Research in Vestibular Science Vol. 16, No. 3, September 2017 Review pissn 2092-8882, eissn 2093-5501 https://doi.org/10.21790/rvs.2017.16.3.73 신경성기립저혈압의치료 강동경희대학교병원신경과 변정익, 김상범 Treatment of Neurogenic Orthostatic Hypotension Jung-Ick Byun, Sang Beom Kim Department of Neurology, Kyung Hee University Hospital at Gangdong, Seoul, Korea Received Aug 8, 2017 Revised Aug 29, 2017 Accepted Aug 31, 2017 Corresponding Author: Sang Beom Kim Department of Neurology, Kyung Hee University Hospital at Gangdong, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, Korea Tel: +82-2-440-6168 Fax: +82-2-440-7242 E-mail: sbkim@khu.ac.kr Copyright c 2017 by The Korean Balance Society. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Orthostatic hypotension () is a common feature of sympathetic autonomic dysfunction and can lead to lightheadedness, weakness, dizziness, and syncope. It is defined as decrease in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing. is associated with an increased incidence of cerebrovascular disease, myocardial infarction, and mortality. Non-pharmacological treatments may alleviate -related symptoms; however, are not sufficient when used alone. Pharmacological treatment is essential in managing. In this review, we aimed to discuss non-pharmacological and pharmacological treatment options for. Res Vestib Sci 2017;16(3):73-79 Keywords: Hypotension; Orthostatic; Therapeutics; Supine position; Hypertension 서론기립어지럼 (orthostatic dizziness) 은앉거나바로누운상태에서빠르게일어설때현기증, 어지럼이발생하고, 다시앉거나누우면호전되는증상이다 [1]. 일반적으로일어설때 500 1,000 ml의혈류가복부나하지정맥으로이동하게된다. 이에따라수축기, 이완기혈압의감소와심장으로의정맥환류량 (venous return) 이줄어들게되며일시적으로심박출량과혈압이감소한다. 정상적으로는기립시에자율신경계, 심혈관계, 내분비계의보상기전이일어나심박수가빨라지고말초혈관저항성이커져정맥환류량을증가 시킨다 [2]. 기립저혈압 (orthostatic hypotension, ) 은기립어지럼의중요한원인중의하나로누워있다가일어서서또는 60 이상의경사대검사에서 3분이내에수축기혈압이 20 mm Hg 이상또는이완기혈압이 10 mm Hg 이상떨어지는경우로정의한다 [3]. 정상적으로기립시에일시적으로수축기혈압은 10 15 mm Hg, 이완기혈압은 5 10 mm Hg 정도저하될수있으며맥박은분당 10 25회증가할수있다. 자율신경장애등의원인에의해심박출량-말초혈관저항성의부조화가나타날경우이러한정상적혈압저하가과장되게나타날수있다 [4]. 기립저혈압의유병률은지역사회인구 73
Res Vestib Sci Vol. 16, No. 3, Sep. 2017 의 5% 30% 로알려져있으며 [5,6], 요양원또는병원환자대상으로 41% 50% 까지도보고되고있다 [7,8]. 다양한원인에의하여기립저혈압이나타날수있으며, 임상에서는흔히탈수, 또는전립선약, 혈압약등의약물에의한경우가많다 (Table 1) [9,10]. 신경성기립저혈압 (neurogenic ) 은자율신경기능부전으로인하여나타나는것으로말초신경병 ( 당뇨병성또는자가면역성자율신경병등 ) 이나중추성병변 ( 파킨슨병, 다계통위축증등 ) 과동반하여나타나는것을말한다 [11]. 기립저혈압은일시적으로뇌혈류가감소하는것으로기립어지럼뿐만아니라, 전신쇠약, 심할경우의식소실을일으킬수있으며 [12], 심혈관질환이환율과사망률을높이는것으로알려져있다 [13]. 적절한치료는어지럼개선뿐만아니라, 우울감을해소하고삶의질을높일수있으며, 기립저혈압과동반된위험성과사망률을낮출수있어중요하다. 기립저혈압의치료목적은단순히기립시혈압저하를방지하는것뿐만아니라누운자세에서고혈압이생기지않으면서기립시발생하는증상과실신, 낙상위험을줄여서삶의질을개선하는데에있다. 즉기립저혈압의동반증상을완화하면서, 누운자세에서혈압이 180/110 mm Hg을넘지않도록하고있다 [14]. 본종설에서는신경성기립저혈압환자에서적절한비약물성과약물성치료에대하여논하고자한다. 본론 1. 비약물성치료혈압은아침-저녁시간, 식사, 온도등에따라변하기때문에약물치료단독으로는부족한경우가많으며, 비약물성치료를먼저시도하거나병행하는것이필요하다 [11]. 몇가지비약물성치료가연구되었으나, 환자증상, 기저질환등에따라개별적으로선택하여야하며, 환자교육또한중요하다. 1) 행동치료및운동우선서서히일어나도록교육하는것이필요하다. 기립시가슴까지고개를숙인채일어나면복부를압박하여정맥환류량을증가시킬수있다 [15]. 침대에서일어날때도바로일어나지않고침대에수분간앉았다가서서히일어나는게좋다. 가능하다면무리하지않도록운동하는것이좋으며하지근육수축을증가시키는운동이정맥환류량을늘려도움을줄수있다. 다리근육수축하기, 발등굽힘, 다리를꼬고일어나기 [16], 웅크림 (squatting) 등이추천된다 (Fig. 1) [11,15,17]. 심한기립저혈압이있는노인의경우지팡이를사용하는것도도움이된다. 2) 압박스타킹일부환자에서압박스타킹으로기립저혈압과동반된증상을호전시킬수있다. 발목압력 40 60 mm Hg, 엉덩이압력 30 40 mm Hg로평균압력 30 mm Hg 이상으로조이는스타킹이기립시혈압저하와동반증상을호전시킨다는보고가있으며, 압박스타킹을착용한환자 60% 이상에 Table 1. Common cause that may cause or exacerbate orthostatic hypotension [9,10] Medication Diuretics Thiazide, furosemide, acetazolamide, spironolactone Vasodilators Amlodipine, nifedipine, hydralazine, alpha-1 antagonist (terazosin, alfuzosin, doxazosin, prazosin, tamsulosin), minoxidil Anti-depressants Tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine) Dopaminergic agents Levodopa, ropinirole, pramipexole Beta-blockers Propranolol, metoprolol, atenolol, bisoprolol (also vasodilator), nebivolol, carvediolol (also alpha-1 antagonist), labetalol (also alpha-1 antagonist) Others Nitroprusside, sildenafil, clonidine Clinical states Hypovolemia Dehydration, bleeding Impaired cardiac output Heart failure, cardiac arrhythmia, aortic stenosis Venous pooling Fever 74
변정익 외 1인. 신경성기립저혈압의 치료 으로는 기립저혈압 치료에 부족할 수 있다[21]. 물을 500 ml 정도 마시면 30분 후 교감신경 활동이 증가하여 2시간 동안 수축기 혈압을 20 mm Hg 정도 높인다고 알려져 있으 나[22], 자율신경장애가 있는 기립저혈압 환자에서 효과가 있는지에 대해서는 논란의 여지가 있다. 머리를 10 20 cm 정도 올려서 자면 신장 혈류량을 줄이고 밤중 이뇨작용을 줄여주어 효과가 있다는 보고가 있으나 증거가 충분하지 않다. 식사는 적은 양을 자주 복용하는 것이 필요하며 고탄 수화물 식사와 술은 피하는 것을 추천한다. 2. 약물성 치료 비약물성 치료에도 증상이 지속된다면 약물치료를 시작 할 수 있다. 흔히 사용하는 약물은 미도드린(midodrine), 피 리도스티그민(pyridostigmine), 플루드로코티손(fludrocortisone) 이 있다. 1) 미도드린(midodrine, Midron) (1) 기전 미도드린은 섭취시에 활성 대사산물인 desglymidodrine 으로 대사되어 직접 알파1 아드레날린 수용체(alpha 1 adrenoreceptor)를 활성화하게 되며, 이는 말초 혈관저항성을 높여 하지, 복부 정맥으로 혈류를 줄이고 혈압을 유지한다 Fig. 1. Physical countermaneuvers that can raise orthostatic blood pressure. (A) Leg-cross. (B) Toe-raise. (C) Squat. (D) Forward lean. 서 큰 불편감 없이 착용하였다[18]. 또한, 복대는 복부정맥 [23,24]. 미도드린은 무작위비교 임상시험에서 효과가 검증 되어 처음으로 기립저혈압에 대하여 미국식품의약국(Food and Drug Administration, FDA)의 승인을 받은 약물이다. (2) 용량 으로 혈류가 몰리는 것을 줄여 도움이 되며, 정맥혈전방지 처음 2.5 5 mg 하루 2 3차례 복용하는 것으로 시작할 수 스타킹이 일반적으로 흔히 사용되지만, 경한 기립저혈압 있으며 최대 10 mg 하루 3차례까지 사용할 수 있다. 최소 에서만 연구되었다[19]. 효능 용량은 5 mg이지만 이전 연구에 따르면 10 mg에서 효과가 있다고 알려져 있다. 미도드린의 효능은 30분 1시 3) 수분, 염분 섭취 및 식이조절 간 사이 나타나며 4시간까지 지속되며 작용시간이 길지 않다. 일반적으로 하루 1.5 2 L의 물을 섭취하도록 권유하며 충분한 염분 섭취도 필요하다. 환자의 기저 질환을 고려하 (3) 부작용 여 문제가 없다면 식사 중 소금을 첨가하거나 0.5 1 g의 소 대표적인 부작용은 누운자세고혈압이다. 따라서 아침에 금을 추가로 섭취하도록 한다. 염분 부족이 원인인지 파악 일어나서, 점심 전, 그리고 늦은 오후(늦어도 취침 4시간 하려면 24시간 소변 나트륨 농도를 측정하여 판정할 수 있 전)에 복용해야 한다. 또한, 혈압이 180/110 mm Hg 이상으 으며, 170 mmol 이하인 경우 나트륨 1 2 g을 하루 2 3회 로 측정되면 약을 일시적으로 중단해야 한다[11]. 다른 부 복용하는 것이 도움이 된다[20]. 하지만 염분, 수분보충만 작용으로는 저림과 소름끼침, 가려움과 복부불편감이 있 75
Res Vestib Sci Vol. 16, No. 3, Sep. 2017 으며, 심부전, 요폐쇄, 갑상선기능항진증, 급성심부전이있는경우금기로되어있다. 또한, 베타차단제와칼슘길항제와병용할때는느린맥이나부정맥이악화될수있어주의가필요하다 [14]. (4) 임상근거다양한연구에서 (Table 2) 미도드린의효과를검증하였으며 [12,23,25-27], 최근발표된메타연구에따르면미도드린투여전후기립시수축기혈압이 21.5 mm Hg 변화하였으며, 미도드린투여에따라유의한증상호전이있었으나, 증거수준은낮았다 [28]. 다른메타연구에서는미도드린이교차비 (odds ratio) 3.9로기립저혈압증상을호전시켰다 [29]. 2) 피리도스티그민 (pyridostigmine, Mestinon) (1) 기전자율신경절에서신경전달은아세틸콜린으로이루어지기때문에항콜린에스테라아제 (anticholinesterase) 인피리도스티그민은아세틸콜린을증가시켜자율신경절신호전달을증진시킬수있다. 자율신경계압력반사 (baroreflex) 는기립시에주로작용하며, 바로누운자세에서는거의나타나지않기때문에이론적으로피리도스티그민효과는기립시에만작용하게되며누운자세고혈압이나타나지않으면서기립시혈압저하를완화할수있다 [30]. 피리도스티그민은기립저혈압에대하여 FDA와국내에서승인되지않아허가외로사용한다. Table 2. Design and baseline characteristics of clinical trials Study design Year Participants Intervention/comparison Follow-up Level of evidence a) /results Midodrine [29] RCT, parallel [25] 1993 97 Adults with symptomatic and history or syncope or near syncope RCT, parallel [26] 1997 171 Adults with symptomatic RCT, crossover [27] 1998 25 Adults with symptomatic Pyridostigmine Open label [30] 2003 15 Adults with neurogenic RCT, crossover [31] 2006 58 Adults with neurogenic RCT, crossover [32] 2010 31 Adults with neurogenic RCT, crossover [33] 2017 9 Parkinson disease patients with Fludrocortisone RCT, crossover [34] 1975 5 Adults with symptomatic RCT, crossover [35] 2007 13 Parkinson disease with symptomatic RCT, crossover [33] 2017 9 Parkinson disease patients with Midodrine 2.5, 5, 10 mg tid/placebo Midodrine 10 mg tid/placebo Midodrine 2.5, 10, 20 mg qd/placebo 4 wk B/10 mg midodrine tid 4 wk: standing SBP drop, Sx. 6 wk B/10 mg midodrine tid 2 wk: standing SBP drop, Sx. 6 day B/10 mg midodrine: standing SBP drop Pyridostigmine 60 mg 1 hr C/standing SBP, DBP drop, Sx. Pyridostigmine 60 mg with 6 hr B/60 mg pyridostigmine ±5 mg and without 2.5, 5 mg midodrine: standing DBP midodrine/placebo drop Pyridostigmine 60 mg; yohimbine 5.4 mg/placebo Fludrocortisone 0.2 mg qd; pyridostigmine 60 mg tid Fludrocortisone 0.1 mg bid/placebo Fludrocortisone 0.1 mg; domperidone 10 mg/nonpharmacologic therapy Fludrocortisone 0.2 mg qd; pyridostigmine 60 mg tid 1 hr B/60 mg pyridostigmine: standing DBP drop 2 wk B/pyridostigmine 60 mg tid 2 wk standing DBP drop 3 wk B/fludrocortisone 0.1 mg bid 3 wk: standing SBP, DBP drop 3 wk B/fludrocortisone 0.1 mg qd 3 wk: autonomic Sx. 2 wk B/fludrocortisone 0.2 mg qd 2 wk: standing SBP drop RCT, randomized controlled trial;, orthostatic hypotension; tid, 3 times a day; SBP, systolic blood pressure;, improved; Sx., symptom; qd, once a day; DBP, diastolic blood pressure;, no change; bid, 2 times a day. a) Level of evidence A, data derived from multiple randomized clinical trials or meta-analyses of such studies; B, data derived from one or more randomized or non-randomized trials or meta-analysis of such studies; C, non-randomized observational studies with limitation in design or consensus opinion of experts based on clinical experience. 76
변정익외 1 인. 신경성기립저혈압의치료 (2) 용량처음 30 mg 하루 2 3번으로시작할수있으며, 60 mg 하루 3번까지증량할수있다. (3) 부작용콜린성기전으로인한설사, 메스꺼움, 구토가있고근육경련등이나타날수있다. 드물지만방실차단 (atrioventricular block) 이나타날수있어부정맥환자에서주의해야하며, 신기능장애, 천식과같은호흡기장애환자에서주의해야한다 [14]. (4) 임상근거피리도스티그민 60 mg은단기간기립저혈압증상을호전시켰으며말초혈관저항성을증가시켰다 [30]. 이는무작위비교임상시험에서도증명되었으며, 그결과피리도스티그민단독또는피리도스티그민과미도드린 5 mg을병용하였을때기립저혈압환자에서이완기혈압저하가감소하였으며, 혈압저하정도는증상호전과연관성이있었다 [31]. 또한설문조사결과 85% 가량의환자에서피리도스티그단독복용후중등도이상으로기립저혈압증상의호전을보고하였다 [36]. 압환자에서사용할때주의가필요하다 [14]. (4) 임상근거소규모의임상연구가있었으며, 5명의기립저혈압이동반된당뇨병환자에서기립시혈압저하를호전시켰으나 [34], 다른연구에서는파킨슨병환자에서 3분째혈압저하에유의한차이가없었다 [35]. 최근파킨슨병환자에서 0.2 mg 플루드로코티손사용이기립이완기혈압감소를줄여주는것으로보고되었다 [33]. 4) 기타약물성치료노르에피네프린 (norepinephrine) 전구체인드록시도파 (droxidopa) 가 2014년원발자율신경부전 (primary autonomic failure), 비당뇨병성자율신경병으로인한기립저혈압에대한치료제로 FDA의승인을받았으며초기 100 mg 하루 3차례복용하며최대 600 mg 하루 3차례까지복용할수있다. 최근드록시도파의효능성을보고하는메타연구도나와치료 1주차에기립저혈압증상과기립시수축기혈압저하의감소를보고하였다 [39]. 이외에요힘빈 (yohimbine) [32], 인도메타신 (indomethacin), 소마토스타틴 (somatostatin) 등의약제가연구되고있다 [14]. 3) 플루드로코르티손 (fludrocortisone, Florinef) 3. 기립저혈압과누운자세고혈압 (1) 기전합성광물코르티코이드 (mineralocorticoid) 로신장에서나트륨재흡수를촉진시켜혈장량을증가시키고알파아드레날린수용체의민감도를증가시켜혈관수축제에보완적인역할을할수있다 [14,37]. 플루드로코르티손또한기립저혈압에대하여 FDA와국내에서승인되지않아허가외로사용한다. (2) 용량처음하루 0.1 mg 하루 1회부터하루 0.3 mg까지증량할수있다. 최고용량은하루 1 mg으로알려져있으나 0.3 mg 이상의용량은부작용이심하여추천하지않는다 [38]. (3) 부작용플루드로코티손또한누운자세고혈압이나타날수있으며특히저칼륨혈증이높은용량에서흔히나타난다. 또한체중증가, 부종이나타날수있으며심부전, 신부전, 고혈 자율신경장애환자에서는압력반사작용이손상되어혈압변동이크기때문에바로누운자세에서고혈압이흔히동반된다. 원발자율신경부전과다계통위축증환자의절반가량에서누운자세고혈압이동반된다고알려져있다 [40]. 또한기립저혈압에대한치료제는혈압을높이는작용을하기때문에모든신경성기립저혈압환자에서누운자세고혈압여부를평가하여야한다. 일반적으로누운자세고혈압은바로누운자세에서수축기혈압 150 mm Hg 이상또는이완기혈압 90 mm Hg 이상으로정의한다. 하지만일반적으로고혈압은장기적으로건강에영향을주지만, 기립저혈압의경우즉각적인영향을주기때문에기립저혈압치료를우선하는경향이있다. 따라서전문가들은기립저혈압환자에서증상호전이있을경우수축기혈압 160 mm Hg까지는치료없이보는경우가많다 [10]. 1) 비약물성치료누운자세고혈압에대한가장좋은치료는예방이다. 적 77
Res Vestib Sci Vol. 16, No. 3, Sep. 2017 어도낮시간동안바로누운자세를최대한피하는것을추천하며, 수면중최대한머리를높게유지하여자도록교육해야한다 [41]. 잠들기전고탄수화물간식을먹거나약한혈관이완제인포도주등도도움이될수있다. 잠들기 1시간전수분섭취는자제하는것이좋다. 또한미도드린과플루드로코르티손은잠들기 4시간내에는복용하지말아야한다 [14]. 2) 약물성치료수축기혈압 160 180 mm Hg, 이완기혈압 90 100 mm Hg 이상의누운자세고혈압에서는개인특성에따라속효성혈압약을사용을고려할수있다. 수축기혈압 180 mm Hg 또는이완기혈압 110 mm Hg 이상의심한누운자세고혈압에서는속효성고혈압약제를저녁에사용할수있으며, 이러한환자에서는기립저혈압도심한경우가많아낙상을방지하기위하여밤중에화장실가는것에대한주의가필요하다. 약물은취침전 Losartan 50 mg, Captopril 25 mg, 또는 Hydralazine 25 mg을사용할수있다 [10,42]. 결론신경성기립저혈압의치료는환자특성에따라개별화되어야하며, 일반적으로운동, 압박스타킹등의비약물성치료와약물성치료를병행해야한다. 기립저혈압에대한약물은아직까지는사용근거가부족하지만최근미도드린에대한추가임상시험이진행중이며, 드록시도파에대한연구도시행되고있다. 신경성기립저혈압의경우누운자세고혈압이동반되는경우가많아이에대한평가와예방요법이추천되며심한누운자세고혈압이나타날경우속효성혈압강하제투여에대한고려가필요하다. 중심단어 : 저혈압, 기립, 치료, 누운자세, 고혈압 CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Benarroch EE. The clinical approach to autonomic failure in neurological disorders. Nat Rev Neurol 2014;10:396-407. 2. Smit AA, Halliwill JR, Low PA, Wieling W. Pathophysiological basis of orthostatic hypotension in autonomic failure. J Physiol 1999;519 Pt 1:1-10. 3. 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. 4. Wieling W, Krediet CT, van Dijk N, Linzer M, Tschakovsky ME. Initial orthostatic hypotension: review of a forgotten condition. Clin Sci (Lond) 2007;112:157-65. 5. Hiitola P, Enlund H, Kettunen R, Sulkava R, Hartikainen S. Postural changes in blood pressure and the prevalence of orthostatic hypotension among home-dwelling elderly aged 75 years or older. J Hum Hypertens 2009;23:33-9. 6. Veronese N, De Rui M, Bolzetta F, Zambon S, Corti MC, Baggio G, et al. Orthostatic changes in blood pressure and mortality in the elderly: The Pro.V.A Study. Am J Hypertens 2015;28:1248-56. 7. 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;277:1299-304. 8. Jodaitis L, Vaillant F, Snacken M, Boland B, Spinewine A, Dalleur O, et al. Orthostatic hypotension and associated conditions in geriatric inpatients. Acta Clin Belg 2015;70:251-8. 9. Jones PK, Shaw BH, Raj SR. Orthostatic hypotension: managing a difficult problem. Expert Rev Cardiovasc Ther 2015;13:1263-76. 10. Gibbons CH, Schmidt P, Biaggioni I, Frazier-Mills C, Freeman R, Isaacson S, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017;264:1567-82. 11. Low PA, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol 2008;7:451-8. 12. Low PA, Opfer-Gehrking TL, McPhee BR, Fealey RD, Benarroch EE, Willner CL, et al. Prospective evaluation of clinical characteristics of orthostatic hypotension. Mayo Clin Proc 1995;70:617-22. 13. Ricci F, Fedorowski A, Radico F, Romanello M, Tatasciore A, Di Nicola M, et al. Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies. Eur Heart J 2015;36:1609-17. 14. Hale GM, Valdes J, Brenner M. The treatment of primary orthostatic hypotension. Ann Pharmacother 2017;51:417-28. 15. Wieling W, van Dijk N, Thijs RD, de Lange FJ, Krediet CT, Halliwill JR. Physical countermeasures to increase orthostatic tolerance. J Intern Med 2015;277:69-82. 16. Krediet CT, van Lieshout JJ, Bogert LW, Immink RV, Kim YS, Wieling W. Leg crossing improves orthostatic tolerance in healthy subjects: a placebo-controlled crossover study. Am J Physiol Heart Circ Physiol 2006;291:H1768-72. 17. Benditt DG, Nguyen JT. Syncope: therapeutic approaches. J 78
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