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. 2017 Dec 4;2017(12):CD012868. doi: 10.1002/14651858.CD012868

Fludrocortisone for orthostatic hypotension

Stephanie Veazie 1, Kim Peterson 2, Yasmin Ansari 3, Kathryn A Chung 4, Christopher H Gibbons 5, Satish R Raj 6, Mark Helfand 7,✉
PMCID: PMC6486125

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To identify and evaluate the benefits and harms of fludrocortisone for orthostatic hypotension.

Background

Description of the condition

Orthostatic, or postural, hypotension is a condition in which a prolonged fall in blood pressure occurs upon standing after sitting or lying down. The consensus definition is a sustained reduction of systolic blood pressure (BP) of at least 20 mmHg or diastolic BP of 10 mmHg within three minutes of standing or head‐up tilt to at least 60° on a tilt table (American Autonomic Society, American Academy of Neurology, Gibbons 2017). Orthostatic hypotension is detected by clinical examination, and may or may not cause symptoms (Freeman 2011). In people who have high blood pressure when lying down (supine hypertension), a reduction in systolic BP of 30 mmHg may be a more appropriate criterion for orthostatic hypotension because the size of the orthostatic BP fall is dependent on the baseline BP (Frith 2015).

The prevalence of orthostatic hypotension in people 65 years and older has been reported to be in the range of 5% to 30%, with higher prevalence linked to increasing age of the study population (Low 2008; Tilvis 1996). Orthostatic hypotension is more common in the institutionalized elderly (Freeman 2011). Orthostatic hypotension is frequently a comorbid factor for falls in the elderly (Gupta 2007). Recent evidence has suggested that traditional symptoms of orthostatic hypotension may be present in less than 50% of people with severe, chronic orthostatic hypotension (Arbogast 2009).

Orthostatic hypotension is the result of an excessive fall of cardiac output or defective or inadequate vasoconstrictor mechanisms, for which there are many causes and contributing mechanisms (Freeman 2011). Medications such as antihypertensive drugs and diuretics, antiparkinsonian medication (dopamine and dopamine agonists), antidepressants (particularly tricyclic agents), and sympatholytic agents and other vasodilators can cause or contribute to orthostatic hypotension (Gibbons 2017). Orthostatic hypotension can also occur because of inadequate fluid intake, particularly in elderly people. Other variables that affect orthostatic hypotension are gender, cardiac and vascular stiffness, prolonged lying, high ambient temperature, and deconditioning (loss of strength and function that occurs when a person is very inactive) (Freeman 2011).

The autonomic nervous system contributes to the regulation of body states and processes including blood pressure. Orthostatic hypotension can also therefore occur in people with neurodegenerative disorders affecting the autonomic nervous system. These conditions include multiple system atrophy, Parkinson’s disease and pure autonomic failure, and some neuropathies and ganglionopathies that affect autonomic nerves (Freeman 2007; Freeman 2011; Kaufmann 2003).

Characteristic symptoms of orthostatic hypotension include dizziness, light‐headedness, presyncope (faintness) and syncope (loss of consciousness) (Freeman 2008). Loss of consciousness is typically of gradual onset over seconds to minutes but can occur suddenly (Freeman 2011). Some people present with more general complaints such as weakness, fatigue, headache, visual blurring, cognitive slowing, leg buckling, neck pain, orthostatic dyspnea (breathlessness) or chest pain (Freeman 2008).

Symptoms of orthostatic hypotension subside as BP normalizes, typically when the person returns to a seated or a lying position (Wieling 1993).

Description of the intervention

Fludrocortisone acetate is a synthetic adrenocortical steroid with high mineralocorticoid activity that results in an increase in plasma volume and increased sensitivity of α‐adrenoreceptors. Fludrocortisone is dosed by mouth at between 50 µg and 300 µg per day. Adverse events associated with fludrocortisone include hypertension, edema (swelling), congestive heart failure, hypokalemia (low potassium), headache, insomnia, and increased sweating.

Other than fludrocortisone, common therapies for orthostatic hypotension include midodrine hydrochloride and droxidopa. Midodrine hydrochloride is an α‐1 adrenergic agonist and is the most well established sympathomimetic agent used to treat orthostatic hypotension, approved by the US Food and Drug Administration (FDA) for this purpose (Low 1997). Its mechanism of action is direct stimulation of vascular α‐adrenergic receptors with a resultant increase in flow resistance and BP (McTavish 1989). Droxidopa (L‐threo‐dihydroxyphenylserine) or L‐DOPS, is a synthetic amino acid also FDA approved for treatment of orthostatic hypotension. Droxidopa is a precursor for norepinephrine requiring enzymatic conversion to the active amine by aromatic l‐amino acid decarboxylase. It raises norepinephrine levels in postganglionic sympathetic neurons and enhances central nervous system norepinephrine production. The increase in circulating norepinephrine may also act as a hormone with BP raising activity (Jordan 1998).

Less commonly‐used therapies include direct or indirect adrenoreceptor agonists and other sympathomimetic agents phenylephrine, ephedrine, pseudoephedrine, phenylpropanolamine, methylphenidate, and dextroamphetamine (Biaggioni 1987; Davies 1978; Freeman 1999; Ghrist 1928; Jordan 1998). Treatments with any of the sympathomimetic agents can result in severe supine hypertension, so should not be used while lying down (Sandroni 2001). Pyridostigmine may act through potentiation of sympathetic cholinergic ganglionic transmission, leading to increased vascular tone, but only in the upright position (Singer 2003). The benefit of this therapy is a lower risk of supine hypertension than is seen with agents that result in direct vasoconstriction (Schondorf 2003).

Additional agents that may have efficacy in the treatment of orthostatic hypotension through other mechanisms include erythropoietin, non‐steroidal anti‐inflammatory agents, octreotide, and vasopressin (Armstrong 1991; Freeman 2003).

How the intervention might work

Fludrocortisone acetate alters BP through a variety of mechanisms including mineralocorticoid‐induced sodium and water retention. Fludrocortisone binds to the aldosterone receptor, which increases activity of the distal tubule of the kidney, causing enhanced sodium ion and water transport into the plasma, and increasing urinary excretion of potassium and hydrogen ions (Campbell 1975). Its effect on alleviating orthostatic hypotension is largely thought to be modulated through these actions. With chronic use, a BP‐raising effect may persist, even though sodium retention and overall plasma volume normalizes through increased peripheral vascular resistance (Armstrong 1991; Chobanian 1979; Freeman 2003; Hoeldtke 1993). Other potential mechanisms may include sensitization of the vasculature to angiotensin II and norepinephrine (Hickler 1959; Van Lieshout 2000). Because orthostatic hypotension is a condition that results from multiple underlying diseases and conditions, it is important to analyze the effect of fludrocortisone by mechanism (peripheral versus central autonomic failure), by condition (Parkinson’s Disease, diabetes, amyloid‐induced orthostatic hypotension, pure autonomic failure, Lewy body disease, or multiple system atrophy), and by age, as both the benefits and potential for harm may vary by subgroups. As an example, the BP‐raising properties of fludrocortisone could potentially increase the risk of supine hypertension in certain subgroups, particularly the elderly.

Why it is important to do this review

There is inconsistent guidance on the use of fludrocortisone as first‐line pharmacological treatment for orthostatic hypotension (Lanier 2011; Moya 2009; NICE 2013; Zesiewicz 2010). The evidence for the efficacy of fludrocortisone has not been evaluated in a Cochrane Systematic Review. This review will evaluate the current evidence available on the efficacy of fludrocortisone for the treatment of orthostatic hypotension to better inform treatment recommendations and to highlight gaps in knowledge that require further investigation.

Objectives

To identify and evaluate the benefits and harms of fludrocortisone for orthostatic hypotension.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomized controlled trials (RCTs) and quasi‐RCTs of fludrocortisone for orthostatic hypotension including cross‐over and cluster‐randomized trials. When data from RCTs and quasi‐RCTs are lacking or at high risk of bias (i.e. there are gaps in the evidence), we will include certain types of non‐randomized studies (NRS). Current guidance for treating orthostatic hypotension is based on a small number of short‐term RCTs (NICE 2013). Therefore, summarizing and evaluating NRS could provide decision‐makers with information on long‐term benefits and harms, as well as dosing and other clinical approaches not adequately addressed in these trials. To reduce the likelihood of NRS susceptibility to bias, we will include prospective NRS that compare distinct groups of participants who did and did not receive fludrocortisone. In the absence of these types of studies, we will include other types of uncontrolled NRS with more than one participant. All our selected PICOS (population, intervention, comparators and outcomes) will apply to RCTs, quasi‐RCTs and NRS, with the exception of comparators, as we will include uncontrolled NRS if evidence from RCTs, quasi‐RCTs and controlled NRS are lacking or at high risk of bias.

Types of participants

We will include all participants with orthostatic hypotension due to a chronic (non‐acute, defined as present for at least eight weeks or more) peripheral neuropathy, a central autonomic neuropathy, or autonomic failure from other causes (e.g. amyloid‐induced or due to diabetes). We will exclude from evaluation participants with medication‐induced orthostatic hypotension and those with orthostatic hypotension from acute volume depletion or blood loss. We will include both children and adults of any age.

We will include studies that include only a subset of eligible participants if outcomes for eligible participants are reported separately, or at least 75% of the study population consists of relevant participants.

Types of interventions

We will include fludrocortisone compared to placebo, no treatment, another treatment or combination of treatments. If more than one treatment is included in the treatment arm, the same treatment (other than the fludrocortisone) must be included in the comparator arm. In the event data from RCTs, quasi‐RCTs, and controlled NRS are lacking or at high risk of bias, we will accept studies without a comparator. Our preferred minimum treatment duration will be three weeks; however, we will accept all durations of treatment. We will accept all treatment dosages.

Types of outcome measures

We will include all studies that meet the above criteria. We will still include studies that do not include our prespecified outcome criteria but these will not be included in any formal analysis. We we will report on the seven outcomes listed below in the 'Summary of findings' table. If a study does not report any of our outcomes of interest, we will contact the study authors to collect this information, if it is available. For all outcomes, we will give preference to studies that measure the outcome at least three weeks after initiating treatment; however, we will accept all time points. We will also give preference to studies that use validated scales for measurement of outcomes; however, we will accept all measurements. We will perform sensitivity analyses to capture differences in studies based on study length and outcome validity.

We will define the frequency of an event (i.e. postural light‐headedness, dizziness, or presyncope; syncope; and falling) as the number of times an event occurs during a given time period, which we will convert to a standard measurement (number of events per week).

The pretreatment to post‐treatment period refers to the time immediately before treatment initiation (pretreatment) to the last time a particular outcome measurement is collected for participants actively receiving treatment (post‐treatment), even if participants continued to receive treatment after the final measurement was collected.

We prespecify our definitions of minimum important differences here. To date, no specific numerical value has been validated as the minimum important difference for change in systolic or diastolic BP. Therefore, we will not define a clinically important reduction in the change in BP but will simply report the change with 95% confidence intervals (CI). When validated scales are used to measure change in severity of postural light‐headedness, dizziness or presyncope; quality of life or overall well‐being; functionality; and overall orthostatic symptoms, we will use the definitions of minimum important difference pre‐specified by individual scales. When other measurements are used, we will consider a 10% improvement as the minimum important difference. For change in frequency of postural light‐headedness, dizziness or presyncope; syncope; and falling, we will consider a reduction of one event per week as the minimum important difference. For adverse events, we will consider a statistically significant reduction in the likelihood of an event occurring as an important difference. We will accept any form of data aggregation (including but not limited to: median, mean, or percentage of participants meeting a certain target).

Primary outcomes

  1. BP outcomes: change between pre‐ and post‐treatment systolic BP/diastolic BP in the upright (standing or tilt) position, two to three minutes after standing or tilting is our preferred BP measurement after at least three weeks of treatment. However, we will accept any BP measurement method, including the pre‐ to post‐treatment change in the drop in systolic BP/diastolic BP after moving from supine to upright, or from sitting to upright, and measurements taken outside the two to three minute range (i.e. between one and five minutes).

Secondary outcomes

  1. Change in frequency and severity of postural light‐headedness, dizziness, or presyncope between pre‐ and post‐treatment, measured as number of events per week (frequency) and with a validated tool or other measurement (severity)

  2. Change in frequency of syncope between pre‐and post‐treatment, measured as number of events per week

  3. Change in frequency of falling between pre‐ and post‐treatment, measured as number of events per week

  4. Change in quality of life or overall well‐being between pre‐ and post‐treatment, measured with a validated scale (e.g. 36‐item or 12‐item Short Form Health Survey (SF‐36 or SF‐12), EuroQol five dimensions questionnaire (EQ‐5D), Clinical Global Impression rating scale (CGI), Patient Global Impression of Change (PGIC)) or other measurement

  5. Change in functionality between pre‐ and post‐treatment, measured with a validated scale or other measurement

  6. Change in overall orthostatic symptoms between pre‐ and post‐treatment measured with a validated scale (e.g. Composite Autonomic Symptom Scale‐Orthostatic Domain (COMPASS‐OD)) or other similar measurement

  7. Adverse events due to treatment, regardless of association to treatment. We will analyze categories of: all adverse events, severe or serious adverse events that lead to hospitalization or death, and adverse events leading to cessation of treatment.

Search methods for identification of studies

Electronic searches

We will search:

  1. Cochrane Neuromuscular Specialised Register;

  2. Cochrane Register of Controlled Trials (CENTRAL; most recent year and issue in the Cochrane Register of Studies Web Online (CRSW));

  3. MEDLINE (1966 to present); and

  4. Embase (January 1980 to present);

  5. Cumulative Index to Nursing and Allied Health Literature (CINAHL).

The electronic search strategies can be found in:

  1. Appendix 1 (CRSO);

  2. Appendix 2 (MEDLINE); and

  3. Appendix 3 (Embase).

Searching other resources

We will search US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov); the World Health Organization International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch); and the ISRCTN registry (www.isrctn.com); review the bibliographies of the relevant RCTs and non‐randomized studies identified as well as relevant textbooks; and contact known experts in the field.

Data collection and analysis

Selection of studies

Two review authors, including one clinician (YA or KAC) and one methodologist (KP or SV) will independently review titles and abstracts retrieved by the search to identify relevant articles using the eligibility criteria described above. We will retrieve full‐text articles of potentially relevant citations and both reviewers will independently assess them for inclusion. If there is disagreement, a third review author (MH, CHG, or SRR) will adjudicate. There are no language restrictions and we will translate non‐English articles into English as needed.

Data extraction and management

Two review authors, including one clinician (YA or KAC) and one methodologist (KP or SV) will independently extract data on population characteristics using a data extraction form that has been piloted. We will gather information on interventions, comparators, participant characteristics, outcomes, follow‐up durations, settings, and study design, eligibility criteria, conflicts of interest and funding. If there is disagreement, a third review author (MH, CHG, or SRR) will adjudicate.

Assessment of risk of bias in included studies

Two review authors, including one clinician (YA or KAC) and one methodologist (KP or SV) will independently assess risk of bias of all included studies according to the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). For RCTs, we will address the following domains as described in the Cochrane Handbook for Systematic Reviews of Interventions: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. For non‐randomized studies, we will use the Risk of Bias in Non‐randomized Studies of Interventions (ROBINS‐I) assessment tool to assess bias due to confounding, participant selection, classification of interventions, deviation from intended interventions, missing data, outcome measurement, and reporting of results (Sterne 2016). Key confounders include: disease state; severity of underlying illness; and presence of cardiac disease, smoking, diabetes, or other comorbidities. Relevant co‐interventions include both non‐pharmacological interventions (such as wearing compression socks, maintaining hydration, sleeping with the head elevated, and behavioral changes such as rising slowly) and pharmacological interventions (such as direct or indirect sympathomimetic pressor agents). If there is disagreement, a third review author (MH, CHG or SRR) will adjudicate.

Measures of treatment effect

We will analyze all the primary and secondary outcomes under consideration. We will undertake meta‐analysis when at least two adequately homogeneous studies are available. We will use our clinical and methodological expertise when examining included studies’ populations, interventions, comparators, and outcomes to determine if studies are adequately homogeneous. For dichotomous outcome measures, we will calculate the risk ratios (RR) and risk differences (RD) with 95% CI. For continuous measures, we will report the mean difference (MD) and 95% CI, or standardized mean difference (SMD) and 95% CI when different measurement scales are used for the same outcome. We will use the Cochrane statistical package, Review Manager 5 (RevMan 5) (RevMan 2014) for data analysis.

'Summary of findings' table

Two review authors, including one clinician (YA or KAC) and one methodologist (KP or SV) will independently rate the quality of the evidence for the important outcomes across studies according to the GRADE approach, which considers methodological quality (study design and risk of bias), consistency, precision, directness, and reporting bias (GRADEPro GDT 2015). If there is disagreement, a third review author (MH, CHG, or SRR) will adjudicate.

We will summarize strength of evidence ratings in 'Summary of findings' tables using GRADEpro GDT software. The 'Summary of findings' table will include the following outcome measurements for our primary comparison of interest (fludrocortisone versus placebo). If sensitivity analyses indicate outcomes measured at less than three weeks are unreliable (an important source of heterogeneity), in the 'Summary of findings' table we will only report measurements taken at three weeks or longer. We will use the assumed risks as reported in included studies.

  1. BP outcomes: change in systolic BP/diastolic BP between pre‐ and post‐treatment, as measured in the upright (standing or tilt) position, two to three minutes after standing/tilting

  2. Change in frequency and severity of postural light‐headedness, dizziness, or presyncope between pre‐ and post‐treatment, measured as number of events per week (frequency) and through a validated scale (severity)

  3. Change in frequency of syncope between pre‐ and post‐treatment, measured as number of events per week

  4. Change in quality of life or overall well‐being between pre‐ and post‐treatment, measured through validated scales (e.g. SF‐36 or SF‐12, EQ‐5D, CGI, or PGIC)

  5. Change in overall orthostatic symptoms between pre‐ and post‐treatment using a validated scale (e.g. COMPASS‐OD) or other similar measurement

  6. Serious or severe adverse events due to treatment

Unit of analysis issues

The unit of analysis will be the participant. For RCTs we will take into account the level at which randomization occurred, and take into account trial design such as cross‐over trials, cluster‐randomized trials and multiple observations for the same outcome. For cross‐over trials, we will prefer results from the first randomization period when available. For cluster‐randomized trials, we will only include in our meta‐analyses those that use statistical methods that correctly account for the clustering in the data. For studies with multiple observations of the same outcome, we will include all time points. We will conduct separate meta‐analyses for each intervention‐comparator pair of interest if at least two adequately homogeneous studies are identified.

Dealing with missing data

In the case of missing data that we can identify, we will request data from study authors. If data are unavailable, we will assess whether data are likely to be missing at random. If yes, we will only analyze the available data. If data are not missing at random, we will perform sensitivity analyses to assess how sensitive results are to imputations of the missing data, with all good outcomes, poor outcomes and the mean. We will then analyze the potential impact of missing data as part of the 'Risk of bias' assessment in included studies.

Assessment of heterogeneity

We will assess heterogeneity using the Chi² test and I² statistic (Higgins 2003). Where significant heterogeneity is present, we will attempt to determine potential reasons by examining population and study characteristics and perform subgroup analyses to explore their influence when possible (Deeks 2017).

Assessment of reporting biases

For quantitative analyses, we will inspect forest plots and prepare funnel plots to look for evidence of reporting bias. We will present funnel plots if 10 or more studies are identified (Sterne 2017).

Data synthesis

When available and sufficiently clinically homogeneous, we will combine data from included RCTs in meta‐analyses. As we are anticipating some natural heterogeneity among the study populations, we have chosen a random‐effects model for our statistical analyses. We will conduct analyses using RevMan 5 software (RevMan 2014) for all statistical analyses. We will use a narrative synthesis approach to review the literature for all non‐randomized studies and for randomized studies that provide insufficient data to conduct a meta‐analysis. Results from RCTs and non‐randomized studies will be reported in the results section (Deeks 2017).

Subgroup analysis and investigation of heterogeneity

As data permits, we will carry out the following a priori subgroup analyses on all outcomes.

  1. Peripheral autonomic failure versus central autonomic failure

  2. Disease state (e.g. Parkinson’s Disease, diabetes, amyloid‐induced orthostatic hypotension, pure autonomic failure, Lewy body disease, or multiple system atrophy)

  3. Age 65 years or over versus under 65 years

To detect differences between two subgroups, we will consider both the difference in the magnitude of effect as well as the overlap in confidence intervals. To detect differences between three or more subgroups, we will use the formal test for subgroup interactions in RevMan 5 (RevMan 2014).

Sensitivity analysis

As data permits, we will perform sensitivity analyses that are restricted to studies with unclear to low risk of bias, those conducted in the US, UK or other high‐income country, those with non‐industry funding, or English‐language studies, those with attrition rates greater than 20%, those with missing data, those more than 3 weeks long, and those that use validated measurements, to explore their influence on effect size.

Acknowledgements

We thank Dr Michael Benatar and Dr Hans Lahrmann, co‐authors with SR and CG of the Cochrane protocol 'Pharmacological treatments for postural hypotension' (Gibbons 2010), which we revised to create this protocol.

This project was supported by the National Institute for Health Research (NIHR) via Cochrane Infrastructure funding to Cochrane Neuromuscular. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service, or the Department of Health. Cochrane Neuromuscular is also supported by the MRC Centre for Neuromuscular Diseases.

Appendices

Appendix 1. Cochrane Register of Controlled Trials (CENTRAL in CRS Web Online) search strategy

#1 orthostatic NEAR hypotension AND CENTRAL:TARGET #2 orthostatic NEAR intolerance AND CENTRAL:TARGET #3 postural NEAR hypotension AND CENTRAL:TARGET #4 neurally NEAR mediated NEAR hypotension AND CENTRAL:TARGET #5 autonomic NEAR hypotension AND CENTRAL:TARGET #6 #1 OR #2 OR #3 OR #4 OR #5 AND CENTRAL:TARGET #7 fludrocortisone or florinef or fluorocortisol or fluorohydrocortisone AND CENTRAL:TARGET #8 #6 AND #7 AND CENTRAL:TARGET

Appendix 2. MEDLINE (OvidSP) search strategy

1 Hypotension, Orthostatic/ (5747) 2 orthostatic hypotension.mp. (5087) 3 postural hypotension.mp. (1559) 4 orthostatic intolerance.mp. (1304) 5 neurally mediated hypotension.mp. (57) 6 autonomic hypotension.mp. (1) 7 or/1‐6 (10118) 8 (fludrocortisone or florinef).mp. (2182) 9 (fluorocortisol or fluorohydrocortisone).mp. (279) 10 8 or 9 (2283) 11 7 and 10 (331) 12 exp animals/ not humans.sh. (4742139) 13 11 not 12 (331) 14 remove duplicates from 13 (302)

Appendix 3. Embase (OvidSP) search strategy

1 Orthostatic Hypotension/ (889) 2 orthostatic hypotension.tw. (348) 3 postural hypotension.mp. (295) 4 orthostatic intolerance.mp. (20) 5 neurally mediated hypotension.mp. (0) 6 autonomic hypotension.mp. (0) 7 or/1‐6 (905) 8 (fludrocortisone or florinef).mp. (404) 9 (fluorocortisol or fluorohydrocortisone).mp. (263) 10 8 or 9 (423) 11 exp animal/ or exp invertebrate/ or animal.hw. or non human/ or nonhuman/ (522983) 12 human/ or human cell/ or human tissue/ or normal human/ (157291) 13 11 not 12 (366509) 14 10 not 13 (294) 15 limit 14 to (conference abstracts or embase) (294) 16 remove duplicates from 15 (286)

Contributions of authors

SRR and CHG conceived the review and drafted the initial protocol and the search strategy with assistance from the Cochrane team.

All review authors revised the draft. All review authors have approved publication of the protocol.

Dr. Mark Helfand will be the guarantor of the review.

Sources of support

Internal sources

  • The authors will complete this review within their own time, as there is no allocated time or funding for such activities within their jobs, Other.

External sources

  • No sources of support supplied

Declarations of interest

MH: none known

YA: none known

KAC: none known

CHG: Dr. Gibbons has served on an advisory board for Lundbeck on the treatment of orthostatic hypotension.

SRR: Dr. Raj has served on the Board of Directors of multiple professional scientific organizations (American Autonomic Society and the Association of Clinical & Translational Sciences) and as a Medical Advisor for multiple Patient Advocacy Groups. He was not financially compensated for these activities. He has received grants from the National Institutes of Health (USA) Canadian Institutes for Health Research for studies on Postural Tachycardia Syndrome and his colleague has received funding from the Canadian Institutes for Health Research for a study of fludrocortisone in vasovagal syncope. Dr. Raj has also received study drug from Apotex Pharmaceuticals for a study of atomoxetine in vasovagal syncope. He has been compensated for and served as a consultant for Lundbeck Pharmaceuticals, GE Healthcare and Medtronic Inc. Dr. Raj has been compensated for and served as an expert witness in a case involving whether a car accident caused Postural Tachycardia Syndrome in a patient.

KP: none known

SV: none known

New

References

Additional references

  1. Arbogast SD, Alshekhlee A, Hussain Z, McNeeley K, Chelimsky TC. Hypotension unawareness in profound orthostatic hypotension. American Journal of Medicine 2009;122(6):574‐80. [PUBMED: 19486719] [DOI] [PubMed] [Google Scholar]
  2. Armstrong E, Mathias CJ. The effects of the somatostatin analogue, octreotide, on postural hypotension, before and after food ingestion, in primary autonomic failure. Clinical Autonomic Research 1991;1(2):135‐40. [PUBMED: 1822761] [DOI] [PubMed] [Google Scholar]
  3. Biaggioni I, Onrot J, Stewart CK, Robertson D. The potent pressor effect of phenylpropanolamine in patients with autonomic impairment. Journal of the American Medical Association 1987;258(2):236‐9. [PUBMED: 3599310] [PubMed] [Google Scholar]
  4. Campbell IW, Ewing DJ, Clarke BF. 9‐Alpha‐fluorohydrocortisone in the treatment of postural hypotension in diabetic autonomic neuropathy. Diabetes 1975;24(4):381‐4. [PUBMED: 1094320] [DOI] [PubMed] [Google Scholar]
  5. Chobanian AV, Volicer L, Tifft CP, Gavras H, Liang CS, Faxon D. Mineralocorticoid‐induced hypertension in patients with orthostatic hypotension. New England Journal of Medicine 1979;301(2):68‐73. [PUBMED: 449947] [DOI] [PubMed] [Google Scholar]
  6. Davies B, Bannister R, Sever P. Pressor amines and monoamine‐oxidase inhibitors for treatment of postural hypotension in autonomic failure. Limitations and hazards. Lancet 1978;1(8057):172‐5. [PUBMED: 74603] [DOI] [PubMed] [Google Scholar]
  7. Deeks JJ, Higgins JPT, Altman DG (editors) on behalf of the Cochrane Statistical Methods Group. Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors), Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017), Cochrane, 2017. Available from www.training.cochrane.org/handbook.
  8. Freeman R, Landsberg L, Young J. The treatment of neurogenic orthostatic hypotension with 3,4‐DL‐threo‐dihydroxyphenylserine: a randomized, placebo‐controlled, crossover trial. Neurology 1999;53(9):2151‐7. [PUBMED: 10599797] [DOI] [PubMed] [Google Scholar]
  9. Freeman R. Treatment of orthostatic hypotension. Seminars in Neurology 2003;23(4):435‐42. [PUBMED: 15088264] [DOI] [PubMed] [Google Scholar]
  10. Freeman R. Autonomic peripheral neuropathy. Neurologic Clinics 2007;25(1):277‐301. [PUBMED: 17324728] [DOI] [PubMed] [Google Scholar]
  11. Freeman R. Clinical practice. Neurogenic orthostatic hypotension. New England Journal of Medicine 2008;358(6):615‐24. [PUBMED: 18256396] [DOI] [PubMed] [Google Scholar]
  12. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clinical Autonomic Research 2011;21(2):69‐72. [PUBMED: 21431947] [DOI] [PubMed] [Google Scholar]
  13. Frith J. Diagnosing orthostatic hypotension: a narrative review of the evidence. British Medical Bulletin 2015;115(1):123‐34. [PUBMED: 25995335] [DOI] [PubMed] [Google Scholar]
  14. Ghrist DG, Brown GE. Postural hypotension with syncope: its successful treatment with ephedrine. American Journal of Medical Science 1928;175:336‐49. [Google Scholar]
  15. 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. Journal of Neurology 2017;264(8):1567‐82. [DOI: 10.1007/s00415-016-8375-x; PUBMED: 28050656] [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McMaster University (developed by Evidence Prime). GRADEpro GDT. Version accessed 30 May 2017. Hamilton (ON): McMaster University (developed by Evidence Prime), 2015.
  17. Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly: diagnosis and treatment. American Journal of Medicine 2007;120(10):841‐7. [PUBMED: 17904451] [DOI] [PubMed] [Google Scholar]
  18. Hickler RB, Thompson GR, Fox LM, Hamlin JT. Successful treatment of orthostatic hypotension with 9‐alpha‐fluorohydrocortisone. New England Journal of Medicine 1959;261:788‐91. [PUBMED: 14401690] [DOI] [PubMed] [Google Scholar]
  19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327:557‐60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors), Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017), Cochrane, 2017. Available from www.training.cochrane.org/handbook.
  21. Hoeldtke RD, Streeten DH. Treatment of orthostatic hypotension with erythropoietin. New England Journal of Medicine 1993;329(9):611‐5. [PUBMED: 8341335] [DOI] [PubMed] [Google Scholar]
  22. Jordan J, Shannon JR, Biaggioni I, Norman R, Black BK, Robertson D. Contrasting actions of pressor agents in severe autonomic failure. American Journal of Medicine 1998;105(2):116‐24. [PUBMED: 9727818] [DOI] [PubMed] [Google Scholar]
  23. Kaufmann H, Biaggioni I. Autonomic failure in neurodegenerative disorders. Seminars in Neurology 2003;23(4):351‐63. [PUBMED: 15088256] [DOI] [PubMed] [Google Scholar]
  24. Lanier JB, Mote MB, Clay EC. Evaluation and management of orthostatic hypotension. American Family Physician 2011;84(5):527‐36. [PUBMED: 21888303] [PubMed] [Google Scholar]
  25. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double‐blind multicenter study. Midodrine Study Group. Journal of the American Medical Association 1997;277(13):1046‐51. [PUBMED: 9091692] [PubMed] [Google Scholar]
  26. Low PA. Prevalence of orthostatic hypotension. Clinical Autonomic Research 2008;18 Suppl 1:8‐13. [PUBMED: 18368301] [DOI] [PubMed] [Google Scholar]
  27. McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use. Drugs 1989;38(5):757‐77. [PUBMED: 2480881] [DOI] [PubMed] [Google Scholar]
  28. Moya A, Sutton R, Ammirati F, Blanc J‐J, Brignole M, Dahm JB, et al. Guidelines for the diagnosis and management of syncope (version 2009). European Heart Journal 2009;30(21):2631‐71. [PUBMED: 19713422] [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. NICE. Postural hypotension in adults: fludrocortisone. Evidence summary [ESUOM20]. 2013 October. www.nice.org.uk/advice/esuom20/chapter/Key‐points‐from‐the‐evidence (accessed 25 Sep 2017).
  30. Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  31. Sandroni P, Benarroch EE, Wijdicks EF. Caudate hemorrhage as a possible complication of midodrine‐induced supine hypertension. Mayo Clinic Proceedings 2001;76(12):1275. [PUBMED: 11761508] [DOI] [PubMed] [Google Scholar]
  32. Schondorf R. Acetylcholinesterase inhibition in the treatment of hypotension. Journal of Neurology, Neurosurgery, and Psychiatry 2003;74(9):1187. [PUBMED: 12933916] [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Singer W, Opfer‐Gehrking TL, McPhee BR, Hilz MJ, Bharucha AE, Low PA. Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension. Journal of Neurology, Neurosurgery, and Psychiatry 2003;74(9):1294‐8. [PUBMED: 12933939] [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS‐I: a tool for assessing risk of bias in non‐randomised studies of interventions. BMJ 2016;355:i4919. [DOI: 10.1136/bmj.i4919; PUBMED: 27733354] [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sterne JAC, Egger M, Moher D, Boutron I (editors). Chapter 10: Addressing reporting biases. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors), Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017), Cochrane, 2017. Available from www.training.cochrane.org/handbook.
  36. Tilvis RS, Hakala SM, Valvanne J, Erkinjuntti T. Postural hypotension and dizziness in a general aged population: a four‐year follow‐up of the Helsinki Aging Study. Journal of the American Geriatrics Society 1996;44(7):809‐14. [PUBMED: 8675929] [DOI] [PubMed] [Google Scholar]
  37. Lieshout JJ, Harkel AD, Wieling W. Fludrocortisone and sleeping in the head‐up position limit the postural decrease in cardiac output in autonomic failure. Clinical Autonomic Research 2000;10(1):35‐42. [PUBMED: 10750642] [DOI] [PubMed] [Google Scholar]
  38. Wieling W, Lieshout JJ, Leeuwen AM. Physical manoeuvres that reduce postural hypotension in autonomic failure. Clinical Autonomic Research 1993;3(1):57‐65. [PUBMED: 8477182] [DOI] [PubMed] [Google Scholar]
  39. Zesiewicz TA, Sullivan KL, Arnulf I, Chaudhuri KR, Morgan JC, Gronseth GS, et al. Practice Parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2010;74(11):924‐31. [PUBMED: 20231670] [DOI] [PubMed] [Google Scholar]

References to other published versions of this review

  1. Gibbons CH, Raj SR, Lahrmann H, Benatar M. Pharmacological treatments of postural hypotension. Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI: 10.1002/14651858.CD008269] [DOI] [Google Scholar]

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