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ORTHOSTATIC HYPOTENSION Emmanuelle VIDAL-PETIOT, MCU-PH Physiologie – Explorations fonctionnelles Hôpital Bichat
ORTHOSTATIC
HYPOTENSION
Emmanuelle VIDAL-PETIOT, MCU-PH
Physiologie – Explorations fonctionnelles
Hôpital Bichat
Orthostatic hypotension
Epidemiology
Pathophysiology
Etiologies
Treatment
Diagnosis
Orthostatic hypotension
Epidemiology
Pathophysiology
Etiologies
Treatment
Diagnosis
hypertension / orthostatic hypotension
Hypertension
After 5 minutes of rest
In the sitting position
BP ≥ 140/90 mmHg
Orthostatic hypotension
Drop in BP upon standing up
≥20mmHg SBP / ≥10mmHg DBP
within 3 minutes
Usually asymptomatic
Treat to prevent long-term complications
Treat to improve immediate quality of life
May be symptomatic or not…
Prevalence of orthostatic hypotension
Middle-aged diabetics 10-20% General population 6% Parkinson’s 35%
Low - Clin Auton Res 2008;18[S1]:8–13
Elderly 5-30%
Risk factors age, diabetes, hypertension, smoking status, low BMI, multiple medications, number of comorbidities, neurological disorders (Parkinson’s, MSA…)
Risk factors of orthostatic hypotension
Age
From Rutan et al Hypertension 1992
Cardiovascular Health Study 5000 participants ≥ 65 years
Masaki et al Circulation 1998
Honolulu Heart Program Japanese american men 71-93 years
Risk factors of orthostatic hypotension
Diabetes
Neurological disorders
Low - Clin Auton Res 2008;18[S1]:8–13
Risk factors of orthostatic hypotension
Number of comorbidities
3,775 women aged 60–80 years from the British Women’s Heart and Health Study Prevalence of OH=28%
Kamaruzzaman et al Age and Ageing 2010; 39: 51–56
OR (95% CI)
Number of medications
Orthostatic hypotension: prognosis
Orthostatic hypotension is associated with increased morbidity (hospital admissions, CV disease, CKD) and mortality
Orthostatic hypotension: prognosis
Orthostatic hypotension is associated with increased morbidity (hospital admissions, CV disease, CKD) and mortality
Mechanisms of OH-induced morbidity and mortality
All-cause mortality
Masaki et al Circulation 1998;98:2290-2295
Honolulu Heart Program (n=3522) Japanese american men 71-93 yo
All-cause mortality: a dose-response curve
Masaki et al Circulation 1998;98:2290-2295
Honolulu Heart Program Japanese american men 71-93 years
OH is a risk factor for mortality
Rose et al Circulation 2006; 114:630–636
13000 middle-aged adults from the Atherosclerosis Risk In Communities (ARIC) Study
Kapalan-Meir survival curves by OH status over 13 years of follow-up
12% mortality
32% mortality
Orthostatic hypotension
Epidemiology
Pathophysiology
Etiologies
Treatment
Diagnosis
Physiological background
cardiac output
Mean BP (-RAP)
peripheral resistance
HR SV 1/r4 µ
Determinants of blood pressure
volemia
cardiac output
Blood pressure
peripheral resistance
autoregulation
natriuretic systems
anti-natriuretic systems
Na reabsorption
Physiology of standing
Robertson et al, Clin Auton Res 2008
Physiology of standing
60
100
140
Stroke volume (ml)
Head up tilt test
Normal response to orthostatism
compensatory mechanisms
0
40
80
120
160
0 120 240 360 480 600 720 840 960
60
80
100
120
140
160
Time (sec)
0
50
100
150
60
80
100
120
4
6
8
10
0
0.5
1
1.5
0 200 400 600 800 1000 sec
TILT TEST
Healthy subject
Mea
n B
P
(m
mH
g)
Hea
rt R
ate
(b
pm
)
Car
dia
c o
utp
ut
(l/m
in)
Pe
rip
h r
es
(mm
Hg
.se
c/m
l)
60
100
140
Stro
ke v
ol
(ml)
BP
HR
Regulation of blood pressure
volemia
cardiac output
Blood pressure
peripheral resistance
autoregulation
natriuretic systems
anti-natriuretic systems
Na reabsorption
Cardiac and arterial baroreflex loops
No baroreflex: extreme variability
Guyton and Hall, textbook of medical physiology
Human
Dog
Arterial baroreceptors
Cardiac and arterial baroreflex loops
Low and Singer – Lancet Neurol 2008; 7:451-58
BAROREFLEX
baroreceptors
voloreceptors
para
volemia
cardiac output
Blood pressure
peripheral resistance
autoregulation
Na reabsorption
Vascular renin-angiotensin system
renin
angio 1
β1 ↓ GFR BP
+
+ angio 2 angiotensinogen
ACE
+
sympathetic activity
vasoconstriction
+
+
Vascular renin-angiotensin system
renin
angio 1
β1 ↓ GFR BP
+
+ angio 2 angiotensinogen
ACE
+
sympathetic activity
vasoconstriction
+
+
BP
Renin-angiotensin-aldosterone system
renin
angio 1
β1 ↓ GFR
volemia
+
+ angio 2 angiotensinogen
ECA
+
sympathetic activity
vasoconstriction
-
aldosterone
Na reabsorption
+
+
+
BP
BAROREFLEX
baroreceptors
voloreceptors
para
volemia
cardiac output
Blood pressure
peripheral resistance
autoregulation
Na reabsorption
vasc RAS
ang2
Juxta-glomerular app.
BAROREFLEX
baroreceptors
voloreceptors
para
volemia
cardiac output
Blood pressure
peripheral resistance
autoregulation
Na reabsorption
RAAS
ang2
Juxta-glomerular app.
ang2, aldo
Natriuretic peptides
ANP, BNP
renin synthesis
natriuresis
-
+
+ volemia
vasodilation
volemia
BP
+
BAROREFLEX
baroreceptors
voloreceptors
para
volemia
cardiac output
Blood pressure
peripheral resistance
autoregulation
Na reabsorption
RAAS
ang2
Juxta-glomerular app.
ang2, aldo
NA PEPTIDES
cardiomyocytes
Regulation of BP: temporal integration
Time after initial change in BP
Gain
of th
e f
eedback s
yste
m
seconds minutes hours days
BAROREFLEX
VASCULAR RAS
RENAL RAAS
NA PEPTIDES
∞
From physiology to pathology
failure of compensatory mechanisms
Orthostatic hypotension
Epidemiology
Pathophysiology
Etiologies
Treatment
Diagnosis
Diagnosis: clinical presentation
Altered mentation
Blurred vision
headaches
« coat hanger » pain
Light-headedness, dizziness
Low BP
Fatigue
Fainting, syncope
May also be asymptomatic
Diagnosis: clinical presentation
Altered mentation
Blurred vision
headaches
« coat hanger » pain
Light-headedness, dizziness
Low BP Sympathetic activation
Sweating
Nausea
Abdominal discomfort
Tachycardia
Fatigue
Fainting, syncope
Diagnosis: clinical presentation
Altered mentation
Blurred vision
headaches
« coat hanger » pain
Light-headedness, dizziness
Low BP Sympathetic activation
Sweating
Nausea
Abdominal discomfort
Tachycardia
Fatigue
Fainting, syncope
All symptoms are alleviated upon sitting back down
Aggravating factors
Rich meal
Alcohol
Hot weather
Morning
Diagnostic criteria
Orthostatic hypotension
Drop in BP upon standing up
≥20mmHg SBP / ≥10mmHg DBP
Within 3 minutes
In hypertensive patients:
drop in SBP ≥30mmHg
Repeated testing is recommended
Clinical variants: initial OH
Wieling et al Clin Sci (2007) 112, 157–165
Initial OH
TRANSIENT decrease in BP
≥40mmHg SBP
and/or ≥20mmHg DBP
within 15 seconds
of standing up
Clinical variants: delayed OH
Gibbons and Freeman Neurology 2006;67:28–32
normal subject
Delayed OH
OH
Diagnosis: neurogenic or non-neurogenic OH
Orthostatic hypotension Drop of systolic BP > 20 mmHg (30 for hypertensive patients) or diastolic BP > 10 mmHg
Increased heart rate: Non-neurogenic (sympathotonic)
hypotension
No increase in heart rate : Neurogenic hypotension
Exclude medications
Differential diagnosis
Orthostatic intolerance Orthostatic hypotension ≠
Postural orthostatic tachycardia syndrome (POTS)
Neurally-mediated syncope
Freeman et al Clin Auton Res 2011 ; 21:69–72
Orthostatic hypotension
Epidemiology
Pathophysiology
Etiologies
Treatment
Diagnosis
Etiologies: medications
Orthostatic hypotension Drop of systolic BP > 20 mmHg (30 for hypertensive patients) or diastolic BP > 10 mmHg
Exclude medications
Anti-hypertensive drugs: Beta-blockers
Centrally acting
Alpha-blockers
Diuretics
All BP lowering drugs…
Other drugs: Antidepressants
Neuroleptics
Parkinson’s drugs
Vasodilators
Anticholinergic
Opioids
…
! Number of medications
Drugs and orthostatic hypotension
342 veterans aged ≥ 75 years attending a geriatric clinic Prevalence of OH=55%
Poo, et al J Clin Pharm Therap 2005; 30, 173–178
Drugs and orthostatic hypotension
3,775 women aged 60–80 years from the British Women’s Heart and Health Study Prevalence of OH=28%
Kamaruzzaman et al Age and Ageing 2010; 39: 51–56
Etiologies: non-antihypertensive drugs
Therapeutic class Drugs Indication Mechanism for hypotension
Levodopa and dopamine-agonists
Levodopa (Modopar)
Ropinirole (Adartrel)
Bromocriptine (Parlodel)
Parkinson’s disease Vasodilation (renal, mesenteric
and cerebral arteries)
Phenothiazines
Chlorpromazine (Largactil)
Cyamemazine (Tercian)
Acute or chronic psychotic disorder
Vasodilation (dopaminergic effect)
Phosphodiesterase 1 inhibitor
Sildenafil (Viagra, Revatio) Erectile dysfunction
Pulmonary hypertension Vasodilation
(inhibition of cGMP degradation)
Tryciclic and MAOI antidepressants
Amitriptyline (Laroxyl)
Moclobemide (Moclamine) Depression
Vasodilation (anticholinergic + dopaminergic)
Anti-arrhythmic Sotalol (Sotalex)
Ventricular and supraventricular
tachycardia
Lack of chronotropic adaptation upon rising
Anticholinergics
Biperidene Chlorhydrate
(Akineton)
Oxybutinine (Ditropan)
Ipratropium (Atrovent)
Parkinson’s disease Overactive bladder Chronic obstructive Pulmonary disease
Vasodilation (M3 muscarinic receptor)
Alpha-blockers Alfuzosine (Xatral)
Tamsulosine (Josir, Mecir) Prostatic hyperplasia Vasodilation
Etiologies: non-neurogenic OH
Orthostatic hypotension Drop of systolic BP > 20 mmHg (30 for hypertensive patients) or diastolic BP > 10 mmHg
Exclude medications
No increase in heart rate : Neurogenic hypotension
Increased heart rate: Non-neurogenic (sympathotonic)
hypotension
Etiologies: non-neurogenic OH
Orthostatic hypotension Drop of systolic BP > 20 mmHg (30 for hypertensive patients) or diastolic BP > 10 mmHg
Exclude medications
Hypovolemia: Absolute fluid loss: - Digestive : vomiting, diarrhea, ileostomy - Renal : salt-wasting nephropathy, adrenal insufficiency - Cutaneous : severe burns
Relative : Congestive heart failure, nephrotic syndrome, cirrhosis Vasodilation : carcinoid syndrome, mastocytosis Age-related physiological changes
No increase in heart rate : Neurogenic hypotension
Increased heart rate: Non-neurogenic (sympathotonic)
hypotension
A rare cause of OH: pheochromocytoma
Etiologies: neurogenic OH
Orthostatic hypotension Drop of systolic BP > 20 mmHg (30 for hypertensive patients) or diastolic BP > 10 mmHg
Exclude medications
No increase in heart rate : Neurogenic hypotension
Increased heart rate: Non-neurogenic (sympathotonic)
hypotension
Neurogenic OH
Sym
pat
het
ic s
yste
m
Par
asym
pat
het
ic s
yste
m
Nervous system: an overview
nOH: a lack of norepinephrine
Kvetnansky et al, Physiol Rev 2016
Biosynthesis of catecholamines
Kvetnansky et al, Physiol Rev 2016
hydroxylation
decarboxylation
hydroxylation
Méthylation
Etiologies: neurogenic OH
2014
Orthostatic hypotension Drop of systolic BP > 20 mmHg (30 for hypertensive patients) or diastolic BP > 10 mmHg
Exclude medications
No increase in heart rate : Neurogenic hypotension
Increased heart rate: Non-neurogenic (sympathotonic)
hypotension
Peripheral neuropathies
Diabetes Amyloidosis
Paraneoplastic disorders Vitamin B12 deficiency
Toxic neuropathies …
Parkinson’s disease Multiple system
atrophy Dementia with
Lewy bodies Spinal cord injury
With CNS involvement Without CNS involvment
Autoimmune autonomic ganglionopathies
Paraneoplastic disorders Primary autonomic failure
Toxic neuropathies …
Isolated autonomous nervous system alteration
Orthostatic hypotension
Epidemiology
Pathophysiology
Etiologies
Treatment
Diagnosis
Traitement de l’hypotension orthostatique
Non pharmacological treatment
Remove drugs when feasible
Avoid caffeine
Avoid alcohol
Rehydration (water and salt intake)
Exercise (avoid bed rest and physical deconditionning)
Physical counter maneuvers
Avoid heated atmosphere
Sleeping head up
Physical countermaneuvers
Change position gradually
Drink a glass of water
Leg-crossing
Whole body, buttock clenching
Squatting
Contention of legs and abdomen
Isometric contraction
Physical countermaneuvers
Change position gradually
Drink a glass of water
Leg-crossing
Whole body, buttock clenching
Squatting
Contention of legs and abdomen
Isometric contraction EDUCATION OF THE PATIENT
Compression of venous capacitance beds
Okamoto et al - Hypertension- 2016;68:418-426
Compression of venous capacitance beds
Okamoto et al - Hypertension- 2016;68:418-426
Automated inflatable abdominal binder that provides sustained servo-controlled
venous compression (40 mm Hg) and can be activated only on standing
Pharmacological treatment
Orthostatic hypotension Drop of systolic BP > 20 mmHg (30 for hypertensive patients) or diastolic BP > 10 mmHg
Increased heart rate: Non-neurogenic (sympathotonic)
hypotension
Exclude medications
No increase in heart rate : Neurogenic hypotension
Pharmacological treatment: cornerstone
Midodrine (Gutron®)
Fludrocortisone (Flucortac®)
Pressor agent: midodrine
L Tyrosine DOPA
L Dopamine
Norepinephrine Epinephrine
Normetanephrine Metanephrine
Tyrosine
hydroxylase
L DOPA
decarboxylase
Dopamine
hydroxylase
PNMT
COMT COMT
Chromaffin cell
α1 R
α2 R
β1 R
β2 R
β3 R
Adrenergic receptors
Pressor agent: midodrine
Vidal-Petiot et al, MCED 2012
Pressor agent: midodrine
α1 adrenergic receptor agonist
Adverse events: supine hypertension – urine retention
2.5 mg pills – max 15 pills per day
Mineralocorticoid agonist: fludrocortisone
Synthetic mineralocorticoid
Adverse events: supine hypertension – hypokalemia
50 µg pills – 50-300µg per day
Mineralocorticoid agonist: fludrocortisone
K+
ROMK
ENaC Na+
+ - 10-30 mV
3 Na+ 3 Na+
2 K+ 2 K+ MR
Fludro
Pharmacological treatment: droxidopa
Midodrine (Gutron®)
Fludrocortisone (Flucortac®)
Droxidopa (L-DOPS)
Droxidopa: a norepinephrine precursor
hydroxylation
decarboxylation
hydroxylation
Méthylation
AAAD DOPA-decarboxylase
Pharmacokinetics of droxidopa
From Kaufmann et al - Circulation 2003
Effect of droxidopa on standing BP
From Kaufmann et al - Circulation 2003
Mechanisms of action of droxidopa
Kaufmann et al - Expert Rev Cardiovasc Ther. 2015
Droxidopa: metaanalysis of RCTs
2014 - FDA
accelerated
approval
Elgebaly et al – Clin Auton res- 2015
Orthostatic hypotension questionnaire
Elgebaly et al – Clin Auton res- 2015
Change in standing SBP
Elgebaly et al – Clin Auton res- 2015
Other treatments: erythropoeitin
Hoeldtke and Streeten– N Engl J Med- 1993; 329:611-5
autonomic neuropathies anemia
Treatment algorithm
Merci pour votre attention
et merci au Pr Jean-Luc Elghozi
