Drugs Aging DOI 10.1007/s40266-015-0263-z

REVIEW ARTICLE

Current Pharmacological Management of Hypotensive Syndromes in the Elderly Kannayiram Alagiakrishnan1,2

 Springer International Publishing Switzerland 2015

Abstract Hypotensive syndromes are common among older adults. Symptomatic drop in blood pressure with standing, eating and head turning is very common in older adults. These conditions cause significant morbidity like dizziness, syncope and falls as well as a resultant decrease in function. Blood pressure dysregulation due to autonomic function abnormalities plays a role in causing these conditions. Non-pharmacological measures should be the first line of management, but it is not always sufficient for subjects with symptomatic hypotensive syndromes. Different medication groups have been shown to be useful. This article focuses mainly on the medication management of these conditions based on efficacy and tolerability evidence in the literature. Standard medication management recommendations based on evidence are lacking for many medications used in treating these hypotensive syndromes.

Key Points Quality of outcome measures should be better studied in clinical trials related to hypotensive syndromes. Long-term follow-up medication studies are needed in older hypotensive adults.

& Kannayiram Alagiakrishnan [email protected] 1

Division of Geriatric Medicine, Department of Medicine, University of Alberta, Edmonton, Canada

2

University of Alberta Hospital, B139, Clinical Sciences Building, 8440-112 Street, Edmonton T6G 2G3, Canada

1 Introduction Hypotensive syndromes are low blood pressure conditions seen in the supine or with position changes in older adults. It is defined as lower blood pressure than usual in lying and standing positions, head turning and after meals. The common hypotensive syndromes seen in older adults (65 years and older) are orthostatic hypotension (OH), postprandial hypotension (PPH), hypotension with carotid sinus syndrome (CSS) and vasovagal syncope type 1. Prevalence of these conditions (OH 5–50 %, PPH 38–69 %, CSS 30–40 %) varies with age, different comorbid conditions and different living situations [1–3]. The elderly are prone to these hypotensive syndromes, mainly because of cardiovascular, hemodynamic and autonomic changes seen with aging. Chronic hypotensive syndromes can also be rarely seen with certain endocrine conditions like adrenal failure, hypoaldosteronism (associated with low sodium and high potassium), and carcinoid syndrome (flush with hypotension) in the elderly. In an observational cross-sectional study, where they studied three hypotensive syndromes (OH, PPH and CSS) together, they found that there was no significant association with cardiac autonomic dysfunction when they compared subjects with and without these hypotensive syndromes [4]. These hypotensive episodes often lead to decreased cerebral perfusion, which can cause syncope, dizziness and falls in older adults [5, 6]. In this review, we will focus on the definition of hypotensive syndrome conditions, the common causes of these conditions, the morbidity and mortality associated with them, as well as the medication management. Guidance on pharmacological treatment options based on efficacy and tolerability evidence has been discussed. There are only a few drug studies done exclusively on elderly subjects. Most of the medication studies on hypotensive

K. Alagiakrishnan

syndrome conditions are done in a population consisting of adults and elderly.

a significant risk with cardiovascular mortality (RR 1.20, 95 % CI 0.72–20.00, p = 0.47) [16].

1.1 Search Strategy

2.3 Morbidity

The literature was searched using the electronic databases MEDLINE (1966–August 2014), EMBASE and SCOPUS (1965–August 2014), and DARE (1966–August 2014). The main search items were orthostatic hypotension, postural hypotension, vasovagal syncope, postprandial hypotension, carotid sinus syndrome, medication management and treatment. Articles not in English were excluded from this review.

2.3.1 Cardiovascular Diseases

The acute causes could be due to dehydration, drugs and deconditioning. The chronic causes could be due to nonneurogenic and neurogenic causes. Non-neurogenic causes could be arrhythmias, aortic stenosis, heart failure, varicose veins, adrenal insufficiency and post-dialysis OH. Neurogenic causes could be due to preganglionic condition like multiple system atrophy (MSA) and postganglionic conditions like pure autonomic failure and Parkinson’s disease (PD) [13].

In the Rotterdam prospective community-based study, during a follow-up of 6 years, OH increased the risk of coronary artery disease by 31 % [hazard ratio (HR) 1.31, 95 % CI 1.08–1.57] [17]. A prospective population-based study in elderly persons showed an increased risk of myocardial infarction with OH (HR 2.00, 95 % CI 1.11–5.39) over a period of 3.5 years [18]. In elderly hypertensive subjects, OH may significantly elevate the risk of developing silent cerebrovascular disease [19]. In nursing home residents, orthostatic blood pressure variability predicts an increased risk of stroke (RR 3.7, 95 % CI 1.6–8.4) [20]. In a study on community-dwelling older adults, symptomatic OH was associated with a higher independent risk of newonset heart failure (HR 1.57, 95 % CI 1.16–2.11, p = 0.003), but the association was not significant with asymptomatic OH (HR 1.17, 95 % CI 0.99–1.39, p = 0.069) [21]. OH was a cause of syncope in 24 % of patients who visited the emergency department with this symptom [22]. In this study, 12 % had postprandial hypotension. The prevalence of OH in diabetic older adults was around 28 % [23]. In the longitudinal populationbased Cardiovascular Health Study (CHS) in the elderly, OH was associated with systolic hypertension (OR 1.35, 95 % CI 1.09–1.67), diabetes (OR 1.18, 95 % CI 1.00–1.40) and carotid artery stenosis (OR 1.67, 95 % CI 1.23–2.26) [24]. However, in a recent population-based study over 12 years, OH was not a risk factor for cerebrovascular events, coronary events, heart failure, arrhythmias and syncope, and did not increase the cardiovascular risk at a population level [25].

2.2 Mortality

2.3.2 Non-cardiovascular Diseases

In the Honolulu Heart Program Study on 3522 elderly Japanese men, Masaki et al. [14] found a significant relationship between OH and 4-year all-cause mortality [relative risk (RR) 1.64, 95 % confidence interval (CI) 1.19–2.26], but they did not evaluate cause-specific mortality. Another study on subjects who got discharged from an acute geriatric ward did not show an increased risk for vascular and non-vascular mortality [15]. A recent metaanalysis of cohort studies on middle-aged and elderly subjects showed OH was significantly associated with an increased risk of all-cause mortality (RR -1.40, 95 % CI 1.30–3.68, p \ 0.001) and non-cardiovascular mortality (RR 1.18, 95 % CI 1.00–1.38, p = 0.05), but did not show

OH was more prevalent in different types of dementia [26, 27]. In a study on Chinese elderly, hypotension in general with OH increased the odds of cognitive impairment (OR 4.1, 95 % CI 1.11–15.1) when compared with hypertension with OH [28]. The Irish Longitudinal Study on Aging (TILDA) study reported a significant negative association between OH and global cognitive function (b = 0.21, p = 0.01) [29]. In the study by Mehrabian et al. [30] on elderly subjects, OH was present in 22 % of vascular dementia, 15 % of Alzheimer’s dementia and 12 % of mild cognitive impairment and 4 % in the normal subjects (p \ 0.01). In a longitudinal study of 5 years’ duration in elderly women, OH and low beta activity in

2 Upright Hypotensive Syndrome: Orthostatic Hypotension (OH) OH is a drop in systolic blood pressure of 20 mm of Hg or more or a diastolic blood pressure drop of 10 mmHg or more within 3 min after standing or head-up tilt of 60 on a tilt table [7, 8]. In the community, it is seen in 16 % of older adults [9]; in hospitals, the annual prevalence rate in the USA is 36 per 100,000 adults [10, 11]; and in nursing homes, it is seen in 52 % of subjects [12]. 2.1 Common Causes of OH

Drug Therapy of Hypotensive Syndromes

Electroencephalogram (EEG) are risk factors for cognitive decline [31]. In a study on community elderly individuals, subjects with postural hypotension had poorer scores on neurobehavioral function tests and more advanced leukoaraiosis demonstrated on magnetic resonance imaging (MRI) [32]. OH was seen in newly diagnosed PD patients [33], as well as seen with severe PD [34]. OH was also seen when PD medications like levodopa [35] and dopamine agonists were started [36]. In PD, OH has been shown to be a well-recognized adverse effect of all available dopamine agonists, including bromocriptine, pergolide mesylate, and the newer agents, pramipexole dihydrochloride and ropinirole hydrochloride [37, 38]. Few studies in PD reported that OH caused significant differences in sustained attention and visuospatial memory tasks [39, 40]. Falls were the presenting feature in 64 % of subjects with OH [41]. Ooi et al. [42], in their study on nursing home residents, showed OH was associated with a two-fold increase in subsequent falls. Also, in the community-dwelling elderly, OH has been shown to be associated with increased risk of falls (OR 7.77, 95 % CI 3.98–15.17) [43, 44]. In a recent cross-sectional cohort study, presence of OH was associated with reduced ability to maintain standing balance [45]. 2.4 Medication or Drug Management 2.4.1 Fludrocortisone Fludrocortisone is a mineralocorticoid that retains sodium and causes expansion of plasma volume, but its long-term effects are attributed to sensitization of the vasculature to norepinephrine and angiotensin II [46]. The starting dose is 0.1 mg/day, and it can be titrated up to 0.3–0.6 mg p.o./day. It has a long duration of action, so a single daily dosing is sufficient. Dosage increase increments, if necessary, should be done weekly. A weight gain of 2–3 pounds is expected, and it is due to the effect of the medication. The common side effects are hypokalemia, hypertension and worsening of heart failure. So, older adults should be closely monitored for symptoms and signs of heart failure. Efficacy Studies There are three small randomized controlled trials (RCTs) so far, done for a duration of 1–3 weeks. Only one study by Campbell et al. [47] used fludrocortisone alone, another study compared fludrocortisone versus fludrocortisone and midodrine [48] and a third study compared fludrocortisone versus domperidone [49]. The study by Campbell et al. [47] showed a good response, with a significant reduction in drop in blood pressure, whereas studies by Kaufmann et al. [48] and Schoffer et al. [49] showed variable response, with some improvement in the symptoms and blood pressure drop.

Tolerability Studies A study on octogenarians showed poor tolerability in this group, with a 20 % mortality and a 30 % discontinuation of the medication in 3 months’ time due to side effects like hypertension, heart failure and depression [50]. With enhanced sensitivity of the blood vessels to circulating catecholamines, an increased peripheral vascular resistance and development of supine hypertension may result, and dosage adjustment will be necessary [51]. 2.4.2 Midodrine Midodrine is a short-acting vasoconstrictor drug (alpha-1adrenergic antagonist). It is the only drug approved by the FDA for the treatment of OH [52]. The starting dose is 2.5 mg orally three times daily, and it can be increased up to 10 mg orally three times daily. Midodrine has a short half-life of around 3 h, which necessitates a three-timesdaily regimen. The last dose should be administered at least 4 h before going to sleep. Efficacy Studies In a randomized, double-blind, multicenter study on subjects with neurogenic hypotension, 47 % showed decreased blood pressure drop with midodrine, compared with 28 % of patients taking placebo. The 10-mg dose of midodrine increased systolic blood pressure by a mean of 18 mmHg [53]. Further clinical trials yielded mixed results. In a recent meta-analysis of clinical trials on midodrine, significant improvement in standing blood pressure of 21.5 mmHg (95 % CI 15.11–27.81, p \ 0.001) was seen before and after giving midodrine [54]. Overall, there is limited efficacy for midodrine in the management of OH. Tolerability Studies Midodrine can cause side effects like piloerection, paresthesias, urinary retention, scalp pruritus and chills. Midodrine is contraindicated in patients with severe heart disease such as heart blocks, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis. Supine hypertension is common (25 %) and may be severe. So blood pressure should be monitored [13]. Two studies have done adverse events analysis [48, 55]. Random-effects meta-analysis showed an increased incidence of piloerection (pooled risk ratio) (RR 10.53), scalp parasthesia (RR 8.28), scalp pruritus (RR 6.45), supine hypertension (RR 6.38) and urinary hesitancy/retention (RR 5.85) [54]. Different adverse events resulted in dropping of subjects, 6.8 % in one study [56] and 14 % in another study [53]. Healthcare workers should watch for these adverse effects, when administering Midodrine. 2.4.3 Erythropoietin Erythropoietin increases red cell mass and blood volume. In addition, by mediating the interaction between hemoglobin and vasodilator nitric oxide, it also regulates

K. Alagiakrishnan

vascular tone. So the effect of an increase in blood pressure is due to an increase in red cell mass and central blood volume as well as to the neurohumoral effects on the blood vessel wall [57]. Recombinant human erythropoietin, erythropoietin alpha, is administered subcutaneously or intravenously at doses between 25 and 75 units per kg three times a week until a hematocrit that approaches normal is attained. Lower maintenance doses (approximately 25 units per kg three times a week) may then be used. Iron supplementation is usually required, particularly during the period when the hematocrit is increasing. Efficacy Studies Erythropoietin has been used to treat OH due to autonomic failure associated with decreased red cell mass or anemia. Erythropoietin increases standing blood pressure and improves orthostatic tolerance in patients with OH [58]. In the study by Hoeldtke and Streeten [59], fludrocortisone was used in addition to erythropoietin to treat OH. Erythropoietin therapy appears to help with the symptoms of orthostasis in selected patient populations like those with anemia. None of these studies have been randomized or blinded. Tolerability Studies Supine hypertension may accompany the use of erythropoietin [58, 59]. 2.4.4 Dihydroxy-phenyl Serine (DOPS)/Droxidopa Dihydroxy-phenyl serine (DOPS) is a prodrug that is converted by DOPA decarboxylase to noradrenaline. In the treatment of OH, DOPS is used at a dosage between 100–600 mg t.i.d. [60]. Efficacy Studies Both short-term (4 weeks) [61] and long-term (24–52 weeks) [62] studies showed efficacy in reducing orthostatic blood pressure drop as well as OH symptoms. In neurogenic OH, secondary to MSA, the benefit was also seen, and the maximum benefit was seen with droxidopa 300 mg orally twice a day [63]. In 20 % of patients with PD, symptomatic OH occurs. In neurogenic OH due to PD, several trials have shown evidence for short-term efficacy in reducing drop in blood pressure and improving symptoms. Long-term trials are ongoing [64, 65]. In a recent randomized, placebo-controlled trial, droxidopa improved symptomatic neurogenic OH due to PD, MSA, pure autonomic failure or non-diabetic autonomic neuropathy [66]. In another study, subjects on droxidopa showed a trend for fewer falls [67]. Tolerability Studies No major side effects were reported in the above mentioned studies. Headache, nausea and supine hypertension were seen in some patients. In 2014, FDA approved droxidopa for the treatment of neurogenic OH due to PD, MSA and primary autonomic failure.

2.4.5 Pyridostigmine Pyridostigmine is an acetylcholinesterase inhibitor. It facilitates cholinergic sympathetic neurotransmission at the autonomic ganglia. The recommended dose is 30–90 mg orally two or three times daily. Efficacy Studies In a double-blind, randomized, fourway cross-over study, when pyridostigmine was tested against midodrine and placebo, pyridostigmine improved standing blood pressure without worsening supine blood pressure. The fall in postural blood pressure was less and orthostatic symptoms were decreased in the treatment groups with pyridostigmine alone and in combination with midodrine [68]. Pyridostigmine efficacy is modest and may not be effective in patients with severe autonomic failure. In a single-blind, randomized, cross-over trial of 31 patients with severe autonomic failure, a single dose of 60 mg of pyridostigmine did not increase the standing diastolic blood pressure [69]. Not enough data are available to characterize the consequences of chronic administration of pyridostigmine, so further studies are needed before considering using it clinically over a long time. For initial therapy, it can be combined with midodrine 2.5 or 5 mg orally twice a day in improving orthostatic symptoms without causing supine hypertension [68]. Tolerability Studies Cholinergic side effects like hypersalivation, diarrhea and muscle cramping may be seen [70]. 2.5 Additional Drugs Useful in OH 2.5.1 Octreotide Octreotide is a somatostatin analog that inhibits the release of vasodilatory peptides and produces direct vasoconstriction and increases cardiac output. Two studies have showed that octreotide decreased orthostatic drop in blood pressure in patients with MSA [71, 72]. When combined with midodrine, it was found to be more effective in reducing OH than either drug alone [55]. The dose used is 25–50 lg subcutaneously. Side effects include nausea and abdominal cramps. Therapy with octreotide is expensive and requires frequent subcutaneous injections. 2.5.2 Yohimbine Yohimbine is an alpha-2-adrenoceptor antagonist and has been used in OH due to severe autonomic failure. The dose used is 8 mg p.o. daily [73, 74]. A single-blinded, randomized, placebo-controlled, cross-over trial with yohimbine 5.4 mg improved diastolic blood pressure, and there was no synergistic effect when combined with pyridostigmine [69].

Drug Therapy of Hypotensive Syndromes

2.5.3 Caffeine

Table 1 Drug management of OH with different co-morbid conditions

Caffeine is a methylxanthine and CNS stimulant. It has a pressor effect in patients with autonomic failure [75], may help to improve OH and may be helpful when patients have combined OH and PPH. It can be given as a beverage or as tablets three times a day. The last dose should be given in the evening to avoid disturbance in sleep with caffeine.

OH ? co-morbid condition

Medications

OH ? anemia

Erythropoietin

OH ? renal failure

Erythropoietin, Droxidopa*

Neurogenic OH

Midodrine, pyridostigmine, Droxidopa

OH ? MSA

Octreotide, Droxidopa

OH ? Parkinson’s disease

Droxidopa

MSA multiple system atrophy, OH orthostatic hypotension

2.5.4 Atomoxetine

* Useful in mild to moderate renal failure

Atomoxetine is a nonepinephrine reuptake inhibitor. In patients with autonomic failure, yohimbine and atomoxetine combination increases seated blood pressure and improves standing time and symptoms [76]. In a recent study that compared atomoxetine versus midodrine in the treatment of OH in autonomic failure, atomoxetine showed greater upright systolic blood pressure (7.5 mmHg, 95 % CI 0.6–15, p = 0.03) than midodrine [77].

studied in a RCT [53]. Fludrocortisone has been long used in clinical practice and has been evaluated in open-label trials and three small RCTs [47–49]. Most of the current drug management regimens have not been adequately evaluated in large, randomized clinical trials, and the longterm efficacy of these medications is not known [84]. Most studies did not report the effect of drugs in the magnitude of reduction in postural drop in blood pressure as well as patient symptom improvement. Not all the studies examine the symptoms response and functional ability, and future studies should focus on these areas. The continued effectiveness of these medications should be assessed periodically. See Table 1 for a summary of the drugs used in OH with co-morbid conditions. Goals of pharmacological management should include decreasing symptoms, increasing standing time, and targeting standing blood pressure or decreasing blood pressure drop upon standing. If normal standing blood pressure cannot be achieved for some individuals, then treatment should aim for the standing blood pressure, which could preserve function and quality of life for those individuals [85].

2.5.5 Dihydroergotamine This drug is a direct agonist of alpha-adrenoceptors and causes sympathomimetic vasoconstrictor on venous vessels. It has been found to be useful in severe OH. The dose used was 3–5 mg orally three times a day [78–80]. Ergot alkaloids can cause severe vasospasm, gangrene and convulsions. So long-term use should be avoided. 2.5.6 Metoclopramide This drug is a dopamine antagonist [81] and may be effective in OH, but its side effect profile limits long-term use in these conditions. 2.5.7 Desmopressin As a vasopressin analog, this drug acts on renal tubules and reduces nocturnal polyuria. It can be used at night-time as a spray (5–40 lg daily) or as oral medication (100–800 lg daily) [82]. 2.5.8 Salt Tablets A 1-g tablet of sodium chloride (NaCl) equals 17 mEq of sodium. Dosing usually starts at 1 g twice a day and can be increased as tolerated [83].

3 Supine Hypotensive Syndrome: Postprandial Hypotension (PPH) PPH is a condition in which there is a systolic blood pressure drop of 20 mmHg in supine position within 2 h after eating a meal or a decrease to \90 mmHg when the preprandial blood pressure is C100 mmHg within 2 h of a meal [86–88]. In a study on frail hospitalized older adults, PPH was more commonly seen than postural hypotension [89]. In nursing home subjects, the prevalence of PPH ranges from 24–36 % [90, 91]. 3.1 Causes

2.6 Summary The goal of treatment in OH is to improve symptoms and functional status. Midodrine is the medication that has been

PPH is seen more commonly in individuals with diabetes, hypertension, PD, dialysis and autonomic insufficiency [85].

K. Alagiakrishnan

3.2 Mortality PPH is an independent predictor of all-cause mortality, with an RR of 1.79 (95 % CI 1.19–2.68, p = 0.001) [92]. Studies have shown that both OH and PPH are independent predictors of all-cause mortality in older adults.

established, but long-term efficacy studies in the management of PPH are needed. Tolerability Studies Abdominal distension, diarrhea and increased farting are seen in a few patients. The incidence of gastrointestinal side effects is low in the elderly [106]. 3.4.3 Octreotide

3.3 Morbidity A study showed that half of the older adults with unexplained syncope had PPH [93]. In another study on octogenarians, PPH was significantly higher in the syncope/falls group than in the control group (23 vs. 9 %, p = 0.03) [5, 94–96]. 3.4 Medication or Drug Management 3.4.1 Caffeine Either as tablets or as coffee, caffeine can be used in the management of PPH. The doses evaluated in the studies range from 50 to 250 mg. By its effect on sympathetic system stimulation, it reduces the postprandial drop in blood pressure [97]. Efficacy Studies Both coffee and tea have been shown to reduce postprandial drop in systolic blood pressure significantly [97]. A double-blind RCT in both healthy elderly and frail elderly subjects showed caffeine 100 mg given as coffee or decaffeinated coffee as placebo with meals showed a significant effect in reducing postprandial drop in blood pressure [98, 99]. However, an RCT that examined the hemodynamic and neurohumoral effects of caffeine did not show the benefit of reducing splanchnic blood pooling or postprandial hypotension [100]. 3.4.2 Alpha-Glucosidase Inhibitors Acarbose and voglibose cause slowing of gastric emptying and a delay in intestinal disaccharide absorption, which can cause a reduction in splanchnic blood flow and thereby attenuates the postprandial drop in blood pressure [101]. Efficacy Studies In a study on neurological elderly patients and healthy elderly controls, voglibose significantly reduced postprandial hypotension [102]. In a randomized, cross-over trial in subjects with severe autonomic failure, 100 mg of acarbose successfully reduced postprandial drop in blood pressure [103]. In elderly nursing home residents, acarbose 50 mg with each meal has been shown to be effective in reducing postprandial drop in blood pressure [104]. In a recent non-randomized, cross-over study of MSA subjects, acarbose 100 mg before meals reduced postprandial drop in blood pressure significantly compared with no treatment [105]. Short-term efficacy has been

Efficacy Studies A few small studies have shown a significant difference in the reduction of the postprandial blood pressure drop between octreotide and placebo. No adverse effects were also reported in these studies [107, 108]. 3.4.4 Guar Gum Guar gum works by slowing gastric absorption and reducing glucose absorption. A randomized, cross-over study in healthy elderly subjects showed a significant reduction in the magnitude of fall in blood pressure after oral glucose intake [109]. Another study on type 2 diabetic subjects also showed attenuation in the fall in postprandial blood pressure [110]. 3.4.5 3,4-DL-Threo-dihydroxy-phenyl Serine (DL-DOPS) In a double-blind RCT, 3,4-DL-threo-dihydroxy-phenyl serine (DL-DOPS) 1000 mg given 3 h before meals has been shown to be effective in reducing postprandial drop in blood pressure [111]. 3.4.6 Dipeptidyl Peptidase IV (DPP-IV) inhibitor In a recent case report, the dipeptidyl peptidase IV (DPP-IV) inhibitor vildagliptin was shown to reduce the hypotensive response after meals in an elderly patient without diabetes mellitus. The mechanism that is postulated involves an increase in glucagon-like peptide-1. No adverse effects like hypoglycemia or gastrointestinal symptoms were seen with this subject [112]. 3.5 Summary Pharmacological management studies showed different medications can attenuate postprandial reductions in blood pressure. A limitation of most of these studies was that they did not include subjects with symptomatic PPH.

4 Hypotension Due to Head Turning: Carotid Sinus Syndrome/Carotid Sinus Hypersensitivity (CSH) CSS is a condition that is defined by changes in heart rate and blood pressure response to carotid sinus massage or carotid sinus baroreceptor stimulation. Head turning is an

Drug Therapy of Hypotensive Syndromes

important trigger for hypotension in elderly with CSH. There are three types of CSS. The first type, cardio-inhibitory CSS, is diagnosed by a C3-s asystole or pause. The second type, vasodepressor CSS, is diagnosed by a reduction in blood pressure of at least 50 mmHg in the absence of bradycardia. The third type, mixed CSS, is where there is a 3-s pause with a decrease in systolic blood pressure of 50 mmHg upon rhythm resumption [113]. The prevalence of CSS in elderly varies from 25–48 % in subjects referred to hospital for dizziness, unexplained syncope or falls [114, 115]. The vasodepressor and mixed types of CSS are the types that cause hypotension with head or neck turning [116]. 4.1 Causes The definite pathophysiology of CSS has not been established, but a study has shown that it may be related to autonomic dysfunction [117]. 4.2 Mortality A retrospective cohort study showed that CSS in general or its subtypes was not associated with higher mortality than that in the general population [118].

and falling heart rate. The combination of a sympathetic surge followed by a parasympathetic over-reaction, which leads to an abrupt withdrawal of sympathetic tone and vasodilation, known as Bezold-Jarisch reflex, can lead to hypotension. 5.1 Causes Standing for long periods of time, sight of blood, sudden fear and heat exposure can cause vasovagal syncope. 5.2 Morbidity and Mortality Vasovagal syncope has a benign prognosis with risk of death similar to that in the general population [128]. 5.3 Medication or Drug Management The main management is avoidance of triggers known to precipitate vasovagal syncope, adequate hydration and sodium chloride (including salt tablets) to enhance volume expansion and retention. Fludrocortisone and midodrine can be tried in patients with recurrent vasovagal syncopes Table 2 Medications used in different hypotensive syndromes Medications

OH

PPH

Vasovagal syncope

CSS

Fludrocortisone

Yes

No

Yes

Yes

Midodrine

Yes

Yes

Yes

Yes

Droxidopa

Yes

Yes

No

No

4.3 Morbidity Dizziness, syncope and falls are the common morbidities seen with CSS [119]. Precipitating factors are head turning, shaving or the wearing of a tight neck collar [120–122]. In unexplained falls, hypotensive syndrome due to carotid sinus hypersensitivity can be a causal or contributing factor for falls [3, 123].

Octreotide

Yes

Yes

No

No

Caffeine

Yes

Yes

No

No

Salt tablets

Yes

No

Yes

No

CSS carotid sinus syndrome, OH orthostatic hypotension, PPH postprandial hypotension

4.4 Medication or Drug Management A small study showed some benefits in symptomatic carotid vasodepressor CSS. In 11 subjects, 100 lg of fludrocortisone showed significant decrease in the blood pressure fall (56 vs. 32 mmHg, p \ 0.01) and fewer symptoms [124]. A pilot double-blind, randomized, controlled, crossover trial with midodrine showed reduction in symptom reporting and the degree of vasodepression in CSS [125].

5 Hypotension Due to Vasovagal Syncope Vasovagal syncope is one of the common causes of hypotension in older adults. It affects 20 % of elderly at some time in their lives [126, 127]. Vasovagal syncope type 1 is a condition where there is loss of consciousness due to decreased perfusion to the brain, with blood pressure drop

Table 3 Dosage of medications used in different hypotensive syndromes Medications

Dosage

Fludrocortisone

0.1–0.6 mg orally once daily

Midodrine

2.5–10 mg orally three times daily

Erythropoietin

25–75 U/kg three times a week

Caffeine

100–250 mg orally three times daily

Octreotide

12.5–25 lg subcutaneously before meals

Pyridostigmine

30–90 mg orally three times daily

Droxidopa

100–600 mg orally three times daily

Yohimbine

8 mg orally three times daily

Atomoxetine

20–40 mg orally once daily

Salt tablets

1 g orally twice daily

For detailed information on doses and dosage adjustments based on pharmacokinetic changes, please refer to product monograph package insert

K. Alagiakrishnan Table 4 Selected drug trials in hypotensive syndromes Pharmacological class

Type of hypotension

Study population characteristics

Fludrocortisone (Campbell et al. [47])

OH due to autonomic neuropathy

Double-blind, cross-over study

Fludrocortisone (DaCosta et al. [124])

CSS

Symptomatic vasodepressor CSS subjects

Midodrine (Parsalk et al. [54])

OH

Midodrine (Moore et al. [125])

CSS

Pilot double-blind, randomized, controlled, cross-over trial

Erythropoietin (Hoeldtke and Streeten [59])

OH due to autonomic neuropathy

Non-randomized trial

Octreotide (Bordet et al. [72])

OH due to MSA

Octreotide (Jansen et al. [107])

PPH

Number of subjects 6

Outcomes

Improvement in OH symptoms

Age range 33–64 years 11

Significant decrease in the BP fall (56 vs. 32 mmHg, p \ 0.01) and fewer symptoms

Mean age 83 ± 5 years Meta-analysis of clinical trials

325

Mean age 53 years 10

After carotid sinus massage, the differences were significant, with mean SBP (p = 0.03) and decrease in symptoms (p \ 0.01)

12

SBP increased 81 ± 11 to 100 ± 24 mmHg (p \ 0.01). DBP increased 46 ± 10 to 63 ± 18 mmHg (p \ 0.01)

Mean age 75 years Age range 17–68 years Cross-over study

Changes in standing SBP by 21.5 mmHg (p \ 0.001)

9

Octreotide increases supine BP

Mean age 70 years Double-blind, randomized study in normotensive and hypertensive subjects

20

Benefit may be seen in subjects with symptomatic PPH

58

Significant reduction in BP fall 27.6 mmHg (Pyr) vs. 34.0 mmHg with placebo (p = 0.04), 27.2 mmHg (Pyr ? Mid) vs. 34.0 mmHg with placebo (p = 0.002)

31

Yohimbine improved standing DBP (11 ± 3 mmHg, 95 % CI 6–16, p \ 0.001). Pyridostigmine did not. No evidence of synergy

35

Decrease in OH; maximum effect seen with 300 mg orally twice daily (-22 ± 28 mmHg reduction from a baseline decrease of SBP 54.3 ± 27.7 mmHg, p = 0.0001)

Mean age 74 ± 4 years Pyridostigmine/ pyridostigmine and midodrine (Singer et al. [68])

OH, neurogenic

Double-blind RCT with cross-over design

Yohimbine/ ?pyridostigmine (Shibao et al. [69])

Severe OH due to PD, MSA and PAF

Single-blind, randomized, placebocontrolled, cross-over study

Droxidopa (Mathias et al. [63])

OH, neurogenic, due to PAF and MSA

Dose-ranging study: 100 mg orally twice daily, 200 mg orally twice daily, 300 mg orally twice daily

Droxidopa (Kaufmann et al. [66])

OH, neurogenic, due to PD, PAF and MSA

Randomized, placebo-controlled, parallel-group trial

Caffeine (Rakic et al. [97])

PPH

Caffeine (Heseltine et al. [98])

PPH

Guar gum (Russo et al. [110])

PPH

Acarbose (Shibao et al. ([103]))

PPH with autonomic failure

Randomized cross-over study

Metoprolol (Sheldon et al. [130])

Vasovagal syncope

Prevention Of Syncope Trial POST); observational cohort study Mean age \42 and [42 years

Mean age 59 ± 11 years, Pyridostigmine (Pyr) vs. pyridostigmine ? midodrine (Pyr ? Mid)

Mean age 66 years

Age 18–75 years 263

Mean standing SBP increased by 11.2 vs. 3.9 mmHg (p \ 0.001)

171

Significant reduction in postprandial fall in supine SBP 4.1 ± 1.1 mmHg

20

Caffeine ?2 ± 3 mmHg SBP vs. -11 ± 3 mmHg with placebo (p \ 0.01). Prevents symptomatic BP reduction with PPH

11

Magnitude of fall in BP postprandial was less with guar gum (p \ 0.05)

13

Acarbose reduced mean postprandial fall of SBP by 17 mmHg (95 % CI: 7–28, p = 0.003) and DBP by 9 mmHg (95 % CI: 5–14, p = 0.001)

153

Reduction in syncope estimate in \42 years: HR 1.58 (CI, 1.00–2.31) vs. [42 years: HR 0.52 (95 % CI 0.27–1.01), p = 0.007

Age range 18–91 years RCT Mean age 75 years Double-blind, randomized, crossover study Mean age 84 ± 5 years Type 2 DM subjects Mean age 62 years Mean 65 ± 3 years

BP blood pressure, CI confidence interval, CSS carotid sinus syndrome, DBP diastolic blood pressure, DM diabetes mellitus, HR hazard ratio, MSA multiple system atrophy, OH orthostatic hypotension, PAF primary autonomic failure, PD Parkinson’s disease, PPH postprandial hypotension, RCT randomized controlled trial, SBP systolic blood pressure

Drug Therapy of Hypotensive Syndromes

with hypotension, but this is not well studied. Betablockers, by involving the sympathetic nervous system and the central inputs into the Bezold–Jarisch reflex, are another potential pharmacological target. A RCT pointed out the age dependent effects of beta blockers in preventing vasovagal syncope are seen in subjects above 42 years [129, 130].

6 Steps to Prevent Supine Hypertension Due to Medications Used to Treat Different Hypotensive Syndromes Many medications used to treat hypotensive syndromes can cause supine hypertension. Different therapeutic steps are discussed below, but no treatment approach has been studied in detail. •

•

•

•

Combining fludrocortisone with midodrine will have a synergistic effect and will also allow lower dosage of the medications used [48]. Certain medications have been suggested as management strategies in the hypertension of autonomic failure. One suggested strategy is to try transdermal nitroglycerine patch (0.025–0.1 mg/h) at night-time and removed in the morning, before the patient stands up [131, 132]. Until we have more evidence, this strategy may not be a good strategy, as postural hypotension is more commonly seen in the morning hours and nitroglycerine can worsen OH [13]. Another strategy that can be tried and has to be individually tailored is the addition of short-acting antihypertensives [133], which does not cause OH. Raising the head of the bed to 10–20 degrees may protect the brain from the effect of supine hypertension [134, 135]. Pyridostigmine may reduce the postural drop in blood pressure without causing supine hypertension [66].

7 Summary Hypotension due to blood pressure dysregulation syndrome is characterized by abnormal swings in blood pressure following postural changes, meals and neck turning. These are common conditions seen in the elderly. Non-pharmacological management should be considered in all subjects with hypotensive syndromes. Changing, stopping or decreasing the dose of offending medications that cause hypotensive syndromes is the first step in medical management. Overtreatment of hypertension, especially in the frail elderly, can also result in hypotensive syndromes like OH and PPH [136]. Management should be

individualized and concurrent illness should be considered. Different drug treatments can be considered (see Tables 2 and 3). Current medication management of these symptomatic hypotensive syndromes remains suboptimal. Most of the current medications used for hypotensive syndromes were evaluated in small clinical trials (see Table 4), and there is a need for high-quality large, randomized, clinical studies for these medications. The predominant outcome measure used in these studies related to postural blood pressure values or absolute blood pressure values. Only a few studies have used symptom or function improvement as an outcome measure. Another limitation of most of these medications is the severe increase in supine blood pressure. Long-term follow-up studies are lacking with the medications used to treat hypotensive syndromes. Conflict of interest No external funding was used in the preparation of this manuscript. The author has no potential conflict of interest that might be relevant to the contents of this review.

References 1. Low PA. Prevalence of orthostatic hypotension. Clin Auton Res. 2008;18(suppl 1):8–13. 2. Vloet LC, Pel-little RE, Jansen PA, et al. High prevalence of postprandial and orthostatic hypotension among geriatric patients admitted to Dutch hospitals. J Gerontol A Biol Sci Med Sci. 2005;60(10):127–1277. 3. Kenny RA, Richardson DA. Carotid sinus syndrome and falls in older adults. Am J Geriatr Cardiol. 2001;10(2):97–9. 4. Lagro J, Meet-vanden Abeelen A, de Jong DL, Schalk BW, Olde Rikkert MG, Classen JA. Geriatric hypotensive syndromes are not explained by cardiovascular autonomic dysfunction alone. J Gerontol A Biol Sci Med Sci. 2013;68(5):581–9. 5. Le Couteur DG, Fisher AA, Davis MW, McLean AJ. Post prandial systolic blood pressure responses of older people in residential care association and risk of falling. Gerontology. 2003;49:260–4. 6. Kenny RA, Richardson DA. Carotid sinus syndrome and falls in older adults. Am J Geriatr Cardiol. 2001;10:97–9. 7. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Neurology. 1996;46(5):1470. 8. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neutrally mediated syncope and the postural tachycardia syndrome. Auton Neurosc. 2011;161:46–8. 9. Rutan GH, Hermanson B, Bild DE, et al. Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Colloborative Research Group. Hypertension. 1992;19:508–19. 10. Shibao C, Grijalva CG, Raj SR, et al. Orthostatic hypotension related hospitalizations in the United States. Am J Med. 2007;120:975–80. 11. Feldstein C, Weder AB. Orthostatic hypotension: a common, serious and under recognized problem in hospitalized patients. J Am Soc Hypertens. 2012;6:27–39. 12. Ooi WL, Barett S, Hossain M, Reiley-Gagnon M, Lipsitz LA. Patterns of orthostatic blood pressure change and their clinical

K. Alagiakrishnan

13. 14.

15.

16. 17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

correlates in a frail, elderly population. JAMA. 1997;277(16): 1299–304. Sclater A, Alagiakrishnan K. Orthostatic hypotension. A primary care primer for assessment and treatment. Geriatrics. 2004;59(9):22–7. Masaki KH, Schatz IJ, Burchfield CM, et al. Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation. 1998;98:2290–5. Weiss A, Beloosesky Y, Kornowski R, et al. Influence of orthostatic hypotension on mortality among patients discharged from an acute geriatric ward. J Gen Intern Medicine. 2006;21:602–6. Xin W, Lin Z, Mi S. Orthostatic hypotension and mortality risk: a meta-analysis of cohort studies. Heart. 2014;100:406–13. Verwoert GC, Mattace-Raso FU, Hofman A, Heeringa J, Stricker BH, Breteler MM, et al. Orthostatic hypotension and risk of cardiovascular disease in elderly people: the Rotterdam Study. J Am Geriatr Soc. 2008;56:1816–20. Luukinen H, Koski K, Laippala P, Airaksinen KE. Orthostatic hypotension and the risk of myocardial infarction in the homedwelling elderly. J Intern Med. 2004;255:486–93. Kario K, Eguchi K, Hoshide S, Hoshide Y, Umeda Y, Mitsuhashi T, Shimada K. U-curve relationship between orthostatic blood pressure change and silent cerebrovascular disease in elderly hypertensives: orthostatic hypertension as a new cardiovascular risk factor. J Am Coll Cardiol. 2002;40:133–41. Hossain M, Ooi WL, Lipsitz LA. Intra-individual postural blood pressure variability and stroke in elderly nursing home residents. J Clin Epidemiol. 2001;54:488–94. Alagiakrishnan K, Patel K, Desai RV, et al. Orthostatic hypotension and incident heart failure. J.Gerontol A Biol Sci Med Sci. 2014;69A(2):223–30. Sarasin FP, Louis-Simonet M, Carballo D, et al. Prevalence of OH among patients presenting with syncope in the ED. Am J Emerg Med. 2002;20:497–501. Van Hatteran KJ, Kleefstra N, Blanker MH, et al. Orthostatic hypotension, diabetes and falling in older adults : a cross-sectional study. Br J Gen. Practice. 2012. doi:10.3399/bjgp12x656838. Rutan GH, Hermanson B, Bild DE, et al. Orthostatic hypotension in older adults. The Cardiovascular Health Study, CHS Collobarative Research Group. Hypertension. 1992;19:508–19. Casiglia E, Tikhonoff V, Caffi S, et al. Orthostatic hypotension does not increase cardiovascular risk in the elderly at a population level. Am J Hypertens. 2014;27(1):81–8. Sonnesyn H, Nilsen DW, Rongve A, Nore S, Ballard C, Tysnes OB, Aarsland D. High prevalence of orthostatic hypotension in mild dementia. Dement Geriatr Cogn Disord. 2009;28:307–13. Andersson M, Hansson O, Minthon L, Ballard CG, Londos E. The period of hypotension following orthostatic challenge is prolonged in dementia with lewy bodies. Int J Geriatr Psychiatry. 2008;23:192–8. Yap PL, Niti M, Yap KB, et al. Orthostatic hypotension, hypotension and cognitive status: early comorbid markers of primary dementia? Dement Geriatr Cogn Disord. 2008;26:239–46. Frewen J, Savya GM, Boyle G, et al. Cognitive performance in orthostatic hypotension. Findings from a nationally representative sample. J Am Geriatr Soc. 2014;62(1):117–22. Mehrabian S, Duron E, Labouree F, et al. Relationship between orthostatic hypotension and cognitive impairment in the elderly. J Neurol Sci. 2010;299:45–8. Elmstahl S, Rosen I. Postural hypotension and EEG variables predict cognitive decline: results from a 5-year follow-up of healthy elderly women. Dement Geriatr Cogn Disord. 1997;8:180–7. Matsubayashi K, Okumiya K, Wada T, et al. Postural dysregulation in systolic blood pressure is associated with worsened scoring on neurobehavioral function tests and leukoaraiosis in the older elderly living in a community. Stroke. 1997;28:2169–73.

33. Bonuccelli U, Lucetti C, Del DP, Ceravolo R, Gambaccini G, Bernardini S, Rossi G, Piaggesi A. Orthostatic hypotension in de novo Parkinson’s disease. Arch Neurol. 2003;60:1400–4. 34. Goldstein DS, Eldadah BA, Holmes C, Pechnik S, Moak J, Saleem A, Sharabi Y. Neurocirculatory abnormalities in Parkinson disease with orthostatic hypotension: independence from levodopa treatment. Hypertension. 2005;46:1333–9. 35. Mehagnoul-Schipper DJ, Boerman RH, Hoefnagels WH, Jansen RW. Effect of levodopa on orthostatic and postprandial hypotension in elderly Parkinsonian patients. J Gerontol A Biol Sci Med Sci. 2001;56:M749–55. 36. Kujawa K, Leurgans S, Raman R, Blasucci L, Goetz CG. Acute orthostatic hypotension when starting dopamine agonists in Parkinson’s disease. Arch Neurol. 2000;57:1461–3. 37. Dooley M Markham A. Pramipexole: a review of its use in the management of early and advanced Parkinson’s disease. Drugs Aging. 1998;12:495–514. 38. Johns DW, Ayers CR, Carey RM. The dopamine agonist bromocriptine induces hypotension by venous and arteriolar dilation. J Cardiovasc Pharmacol. 1984;6:582–7. 39. Allcock LM, Kenny RA, Mosimann UP, Tordoff S, Wesnes KA, Hildreth AJ, Burn DJ. Orthostatic hypotension in Parkinson’sdisease: association with cognitive decline? Int J Geriatr Psychiatry. 2006;21:778–83. 40. Pilleri M, Facchini S, Gasparoli E, Biundo R, Bernardi L, Marchetti M, Formento P, Antonini A. Cognitive and MRI correlates of orthostatic hypotension in Parkinson’s disease. J Neurol. 2013;260:253–9. 41. Low PA, Opter-Gehrking H, Mcphee BR, et al. Prospective evaluation of clinical characteristics of orthostatic hypotension. Mayo Clin Proc. 1995;70(7):617–22. 42. Ooi WL, Hossain M, Lipsitz LA. The association between orthostatic hypotension and recurrent falls in nursing home residents. Am J Med. 2000;108:106–11. 43. Gangavati A, Hajjar I, Quach L, Jones RN, Kiely DK, et al. Hypertension, orthostatic hypotension, and the risk of falls in a community-dwelling elderly population: the maintenance of balance, independent living, intellect, and zest in the elderly of Boston study. J Am Geriatr Soc. 2011;59:383–9. 44. van Hateren KJ, Kleefstra N, Blanker MH, Ubink-Veltmaat LJ, Groenier KH, et al. Orthostatic hypotension, diabetes, and falling in older patients: a cross-sectional study. Br J Gen Pract. 2012;62:e696–702. 45. Pasma JH, Bijlsma AY, Klip JM, Stijintjes M, Blauw GJ, Muller M, et al. Blood pressure associated with standing balance in elderly outpatients. PLoS One. 2014;9(9):e106808. 46. Arnold AC, Shibao C. Current concepts in orthostatic hypotension management. Curr Hypertens Rep. 2013;15:304–12. 47. Campbell IW, Ewing DJ, Clarke BF. 9-Alpha–fludrocortisone in the treatment of postural hypotension in diabetic autonomic neuropathy. Diabetes. 1975;24:381–4. 48. Kaufmann H, Brannan T, Krakoff L, Yahr MD, Mandeli J. Treatment of orthostatic hypotension due to autonomic failure with a peripheral alpha-adrenergic agonist (midodrine). Neurology. 1988;38:951–6. 49. Schoffer KL, Henderson RD, O’Maley K, O’Sullivan ID. Non pharmacological treatment, fludrocortisone, and domperidone for orthostatic hypotension in Parkinson’s disease. Mov Disorder. 2007;22:1543–9. 50. Hussain RM, McIntosh SJ, Lawson J, Kenny RA. Fludrocortisone in the treatment of hypotensive disorders in the elderly. Heart. 1996;76(6):507–9. 51. Chobanian AV, Volicer L, Tifft CP, et al. Mineralocorticoidinduced hypertension in patients with orthostatic hypotension. N Engl J Med. 1979;301:68.

Drug Therapy of Hypotensive Syndromes 52. McClellan KJ, Wiseman LR, Wilde MI. Midodrine. A review of its therapeutic use in the management of orthostatic hypotension. Drugs Aging. 1998;12(1):76–86. 53. Low PA, Gilden JL, Freeman R, Sheng RN, McElligot MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multi-centre study. Midodrine Study Group. JAMA. 1997;277(13):1046–51. 54. Parsalk AK, Singh B, Altayar O, Mascarenhas SS, Singh SK, Erwin PJ, Murrad MH. Midodrine for orthostatic hypotension: a systematic review and meta-analysis of clinical trials. J Gen Intern Med. 2013;28(11):1496–503. 55. Hoeldtke RD, Horvath GG, Bryner KD, Hobbs GR. Treatment of orthostatic hypotension with midodrine and octreotide. J Clin Endocrinol Metab. 1998;83:339–43. 56. Jankovie J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind. placebo-controlled study with midodrine. Am J Med. 1993;95:38–48. 57. Rao SV, Stamler JS. Erythropoietin, anemia, and orthostatic hypotension: the evidence mounts. Clin Auton Res. 2002;12:141–3. 58. Perera R, Isola L, Kaufmann H. Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure. Clin Auton Res. 1995;5:211. 59. Hoeldtke RD, Streeten DH. Treatment of orthostatic hypotension with erythropoietin. N Engl J Med. 1993;329:611–5. 60. Biaggioni I, Freeman R, Mathias CJ, et al. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension. 2015;65(1):101–7. 61. Akizawa T, Koshikawa S, Iida N, et al. Clinical effects of Lthreo-3,4-dihydroxyphenylserine on orthostatic hypotension in hemodialysis patients. Nephron. 2002;90:384–90. 62. Lida N, Koshikawa S, Akizawa T, et al. Effects of L-threo 3,4dihydroxyphenylserine on orthostatic hypotension in hemodialysis patients. Am J Nephrol. 2002;22:338–46. 63. Mathias CJ, Senard JM, Braun S, et al. L-threo-dihydroxyphenylserine (L-threo-DOPS), droxidopa in the management of neurogenic orthostatic hypotension: a multi-national, multicentre, dose-ranging study in multiple system atrophy and pure autonomic failure. Clin Auton Res. 2001;11:235–42. 64. Isaacson SH, Skettini J. Neurogenic orthostatic hypotension in Parkinson’s disease: evaluation, management and emerging role of droxidopa. Vasc Health Risk Manag. 2014;10:169–76. 65. Isaacson S, Hauser RA, Szakacs CBN, Cioffi CC. Impact of droxidopa treatment in patients with Parkinson’s disease and symptomatic neurogenic orthostatic hypotension (study 306). Mov Disorder. 2013;28(Suppl 1):468. 66. Kaufmann H, Freeman R, Biaggioni I, et al. Droxidopa for neurogenic orthostatic hypotension. A randomized, placebocontrolled, phase 3 trial. Neurology. 2014;83(4):328–35. 67. Hauser RA, Hewitt LA, Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson’s disease. J Parkinsons Dis. 2014;4(1):57–65. 68. Singer W, Sandroni P, Opfer-Gehrking TL, et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol. 2006;63(4):513–8. 69. Shibao C, Okamoto LE, Gamboa A, et al. Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2010;56:847–51. 70. Gales BJ, Gales MA. Pyridostigmine in the treatment of orthostatic intolerance. Ann Pharmacother. 2007;41(2):314–8. 71. Bordet R, Benhadjali J, Libersa C, Destee A. Octreotide in the management of orthostatic hypotension in multiple system atrophy; pilot trial of chronic administration. Clin Neuropharmacol. 1994;17:380–3.

72. Bordet R, Benhadjali J, Destee A, belabbas A, Libersa C. Octreotide effects on orthostatic hypotension in patients with multiple system atrophy: a controlled study of acute administration. Clin Neuropharmacol. 1995;18:83–9. 73. Onrol J, Goldberg MR, Biaggioni I, et al. Oral yohimbine in human autonomic failure. Neurology. 1987;37:215. 74. Jordan J, Shannon JR, Biaggioni I, Norman R, Black BK, Robertson D. Contrasting actions of pressor agents in severe autonomic failure. Am J Med. 1998;105:116–24. 75. Robertson D, Frolich JC, Carr RK, et al. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med. 1978;298:181–6. 76. Okamoto LE, Shibao C, Gamboa A, et al. Synergistic effect of norepinephrine transporter blockade and alpha-2 antagonism on blood pressure in autonomic failure. Hypertension. 2012;59:650–6. 77. Ramirez CE, Okamoto LE, Arnold AC, et al. Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2014 (in press). 78. Conte JJ, Fournie GJ, Maurette MH. Dihydroergotamine: an effective treatment for postural hypotension due to antihypertensive drugs (ganglion-blocking agents excepted). Cardiology. 1976;61(Suppl. 1):342–9. 79. Lubke KO. A controlled study with Dihydergot on patients with orthostatic dysregulation. Cardiology. 1976;61(Suppl. 1):333–41. 80. Victor RG, Talman WT. Comparative effects of clonidine and dihydroergotamine on venomotor tone and orthostatic tolerance in patients with severe hypoadrenergic orthostatic hypotension. Am J Med. 2002;112:361–8. 81. Lopes de Farina SR, Zanella MT, Andriolo A, et al. Peripheral dopaminergic blockade for the treatment of diabetic orthostatic hypotension. Clin Pharmacol Ther. 1988;44:670. 82. Mathias CJ, Fosbracy P, da Costa DF, Thornley A, Bannister B. The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension in patients with autonomic failure. Br Med J (Clin Res Ed). 1986;293:353–4. 83. Low PA, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 2008;7(5):451–8. 84. Logan IC, Witham MD. Efficacy of treatments for orthostatic hypotension: a systematic review. Age Ageing. 2012;41:587–94. 85. Alagiakrishnan K. Postural and postprandial hypotension: approach to management. Geriatr Aging. 2007;10(5):298–304. 86. Lipsitz LA, Nyquist RP Jr, Wei JY, et al. Postprandial reduction in blood pressure in the elderly. N Engl J Med. 1983;309:81–3. 87. Jansen RW, Lipsitz LA. Postprandial hypotension: epidemiology, pathophysiology and Clinical management. Ann Intern Med. 1995;122:286–95. 88. Luciano GL, Brennan MJ, Rothberg MB. Postprandial hypotension. Am J Med. 2010;123:281e1–6. 89. Vloet LC, Pei-Little RE, Jansen PA, et al. High prevalence of postprandial and orthostatic hypotension among geriatric patients admitted to Dutch hospitals. J Gerontolgical A Biol Sci Med Sci. 2005;60:1271–7. 90. Aronow WS, Ahn C. Postprandial hypotension in 499 elderly persons in a long-term healthcare facility. J Am Geriatr Soc. 1994;42:930–2. 91. Vaitkeviclus PV, Esserwein DM, Maynard AK, et al. Frequency and importance of postprandial blood pressure reduction in elderly nursing home patients. Ann Intern Med. 1991;115:865–70. 92. Fisher AA, Davis MW, Srikusalanukul W, et al. Postprandial hypotension predicts all-cause mortality in older, low-level care residents. J Am Gerontol Soc. 2005;53:1313–20. 93. Jansen RW, Connelly CM, Kelly-Gagnon MM, et al. Postprandial hypotension in elderly patients with unexplained syncope. Arch Intern Med. 1995;155:945–52. 94. Pulsieux F, Bulckaen, Fauchais AL, et al. Ambulatory blood pressure monitoring and postprandial hypotension in elderly

K. Alagiakrishnan

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

persons with falls or syncopes. J Gerontol A Biol Sci Med Sci. 2000;55A:M535–40). Aronow WS, Ahn C. Association of postprandial hypotension with incidence of falls, syncope, coronary events, stroke, and total mortality at 29-months follow-up in 499 older nursing home residents. J Am Geriatr Soc. 1997;45:1051–3. Tabara Y, Okada Y, Detani E, Nagai T, Igase M, Kido T, et al. Postprandial hypotension as a risk marker for asymptomatic lacunar infarction. J Hypertens. 2014;32:1084–90. Rakic V, Beilin IJ, Burke V. Effect of coffee and tea drinking on postprandial hypotension in older men and women. Clin Exp Pharmacol Physiol. 1996;23:559–63. Heseltine D, Dakkak M, Woodhouse K, et al. The effect of caffeine on post prandial hypotension in the elderly. J Am Geriatr Soc. 1991;39:160–4. Heseltine D, el-Jabri M, Ahmed F, Knox J. The effect of caffeine on post prandial blood pressure in the frail elderly. Postgrad Med J. 1991;67:543–7. Lipsitz LA, Jansen RW, Connelly CM, et al. Haemodynamic and neurohumoral effects of caffeine in elderly patients with symptomatic postprandial hypotension: a double-blind, randomized, placebo-controlled study. Clin Sci (Lond).1994;87:259–67. Gentilcore D, Bryant B, Wishart JM, et al. Acarbose attenuates the hypotensive response to sucrose and slows gastric emptying in the elderly. Am J Med. 2005;118:1289. Maruta T, Komai K, Takamori M, Yamada M. Voglibose inhibits postprandial hypotension in neurological disorders and elderly people. Neurology. 2006;66:1432–4. Shibao C, Gamboa A, Diedrich A, et al. Acarbose, an alphaglucosidase inhibitor attenuates postprandial hypotension in autonomic failure. Hypertension. 2007;50:54–61. Jian ZJ, Zhou BV. Efficacy and safety of acarbose in the treatment of elderly patients with postprandial hypotension. Chin Med J (Engl). 2008;121:2054–9. Fukushima T, Asahina M, Fujinuma Y, et al. Role of intestinal peptides and the autonomic nervous system in post prandial hypotension in patients with multiple system atrophy. J Neurol. 2012;260:475–81. Jian ZJ, Zhou BV. Efficacy and safety of acarbose in the treatment of elderly patients with postprandial hypotension. Chin Med J (Engl). 2008;121:2054–9. Jansen RWMM, Peeters TL, Lenders JWM, et al. Somatostatin analog octreotide (SMS 201-995) prevents the decrease in blood pressure after oral glucose loading in the elderly. J Clin Endocrinol Metab. 1989;68:752–6. Jansen RWMM, Lenders JWM, Peeters TL, et al. SMS 201-995 prevents postprandial blood pressure reduction in normotensive and hypertensive elderly subjects. J Hypertens. 1988;S6:S669–72. Jones KL, Macintosh C, Su YC, Wells F, Chapman IM, Tonkin A, Horowitz M. Guar gum reduces post prandial hypotension in older people. J Am Geriatr Soc. 2001;49(2):162–7. Russo A, Stevens JE, Wilson T, Wells F, Tonkin A, Horowitz M, Jones KL. Guar attenuates fall in postprandial blood pressure and slows gastric emptying of oral glucose in type 2 diabetes. Dig Dis Sci. 2003;48(7):1221–9. Freeman B, Young J, Landsberg L, Lipsitz L. The treatment of postprandial hypotension in autonomic failure with DL-threo dihydroxy phenyl serine. Neurology. 1996;47:1414–20. Yonenaga A, Ota H, Honda M, et al. Marked improvement of elderly postprandial hypotension by dipeptidyl peptidase IV inhibitor. Geriatr Gerontol Int. 2013;13(1):227–9. Brignole M, Alboni P, Benditt DG, et al. Guidelines on management (diagnosis and treatment) of syncope-update 2004: executive summary. Eur Heart J. 2004;25:2054–72. Kenny RA, Traynor G. Carotid sinus syndrome—clinical characteristics in elderly patients. Age Ageing. 1991;20:449–54.

115. McIntosh SJ, Lawson J, Kenny RA. Clinical characteristics of vasodepressor, cardio inhibitory and mixed carotid sinus syndrome in the elderly. Am J Med. 1993;95:203–8. 116. Schoon Y, Olde Rikkert MGM, Rongen S, Lagro J, Schalk B, Classen JAHR. Head turning induced hypotension in elderly people. Plos One. 2013;8(8):e72837. 117. Tan MP, Kenny RA, Chadwick TJ, et al. Carotid sinus hypersensitivity disease state or clinical sign of ageing? Insights from a controlled study of autonomic function in symptomatic and asymptomatic subjects. Eurospace. 2010;12:1630–6. 118. Hampton JL, Brayne C, Bradley M, Kenny RA. Mortality in carotid sinus hypersensitivity: a cohort study. BMJ Open. 2011;1:e000020. 119. McIntosh S, Da Costa D, Kenny RA. Outcome of an integrated approach to the investigation of dizziness, falls and syncope in elderly patients referred to a syncope clinic. Age Ageing. 1993;22:53–8. 120. Kenny RA, Traynor G. Carotid sinus syndrome—clinical characteristics in elderly patients. Age and Ageing. 1991;20:449–54. 121. Classen JA, Jansen RW. Carotid sinus syndrome: looking sideways is sufficient cause for syncope. J Am Geriatr Soc. 2006;54:188–9. 122. Schoon Y, Marcel GM, Rikkert O, Rongen S, Lagro J, Schalk B, Classen JA. Head turning-induced hypotension in elderly people. PLoS One. 2013;8(8):e72837. 123. Kerr SR, Pearce MS, Brayne C, Davis RJ, Kenny RA. Carotid sinus hypersensitivity in asymptomatic older persons. Arch Intern Med. 2006;166:515–20. 124. DaCosta D, McIntosh S, Kenny RA. Benefits of fludrocortisone in the symptomatic vasodepressor carotid sinus syndrome. Br Heart J. 1993;69:308–10. 125. Moore A, Watts M, Sheehy T, et al. Treatment of vasodepressor carotid sinus syndrome with midodrine: a randomized controlled pilot study. J Am Geriatr Soc. 2005;53:114–8. 126. Sheldon R, Morillo CA, Krahn A. Management of vasovagal syncope: 2004. Expert Rev Cardiovasc Ther. 2004;2(6):915–23. 127. Duncan GW, Tan MP, Newton JL, et al. Vasovagal syncope in the older persons: differences in presentation between older and younger patients. Age and Ageing. 2010;39:465–70. 128. Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med. 2002;347(12):878–85. 129. Sheldon R, Connoly S, Rose S, et al. POST Investigators, Prevention of Syncope Trial (POST): a randomized, placebocontrolled study in the prevention of vasovagal syncope. Circulation. 2006;113:1164–70. 130. Sheldon R, Morillo C, Klingenheben T, et al. Age-dependent effect of beta-blockers in preventing vasovagal syncope. Circ Arrhythm Electrophysiol. 2012;5:920–6. 131. Shannon J, Jordan J, Costa F, et al. The hypertension of autonomic failure and its treatment. Hypertension. 1997;1062:30. 132. Jordan J, Shannon JR, Pohar B, et al. Contrasting effects of vasodilators on blood pressure and sodium balance in the treatment of hypertension of autonomic failure. J Am Soc Nephrol. 1999;10:36. 133. Nwazue VC, Raj SR. Confounders of vasovagal syncope: orthostatic hypotension. Cardiol Clin. 2013;31:89. 134. Fan CW, Walsh C, Cunnigham CJ. The effect of sleeping with the head of the bed elevated six inches on elderly patients with orthostatic hypotension: an open randomized controlled trial. Age Ageing. 2011;40:187. 135. Bannister R, Ardill L, Fenten P. An assessment of various methods of treatment of idiopathic orthostatic hypotension. Quart J med. 1969;38:377–95. 136. Morley JE. Hypertension—is it overtreated in the elderly. JAMDA. 2010;11:147–152.