GERIATRIC MEDICINE GRAND ROUNDS January 5 th , 2012 TOPIC ORTHOSTATIC HYPOTENSION IN ELDERLY

1. GERIATRIC MEDICINE GRAND ROUNDSJanuary 5th, 2012 TOPICORTHOSTATIC HYPOTENSION IN ELDERLY PRESENTER AmanHaider, MD 1st Year Fellow – Geriatric Medicine Baylor College of Medicine

2. Sections • Introduction , Definitions & Background of Orthostatic Hypotension (OH) • Epidemiology of OH • Pathogenesis of OH • Etiology of OH • Clinical Presentation of OH • Evaluation of OH • Management of OH

3. INTRODUCTION , DEFINITION & BACKGROUND OF ORTHOSTATIC HYPOTENSION

4. Introduction • Orthostatic (postural) hypotension (OH) is a common disorder. • Frequently under diagnosed. • Frequent cause of syncope. • Contributes to morbidity, disability and even mortality. • It is a SYNDROME, and its prognosis depends on : • Its Specific Cause • Its Severity • The Distribution of its Autonomic or Non-Autonomic involvement.

5. Definition • ORTHOSTATIC HYPOTENSION is a reduction of … • Systolic blood pressure of at least 20 mm Hg OR • Diastolic blood pressure of at least 10 mm Hg • Within 3 minutes of standing. • An acceptable alternative to STANDING : • Demonstration of a similar drop in blood pressure within 3 minutes • Using a tilt table in the head-up position • At an angle of at least 60 degrees 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;46:1470

6. Limitations of Definition • Limitations: • Does not take into account : • The possibility that different blood pressure declines may have different clinical significance. • Blood pressure changes that may occur after 3 minutes of standing. 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;46:1470

7. Confounding Variables • Should be considered before making the diagnosis : • Food ingestion • Recent recumbency • Time of day • State of hydration • Ambient temperature • Postural deconditioning • Hypertension and anti-hypertensive medications • Gender • Age 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;46:1470

8. EPIDEMIOLOGY OFORTHOSTATIC HYPOTENSION

9. Prevalence Among Nursing Home Residents • One Study to “Determine Patterns Of Within-day Orthostatic Blood Pressure Changes” • Cross Sectional study with 911 residents from 45 nursing homes . • Aged 60 years or older, able to stand for at least 1 minute. • Supine ,1-minute and 3-minute standing BP + HR were measured. • Before and after breakfast and before and after lunch. • No OH = 48.5% • Only once = 18.3% • 2-3 times = 19.9% • 4 or more times = 13.3% • Most prevalent before breakfast, especially 1 minute after standing (21.3%) • Least prevalent after lunch, after 3 minutes of standing (4.9%) Ooi WL, Barrett S, Hossain M, Kelley-Gagnon M, Lipsitz LA. Patterns of orthostatic blood pressure change and their clinical correlates in a frail, elderly population. JAMA. 1997 Apr 23-30; 277(16):1299-304.

10. Prevalence In Community- Dwelling Elderly • A study to “Assess Prevalence of Orthostatic Hypotension and its Associations”. • A multicenter, observational, longitudinal study . • Enrolled 5,201 men and women aged >65 yrs. • Prevalence 14.8% for those age 65 to 69and 26% for those age >85 • OH was associated significantly with : • Difficulty walking (odds ratio, 1.23) • Frequent falls (odds ratio, 1.52) • H/o MI (odds ratio, 1.24) • H/o TIA (odds ratio, 1.68) • Isolated systolic hypertension (odds ratio, 1.35) • Major EKG abnormalities (odds ratio, 1.21) • Presence of carotid artery stenosis based on ultrasound (odds ratio, 1.67) • Negatively associated with weight. Rutan GH, et al. Orthostatic hypotension in older patients. The cardiovascular health study. CHS collaborative research group. Hypertension. 19(6 Pt 1):508-519, June 1992

11. PATHOGENESIS OFORTHOSTATIC HYPOTENSION

12. Normal Postural Changes in BP • Normal BP response on moving from a supine to a standing position : • Small reduction (<10 mm Hg) in SBP & increase in DBP (~ 2.5 mm Hg). • Gravity Induced Drop  Approximately 500 to 1000 ml of blood is pooled in the lower extremities and in the splanchnic and pulmonary circulations. • Response (Baroreflex) : • Gravity Induced Drop • Decreased venous return to the heart • Transient reduction in CO and BP • Stimulation of the baroreceptors in carotid arteries and aorta • Reflexively increased sympathetic tone  Increased PVR (Vasoconstriction) • Inhibits parasympathetic activity  Increased HR • Restoration of CO and BP by an increase in HR and PVR.

13. Postural Changes in Elderly • “Age-Related Changes” that can effect normal BP Regulation :

14. ETIOLOGYOFORTHOSTATIC HYPOTENSION

15. Etiology Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly: diagnosis and treatment. Am J Med 2007 Oct; 120 (10):841-847.

16. Drug that may Worsen OH Figueroa JJ, Basford JR, Low PA, Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleve Clin J Med, 77:2010, 298-306.

17. CLINICAL FEATURESOFORTHOSTATIC HYPOTENSION

18. Symptoms • Symptoms that develop … • On assuming erect posture, OR • Following head-up tilt, and usually • Resolve on resuming the recumbent position. • Symptoms include : • Lightheadedness, dizziness, blurred vision, weakness, fatigue, cognitive impairment, nausea, palpitations, tremulousness, headache, and neck ache (Coat Hanger Ache) 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;46:1470. • In Elderly, disturbed speech, visual changes, falls, confusion, and impaired cognition are more common. Rutan GH, Hermanson B, Bild DE, et al. Orthostatic hypotension in older adults. The Cardiovascular Health Study. Hypertension. 1992; 19:508-519.

19. OH – A Predictor of Mortality Orthostatic Hypotension Predicts Mortality in Elderly Men The Honolulu Heart Program • A cohort of 3522 Japanese American men 71 to 93 years old. • Total of 473 deaths in the cohort over 4 years. • 52 of those who died had orthostatic hypotension • 4 year all cause mortality = Relative Risk 1.64 ( 95% CI 1.19 to 2.26 ** ) ** With the use of Cox proportional hazards models, after adjustment for age, smoking, diabetes mellitus, body mass index, physical activity, seated systolic blood pressure, antihypertensive medications, hematocrit, alcohol intake, and prevalent stroke, coronary heart disease and cancer Masaki KH, Schatz IJ and Burchfiel CM. Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation. 1998; 98: 2290-2295

20. Prognosis Of OH • In patients who have extrapyramidal and cerebellar disorders (eg, PD , MSA) • The earlier and the more severe the involvement of the autonomic nervous system, the poorer the prognosis - Sandroni P, Ahlskog JE, Fealey RD, Low PA. Autonomic involvement in extrapyramidal and cerebellar disorders. ClinAuton Res 1991; 1:147–155. - Saito Y, Matsuoka Y, Takahashi A, Ohno Y. Survival of patients with multiple system atrophy. Intern Med 1994; 33:321–325. • In hypertensive patients with diabetes mellitus, the risk of death is higher if they have orthostatic hypotension. Luukinen H, Koski K, Laippala P, Kivelä SL. Prognosis of diastolic and systolic orthostatic hypotension in older persons. Arch Intern Med 1999; 159:273–280. • Diastolic OH is associated with a higher risk of vascular death in older persons. Hoeldtke RD, Streeten DH. Treatment of orthostatic hypotension with erythropoietin. N Engl J Med 1993; 329:611–615.

21. EVALUATIONOFORTHOSTATIC HYPOTENSION

22. Evaluation In ER Setting • Syncope may be the initial presentation. • A study to evaluate cause of syncope in 611 patients presenting at the ER. • 24 % had orthostatic hypotension. Sarasin FP, Louis-Simonet M, Carballo D, et al. Prospective evaluation of patients with syncope: a population-based study. Am J Med. Aug 15 2001;111(3):177-84

23. Evaluation In Inpatient Care Setting • The annual nationwide inpatient sample (NIS), sponsored by the AHRQ • During 2004, 80,095 orthostatic hypotension- related hospitalizations. • OH listed as the primary diagnosis in 28,073 (35%) hospitalizations. • Most frequent secondary diagnoses were : • Atrial fibrillation (10.7%) • Hypertension (8.9%) • Syncope (8.2%) • Chronicobstructive pulmonary disease (7.7%) • Congestive heart failure (6.7%) • Urinary tract infection (4.6%) Shibao C, Grijalva CG, Raj SR, Biaggioni I, Griffin MR. Orthostatic hypotension-related hospitalizations in the United States. Am J Med. 2007 Nov;120(11):975-80

24. Evaluation In Outpatient Care Setting • More likely to have Chronic Etiologies • Referred from the ER or hospital upon discharge for further testing. • Usually have vague/ undifferentiated symptom description. • Discontinuing vs changing medications • MRI can be used to assess for possible etiologies of neurogenic orthostatic hypotension. • Further testing as indicated.

25. Evaluation • Evaluation Of Suspected OH • Begins by identifying reversible causes • Underlying associated medical conditions. • In addition to assessing for symptoms of orthostasis • Elicit symptoms of autonomic dysfunction involving the GI and GU tract. • Detailed assessment of the motor nervous system should be performed to evaluate for signs of parkinson’s disease, as well as cerebellar ataxia.

26. Evaluation of Orthostatic Hypotension Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly: diagnosis and treatment. Am J Med 2007 Oct; 120 (10):841-847.

27. HistorY Evaluation and Management of Orthostatic Hypotension ; American Family Physician Volume 84, Number 5 ; September 1, 2011

28. PHYSICAL EXAM • Obtain Orthostatic Vital Signs. • Supine Blood Pressure and pulse after 3 minutes • Standing Blood Pressure and pulse after 3 minutes • As many as 2/3rd of patients may go undetected if BP is not measured while supine. Carlson JE. Assessment of orthostatic blood pressure:measurement technique and clinical applications. South Med J 1999; 92: 167–173. • One retrospective review of 730 patients found that vital signs had poor test characteristics when compared with tilt-table testing for the diagnosis of OH. • PPV = 61.7 % • NPV= 50.2 % Cooke J, Carew S, O’Connor M, Costelloe A, Sheehy T, Lyons D. Sitting and standing blood pressure measurements are not accurate for the diagnosis of orthostatic hypotension. QJM. 2009;102(5):335-339.

29. Physical Exam Evaluation and Management of Orthostatic Hypotension ; American Family Physician Volume 84, Number 5 ; September 1, 2011

30. Ancillary Tests / Imaging Evaluation and Management of Orthostatic Hypotension ; American Family Physician Volume 84, Number 5 ; September 1, 2011

31. Head Up-Tilt (HUT) • Indications for Head-up tilt testing • High probability of OH despite an initial negative evaluation (e.g., PD) • Patients with significant motor impairment that precludes them from having standing vital signs obtained. Lahrmann H.; Cortelli P.; Hilz M.; Mathias C.J.; Struhal W.; Tassinari M. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur. J. Neurol. 2006, 13, 930-936 • To monitor the course of an autonomic disorder and its response to therapy. Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly: diagnosis and treatment. Am J Med 2007 Oct; 120 (10):841-847

32. Procedure of HUT • Perform tilt-table testing in a quiet room with a temperature of 68°F to 75°F. • The patient should rest while supine for 5 minutes before testing is started. • Continuous HR monitoring and blood pressure monitoring at regular intervals. • The table should be slowly elevated to an angle between 60 to 80 * for 3 minutes. • The test is considered Positive if systolic blood pressure falls 20 mm Hg below baseline or if diastolic blood pressure falls 10 mm Hg below baseline. • Measurement of plasma noradrenaline levels while supine and upright may be of some value. • If symptoms occur during testing, the patient should be returned to the supine position immediately.

33. Evaluation • The procedure is generally considered safe, but serious adverse events such as syncope and arrhythmias have been reported.

34. Responses to Head-Up Tilt Table Testing

35. Management of Orthostatic Hypotension

36. GOALS • DO NOT CHASE THE NUMBERS ….!!!! • Goals should be directed towards : • Ameliorating symptoms • Relieving orthostatic symptoms • Improving the patient’s functional status • Improving standing time • Reducing the risk of complications. • Improving OH without excessive hypertension • Correcting any underlying cause • No specific or single treatment is currently available that achieves all these goals. • Drugs alone are never completely adequate. .

37. Supine Hypertension • Supine hypertension is a problem. • Resulting from medication and/or being part of the disease. • 24 h measurement of BP is best if diagnosis uncertain. • After starting a new therapy. • Patients may self-monitor BP, daily at about the same time, and • when they experience symptoms. • Pressor medications should be avoided after 6pm and the bed head elevated (20–30 cm). • On occasion, short acting antihypertensive drugs may be considered (e.g. • Nitro-glycerine sublingual). Lahrmann H.; Cortelli P.; Hilz M.; Mathias C.J.; Struhal W.; Tassinari M. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur. J. Neurol. 2006, 13, 930-936 .

38. Management Pneumonic A B C D E F • A  Abdominal compression • B  Bolus of water • B  Bed up • C  Countermaneuvers • D  Drugs • E  Education • E  Exercise • F  Fluids and salt .

39. Non-Pharmacologic Treatment • A : Abdominal and Lower Extremity Binders Podoleanu C, Maggi R, Brignole M, et al. Lower limb and abdominal compression bandages prevent progressive orthostatic hypotension in elderly persons: a randomized single-blind controlled study. J Am CollCardiol. 2006;48(7):1425-1432. • B : Upto 1 to 2 L of fluid/ day to balance expected 24-hour urine losses  increase • standing SBP by > 20 mm hg for approx. two hours. Shannon JR, Diedrich A, Biaggioni I, et al. Water drinking as a treatment for orthostatic syndromes. Am J Med. 2002;112(5):355-360 • B : Raise the head of the bed 10 to 20 degrees (~ 4 inches )  pts with autonomic • failure and supine hypertension  reduce nocturnal hypertension and diuresis •  helps restore morning blood pressure upon standing. • Van Lieshout JJ, Ten Harkel AD, Wieling W. Fludrocortisone and sleeping in the head-up position limit the postural decrease in • cardiac output in autonomic failure. Clin AutonRes 2000; 10:35–42. • C : - Isometric exercises involving the arms, legs, and abdominal muscles. • - Active standing with legs crossed, with or without leaning forward. • Low PA, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 2008;7(5):451-458. .

40. Non-Pharmacologic Treatment • D : D/c culprit medications  If unable to D/C culprit medications; advise patient to • take at bedtime such as anti-hypertensives. • Freeman R. Clinical practice. Neurogenic orthostatic hypotension. N Engl J Med. 2008;358(6):615-624. • E : Education • Symptom diary  avoid identified precipitating factors • Avoid large carbohydrate-rich meals (to prevent postprandial hypotension) • Limit alcohol intake Lahrmann H.; Cortelli P.; Hilz M.; Mathias C.J.; Struhal W.; Tassinari M. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur. J. Neurol. 2006, 13, 930-936 • E : Exercise programs improves conditioning. • Squatting has been used to alleviate symptomatic OH • Toe raises, thigh contractions, and bending over at the waist are recommended Low PA, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 2008;7(5):451-458 .

41. Non-Pharmacologic Treatment • F : Fluid & Salts • Upto 1 to 2 L of fluid/ day  increase standing SBP by > 20 mm hg. Shannon JR, Diedrich A, Biaggioni I, et al. Water drinking as a treatment for orthostatic syndromes. Am J Med. 2002;112(5):355-360 • Sodium supplementation  adding extra salt to food or taking ~ 1 to 2 gms of salt • tablets TID. • A 24-hour urine sodium level can aid in treatment. • Value of <170 mmol per 24 hours, should be placed on 1 to 2 g of • supplemental sodium three times daily • Reevaluate in one to two weeks • Goal of raising urine sodium to between 150 and 200 meq. • Patients should be monitored for weight gain and edema. Low PA, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 2008;7(5):451-458 .

42. FLUDROCORTISONE • A synthetic mineralocorticoid. • Reducing salt loss and expanding blood volume. • Hussain RM, McIntosh SJ, Lawson J, Kenny RA. Fludrocortisone in the treatment of hypotensive disorders in the elderly. • Heart 1996; 76:507–509. • Sensitization of alpha-adrenoceptors. • First line therapy (monotherapy) approved by FDA in 1955. • Initial dose is 0.1 mg per day with increments of 0.1 mg every week. • May be increased to 0.4 to 0.6 mg/day in refractory cases. • Dose titration needed until : • Resolution of the symptoms OR • Patient develops trace peripheral edema OR • Weight gain of 4 to 8 lbs OR • The maximum dose of 1 mg per day is reached. Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly: diagnosis and treatment. Am J Med 2007 Oct; 120 (10):841-847. .

43. FLUDROCORTISONE • After oral administration, • Peak plasma levels ~ 45 min • Elimination half-life ~ 7 h. • Adverse effects include : • Headache • Supine hypertension • Congestive heart failure • Hypokalemia • Dose-dependent • In one study, hypokalemia in 24% of patients with mean onset at 8 • months. Hussain RM, McIntosh SJ, Lawson J, Kenny RA. Fludrocortisone in the treatment of hypotensive disorders in the elderly [published correction appears in Heart. 1997;77(3):294]. Heart. 1996;76(6):507-509. .

44. MIDODRINE • Prodrug with an active metabolite, Desglymidodrine. • Peripheral selective alpha-1 adrenergic agonist; cause vasoconstriction. • Absolute bioavailability ~ 93% • The elimination half-life ~ 2–3 h • Duration of action ~ 4 h. • First approved by FDA in 1996. • Significantly increase systolic BP  avoid last dose after 6 pm to avoid supine HTN. • Improve symptoms in patient with Neurogenic Hypotension. • Synergistic effect when combined with fludrocortisone. • Starting dose = 2.5 mg 3 times per day. • Then 2.5 mg weekly increments until a max. of 10 mg TID is reached. • Before arising from bed in morning ---- Before lunch ---- Mid-afternoon .

45. MIDODRINE • Adverse effects : • Supine Hypertension (25%) • Piloerection/ goose bumps (13%) • Pruritis (scalp-10% & general- 2%) • Paresthesia (9%) • Contraindications : • Coronary Artery Disease • Urinary Retention (worsens urinary retention) • Thyrotoxicosis • Acute Renal Failure (Excreted in urine) • FDA has issued a recommendation to withdraw midodrine from the market because • of a lack of post-approval effectiveness data. U.S. Food and Drug Administration. Drug safety and availability. Midodrine update. September 2010. .

46. PROSTAGLANDIN INHIBITORS • Block the vasodilating effects of prostaglandins  raise the BP in some patients. • Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly: diagnosis and treatment. Am J Med 2007 Oct; 120 (10):841-847. • In elderly patients, indomethacin should be avoided because of associated • confusion. • All NSAIDS should be used with caution due to gastrointestinal and renal side • effects. .

47. CAFFEINE • Adenosine-receptor blocker . • Inhibits adenosine induced vasodilatation by blocking these receptors. • Methylxanthine Caffeine • Administered in a dose of 200 mg every morning as 2 cups of brewed coffee • or by tablet. • May attenuate symptoms in some patients. • To avoid tolerance and insomnia, caffeine should not be given more then • once in the morning. .

48. ERYTHROPOIETIN • Exact mechanism of action is unknown • Effect is probably due to increased red cell mass and blood volume. • Shown to be effective in a subgroup of patients with anemia and autonomic • dysfunction. • Hoeldtke RD, Streetan DHP. Treatment of orthostatic hypotension with erythropoietin. N Engl J Med. 1993;329:611-615. • Principal disadvantage of this drug is the Parenteral route of administration. • Serious side effects include: • Hypertension • Stroke • Myocardial infarction .

49. PYRIDOSTIGMINE • Cholinesterase inhibitor • Potentiates sympathetic baroreflex pathway. • Approved by FDA : • Myaesthenia Gravis (1955) • Bioterrorism Increase survival after exposure to Soman "nerve gas" poisoning (2003) • Off-Label use for Orthostatic Hypotension • Used for patients with mild to moderate hypotension due modest pressor effect. • Does not aggravate supine hypertension. • Enhanced effect when taken with Midodrin 5 mg. • Starting Dose : 30 mg TID  increased to 60 mg TID. • 180 mg slow release pyridostigmine (MestinonTimespan) can be taken once a day. .

50. PYRIDOSTIGMINE • Adverse effects : • Loose stools • Diaphoresis • Hypersalivation • Fasciculations .