international nonproprietary name; LUTS, Identifying and managing OH in . The mean age among patients was 71.3 years, 40.1% were female, and patients were treated for either heart failure, cor pulmonale, or acute delirium (S1 Table). Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. Conversely, a HR/SBP ratio of <0.5 beats per minute/mm Hg strongly suggests neurogenic orthostatic hypotension.43, Distinguishing Features of Neurogenic and Non-neurogenic Orthostatic Hypotension. We provide a pragmatic guide on patient education and the patient-orientated approach to the moment to moment management of OH. Elgebaly A, Abdelazeim B, Mattar O, et al. If sustained orthostatic hypotension is confirmed, it is key to establish whether the cause is a pathologic lesion in sympathetic neurons (ie, neurogenic orthostatic hypotension) or if it is secondary to other medical causes (ie, non-neurogenic orthostatic hypotension), such as anemia- or dehydration-related volume depletion, excessive venous pooling sometimes aggravated by varicose veins, or medication side effects (eg, from alpha-blockers for benign prostate hyperplasia, antihypertensive agents, diuretics, tricyclic antidepressants, opioids, benzodiazepines, and antiparkinsonian agents). At night, elevating the head of the bed at least 30 to 45 degrees (accomplished with an electric bed or mattress) is effective to lower the blood pressure.64 Avoiding nocturnal supine hypertension with postural changes reduces the exaggerated nocturnal diuresis and natriuresis characteristic of these patients, therefore reducing the overnight fluid loss and ameliorating orthostatic hypotension in the morning. Patients can sit in a reclining chair with their feet on the floor if they need to nap or rest. Ramirez CE, Okamoto LE, Arnold AC, et al. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. The https:// ensures that you are connecting to the Despite removal of aggravating factors and implementing nonpharmacologic methods, many patients remain symptomatic and require pharmacologic treatment.44 Current pharmacologic approaches are based on two complementary strategies: (1) expanding intravascular volume with fludrocortisone and (2) increasing peripheral vascular resistance with midodrine, droxidopa, or norepinephrine reuptake inhibitors. A carbohydrate-rich snack or an alcoholic drink before bedtime lowers blood pressure. Current consensus states that beta-blockers should not be prescribed in preference for hypertension, due to both its potential to cause harm and lack of efficacy relative to other antihypertensives [27]. Bethesda, MD 20894, Web Policies A 63-year-old man presented for evaluation 10 days after an episode of brief unresponsiveness and collapse. Therefore, the relationship between SGLT-2 use and OH in patients with T2DM is complex, similar to antihypertensives. Data were extracted on study characteristics, drug, dose, participant characteristics (age, sex, comorbidities), study setting, pharmaceutical sponsorship, and reporting of OH. Alcohol should be avoided during the daytime as it is a vasodilator. Competing interests: The authors have declared that no competing interests exist. In patients with severe prolonged supine hypertension at night despite elevation of the head of the bed (systolic blood pressure of at least 180 mm Hg or diastolic blood pressure of at least 110 mm Hg), short-acting antihypertensives (eg, captopril 25 mg, losartan 50 mg, or nitroglycerin patch 0.1 mg/h) at bedtime could be considered, particularly in patients who already have target organ damage, although none of these approaches has been studied in large controlled trials.94-96 Patients should be advised about the augmented risk of hypotension and falls if they stand up at nighttime (eg, to urinate). CHS Collaborative Research Group, Orthostatic hypotension and anti-hypertensive therapy in the elderly. official website and that any information you provide is encrypted clinicaltrials.gov/ct2/show/NCT02/84535?cond=02/84535&rank=1, Usually chronic; acute or subacute with immune-mediated etiology, Physical deconditioning, antihypertensive medications, intravascular volume loss (eg, dehydration, anemia), blood pooling (eg, large varicose veins, skeletal muscle atrophy), advanced heart failure, adrenal insufficiency, Reduced norepinephrine release from sympathetic postganglionic nerves when standing up, Resolves when underlying cause is corrected, Gastrointestinal dysfunction, urinary dysfunction, sudomotor abnormalities, erectile dysfunction (men), None (or, if present, they are unrelated to orthostatic hypotension), May have none, or may have parkinsonism, cerebellar signs, cognitive impairment, sensory neuropathy, Liberalization of water intake (up to 2.5 L/d), Acute water bolus (drinking 500 mL water), Sleeping with the head of the bed raised 30 to 45 degrees with the help of an electric bed or mattress, Physical activity with recumbent exercises (eg, stationary bicycle, rowing machine) or in a swimming pool, Physical countermaneuvers (eg, standing up slowly, leg crossing, buttock clenching), Waist-high compression stockings producing at least 15 mm Hg to 20 mm Hg pressure, 2.5-15 mg 2 or 3 times a day (dosed morning, midday, and 3-4 hours before bedtime) or tailored to the patiens needs, Supine hypertension, piloerection (goose bumps), scalp itching, urinary retention; caution in congestive heart failure and chronic renal failure, 100600 mg 3 times a day (dosed morning, midday, and 34 hours before bedtime) or tailored to the patients needs, Supine hypertension, headache, nausea, fatigue; caution in congestive heart failure and chronic renal failure, Supine hypertension, insomnia, irritability, decreased appetite, 0.050.2 mg once a day; no benefit with dosages higher than 0.2 mg/d, Synthetic mineralocorticoid, volume expander that increases sodium and water reabsorption, Supine hypertension, hypokalemia, renal failure, edema, target organ damage; caution in congestive heart failure, Abdominal cramps, diarrhea, sialorrhea, excessive sweating, urinary incontinence, Preserved sympathetic innervation in most patients. Elastic compression stockings apply counterpressure to the lower limbs and abdomen, reducing venous pooling.54 High-waist stockings producing at least 15 mm Hg to 20 mm Hg compression are effective to increase venous return and increase blood pressure. Beta-blockers were associated with higher odds of OH compared to placebo (OR 7.76 [95% CI 2.51, 24.03]) (Fig 3). Research Department of Primary Care and Population Health, University College London, United Kingdom, Roles A further narrative review found that evidence for OH induced by antihypertensives was weak [11], and a recent meta-analysis of randomised controlled trials (RCTs) found that intensive BP-lowering treatment reduces OH risk [12]. Inclusion in an NLM database does not imply endorsement of, or agreement with, However, in patients with central autonomic dysfunction, norepinephrine reuptake inhibitors result in only peripheral vasoconstriction, making them particularly suitable for patients with multiple system atrophy. After a large and typical Thanksgiving dinner, he stood up, walked a few steps, and suddenly collapsed to the floor. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome, Hemodynamic effects of varicose veins and results of radical surgery, Autonomic failure in neurodegenerative disorders. Beta-blockers induce OH through sympathetic inhibition decreasing heart rate and contractility, alongside combined independent vasodilatory effects [10,26]. Pharmacologic options include volume expansion with fludrocortisone and sympathetic enhancement with midodrine, droxidopa, and norepinephrine reuptake inhibitors. His supine blood pressure was 157/102 mm Hg with a heart rate of 72 beats/min and after standing for 3 minutes was 119/75 mm Hg with a heart rate of 79 beats/min (change in heart rate [HR]/change in systolic blood pressure [SBP] ratio of 0.18 beats per minute/mm Hg). Distinguishing whether neurogenic orthostatic hypotension is caused by central or peripheral dysfunction has therapeutic implications. Kaufmann H, Norcliffe-Kaufmann L, Palma JA. The mean age of patients was 56.1 years, 34.5% were female, and all trials (excluding 1 with healthy volunteers) were in people with type 2 diabetes mellitus (T2DM) and studied high-dose SGLT-2 inhibitors (S1 Table). When planning therapeutic strategies in patients with neurogenic orthostatic hypotension, localization of the autonomic lesion is important and has therapeutic implications (TABLE 9-4). Short-term controlled clinical trials have shown that atomoxetine (10 mg to 18 mg, 2 times a day), a short-acting norepinephrine reuptake inhibitor, increases standing blood pressure and reduces the burden of symptoms compared to placebo in patients with neurogenic orthostatic hypotension.81-83 The higher the norepinephrine level, the greater the pressor effect and symptomatic improvement with atomoxetine, which makes it a particularly attractive option for patients with neurogenic orthostatic hypotension caused by autonomic decentralization (eg, multiple system atrophy).84 A multicenter controlled trial to confirm the efficacy of atomoxetine in patients with neurogenic orthostatic hypotension is under way.85 A phase 2 trial with ampreloxetine (TD-9855), a long-acting investigational norepinephrine reuptake inhibitor, showed that this compound was safe and increased blood pressure and orthostatic tolerance in patients with neurogenic orthostatic hypotension; a large multicenter phase 3 study to confirm its efficacy is ongoing.86. The peak pressor response occurs within approximately 3.5 hours after oral administration. Visualization, He was taken by ambulance to a local hospital, where his blood pressure was 160/95 mm Hg. Sarasin FP, Louis-Simonet M, Carballo D, et al. Further research is needed to explore the underlying mechanisms and potential therapeutic strategies to mitigate the impact of OH on dementia risk in individuals with CVD. Clin Auton Res. New simplified screening method for postprandial hypotension in older people, Treatment of orthostatic hypotension with octreotide, Local Heat Stress in Autonomic Failure Patients With Supine Hypertension, {"type":"clinical-trial","attrs":{"text":"NCT02417415","term_id":"NCT02417415"}}, Management approaches to hypertension in autonomic failure, Neurogenic orthostatic hypotension: the very basics, Treatment of supine hypertension in autonomic failure: a case series. We are grateful to Jennifer Ford (University College London) and Dr Alexander Procter (University College London Hospital) for assistance with the literature search; Professor Richard McManus (University of Oxford) for help with data presentation and interpretation; and Professor Irwin Nazareth and Dr April Slee (University College London) for assistance with data analysis. https://doi.org/10.1371/journal.pmed.1003821.s003, https://doi.org/10.1371/journal.pmed.1003821.s004, https://doi.org/10.1371/journal.pmed.1003821.s005, https://doi.org/10.1371/journal.pmed.1003821.s006. Palma JA, Gomez-Esteban JC, Norcliffe-Kaufmann L, et al. sodiumglucose cotransporter-2; SSRI, Chemical pharmacotherapy for the treatment of orthostatic hypotension. Thus, we aimed to evaluate the association between orthostatic hypotension and arterial stiffness in the adult population. Bengtsson-Lindberg M, Larsson V, Minthon L, et al. Continuum (Minneap Minn). Drugs that reduce intravascular volume (eg, diuretics) or induce vasodilatation (eg, -adrenergic blockers, nitrates, phosphodiesterase-5 inhibitors, tricyclic antidepressants, centrally acting -adrenergic agonists) exacerbate orthostatic hypotension and worsen symptoms; thus, they should be reduced or discontinued. Subgroup analysis on trials with measured and validated OH outcomes showed no difference in odds of OH between antipsychotics and placebo (OR 1.69 [95% CI 0.90 to 3.18]) (S2 Fig). There were 9 eligible trials including 2,508 patients comparing a second-generation antipsychotic to placebo. There were 3 eligible trials including 2,020 patients comparing a centrally acting antihypertensive to placebo. To our knowledge, this is the first systematic review providing an overview of which drugs are associated with OH. Krassioukov A, Eng JJ, Warburton DE, et al. This type of orthostatic hypotension happens with many common chronic conditions, especially Type 2 diabetes and Parkinson's disease. Table A. GRADE assessments. Mineralocorticoid-induced hypertension in patients with orthostatic hypotension. https://dunhillmedical.org.uk/ The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Orthostatic hypotension (postural hypotension) - Symptoms and causes - Mayo Clinic This form of low blood pressure might cause dizziness, lightheadedness or fainting when rising from sitting or lying down. Nonpharmacologic treatments for orthostatic hypotension are listed in TABLE 9-2.52-54, Nonpharmacologic Treatments for Orthostatic Hypotension. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Centrally acting antihypertensives were associated with increased odds of OH compared to placebo (OR 2.40 [95% CI 1.55, 3.74]) (Fig 3). Over 250 medications are associated with OH. Cardiovasc Hematol Disord Drug Targets. Studies were assigned an overall score: low, some concerns, or high.. official website and that any information you provide is encrypted A search strategy for general drug terms, individual drug names (identified by the international nonproprietary name (INN) in the British National Formulary (BNF) and US National Library of Medicines) were used, and drugs with name changes were accounted for [17]. Writing review & editing, Affiliation Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. . e1003821. The FDA approved midodrine in 1996 for the treatment of symptomatic orthostatic hypotension after clinical trials showed efficacy to increase standing blood pressure and improve orthostatic tolerance.70 As with other drugs for orthostatic hypotension, administration of midodrine increases blood pressure in all positions. 1 Thus, a diagnosis of orthostatic hypotension requires blood pressure measurements. RCTs comparing any drug with placebo, reporting OH as an adverse effect or outcome in adults (18 years), were included. Kamaruzzaman S, Watt H, Carson C, Ebrahim S. The association between orthostatic hypotension and medication use in the British Womens Heart and Health Study. Pathophysiology and Treatment of Orthostatic Hypotension in Parkinsonian Disorders. Palma JA, Norcliffe-Kaufmann L, Martinez J, Kaufmann H. Supine plasma NE predicts the pressor response to droxidopa in neurogenic orthostatic hypotension. lower urinary tract symptoms; OH, In patients with neurogenic orthostatic hypotension, it is imperative to perform a careful neurologic examination with particular attention to subtle signs of parkinsonism or cerebellar ataxia as well as cognitive impairment or dream-enactment behavior indicative of probable rapid eye movement (REM) sleep behavior disorder. The mean age among patients was 58.3 years, and 44.7% were female (S1 Table). Reference lists of eligible reports were reviewed, and authors were contacted to supplement incomplete papers. Lamotte G, Holmes C, Sullivan P, Goldstein DS. Drug therapy alone is never adequate. This review has several limitations. benign prostatic hypertrophy; CCB, It hampers the quality of life and increases the risk of falls, cardiovascular diseases, dementia, depression, and death. 2023 Apr;80(4):792-801. doi: 10.1161/HYPERTENSIONAHA.122.20098. Fludrocortisone is associated with a higher risk of all-cause hospitalizations compared with midodrine in patients with orthostatic hypotension, Clinical benefit of midodrine hydrochloride in symptomatic orthostatic hypotension: a phase 4, double-blind, placebo-controlled, randomized, tilt-table study. Unauthorized use of these marks is strictly prohibited. Eating high glycemic index carbohydrate snacks or drinking a glass of wine right before going to bed contributes to hypotension and can therefore be harnessed to decrease nocturnal supine hypertension. Hartley P, Forsyth F, O'Halloran A, Kenny RA, Romero-Ortuno R. Age Ageing. OH and its resulting cerebral hypoperfusion is linked to falls [4.5], fractures [5], ischaemic events [2,5], cognitive impairment [6], and mortality [5]. 1995;45(4 Suppl 5):S4S5. The use of pressor agents should be avoided within at least 4 hours before bedtime. An official website of the United States government. A significant drop in blood pressure is seen right after breakfast, lunch, and dinner (arrows), consistent with postprandial hypotension. Both these groups induce OH through combined mechanisms of sympathetic inhibition and vasodilatory effects suggesting that OH risk rises with cumulative drug targets. Orthostatic hypotension (OH) occurs when mechanisms for the regulation of orthostatic BP control fails. Neurogenic orthostatic hypotension is common in patients with diseases affecting central or peripheral sympathetic neurons. Subgroup analysis on trials with measured and validated OH outcomes, low dose (excluding high dose), and in patients at greater risk of OH (hypertension; angina; heart failure) showed similar results (S2 Fig). Baroreflex pathways for postural normotension. The extent to which specific medications are associated with OH remains unclear. A heart rate increase of at least 0.5 beats/min for each mm Hg fall in systolic blood pressure (ie, change in heart rate [HR]/change in systolic blood pressure [SBP] ratio of 0.5 beats per minute/mm Hg) has very high sensitivity and specificity to diagnose non-neurogenic orthostatic hypotension (CASE 9-1). Patients with chronic autonomic failure without motor, cognitive, or sensory symptoms receive a diagnosis of pure autonomic failure; this may remain as a restricted autonomic syndrome or patients may develop a CNS synucleinopathy years later.4 In rare cases, patients with isolated autonomic failure have a chronic form of an autoimmune autonomic neuropathy.35,36 If sensory symptoms accompany neurogenic orthostatic hypotension, a small fiber neuropathy should be suspected.37 Most commonly, as in diabetes mellitus or amyloidosis, sensory symptoms are length dependent (affecting the distal areas of extremities) and can include burning pain or absent/reduced pain and temperature sensation. Higher dosages do not improve therapeutic effects but intensify side effects. Disagreements were resolved by discussion with an adjudicator (KW) when necessary. He reported moderate constipation, erectile dysfunction, and nocturia. Orthostatic hypotension, also called postural hypotension, is a drop in blood pressure on standing to a certain extent. Less commonly, as in paraneoplastic and immune-mediated neuropathies or ganglionopathies, sensory symptoms can be patchy and diffuse, sometimes severe and widespread, resulting in devastating sensory proprioceptive ataxia.38 A family history of neurogenic orthostatic hypotension and sensory symptoms suggests hereditary transthyretin amyloidosis. Patients should avoid sugary beverages (eg, sodas, bottled juices) as high glycemic index carbohydrates can induce or worsen hypotension.59 Water and salt liberalization are necessary to expand intravascular volume. The search strategies (S1 Text) were developed without language restrictions, and the databases EMBASE, MEDLINE, and Web of Science were searched from inception to November 23, 2020. Grijalva CG, Biaggioni I, Griffin MR, Shibao CA. Symptoms appear exclusively upon standing up and abate when sitting and lying down. It causes a reduction in blood pressure (BP) on standing, which results in reduced cerebral blood flow that is linked to falls, strokes, cognitive impairment, and increased mortality. Orthostatic hypotension (OH) occurs when mechanisms for the regulation of orthostatic BP control fails. Validation, OH is common in the elderly and is associated with an increase in mortality rate. Conversion of droxidopa to norepinephrine occurs in the remaining sympathetic postganglionic terminals as well as in non-neuronal tissues, particularly the kidney.72 Droxidopa was approved in Japan in 1989 for the treatment of neurogenic orthostatic hypotension in hereditary amyloidosis, Parkinson disease, and multiple system atrophy.71 The FDA approved droxidopa in 2014 after clinical trials showed its efficacy to improve symptoms of orthostatic dizziness, lightheadedness, or feeling about to faint in adult patients with symptomatic neurogenic orthostatic hypotension caused by Parkinson disease, multiple system atrophy, pure autonomic failure, and other rare disorders affecting norepinephrine production, such as dopamine -hydroxylase deficiency characterized by defective norepinephrine release from sympathetic nerves upon standing.73-76, Similar to midodrine, droxidopa is a short-acting agent (FIGURE 9-477,78). Both medications have a fast pressor effect beginning approximately 1 hour after oral administration (green arrows). Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. https://doi.org/10.1371/journal.pmed.1003821.g003. The prevalence of neurogenic supine hypertension is 30% to 50% in Parkinson disease, 40% in multiple system atrophy, and 50% to 70% in pure autonomic failure. Funding acquisition, 1 Acute, unexpected, episodic falls in blood pressure while standing, as in neurocardiogenic syncope, do not satisfy criteria for OH. Drugs prescribed widely for common conditions including lower urinary tract symptoms, mental health conditions, pain, and insomnia are associated with significantly increased risk of OH; alternative prescribing, shorter treatment, and postural BP checks should be considered to manage this risk. In patients with neurogenic orthostatic hypotension, however, vasoconstriction is deficient, and some patients become hypotensive within 2 hours of eating.1,57 This is referred to as postprandial hypotension, and it is particularly pronounced after high glycemic index carbohydrate-rich meals. Chobanian AV, Volicer L, Tifft CP, et al. There was substantial agreement between reviewers at the title and abstract stage ( = 0.88) and full-text review stage ( = 0.87). Council on Scientific Affairs, American Medical Association, Acarbose, an alpha-glucosidase inhibitor, attenuates postprandial hypotension in autonomic failure, The osmopressor response to water drinking, The efficacy of nonpharmacologic intervention for orthostatic hypotension associated with aging, Elastic abdominal binders attenuate orthostatic hypotension in Parkinson's disease. Aung AK, Corcoran SJ, Nagalingam V, et al. She had been diagnosed with Parkinson disease 2 years earlier and was taking carbidopa/levodopa 25 mg/100 mg 3 times a day with excellent response and remaining very active. Methods and findings Recombinant human erythropoietin is administered subcutaneously at doses between 25 U/kg and 75 U/kg 3 times a week until the patients hematocrit returns to normal levels. Please enable it to take advantage of the complete set of features! Short-term side effects are frequent and include supine hypertension, hypokalemia, and ankle edema.67 Patients receiving fludrocortisone must eat potassium-rich foods or take potassium supplements (potassium chloride 20 mEq/d) to reduce the risk of hypokalemia. 1. type 2 diabetes mellitus. Lack of orthostatic symptoms in dementia patients with orthostatic hypotension. In patients with refractory neurogenic orthostatic hypotension, norepinephrine reuptake inhibition could theoretically be combined with droxidopa or midodrine, with or without fludrocortisone or pyridostigmine. In a minority of patients, orthostatic hypotension is due to reduced norepinephrine release from postganglionic sympathetic nerves, resulting in defective vasoconstriction when assuming the upright position.1 This is referred to as neurogenic orthostatic hypotension3 and is most frequently seen in patients with diabetes mellitus; neurodegenerative disorders caused by abnormal accumulation of -synuclein (ie, synucleinopathies); and small fiber neuropathies caused by amyloid, autoimmune, or paraneoplastic diseases.3,4 Patients with high spinal cord lesions can experience neurogenic orthostatic hypotension when sitting or when placed in an upright position for rehabilitation due to lack of baroreflex-mediated activation of spinal sympathetic neurons.5 Complicating the management of neurogenic orthostatic hypotension is neurogenic supine hypertension, which occurs in approximately 50% of patients with neurogenic orthostatic hypotension.6, In the general population, the prevalence of orthostatic hypotension increases with age, and the numbers vary according to different clinical settings.1,7,8 In large epidemiologic studies, such as the Cardiovascular Health Study, the prevalence of orthostatic hypotension in patients older than 65 years of age was approximately 20%, although only 2% had symptoms.9 One factor influencing the high prevalence of orthostatic hypotension in the elderly is the frequency of use of antihypertensive medications.10 Vasodilators (eg, -adrenergic blockers, calcium channel blockers, nitrates), opioids, tricyclic antidepressants, and alcohol are frequently associated with orthostatic hypotension. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Yes To avoid this, the use of a urinal or bedside commode should be encouraged. Although no specific studies have been done, concomitant use of droxidopa with norepinephrine reuptake inhibitors (eg, atomoxetine, venlafaxine) or adrenergic agonists (eg, midodrine) may enhance the pressor effect; caution is advised. Hauser RA, Biaggioni I, Hewitt LA, Vernino S. Integrated analysis of droxidopa for the treatment of neurogenic orthostatic hypotension in patients with Parkinson disease. Before See this image and copyright information in PMC. This is a sudden drop in blood pressure when standing from a sitting position or after lying down. The prevalence of neurogenic orthostatic hypotension is 50% in Parkinson disease (ie, 500,000 people in the United States), 70% in multiple system atrophy, and 100% in pure autonomic failure. Park JW, Okamoto LE, Kim SH, Baek SH, Sung JH, Jeon N, Gamboa A, Shibao CA, Diedrich A, Kim BJ, Biaggioni I. We also grouped drugs by classes and acknowledge that not all individual drugs within a class will be similarly associated with OH. Patients should be instructed to change positions gradually and briefly sit before standing. Using the revised Cochrane risk-of-bias tool for randomised trials (RoB 2) [18,19], CB assessed all articles for risk of bias, and 3 reviewers (DN, HH, and SM) independently assessed 10% of articles. These findings are based on varied certainty of evidence, which ranged from low to high. His ECG, complete blood cell count, and metabolic panel were normal. Panel B modified with permission from Kaufmann H, et al, Circulation.78 2003 American Heart Association, Inc. Droxidopa may be less effective in patients with neurogenic orthostatic hypotension and parkinsonism receiving high dosages of carbidopa (higher than 200 mg/d) as carbidopa blocks the conversion of droxidopa to norepinephrine.75,76,78,79 The most common side effects of droxidopa are hypertension, headache, and nausea. 11 . Leg crossing improves orthostatic tolerance in healthy subjects: a placebo-controlled crossover study, Use of lower abdominal compression to combat orthostatic hypotension in patients with autonomic dysfunction, Clinical practice. Panel A modified with permission from Wright RA, et al, Neurology.77 1998 American Academy of Neurology. Skip to content Care at Mayo Clinic Autonomic Dysfunction. Common short-term side effects include hypokalemia; long-term side effects include left ventricular hypertrophy and renal failure. 2007;82:308313. The primary aim of this study was to provide an overview of all drug groups and their relative association with OH. government site. 1996;46:1470. No, Is the Subject Area "Systematic reviews" applicable to this article? The mean age among patients was 53.7 years, 47.7% were female, and all trials studied major depressive disorder (S1 Table). Patients with central autonomic dysfunction (ie, decentralization) have a more pronounced pressor response to norepinephrine reuptake inhibitors, whereas patients with peripheral autonomic dysfunction (ie, denervation) have a more pronounced pressor response to norepinephrine enhancers and agonists. Methodology, Correction of aggravating factors can increase blood pressure sufficiently to improve orthostatic tolerance in some patients and should be the first step in the management of neurogenic orthostatic hypotension. However, many studies suggest a protective postural effect associated with ACE inhibitors [9,24]. Among the drugs identified, alpha-blockers were associated with least risk. government site. The drugs associated with highest odds of OH in our study (alpha-blockers, alpha-agonists, antipsychotics, beta-blockers, and TCAs) all share a common key mechanism of sympathetic inhibition causing cardioinhibitory effects [10,26]. Previous observational studies with strict measurement of postural BP have reported that beta-blockers are strongly associated with OH, independent of comorbidities, consistent with our results [13,27]. Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Midodrine (A) and droxidopa (B) have a similar short-acting pressor effect profile. In a normal response, activation of BP-regulating reflexes leads to stimulation of the sympathetic system, increasing heart rate, venous return, cardiac contractility, and vascular tone, eventually restoring BP within seconds [8]. Dr Palma receives research/grant support from the Familial Dysautonomia Foundation, Inc; the Michael J. The application of an abdominal heating pad to lower blood pressure by inducing splanchnic vasodilation is being currently studied in a clinical trial.93. Distinguishing Features of Peripheral and Central Autonomic Lesions Causing Neurogenic Orthostatic Hypotension. The patient was instructed to discontinue furosemide and tamsulosin and switch amitriptyline to fluoxetine 20 mg/d. Treatment of postprandial hypotension includes reducing high glycemic index carbohydrates, eating smaller and more frequent meals, and using the -glucosidase inhibitor acarbose. These patients require close follow-up as they may develop worsening symptoms of orthostatic hypotension at times other than after meals. P01 NS044233/NS/NINDS NIH HHS/United States, U54 NS065736/NS/NINDS NIH HHS/United States, UL1 TR000135/TR/NCATS NIH HHS/United States, Low PA. Update on the evaluation, pathogenesis, and management of neurogenic orthostatic hypotension: introduction. Epub 2023 Jan 25. Resources, Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. He was unresponsive but came to in a few seconds, startled but not confused. Subgroup analysis on trials reporting measured and validated OH outcomes, low versus high dose, and populations at greater risk of OH (hypertension; pulmonary hypertension; older patients with falls risk) showed similar results (S2 Fig). Zero total event trials were included in the meta-analysis since this can move the pooled estimate of treatment effect closer to nil, decrease its confidence interval, and decrease between-study heterogeneity [20]. Federal government websites often end in .gov or .mil. Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing compared with. For duplicate studies or pooled analyses, we included the report with the most complete data. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. Severely afflicted patients are unable to leave the supine position without experiencing presyncopal symptoms or losing consciousness. When the patient is in the supine position, both blood pressure (121/84 mm Hg) and mean velocity (Vm) of MCA blood flow (54 cm/s) are normal. Fox Foundation for Parkinson's Research; the Multiple System Atrophy Coalition; the National Institutes of Health (R01HL103988, U54NS065736); Theravance Biopharma; and the US Food and Drug Administration (FDR3731-01) and publishing royalties from UpToDate, Inc. Dr Kaufmann has served as an expert witness for the Department of Justice regarding the alleged relationship between human papilloma virus vaccination and autonomic disorders. and transmitted securely. Dr Kaufmann serves as editor-in-chief of Clinical Autonomic Research and as a consultant for and on the scientific advisory boards of Biogen, Biohaven Pharmaceuticals, Lundbeck, and Pfizer Inc. Dr Kaufmann receives research/grant support from the Familial Dysautonomia Foundation, Inc; the Michael J. Writing review & editing, Roles The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Abbas R, Tanguy A, Bonnet-Zamponi D, et al. During the daytime, the best treatment is to avoid the supine position. Dr Palma serves as managing editor for Clinical Autonomic Research and as a consultant for Biogen, Dr Reddys Laboratories Ltd, Lundbeck, and PTC Therapeutics. Use of Valsalva Maneuver to Detect Late-Onset Delayed Orthostatic Hypotension. For this, we . At night, tilting the head of the bed to a 30- or 45-degree angle lowers blood pressure.64 This is best accomplished with an electric bed or mattress. Our study suggests that drugs with combined mechanisms targeting different parts of the orthostatic BP reflex pathway may carry a harmful cumulative risk of OH. Autonomic testing confirmed neurogenic orthostatic hypotension with plasma norepinephrine levels of 102 pg/mL when supine and 138 pg/mL when standing. As polypharmacy rises worldwide in the ageing population [7], drug-induced OH is of greater concern. In patients reporting typical symptoms but without a fall in blood pressure within 3 minutes of standing, a more prolonged orthostatic stress with a tilt-table test may be necessary to define the condition. After 3 minutes in the standing position, her blood pressure was 101/81 mm Hg with a heart rate of 72 beats/min and she remained asymptomatic. https://doi.org/10.1371/journal.pmed.1003821, Academic Editor: Joshua Z. Willey, Columbia University, UNITED STATES, Received: May 17, 2021; Accepted: September 22, 2021; Published: November 9, 2021. TCAs similarly exert their effects on postural BP through combined sympathetic inhibition and reduced vascular resistance [26]. His symptoms abated after sitting or lying down, and he had never lost consciousness until the episode that took him to the hospital. Reports on antihypertensives and risk of OH in the literature are conflicted. Hypertension. Hypertensive cardiovascular damage in patients with primary autonomic failure. Because norepinephrine is released by postganglionic sympathetic neurons, low levels of plasma norepinephrine in a patient with neurogenic orthostatic hypotension indicates sympathetic denervation (ie, a peripheral lesion), whereas normal or elevated norepinephrine levels indicate decentralization (ie, a central lesion),65 although considerable overlap exists. -, Low PA. Subgroup analyses on trials with measured and validated outcomes only, at low risk of bias, in older patients and patients at greater risk of OH due to cardiovascular conditions showed similar results (S2 Fig). FOIA Because activation of renal mineralocorticoid receptors results in inflammation and fibrosis and may have a direct nephrotoxic effect leading to a faster decline in renal function and hypertension,66 fludrocortisone should be used with extreme caution in the treatment of orthostatic hypotension, preferably for short-term periods, and the dosage should never be higher than 0.2 mg/d. Orthostatic hypotension is defined as a sustained reduction in systolic blood pressure of at least 20 mm Hg or a reduction in diastolic blood pressure of at least 10 mm Hg, usually within the first 3 minutes of standing or head-up tilt on a tilt table.1 Thus, a diagnosis of orthostatic hypotension requires blood pressure measurements. Sometimes, medications are needed to treat orthostatic hypotension. Prevalence of orthostatic hypotension. Formal analysis, Droxidopa is an oral synthetic amino acid that converts to norepinephrine.71 Droxidopa is decarboxylated to norepinephrine by the enzyme aromatic L-amino acid decarboxylase, the same enzyme that converts levodopa to dopamine. In patients with vasovagal syncope, prolonged tilt may reproduce an episode.39,40 Not infrequently, patients may present with symptoms mimicking those of orthostatic hypotension but without an identified fall in blood pressure, including patients with vestibular disorders, gait abnormalities, CNS depression from alcohol and drug use, and the inebriationlike syndrome (in which patients with parkinsonism report feeling imbalanced and unsteady, as if they were slightly inebriated, but unrelated to alcohol intake).41 Conversely, patients with cognitive impairment may not accurately identify symptoms of organ hypoperfusion, despite low blood pressure when standing.42. Gibbons CH, Schmidt P, Biaggioni I, et al. Conflicts of Interest: The authors have no financial conflicts of interest. Drugs that delay or block the release of insulin, a known vasodilator, such as the -glucosidase inhibitor acarbose (50 mg to 100 mg before meals), decrease gastrointestinal absorption of glucose and are useful to treat postprandial hypotension (CASE 9-3).59 Midodrine taken right before or during meals may also help. odds ratio; PD, Disordered cardiovascular control after spinal cord injury. The https:// ensures that you are connecting to the The relationship between antihypertensives and antidiabetic drugs and OH is more complex. It impairs quality of life and increases risk of falls, cardiovascular disease, depression, dementia, and death. Our study has characterised a range of commonly prescribed drug classes according to OH risk to guide selective prescribing and monitoring of postural BP in practice. Data curation, Marked worsening occurs after prolonged bed rest that results in striatal and myocardial muscle atrophy. The red tracing denotes systolic and the blue tracing denotes diastolic blood pressure readings throughout one day. There have been reports of OH with ACE inhibitors [12] and diuretics [14,9] that were not replicated in our study. Drugs Aging. The recommended dosage varies from 100 mg to 600 mg up to 3 times a day. Alternatively, ambulatory blood pressure monitors can be employed. It appears to have synergistic effects when combined with midodrine or atomoxetine. There were 10 eligible studies including 22 trials (some studies were pooled analyses including unpublished pharmaceutical data where the original study could not be located) with 9,641 patients, comparing an SGLT-2 inhibitor with placebo. TABLE 9-1 lists features that are useful to distinguish neurogenic versus non-neurogenic orthostatic hypotension. Studies on the drug treatment of OH (such as midodrine, fludrocortisone, droxidopa, erythropoietin, pyridostigmine) and investigational or withdrawn drugs were excluded. 2023 Mar 1;52(3):afad037. Flowchart of the management of neurogenic orthostatic hypotension. 2007 Mar;7(1):63-70. doi: 10.2174/187152907780059029. Two strategies can be used to expand intravascular volume in patients with orthostatic hypotension: fludrocortisone and erythropoietin. Symptoms are a consequence of hypoperfusion of the brain (causing dizziness, lightheadedness, cognitive slowing,33 [FIGURE 9-1] and syncope), the retina and visual pathways (causing blurry, dimmed vision), the upper body muscles (causing coat hanger pain), the lungs (causing fatigue and dyspnea due to hypoperfusion of the apices), and, rarely, the heart (causing angina even with patent coronary arteries). The Cohens statistic addressed inter-rater agreement regarding eligibility. 2008;18(Suppl 1):813. Orthostatic hypotension is frequent in the elderly due to a variety of medical conditions, such as intravascular volume depletion, blood pooling (ie, varicose veins2), severe anemia, antihypertensive medications, and physical deconditioning; in these patients, orthostatic hypotension improves dramatically or resolves after the underlying cause is treated. When medications for neurogenic orthostatic hypotension are implemented, patients should be taught to avoid the horizontal position, sleep with the head of the bed raised 30 to 45 degrees, and measure their own blood pressure. Data curation, The study protocol is publicly available on PROSPERO (CRD42020168697). Orthostatic hypotension is characterized by symptoms that occur after standing (from lying or sitting), particularly when done rapidly. However, improved glucose control and other positive effects on body weight related to SGLT-2 therapy can reduce the risk of neuropathic complications [34]. 2020 The Authors. The extent to which specific medications are associated with OH remains unclear. Removal of aggravating factors and initiation of nonpharmacologic measures must always precede the use of pharmacologic agents. Causes include dehydration, long-term bed rest, pregnancy, certain medical conditions and some medications. Patients with a moderate burden of symptoms typically require a combination of nonpharmacologic and pharmacologic therapies (eg, the synthetic mineralocorticoid fludrocortisone and the pressor agents midodrine, droxidopa, or atomoxetine). However, a major problem with the use of compression stockings is noncompliance. Validation, and transmitted securely. Terkelsen AJ, Karlsson P, Lauria G, et al. Methodology, Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. Evaluation and management in older adults. Second-generation antipsychotics were associated with higher odds of OH compared to placebo (OR 2.38 [95% CI 1.38, 4.11]) (Fig 3). An in-depth understanding of the various interacting pathophysiological pathways contributing to OH-related falls is essential to guide improvements in diagnostic and treatment opportunities. Peripheral sympathetic neurons are affected in Lewy body disorders (Parkinson disease, dementia with Lewy bodies, pure autonomic failure) as well as in amyloidosis and autoimmune autonomic neuropathies but typically are spared in multiple system atrophy. Pilleri M, Facchini S, Gasparoli E, et al. (2021) Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials. Concurrent iron supplementation is typically required during the period when the hematocrit is increasing. There were 5 eligible RCTs including 721 patients comparing a CCB to placebo. We therefore excluded head-to-head drug comparisons, which are likely to be newer RCTs comparing drugs to existing treatment. Midodrine is an oral prodrug converted peripherally into the active metabolite desglymidodrine, a selective 1-adrenoceptor agonist that constricts arteriolar and venous vasculature, thus increasing blood pressure. Orthostatic hypotension is a disabling disorder that occurs frequently in the elderly as a consequence of drug effects, volume depletion, or cardiovascular deconditioning. 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