In 1999, the 4th edition of the textbook Autonomic failure was published, edited by Sir Roger Bannister—recipient of a lifetime achievement award for his work on autonomic disorders—and Christopher Mathias, Professor of Neurovascular Medicine and director of the two largest clinical autonomic units in the country (Mathias and Bannister, 1999). At more than 500 pages long, the book covers everything from neurobiology of the autonomic nervous system to its pathophysiology and clinical assessment, with 20 new chapters being added since the 1992 edition.
Orthostatic hypotension is described in the book as an often-cardinal feature of autonomic failure, and so reference is made throughout the book to the condition, with the reader learning about its manifestation, investigation and prevention.
Almost 20 years later, the American College of Cardiology, alongside authors from Harvard Medical School, Standford Medical Centre, Saudi Arabia and Texas, published a ‘state-of-the-art review’ into orthostatic hypotension (Freeman et al, 2018). Many of the concepts remain the same, and this article will draw together both texts, alongside other references, to form an overview of the highly prevalent and disabling condition that is orthostatic hypotension.
Normotension
‘The prime concern of the cardiovascular system is tissue perfusion, with blood pressure and blood flow therefore being of critical importance. These are influenced by a number of factors, with beat-to-beat control of blood pressure dependent upon the autonomic nervous system and, in particular, the sympathetic efferent pathways’ (Mathias and Bannister, 1999).
The vital role of the baroreflex in short-term blood pressure control is described in both texts, with Freeman et al (2018) describing the ‘unloading’ of the arterial baroreceptors during low blood pressure. The resulting reduction in afferent impulses to the nucleus of the tractus solitarius triggers an increase in sympathetic outflow to the heart and blood vessels, as well as a decrease in vagal outflow, and blood pressure is restored. Mathias and Bannister (1999) emphasise the existence of other afferents distinct from the baroreceptors, including those from skeletal muscle, skin and viscera. Their stimulation may induce autonomic dysreflexia (acute episodes of uncontrolled hypertension) in patients with cervical or high thoracic spinal cord transection (Solinsky et al, 2018).
Secondary mechanisms, including systemically acting hormones such as angiotensin II and aldosterone, and locally-acting substances such as prostaglandins, nitric oxide and endothelin are also described, with the ‘renal-body-fluid system’ playing an important role in slow, long-term blood pressure control (Mathias and Bannister, 1999).
Hypotension
‘Neurogenic orthostatic hypotension is due to degeneration of central and/or peripheral autonomic pathways that leads to inadequate release of noradrenaline from sympathetic neurons, and consequent failure to maintain adequate peripheral vascular resistance in response to a postural challenge’.
In both texts, the condition is defined as a fall of more than 20mmHg systolic blood pressure or 10 mmHg diastolic blood pressure within 3 minutes of standing or head-up tilt.
Freeman et al (2018) describe other variants of orthostatic hypotension including delayed (where the reduction in blood pressure occurs after 3 minutes of standing or upright tilt) and initial (where the systolic blood pressure falls by more than 40 mmHg, or the diastolic by more than 20 mmHg, within 15 seconds of standing).
Impairment of baroreflex-mediated vasoconstriction of the skeletal muscle and splanchnic circulation is the primary cause of neurogenic orthostatic hypotension: one half to one litre of thoracic blood is transferred to the regions below the diaphragm during standing with the bulk of venous pooling occurring within the first 10 seconds (Smit et al, 1999) and, in orthostatic hypotension, the inability to raise peripheral vascular resistance allows for considerable venous pooling. Impaired inotropic and chronotropic cardiac responses may play a minor role in the development of orthostatic hypotension, but it has been shown that patients with cardiac transplants do not develop it, despite not being able to increase heart rate in the upright posture (Smit et al, 1999).
During prolonged standing, the neurohumoral system reinforces the action of the cardiovascular reflexes through additional constriction of blood vessels and minimisation of the loss of body water. In autonomic failure, renin release and aldosterone secretion may be reduced (Mathias and Bannister, 1999).
Non-neurogenic orthostatic hypotension can also occur, and is caused not by impairment in the baroreflex, but by volume depletion (through dehydration and blood loss) or by vasodilators and diuretic agents (Lowry et al, 2016).
Manifestation
‘The increasing availability of home blood pressure monitors should, in general, be discouraged, as unfortunately there are many patients shackled to monitors that inadvisedly have been recommended; these are not even a poor second to the patient's symptoms!’.
Patient symptoms and the ability to function independently are more important than blood pressure readings in orthostatic hypotension, though measurements are crucial to diagnosis and to the evaluation of therapy. Some patients can tolerate a standing blood pressure as low as 70 mmHg without dizziness or syncope, presumably because of improved cerebral autoregulation—a homeostatic process that regulates and maintains cerebral blood flow across a range of blood pressures (Armstead, 2016). Preservation of autoregulation in orthostatic hypotension may be due to changes in vessel innervation occurring as a result of prolonged exposure to lower-than-normal arterial pressures. Hormones that influence blood vessels, intravascular volume and the kidneys may also help to buffer the impairment of cardiovascular reflex activity (Mathias and Bannister, 1999).
Impaired perfusion of various organs in orthostatic hypotension can result in dizziness, syncope, fatigue, visual blurring, confusion, neck and shoulder pain, chest pain and shortness of breath. Symptoms are often worse in the early morning, probably because of recumbency-induced diuresis (Freeman et al, 2018).
Investigation
Blood pressure measurements—whether through the use of automated machines, through intra-arterial (radial or brachial) catheterisation, or via a non-invasive technique that measures finger arterial blood pressure (Finapres, 2012)—are essential in the diagnosis of orthostatic hypotension, being used during the head-up postural challenge and during the Valsalva manoeuvre (Mathias and Bannister, 1999).
In both cases, basal blood pressure measurements are important and, in the supine position (before head-up tilt or standing), recumbent hypertension resulting from impairment of the baroreflex may be observed in the patient with autonomic failure. Postural change is induced by tilt table or by asking the subject to stand; the Valsalva manoeuvre (in which intrathoracic pressure is raised) can be achieved by asking the patient to blow with an open glottis into a syringe connected to the mercury column of a sphygmomanometer. In patients with a normal baroreflex, postural change results in a minimal change in blood pressure; in neurogenic orthostatic hypotension, blood pressure is seen to fall because of a lack of sympathetic vasoconstriction. In neurogenic orthostatic hypotension, the response to the Valsalva manoeuvre lacks the expected blood pressure overshoot or compensatory bradycardia (Kim et al, 2016).
Reduced plasma noradrenaline and aldosterone levels, and plasma renin activity, can indicate autonomic failure; evaluating the blood pressure response to food ingestion and exercise is also important, since postprandial hypotension and exercise-induced hypotension commonly co-exist with orthostatic hypotension (Mathias and Bannister, 1999).
Prevention
‘Education is the cornerstone of the management of neurogenic orthostatic hypotension’.
Being aware that rapid positional change, a warm environment (leading to cutaneous vasodilatation), food and alcohol ingestion (resulting in splanchnic vasodilatation), exercise (and subsequent skeletal muscle vasodilatation) and micturition and defaecation (triggering a Valsalva manoeuvre), may precipitate orthostatic hypotension can result in lifestyle changes (such as eating smaller meals) and in extra care being taken to reduce risk of harm.
In their book, Mathias and Bannister (1999) describe several ‘physical countermeasures’ to raise blood pressure by increasing vascular resistance or venous return. Crossing the legs while standing, abdominal compression, bending forward, placing one foot on a chair and stooping as if to tie shoe laces and pumping leg muscles are all suggested. Using the head-up tilt at night in order to reduce renal arterial pressure and promote renin release and consequent angiotensin II formation (leading to increased blood volume) may help combat orthostatic hypotension, but benefits may be lost after sleeping flat for a night (Mathias and Bannister, 1999).
Blood volume can also be increased by eating high-sodium foods or salt tablets and by increasing fluid intake: Freeman et al (2018) recommend at least 3g of sodium per day and 2–2.5 litres/day of fluid, although cardiac history must be taken into account.
Review of hypotensive medications may be helpful; commencement of antihypotensives may aggravate recumbent hypertension—a problem not easily solved by co-administration of nocturnal anti-hypertensives since they may increase the risk of falls for patients with nocturia (Mathias and Bannister, 1999).
When symptoms demand pharmacological measures, fludrocortisone is known to augment the action of noradrenaline and, at higher doses, to expand blood volume. Side effects include supine hypertension, hypokalaemia and oedema. Repletion of central blood volume can also be achieved by desmopressin; other sympathomimetic agents include midodrine, droxidopa and pyridostigmine (Freeman et al, 2018).
Evaluation
Orthostatic hypotension can be incapacitating, and can indicate autonomic failure, affecting many different parts of the body, including the heart, kidneys, pancreas, bladder, gut and the pupils. Prevalence of orthostatic hypotension in the inpatient setting can be as high as 64%, and it is common in people with diabetes, with up to 30% of people affected through diabetic autonomic neuropathy (Gaspar et al, 2016).
Orthostatic hypotension can also be associated with Parkinsonism, multiple system atrophy and dementia with Lewy bodies. In one study, 6204 healthy older people (mean age 68.5 years) were assessed for orthostatic hypotension and subsequent dementia. Having orthostatic hypotension at the start of the study increased the likelihood of dementia over the next 25 years by 15% (Mayor, 2016). That orthostatic hypotension is causative in dementia is not yet clear: the observed association may instead be due to shared cardiovascular risk factors such as diabetes, smoking and hypertension (Young, 2018). However, in Parkinson's, multiple-system atrophy and dementia with Lewy bodies, there is known intracellular deposition and aggregation of the protein alpha-synuclein within the nervous system, which may contribute to autonomic failure (Freeman et al, 2018).
The cardiovascular burden of orthostatic hypotension should not be underestimated. Supine hypertension is a frequent concomitant feature; it may impair renal function and lead to left ventricular hypertrophy and diastolic dysfunction. In one meta-analysis of 13 prospective studies (121913 patients), orthostatic hypotension increased all cause mortality at 5-year follow-up by 1.5 times, and incident coronary heart disease, stroke and heart failure were also more likely (Ricci et al, 2015). Increased falls risk with resulting fractures and head injury surely also underlie much morbidity and mortality in those with orthostatic hypotension. An estimated 646 000 individuals die from falls globally each year, while approximately 37.3 million falls are severe enough to require medical attention (World Health Organization, 2018). Having orthostatic hypotension can increase risk of recurrent falls by 2.5 times (Ooi et al, 2000).