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The Cochrane Database of Systematic Reviews logoLink to The Cochrane Database of Systematic Reviews
. 2010 Jan 20;2010(1):CD008269. doi: 10.1002/14651858.CD008269

Pharmacological treatments of postural hypotension

Christopher H Gibbons 1,✉, Satish R Raj 2, Heinz Lahrmann 3, Michael Benatar 4
PMCID: PMC6494539

Abstract

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

We seek to identify and evaluate the benefits and harms of all pharmacologic treatments for postural hypotension.

Background

Description of the condition

Orthostatic, or postural, hypotension is defined as a drop in systolic blood pressure of at least 20 mmHg and/or diastolic blood pressure of at least 10 mmHg within three minutes of standing or upright tilt table testing to 60‐75 degrees (Position Paper 1996). Orthostatic hypotension may be seen in acute conditions, such as blood loss and volume depletion, or the fall in blood pressure may be secondary to a disturbance in autonomic regulation seen in central or peripheral diseases of the autonomic nervous system such as multiple system atrophy, Parkinson’s disease, Dementia with Lewy Bodies, pure autonomic failure, autoimmune autonomic ganglionopathy, amyloidosis and diabetic autonomic neuropathy (Freeman 2007; Kaufmann 2003). Often orthostatic hypotension is caused by medication (e.g. antihypertensive drugs, dopamine and agonists) or lack of adequate fluid intake, particularly in elderly patients.

The prevalence of postural hypotension in patients 65 years and older has been reported to range from 5% to 30%, with higher prevalences linked to increasing age of the studied population (Low 2008; Tilvis 1996). The incidence of orthostatic hypotension in the general population has been less well characterized (Gupta 2007). The incidence of 'first dose' orthostatic hypotension during initiation of some antihypertensive medications has been reportedly as high as 40% (Krum 1994). The rate of orthostatic hypotension‐related hospitalizations increases with age, and over 80,000 hospitalizations were reported in the U.S. in 2004 for this problem. In patients over 75 years of age, 233 per 100,000 patients were admitted to the hospital for problems related to orthostatic hypotension, an estimated prevalence in this population of 0.23% (Shibao 2007). 

The normal response to standing is a drop in systolic blood pressure of 5‐10 mmHg and an increase in diastolic blood pressure of 5‐10 mmHg (Borst 1982). The transition from a horizontal to vertical posture results in a sudden shift of 500‐1000 ml of blood from the central to the peripheral vascular system, with pooling of blood in the veins of the legs, pelvic and splanchnic circulations (Borst 1984). Orthostatic stress results in an increase in heart rate and an increase in vascular resistance. Patients with diseases affecting the autonomic nervous system have impaired cardiovascular and peripheral vascular responsiveness, resulting in falls in both systolic and diastolic blood pressure in the upright position (Smit 1999).

Symptoms of postural hypotension include lightheadedness, dizziness, syncope, visual blurring, weakness, gait instability, the “coat hanger headache” due to ischemia of strap muscles of the neck, and shortness of breath in the upright position (platypnea) (Gibbons 2005; Mathias 1999). Orthostatic hypotension is a frequent comorbid factor for falls in the elderly (Gupta 2007). Symptoms of orthostatic hypotension subside as blood pressure normalizes, typically through returning to a seated or recumbent position (Wieling 1993). Unfortunately, there are no published validated tools for symptoms of orthostatic hypotension, although recent evidence has suggested traditional symptoms of orthostatic hypotension may be present in less than 50% of patients with severe orthostatic hypotension (blood pressure falls greater than 60 mmHg systolic; Arbogast 2009).

Description of the intervention

A variety of treatments for postural hypotension have been reported in the literature including physical counter‐maneuvers, increasing water and salt intake, and the use of pharmacological agents (Lahrmann 2006). These treatments typically raise blood pressure in both the supine and standing position, but will not necessarily reduce the fall in blood pressure with positional change. Therefore agents used in the treatment of postural hypotension are evaluated based on their ability to improve symptoms associated with orthostatic hypotension or their ability to improve standing blood pressure, not on their capacity to reduce the fall in blood pressure associated with standing (Wright 1998).  

Midodrine hydrochloride, an alpha‐1 adrenergic agonist, is the most well established sympathomimetic agent used to treat orthostatic hypotension (Low 1997). The mechanism of action is direct stimulation of alpha adrenergic receptors of the arteriolar and venous vasculature, resulting in an increase in vascular resistance and blood pressure (McTavish 1989). Phenylephrine is another direct alpha‐1 adrenoreceptor agonist used in the treatment of orthostatic hypotension (Jordan 1998). Droxidopa is an L‐norepinephrine precursor that results in an increase in circulating norepinephrine levels and a corresponding increase in blood pressure (Freeman 1999; Gibbons 2005b). Other agents with both direct and indirect effects on the alpha adrenoreceptor include ephedrine, pseudoephedrine and phenylpropanolamine (Biaggioni 1987; Davies 1978; Ghrist 1928). Finally, there are sympathomimetic agents that act indirectly through the release of norepinephrine from post ganglionic neurons such as methylphenidate and dextroamphetamine sulfate (Jordan 1998). Treatments with any of the sympathomimetic agents can result in severe supine hypertension, so should not be used at all during periods of recumbency (Sandroni 2001).

Pyridostigmine has reported effectiveness in the treatment of postural hypotension through potentiation of sympathetic cholinergic ganglionic transmission, also leading to increased vascular tone, but only in the upright position (Singer 2003). The clear benefit of this targeted therapy is a lower risk of supine hypertension that is seen with agents that result in direct vasoconstriction (Schondorf 2003).

Plasma volume expansion has also been used as a treatment for postural hypotension. The most widely used agent, fludrocortisone acetate, has mineralocorticoid effects that result in an increase in plasma volume and a reduction in orthostatic hypotension (Hickler 1959). Additional agents used in the treatment of orthostatic hypotension include erythropoietin, non‐steroidal anti‐inflammatory agents, octreotide and vasopressin (Armstrong 1991; Freeman 2003; Hoeldtke 1993).

How the intervention might work

Pharmacologic treatments generally alter blood pressure through an increase in either plasma volume or an increase in peripheral vascular resistance (Freeman 2003). The treatments typically raise blood pressure in both the supine and standing positions. Agents that increase plasma volume work through a variety of mechanisms, including mineralocorticoid induced water and salt retention, increased red cell mass, alterations in renal fluid retention and a variety of other less well established mechanisms (Armstrong 1991; Freeman 2003; Hoeldtke 1993). Agents that increase peripheral vascular resistance may work through direct activation of alpha adrenoreceptors on blood vessels, or alterations to circulating or local catecholamine levels with corresponding vasoconstriction (Biaggioni 1987; Davies 1978; Ghrist 1928; McTavish 1989; Sandroni 2001).

Why it is important to do this review

To evaluate the current level of evidence available for the treatment of postural (orthostatic) hypotension. To identify the risks and benefits associated with treatments for postural hypotension, and to highlight gaps in knowledge that require further investigation.

Objectives

We seek to identify and evaluate the benefits and harms of all pharmacologic treatments for postural hypotension.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomized controlled trials (RCTs) or quasi‐randomized trials of any pharmacological intervention for postural (orthostatic) hypotension. If there are insufficient RCTs to allow adequate conclusions, we will describe the results of observational studies in the Discussion section.

Types of participants

We will include all participants with orthostatic hypotension due to a chronic peripheral or central autonomic neuropathy. We will exclude patients with orthostatic hypotension from acute volume depletion or blood loss from evaluation. We will include both children and adults.

Types of interventions

We will include any pharmacological intervention or combination of pharmacological interventions compared to placebo, no treatment, or another treatment or combination of treatments.

Types of outcome measures

Primary outcomes

Change in mean systolic and/or diastolic blood pressure in the upright (standing or tilt) position between pre‐ and post‐treatment periods during acute treatment (up to 12 weeks). 

Secondary outcomes

1.      Change in postural light‐headedness and a symptomatic global impression score during acute treatment (up to 12 weeks). Postural lightheadedness is measured on an 11‐point Likert scale (0‐10) while the global impression score is rated on a six‐point scale (0‐5).

2.      Change in systolic and/or diastolic blood pressure in the upright (standing or tilt) position between pre‐ and post‐treatment periods during chronic treatment (beyond 12 weeks).

3.      Adverse events due 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

We will search the Cochrane Neuromuscular Disease Group Trials Specialized Register using the following search terms: orthostatic hypotension, postural hypotension, orthostatic intolerance, neurally mediated hypotension and autonomic hypotension. We will adapt this strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), MEDLINE (1966 to present) and EMBASE (January 1980 to present).

Electronic searches

The electronic search strategies can be found in Appendix 1, Appendix 2 and Appendix 3

Searching other resources

We will review the bibliographies of the RCTs identified; contact known experts in the field; and approach pharmaceutical companies to identify additional published or unpublished data.

Data collection and analysis

Selection of studies

Two review authors will identify those articles which are potentially relevant from all the titles and abstracts retrieved by the search. If there is disagreement, a third review author will adjudicate. We will retrieve the full text for all selected articles and translate into English if necessary. 

Data extraction and management

Two authors will extract data independently to eliminate transcription errors. A data extraction form will include the type of study, the quality criteria described below, number, age and sex of participants, diagnoses, severity of orthostatic hypotension, type of intervention used including dosage, duration and route of administration for drugs, outcome measures and results. One review author will enter the data into the Review Manager (RevMan 2008) program and a second author will check the data entry.

Assessment of risk of bias in included studies

We will follow the current guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) for assessing risk of bias in the included studies. We will address the following domains as described in the handbook: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other sources of bias. We will judge each domain to determine if the criteria have been met. A judgment of 'Yes’ would indicate low risk of bias, while 'No’ would indicate high risk of bias, and 'Unclear’ would indicate unclear or unknown risk of bias. We will include the judgment on each domain in a risk of bias table along with a description or quote of what was reported to happen in the study.

We will base specific rules for evaluating methodological characteristics of studies on the following criteria.

  1. Sequence generation: was the allocation sequence adequately generated?

    1. Yes: randomly generated through a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; or minimization to produce comparable groups.

    2. No: sequence generated by odd or even date of birth. Sequence generated by some rule based on date (or day) of admission. Sequence generated by some rule based on hospital or clinic record number. Allocation by judgment of the clinician. Allocation by preference of the participant. Allocation based on the results of a laboratory test or a series of tests. Allocation by availability of the intervention.

    3. Unclear: insufficient information about the sequence generation process to permit judgement of ‘Yes’ or 'No.'

  2. Allocation concealment: was the allocation concealed adequately to prevent prediction of allocations in advance of or during enrollment?

    1. Yes: central allocation (including telephone, web‐based and pharmacy‐controlled randomization). Sequentially numbered drug containers of identical appearance. Sequentially numbered, opaque, sealed envelopes.

    2. No: using an open random allocation schedule (e.g. a list of random numbers). Assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or not sequentially numbered). Alternation or rotation: date of birth, case record number. Any other explicitly unconcealed procedure.

    3. Unclear: insufficient information to permit judgment of ‘Yes’ or ‘No.’

  3. Blinding: was knowledge of the allocated intervention adequately prevented during the study?

    1. Yes: no blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding. Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken. Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non‐blinding of others unlikely to introduce bias.

    2. No: no blinding or incomplete blinding, and the outcome or outcome measurement is likely to be influenced by lack of blinding. Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken. Either participants or some key study personnel were not blinded, and the non‐blinding of others likely to introduce bias.

    3. Unclear: insufficient information to permit judgement of ‘Yes’ or ‘No.’

  4. Incomplete outcome data: were incomplete outcome data adequately addressed?

    1. Yes: no missing outcome data. Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias). Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate. For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size. Missing data have been imputed using appropriate methods.

    2. No: reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups. For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate. For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size. ‘As‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomization. Application of potentially inappropriate data imputation strategies.

    3. Unclear: insufficient reporting of attrition/exclusions to permit judgment of ‘Yes’ or ‘No’ (e.g. number randomized not stated, no reasons for missing data provided). The study did not address this outcome.

  5. Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?

    1. Yes: the study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way. The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).

    2. No: not all of the study’s pre‐specified primary outcomes have been reported. One or more primary outcomes are reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre‐specified. One or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect). One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis. The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

    3. Unclear: insufficient information to permit judgement of ‘Yes’ or ‘No.’

  6. Other sources of bias: was the study apparently free of other problems that could put it at a high risk of bias?

    1. Yes: the study appears to be free of other sources of bias.

    2. No: had a potential source of bias related to the specific study design used. Stopped early due to some data‐dependent process (including a formal‐stopping rule). Had extreme baseline imbalance. Has been claimed to have been fraudulent. Had some other problem.

    3. Unclear: insufficient information to assess whether an important risk of bias exists; or insufficient rationale or evidence that an identified problem will introduce bias.

Measures of treatment effect

We will analyze all the primary and secondary outcomes under consideration.  We will calculate a weighted treatment effect across trials using the Cochrane statistical package, Review Manager (RevMan 2008). We will calculate the mean differences (MD) and 95% confidence intervals (CI) for mean changes in systolic and diastolic blood pressure between pre‐ and post‐treatment periods. We will classify symptoms of orthostatic hypotension as either present or absent and also as improved or not improved, with the latter category including both those who show no change in symptoms and those whose symptoms worsen. We will categorize adverse events as either present or absent. We will calculate the risk ratios (RR) and risk differences (RD) with 95% CI for these dichotomous outcome measures.

As RCTs are often short‐term, they may be inadequate to capture information about adverse events due to treatment. To overcome this, we will consider non‐randomized evidence in the discussion. 

We will construct a summary of findings table using GRADEpro software. The table will include the following meaningful outcomes.

1) Change in mean systolic blood pressure in the upright (standing or tilt) position between pre‐ and post‐treatment periods during acute treatment (up to 12 weeks).

2) Change in mean diastolic blood pressure in the upright (standing or tilt) position between pre‐ and post‐treatment periods during acute treatment (up to 12 weeks).

3) Change in mean lightheadedness between pre‐ and post‐treatment periods during acute treatment (up to 12 weeks).

4) Change in mean global impression score between pre‐ and post‐treatment periods during acute treatment (up to 12 weeks).

5) Change in mean systolic blood pressure in the upright (standing or tilt) position between pre‐ and post‐treatment periods during chronic treatment (beyond 12 weeks).

6) Change in mean diastolic blood pressure in the upright (standing or tilt) position between pre‐ and post‐treatment periods during chronic treatment (beyond 12 weeks).

7) Adverse events leading to cessation of treatment.

Unit of analysis issues

Primary units of analysis will include systolic and diastolic blood pressures (in mmHg).

Dealing with missing data

We will analyze missing data as part of the assessment of risk of bias in included studies (section 4a to 4c).

Assessment of heterogeneity

If sufficient RCTs of the same intervention and same underlying disease are available, we will test for heterogeneity by inspecting the forest plots and applying the Chi2 test and I2 statistic.

Assessment of reporting biases

If there are sufficient RCTs, we will inspect forest plots and prepare funnel plots to look for evidence of reporting bias.

Data synthesis

When there is more than one trial with a specific agent or similar class of agents, we plan to calculate a weighted treatment effect using a fixed‐effect model, or a random‐effects model if heterogeneity is present using RevMan software (RevMan 2008).

Subgroup analysis and investigation of heterogeneity

We will consider the following two diagnostic subgroups separately if trial data are heterogeneous (if the data are heterogeneous, we will seek to explain it from the differences in trial participants and trial designs).

  1. Peripheral autonomic failure (including, but not limited to):

    1. toxic/metabolic (such as diabetes or chemotherapy induced);

    2. pure autonomic failure;

    3. autoimmune autonomic ganglionopathy;

    4. Guillain‐Barré syndrome and other peripheral demyelinating neuropathies;

    5. Parkinson's disease;

    6. dementia with Lewy bodies.

  2. Central autonomic failure (including, but not limited to):

    1. multiple system atrophy.

We will consider additional subgroups as appropriate.

Sensitivity analysis

We will examine the impact of including trials with high risk of bias in the meta‐analysis by first including and then excluding those RCTs with a high risk of bias.

Appendices

Appendix 1. OVID MEDLINE search strategy

1.      randomized controlled trial.pt. 2.      controlled clinical trial.pt. 3.      randomized.ab. 4.      placebo.ab. 5.      drug therapy.fs. 6.      randomly.ab. 7.      trial.ab. 8.      groups.ab. 9.      or/1‐8 10.  (animals not (animals and humans)).sh. 11.  9 not 10 12.  Hypotension, Orthostatic/ 13.  orthostatic hypotension.mp. 14.  postural hypotension.mp. 15.  orthostatic intolerance.mp. 16.  neurally mediated hypotension.mp. 17.  autonomic hypotension.mp. 18.  or/12‐17 19.  11 and 18

Appendix 2. OVID EMBASE search strategy

1.      randomized controlled trial.pt. 2.      controlled clinical trial.pt. 3.      randomized.ab. 4.      placebo.ab. 5.      drug therapy.fs. 6.      randomly.ab. 7.      trial.ab. 8.      groups.ab. 9.      or/1‐8 10.  (animals not (animals and humans)).sh. 11.  9 not 10 12.  Hypotension, Orthostatic/ 13.  orthostatic hypotension.mp. 14.  postural hypotension.mp. 15.  orthostatic intolerance.mp. 16.  neurally mediated hypotension.mp. 17.  autonomic hypotension.mp. 18.  or/12‐17 19.  11 and 18

Appendix 3. Cochrane Central Register of Controlled Trials (CENTRAL) search strategy

#1 orthostatic NEAR/1 hypotension #2 orthostatic NEXT intolerance #3 postural NEXT hypotension #4 neurally NEXT mediated NEXT hypotension #5 autonomic NEXT hypotension #6 (#1 OR #2 OR #3 OR #4 OR #5)

What's new

Date Event Description
2 May 2018 Amended Withdrawn. See Published notes
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Contributions of authors

Christopher Gibbons wrote the first draft of the protocol. Satish Raj, Heinz Lahrmann and Michael Benatar each provided critical review of this draft and contributed substantial edits. Christopher Gibbons prepared the final draft, which was approved by the other three authors.

Sources of support

Internal sources

  • The authors (CG, SJ, MB) have no internal sources of support, USA.

    Author HL has no internal sources of support, Austria

External sources

  • MB, has no external sources of support, USA.

    HL has no external sources of support, Austria

  • CG, USA.

    NIH K23 NS050209 grant to support early career development.

  • SR, USA.

    NIH K23 RR020783 grant to support early career development.

Declarations of interest

Christopher Gibbons and Michael Benatar have no known conflicts of interest or disclosures to make.

Satish Raj has served as a legal expert witness stating that yohimbine can increase blood pressure. Dr Raj has been involved with the design and conduct of studies to increase blood pressure in patients with orthostatic hypotension.

Heinz Lahrmann is an investigator in a study (NCT00782340) of droxidopa for patients with neurogenic orthostatic hypotension, which may become eligible for inclusion in this review.

Notes

This protocol has been withdrawn, as separate reviews of specific interventions are planned. One protocol, Fludrocortisone for orthostatic hypotension was published: Veazie S, Peterson K, Ansari Y, Chung KA, Gibbons CH, Raj SR, Helfand M. Fludrocortisone for orthostatic hypotension (Protocol). Cochrane Database of Systematic Reviews 2017, Issue 12. Art. No.: CD012868. DOI: 10.1002/14651858.CD012868.

Edited (no change to conclusions)

References

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