ignore the transition periods, ie, falling asleep and waking up. 3"27-29 Both were shown to be inferior to the individualized approach in terms of average fall of BP during night/sleep and in their ability to correctly identify dippers and nondippers. Even though we did not directly compare both fixed time schemes, the narrow fixed scheme appeared to fare better than the wide fixed scheme in terms of reduction of blood pressure during night. It will require further study to assess long-term stability of the fall in blood pressure during sleep/night with all methods of analysis, ie, individualized, fixed wide, or fixed narrow. A third approach to circumvent the problem of divergent sleep patterns, which we were not able to address in this study exists: to direct patients to go to bed not later than 23: This, however, has the disadvantage of disrupting the patients' lifestyle un- TABLE 3. COMPARISON OF FALL OF BP BETWEEN THE INDIVIDUALIZED SCHEME AND BOTH FIXED TIME SCHEMES (WIDE AND NARROW) FOR ALL FOUR DISTINCT GROUPS OF PATIENTS: NORMOTENSIVE VOLUNTEERS (NT), BORDERLINE HYPERTENSIVES (BH), ESSENTIAL HYPERTENSIVES (EH), AND RENAL TRANSPLANT RECIPIENTS (RT)* A Systolic (mm Hg) Diastolic (mm Hg) Individual Wide Fix Narrow Fix Individual Wide Fix Narrow Fix NT *** 17.7 ± ± *** BH ± 8.6** ± 7.0** EH "** ** * RT ± 9.8* 7.1 ± * * *Two-tailed probabilities (p) of a paired samples t test between a fixed and the individualized scheme within each group of patients: *P <.05, **P "~.01, ***P <.001.

5 670 GATZKA AND SCHMIEDER AJH-JULY 1995-VOL. 8, NO. 7._o. 40 tm 1 On 1 O0 I Individualized 100 I * * C3Fixed Narrow 80 I ** [Z]Fixed Wide NT BH EH RT Patient Group FIGURE 1. Comparison of the percentage of dippers in all four distinct groups of patients: normotensive volunteers (NT), borderline hypertension (BH), essential hypertension (EH), and renal transplant recipients (RT). Dippers are patients with a fall of mean arterial pressure during nighttime (while asleep) of 10% or more of daytime (awake) values. Wide time spans are defined as day 06:0I to 22:00, night 22:0I to 06:00, narrow time spans as day I0:00 to 22:59, night 01:00 to 06:59, the individualized approach considers each patients" sleep pattern individually. Cochran Q for the comparison between a fixed and the individualized scheme within each group of patients: *P <.05, **P <.01, ***P <.001. necessarily, which may be one reason for the low reported reproducibility of night time blood pressure in that study. The improvement observed in this study by the application of the individualized analysis occurred despite the fact that the subjects' estimate of their own sleep times may have been inaccurate as we did not actually measure the sleep times. It would enhance our understanding to pursue this issue by means of objective measures of sleep, ie, in the sleep laboratory or with an accelerometer. However, as most contemporary ambulatory blood pressure equipment does not have this feature, this cannot be recommended for general use at present. The use of diaries requires additional effort on the patients' side without a substantial diagnostic yield and might by itself influence the patients' activities. The exact mechanism of the nocturnal fall in BP has not yet been elucidated. Sleep itself seems to be the most important variable related to the decrease in BP, with different levels of BP reductions attained in the various phases of sleep. Time of day, in and of itself, appears to have no or only a minor effect on the BP pattern throughout the 24 h. 1'2"5"19'21'33-35 Nevertheless, fixed time of day schemes have been used almost exclusively during the last decade for the analysis of ABPM. Our data suggest that this approach may be undesirable and that it obscures the extent of the fall in BP during sleep. We have shown that misclassification of subjects as nondippers can be avoided by simply applying an individualized scheme. A correct classification is important in the management of hypertensive patients. If for no other reason, unnecessary diagnostic procedures can be avoided. Further, hypertensive patients without a demonstrable nocturnal decrease in BP may have more extensive end-organ damage and a worse cardiovascular prognosis compared to dippers. 2-2s This group of hypertensive patients may warrant more aggressive treatment. Thus, the accuracy of classification may also have therapeutic implications. ACKNOWLEDGMENT The authors thank Ms. Anja Friedrich for her management of the study as research nurse. REFERENCES 1. Pickering TG, Harshfield GA, Kleinert HD, et al: Blood pressure during normal daily activities, sleep, and exercise. Comparison of values in normal and hypertensive subjects. JAMA 1982;247: Weber MA: Evaluating the diagnosis and prognosis of hypertension by automated blood pressure monitoring: outline of a symposium. Am Heart J 1988;116: Consensus document on non-invasive ambulatory blood pressure monitoring. J Hypertens 1990(suppl); 8:$135-$ Littler WA, Honour AJ, Carter RD, Sleight P: Sleep and blood pressure. Br Med J 1975;3: Littler WA- Sleep and blood pressure: further obsrvations. Am Heart J 1979; Baumgart P: 24-Stunden-Blutdruck bei prim/irer and sekund/irer Hypertonie. Herz 1989;14: Schrader J, Person C, Pfertner U, et al: Fehlender n/ichtlicher Blutdruckabfall in der 24-Stunden Blutdruckmessung- Hinweis auf eine sekund/ire Hypertonie. Klin Wochenschr 1989;67: Staschen CM, Spieker C, Zidek W, Vetter H: Computergest(itzte Auswertung von 24-Stunden-Blutdruckprofilen bei essentiellen und sekund/iren Hypertonikern. Schweiz Med Wochenschr 1987;117: Schrader J, Schoel G, Buhr-Schinner H, et al: Ambulante kontinuierliche 24 h Blutdruckregistrierung in der Diagnostik and Therapie der arteriellen Hypertonie und die Beeinflussung durch die Antihypertensiva Enalapril, Metoprolol, Mepindolol und Nitrendipin. Klin Wochenschr 1988;66: Rosansky SJ: Nocturnal hypertension in patients receiving chronic hemodialysis (letter). Ann Intern Med 1991;114: Rath W, Schrader J, Guhlke U, et al: 24-Stunden Blutdruckrnessungen im Verlauf der normalen Schwangerschaft und bei hypertensiven Schwangeren. Klin Wochenschr 1990;68: Redman CW, Beilin LJ, Bonnar J: Reversed diurnal blood pressure rhythm in hypertensive pregnancies. Clin Sci Mol Med 1976(suppl);3:687S-689S. 13. Mancia G, Ferrari A, Gregorini L, et al: Prolonged in-

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