CLINICAL PRACTICE

76 Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine

Nocturnal Hypertension: Neglected Issue in Comprehensive
Hypertension Management

Andi Kristanto1, Randy Adiwinata1, Silvia Suminto1, Benny N. Kurniawan1,
Finna Christianty1, Robert Sinto2

1 Faculty of Medicine, Atmajaya Catholic University of Indonesia, Jakarta, Indonesia.
2 Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital,
Jakarta, Indonesia.

Corresponding author:
Robert Sinto, MD. Department of Internal Medicine, Faculty of Medicine Universitas Indonesia - Cipto
Mangunkusumo Hospital. Jl. Diponegoro No. 71, Jakarta 10430, Indonesia. email: rsinto@yahoo.com,
andi_kris@hotmail.com.

ABSTRAK
Irama sirkadian dalam tubuh, mempengaruhi variasi tekanan darah baik pada siang dan malam hari,

sehingga didapatkan pola tekanan darah yang berbeda. Hipertensi nokturnal adalah peningkatan tekanan darah
>120/70 mmHg pada malam hari akibat terganggunya irama sirkadian, dan berkaitan dengan peningkatan
kejadian kardiovaskular, serebrovaskular, serta mortalitas pada pasien hipertensi. Hipertensi nokturnal dan
perubahan pola penurunan tekanan darah, hanya dapat diketahui dengan cara melakukan pemeriksaan tekanan
darah secara kontinyu selama 24 jam yang dikenal sebagai ambulatory blood pressure measurement (ABPM).
Kronoterapi, menjadi salah satu strategi dalam menangani pasien dengan hipertensi nokturnal, yaitu dengan
meminum obat anti hipertensi pada malam hari untuk mendapatkan penurunan tekanan darah yang sesuai
irama sirkadian untuk meningkatkan kontrol tekanan darah.

Kata kunci: hipertensi nokturnal, pengukuran tekanan darah ambulatori, non-dipping, kronoterapi.

ABSTRACT
The body circardian rhythm affects blood pressure variability at day and night, therefore blood pressure at

day and night might be different. Nocturnal hypertension is defined as increase of blood pressure >120/70mmHg
at night, which is caused by disturbed circadian rhythm, and associated with higher cardiovascular and
cerebrovascular events also mortality in hypertensive patients. Nocturnal hypertension and declining blood
pressure pattern, can only be detected by continuous examination for 24 hours, also known as ambulatory blood
pressure measurement (ABPM). Chronotherapy, has become a strategy for managing the hypertensive nocturnal
patients, by taking hypertensive medication at night to obtain normal blood pressure decrease in accordance
with the normal circadian rhythm and, improving blood pressure control.

Keywords: nocturnal hypertension, ambulatory blood pressure measurement, non-dipping, chronotherapy.

Vol 48 • Number 1 • January 2016 Nocturnal hypertension

INTRODUCTION
Hypertension has been for long time well

studied as one of the major cardiovascular
disease risk factor, thus hypertension treatment in
controlling blood pressure is important to prevent
cardiovascular disease progression.1 However,
the diagnosis of nocturnal hypertension tend to
be missed although it is an important predictor
of all cause mortality and/or cardiovascular
mortality.2 Lack of awareness with hypertension
cause patients to measure their blood pressure
only during hospital visit. This factor contributed
to the limited use of ambulatory blood pressure
measurement (ABPM), and the possibility of
nocturnal hypertension became overlooked.3
In this review, we described the definition,
epidemiology, pathophysiology, clinical
significance, diagnosis, and anti hypertension
management of nocturnal hypertension.

DEFINITION

Hypertension is a major independent risk
factor for the development of cardiovascular
disease, and its variation at day or night of
the blood pressure depends on circadian
rhythm, which is associated with interaction
of sympathetic nervous system and renin-
angiotensin systems.4 This blood pressure
variation phenomenon consist of dipping,
extreme dipping, non dipping and riser or reverse
dipping. Dipping phenomenon is defined as a
decrease in systolic nighttime blood pressure 10-
20% from daytime blood pressure and occurs as
normal physiologic changes. The term “extreme
dipping” is used when nighttime blood pressure
decrease more than 20%. Meanwhile, in non
dipping pattern, the decrease in blood pressure
is only approximately 0-10% and the increase
in blood pressure at night is called reverse
dipping or riser. The latter pattern (non dipping
and reverse dipping/riser) were associated with
nocturnal hypertension. Nocturnal hypertension
is defined as increase of blood pressure >120/70
mmHg at night.5-7

EPIDEMIOLOGY

As discussed above, the blood pressure
changes at night was a physiologic changes

that occurs in healthy individual. However,
these changes did not occur in some people.
The non dipping pattern was found higher
in Chinese, Japanese, and South Africans
compared in Western and Eastern Europeans
with the prevalence of 10.9% vs. 6.0%. The
higher sodium and lower potassium intake
among Asian than other population might be
contribute to it.8 In a cohort study of Spanish
Society of Hypertension Ambulatory Blood
Pressure Monitoring Registry reported that from
42,947 hypertensive patients, there were 50.2%
untreated patients and 40% treated patients had
dipping pattern. At the same time, there were also
35% untreated patients and 40% treated patients
had non dipping pattern.9 Non dipping pattern
was associated with more severe target organ
damage from chronic kidney disease (CKD),
cardiovascular and cerebrovascular disease
induced by hypertension.10

Non dippers were more prevalent in
individuals with CKD and diabetic patients.
Liu et al11 found that non dipping phenomenon
was commonly found in patients undergoing
hemodialysis with the prevalence up to 70%.
The possible mechanism is due to an inadequate
blood pressure as a consequence of baroreflex
or autonomic dysfunction in CKD patients, thus
maintaining more adequate hemodialysis in these
patients is needed to decrease cardiovascular
complications. Also, in a study conducted by
Cuspidi et al, found that non dipping prevalence
was higher in hypertensive diabetic subjects
than in hypertensive nondiabetic subjects after
24 hours ambulatory blood pressure monitoring.
Renal hemodynamics, blood flow distribution,
and plasma volume are thought to be affected
by hyperglycemia state in diabetic patients.12,13

PAT H O P H Y S I O L O G Y O F N O C T U R N A L
HYPERTENSION

Many factors were postulated in disrupting
the circadian rhythm, which in turn lead to
attenuation of nocturnal blood pressure lowering
phenomenon. The causes of abnormal circadian
rhythm of blood pressure can be divided to
hormonal metabolic factors and external factors
such as smoking or aging. Some disease are
implicated in the disruption, such as diabetes

Andi Kristanto Acta Med Indones-Indones J Intern Med

mellitus, metabolic syndrome, chronic kidney
disease, and obstructive sleep apnea (OSA).14 In
this paper, we described the two most reported
mechanisms of nocturnal hypertension, which
were imbalance of nocturnal autonomic nervous
system and limited sodium metabolism by
kidneys.

Imbalance of Nocturnal Autonomic Nervous
System Activation

In physiologic state, blood pressure levels
is fluctuated along the day with peak in early
morning and low during sleeping. Circadian
rhythm is one of the contributors of the fluctuation
which controlled from suprachiasmatic nuclei
(SCN) of the anterior hypothalamus. Circadian
rhythm mainly influenced by autonomic nervous
system.15 In general, autonomic nervous system
composed of sympathetic and parasympathetic
nerves, which keep in balance to maintain
physiologic state. Over dominance of sympathetic
activation was postulated as the cause of
nocturnal hypertension and attenuated the blood
pressure dipping. Vardhan et al reported that,
patients with obstructive sleep apnea (OSA) were
having higher catecholamines plasma and urinary
levels compared with control. This findings were
correlated with hypertension in patient with
OSA.16 Nielsen et al17, found that low degree of
blood pressure dipping were related to sustained
adrenergic activity which reflected by higher
noradrenaline level and lead to decreased the
peripheral vasodilatation capacity. Doxazosin, an
alpha-1 adrenergic blocker drug, will effectively
block the sympatethics activity which in turn
lower the blood pressure while sleeping.18 These
studies showed that non dipping phenomenon
is caused by sympatethics system over activity.

Limited Sodium Metabolism
Kidneys have a role in maintaining blood

pressure, regulated by renin-angiotensin-
aldosteron system and influenced by circadian
rhythm. Non dipping patients are thought to
be related with impaired capacity of kidneys
to excrete sodium during daytime or increased
tubular sodium reabsorption which was
commonly caused by hyperaldosteronism.19 This
theory was supported by data that the prevalence
of non-dipper was increased in patient with low

glomerular filtration rate (GFR).20 Wang et al21
reported among 540 Chinese CKD patients, total
of 21.9% patients were riser, 36.1% patients were
dipper, and 42% of patients were non-dipper.21
However, increased daily salt intake also found
to be related with nocturnal hypertension.
Kidneys will compensate high sodium intake
by enhancing natriuresis during the night. Thus,
blood pressure will remain elevated until kidneys
succeed in reducing excess sodium.22,23

CLINICAL IMPLICATIONS OF NOCTURNAL
HYPERTENSION

Nocturnal hypertension phenomenon results
in several clinical implications that have to be
taken into consideration to predict complications
and approach strategy to treat every individual
with hypertension. There have been many
studies conducted about circadian patterns
and its clinical implications, especially those
associated with cardiovascular, cerebrovascular,
and renal diseases. Fagard et al24, mentioned that
cardiovascular complication in subject with non
dipping circadian pattern is higher compared to
subjects with dipping pattern. This statement is
also supported by one of the studies that showed
increasing 10 mmHg of nighttime systolic
blood pressure would rise 35% possibility of
cardiovascular risk in diabetic population.25

The negative effect of cardiac function
was described by Verdecchia et al26. that non
dipping group had greater risk of left ventricular
hypertrophy (LVH) compared with dipping
group. Groups with dipping circadian pattern
had LVH risk at about 4%, while the risk of
group with non dipping pattern increased to
15%. The thickening of carotid intima (>0.8
mm) also found higher in non dipping pattern
than dipping, that will lead to atherosclerosis.
OPERA study showed on their population based
cohort study of 900 middle aged individuals, that
mean carotid intima media thickness were higher
in non-dipper (90 mm) compared to dipper (80
mm).27 The association between carotid intima
thickening and atherosclerosis plaque formation
is supported by Salvetti et al28. The results of
ultrasonography showed that thickening of
carotid intima and formation of plaque presence
were 55% and 56% respectively in uncontrolled

Vol 48 • Number 1 • January 2016 Nocturnal hypertension

hypertensive patients with non dipping circadian
pattern, whereas in dipping circadian pattern
were 24% and 33% respectively.

Persons who have high blood pressure in the
night, which includes reverse dipping and non
dipping had an increased risk of intracerebral
hemorrhage (ICH). Sun et al6, found that
probability of silent ICH in non dipping and
reverse dipping group was 50.8%. Meanwhile,
Tsivgoluis et al conducted a research on patients
with ICH, and found that 74.4% of the patients
with ICH were non dippers, while 43.8% of the
patients were dippers.29 Another study by Ma
et al30 showed, that several subjects with non
dipping pattern had silent cerebral infarct. Non
dipping are associated with lacunar cerebral
infarct eventwhich may leads to decline in verbal
memory function.31

Kidney failure was also considered as
another important clinical implication of the non
dipping circadian pattern, reflected by presence
of microalbuminuria and decreasing GFR.
Kastarinen et al did a research of renal function
on 460 subjects where 18.7% of the study
population were non dipper. The mean eGFR
of non dippers in this study were significantly
lower compared with a mean eGFR in dipper
patients.32 Meanwhile, Afsar et al33 compared
patterns of non dipping and 24 hour urinary
albumin excretion (UAE) in 158 hypertensive
patients (104 dippers; 54 non dippers). Among
patients in the non dipper group, 17 patients had
microalbuminuria, while only 9 patients in dipper
group had microalbuminuria (P<0.0001). The
median UAE of dipper group was significantly
lower (5.25 mg/day) when compared with non
dipper group (23 mg/day).

SIGNIFICANCE OF AMBULATORY BLOOD
PRESSURE MONITORING IN NON DIPPING
HYPERTENSIVE PATIENT

There are several modalities of measuring
blood pressure, which is divided into two
categories, the clinic based measurement
(auscultatory method, oscillometric method)
and non clinic-based measurement (home blood
pressure monitoring, ABPM).34 ABPM itself has
gained popularity as an alternative to traditional
method for measuring blood pressure in clinical

setting.35 In the ABPM technique, the patient
wears a portable blood pressure measuring
device for a certain period (usually 24 h). This
periodically measures blood pressure (every
15–30 min during the day and every 30–60
min overnight) automatically and may provide
information of blood pressure during normal
daytime activities and importantly during
sleep.36,37 The term ‘nocturnal hypertension’
or ‘non dipping’ pattern as described in above
section become an important phenomenon to be
considered by all clinicians and it can only be
identified by 24 hour ABPM or other methods of
recording the sleep blood pressure.38,39

Many studies compared ABPM and clinic-
based measurement and concluded that ABPM
is more superior in predicting cardiovascular
event or other prognostic factor. ABPM may also
reduce the incidence of white-coat effect and
masked hypertension that were not detected in
clinic-based measurement, and also predict all-
cause mortality especially due to cardiovascular
event than awake or clinic blood pressure.24,34,40
The results of the study showed that patients
with an absence of normal dipping has higher
mortality than the dipping one. The pattern
of dipping that was detected will add clinical
predictive information and further reinforcing
the use of ambulatory monitoring in patient
management. 40 Therefore, importance of
nocturnal hypertension or ‘non dipping pattern’
of blood pressure strengthens the need for 24
hours ABPM.

T H E I M P R O V E D S T R A T E G Y I N
HYPERTENSION MANAGEMENT

Standard Treatment of Hypertension
Nowadays, there are many different classes

of antihypetensive drugs, such as diuretics,
angiotensin-converting enzyme (ACE) inhibitor,
angiotensin II-receptor-blockers (ARBs),
β-blocker, and calcium antagonist, that have
been used for the intitiation and maintenance
of antihypertensive treatment. Generally, a
long-acting antihypertensive drug with 24 hours
duration is used as a initial standard treatment of
hypertensive patients in order to maintain blood
pressure variability and adherence to therapy.41,42

Andi Kristanto Acta Med Indones-Indones J Intern Med

However, antihypertensive drugs used once
daily are rarely effective from the morning
dosing until the following morning. Many of
the hypertensive patients, especially non dipper
patients on standard antihypertensive drugs still
have raised blood pressure on the morning. It is
because the effect of antihypertensive drugs on
the diurnal variation of blood pressure, depends
not only on the mechanism of action of the drugs,
but also on the time of administration, and the
pharmacokinetics and pharmacodymamics of
the drug.43

In this regard, choosing the optimal timing
for drug administration, especially a single dose
antihypertensive drug, such as several kind of
ACE inhibitor, ARB, or calcium antagonist
should be considered. Also, we have discussed
that the blood pressure (BP) is regulated by many
different systems and its activity vary throughout
the day. As drugs are developed that selectively
block these systems, the reduction on the BP may
not be consistent over 24 hours.4,44

Chronotherapy: Improving the Hypertension
Management

Chronotherapy is defined as administering
drug while considering the optimal dosing
time in purpose to enhance drugeffectiveness
and tolerance. In hypertension, chronotherapy
defined as taking hypertensive medication at
night to obtain normal BP decrease in line with
circadian rhythms, reduce the morbidity and
mortality.45,46

T h e M A P E C s t u d y c o m p a r e d t h e
administration time between morning dose
(taking all prescribed drugs in the morning) and
bedtime doses (taking more than one drug at
bedtime), and concluded that after a mean follow
up of 5.6 years in 2156 subjects, the bedtime
dose achieved better overall BP control. Also,
subjects taking more than one drug at bedtime
showed significantly lower relative risk of total
cardiovascular disease events, compared to those
taking all drugs in the morning. The prevalence
of non-dipping significantly reduced in those
receiving medication in the bedtime (34%
vs. 62%) and higher prevalence of controlled
ambulatory BP (62% vs. 53%).45

The possibility to achieve better BP control
using telmisartan administered at bedtime was

assessed in a study, in which telmisartan 80
mg given in 215 patients randomized to take
the drug in the morning or bedtime. After 12
weeks of treatment, the reduction of BP was
similar for both groups. However, subjects
taking bedtime dose had reduced prevalence
for non-dipper by 76%, without loss in 24 hour
efficacy of telmisartan.47 Similar results were
found in other studies, in which olmesartan or
valsartan taken at night provided 24 hours BP
reduction while improving nocturnal BP fall
more significantly than morning dosing, thus
reducing the prevalence of non dipper.48,49

T h e u s e o f c h r o n o t h e r a p y i n o t h e r
hypertensive drugs regimens had shown similar
beneficial effects. Bedtime dosing of ramipril
in at least two different studies were found
to be effective in achieving nocturnal BP
regulation.50,51 The role of chronotherapy in
nifedipine GITS (Gastrointestinal-Therapeutic-
System) formulation and amlodipine as calcium
channel blocker class drugs also showed greater
reduction of 24-hours ABPM and greater BP
reduction at night compared with morning
dosing.52,53

A chronotherapy trial using combination
antihypertensive drug also has been conducted
by Hermida et al54, using valsartan/amlodipine
combination in 203 hypertensive subjects, and
resulted that BP-lowering efficacy was highest
when both antihypertensive drugs ingested
at bedtime, compared to both ingested on
awakening, or either of the drugs ingested on
awakening and the other at bedtime. Moreover,
chronotherapy was found to have useful effect
in treatment of resistant hypertension. In a study
of 250 patients with resistant hypertension that
received three hypertensive drugs, ambulatory
BP reduced by 9.4/6.0 mmHg when one of
the drugs was administered at bed time. The
percentage of dippers increased from 16% to
57% after 12 weeks of administering one drug
at bedtime.55

CONCLUSION
As conclusion, identifying the nocturnal

hypertension as well dipping or non dipping status
of patients are important for aiding the decision
on the necessity of chronotherapy, withdrawal

Vol 48 • Number 1 • January 2016 Nocturnal hypertension

or reduction of unnecessary medication, and
monitoring hypertension treatment. Taking
the antihypertensive medication in the night
significantly improves the dipping pattern of
hypertensive patient, thus chronotherapy is a
improved strategy in hypertension management.

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