Hemodynamic Effects of the Osmopressor Response: A Systematic Review and Meta‐Analysis

Abstract

Background

Rapidly consuming water may offer practical orthostatic hypotension therapy. However, its efficacy across disorders remains uncertain. This study aims to assess the impact of rapid 350‐ to 500‐mL water intake on systolic and diastolic blood pressure (BP) and heart rate (HR) through a systematic review and meta‐analysis.

Methods and Results

We systematically reviewed MEDLINE and Embase up to June 2023, including randomized controlled trials and prospective cohort studies. Using random‐effects meta‐analysis, we calculated pooled mean differences (MDs) for maximum hemodynamic effects of rapid 350‐ to 500‐mL water bolus consumption. Participants with orthostatic hypotension experienced increased systolic BP (MD, 24.18 [95% CI, 15.48–32.88]) and diastolic BP (MD, 11.98 [95% CI, 8.87–15.09]) with decreased HR (MD, −3.46 [95% CI, −5.21 to −1.71]). Similar results were observed in multiple system atrophy and pure autonomic failure subgroup analysis. Healthy participants showed modest increases in systolic BP (MD, 2.33 [95% CI, 1.02–3.64]) and diastolic BP (MD, 2.73 [95% CI, 1.15–4.30]), but HR changes were not significant (MD, −2.06 [95% CI, −5.25 to 1.13]). Water had no significant hemodynamic effects in patients with seated or supine postural tachycardia syndrome, although standing effects were unassessed. Our data do not exclude water's potential standing effect in postural tachycardia syndrome.

Conclusions

In patients with orthostatic hypotension, rapid water intake elevated short‐term systolic BP and diastolic BP, with mild HR reduction when seated or supine. Healthy participants exhibited similar but milder effects. However, patients with postural tachycardia syndrome did not experience these changes in seated or supine positions. Further research is needed to evaluate the promising impact of rapid water ingestion on patients with postural tachycardia syndrome in a standing position, which was not addressed in our study.

Nonstandard Abbreviations and Acronyms

HR

heart rate

HUT

head‐up‐tilt

MD

mean difference

MSA

multiple system atrophy

OH

orthostatic hypotension

PAF

pure autonomic failure

POTS

postural tachycardia syndrome

PROSPERO

The International Prospective Register of Systematic Reviews

Clinical Perspective.

What Is New?

• Consuming a rapid 350‐ to 500‐mL bolus raises systolic blood pressure (mean difference [MD], 24.18 [95% CI, 15.48–32.88]) and diastolic blood pressure (MD, 11.98 [95% CI, 8.87–15.09]), while also lowering heart rate (MD, −3.46 [95% CI, −5.21 to −1.71]) in participants with orthostatic hypotension.

• In healthy participants, rapid 350‐ to 500‐mL water bolus consumption slightly raises systolic blood pressure (MD, 2.33 [1.02–3.64]) and diastolic blood pressure (MD, 2.73 [1.15–4.30]), with no impact on heart rate (MD, −2.06 [95% CI, −5.25 to 1.13]).

• Rapid water bolus ingestion had no significant hemodynamic effects in patients with postural tachycardia syndrome in the supine or seated position, but other studies suggest potential benefits when combined with standing, which our research did not assess.

What Are the Clinical Implications?

• Individuals with orthostatic hypotension should consume water before meals and when experiencing orthostatic symptoms.

• Drinking water in the morning before getting out of bed may be helpful for patients with orthostatic hypotension, considering that the greatest increase in blood pressure due to water consumption occurs when other blood pressure–increasing agents may have just begun to take effect.

Orthostatic hypotension (OH) is a crucial feature of cardiovascular autonomic failure. It is prevalent among various patient populations and is associated with an increased risk of morbidity and death. ¹ Guidelines define OH as a sustained systolic blood pressure (SBP) fall of ≥20 mm Hg or diastolic blood pressure (DBP) drop of ≥10 mm Hg within 3 minutes of active standing or head‐up tilt (HUT) to at least 60  °C on a tilt table. OH may have a prevalence of 30% among those aged ≥65 years, to a prevalence of 70% in institutionalized patients. ² , ³ When considering patients with neurogenic OH (OH due to autonomic nervous system damage), the prevalence rises to 80% of patients with multiple system atrophy (MSA), ⁴ , ⁵ , ⁶ 30% of patients with Parkinson disease, ⁷ and 100% of patients with pure autonomic failure (PAF). ⁸ Although it is possible to have asymptomatic OH, symptoms caused by low blood flow to the brain include presyncope, visual and auditory disturbances, fatigue, light‐headedness, and loss of consciousness. ⁹ , ¹⁰ As such, OH may have a significant negative impact on a patient's quality of life. ¹⁰ , ¹¹

Various pharmacological and nonpharmacological treatments exist for the management of OH. It has been demonstrated that in patients with OH, rapidly drinking 300 to 500 mL of plain, unsalted water increases SBP by approximately 35 mm Hg and buffers postprandial hypotension. ¹⁰ , ¹² , ¹³ The pressor effect begins after 10 to 15 minutes, peaks around 25 to 40 minutes, and largely dissipates within 90 minutes. ¹² A case report also demonstrated that rapid consumption of 8 oz (236.6 mL) of water in a patient with postural tachycardia syndrome (POTS) eliminated standing tachycardia within 10 minutes. ¹⁴ Finally, a study of healthy individuals suggested that water consumption may be a simple and effective way to prevent vasovagal reactions, especially in situations such as blood donation, where vasovagal reactions occur more frequently. ¹⁵ The investigators found that of 22 healthy adult participants, 8 experienced hypotension or bradycardia within the first 30 minutes of HUT when they did not consume water beforehand. However, only 1 of the 22 participants experienced these symptoms within the first 30 minutes of HUT when they consumed water before the test. ¹⁵ This phenomenon has been termed the osmopressor response and is a point of interest for research throughout orthostatic dysregulation literature. ⁹ , ¹² , ¹³ , ¹⁶

Studies have shown that sympathetic activation following water ingestion may cause changes in systemic vascular resistance, which may be more pronounced in older individuals with age‐related changes in baroreflex regulation or in patients with severe baroreflex abnormalities caused by neurodegenerative diseases. ¹⁶ The underlying mechanism is likely through the rapid‐onset hypo‐osmolality of the portal vein following water bolus ingestion, which may be mediated by the osmo‐sensitive transient receptor potential vanilloid 4 channel. ¹² Subsequently, the ingested water triggers efferent sympathetic nervous system activity and increases SBP. ¹² , ¹⁶

The efficacy of water bolus ingestion as a treatment for OH has only been evaluated in small studies, with no meta‐analyses performed to date. The purpose of this systematic review and meta‐analysis was to determine the effect of rapid ingestion of 350 to 500 mL of water on SBP, DBP, and heart rate (HR) across various clinical populations.

Methods

The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) on December 17, 2021 (CRD42022298840). The registered protocol includes details on the search strategy, criteria for study selection, statistical methodology, and risk of bias assessments. Informed consent was not required, and this study was exempt from institutional review board approval as all data and analytic software are publicly available. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Literature Search Strategy

A systematic electronic search was performed without language restriction in the MEDLINE and Embase databases from inception until June 2023. The Medical Subject Headings terms and keywords were related to orthostatic hypotension, “osmopressor response,” “blood pressure,” “autonomic dysfunction,” and “water ingestion.” Search results were then imported into Covidence (Covidence Systematic Review Software, Veritas Health Innovation, Melbourne, Australia), and further screenings of Google Scholar and references from selected articles were analyzed to identify potential gray literature. Database‐specific search terms and results are listed in Tables S1 and S2.

Eligibility Criteria

Studies selected for review and meta‐analysis were randomized controlled trials (RCTs) and prospective cohort studies. Two authors (O.A.O. and L.Y.L.) independently completed a selection process using Covidence. First, titles and abstracts were screened to identify studies that investigated the osmopressor effects on participant hemodynamics. Next, full‐text review was completed to validate the collection of relevant participant populations, study designs, and continuous hemodynamic outcomes. Studies were included if (1) the intervention included per‐oral or nasogastric tube rapid water consumption between 200 and 500 mL without the addition of salt or sugars; (2) participants were healthy or diagnosed with either OH, POTS, PAF, MSA, or spinal cord injury; (3) the study outcome measures included SBP, DBP, and HR in the seated or supine position; (4) the investigators recorded hemodynamic outcomes for a minimum of 15 minutes following water ingestion.

Quality Assessment

Quality assessment was conducted independently by 2 reviewers (O.A.O. and L.Y.L.) to evaluate each selected study using the Cochrane Collaboration's risk‐of‐bias tool for RCTs or a modified Newcastle–Ottawa Scale for assessing the quality of nonrandomized studies. The maximum score on the modified Newcastle–Ottawa Scale was set to 9 (highest quality); scores of 0 to 3 were assigned for low‐quality studies, 4 to 6 for moderate‐quality studies, and 7 to 9 for high‐quality studies. In case of disagreement, a discussion was commenced to reach a consensus. ¹⁷ The quality of evidence for each outcome was graded using the Grading of Recommendations, Assessment, Development, and Evaluation framework.

Statistical Analysis

Mean changes in blood pressure (BP) and HR before and after water bolus ingestion were extracted from each study. For pooled analyses, the difference in BP and HR changes from 0 were expressed as mean difference (MD) using random‐effects models with 95% CIs. R software (R Foundation for Statistical Computing, Vienna, Austria) was employed for these statistical analyses. We also performed subgroup analyses for MSA and PAF. For RCTs, the difference between before and after intervention versus before and after control was expressed as MD using random‐effects models with 95% CI. Study heterogeneity was estimated using the I ² statistic. Values <25% were considered to represent low heterogeneity, 25% to 50% moderate heterogeneity, and >75% high heterogeneity. ¹⁸

Results

Study Selection and Characteristics of Included Studies

Among the 432 studies initially retrieved by the search strategy, 35 full‐text articles were assessed for eligibility, and 17 studies met the inclusion criteria. ¹³ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ Jordan et al ²³ was later excluded from the meta‐analysis due to incomplete data. An additional paper was added from the gray literature to make a total of 17 eligible studies (Figure 1). ³⁴ The characteristics of included studies are presented in the Table. A total of 12 prospective cohort studies and 5 RCTs met the inclusion criteria. Of the studies that included patients with OH, 7 studies reported both BP and HR measures. ¹³ , ²⁰ , ²² , ²⁴ , ²⁶ , ³⁰ , ³¹ , ³³ In trials with healthy participants, 8 papers reported BP measures, ¹⁹ , ²⁷ , ²⁸ , ²⁹ , ³² , ³⁴ while 7 reported HR measures. ¹⁹ , ²⁷ , ²⁹ , ³² , ³⁴ Patients with POTS were studied in 4 papers. ²⁷ , ³⁰ , ³³ Individual characteristics of each study, including design, reported outcomes, and protocol regimens are summarized in the Table and further detailed in Table S3.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta‐analyses flow diagram for systematic reviews and meta‐analysis.

Table .

Characteristics of Included Studies

Study	Study design	Position	Interventions		Sample size of water bolus recipients, n		Age in years (mean±SD)	Dosing strategy (NG, PO)	Water bolus ingestion time (include breaks)
			Water bolus volume	Control	Water bolus	Control
Callegaro, 2007 19	Prospective cohort	Supine	500 mL mineral water	Preintervention measurements	10	10	37±6	PO	<5 min
Cariga, 2001 20	Prospective cohort	Supine	500 mL distilled water	Preintervention measurements	14	14	64 (range: 39–78)	PO	3–4 min
Claydon, 2006 21	Single‐blind RCT	Supine	500 mL nonsparkling mineral water	50 mL nonsparkling mineral water	9	9	36.8±4.2	PO	N/A
Deguchi, 2007 22	Prospective cohort	Seated	350 mL tap water	Preintervention measurements	5	5	63 (range, 49–75)	PO	<5 min
Jordan, 2004 23	Prospective cohort	Seated	480 mL tap water	Preintervention measurements	5*	5*	N/A	PO	<5 min
Jordan, 2000 13	Prospective cohort	Seated	480 mL tap water	Preintervention measurements	MSA=28, PAF=19	MSA=28, PAF=19	MSA=66±1, PAF=72±2	PO	“As quickly as possible”
Lipp, 2005 24	Prospective cohort	Supine	500 mL normal saline or distilled water	Preintervention measurements	10	10	N/A	NG	<5 min
Newton, 2018 25	Prospective cohort	Supine	248–480 mL tap water	Preintervention measurements	25	25	N/A	PO	<5 min
Raj, 2006 26	Open‐label RCT	Seated	473 mL distilled water	Preintervention measurements	9	9	65±3	PO	Rapidly (<2–3 min)
Rodriguez, 2019 27	Prospective cohort	Supine	500 mL still mineral water	Preintervention measurements	POTS=8, Healthy=8	POTS=8, Healthy=8	POTS=25.3 (range, 18–45), Healthy=24.4 (range, 23–28)	PO	<5 min
Routledge, 2002 28	Open‐label RCT	Semisupine	500 mL tap water	20 mL tap water	10*	10*	Healthy=range, 24–34	PO	“As quickly as possible”
Schroeder, 2002 29	Single‐blind RCT	Supine	500 mL nonsparkling mineral water	50 mL nonsparkling mineral water	13	13	31±3	PO	N/A
Shannon, 2002 30	Prospective cohort	Seated	480 mL tap water	Preintervention measurements	MSA=5, PAF=6, POTS=9	MSA=5, PAF=6, POTS=9	N/A	PO	<5 min
Tank, 2003 31	Prospective cohort	Supine	500 mL tap water	Preintervention measurements	13	13	38±16	PO	<5 min
Vianna, 2013 32	Prospective cohort	Supine	500 mL bottled water	500 mL saline water	9	9	24±2	PO	<5 min
Z'Graggen, 2010 33	Prospective cohort	Supine with upper body elevation at 45–60 °C	450 mL still mineral water	Preintervention measurements	MSA=7, POTS=7	MSA=7, POTS=7	MSA =64±9.5, POTS =37.7±6.6	PO	“Rapid ingestion”
Parsons, 2022 34	Single‐blind RCT	Supine	500 mL	Preintervention measurements	14	14	19–50	PO	<2 min
Rodriguez, 2022 35	Prospective cohort	Supine	500 mL still mineral water	Preintervention measurements	Healthy=15, POTS=13	Healthy=15, POTS=13	>18, <60	PO	<5 min

MSA indicates multiple system atrophy; N/A, not applicable; NG, nasogastric; PAF, pure autonomic failure; PO, per‐orally; POTS, postural orthostatic tachycardia syndrome; and RCT, randomized controlled trial.

^*Sample size of only the patients included in our meta‐analysis.

Quality‐of‐Evidence Assessments

Two reviewers independently assessed the risk of bias in each study according to a modified Newcastle–Ottawa Scale for nonrandomized studies. All cohort studies had a moderate to high risk of bias. The Cochrane Collaboration's risk‐of‐bias tool was used to assess the RCTs and found that all RCTs except for Parsons et al had unclear risks of selection bias and high risks of performance bias due to unspecified randomization methods and lack of blinding, respectively. ³⁴ The RCTs were determined to be of low risk of bias in all other domains. The Grading of Recommendations, Assessment, Development, and Evaluations quality of evidence assessments for all outcomes are presented in Table S4. There were varying degrees of evidence quality. All RCTs displayed high levels of evidence. In contrast, the prospective cohort studies ranged from very low to low levels of evidence due to insufficient sample sizes, risk of bias, and the inherent deficiencies of observational studies. Finally, the funnel plots for DBP and HR were symmetric, while the plot for SBP seemingly indicated a relative abundance of small studies reporting nonsignificant effect estimates. However, this asymmetry was due to heterogeneity in intervention effect among subgroups. The independent funnel plots for each subgroup (OH versus POTS versus healthy participants) were symmetrical. Consequently, there was no indication of publication bias (Figure S1).

Effects of Rapid Water Consumption on BP

In participants with OH (Figure 3A and 3B), the intervention was found to substantially increase both SBP (MD, 24.18 [95% CI, 15.48–32.88]) and DBP (MD, 11.98 [95% CI, 8.87–15.09]). However, high heterogeneity was detected between studies (I ²=94% and I ²=86%, respectively). Subgroup analyses for MSA and PAF (Figure 2A and 2B) yielded similar findings, with significant increases in both SBP (MD, 24.17 [95% CI, 5.69–42.66] and MD, 28.69 [95% CI, 12.04–45.35], respectively) and DBP (MD, 14.12 [95% CI, 8.60–19.64] and MD, 11.75 [95% CI, 6.87–16.62], respectively). However, between‐study heterogeneity remained high for both subgroups in all measured parameters except for DBP in the MSA group, which was moderate‐high.

Figure 3. Forest plot of all studies in healthy individuals with OH and POTS.

The mean difference in systolic blood pressure (A), diastolic blood pressure (B), and heart rate (C); pre‐ and post‐intervention, including subgroups for healthy participants, OH and POTS. Mean difference is described as the difference between baseline blood pressure or heart rate and post‐intervention blood pressure or heart rate. Mean difference was calculated using random‐effects models with 95% CIs. Study heterogeneity was estimated using the I² statistic and 95% CIs. R software was employed for statistical analyses and figure creation. In OH participants, the intervention substantially increased systolic blood pressure and diastolic blood pressure while significantly decreasing heart rate. In healthy participants, there were small increases in systolic blood pressure and diastolic blood pressure, but no significant findings for heart rate were observed. Water bolus ingestion had no significant effects on systolic blood pressure, diastolic blood pressure or heart rate in patients with POTS in the seated or supine positions. OH indicates orthostatic hypotension; and POTS, postural orthostatic tachycardia syndrome.

Figure 2. Forest plot of MSA and PAF subgroups.

Subgroup analysis of OH for the mean systolic blood pressure (A), diastolic blood pressure (B), and heart rate (C); pre‐ and post‐intervention. Mean difference is described as the difference between baseline blood pressure or heart rate and post‐intervention blood pressure or heart rate. Mean difference was calculated using random‐effects models with 95% CIs. Study heterogeneity was estimated using the I² statistic and 95% CIs. R software was employed for statistical analyses and figure creation. Both MSA and PAF yielded significant increases in systolic blood pressure and diastolic blood pressure. There were no significant heart rate findings in the MSA group. Alternatively, there was a statistically significant decrease in heart rate for the PAF group. MSA indicates multiple system atrophy; OH, orthostatic hypotension; and PAF, pure autonomic failure.

In a subgroup analysis of healthy participants (Figure 3A and 3B), there were small increases in SBP (MD, 1.87 [95% CI, 0.33–3.42]; I ²=60%) and DBP (MD, 2.99 [95% CI, 2.33–3.65]; I ²=50%). Similarly, the 3 rigorous RCTs (Figure 4A and 4B) including healthy participants (n=32) reported increases in both SBP (MD, 2.33 [95% CI, 1.02–3.64]; I ²=0%) and DBP (MD, 2.73 [95% CI, 1.15–4.30]; I ²=56%).

Figure 4. Forest plot of randomized controlled trials in healthy individuals.

The mean difference systolic blood pressure (A) and diastolic blood pressure (B) for the intervention vs a control in healthy participants. The mean difference as described here is the difference between pre‐ and post‐intervention vs pre‐ and post‐control. Mean difference was calculated using random‐effects models with 95% CIs. Study heterogeneity was estimated using the I² statistic and 95% CIs. R software was employed for statistical analyses and figure creation. Pooled results for the 3 randomized controlled trials reported increases in both systolic blood pressure and diastolic blood pressure.

Water bolus ingestion had no significant effects on SBP (MD, 2.79 [95% CI, −0.96 to 6.53]; I ²=0%) or DBP (MD, 2.49 [95% CI, −0.17 to 5.15]; I ²=0%) in patients with POTS in the seated or supine position (Figure 3A and 3B).

Effects of Rapid Water Consumption on HR

In patients with OH (Figure 3C), the intervention significantly decreased HR (MD, −3.46 [95% CI, −5.21 to −1.71]). However, considerable between‐study heterogeneity was observed (I ²=97%). Subgroup analyses (Figure 2C) demonstrated that there were no significant HR findings (MD, −1.19 [95% CI, −9.39 to 7.00]; I ²=91%) in the MSA group (n=35). In contrast, independent analysis of the PAF group (n=33) showed that there was a statistically significant decrease in HR (MD, −3.38 [95% CI, −6.31 to −0.45]; I ²=91%).

No significant findings for HR (Figure 3C) were observed in healthy participants (MD, −2.06 [−5.25 to 1.13]; I ²=70%). Similarly, water bolus ingestion had no significant HR effects on patients with POTS (Figure 3C) in the seated or supine position (MD, −1.40 [95% CI, −5.39 to 2.58]; I ²=0%).

Sensitivity Analysis

Post hoc sensitivity analysis was done within the OH group by removing the Deguchi et al and Lipp et al papers. ²² , ²³ Deguchi et al was removed due to the continued use of vasoactive medication in their participants during the intervention. Consequently, the paper showed the highest response rates to the intervention, making it difficult to generalize and determine the accuracy of their results relative to the other included studies. Lipp et al was removed due to being the only study that administered the water bolus using a nasogastric method. Removal of these papers did not substantially decrease the between‐study heterogeneity in either SBP or DBP (I ²=91% and I ²=86%, respectively), and did not change the statistical significance of the pooled effect estimates for BP. Sensitivity analysis of exclusively RCTs was not performed because only a single study met the criteria.

Discussion

Key BP Findings

Our meta‐analysis of 7 studies assessing the osmopressor response in patients with OH showed a statistically significant increase in SBP and DBP after water bolus ingestion (Figure 3A and 3B). Subgroup analyses of MSA and PAF also demonstrated significant increases in both SBP and DBP (Figure 2A and 2B). Similarly, observational data demonstrated that these increases in BP were also present in healthy participants (Figure 3A and 3B), which was corroborated by RCT data (Figure 4A and 4B). High degrees of between‐study heterogeneity (I ²=86%–97%) were observed for outcomes analyzed within the OH group, and subgroup analyses did not significantly decrease this heterogeneity. One possible explanation for the variance observed in the pooled data set is the differing times of hemodynamic data retrieval following intervention from each independent study. Due to the various approaches for outcome reporting in the included studies, we elected to extract data from the time of maximal hemodynamic effect. This was because certain studies, such as Schroeder et al, ²⁹ reported hemodynamic data for only a single time point or a few arbitrarily selected time points.

Analysis of healthy participants showed small but statistically significant increases in SBP and DBP when robust RCT data were pooled (Figure 4A and 4B). These results align with previous research where the osmopressor response was shown to be most profound in patients with autonomic failure ¹⁰ , ¹³ but was still observable to a lesser extent in older, relatively healthy individuals. ¹³ , ³⁶ The osmopressor response likely appears more blunted in healthy participants due to their increase in peripheral vascular resistance with intact baroreflexes, thereby masking the increase in BP. ¹⁵ The increase in systemic vascular resistance that is likely mediated by the osmopressor response is more apparent in individuals with age‐related reduced baroreceptor sensitivity and unmasked due to efferent baroreflex failure in those with OH caused by neurodegenerative disease. ¹⁶ , ³⁷

The BP effects of water bolus ingestion were not observed in patients with POTS. Various reasons may account for this lack of response. Importantly, these values were collected only for patients with POTS in the seated or supine position. Furthermore, the small population size may account for the lack of measured response, considering that this subgroup included only 37 participants. The average age of participants in this group was ≈33 years, and we expect a lesser BP response in younger individuals, as discussed previously. ³ , ¹⁶ Rodriguez et al ²⁷ appeared to have taken hemodynamic measurements for participants with POTS roughly 40 minutes after water bolus ingestion, which is near the downward inflection of the expected osmopressor response. ¹² Further issues regarding the timing of water bolus ingestion for POTS subjects were evident in the Z'Graggen et al ³³ paper where rapid ingestion was the only descriptor reported in their methodology.

Key HR Findings

Pooled analysis of patients with OH demonstrated a statistically significant decrease in HR (Figure 3C). Subgroup analyses found that the decline in HR was statistically significant in patients with PAF but nonsignificant for MSA (Figure 2C). This was likely confounded by Z'Graggen et al ³³ reporting a nonsignificant increase in HR following water ingestion (MD, 3.40 [95% CI, −1.64 to 8.44]), although the larger Jordan et al paper found a significant decrease in HR in response to fluid bolus ingestion (MD, −5.00 [95% CI, −5.19 to −4.81]). ¹³

Analysis of 7 papers assessing HR in healthy participants found no statistically significant change in HR (Figure 3C). This may be explained by the already blunted response in SBP and DBP in healthy participants. As discussed earlier, previous researchers have hypothesized that young participants mask increases in BP due to intact baroreflexes. ¹² , ¹⁵ Due to age‐related reduced baroreceptor sensitivity, we may expect older healthy individuals to demonstrate relatively greater hemodynamic responses to bolus water drinking compared with their younger counterparts. It is worth noting, however, that these responses are still expected to be less pronounced compared with individuals with autonomic dysfunction.

Rapid water bolus ingestion did not coincide with a change in HR in patients with POTS in the supine ²⁷ , ³³ or seated position ³⁰ (Figure 3C). While out of the scope of this meta‐analysis, these findings would likely be different if studies were conducted in the standing position. In one case report, Ziffra and Olshansky ¹⁴ reported on a patient with POTS whose HR initially doubled upon standing, which then resolved after drinking 236.6 mL of water. Similarly, in the Shannon et al paper, the osmopressor response induced a decrease in HR from 123±23 bpm to 108±23 bpm in 9 patients with POTS while standing. ³⁰ These findings are similar to those in Z'Graggen et al, where there were nonsignificant HR changes while supine but a significant decrease in HR during HUT following water ingestion. Their findings demonstrated an 11.6±7.6 bpm reduction in HR following rapid water ingestion at 3 minutes of HUT. ³³ Furthermore, Rodriguez et al also reported a decrease in HR during HUT before and after water ingestion from 111±9.38 bpm to 92.88±9.88 bpm. ²⁷ The aforementioned papers demonstrate a decrease in HR following water bolus ingestion that was more significant than what was reported in the papers included in our analysis. This may align with expectations for POTS as the characteristic HR increase occurs in the standing position.

Clinical Significance

Findings in our analysis may suggest that patients with OH should consume water before meals and when experiencing symptoms related to changes in position (ie, orthostatic symptoms). May and Jordan described that many patients experience severe symptoms related to positional changes in the morning, which are attributed to the loss of sodium during the night. ¹⁶ Therefore, it may be helpful to drink water in the morning before getting out of bed, with or without taking pressor medications, considering that the highest increase in BP due to water ingestion occurs when other BP‐increasing agents have just begun to take effect. ¹⁶ However, objectively determining a numerically significant increase in BP after water ingestion is challenging because the primary treatment goal for patients with OH should be a reduction in orthostatic symptoms. Therefore, it would be more appropriate to rely on symptom scores or quality‐of‐life ratings to assess the efficacy of water bolus ingestion as a therapy option, but these data were not readily available in the analyzed studies. Otherwise, any arbitrary BP increase has the potential to be clinically relevant, so long as it improves OH symptoms in patients.

Limitations

This systematic review is not free from limitations. Assessing publication bias can be challenging for reviews that include fewer studies, as there are insufficient data to evaluate it accurately. Furthermore, our review mainly included nonrandomized studies and thus faces increased potential interference from confounding variables. It is worth noting that the studies included in our analysis recruited between 5 and 28 participants. While this may seem small by the standards of cardiovascular research, it is the typical size for studies in the autonomic physiology space. However, additional data would further increase our confidence in the study results. Our study also encountered methodological limitations. It relied on only 2 databases to gather potential studies and did not include clinical trial or thesis databases to identify ongoing or completed studies that have not been published. The search for additional sources of information, such as gray literature, was also limited. Expanding the search to more databases could address these limitations, as it may enable the inclusion of a greater number of studies and provide a more comprehensive view of the available evidence. We extracted BP and HR measurements at the point of maximal effect from each study's measurement timelines. The timing of the peak effect on BP and HR differed between studies; thus, hemodynamic data were collected at various times after intervention, ranging from 15 to 40 minutes. It would have been preferable to have raw data for continuous hemodynamic measurements following water ingestion for a minimum of 60 minutes. Unfortunately, due to this limitation, we were unable to conduct subanalyses of time–response findings for the osmopressor response.

Future Directions of Enquiry

Future research in this area would benefit from collecting raw, continuous hemodynamic data and dose–response iterations. It would also be beneficial to assess long‐term water bolus ingestion alongside traditional therapy for long‐term outcomes, particularly collecting data on reductions in OH symptoms and impacts on quality of life. A deeper analysis of POTS and the osmopressor response may also be warranted, especially with standing and HUT positioning during the study.

Conclusions

Rapid consumption of a 350‐ to 500‐mL water bolus produced a short‐term increase in SBP and DBP, while also decreasing HR in patients with OH. Similar but more modest changes were seen in healthy participants. However, these effects were absent in patients with POTS when seated or supine. Further investigations are needed to assess water ingestion's potentially promising impact on POTS patients in a standing position, an aspect not covered in our study.

Sources of Funding

None.

Disclosures

Dr Raj serves as a consultant to Lundbeck LLC, Theravance Biopharma, and Amneal Pharma related to neurogenic orthostatic hypotension; and as a consultant to Servier Affaires Medicales, Regeneron, and argenx BV related to postural orthostatic tachycardia syndrome. Dr Raj also reports honoraria from Spire Learning and Medscape for developing continuing medical education materials on neurogenic orthostatic hypotension, is DMSB chair for a phase 2 study of an irritable bowel syndrome medication for Arena Pharmaceuticals with compensation, and is Past‐President of the American Autonomic Society without financial compensation. The remaining authors have no disclosures to report.

Supporting information

Tables S1–S4

Figure S1

Figure S1