Diagnosis and Treatment of Syncope. Chang Gung Memorial Hospital, Chiayi Department of Pharmacy Serve Speaker: Yi-Shiou Chen Date:2013/11/27

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1 Diagnosis and Treatment of Syncope Chang Gung Memorial Hospital, Chiayi Department of Pharmacy Serve Speaker: Yi-Shiou Chen Date:2013/11/27

2 Basic information Classification of Syncope Diagnosis Treatment Conclusions

3 Definition Syncope (derived from the Greek words, syn meaning with and the verb koptein meaning to cut or more appropriately in this case to interrupt ) is a symptom. It s defined as a transient, self-limited loss of consciousness, usually leading to falling. The onset of syncope is relatively rapid, and the subsequent recovery is spontaneous, complete, and usually prompt. Brocklehurst's Textbook of Geriatric Medicine and Gerontology-SEVENTH EDITION, CHAPTER 46,

4 Pathophysiology

5 Classification of syncope Syncope must be differentiated from other non-syncopa conditions which also lead to transient loss of consciousness. Pathophysiological classification is based on the principal causes of the transient loss of consciousness. Eur Heart J 2001: 22:

6 Classification of transient loss of consciousness Real or apparent Transient loss of consciousness commonly misdiagnosd as syncope Syncope Neurally mediated (reflex) Orthostatic Hypotension Cardiac arrhythmias Structural cardiac or cardiopulmonary disease Cerebrovascular Non-syncopal Disorders resembling syncope with impairment or loss of consciousness, e.g. seizure Disorders resembling syncope without loss of consciousness, e.g. psychogenic "syncope" Eur Heart J 2001: 22:

7 Classification of syncope Neurally mediated reflex syncope (17-22%) Vasovagal (14%) Situational Carotid sinus syndrome Orthostatic Hypotension (11%) Cardiac (17%) Arrhythmias Structural heart diseases Neurologic (7%) Seizure Transient ischemic attack (TIA) Subclavian steal Migraine Unknown (39%) Circulation. 2002; 106:

8 Epidemiology and Natural History Syncope is a common presenting problem, accounting for approximately 3% of all emergency room visits and 1% of all hospital admissions. The peak incidence in the young occurs between ages 10 and 30 years, with a median peak around 15 years. Neurally mediated syncope is the etiology in the vast majority of these cases. Harrison's Online:chapter 20. syncope

9 Common causes of syncope by patient age Syncope: Mechanisms and Management, Second Edition

10 Medications that may induce syncope Cardiovascular agents Beta-blockers Vasodilators (beta-blockers, calcium channel blockers, nitrates, hydralazine, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, phenothiazines, phosphodiesterase inhibitors) Diuretics Central antihypertensives (clonidine, methyldopa) Other antihypertensives (guanethidine) QT-prolonging agents (amiodarone, disopyramide, flecainide, procainamide, quinidine, sotalol) Other antidysrhythmics Anticonvulsants (carbamazepine, phenytoin) Antiparkinsonian agents Central nervous system depressants (barbiturates, benzodiazepines) Monoamine oxidase inhibitors Antidepressants Narcotic analgesics Sedating and nonsedating antihistamines Cholinesterase inhibitors (donepezil, tacrine, galantamine) Drugs of abuse (cannabis, cocaine, alcohol, heroin) Digitalis Insulin and oral hypoglycemics Neuropathic agents (vincristine) Nonsteroidal anti-inflammatory drugs Bromocriptine Marx: Rosen's Emergency Medicine Concepts and Clinical Practice, 8th ed.

11 Two general categories Vasovagal Syncope Orthostatic hypotension

12 Vasovagal Syncope (VVS) Most frequent cause of syncope Also known as the common faint, reflex syncope, and vasovagal syncope. It is likely caused by reflex activation of vagal efferent pathways and sympathetic inhibition triggered by various neurologic inputs. Who is most affected: pediatric and young patients possible bimodal age: and > 70 years A Practical Approach to Cardiovascular Medicine, First Edition.

13 Orthostatic hypotension Orthostatic hypotension (OH) is defined as a sustained reduction of systolic blood pressure (SBP) of at least 20 mm Hg or diastolic blood pressure (DBP) of 10 mm Hg within 3 minutes of standing or head-up tilt to at least 60 on a tilt Table. Journal of the American Society of Hypertension. 2013, 7(4): Common causes are: Autonomic dysfunction (diabetic neuropathy) Volume depletion (diarrhea, hemorrhage) Postural orthostatic tachycardia syndrome (POTS) Drug - induced

14 Diagnosis

15 Initial evaluation History: Is loss of consciousness attributable to syncope or not? Is heart disease present or absent? Are there important clinical features in the history that suggest the diagnosis? Physicsl examination Supine and upright BP Standard ECG

16 The diagram of the evaluation of syncope Eur Heart J 2001: 22:

17 Treatment Lifestyle modifications Nonpharmacological therapy Pharmacological therapy

18 Lifestyle modifications Avoidance of excessively hot environments, carbohydrate-rich meals, alcohol. Rising slowly, raising the head of the bed Using elastic stockings. Increased exercise

19 Lifestyle modifications Water intkae Water supplements: L/day Minimum daily water consumption goal L for older adults Water bolus- one 480 mlgalss of water or two 250 ml glasses of cool water in rapid succession

20 Lifestyle modifications Salt tablets Salt stimulates water retention and thereby increases plasma volume as well as orthostatic tolerance. Salt tablet supplements: g 1-2 g of supplemental sodium 3 times per day in patients with urine sodium levels< 170 mmol per 24hours

21 Nonpharmacological therapy

22 Physical counter-pressure maneuvers (PCM) There are intended to reduce lower-extremity venous pooling and therefore improve cardiac output and prevent vasovagal syncope. Leg crossing (with simultaneous tensing of leg, abdominal, and buttock muscles) Handgrip (which consists of maximum grip on a rubber ball or similar object. ) Arm tensing (which involves gripping one hand with the other while simultaneously abducting both arms )

23 The subject is depicted using leg-crossing with lower body muscle tensing (left) or squatting (right) to enhance blood pressure. Journal of the American College of Cardiology. 2009;53 (19):

24 Arm tensing consists of isometric contraction of the 2 arms accomplished by gripping on hand with the other and concurrently abducting the arms. Journal of the American College of Cardiology. 2009;53 (19):

25 Tilt-Training (Standing-Training) It is to enhance neurovascular response to orthostatic stress The target is 20 to 30 min twice daily Thereafter, 20 min sessions 3 to 4 times/week. Journal of the American College of Cardiology. 2009;53 (19):

26 Pharmacological therapy Alpha-adrenergic agonists Beta Blockers Selective Serotonin Reuptake Inhibitors Disopyramide Anticholinergic Agents Fludrohydrocortisone

27 Alpha-adrenergic agonists The binding of α-adrenergic agonists to receptors of arteriolar and venous vasculature could enhance peripheral vascular tone thereby helping to maintain blood pressure. Midodrine is currently the only US Food and Drug Administration approved medication for the treatment of orthostatic hypotension. Midodrine 2.5 mg/tab

28 Beta-blocker Inhibiting myocardial contractility: diminished hypercontractile activation of mechanoreceptors Intagonizing the initial catecholamine surge: catecholamine withdrawal and parasympathetic dominance. Metoprolol Betaloc ZOK 25mg/tab Pharmacotherapy 2000;20 (2):

29 Selective serotonine re-uptake inhibitors (SSRIs) Serotonin is known to modulate central nervous system BP and heart rate. This results in a downregulating postsynaptic central serotonin receptor levels, blunting the response to abrupt changes in central serotonin levels. Paroxetine; Sertraline; fluoxetine Seroxate 12.5mg/tab, 20mg/tab CenZoft Concentrate Solution Sinzac 20mg/cap

30 Disopyramide Disopyramide may be useful due to its negative inotropic (inhibition of myocardial mechanoreceptors) and anticholinergic properties. JAMA 1992 Nov 11;268(18):2553. These effects could prevent the occurrence of neurallymediated reflex syncope. Disopyramide 100mg/cap

31 Anticholinergic agents Blocking the activity of the nervus vagus with anticholinergic agents could prevent the bradycardia occurring in patients with neurally mediated reflex syncope. anticholinergic agents may be more useful in patients with profound bradycardia during upright tilt table testing. transdermal scopolamine, IV atropine

32 Fludrocortisone Fludrocortisone is a fluorinated corticosteroid with primarily mineralocorticoid activity, with resultant sodium and water retention and potassium excretion. Increasing renal reabsorption of sodium, thereby increasing blood volume, although it also may affect baroreceptor sensitivity. Florinef 0.1 mg/tab

33 Drug therapy: Vasovagal syncope Drug Dose Side effects Comment Metoprolol PO 25 mg BID Depression Fatigue Midodrine PO mg Q4H 3/day supine hypertension nausea Fludrocortisone PO mg QD Hypokalemia, supine hypertension Disopyramide PO150 mg TID CHF hypotension would use in the elderly or hypertensive patient avoid within 4 5 h of bedtime It poorly tolerated by older people Negative effects on postural blood pressure changes Paroxetine PO 20 mg QD headache would only use if psychosocial are present issues

34 Drug therapy: Vasovagal syncope β-adrenergic blockers: A recent meta-analysis demonstrated a statistically significant difference in response in those aged <42 years and 42 years (test of interaction P=0.007). beta-blockers are one of the few pharmacological treatments for VVS that do not increase BP, so beta- blockers might be a reasonable choice for older patients with comorbid hypertension. Progress in Cardiovascular diseases. 2013; 55(4):

35 Drug therapy: Vasovagal syncope β-adrenergic blockers: In 2006, a randomized, placebo-controlled, double-blinded trial assessing the usefulness of metoprolol in preventing syncope showed no benefit compared with placebo. β-adrenergic blockers is probably unhelpful and they should not be used as first-line therapy. Pediatric Cardiovascular Medicine, Second Edition.

36 Drug therapy: Vasovagal syncope Selective serotonine re-uptake inhibitors (SSRIs) Small randomized trials have shown reduction of syncope and/or improvement in tilt table syncope with selective serotonin reuptake inhibitors, but their clinical use in syncope is not well established. SSRIs might be helpful in dealing with the psychosocial stress that can result from recurrent syncope.

37 Drug therapy: Orthostatic hypotension Drug Dose Side effects Comment Fludrocortisone Start at 0.1 mg per day, titrate in increments of 0.1 mg per week to maximum dosage of 1mg per day. Hypokalemia, supine hypertension, heart failure, headaches Potassium supplements Midodrine Start at 2.5 mg 3 times per day, titrate with 2.5 mg increments weekly unit maximum dosage of 10 mg 3 times per day. supine hypertension nausea avoid within 4 5 h of bedtime Pyridostigmine 30 mg 2-3 times per day, titrate 60mg 3 times per day. nausea, vomiting, loose stools, urinary urgency, No increase in supine BP

38 Drug therapy: Orthostatic hypotension Fludrocortisone: It has several pharmacologic effects that can act to improve orthostatic BP control for patients with autonomic failure. The action is not immediate and takes some days to be manifest, and the full effect requires a high dietary salt intake. Higher doses (>0.3 mg/d) may cause corticosteroid-like effects and should be avoided. It increases both daytime and nighttime BP, it can exacerbate supine hypertension.

39 Drug therapy: Orthostatic hypotension Midodrine Midodrine (5 10 mg) is often added to fludrocortisones ( mg each morning) as a second - line agent for orthostatic hypotension. Multiple studies have shown that midodrine increases BP in OH patients. Avoid usage in patients with coronary disease, heart failure.

40 Drug therapy: Orthostatic hypotension Pyridostigmine Singer et al. have shown: Pyridostigmine did significantly reduce the fall in standing diastolic BP. This finding was seen both with pyridostigmine alone and with concurrent midodrine Progress in Cardiovascular diseases. 2013; 55(4):

41 Conclusion Syncope is a common problem that affects all age groups. Although prognosis is generally favorable, it can lead to significant morbidity, reduced quality of life, and a burden on resources. Counterpressure measures should be advised to all patients, particularly those with extended prodromal symptoms. For patients requiring pharmacologic management, midodrine is likely the most efficacious first-line therapy based on available evidence. Routine use of β-blockers, SSRIs, fludrocortisone is discouraged.

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43 Exercise for weakness and orthostatic hypotension after prolonged bed rest. Patient must be out of bed 2 hours a day, morning, afternoon, and evening. Exercises are done three times a day. Principles of Ambulatory Medicine