orthostatic hypotension: definition, diagnosis and management

CE: Swati; JCM-D-13-00295; Total nos of Pages: 8;

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Orthostatic hypotension: definition, diagnosis andmanagementAQ1

Khalil Kanjwala, Anil Georgea, Vincent M. Figueredoa and Blair P. Grubbb

Orthostatic hypotension commonly affects theelderly patients and those suffering from diabetesmellitus and Parkinson’s disease. It is a cause ofsignificant morbidity in the affected patients. The goal ofthis review is to outline the pathophysiology, evaluation, andmanagement of the patients suffering from orthostatichypotension.

J Cardiovasc Med 2014, 15:000–000

Keywords: hypotension, orthostatic, syncope

aDivision of Cardiology, Heart and Vascular Institute, Einstein Medical centerPhiladelphia, Pennsylvania and bDivision of Cardiology, University of ToledoMedical Center, Toledo, Ohio, USA

Correspondence to Khalil Kanjwal, MD, Heart and Vascular Institute, EinsteinMedical Center, Philadelphia, PA, USATel: +1 4193405511; fax: +1 2154503781; e-mail: [email protected]

Received 13 May 2013 Revised 28 August 2013Accepted 28 August 2013

IntroductionOrthostatic hypotension is defined as a reduction in SBPof at least 20mmHg or DBP of at least 10mmHg within3min of assuming upright posture. Orthostatic hypoten-sion commonly affects the elderly and those sufferingfrom diabetes mellitus and Parkinson’s disease and isassociated with significant morbidity. The goal of thisreview is to outline the pathophysiology, evaluation, andmanagement of the patients affected with orthostatichypotension. It is emphasized that treatment optionsare symptom oriented and palliative. Therefore, settingrealistic targets helps avoid frustrations and fallouts frompatient expectations.

Physiology of standingIn a normal individual, 25–30% of the circulating bloodvolume is in the thoracic cavity while supine.1 With theassumption of upright posture, 300–800ml of blood isdisplaced (or 6–8ml/kg) to both the abdomen and thedependent extremities causing a state of relative centralhypovolemia.2 This results in a fall in venous returnand cardiac output by as much as 40%. Assumption ofupright posture also causes a significant increase intransmural capillary pressure in the dependent areasof the body, producing a substantial increase in fluidfiltration into tissue spaces. This shift reaches equi-librium after 30min of standing and can result in a netdecline of plasma volume of up to 10%.1 In normalindividuals, orthostatic stability is achieved within 60 sof standing and involves compensatory neurohumoral aswell as enhanced venous pump (muscle contraction)activation.1,4 The active processes involved in standingdiffer from those seen with the more passive process ofupright tilt.

Immediately following a head-up tilt testing, cardiacstroke volume remains constant despite the fall in venousreturn (believed to occur because of the blood remaining

in the pulmonary circulation)3 followed by a gradualdecline in both arterial pressure and cardiac filling. Thesechanges result in activation of high pressure barorecep-tors in the carotid sinus and aortic arch and low pressurebaroreceptors in the heart and lungs.

The mechanoreceptors that are linked by unmyelinatedvagal afferents provide a chronic inhibitory effect onthe cardiovascular centers of the medulla notably thenucleus tractus solitarii. This stimulates the cardiovagalneurons of the dorsal vagal nucleus and the nucleusambiguous, simultaneously inhibiting the sympathoexci-titoary neurons in the rostral ventrolateral medulla.

During standing, the reduction in venous return andcardiac filling pressures causes a reduction in stretch onthe receptors in these beds. As firing rates decline, thechange in medullary input results in an increase insympathetic outflow, which results in an increase invascular constriction in both the resistance vessels andthe splanchnic capacitance vessels. An additional localaxon reflex, termed the venoarteriolar axon reflex,results in constriction of arterial flow to muscle, skin,and adipose tissue, which causes almost half theincrease in vascular resistance in the limbs seen afterstanding.1

During head-up tilt testing there also seems to be acti-vation of the high pressure receptors located within thecarotid sinus.4 Stretch on the arterial wall generatesafferent impulses from mechanoreceptors that travelthrough the sensory fibers of the carotid sinus nerve.5,6

These afferent nerves lead to the medulla, terminating inthe nucleus tractus solitarii, close to the dorsal andambiguous nuclei.5 The initial rise in heart rate (HR) AQ2seen with upright tilt is believed to be a product of thedecline in carotid artery pressure. The gradual rise inDBP observed during a tilt appears to be related to anincrease in peripheral vascular resistance.3

Narrative review

1558-2027 ! 2014 Italian Federation of Cardiology DOI:10.1097/01.XEB.0000444823.11681.af

mailto:[email protected]

http://dx.doi.org/10.1097/01.XEB.0000444823.11681.af


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The continuation of upright posture results in activationof neurohormonal changes, which vary in intensitydepending on the volume status of the patient.6 Themore pronounced the volume depletion, the greater thedegree of activation of the renin–angiotensin–aldoster-one system (as well as vasopressin). Nonetheless, theprincipal mechanism by which the body compensates forprolonged orthostatic stress relies on the arterial baror-eceptor (in particular the carotid sinus) effects on per-ipheral vascular resistance.

A failure of any component of this complex system canresult in failure of normal compensatory responses toeither an initial or prolonged orthostatic challenge, withsubsequent hypotension, cerebral hypoperfusion, andultimately syncope. The term dysautonomia refers toany disturbance in autonomic function that adverselyaffects health.7,8

Disturbances of orthostatic controlThe system of organization has proven both clinicallyuseful and follows the basic guidelines established by theAmerican Autonomic Society.9 Reflex syncope (such asneurocardiogenic syncope and carotid sinus sensitivity)and postural orthostatic tachycardia syndromes are dis-cussed in detail elsewhere.10,11

All autonomic disorders can be thought of as beingeither primary or secondary in nature.12 Primary formsare often idiopathic and can be subdivided into acuteand chronic forms. The secondary forms are those thatare seen in association with other disease processes(diabetes, amyloidosis), medications (antihypertensive,antidepressant, and chemotherapeutic agents), or expo-sure to toxic compounds (alcohol, heavy metals).

Orthostatic hypotension may occur in association withany condition that causes a significant decline in blood orextracellular fluid volume, or in conditions that make aperson bedridden or immobile for an extended period.Orthostatic hypotension is one of the principal clinicalmanifestations of autonomic neurocirculatory dysfunc-tion and in the absence of any other identifiable causesis considered a form of autonomic failure.

Primary autonomic failure: chronicBradbury and Eggleston13 initially reported chronic auto-nomic failure in 1925. They employed the term ‘idio-pathic orthostatic hypotension’ because of its apparentlack of effect on other organ systems. However, the termwas inadequate to describe the fact that these patientshave a generalized state of autonomic failure manifestedby disturbed bladder, bowel, sudomotor, and sexualfunction that occur in the absence of somatic nerveinvolvement. The condition is now referred to as ‘pureautonomic failure (PAF)’.14

Symptoms of PAF usually begin in middle age, with mostcases being diagnosed between the ages of 50 and

70 years. PAF is twice as common among men thanwomen. The disease is frequently slow and insidiousin onset, most often starting with complaints of ortho-static weakness, fatigue, dizziness, and lightheaded-ness.15

Orthostatic hypotension is often the most debilitatingsymptom of PAF, and while it may not be the earliestsymptom, it is usually the one that prompts the patient toseek medical attention. In men, erectile dysfunction anddiminished libido are the earliest symptoms, whereas inwomen it is urinary retention. Presyncope and syncopeare often themost common presenting complaints, occur-ring more frequently in the morning, after meals, in hotweather, and after a hot bath or shower.

In contrast to neurocardiogenic syncope, patients withPAF do not experience nausea, diaphoresis, or pallorassociated with syncope. These patients experience syn-cope as a gradual fading of consciousness or have amnesiato events preceding syncope, describing it as a ‘dropattack’.16 As the disorder progresses, patients displayeven more significant orthostatic hypotension associ-ated with recurrent syncope and near syncope, fatigue,weakness, neck pain, and blurred vision. Supine hyper-tension is not uncommon. Symptoms of more diffuseautonomic involvement include inability to sweat,temperature intolerance, early satiety, constipation,dry mouth, and urinary retention. The disease usuallyprogresses slowly over decades or more and, whilepotentially causing severe functional impairment, rarelyleads to death.17

A very different situation is seen when primary auto-nomic failure is accompanied by additional defectsin somatic nerve function, first reported by Shy andDrager.17 The term ‘multiple system atrophy’ (MSA) isnow used to describe this devastating disorder.18 Incontrast to PAF, patients with MSA display severe ortho-static hypotension, but also demonstrate urinary andrectal incontinence, iris atrophy, external ocular palsy,rigidity, and tremor, loss of sweating, and erectile dys-function. Patients with MSA often develop symptoms inthe fifth to sixth decade of life. Men are reported todevelop MSA twice as frequently as women. Similar toPAF, MSA patients will most often present to the physi-cian complaining of syncope and near syncope. Althoughthe initial signs and symptoms may be similar to PAF,MSA patients develop progressive defects in somaticnerve, and later central nervous system function.

MSA is currently divided into three major subgroupsbased on the type of somatic involvement.19 The firstsubgroup displays symptoms of autonomic failure inaddition to features that are suggestive of Parkinson’sdisease (also referred to as the ‘striatomigral degenerationform’ based on brain autopsy findings). Many of thesepatients experience stiffness, clumsiness, as well as analteration in handwriting early in the course of the illness.

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As opposed to patients with true Parkinson’s disease,MSA patient tend to exhibit more rigidity than tremor(often associated with a loss of facial expression andachiness of the limbs). Also, the rigidity in MSA tendsto lack the classic ‘cogwheel’ or ‘lead pipe’ featurestypical of Parkinson’s disease.9

The second form of MSA is distinguished by progressivecerebellar and or pyramidal features (also known as‘olivopontocerebellar atrophy’ based on autopsy find-ings). In these patients, there is significant gait disturb-ance with truncal ataxia that can be severe enough toprevent the patient from standing. Slurred speech is notuncommon, often associated with a progressive loss ofdictation. Some patients may exhibit mild intentiontremor in the arms or legs.

The third subgroup of MSA patients appear to have amixed form of the disorder and display both Parkinsonianand cerebellar symptoms in association with autonomicfailure (referred to as ‘mixed’ MSA). Studies suggest thatbetween 7 and 22% of patients thought to have Parkin-son’s disease during life were discovered to have patho-logical changes associated with MSA at autopsy.18 Asopposed to PAF, the natural history of MSA is one ofnear relentless progression, with the majority of patientsdying within 5–8 years of onset. Aspiration and apneaare common and death is usually caused by respiratoryfailure.7,8,18,19

True Parkinson’s disease itself may be associated withorthostatic hypotension.20 Previously it was believed thatorthostatic hypotension in Parkinson’s disease occurredprincipally because of the effects of inactivity or medi-cations. However, it appears that some patients withParkinson’s disease may develop progressive autonomicfailure late in the course of their illness.21

Kaufman22 has suggested that a similar neurodegenera-tive process may underline MSA, PAF, and Parkinson’sdisease, based on the fact that in all three disorderspathological specimens demonstrate cellular accumu-lation of a-synuclein (or related proteins), which maycause degeneration of the catecholamine-containingneurons. This raises the intriguing possibility that thethree chronic primary autonomic failure syndromes aredifferent clinical manifestations of the same disease.

Acute autonomic failureAlthough relatively uncommon, acute autonomic neuro-pathy is quite dramatic. Also referred to as acute panau-tonomic polyneuropathy (and acute pandysautomia),onset is usually sudden, and characterized by widespreadsevere failure of both the sympathetic and parasympa-thetic systems, with little or no somatic nerve involve-ment.23 The majority of cases we have seen have been inrelatively young people who were previously healthy.Many patients report an antecedent febrile illness,followed by acute onset of symptoms.

Orthostatic hypotension in these patients is often soprofound that they are unable to sit up in bed withoutlosing consciousness. Near-total loss of sweating occurs,as does severe bladder and bowel dysfunction, consistingof abdominal pain, bloating, nausea, and constipationalternating with diarrhea. Many patients display a fixedHR of 45–55 beats/min, as well as profound chronotropicincompetence. Some patients will have extremely dilatedpupils that respond poorly to light.7,8

Several recent studies have suggested that the illness isautoimmune in nature. Verino et al.24 have isolated highlevels of autoantibodies to ganglionic acetylcholinereceptors that appear to correlate with disease severityand progression. It is now thought that these antibodiesplay an important role in the pathogenesis of otherautonomic disorders.25

Secondary autonomic syndromesThese encompass a wide variety of different disordersthat can significantly affect autonomic function.14 Theterm secondary autonomic failure is used when thereis a clear association with another illness. Systemicillnesses such as amyloidosis, diabetes mellitus, orrenal failure may disrupt autonomic function such thatorthostatic hypotension results. In some cases, auto-nomic failure may be herald the onset of malignancy,multiple sclerosis or Alzheimer’s disease. In rare casesorthostatic hypotension may develop due to singleenzyme deficiencies (b-hydroxylase deficiency, nervegrowth factor deficiency).26

A variety of drugs can interfere with normal vascularfunction resulting in orthostatic hypotension. A morecomplete discussion on secondary causes of autonomicdysfunction is available elsewhere.7,8,26

Clinical aspectsTraditionally, orthostatic hypotension has been definedas a fall of greater than 20mmHg of SBP or greater than a10-mmHg in fall in DBP within 2–3min after stand-ing.2,21

This definition is somewhat arbitrary, and a less dramaticfall in BP, if associated with symptoms, may be equallyimportant. Some patients will demonstrate a more gra-dual, yet progressive fall in BP over a much longer timeframe (10–15min) that will be associated with symptoms,sometimes referred to as ‘delayed orthostatic hypoten-sion’. Development of symptoms is dependent not onlyon the absolute fall in BP, but also on the acuity of thedrop, and on the ability of the patient’s cerebral vascu-lature to auto regulate. Patients may also display supinehypertension, as well as dramatic swings in BP, or mayexperience excessive responses to a number of pharma-cological or physiological challenges.

Syncopal episodes that occur from orthostatic hypoten-sion will sometimes be described by older patients as

Orthostatic hypotension Kanjwal et al. 3


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‘drop attacks’ that occur with little or no prodrome. Lossof consciousness is often reported by observers as occur-ring over 30–60 s, usually while standing or walking(occasionally while seated). A frequent symptom thatmay precede loss of consciousness is an aching or painfulsensation in the neck that radiates to the occipital area ofthe skull and to the shoulder (’coat hanger’ headache).The cause is thought to be ischemia in continuouslycontracting skeletal muscles. Blurred vision, tunnelvision, and scotomata are common complaints.

Symptoms occur after several minutes of standing orwalking, at which time the patient may stumble, fall orsink to their knees as they lose consciousness. Conscious-ness is regained 3–5min after becoming supine. Symp-toms are more frequent in the morning after waking fromsleep and are exacerbated by any condition that favorsperipheral venous pooling of blood, such as heat, exer-cise, alcohol, or fatigue. Large meals may also result inredistribution of blood to the mesenteric vasculature,resulting in a significant decline in BP (postprandialhypotension).

A common complaint is nocturnal polyuria. This isthought to occur when pooled peripheral blood is redis-tributed to the central areas while supine (a mechanismsimilar to that seen in paroxysmal nocturnal dyspnea).These patients may lose as much as 1 l of urine in a singleevening, exacerbating the tendency toward morninghypotension. As the disease progresses, some patientswill develop a neurogenic bladder and many experiencesevere constipation.

Patient’s suffering from MSA can display a significantamount of progressive muscle wasting, although rarely tothe extent seen in the motor neuron disorders such asamyotrophic lateral sclerosis.18 Dementia is not usuallyassociated with either PAF or MSA, as opposed toParkinson’s disease where intellectual impairment isnot uncommon. Patient’s suffering from either MSA orPAF may develop a significant degree of chronotropicincompetence resulting in a relatively static HR of50–70 beats/min. Patients with MSA often developeither obstructive or central sleep apnea, manifestedby loud snoring or involuntary inspiring gasps duringsleep. Table 2 highlights some of clinical features thatmay help distinguish PAF from MSA and acute auto-nomic neuropathy.AQ3

EvaluationThe most critical step in the evaluation of orthostatichypotension is a detailed history and physical examin-ation. Focused laboratory testing can then be pursued.

Patients with syncope in the setting of structural heartdisease may require evaluation for significant arrhyth-mias. In some older patients, dehydration may contributeto orthostatic hypotension, and can be identified byexamination of skin turgor, mucous membranes, serum

and urine analysis. More detailed descriptions of specificclinical patterns of specific autonomic disorders and theirevaluations can be found elsewhere.2,10,14

As the autonomic centers of the brain are not accessible todirect measurement, evaluation of autonomic function isaccomplished by determining the responses of the sys-tem to a variety of physiological or pharmacologicalchallenges. The simplest of these is to determine theBP and HR in the supine, sitting, and standing positions,as well as at 3 and 5min after standing. The BP should bemeasured with the arm extended horizontally (to reducethe hydrostatic effects that can be produced when thearm is in a dependant position). As the responses seenduring standing and passive tilt may differ, we performtilt table testing in patients in whom we feel furtherevaluation in warranted. Detailed descriptions of tilttable testing are available elsewhere.27,28

Autonomic testingThe evaluation of autonomic system function may beuseful in select patients as a way of measuring the degreeof systemic autonomic nervous system involvement.Sudomotor function can be determined by quantitativethermoregulatory sweat testing or by measurement ofskin conductance, skin resistance, or sympathetic skinpotentials employing methods such as quantitative sudo-motor axon testing. More detailed descriptions of auto-nomic testing can be found elsewhere.7,8,14,19

Serum catecholamineSerum levels of epinephrine, norepinepherine, and dopa-mine should be obtained in both standing and supinepositions as they help determine the type of autonomicfailure. In patients who have defects in the postganglionicsympathetic vasomotor fibers, supine norepinephrinelevels will be low, in contrast to MSA were the level isusually normal. In both conditions the usual increase inplasma norepinephrine levels seen during tilt or standingmay be blunted or absent, reflecting a disturbance insympathetic outflow.

Heart rate variabilityHR variability determinations, as well as bareoreceptorgain evaluation, are useful assessments of the cardiovas-cular autonomic system. More detailed descriptions ofautonomic testing can be found elsewhere.7,8,14,19

TherapyThe initial step in the treatment of orthostatic hypoten-sion is to identify and correct reversible causes. Dehy-dration, drug effects, anemia, and adrenal insufficiencyare all correctable causes. Any drug that could be con-tributing to the problem should be discontinued. Poten-tial underlying causes of orthostatic hypotension shouldbe sought, such as a malignancy or amyloidosis.4



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When no reversible cause is apparent, therapies aimed atreducing symptoms are initiated. Education of thepatient and family as to the nature of the disorder iscritical. Potential aggravating factors such as extremeheat, prolonged standing, and dehydration should beavoided. Patients should be instructed to change posi-tions slowly allowing the system time to adjust and to payattention to subtle symptoms that indicate a decline inBP. As large meals may worsen symptoms, patientsshould be encouraged to eat smaller meals spaced outthrough the day. Alcohol is best avoided, as its vasodilatorand diuretic effects may worsen symptoms.7,8 Patientsand their physicians need to be aware that these disorderstend to be chronic and that treatment is palliative ratherthen curative.

Nonpharmacological measuresSleeping with the head of the bed elevated is reported tobe helpful, as it appears to lessen the sudden pooling ofblood patients experience upon arising after sleep, as wellas reducing the degree of supine hypertension and noc-turnal diuresis. Elevating the bed by 10–15 cm (4–6 in)can be accomplished by placing a brick under each backbedpost. If a hospital bed is used, we use an angle of30–45 degrees.

Custom-fitted elastic support hose is useful to establish acountergradient in the lower extremities that reduces thedegree of venous pooling (most effective when waist highand should provide at least 30mmHg ankle counterpressure).25

Physical maneuvers can be used to activate the skeletalmuscle pump and briefly elevate pressures. Theseinclude crossing the legs and pushing them against eachother, arm flexing, and rocking up on the toes. In eachcase the elevation in BP is transient and is intended tomaintain BP long enough to allow the patient to get to asafe place and then to sit or lie down.29

A major focus of therapy is reconditioning using a com-bination of both aerobic and resistance training, workingtoward a goal of performing at least 20–30min of aerobictraining or aquatic exercises three times per week. Fluidintake of approximately 2 l/day is encouraged. Althoughpatients who are purely orthostatic may benefit from anincreased salt intake (3–5 g/day) we do not recommendthis in patients with supine hypertension.

PharmacotherapyOf all the drugs discussed in this section midodrine aloneis approved by the Food and Drug Administration for thetreatment of orthostatic hypotension. One of the mostcommonly used medications is fludrocortisone, a miner-alocorticoid that acts on the distal tubule to promotereabsorbtion of sodium and fluid.7,8,15 It has also beenreported to increase the quantity and sensitivity of per-ipheral a receptors, promoting an increase in vascular

resistance. The usual dose employed is 0.1mg orally onceor twice daily (do not exceed 0.4mg daily as adrenalsuppression may occur). Desmopressin can also providevolume expansion (0.1–0.2mg orally at bedtime) anddecrease the degree of nocturnal polyuria.

A second approach to therapy is to use agents that resultin sympathetic stimulation to increase peripheral vascularresistance.7,8,26 These tend to act by stimulation of aadrenergic receptor sites to augment arteriolar andvenous constriction. Principal among these is the agentmidodrine.30 Midodrine is a prodrug that is metabolizedto the active form, desglymidodrine, which stimulates a-1adrenoreceptors to cause constriction of arterial resistanceand venous capacitance vessels. It is rapidly absorbed(peak concentration within 20–40min, t1/2 of 30min).Dosages are between 2.5 and 10mg orally three to fourtimes daily. Side-effects include nausea, piloerectiontingling of the scalp, and supine hypertension. Patientsshould not lie supine for at least 4 h after a dose ofmidodrine, and the drug is usually not given after 6p.m. In cases where midodrine is poorly tolerated,methylphenidate can be an effective alternative.

Modafinil can also be a useful agent, as it cannot onlyprovide vasoconstriction but may also relieve some of theintense fatigue. Yohimbine can also be effective, as itis both a central and peripheral a-2-adrenoreceptorantagonist that increases BP by stimulating sympatheticoutflow centrally and increasing norepinephrine releasefrom postganglionic sympathetic neurons.

Interestingly, clonidine, an a-2-adrenoreceptor agonist,can actually be used as treatment for orthostatic hypoten-sion that occurs because of postganglionic receptorlesions. Postjunctional a-receptors are common through-out the vasculature and can become hypersensitive inautonomic failure. Although clonidine’s central activityproduces a reduction of sympathetic outflow in normalindividuals (causing a reduction in BP), in patients withautonomic failure who have little remaining sympatheticactivity (in particular PAF and spinal cord lesions) theperipheral effects of the drug will predominate causing anincrease in HR and BP. Clonidine is particularly useful intreating the patient with both orthostatic hypotensionand supine hypertension.

b-Blocker therapy has been reported to be helpful byfostering unopposed a-receptor stimulation. b-Blockersprocessing intrinsic sympathetic activity have beenreported to be more useful than those without.

Serotonin reuptake inhibitors may be useful in managingselect patients with orthostatic hypotension. Fluoxetineand venlafaxine have been reported to be the mosteffective. Bupropion may also be useful in some patients.

Pyridostigmine, an acetylcholinesterase inhibitor thatincreases nerve transmission at the level of the gangliaof both the sympathetic and parasympathetic nerves, has



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shown promise. Several double-blind placebo-controlledtrials have shown it to be remarkably effective in con-trolling orthostatic hypotension without exacerbatingsupine hypertension. The usual starting dose is 30mgorally twice daily and can be slowly titrated to a doseof 90mg orally three times daily. Side-effects includenausea and diarrhea.31,32 A long-acting formulation isavailable that allows for once a day dosing. The drug isusually not given in the evenings before retiring as theeffects on the autonomic ganglia are present only withorthostatic changes in body position.

In several orthostatic hypotension patients in whomother forms of therapy have been ineffective or poorlytolerated, erythropoietin (EPO) has been useful.33 EPOis a polypeptide produced in the kidney that stimulatesred blood cell production.34 It also appears to have avasoconstrictive effect because of its effects on nitricoxide production.35 A series of studies have shown that itcan be remarkably effective in the treatment of hypo-tension.26

Prior to starting EPO one should obtain a complete bloodcount as well as a serum iron, total iron binding capacity,and ferritin level. The usual starting dose is 10 000 unitssubcutaneously weekly (4–6 weeks for manifest effects).Although the increase in red cell count caused by EPO isindependent of its vasoconstrictive effect, the two tend torise in parallel. The best hemodynamic effects of EPOtend to occur when the hematocrit (HCT) is in the low tomid 40s.

Following initiation of EPO therapy, a complete bloodcount should be checked monthly to ensure that theHCT does not exceed 50. If the HCT exceeds 50 whileon EPO therapy, we usually ask the patient to skip dosesuntil the HCT falls below 50, and then resume EPO at areduced dose. The most frequent complaint during EPOtherapy is pain at the injection site. This can be dimin-ished somewhat by allowing EPO (which is storedrefrigerated) to warm up before injection. Additionalmeasures to minimize injection site pain are to applytopical lidocaine, in cream or patch form, 15–30minprior to use of the site, or to place an ice cube overthe site 3–5min before use.

Some patients will require oral iron supplementation toobtain an adequate red cell response. If no hemodynamiceffect is seen from starting EPO after 4–6 weeks, weincrease the weekly dose to 20 000 units (it is rare to haveto go beyond this dose). An occasional patient willdevelop a ‘serum sickness’ reaction to EPO characterizedby fever, nausea, chills, and malaise, which resolvesquickly when the agent is stopped.

The somatostatin analogue octreotide is sometimes use-ful in patients with refractory orthostatic hypotension,because of its vasoconstricitive effects. It is given bysubcutaneous injection usually starting at 50mg two to

three times daily and can be titrated up to 100–200mgthree times daily. The major side-effects are nausea andmuscle cramping. A long-acting form of octreotide (thatworks for several weeks) has also been developed.

The synthetic catecholamine L-threo-3,4-dihydroxyphe-nylserine (L-DOPS) has been shown to increase uprightBP and decrease orthostatic hypotension. The drug isconverted to norepinephrine that is released from sym-pathetic nerves. Currently approved in Japan, the drug isundergoing clinical trials in the United States. It has beenshown to be effective in patients with familial amyo-trophic polyneuropathy and severe orthostatic hypoten-sion.36

Some patients with severe orthostatic hypotension willfail to respond to any of the above therapies. In threepatients Oldenburg et al.37 reported using a controllednorepinephrine infusion pump (the same type of deviceused for ambulatory dobutamine infusions). Ambulatorynorepinephrine was infused intravenously in individuallyadjusted dosages via an indwelling infusion line andportable indwelling infusion pump. We have pursuedthis therapy in a limited number of patients (only inthose without cardiac disease). It has proven remarkablyeffective and appears well tolerated.

In the early stages of the acute autonomic neuropathiesboth intravenous immunoglobulin therapy and plasma-pheresis have been reported to be effective.7,8,38 It wasthought that once the acute phase of the illness hadpassed these treatments were less effective; however,recent evidence has challenged this concept. A recentreport has suggested that immunosuppressive therapymay be effective in chronic autoimmune autonomicneuropathy.39

Supine hypertension with orthostatichypotensionA challenging situation occurs in the patient who suffersfrom both supine hypertension and orthostatic hypoten-sion. In these patients, we tend to combine agents tominimize the swings in BP. We have found that cloni-dine, combined a and b blockers (such as labetalol orcarvedilol) and angiotension receptors blockers limitthe swings upward in BP with only modest effects onorthostatic hypotension. We often combine these withpyridostigmine as it prevents orthostatic hypotensionwithout exacerbating supine hypertension.

It shouldbekept inmind that perfect control ofBP in theseindividuals is often difficult and realistic goals should beset. For example, in severe supine hypertension we try tokeep the supineBP less than170/95mmHg,whilekeepingthe upright BP at whatever minimum level that preventssymptoms. In some patients BPs are so erratic that weconstruct a ‘sliding scale’ of treatment such that when theBP is excessively high we give an additional dose ofclonidine, or additional midodrine when it is excessively



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low. Pyridostigmine can help orthostatic hypotensionwithout causing supine hypertension.

An important, yet often neglected, consequence of thesedisorders is the tremendous social, emotional, and econ-omical toll on both patients and their families. Theattitude of the treating physician can have a profoundeffect on the patient with a chronic autonomic disorder. Apositive yet realistic approach by an empathetic andknowledgeable physician can have a tremendous impacton the patient’s sense of well being. Patients will oftenrequire the services of social workers, psychologists,rehabilitation specialists, and lawyers to address theseaspects of their illness. Treatment goals and expectationswhen set early in the course of the illness will helpmitigate fallout from patient perceived treatment fail-ures. Hope and compassion are powerful medicines thatshould not be neglected.40

ConclusionOrthostatic hypotension may occur either as a primarydisturbance of the autonomic nervous system or as theconsequence of another condition. Successful treatmentinvolves identifying the subtype and pursuing a compre-hensive treatment plan.

Take home message(1) Orthostatic hypotension is defined as a reduction in

SBP of at least 20mmHg or DBP of at least 10mmHgwithin 3 of assuming upright posture.

(2) Orthostatic hypotension commonly affects theelderly and those suffering from diabetes mellitusand Parkinson’s disease.

(3) The most critical step in the evaluation of orthostatichypotension is a detailed history and physical exami-nation.

(4) The most important component of the successfultreatment is withdrawal of precipitating medicationor correction of reversible cause.

(5) Pharmacotherapy is often times successful in amelio-rating symptoms but the management of the patientscan be sometimes challenging for both physicians andthe patient.

(6) A multidisplinary approach to the management oforthostatic hypotension is often times warranted insuch patients.

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