Pure autonomic failure is a degenerative disorder of the peripheral autonomic nervous system. Patients experience symptomatic hypotension that requires them to sit, squat or lie down to prevent syncope. It is associated with characteristic histopathological findings, resulting in neuronal cytoplasmic inclusions in the peripheral autonomic nerves. These lesions are responsible for defects in the synthesis and release of norepinephrine from sympathetic nerve terminals, resulting in significant hypotension. Patients with autonomic failure also have exaggerated blood pressure responses to common stimuli such as food or fluid intake, heat, exercise and medications. Tilt table (head-up) testing is probably the test most commonly used to establish the diagnosis. However, simple office testing is also useful, such as having the patient stand after lying supine with blood pressure monitoring. Treatment options range from simply increasing fluid and salt intake, and using compressive garments, to medications administered orally, subcutaneously or intravenously in more severe cases.
- pure autonomic failure
- blood pressure
- supine hypertension
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A 54-year-old male firefighter gave a 2-year history of progressive loss of energy, intermittent lightheadedness and erratic blood pressure readings. Over the previous 4 months, he also experienced postural headaches with standing. He had been previously well and used alcohol only occasionally. Bedside testing identified a precipitous drop in blood pressure from 138/90 mm Hg to 90/64 mm Hg within 74 s after assuming the standing position, with minimal change in his heart rate. On examination, his strength, reflexes and sensation were normal. Laboratory evaluations, including haemoglobin A1c, full blood count, comprehensive metabolic panel, HIV, ELISA test for Lyme disease, serum protein electrophoresis, erythrocyte sedimentation rate and paraneoplastic panel, were normal or negative. During tilt table testing, in the supine position, his blood pressure was 130/80 mm Hg and his heart rate was 70 beats per minute. After positioning to 60° head-up tilt, he became nauseated and near syncopal. Despite his blood pressure dropping to 88/60 mm Hg, his heart rate remained at an average of 70 beats per minute (figure 2). We diagnosed pure autonomic failure.
A 44-year-old male grade school teacher with primary autonomic failure began treatment with an abdominal binder, 3 L of fluid intake per day and 2 g of salt three times a day. Because his orthostatic symptoms only minimally improved, he was started on fludrocortisone 0.2 mg twice daily. He subsequently gained 7 kg and adherence to fludrocortisone became an issue. Over the next 18 months, his symptoms progressed until he was forced to resign from his job. At that point, he began midodrine 2.5 mg in the morning, subsequently titrated to 10 mg three times a day. He reported a slight increase in his ability to sit but remained unable to stand for longer than 1 min. His mean arterial pressure sitting never exceeded 86 mm Hg. He was referred to a dysautonomia clinic, where he was started on droxidopa (a prodrug, converted to norepinephrine). On last phone conversation, he reported feeling much improved.
Pure autonomic failure
Pure autonomic failure is a degenerative disorder of the peripheral autonomic nervous system. It is characterised by lesions of the peripheral autonomic nervous system, with deficient norepinephrine synthesis and release from sympathetic nerve terminals.1 This results in symptomatic orthostatic hypotension and resultant cerebral hypoperfusion. This loss of adequate cerebral perfusion results from poor arterial resistance, loss of compensatory increase in heart rate and excessive venous pooling when moving from the supine to upright position. These pathological changes culminate in patients having to sit, squat or lie down to prevent frank syncope from occurring within seconds of standing.1–4
It is usually slowly progressive with an insidious onset that presents in midlife, although it can affect younger people.2 5 Occasionally it progresses to a devastating state acutely leaving patients restricted to their home in a reclined state.5
The cause is not known. It is slightly more common in men. Symptoms are worse in the morning and in hot weather. There are no associated cognitive, sensory or motor deficits, but patients frequently report urinary and sexual dysfunction, including excessive nocturia and erectile dysfunction. Patients may also experience an inability to sweat, dry mouth, diarrhoea or constipation.2–4
Pure autonomic failure is a neurodegenerative disease classified as an alpha-synucleinopathy. The characteristic histopathological finding is of insoluble deposits of the protein alpha-synuclein, resulting in neuronal cytoplasmic inclusions called Lewy bodies. These pathological changes occur in the peripheral autonomic nerves, with the largest concentrations of Lewy bodies found in the sympathetic and parasympathetic ganglia and preganglionic and postganglionic autonomic neurones.1 4 6 7 These lesions are responsible for insufficiencies in the synthesis and release of norepinephrine from sympathetic nerve terminals.2
Other diseases in this group of synucleinopathies include Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy.2 6 Patients with multiple system atrophy have similar autonomic impairment to those with pure autonomic failure, but a key diagnostic predictor is that patients with multiple system atrophy have central nervous system involvement leading to movement disorders, including tremor, rigidity and bradykinesia.2 4 In patients with multiple system atrophy, the resultant postural hypotension is secondary to impairment of the central autonomic cardiovascular pathways, but they have intact peripheral postganglionic noradrenergic fibres. In contrast, patients with pure autonomic failure and Parkinson’s disease have intact central pathways but have lesions in the sympathetic nerve tracts of the spinal cord and postganglionic noradrenergic neurones.2
Differential diagnosis of autonomic failure
Pure autonomic failure
Multiple system atrophy
Parkinson’s disease with orthostatic hypotension
Dementia with Lewy bodies
Acute or subacute autonomic neuropathy
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
Systemic lupus erythematosus
Paraneoplastic autonomic neuropathy
Type 1 antineuronal antibodies (ANNA-1 and anti Hu) associated with small cell lung cancer
Neuromuscular junction disorders
Lambert–Eaton myasthenic syndrome
Calcium channel blockers
Phosphodiesterase type 5 inhibitors
Dopamine B hydroxylase deficiency
Blood pressure control
An intact nervous system is critical to controlling adequate blood pressure. Simply stated, when there is loss of adequate blood pressure, the baroreceptors send signals to the central nervous system that result in activation of the sympathetic nervous system and reciprocal inhibition of the parasympathetic nervous system, leading to decreased activity of the baro-afferent pathway. This sympathetic activation stimulates the circulatory system, resulting in immediate arteriole and venous vasoconstriction and cardioacceleration. At the same time there is activation of the renin–angiotensin–aldosterone and arginine–vasopressin systems to help retain body fluids.2 All of these pathways result in a small reduction of systolic blood pressure (5–10 mm Hg), a small increase in diastolic pressure (5–10 mm Hg) and an increase in the heart rate (10–25 beats per minute).7
Classically orthostatic hypotension is defined as a decrease in the systolic blood pressure of 20 mm Hg and/or a decrease in the diastolic pressure of 10 mm Hg within 3 min of standing.4 Initially adjustments to orthostatic stress are mediated exclusively by neural pathways of the autonomic nervous system; however, with prolonged orthostatic stress such as with standing, additional adjustments are mediated by the humoral limb of the autonomic nervous system.3 The baroreflex is essential for short-term regulation of low blood pressure.4 Information from the baroreceptors is relayed to the central nervous system where neuronal cell groups regulate cardiovascular activity through sympathetic and parasympathetic outflow.9 The main sensory receptors involved in the orthostatic neural reflex adjustment are the arterial mechanoreceptors (baroreceptors) of the carotid sinuses and aortic arch, and the mechanoreceptors located in the heart and lungs (cardiopulmonary receptors). The carotid sinus receptors are the most influential in preventing hypotension, with the cardiopulmonary receptors possessing a minor role in the initial reflex adjustment.3 Note that in pure autonomic failure, this buffering system is not just impaired but is lost, and so blood pressure changes result from minute stressors that a healthy individual would not experience.
Orthostatic stress in pure autonomic failure
When people assume an upright posture, there is a resultant pooling of 500–1000 mL of blood in the lower extremities and splanchnic circulation.7 The bulk of the pooling occurs in 10 s and the total transfer occurs within 3–5 min.2 3 Of the pooled blood, 80% is contained in the upper thigh and buttocks and significantly less in the abdomen, pelvis, calves and feet. This pooling initiates a rapid decrease in venous return to the heart, with an associated decrease in right atrial pressure from 5 to 6 mm Hg supine to 0 mm Hg.3 This decreased end-diastolic pressure of the right ventricle results in a 20% fall in cardiac output.3
In pure autonomic failure, the neural systems are not functioning properly as there is no stimulation of the sympathetic nervous system, and the postganglionic sympathetic neurones do not release norepinephrine appropriately.4 The decreased norepinephrine release results in impaired vasoconstriction and reduced intrathoracic vascular volume, both of which contribute to orthostatic hypotension. Also, as hypotension persists, there is the loss of an appropriate reflex-induced increase in heart rate. This loss of compensatory increased heart rate is a useful clinical clue to the presence of pure autonomic failure. However an intact compensatory increase in heart rate during orthostatic stress does not completely exclude autonomic failure.
Unique responses in pure autonomic failure
Patients with pure autonomic failure have exaggerated responses to common stimuli such as food or fluid intake, environmental heat, exercise and medications that result in dramatic changes in blood pressure. Patients may experience blood pressure drops of 50–70 mm Hg secondary to the release of vasodilatory gastrointestinal peptides that result in blood pooling in the splanchnic system.2 The resulting hypotension occurs 30 min after eating, lasting as long as 2 hours.4 This is especially true when consuming meals with large carbohydrate content. Medications that decrease carbohydrate absorption, such as acarbose, can be used to prevent hypotension with meals.10
It is interesting that the reverse situation occurs with drinking fluids. Water ingestion causes a potent pressor effect, with patients experiencing increased blood pressure readings as much as 40 mm Hg within 5 min of ingesting as little as 16 oz of water.2 4 This physiological change can be used to assist patients with pure autonomic failure before assuming the upright position.4
Normally with exercise there is an increase in heart rate, blood pressure and plasma norepinephrine concentrations. In patients with pure autonomic failure, these compensatory changes do not occur, resulting in profound hypotension. In addition, with exercise there is an increase in ventilatory rate and volume that results in decreased carbon dioxide levels. The resultant vasodilation only exacerbates the hypotension that these patients experience with exertion.
Patients with pure autonomic failure also show substantial adrenergic sensitivity, and clinicians should be cautious when exposing these hypotensive patients to pressor agents. For example, low doses of phenylpropanolamine may increase systolic blood pressor as high as 50–70 mm Hg.1 4
Interestingly, when patients with pure autonomic failure assume a supine position, they often show blood pressure readings consistent with hypertension.2 4 This may be attributed to a resultant increased vascular resistance from loss of adequate baroreceptor reflex buffering, or increased adrenergic receptor hypersensitivity and vasopressin release.2
A study by Biaggioni et al gave examples of supine hypertension in patients with autonomic failure by performing 24-hour blood pressure monitoring where hypertensive readings were noted during both sleep and daytime naps with pressures as high as 228/140 mm Hg.4 10 These elevated pressures may also result in a pressure natriuresis with resultant volume depletion and worsening of morning hypotension. For example, urinary excretion during the night was 1200±130 mL as compared with 670±80 mL during the day. In addition, patients with pure autonomic failure showed a twofold increase in sodium excretion at night as compared with the day.4
Unfortunately, the long-term consequences of supine hypertension in patients with pure autonomic failure have been associated with the development of left ventricular hypertrophy and atherosclerosis. A study by Milazzo et al 11 comparing the consequences of essential hypertension and pure autonomic failure found similar cardiac pathology in both groups. The study compared target organ damage and cardiovascular morbidity and mortality in patients with similar 24-hour mean blood pressure values. The conclusion was that both groups developed an increase in left ventricular mass index independent of blood pressure variability, once believed to be the most important factor in developing organ damage. Since most patients with pure autonomic failure do have a good prognosis, the treatment of supine hypertension should be considered, thus avoiding the deleterious effects of hypertension. The study also shows the importance of 24-hour blood pressure monitoring in patients with pure autonomic failure.2 4 10 11
A study by Biaggioni and Robertson4 comparing placebo versus transdermal nitroglycerin 0.05–0.2 mg versus oral nifedipine 30 mg reviewed the effect on controlling supine hypertension at night and morning hypotension. The medications were each given at 20:00 and the patients were instructed to remain supine until 08:00. Of note, the nitroglycerin patch was removed at 06:00. The maximal decrease in systolic blood pressure with the nitroglycerin patch was 36±10 mm Hg and 37±9 mm Hg with nifedipine. Both were recorded 4 hours after taking or applying the medication. The medications were then compared at 08:00 the following morning, at which time the patients were asked to stand. The systolic blood pressure readings of the nitroglycerin group were 88±8 and 79±7 in the placebo group. The systolic blood pressure in the nifedipine group was 77±3 mm Hg compared with 91±12 mm Hg in the placebo group, but 3 out of the 10 patients in the nifedipine group could not stand owing to orthostatic symptoms. This study shows the importance of selecting a medication with the correct effect profile that prevents supine hypertension at night but avoiding ‘pharmacologic tilt’ in the morning.
Patients should be counselled to avoid lying completely supine if resting during the day and to elevate the head of their bed 6–9 inches at night to avoid being in a supine position for an extended period of time.4 In addition, if prescribed compressive stockings or abdominal binders (detailed below), they should be removed during supine positioning.
Diagnosis of pure autonomic failure
Thus many diseases and conditions can lead to hypotension when assuming the upright position, including Parkinson’s disease, multiple system atrophy, dehydration and medications.4 It is very important to review the patient’s medication in detail as orthostatic hypotension is relatively common.2 4
A simple evaluation in the clinic is to ask patients to lie supine for 30 min then asking them to stand. Almost all patients with pure autonomic failure will quickly experience symptoms of hypotension. If patients can remain standing, monitoring their blood pressure and pulse rate will aid in making a diagnosis. In patients with pure autonomic failure, a blood pressure fall of 50 mm Hg or more, with no change in pulse rate, is very common.4 However, the diagnosis should not be excluded based on a single reading.4 Twenty-four-hour blood pressure monitoring is recommended in patients being evaluated for pure autonomic failure to assess for possible patterns with positions, eating or drinking.
Hyperventilation testing, where the patient performs rapid breathing for 30 s, may also help in diagnosing pure autonomic failure. Hyperventilation significantly decreases blood pressure, as the vasodilation caused by the hypocapnea is normally counteracted by the sympathetically mediated reflex vasoconstriction.2
Tilt table head-up testing is probably the most common test used to diagnose pure autonomic failure (figures 1 and 2). The patient lies supine for 5 min and then the head end of the table is elevated to an angle of 60° for 3 min. If the patient’s systolic blood pressure falls by 20 mm Hg or if the diastolic pressure falls by more than 10 mm Hg, the test is considered positive.7 In many centres, there is associated continuous blood pressure and ECG monitoring throughout the test.
Low plasma norepinephrine concentrations are a useful diagnostic modality for patients with suspected pure autonomic failure. A study by Shannnon et al in 1997 showed that patients with pure autonomic failure (n=54) had plasma norepinephrine concentrations of 0.54±0.05 nmol/L supine and 0.84±0.09 nmol/L upright, whereas the values in normal controls (n=18) were 1.29±0.15 nmol/L supine and 2.84±0.23 nmol/L upright.2 4
The goal of treatment in patients with pure autonomic failure is not solely to monitor and act on blood pressure readings but to assist them in living safely and as active as possible. Its treatment requires a detailed history, medication and lifestyle review. Aspects such as fluid and electrolyte balance are especially important. Many of these patients also have other comorbid conditions, and stopping certain medications that may be associated with orthostatic hypotension can be more detrimental to their lifestyle. For example, a medication that is controlling their Parkinson’s disease may prove more helpful to patients than stopping it, even though it may be causing some hypotension. This scenario may require the need to adjust the dose and monitor for an effective balance of both diseases.10
All patients with pure autonomic failure and their families should have a home blood pressure monitor with thorough instructions on its use. Patients should be counselled on basic concepts such as rising slowing and performing isometric exercises before standing. Clinicians should advise on simple modalities such as contraction of muscle groups of the lower extremities and buttocks. Treatment options depend on multiple factors, such as comorbidities and even the time of the day. It is paramount that patients understand that when hypotension does occur they should not try to overcome it, but should sit, lower themselves onto all fours or assume a lying position if needed.10
Most patients should try non-pharmacological interventions initially. Basic principles include avoiding rapid changes in position, hot environments, ensuring proper hydration and avoiding large meals at one sitting, especially those that contain a high carbohydrate load.
Patients should be advised to increase their fluid and salt intake. The general recommendation is to consume salt packets containing 500 mg or 8.5 mEq of sodium chloride with eight 12 oz glasses of water per day (3 L).10 A baseline 24-hour urine study is recommended as you would expect to see a urine output of 2 L and a urinary sodium of greater than 170 mEq with treatment.9 Sodium and fluid intake can be adjusted by monitoring response and also supine blood pressure readings. Patients should be reminded that foods rich in carbohydrates will lower blood pressure, and fluids will increase blood pressure. Trials of caffeinated beverages before standing are an additional treatment option.10
External devices and counter-manoeuvres
Non-pharmacological devices and manoeuvres to treat or prevent hypotension should be considered early in the treatment phase. In addition to measures to expand extracellular volume, it is important to try to reduce the vascular volume space where pooling may occur. This includes physical counter-manoeuvres and external support garments that the patients apply themselves.3
Air-pressurised suits initially used in military aviation are very effective to reduce hypotension but are very cumbersome and expensive. Elastic garments such as compression stockings that apply 40–60 mm Hg on the ankles, and 30–40 mm Hg at the level of the hip, and abdominal binders that apply 20–40 mm Hg have since replaced the pressurised suits and are effective, easy to apply and are aesthetically more acceptable.10 12 These garments are aimed at reducing the pooling of blood in the extremities, pelvis and splanchnic circulation. Although these garments are very effective, some elderly patients or those with arthritic conditions often find the use of compressive stockings too difficult. In this situation compressive abdominal binders are effective and much easier to use.10 Abdominal binders target the splanchnic vascular bed, which is composed of a large compliant venous circulation, which may contain as much as 25% of blood volume at rest.3
Most patients with pure autonomic failure find that immobility worsens their symptoms, whereas bending forward or moving improves their symptoms.3 These patients should be educated with simple diagrams to understand the concept that when walking, lower limb muscle contraction squeezes venous blood upward towards the heart.
For patients who cannot walk, this effect can be duplicated by simply performing isometric or dynamic muscle contractions.3 Examples include activities as simple as leg crossing, which contracts both the agonist and antagonist muscle groups of the lower limbs; this can increase systolic blood pressure by as much as 20 mm Hg. Larger increases can result from adding contraction of the calves, thighs and buttocks.3
There are numerous classes of medications used in the treatment of pure autonomic failure (table 1), each with unique properties that may affect each patient differently. One of the great difficulties in selecting a medication is that it must prevent daytime hypotension without resulting in supine hypertension at night.
Fludrocortisone, although not approved for this indication by the Food and Drug Administration (FDA), increases volume by stimulating sodium retention in the kidneys, along with probable vasoconstriction by sensitisation of blood vessels to catecholamines.2 10 In a small study of eight patients, the combination of head-up tilt and fludrocortisone 0.1–0.2 mg increased standing time from 3 min to 10 min and increased standing systolic blood pressure from 83 to 113 mm Hg.7 It is important to monitor for congestive heart failure, hypokalaemia, supine hypertension and oedema when using fludrocortisone.7 10 Additionally, clinicians must be aware that the onset of action of fludrocortisone can be delayed as long as 2 weeks after initiation.
Midodrine is FDA-approved for the treatment of pure autonomic failure, although due to lack of postapproval effectiveness, its continued approval is under review.7 It is a peripheral selective alpha-1-adrenergic agonist that increases systolic blood pressure.7 The last dose should be taken before 18:00 to avoid possible supine hypertension effects.7 The dose can also be adjusted depending on planned activities of the day, which is probably more effective than regular use as this may avoid associated tachyphylaxis.10 Clinicians should strictly monitor the effects of this medication in patients with coronary disease, peripheral vascular disease, thyrotoxicosis, acute renal failure and men who may develop urinary outlet obstruction.7 10
Pyridostigmine is a cholinesterase inhibitor that enhances ganglionic transmission in the sympathetic baroreflex pathway and improves sympathetic tone during standing.7 10 The greatest effect is on improving diastolic blood pressure without worsening supine hypertension. Pyridostigmine can be combined with midodrine.7 13 However, a study by Singer et al 13 comparing standing blood pressure in patients receiving 60 mg pyridostigmine alone with 60 mg pyridostigmine with 5.0 mg midodrine showed a similar effect in blood pressure reduction, compared with placebo.
Droxidopa is an artificial amino acid converted both peripherally and centrally into norepinephrine. The increase in norepinephrine occurs, even though the postganglionic sympathetic neurones are not intact.14 It became commercially available in the USA in 2014. Droxidopa did yield statistically significant improvement as assessed by patient-reported outcome scores on the Orthostatic Hypotension Questionnaire and by an increase in their standing blood pressure.14 The last dose should be taken a minimum of 3 hours before bedtime to avoid supine hypertension.14
Octreotide stimulates somatostatin receptors that reduce vasodilatory gastrointestinal peptides after subcutaneous administration. The medication is best used to prevent postprandial hypotension. Although it is effective when used alone, the decrease in postprandial blood pressure is significant when combined with 5–10 mg of midodrine.2 10 15 A study by Hoeldtke et al 15 compared the effect of preprandial midodrine, the combination of midodrine with octreotide and octreotide alone. The postprandial sitting blood pressure in the midodrine arm was 69±4 mm Hg, placebo was 63±5, midodrine and octreotide combined sitting blood pressure was 115±9 mm Hg and the octreotide only arm was 102±7 mm Hg.
Yohimbine is an indole alkaloid and acts as an alpha-2-adrenoreceptor antagonist. It increases sympathetic outflow centrally and enhances the release of norepinephrine from adrenergic nerve terminals peripherally.2 16 Patients treated with 5 mg yohimbine orally elevated their mean systolic blood pressure from 136±5 to 169±8 mm Hg and their mean diastolic blood pressure from 77±3 to 93±5 mm Hg. The heart rate increased from 68±4 to 78±6 in the seated position. In addition, plasma norepinephrine concentrations increased from 104±25 to 196±64 pg/mL.16
Desmopressin is a synthetic vasopressin analogue. Nocturnal polyuria is a common symptom of pure autonomic failure that is significant enough to result in weight loss and hypotension on awakening.2 10 17 A study by Mathias et al 17 showed that patients treated with 2–4 μg intramuscular desmopressin at 20:00 had a pronounced reduction in nocturnal polyuria from 867 mL to 498 mL and diminished overnight weight loss from 71 kg to 72.6 kg. In addition there was an increase in early morning sitting blood pressure from 101 mm Hg to 116 mm Hg.17 Clinicians should monitor for side effects such as hyponatraemia.2 10 17
Ambulatory norepinephrine infusions are an alternative treatment for patients who are refractory to conventional treatments. Patients should be trained in an inpatient setting to develop skills and understanding of the physiology of the infusion along with the ability to adjust the infusion rate when moving from supine to sitting, to standing positions.5 18 Each patient requires an individual dosing schedule. Presently the administration of norepinephrine does require the patient to have a permanent subclavian catheter placed that is connected to a portable pump.
Other medications used in the treatment of pure autonomic failure include erythropoietin and acarbose. Erythropoietin increases red blood mass and intravascular volume with resultant increase in venous return and blood pressure, and acarbose shows promise in preventing postprandial hypotension.2 10
Survival rates in patients with pure autonomic failure have been difficult to determine as there have been few studies due to limited literature. Recent data from a longitudinal study conducted at the National Institutes of Health, running from 1994 through 2014, used clinical consensus definitions of pure autonomic failure and assessments of catecholaminergic innervation by pharmacological, neurochemical or neuroimaging tests. The study measured clinical laboratory evidence of the loss of sympathetic noradrenergic innervation by noting low myocardial ‘F’-dopamine-derived radioactivity or low levels of 3,4-dihydroxyphenylglycol or both. The findings concluded that of the different synucleinopathies, survival rates for patients with pure autonomic failure are good, with a median survival rate of 12.48 years.6
Pure autonomic failure is a degenerative disorder that results in symptomatic hypotension. It is associated with pathological changes of the autonomic nervous system. Many patients also develop supine hypertension resulting in end organ damage. The condition may leave patients confined to their homes in a reclined position. There are numerous treatment options, ranging from increasing salt and water intake to norepinephrine infusions. The treatment options should be specifically tailored to each individual patient.
Pure autonomic failure is a devastating disease that may result in a patient being forced to live in a semireclined state.
The disease is a progressive degenerative disorder of the autonomic nervous system.
The diagnosis can be made with in-office procedures.
There are multiple treatment options that can be used either as a single agent or in combination.
The author would like to thank Risa Wolf, MD, and Diana Barratt, MD, for their assistance and guidance.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Gordon Ingle, London, UK.