Water Ingestion As Prophylaxis Against Syncope: Fact or Fancy? J. J

J. J

Introduction

If you faint, it is likely that someone will offer you a glass of water – certain- ly, your grandmother would. Is there a scientific rational for this home reme- dy or is your grandmother completely off the mark? The physiological responses to acute water ingestion has been assessed in a few studies, which suggested that water drinking elicits acute changes in human physiology.

These changes affect different regulatory systems, including metabolism and cardiovascular regulation, and appear to be mediated through sympathetic activation. The cardiovascular response may be exploited to attenuate symp- toms in patients with orthostatic hypotension, the postural tachycardia syn- drome (POTS), or neurocardiogenic (vasovagal) syncope.

Pressor Response to Water Drinking

Patients with severe orthostatic hypotension due to autonomic failure reported that they experienced fewer symptoms after they drank a glass of water. Based on these anecdotes, we decided to probe the effect of water on blood pressure in a systematic fashion. Patients with autonomic failure due to either multiple system atrophy or pure autonomic failure (Bradbury- Eggleston syndrome) were included. Drinking 480 ml tap water within 5 min elicited a profound pressor effect in these patients [1, 2]. Seated systolic blood pressure increased 33 mmHg in multiple system atrophy patients and 37 mmHg in pure autonomic failure patients [2]. The pressor effect had a

Franz-Volhard Clinical Research Center, Medical Faculty of the Charité, Max-

Delbrueck-Centrum, and Helios Klinikum, Berlin, Germany

rapid onset, within 5 min after water drinking, and reached a maximum after 30–40 min. The response was sustained for more than an hour. Our findings in autonomic failure patients were reproduced by another group of investigators [3, 4]. Tetraplegic patients and cardiac transplant recipients showed a moderate pressor response to water drinking [5, 6]. Older control subjects who ingested 480 ml water exhibited a moderate increase in systolic blood pressure, which reached a maximum of 11 mmHg above baseline [1, 2]. In contrast, water drinking had no pressor effect in healthy young sub- jects [2, 7].

Vasoconstriction or Volume Expansion?

One study involving autonomic failure patients suggested that the pressor response to water drinking is mediated through increased systemic vascular resistance [3]. In another study, in healthy young subjects, blood pressure and systemic vascular resistance did not change after water drinking. Yet, calf vascular resistance increased significantly [7]. The paradoxical finding may be explained by compensatory dilatation in another vascular bed. Taken together, the data suggest that water drinking elicits an increase in vascular tone that contributes to the increase in blood pressure in autonomic failure patients.

Theoretical considerations and actual physiological measurements exclude volume expansion as the crucial mechanism explaining the haemo- dynamic response to water drinking. Solute-free water is distributed throughout extra- and intracellular spaces. If one assumes that a water load (500 ml) is absorbed but not excreted, total body water would change by 1%

in a person weighing 175 lbs. Plasma volume would increase by approxi- mately 35 ml. A substantial part of the ingested water is likely to be excreted at the time the maximal physiological response to water is observed. Indeed, plasma volume remained unchanged after water drinking [2]. In another study, water drinking had no effect on thoracic impedance [8], which corre- lates with thoracic blood volume [9]. Finally, it is difficult to explain increased vascular resistance through volume expansion.

Involvement of Sympathetic Mechanisms in Water-Induced Vasoconstriction?

Intuitively, one would think that the pressor response to water drinking in

autonomic failure patients is not mediated by the sympathetic nervous sys-

tem. Indeed, autonomic failure is tantamount to parasympathetic and sym-

pathetic dysfunction. Initially, several vasoactive systems were implicated in the pressor response. However, neither plasma renin activity nor plasma vasopressin concentrations increased after water drinking [2]. More recent studies suggested that sympathetic efferent function is not completely lost in the majority of autonomic failure patients [10]. The incomplete loss in sym- pathetic efferents explains the observation that yohimbine elicits a sympa- thetically mediated pressor response in a large group of such patients [11–13]. Yohimbine increases sympathetic activity through blockade of alpha-2 adrenoreceptors in the central nervous system and at presynaptic sites of adrenergic neurons [13]. Paradoxically, the pressor response to yohimbine in autonomic failure patients is much greater than the response in healthy subjects. Thus, the water-induced pressor response could also be related to sympathetic activation.

We tested the effect of yohimbine and with water on separate days in autonomic failure patients. In patients with a large response to water, yohim- bine profoundly raised blood pressure, whereas patients who did not respond to water exhibited a small pressor response to yohimbine or did not respond at all [2]. The observation suggests that patients who are unable to increase sympathetic activity with yohimbine do not exhibit a pressor response to water. The idea that the water pressor response is related to sym- pathetic activation is supported by experiments with ganglionic blockers.

Interruption of ganglionic transmission with trimethaphan abolished the water-induced pressor response in two autonomic failure patients [2].

Furthermore, alpha-adrenoreceptor blockade with phentolamine attenuated the pressor effect of water drinking in animals [14]. Finally, water drinking has been shown to increase muscle sympathetic nerve traffic [7] and venous plasma norepinephrine concentrations in healthy subjects [2, 7, 15]. Thus, water drinking increases sympathetic activity.

Why is the pressor effect of water drinking enhanced in autonomic fail- ure patients? One possible explanation is that autonomic failure patients were hypersensitive to the released norepinephrine. The hypersensitivity may be related to loss of baroreflex blood pressure buffering [16] and/or increased vascular sensitivity [17].

The sympathetic nervous system is not only involved in cardiovascular

regulation, it also regulates metabolism. Thus, water-drinking-induced

increases in sympathetic activity should also influence metabolism, in par-

ticular energy expenditure. We assessed the effect of drinking 500 ml water

on energy expenditure and on carbohydrate and lipid oxidation rates in

healthy young subjects using whole-room indirect calorimetry [18]. Water

drinking caused a 30% increase in metabolic rate. In men, lipids mainly fuelled

the increase in metabolic rate, while in women carbohydrates were mainly

used as energy source. The total thermogenic response was about 100 kJ.

The time course of the metabolic response resembled that of the haemody- namic response. Systemic beta-adrenoreceptor blockade with metoprolol almost completely attenuated the increase in energy expenditure after water drinking [18]. Taken together, these findings suggest that water drinking increases sympathetic activity, which, in turn, drives the pressor and the thermogenic responses.

Sympathetic Activation Through a Spinal Mechanism?

Activation of the sympathetic nervous system may involve a brainstem- or spinal-reflex-like mechanism. It is less likely that water directly modulates the activity of postganglionic sympathetic neurons. In multiple system atro- phy patients, the lesion to the autonomic nervous system is located in the brainstem [19]. More distal efferent sympathetic structures are, at least in part, intact [10, 20, 21]. In patients with high spinal cord injury, spinal sym- pathetic structures are intact but mechanically disconnected from brainstem input. In these patients, postganglionic sympathetic neurons can be activated through spinal reflexes. For example, bladder distention or muscle spasms below the spinal lesion may profoundly raise blood pressure. Water drinking increases blood pressure in multiple system atrophy patients [2] and in patients with high spinal cord injury [6]. These observations suggest that the activation of sympathetic efferents may not be explained by a brainstem mechanism. Instead, we speculate that sympathetic efferents are activated through a spinal mechanism.

What Stimulates the Sympathetic System?

The exact stimulus that triggers water-drinking-induced sympathetic activa- tion is not known. Initially, we thought that water might elicit an ‘internal cold pressor response.’ However, the response to water drinking in autonom- ic failure patients was similar when patients ingested water at different tem- peratures [2]. Moreover, studies on the thermogenic effect of water drinking suggested that only 40% of the response could be explained by the energy that is required to warm the water to 37°C [18]. Drinking 37°C water also increased the metabolic rate. Clearly, water temperature is probably not the crucial stimulus of water-drinking-induced sympathetic activation.

Gastric distention increases sympathetic activity in humans [22]. The

maximal response to water drinking is observed at a time when only 25% of

the ingested water remain in the stomach [23]. In some autonomic failure

patients, volumes of water as small as 120 ml elicit a substantial and sus-

tained pressor response. Gastric stretch does not fully explains the sympa- thetic activation after water drinking. When fluids with different osmolari- ties were infused into the stomachs of dogs, distilled water was shown to cause a two-fold greater increase in blood pressure than normal saline [24].

In humans, infusion of hypo-osmolar solutions through a gastric tube causes a greater increase of sweat production, a sympathetic response, than infusion of isosmolar solutions [24]. Recently, we conducted similar studies in multi- ple system atrophy patients. In these patients, 500 ml water or isotonic saline were administered through a nasogastric tube. Water elicited a greater pres- sor response than saline [25].

Studies in animals have demonstrated the presence of osmoreceptive afferent nerve fibres [26]. Currently, we are exploring the possibility that water-drinking-induced sympathetic activation is related to stimulation of osmosensitive afferent nerves in the portal tract or in the liver.

Therapeutic Utility of Water Drinking in Autonomic Failure Patients

Water drinking was shown to improve standing blood pressure and orthosta- tic tolerance in a large subgroup of autonomic failure patients [27]. In that study, systolic blood pressure was 83 mmHg after 1 min of standing without water drinking. Upright systolic blood pressure increased to 114 mmHg 35 min after drinking 480 ml water. Water taken just before a meal prevents postprandial hypotension. In six patients, the maximal tolerated standing time increased from 5.1 min before to 11 min after water drinking. Water drinking also improved postprandial hypotension in autonomic failure patients [27]. After a meal, blood pressure decreased by 43/20 mmHg with- out water drinking, compared with 22/12 mmHg with drinking.

Water Drinking Attenuates Orthostatic Tachycardia

Water drinking may have therapeutic utility in postural tachycardia syn-

drome. Among other names, the syndrome is also referred to as POTS, idio-

pathic orthostatic intolerance, and chronic orthostatic intolerance. The syn-

drome is much more prevalent than autonomic failure, and, true to its name,

it is characterised by orthostatic tachycardia rather than orthostatic

hypotension [28–30]. Water drinking decreases upright heart rate in these

patients by 15 beats per minute after 3 min of standing and by 10 beats per

minute after 5 min of standing [27]. The effect of water drinking on ortho-

static tachycardia compares favorably with established therapies, such as

alpha-adrenoreceptor agonists or volume loading [29–31].

Prevention of Neurocardiogenic (Vasovagal) Syncope

So far, water drinking has not been tested in patients with spontaneous neu- rocardiogenic syncope. However, water drinking has been shown to delay or prevent neurocardiogenic presyncope or syncope in healthy subjects under- going head-up tilt testing [8, 32]. In one study, subjects who tolerated stand- ing on the head-up tilt table were subjected to incremental lower-body nega- tive pressure while remaining in the upright position, the so-called Leeds protocol [8]. The time to presyncope or syncope was taken as a measure of orthostatic tolerance. Testing was conducted after subjects had ingested either 50 or 500 ml water. Drinking 500 ml water increased orthostatic tol- erance by 5 min, which is a substantial improvement considering the supra- physiological orthostatic stress. In this study, water drinking also lowered upright heart rate, increased cardiac stroke volume, and improved cerebral blood flow regulation. In another study, healthy subjects with no history of syncope underwent head-up tilt-table testing at 60° for 45 min or until pre- syncope or syncope occurred. Participants were tested with or without 473 ml water drinking 5 min before tilt-table testing in a randomised and cross- over fashion. During the first 30 min of tilt testing, eight of 22 subjects with- out water experienced presyncope compared to only one of 22 who had ingested water. On average, the time participants tolerated head-up tilt was increased 26% with water drinking. Water drinking may also be beneficial in patients with post-exercise syncope [33].

How To ‘Prescribe’ Water?

In patients with orthostatic hypotension, POTS, or neurocardiogenic syn- cope, we use water in conjunction with other nonpharmacological treat- ments before initiation of pharmacological therapy, or as an adjuvant to pharmacological therapy. However, more studies are required to better define the therapeutic utility of water, in particular in POTS and in neuro- cardiogenic syncope. There are no data on the efficacy with long-term use.

In patients with autonomic failure, we usually recommend that the daily fluid intake should be in the range of 2–3 l. However, the timing of the water intake is of major importance. Patients should drink most of the water when their orthostatic symptoms tend to be worst and before meals. In most patients, symptoms are worse in the morning and improve during the day.

We tell our patients to drink a glass of water before getting up in the morn-

ing. In this setting, water may be more efficacious than commonly used pres-

sor agents, given its more rapid onset of action [12]. Water drinking potenti-

ates the effect of pressor drugs, such as phenylpropanolamine and pseu-

doephedrine [34]. The ‘drug’ interaction can be exploited in the treatment of orthostatic hypotension. It may also lead to dangerous elevations in blood pressure. We suggest testing the sensitivity to pressor agents with or without water in each autonomic failure patient. The approach is useful to find a rea- sonable initial drug dose that is large enough to provide symptomatic bene- fit but does not lead to excessive, potentially dangerous increases in blood pressure. We advise patients with supine hypertension not to drink water within an hour before bedtime [10, 35].

Excessive water ingestion might lead to water intoxication, in particular in autonomic failure patients. However, we have not observed this complica- tion in clinical practice.

Conclusions

Water drinking elicits a profound pressor response in autonomic failure patients. It increases blood pressure to a lesser degree in tetraplegic patients, cardiac transplant recipients, and older healthy subjects. Blood pressure does not change in healthy young subjects. The haemodynamic response to water drinking appears to be mediated through sympathetic activation via an unknown mechanism. Water drinking improves orthostatic responses in patients with orthostatic hypotension and orthostatic tachycardia, and delays the onset of neurocardiogenic syncope in healthy subjects. Thus, water drinking may be a promising and essentially cost-free intervention for all these conditions, either as monotherapy or in conjunction with other non-pharmacological or pharmacological treatments.

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