1. Neurogenic Orthostatic Hypotension Dr. Kurt Kimpinski Department of Clinical Neurological Sciences University Hospital, LHSC London, ON April 10 th, 2013

2. Disclosures Relevant Financial Relationship(s) None Off Label Usage Pyridostigmine for treatment of NOH

3. Objectives To provide an approach to the diagnosis of Neurogenic Orthostatic Hypotension (NOH) Review the management of NOH with a focus on Conservative treatment measures Pharmacotherapy Avoidance/treatment of supine hypertension

4. Definitions Neurogenic Orthostatic Hypotension: a fall in postural systolic blood pressure ≥30 mmHg. False positive rate = 1% Other definitions: A fall in postural systolic blood pressure ≥20 mmHg or diastolic ≥10 mmHg. False positive rate = 5%

5. The continuum of orthostasis Normal Orthostatic Intolerance Orthostatic Hypotension POTS Progressive orthostatic dysfunction

6. The continuum of orthostasis

7. Tilt Table: Head-up Tilt (HUT) Orthostatic Intolerance

8. HUT: Postural Tachycardia

9. HUT: Orthostatic Hypotension

10. Prevalence of NOH DisorderPrevalence Aging10-30% NIDDM7.4% Parkinson’s Disease37-48% Multiple Systems Atrophy5-15 per 100 000 Pure Autonomic Failure10-30 per 100 000 Other Autonomic Neuropathies10-50 per 100 000

11. Clinical evaluation I. Autonomic dysfunction with NOH Presence/severity of NOH Onset/progression Associated autonomic dysfunction Distribution Severity

12. Clinical evaluation II. Evaluation of autonomic disorders over time NOH, can be dynamic in its presentation depending on numerous variables Evaluation of autonomic dysfunction on other organ systems NOH can worsen cerebral and other tissue perfusion NOH can be worsened by anemia Evaluation of the effect of NOH on Quality of Life

13. Clinical evaluation: History Orthostatic intolerance/hypotension Gastrointestinal Upper GI dysfunction, dysmotility Genitourinary Erectile dysfunction Distal sensory changes Sudomotor (sweating) anhidrosis

14. Symptoms: Orthostatic Hypotension Lightheadedness…………….88% Weakness or tiredness…….72% Blurred vision………………….47% Cognitive changes…………..47% Headache……………………….25-80% Vertigo……………………………37% Pallor………………………………31% Low et al. 1995, Mayo Clin. Proc. 70:617-622.

15. Diagnose and severity of NOH Take BP supine, 1 min. and 3 min. of standing – Fall in BP by:  30 mm Hg systolic within 3 minutes of standing up Recognize orthostatic stressors time of day (AM) warming (hot day, bath) Meal, Water intake prolonged standing exercise

16. Head-up Tilt: NOH 1. Fall in SBP ≥ 30 mmHg 2. No compensatory HR increase on HUT 3. Prolonged HUT can increase sensitivity for milder NOH

17. NOH: differential diagnosis Hypovolemia Endocrine abnormalities Adrenal insufficiency, hypothyroid Electrolyte disturbances Cardiac abnormalities Arrhythmia, restrictive diseases Medications Beta-blockers, anticholinergics, anti-hypertensives, etc.

18. Clinical evaluation: Clinical Exam Sudomotor dry skin, regions of hyperhidrosis Gastrointestinal - plain film, motility studies Genitourinary – post void residuals Visual pupils (Adies) Acral - small fiber neuropathy

19. Orthostatic Hypotension (OH): Treatment Goals Reduce OH without supine hypertension Increase standing time Improve ADLs Reduce symptoms Improved ability to handle orthostatic stresses Hot days, stressful situations, after meals etc.

20. Safety

21. Patient Education Recognize orthostatic symptoms Manage orthostatic stressors Morning, meal, heat, standing, exercise Blood Pressure log Dietary education (salt/fluids) Medications and situations to avoid Physical counter maneuvers Postural and resistance training

22. BP & Symptom Log Supine and standing (3 min) BP After medications Early AM and QHS Before and after meal When symptomatic Supine BP qhs after lying for 15 minutes To detect supine hypertension

23. Orthostatic Hypotension – Treatment Conservative Measures I. High fluid intake (>40 oz/d); High salt diet (10-20g/d) i.e. normal North American diet Plasma volume: 24 hour urinary Na +2 Volume: 1500-2500 mL/24 h Sodium: > 170 mmoL/24h

24. Orthostatic Hypotension – Treatment Conservative Measures II. Physical counter maneuvers and resistance training Focusing on lower extremity aerobic and anaerobic exercises Compression garments Abdominal binder Elevate head of bed 4 inches to reduce nocturnal hypertension to reduce nocturia

25. Head of Bed Elevated 4 Inches

26. Physical counter maneuvers

27. Pressor Effect of Water Drinking Jordan et al. Circulation 2000 101(5):504-509

28. Orthostatic Hypotension – Treatment Medications Consider pyridostigmine 30-60 mg b.i.d. or t.i.d. Consider midodrine 5-10 mg t.i.d. last dose 6PM Consider fludrocortisone Milder forms of NOH

29. Midodrine Treatment Avoid after 6 PM Reduce dose of fludrocortisone Tailor dose and timing: larger dose at time of maximal need omit during periods of reduced orthostatic stress avoid excessive hypotension Judicious use of BP log supine/standing; orthostatic stress, avoid supine HTN

30. Midodrine: Contraindications Severe ischemia coronary, cerebral, limb, gastrointestinal Aneurysm cerebral, aortic Significant supine hypertension Urinary retention

31. Midodrine: Effect on Standing BP; Multicenter Study Controlled Study Low et al. JAMA 1997 277(13):1046-1050

32. Midodrine: Effect on Standing Symptoms; Multicenter Study Controlled Study Low et al. JAMA 1997 277(13):1046-1050

33. Pyridostigmine for OH Enhancing ganglionic transmission by acetylcholinesterase inhibition traffic through sympathetic ganglia modest in supine position great increase in standing position Vasomotor effects proportional to orthostatic needs

34. Pyridostigmine for OH: Symptoms Improvement Singer et al. JNNP 2003 74(9):1294-1298

35. Pyridostigmine for OH: Effects on Systolic Blood Pressure Singer et al. JNNP 2003 74(9):1294-1298

36. Overall approach to medications Individual medication profiles Side effects, contraindications Milder NOH – pyridostigmine Mild to Moderate NOH Flourinef Midodrine ± pyridostigmine Severe OH or when there is variability of the dosing schedule Midodrine

37. Other drugs with potential in NOH L-DOPS (droxidopa) Currently used in Japan, in phase III U.S. trials Octreotide In NOH with severe GI dysmotility Erythropoetin Correct anemia Vassopressin For AM NOH and reduce nocturia

38. Management of supine hypertension I. In mild NOH pyridostigmine may be the best option or as an adjunct medications Minimal effect on supine BP, may limit the necessity for higher doses of midodrine Avoid medications after 6PM or prior to prolonged periods of being supine midodrine

39. Management of supine hypertension II. Elevate HOB Glass of red wine Hydralazine 25 mg qhs

40. Conclusions. Patient educations is a must. Conservative measures are as important as pharmacology in the treatment of OH. Maximize plasma volume. Avoid or minimize supine hypertension.