ETHICAL CONSIDERENTIONS ON TREATMENT FOR CONTROL BLOOD PRESSURE

VARIABILITY

Alexandru Mincă1, *, Tanasescu Maria-Daniela1, 2, *, Ileana Adela Vacaroiu3, 4, *, Delia

Timofte5, Dragoș-Eugen Georgescu6, 7*, Gabriela Droc 8, 9, Sebastian Isac9, 10, Florentina-Raluca
Tulin11, 12, Daniel Staniloaie13, 14, *, Marcel Palamar15, Dragoș-Constantin Luncă16, 17, Ștefan
Popescu2, Mihai-Teodor Georgescu18 *, Perde Flip19 , Dorin Ionescu1, 2, *

„Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Department 1,

1

DisciplineMedical Semiology, Nephrology - Bucharest Emergency University Hospital,Romania,

2
Nephrology Department, Bucharest Emergency University Hospital, Romania,
3
„Carol Davila” University of Medicine and Pharmacy,Faculty of Medicine, Department 3,
Discipline - Nephrology - Emergency Clinical Hospital Sf.Ioan, Bucharest, Romania,
4
Department of Nephrology and Dialysis, St. Ioan Emergency Clinical Hospital, Bucharest,
Romania,
5
Department of Dialysis, Bucharest Emergency University Hospital, Romania;
6
„Carol Davila” University of Medicine and Pharmacy,Faculty of Medicine, Department 10,
Discipline – Surgery – Hospital „Dr. I. Cantacuzino”,
7
Department of General Surgery, Hospital „Dr. I. Cantacuzino”, Bucharest, Romania,
8
„Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Department 14,
Discipline - Anaesthesia and I.C.U. I - Fundeni Institute,Bucharest, Romania,
9
Department of Anesthesiology and Intensive Care I, Fundeni Clinial Institute, Bucharest,
Romania,
10
„Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Department 1,
Discipline - Physiology, Bucharest, Romania,
11
„Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Department 2,
Discipline – Anatomy,Bucharest, Romania,
12
Emergency Clinical Hospital „Prof. Dr. Agrippa Ionescu”, Bucharest, Romania,
13
„Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Department 10,
Discipline - Surgery I,Bucharest, Romania,
14
1st Department of General Surgery, Bucharest Emergency University Hospital, Romania,
15
Nephrology Department, County Emergency Hospital Deva, Hunedoara, Romania,
16
„Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Department
1,Discipline Pharmacology and Pharmacotherapy,Bucharest, Romania,
17
Department of Ophthalmology, Central Military Emergency Hospital „Dr. Carol Davila”,
Bucharest, Romania,
1
18
„Carol Davila”University of Medicine and Pharmacy, Faculty of Medicine - Department 8,
Discipline - Oncology - Oncological Institute Prof. Dr. Al. Trestioreanu, Bucharest, Romania.
19
Mina Minovici’National Institute of Legal Medicine, Bucharest, Romania

* These authors contributed equallyand thus are main authors

Corresponding author: Dr Daniel Staniloaie, Department of General Surgery, Bucharest

Emergency University Hospital, 169 Splaiul Independentei Street, 050098 Bucharest, Romania
E-mail: daniel.staniloaie@drd.umfcd.ro

ABSTRACT

Blood pressure (BP) is characterized by a fluctuation of values over time, from day to

day, from one minute to another, even at interval of seconds. BP variability (BPV) is a parameter

obtained by multiple evaluations at the medical office or at home or during a day with the help of

the ABPM (Ambulatory BP measurement) device and it is increasingly considered a

cardiovascular risk factor (with prognostic value for cardiovascular mortality and morbidity) and

for target organs damage (e.g. nervous central system). Thus, the presence of possible

correlations between the degree of BP variability, on the one hand, and the progression of chronic

kidney disease (CKD) and the presence of diabetes, on the other hand, was constantly and

systematically sought. There are many complications in patients who have both, diabetes mellitus

(DM) and CKD, and, among them, the vascular disease is very common. In this review we raise

the ethical issue of introducing antihypertensive treatment to control BP variability.

Keywords: ethical issue, iatrogenic, hypertension, blood pressure variability, labile

hypertension, diabetes mellitus, CKD

INTRODUCTION

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 The ethical justification for introducing antihypertensive treatment in patients with

hypertension relates both to treat hypertension as a disease and to control it as a cardiovascular

risk factor, for preventive purposes. However, in order to treat less precise conditions, such as

labile hypertension, clinician face the difficulty in deciding to introduce treatment or not,

knowing that there is no unanimously accepted therapeutic algorithm. On the other hand, it may

be helpful in effectively managing the hypertensive patients at an early stage thereby avoiding

medical negligence.

The Blood pressure (BP) homeostasis is maintained by a complex of cardiovascular

regulatory mechanisms influenced by environmental (e.g. altitude, stress, seasons etc.), emotional

and physical factors, like volemia or posture. Organ perfusion is maintained optimal by these

mechanisms, thus the BP levels can be adjusted according to the demands of different organs

(e.g. BP has a lower value during sleep and a higher value during emotional stress and physical

activity). Therefore, Blood Pressure Variability (BPV) is a feature of the cardiovascular system,

its size differing from subject to subject [1] according to their daily challenges and cardiovascular

control mechanisms. Recent studies have suggested that BPV could be considered as an

independent predictor of cardiovascular risk [2] and it can be also considered as a target for

pharmacological treatment [3].

DEFINITION

Episodic and marked elevations in BP define the terms "labile hypertension" and

"paroxysmal hypertension" [4].

The term "labile hypertension" is widely used as a clinical diagnosis in patients with

considerable variation in their BP readings (e.g., variability in BP that is considered more than

normal). Labile hypertension connotes elevation that is more frequent, more severe, and/or longer

lasting than that which is commonly seen in most patients [5].

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 Patients with paroxysmal hypertension (considered as pseudopheochromocytoma)

typically present with abrupt elevation of BP accompanied by an equally abrupt onset of

distressing physical symptoms, such as dizziness, palpitations, flushing, headache, chest pain,

nausea and diaphoresis. Pheochromocytoma should always be considered in patients who present

with paroxysmal hypertension. These patients affirm that the episodes are not related to their

stress and attacks seems that are not provoked (unlike labile hypertension). Anxiety can occur as

a consequence of the physical symptoms. Between episodes, the BP can be elevated in patients

who also have underlying sustained hypertension but often it is normal. Pheochromocytoma

should always be considered in patients who present with paroxysmal hypertension [6].

Patients who experience recurrent and substantial transient elevations in BP are

considered to have labile hypertension. Frequently BP might be above 160 mmHg, but not

always. Elevated readings can occur with stress and emotional distress (in this case they are

associated with palpitations, flushing or headache), although elevations can also occur without

provocation [5].

PATHOGENESIS

The pathogenesis of labile hypertension is difficult to find since the definition of labile

hypertension is not concise. Most studies considered that BPV is caused byBP reactivity and

emphasis the role of the sympathetic nervous system [7, 8].Labile hypertension is related to

sympathetic’s nervous system involvement in BP reactivity to environmental stressors [9].

EPIDEMIOLOGY

The phenomenon of labile hypertension is widespread and is a common reason for

specialist referral. However, there are no data as to its prevalence because of the absence of

defined criteria for "labile hypertension" in terms of frequency, severity or duration of BP

elevation. The diagnosis remains limited to clinical impression [5].

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 Anxious patients, patients under acute stress, patients who frequently self-monitor their

BP (e.g. multiple times daily) or who tend to measure their BP specifically when they believe it is

elevated are more likely to develop labile hypertension. Labile hypertension commonly leads to

adjustment and readjustment of antihypertensive medications, which can incur the risk of

overmedication and possible hypotension [10]. This can be define as iatrogenic hypotension:

every prescription or therapeutic approach used for a specific patient within the context of

medical knowledge that cause a disease. It can be preventable or not. The cardiovascular risk of

labile hypertension depends on the frequency, severity, and duration of BP elevations [5]. But it

is worth to reduce insufficient proved cardiovascular risk with the price of hypotension in this

category of patients? On the other hand, not treating this patients is not consider medical

negligence?

CLINICAL PRESENTATION

Patients with labile hypertension experience recurrent episodes of transient BP elevation.

Elevations can be accompanied by symptoms such as headache, palpitations, or flushing, but they

are typically asymptomatic, and they are attributed to stress by patient and clinician if they occur

in time of stress [5].

DIAGNOSIS

Excessive variability in BP, with episodes of substantially increased BP are the criteria on

which the clinician diagnoses labile hypertension [11].

There are no unanimously accepted measurable criteria for the diagnosis of labile

hypertension. Thresholds distinguishing "normal" from "abnormal" variability BP are not

established. However, the frequent marked elevation of BP to levels that differ substantially from

a patient usual baseline BP is consistent with a clinical diagnosis of labile hypertension [5].
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 BP VARIABILITY – PREDICTIVE FACTOR FOR TARGET ORGANS DAMAGE

The relationship with outcomes may differ depending on the choice of BPV estimate.

Systolic BPV is being more closely related to outcome, but if we consider 24 h BPV, diastolic

BPV seems more closely related to events, at least in adults, while, in elderly, is suggested a more

prominent role of systolic BP (SBP) variability [12, 13] BPV (in particular systolic BPV)

correlates with arterial stiffness [14], which in turn is related to aging and increasing SBP (but

not diastolic BP) levels. In fact, in patient with worsening renal function, an increase in systolic,

but not in diastolic BPV was shown in a recent large study on the relationship between BPV and

CKD (where arterial stiffness is also relevant) [15]. This might imply that the pathophysiology of

diastolic BVP consists in impaired autonomic function with increased sympathetic activity, and

endothelial dysfunction and systolic BPV reflects primarily vascular stiffness and aging [16].

A study which included 2659 patients [17] found that nighttime BP variability was an

independent predictive factor for cardiac events in hypertensive patients who did not initiate

antihypertensive therapy. In the past, hypertension is thought to influence cardiovascular events

by its mean values, but more recent studies have shown that BP variability can also be considered

as cardiovascular and cerebrovascular risk factor [18, 19](like other CV risk factors: diabetes

mellitus, obesity, smoking [20]).

Diabetic nephropathy is characterized by the presence of arterial hypertension, as shown

by epidemiologic studies that indicate that more than 50% of the diabetic patients are diagnosed

with high BP [21]. Oxidative stress is an important element initiating diabetic microvascular

complications, including diabetic kidney disease [22]. Previous studies have shown that long-

term BP variability (comparing measurements taken at the office during several visits) is a

predictor of cardiovascular events and the evolution of BCR to the final stage of the disease.
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Moreover, a recent study (published in 2019) in 30,851 patients showed that long-term BPV is a

risk factor for the development of chronic kidney disease (CKD) in patients with type 2 diabetes

[23]. It is known that diabetes mellitus has effects on multiple organs, including: cardiovascular

disease, polyneuropathy, proteinuria [24], necrotizing fasciitis [25], retinopathy. All these are

correlate with glycemic poor control [26].

Ambulatory BP measurement (ABPM) has proven to be a useful tool in determining 24-

hour BPV. There are several studies that support the idea that increasing 24-hour BPV (as well as

long-term) can independently constitute cardiovascular (CV) risk factor (RF) [27].

A study of a population of 16,546 found that an increase in short-term BP variability (24-

hour variability) was associated with the progression of chronic kidney disease. BP variability

may contribute to increased CV risk in patients as GFR decreases [15].

Approximately 30% of the hypertensive patients have associated hyperuricemia

[28].Serum uric acid (UA) is independently associated with hypertension and BPV is associated

with CV events and mortality in hypertensive patients [29].

MATHEMATICAL FORMULAS

In present, a reasonable choice could be to use the indices supported by the strongest

outcome evidence. Based on a recent meta-analysis [30], the preferred indices might include the

average real variability (ARV), or SD (specifically, the “weighted” SD mentioned below) for 24-

hour BPV, and SD for the clinic (visit-to-visit) and home BPV. It is also important to consider

that these estimates of BPV are directly correlated with mean BP levels, and therefore it is

important to adjust them for average BP. For evaluation of a patient, we can use a mathematical

correction by calculating the coefficient of variation (CV = SD*100/mean) or by calculating the

variation independent of the mean (VIM).

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 When we use ABPM for evaluate 24-hour BPV, we should consider that 24-hour SD is

confounded by the contribution of nocturnal BP fall and, then, one should not use it for CV risk

assessment [31] ARV or weighted 24-hour SD, as indices that are not affected by day-to-night

changes, should be use, also. It is unclear if we must prefer daytime or nighttime SD, but

nocturnal BPV appeared to be superior to daytime BPV in several studies [32, 33].

DISCUSSIONS

Although BPV was not initially considered to have a significant impact as a

cardiovascular risk factor in the Framingham study [34], recently many studies proved that it

could play a role in influencing cardiovascular morbidity and mortality in hypertensive patients

[35]. Therefore, it is becoming increasingly obvious that a therapeutic regimen (not necessarily

medication / antihypertensive, as BPV has a neurological and psychosomatic implication) is

needed to reduce excessive BP fluctuations.

Ethical reservations about introducing the treatment for controlling blood pressure

variability arise from the following facts:

- This borderline disease, labile hypertension, has no unanimously accepted measurable

criteria, being based more on the subjective evaluation of clinicians.

- Antihypertensive treatment in this category of patients can induce hypotension with

manifestations such as dizziness, fatigue, malaise, headache etc. In elderly patients, hypotension

can be an emergency.

- Clinical trials are still quite timid in stating that BP variability is a consistent

cardiovascular risk factor.

- Cardiovascular risk has not been shown to decrease in patients treated for labile

hypertension.

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 However, clinicians must carefully consider every patient with an individual treatment,

even if this is not on medication basis.

Figure 1: Comparison between two BP profiles (ABPM) with differnt

ARV.Significant variations in BP values compared to the first patient are observed in the

second pacient.

BP = blood pressure, ABPM = Ambulatory BP measurement,

Conflict of interest

The authors declare that they have no conflict of interest

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