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(Circulation. 1997;95:2271-2276.)
© 1997 American Heart Association, Inc.

Articles

Cold Stress Provokes Sympathoinhibitory Presyncope in Healthy Subjects and Hemodialysis Patients With Low Cardiac Output

G. Ligtenberg, MD; P. J. Blankestijn, MD, PhD; P. L. Oey, MD, PhD; G. H. Wieneke, PhD; A. C. van Huffelen, MD, PhD; H. A. Koomans, MD, PhD

From the Departments of Nephrology and Hypertension (G.L., P.J.B., H.A.K.) and Clinical Neurophysiology (P.L.O., G.H.W., A.C. van H.), University Hospital Utrecht, The Netherlands.

Correspondence to H.A. Koomans, MD, Department of Nephrology and Hypertension, University Hospital Utrecht, Room F03.226, PO Box 85500, 3508 GA Utrecht, Netherlands.

	Abstract

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Background Sudden hypotension in progressive hypovolemia or during hemodialysis is attributed to sudden inhibition of sympathetic activity. Critical ventricular underfilling seems responsible for this paradox, but it is unknown why the transition from sympathoactivation accompanying hypovolemia to sympathoinhibition is so abrupt. We studied whether brief fluctuation of sympathetic activity induced by cold pressor test (CPT) evokes sympathoinhibition if applied during low cardiac output.

Methods and Results Fourteen healthy subjects underwent CPT, lower-body negative pressure (LBNP; -45 mm Hg for 60 minutes), or the combination thereof. CPT alone caused vasoconstriction and increased muscle sympathetic nerve activity, followed by uneventful relaxation. When applied during reduced cardiac output, tachycardia, and vasoconstriction induced by prior LBNP for 6 minutes, CPT again caused vasoconstriction, now followed by acute hypotension in 10 subjects, and was associated with vasorelaxation, relative bradycardia, and fall in muscle sympathetic nerve activity. Eight subjects also experienced acute LBNP-induced hypotension in the absence of CPT, but not until 17±6 minutes of LBNP. We also performed CPT before and in the final phase of hemodialysis in 8 patients. Before dialysis, the patients tolerated CPT uneventfully, but during hemodialysis, CPT provoked acute hypotension in 5 cases, showing similar withdrawal of vasoconstriction.

Conclusions This is the first study showing that brief cold stress, tolerated well in normal circulatory conditions, can provoke sudden sympathoinhibition and hypotension when applied during decreased cardiac output induced by LBNP or hemodialysis. We suggest that during conditions of a decreased cardiac output, subtle sympathetic relaxation such as follows cold stress triggers self-enhancing relaxation that cannot be controlled.

Key Words: syncope • cardiac output • reflex • physiology • sympathoinhibition

	Introduction

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Sudden severe hypotension remains a major drawback of hemodialysis, occurring in 20% of treatment sessions.¹ Its pathogenesis is still uncertain. However, it is clear that progressive hypovolemia due to gradual volume withdrawal plays a central role.^{1 2} The physiological response to hypovolemia is sympathetic excitation and vasoconstriction.³ However, in healthy subjects, progressive hypovolemia can evoke sudden withdrawal of sympathetic activity, causing vasodilation, bradycardia, and profound hypotension.³ Such a paradoxical reflex withdrawal has been shown during progressive hemorrhage⁴ and during lower-body negative pressure (LBNP),^{5 6 7} which is used to simulate progressive hypovolemia in humans. The same paradoxical reaction may be involved in dialysis hypotension, because Converse et al⁸ recently described sudden withdrawal of reflex vasoconstriction in seven patients experiencing dialysis hypotension.

Sudden paradoxical sympathoinhibition occurring during hypovolemia is known as the Bezold-Jarisch reflex. The background theory is that progressive emptying of the left ventricle causes forceful contraction and activation of cardiac mechanoreceptors.^{3 9} This inhibits cardiovascular centers through vagal afferents, overruling the stimulation caused by arterial baroreceptor deactivation. However, this concept is hardly complete; whereas the alleged trigger for this event, progressive ventricular emptying, is a gradual process, sympathoinhibition is an abrupt and unpredictable phenomenon. Clinically, it seems that once a vasodilatory reflex starts, it is self-enhancing and does not turn off unless ventricular filling is restored. Indeed, immediate recovery after saline infusion or head-down tilt is well known.^{1 2}

The hypothesis of the present study is that brief, subtle release of the tight sympathetic vasoconstriction during hypovolemia cannot be adequately controlled and triggers a full-blown vasodilatory syncope. We based this hypothesis on the idea that the slightest additional decrease in ventricular filling, caused by subtle fall in afterload, starts an uncontrolled vasodilatory response, whereas normally such relaxation will pass uneventfully. Such a finding would greatly improve our understanding of sudden sympathoinhibitory hypotension, but this possibility has never been tested. In the present study, we induced brief cold stress, causing sympathetic relaxation after brief excitation, in healthy volunteers in whom cardiac output was reduced by LBNP. Strikingly, many of them responded with vasodilatory presyncope. Microneurography, performed in a subset of subjects, demonstrated an exaggerated fall in sympathetic activity after cold stress was stopped. Brief cold stress could also induce sudden hypotension in patients during hemodialysis. It thus appears that sudden dialysis hypotension may arise by brief superimposed fluctuation of sympathetic activity.

	Methods

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Subjects
Studies were performed in 14 healthy volunteers (age, 25±4 years) who were normotensive and had an unremarkable medical history and in 8 hemodialysis patients (42±15 years old; range, 23 to 63 years old). The healthy subjects were studied during venous pooling induced by LBNP and the patients during a regular hemodialysis session. All patients were stable. Causes of kidney disease were glomerulonephritis (2), diabetic nephropathy (1), nephrosclerosis (3), and unknown (2). Duration of dialysis varied from 4 weeks to 5 years (median, 1.1 year). Both protocols were approved by the institutional committee for studies in humans.

Experimental Design in Healthy Subjects
Each subject underwent LBNP twice. To this end, they were positioned supine in an airtight acrylic plastic box to the level of the iliac crests. After the subject had rested for 30 minutes in the LBNP box, -45 mm Hg LBNP was applied for 60 minutes or a shorter period if presyncopal signs occurred. The other LBNP experiment was performed in a similar way, except a cold pressor test (CPT) was performed after 6 minutes of LBNP. Furthermore, a CPT was performed separately from LBNP. The order of these studies was randomized, with a 60-minute recovery period after each LBNP experiment. Presyncope was defined as a systolic pressure decrease of >30 mm Hg in <20 seconds. The CPT consisted of immersion of the left hand up to the wrist into ice slush for 60 seconds.

Arterial pressure and heart rate were recorded continuously on the right upper extremity by use of finger photo plethysmography (Finapres). Cardiac index was measured by thoracic impedance cardiography (Bomed). Forearm blood flow was measured by venous occlusion plethysmography using a mercury-in–silicone elastomer strain gauge. Forearm vascular resistance was calculated by dividing mean arterial pressure by forearm blood flow and was expressed as resistance units. In a subset of subjects (n=8), muscle sympathetic nerve activity (MSNA) was recorded throughout the experiments. A unipolar tungsten microelectrode was inserted into a fascicle of the peroneal nerve posterior to the fibular head by use of the technique of Vallbo et al.¹⁰ The neural signal was filtered (bandwidth, 500 to 2000 Hz), rectified, and integrated (time constant, 0.1 second). Sympathetic bursts were identified by their characteristic morphology and relationship to R waves on the ECG. The correct position of the electrode was confirmed by the characteristic response to a Valsalva maneuver (Fig 1).

View larger version (14K): [in this window] [in a new window]   Figure 1. Registration of muscle sympathetic nerve activity (MSNA) during Valsalva maneuver. The expected fall in blood pressure (BP) and tachycardia during the maneuver are accompanied by MSNA acceleration, and the subsequent blood pressure overshoot is accompanied by a pause in MSNA.

Experimental Design in Hemodialysis Patients
Eight hemodialysis patients underwent a CPT before a regular 4-hour hemodialysis session. A second CPT was performed 30 minutes before the end of dialysis and, if no hypotension occurred, a third CPT followed at 10 minutes before the end of dialysis. During hemodialysis, fluid was removed by constant ultrafiltration to achieve dry weight, which was estimated individually by use of standard clinical methods. Dialysis was performed with polysulfone artificial kidneys using bicarbonate as dialysate buffer. Arterial pressure, cardiac index, and peripheral vascular resistance were recorded as outlined above for 3-minute periods at 0, 1, 2, and 3 hours of dialysis and continuously during the final 30 minutes of dialysis.

Data Analysis
Beat-to-beat recordings of blood pressure and heart rate were averaged per minute. Forearm vascular resistance was calculated per 10 seconds and averaged per minute. Cardiac index was measured once per minute. Data during presyncope were synchronized to the lowest value of systolic blood pressure. Data are presented as mean±SD. Data were analyzed with repeated measures ANOVA and Bonferroni multiple comparison post hoc tests. A value of P<.05 was considered significant.

	Results

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Healthy Volunteers: LBNP Alone
LBNP consistently reduced cardiac index in association with tachycardia, pulse pressure reduction, and peripheral vasoconstriction. Fig 2A shows average data for the first 10 minutes. Six subjects tolerated LBNP for the full preset period of 60 minutes; in the other eight subjects, sudden hypotension developed after 17±6 minutes (range, 11 to 25 minutes), and the experiment had to be stopped. This hypotension was characterized by relative bradycardia and withdrawal of vasoconstriction, whereas cardiac index did not show a further decrease (Table). MSNA, recorded in five of these subjects, increased significantly during LBNP and fell during the hypotensive phase. Fig 3 shows a representative recording.

View larger version (28K): [in this window] [in a new window]   Figure 2. Hemodynamic data in healthy subjects. A, Ten minutes of undisturbed lower-body negative pressure (LBNP) (n=14). B, Cold stress test (vertical bar) in the seventh minute of LBNP followed by vasodilatory presyncope (n=10). C, Cold stress test during LBNP without presyncope (n=4). D, Standard cold stress test (n=14). BP indicates blood pressure; HR, heart rate; FVR, forearm vascular resistance; and CI, cardiac index.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Parameters in Healthy Subjects Undergoing Lower-Body Negative Pressure (LBNP) With and Without a Cold Pressor Test (CPT) and in Patients Undergoing a CPT During Hemodialysis

View larger version (14K): [in this window] [in a new window]   Figure 3. Hemodynamic data and muscle sympathetic nerve activity (MSNA) in a healthy subject experiencing hypotension after 25 minutes of lower-body negative pressure (LBNP). The compensated phase of LBNP is characterized by modestly decreased blood pressure (BP), tachycardia, and elevated MSNA activity. The hypotensive phase is accompanied by a fall in heart rate (HR) and MSNA.

Healthy Volunteers: LBNP Combined With CPT
In the absence of LBNP, the CPT evoked the classic pressor and tachycardic responses, with uneventful normalization to baseline values within two minutes after the test (Fig 2D). MSNA increased from 16±3 to 30±4 bursts/min during CPT (P<.0001) and returned to 17±6 bursts/min in 2 minutes after the CPT was stopped.

When applied in the seventh minute of LBNP, the CPT again caused a pressor response and a further increase in heart rate. However, in 10 subjects, discontinuation of the test was followed by acute hypotension after 100±40 seconds that was associated with vasorelaxation and relative bradycardia (Fig 2B), and LBNP had to be stopped. In the other 4 subjects, LBNP was continued uneventfully (Fig 2C). Notably, hypotension after CPT occurred in all subjects who also experienced hypotension during LBNP alone, but CPT advanced its occurrence to 9±1 minutes (P<.001). Similar to the hypotension occurring "spontaneously" during LBNP, this hypotensive phase was associated with unchanged cardiac index, relative bradycardia, and fall in peripheral vascular resistance (Table). MSNA, recorded in 5 subjects experiencing hypotension, increased significantly during LBNP, showed a further nonsignificant increase during the superimposed CPT, and then dropped during the hypotensive phase. A representative recording is given in Fig 4.

View larger version (17K): [in this window] [in a new window]   Figure 4. Hemodynamic data and muscle sympathetic nerve activity (MSNA) in a subject experiencing sympathoinhibitory hypotension after cold pressor test (CPT). The compensated phase of lower-body negative pressure (LBNP) is characterized by modestly decreased pulse pressure, tachycardia, and increased MSNA. Superimposed cold stress elevates blood pressure (BP) and further increases heart rate (HR) and MSNA. After the CPT, hypotension develops within 140 seconds in association with a fall in heart rate and MSNA.

Hemodialysis Patients
Before dialysis, all eight patients tolerated the CPT uneventfully (data not shown). However, when performed in the final half hour of dialysis, CPT evoked acute hypotension in five patients (30 minutes from the end of dialysis in one patient and 10 minutes from the end of dialysis in four patients). By this time, 3.2±0.5 L (92±2% of the estimated volume excess) had been withdrawn. Sequential changes in these five patients show a fall in cardiac index accompanied by a gradual decrease in blood pressure and an increase in heart rate and vascular resistance (Fig 5). Cold stress caused an increase in blood pressure, heart rate, and vascular resistance. After the cold stimulus was stopped, symptomatic hypotension and vasodilation followed within minutes, necessitating a temporary break in dialysis. The hemodynamic data were very similar to those obtained in the healthy subjects during LBNP and cold stress (Table).

View larger version (20K): [in this window] [in a new window]   Figure 5. Hemodynamic data in five patients during hemodialysis who developed hypotension subsequent to a cold stress test (vertical bar). BP indicates blood pressure; HR, heart rate; FVR, forearm vascular resistance; and CI, cardiac index.

	Discussion

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Our main finding is that brief cold stress, tolerated uneventfully in normal conditions, triggered acute sympathoinhibition when applied during reduced cardiac output. This is a unique observation that has not been reported before. Notably, the possibility of such an interaction was not considered previously, despite the large number of studies dedicated to the intriguing subject of paradoxical sympathoinhibition.^{3 9} Hemodynamic findings characteristic for sympathoinhibition, ie, vasodilation, relative bradycardia, and hypotension, were found after cessation of cold stress in normal subjects during LBNP and in patients during hemodialysis. MSNA, recorded in the normal subjects, confirmed sympathoinhibition directly. A similar sympathoinhibitory response could be evoked by LBNP alone in a number of subjects; however, application of cold stress clearly advanced this reaction.

LBNP and hemodialysis caused cardiac output reduction and vasoconstriction, which are well-known effects.^{3 5 6 7 8 11 12} Increased MSNA, a direct sign of sympathetic excitation, has been shown previously during LBNP^{5 6 7 8} and in a few patients during hemodialysis.⁸ During prolonged LBNP, 8 of the present 14 healthy subjects showed sudden sympathoinhibition, vasodilation, bradycardia, and hypotension. This Bezold-Jarisch reflex, elsewhere coined vasovagal collapse, cardiac depressor reflex,¹³ or ventricular syncope,⁹ is also known from the literature,³ but until now, only a few cases have been reported in which sympathetic withdrawal was actually proven with MSNA.^{6 7 8}

The hypothesis of the present study was that the sympathetic relaxation that automatically follows a bout of sympathetic excitation would trigger sympathoinhibition if it occurred in conditions of reduced cardiac output. To study this, we used brief cold stress. Cold stress increases sympathetic activity through a central neural mechanism.^{14 15} This is independent of the baroreflex, and cold stress is used to test the efferent limb of the sympathetic arc.¹⁶ The usual response to cold stress is sympathetic excitation and vasoconstriction during the stimulus, followed by gradual relaxation over 1 to 2 minutes after it.¹⁴ Normally, the relaxation phase passes uneventfully, probably because in resting conditions, the dependence of the circulation on sympathetic drive is limited. Apparently, and in agreement with the hypothesis, it is different during hemodialysis or LBNP, when cardiac output is decreased and maintenance of arterial pressure depends strongly on tight sympathetic vasoconstriction.^{5 6 7 8 11 12} In such conditions, it may become difficult to control relaxation, which then can proceed to overt sympathoinhibition.

To explain the present findings, we propose that the vasorelaxation that follows the cold stress decreases cardiac afterload and that the resultant ventricular emptying may trigger a Bezold-Jarisch reflex if basal cardiac output and ventricular volume are critically low. Typically, the vasodepressor reflex occurred only if cardiac output was first decreased, either by LBNP or, in the patients, by progressive volume removal during hemodialysis. Brief sympathetic excitation followed by relaxation may thus offset the delicate balance between low ventricular volume and high peripheral resistance that exists during hypovolemia. Another option is that the Bezold-Jarisch reflex was brought about by cold stress–induced adrenaline release.¹⁷ Adrenaline may cause excessive stimulation of cardiac vagal afferents that are preactivated by hypovolemia.^{9 13} High plasma adrenaline levels have been associated with sympathoinhibitory syncope,⁶ and it has been shown that the ß-agonist isoproterenol can induce sympathoinhibition when infused during head-up tilt.¹⁸ We cannot exclude this possibility, but the fact that we never observed presyncope during the cold stress but only in the relaxation phase after it argues against this. In addition, the adrenaline release during cold stress, even when prolonged, is very modest.¹⁷

Underlying the hypothesis of our study was the question why sympathoinhibitory hypotension that occurs in progressive hypovolemia is so abrupt and unpredictable, whereas the alleged stimulus for this reflex, progressive left ventricular emptying, is a gradual process. Although we cannot answer this question directly, our data suggest a likely explanation. It is assumed that hypovolemia, arriving at a certain severe stage, starts to activate cardiac mechanoreceptors and vagal afferents. This opposes the disinhibition of the brain cardiovascular centers established previously by deactivation of cardiac and arterial stretch receptors.^{3 9 13} We surmise that although this start may be gradual, the first slight decrease in sympathetic tone that occurs at this stage can trigger a full sympathoinhibitory reflex, in accordance with the findings described herein after brief cold stress. Thus, the takeover by the vagal inhibitory afferents cannot be gradual, as it tends to be self-enhancing.

The interactive effects of LBNP and acute cold stress or isometric exercise on sympathetic drive received attention in previous studies. Briefly, additive rather than potentiating effects on sympathetic activity were found,^{19 20 21 22} indicating independence of sympathetic excitation by the baroreflex and somatic pressor reflex mechanisms. Notably, in none of the studies was sudden hypotension reported, but LBNP was either moderate and nonhypotensive^{19 21 22} or not continued beyond the additional sympathetic stimulus.²⁰ The orthostatic intolerance that occurs after exhaustive exercise is probably a different phenomenon, as it may still be present after a half hour of recovery.²³ Also different is the phenomenon that sustained mild isometric exercise or cold environment may improve tolerance to LBNP^{24 25} or hemodialysis,¹² probably by enhancing sympathetic drive and vasoconstriction. In none of these studies was the effect of stopping exercise or cold stress mentioned.

The present data help to clarify dialysis hypotension, a major and disabling problem of hemodialysis.^{1 2} Recently, this problem has grown because of the increased use of high-flux dialysis, which shortens dialysis time but increases the risk of a critical decrease in blood volume, and the increased admission of older patients to dialysis. Classically, dialysis hypotension has been ascribed to a progressive decrease in cardiac output, insufficiently compensated for by increased peripheral resistance. For the latter, many factors have been implicated, such as autonomic dysfunction related to uremia,²⁶ electrolyte changes or use of acetate as dialysate buffer,^{26 27} increased body temperature,²⁶ incompatibility of dialysis membranes,²⁶ and, recently, the release of vasodilating substances such as nitric oxide²⁸ and adenosine.²⁹ The present study does not refute these ideas. However, they offer no explanation for the abrupt sympathoinhibitory manifestations of dialysis hypotension, which are the rule rather than the exception.¹¹ Our data indicate that during the progressive hypovolemia that occurs during hemodialysis, subtle fluctuations in vasomotor tone, possibly but not necessarily related to any of the above factors, can trigger acute sympathoinhibition.

Clearly, detailed studies of the initiation of a sympathetic withdrawal reflex will be needed to explore this concept further. In this regard, cold stress is a useful tool, but parallel tests have to be examined too. In theory, fluctuations in vasomotor tone during hemodialysis may be caused by any kind of intermittent stress or the release of small amounts of vasodilators. It remains to be determined whether fluctuations in vasomotor tone can trigger a sympathetic withdrawal reflex in hypovolemic conditions in general rather than exclusively during hemodialysis or LBNP. Furthermore, a similar mechanism should be considered in vasodepressor syncope of exercise, aortic stenosis, infusion of nitro compounds, and myocardial infarction.⁹ Finally, we do not know whether patients with decreased ventricular function will be more sensitive to this phenomenon. Thus, we expect that the present observations will give further impetus to the exploration of this frightening and stressful phenomenon of paradoxical sympathoinhibition.

	Acknowledgments

 
This study was supported by the Dutch Kidney Foundation, grant C93.1281. We are greatly indebted to Prof B.G. Wallin, Department of Clinical Neurophysiology, Sahlgren's Hospital, Göteborg, Sweden, for his invaluable help with the development of the microneurographic technique in our hospital.

Received October 31, 1996; accepted December 2, 1996.

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