circulation research november 1976 vol. 39 no 5 . an...

Circulation Research NOVEMBER 1976

VOL. 39 NO. 5

An Official Journal of the American Heart Association

BRIEF REVIEWS

Cardiovascular and Renal Effects of Head-Out WaterImmersion in Man

Application of the Model in the Assessment of Volume Homeostasis

MURRAY EPSTEIN, M.D.

" . . . If the blood be thus driven (by the bath) from theexternal and internal parts, what becomes of the blood? Theheart and great vessels, it would seem, must be burdened.Such is^aa degree the case; and it-is perhaps thestimulus ofthis fullness and distention or its action on the elasticity ofthose great vessels and the heart that constitutes the reaction(which leads forth the urine in abundant effusion). Suchoverloading of the heart and great organs would be danger-ous in every case if the volume of blood remained the same."

—Henry Hartshorne, 18471

THE USE OF water immersion as a therapeutic agent datesback to man's earliest days. The writings of all the ancientcivilizations, Egyptian, Hebrew, Greek, Persian, Hindu, andChinese, refer to the healing properties of water immersion.During the subsequent 3,000 years "hydrotherapy" haspassed through various phases of fashion and popularity.During the past 15 years, water immersion has becomemore widely used as a means of simulating weightlessness.1'4

Despite its long history, the cardiovascular and renalphysiology of immersion has remained undefined to a greatextent, and its exploitation as an investigative tool in clinicalmedicine has been unrealized.

Over a century ago Hartshorne1 suggested that the heartpossessed volume receptors capable of sensing the fullness ofthe blood stream induced by water immersion.1 The conceptthat water immersion constituted a means of acutelyredistributing blood volume, with a resultant increase incentral blood volume, was largely ignored during the

From the Medical and Research Service*, Miami Veterans Administra-tion Hospital and the Department of Medicine, University of Miami Schoolof Medicine, Miami, Florida.

Work performed in the author's laboratory and reported here wassupported by a grant from the National Aeronautics and Space Administra-tion (NGR 10-007-097) and by designated Veterans Administration ResearchFunds (2456-01). Parts of this study were conducted in the Clinical ResearchUnit of the University of Miami School of Medicine, supported by a grantfrom the General Clinical Research Centers Program of the Division ofResearch Resources, National Institutes of Health (RR-261).

Dr. Epstein is an Investigator of the Howard Hughes Medical Institute.Address for reprints: Dr. Murray Epstein, Veterans Administration

Hospital, 1201 N.W. 16th Street, Miami, Florida 33125.

subsequent 100 years. Largely through the influence ofGauer et al.,!-° the model of water immersion has beenreintroduced to medicine. During the past decade studies byseveral-groups of investigators have addressed themselves tovarious aspects of immersion. The delineation of the im-mersion model and its recent successful application to thestudy of volume homeostasis, as well as its utilization as aninvestigative tool for studying renal physiology in man, hasprompted this review.

I. Elucidation of the "Afferent" Limb of the ImmersionModel

Water immersion to the neck has been shown repeatedlyto produce a profound diuresis.*•" Several lines of evidencehave suggested that these effects are mediated by a redistri-bution of blood volume with a relative increase in centralblood volume.* Although pressure measurements and deter-minations of central hemodynamics were reported,10 the factthat these early studies were carried out using whole bodyimmersion with pressure-breathing equipment renderedthem difficult to interpret. Depending on the pressure used,positive-pressure breathing can abolish the circulatory,renal, and hormonal effects of immersion.11"13 Recently,however, studies by Arborelius and co-workers14 havedemonstrated that following the initiation of head-outimmersion, there is an acute increase in central bloodvolume of 700 ml, with a concomitant increase in centralvenous pressure from 3 to 15 mm Hg. Mean cardiac outputincreases by 32% and mean stroke volume by 35%.14 Bothright atrial and pulmonary arterial transmural pressuregradients increase,14- 15 while systemic vascular resistancedecreases.1" Plethysmographic determinations of peripheralvenous tone revealed a prompt decline in the volumeelasticity coefficient (E',,)* from 16.6 to 13.5 mm Hg/mlper 100 g of tissue with a subsequent gradual decline to 11.8

•The volume elasticity coefficient (E',,) u a measure of venous tonedetermined at an intravenous pressure of 15 mm Hg. During venous occlusionplethysmography, forearm volume is measured with a mercury strain gaugeand venom pressure is recorded simultaneously in a skin vein in the distalthird of the forearm."

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620 CIRCULATION RESEARCH VOL. 39, No. 5, NOVEMBER 1976

after 3 hours of immersion.18 Although E \ B increasedfollowing cessation of immersion, it did not return toprestudy levels during the recovery hour. Lange et al.l< useda biplane roentgenometric technique and calculated that theinitiation of immersion in upright normal subjects resultsacutely in a mean increase in heart volume of 180 ± 62 ml.Examination of the roentgenograms during immersionsuggested that a major component of this increase in heartvolume is localized in the atr ia." More recently, Begin eta l . " have studied central hemodynamics serially during a4-hour immersion period using an acetylene rebreathingmethod. This study confirmed the 25-36% increment incardiac index previously noted to occur acutely duringimmersion14 and demonstrated that this increment was sus-tained throughout the period of study. Pulmonary tissue pluscapillary blood volume (VTPC) was unchanged throughoutthe immersion study.17 Because an increase in VTPC hasbeen described as a sensitive indicator of mild to moderateexpansion of lung water," these findings suggest that thecentral vascular engorgement induced by water immersion isdirected primarily to the larger pulmonary vessels andintracardiac chambers, with only a small quantity ofredistributed blood being directed into the pulmonarycapillaries.

Gauer et al.4 have proposed that this redistribution ismediated primarily by an immersion-induced hydrostaticpressure gradient acting on the vascular columns of thebody. Since the pressure exerted on body surfaces increasesby 22.4 mm Hg for each foot of water depth, the net effect ofthis gradient would be to force blood from the vessels of thelower extremities with the result that more blood returns tooccupy the heart and intrathoracic vasculature. Additionalsupport for this hypothesis recently has been provided byEpstein et al.,19- I0 who attempted to alter the gradient byvarying the conditions of immersion. In one set of experi-ments these workers examined this postulate by studyingrenal sodium handling during immersion in supine subjects,a condition which would tend to minimize this gradient.18

Subjects were studied during a control period and duringwater immersion to the neck under identical conditions ofdiet and timing. Although assumption of the recumbentposition was associated with a gradual increase in sodiumexcretion, the resultant increase did not differ from thatfollowing the assumption of recumbency in the absence ofimmersion (control). Since immersion in the supine posturetends to minimize this hydrostatic pressure gradient effect,these results are consistent with Gauer's postulate. In anattempt to examine this hypothesis further, normal sub-jects were studied serially during immersion at varyingdepths.20 It was anticipated that increasing the depth ofimmersion would increase the hydrostatic pressure gradientacting on the vascular beds of the lower extremities andbody trunk, and thus enhance the rate of sodium excretionduring immersion. Although immersion to the level of themidchest resulted in a significant increase in sodium excre-tion, as compared to both control and waist immersion,immersion to the neck resulted in a further increase insodium excretion. These data lend additional support to thehypothesis that an immersion-induced hydrostatic pressuregradient participates to a great extent in mediating theimmersion-induced redistribution of circulating blood vol-ume. In addition to these findings, it is probable that other

mechanisms including a negative-pressure breathing effectand a redistribution of fluid between body fluid compart-ments may interact in an additive manner to induce theencountered redistribution.

NEGATIVE-PRESSURE BREATHING EFFECT

During immersion, a mean hydrostatic pressure force ofapproximately 20 cm of water is exerted on the thoracic walland abdomen,21- 22 in addition to atmospheric air pressure.However, the air pressure surrounding the subject's unim-mersed head and neck is only 1 atm, and this pressure istransmitted throughout the airways into the alveolar spacesof the lung. The resultant imbalance between the pressure ofthe air in the alveolar spaces and the greater pressure exertedagainst the chest wall creates a condition of negative-pres-sure breathing. Since negative-pressure breathing per se caninduce a natriuresis and diuresis23 (see Section VI), thiseffect may contribute to the natriuresis.

REDISTRIBUTION OF BODY FLUID COMPARTMENTS

Davis and DuBois'4 have speculated that during immer-sion there is a shift of fluid from the interstitial compart-ment to the plasma compartment of the extracellular fluidcompartment. Crane and Harris26 reported a decrease inperipheral hematocrit during immersion, approximating2.7-2.9 vol %, and suggested that these changes reflectedan increase in plasma volume during immersion approxi-mating 430 ml. These authors speculated further that im-mersion causes the transfer of interstitial (and possiblysome intracellular) water into the intravascular space. Thefindings of Behn et al.9 and Kaiser et al.26 militate againstsuch a possibility. These authors demonstrated a small butsignificant increase in hematocrit (3.1 vol % and 2.6 vol%, respectively) after 8 hours of water immersion in thesupine posture. Behn calculated a 15 ± 3% (SD) decreasein plasma volume in slightly dehydrated normal subjectsthat exceeded the decrement anticipated if all fluid com-partments were decreased proportionally during immer-sion. They concluded that the greater than anticipateddecrease in plasma volume could be attributed to a con-comitant shift of extracellular fluid from the plasma to theinterstitial compartment. In contrast to these findings, Ep-stein et al . 1 7 '" failed to observe a significant change inperipheral hematocrit sampled at 2-hour intervals in alarge number of normal subjects undergoing immersion inthe seated posture.

It is possible that differences in the experimental design ofthe above studies, including body position and states ofhydration, may account for the discrepant reports ofchanges in hematocrit during immersion. Thus, while fluidadministration was not mentioned in the study by Crane andHarris,21 it should be noted that the authors reported urineflow rates of less than 1 ml/min in some of their subjectsduring immersion; this finding suggests a profound degree ofdehydration. Similarly, the fluids administered during theactual period of control and immersion are not specified inthe study of Behn et al. ' Moreover, the body position ofthe subjects varied markedly in the different studies; sub-jects were maintained in a "near vertical position" in thestudy by Crane and Harris,18 whereas they were recum-bent in the study by Behn et al.9 Since it is well knownthat postural changes alter the plasma volume as well as


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the concentration of certain blood constituents, includinghematocrit, it is apparent that this variable probablycontributed to the encountered changes. Finally, it should benoted that Behn et al.* did not determine serial hematocritsduring an 8-hour immersion study, but merely reported thechanges after this 8-hour period. Similarly, Crane and Har-ris did not specify the frequency with which hematocritswere determined in their sodium-replete subjects; rather theyreported the "average" hematocrit change associated withimmersion. Future studies, in which body position and hy-dration are standardized and serial determinations ofhematocrit obtained at more frequent intervals duringimmersion (i.e., 30-minute intervals), will probably resolvesome of these apparent discrepant results.

II. Effects on Renal Function

RENAL WATER HANDLING

Chronologically, the initial emphasis on delineating therenal effects of immersion was directed toward documenta-tion of changes in renal water handling.'"' Behn et al."studied renal water handling in normal subjects undergoingimmersion after two different states of hydration for the 3days preceding immersion: a "hydrated state" (water in-take = 3.1 % of body weight/day) and a "hydropenic «taie"(water intake = 1.7% of body weight/day). These workersreported a significant diuresis during immersion for the"hydrated group" that was attributed primarily to an in-crease in free water clearance.' In contrast, the increase inurine flow in the "hydropenic" subjects was smaller andattributable solely to an increase in osmolar clearance.These findings were similar to those of Epstein et al.,17 whonoted that when a cumulative water load averaging 2,000ml (2.9% of body weight, approximately the same loadgiven the hydrated group of Behn et al.) was administered,the increase in urine flow induced by immersion was attrib-utable to both an increase in free water clearance and osmo-lar clearance.2' However, when subjects were studied afterovernight water deprivation, the small but significant in-crease in urine flow noted during immersion was due solelyto an increase in osmolar clearance.10

Mechanism of the Diuresis

Several lines of evidence have suggested that inhi-bition of antidiuretic hormone (ADH) release partici-pates in mediating the diuresis of immersion.2°- 31 Eckert"demonstrated that the administration of vasopressin duringimmersion, either as a single bolus injection (0.5 mU/kg) orby continuous infusion (0.24 mU/kg initially, followed by anintravenous infusion of 0.25 mU/kg for 30 minutes),significantly reduced urine flow from 6 ml/min to 1 ml/min.Subsequently, Kaiser et a l . " reported that immersion didnot significantly enhance the already elevated flow rates insubjects who had been given a large water load prior toundergoing immersion. The latter studies, however, werecarried out under conditions of supine posture,5"- " anexperimental condition which precludes direct inferenceswith respect to immersion in seated posture." Recently,Epstein et al.'° determined urinary ADH excretion in 10normal subjects undergoing immersion after 14 hours ofovernight water restriction. They reported that immersionresulted in a progressive decrease in ADH excretion from 80± 7 to 37 ± 6 //U/min. Cessation of immersion was

associated with a marked rebound, with ADH excretionincreasing from 37 to 177 /iU/min during the recovery hour.These studies are consistent with the suggestion that inhydrated subjects undergoing immersion (for whom ADHradioimmunoassay may not be applicable due to the lowbaseline values), suppression of ADH release also maycontribute to the enhanced free water clearance.10

RENAL SODIUM HANDLING

In 1959 Gowenlock et al.32 reported that the natriuresis ofrecumbency persists when an erect posture is assumedduring immersion in water, in contrast to the usualantinatriuresis caused by quiet standing in air. Subse-quently, Graveline and Jackson' and Hunt7 reported anatriuresis during water immersion. However, because theseearly studies were carried out using whole body immersionwith pressure-breathing equipment, their interpretation isdifficult. In 1969 Behn et al.* reported a significant natriure-sis (53-127% increase above control) in normal subjectsundergoing head-out water immersion. Epstein and co-workers17- " characterized the natriuretic response duringvarying sodium intakes and varying depths of immersion.Studies of sodium-depleted subjects immersed to the neckdisclosed that immersioa produced a marked natriuresis.'3

Although the rate of sodium excretion (UN.V) duringimmersion by subjects in balance on a 10-mEq sodium dietwas 20-fold greater than during the control period, theabsolute increase in sodium excretion during water immer-sion was exceedingly small; this reflected the limitationsimposed by the sodium-depleted and volume-contractedstate of the subjects. This interpretation was supported byresults of an additional study during which sodium intakemore nearly approximated that of the normal diet (150mEq/day).17 Sodium-replete normal subjects demonstratedan earlier (hour 1 vs. hour 4) and more profound (72 mEq/6hours vs. 7 mEq/6 hours) increase in sodium excretion thandid comparable subjects studied during sodium depletion.

When the depth of immersion was varied, it was demon-strated that water immersion to the waist did not induce anatriuresis in either sodium-depleted33 or sodium-repletesubjects.20

Mechanism of the Natriuresis

The demonstration of a highly significant increase infractional excretion of sodium during immersion indicatesthat the natriuresis is attributable primarily to an increasedtubular rejection of sodium rather than to alterations infiltered sodium load.17-2S Although the natriuresis observedduring immersion is associated with a suppression ofaldosterone release,2'-33 the rapidity of onset of the natriure-sis (initial hour of immersion) and the concomitant kaliure-sis suggest that the natriuresis cannot be attributed solely todecreased aldosterone levels.*7 In an attempt to delineate thequantitative contribution of aldosterone suppression to thenatriuresis of water immersion, renal sodium handling wasexamined in subjects undergoing immersion, before andafter administration of exogenous mineralocorticoid (deox-ycorticosterone acetate)." These studies demonstrated thatpharmacological doses of a potent mineralocorticoid failedto abolish the natriuresis of water immersion (Fig. 1).

Several lines of evidence have suggested the presence of acirculating natriuretic factor that normally depresses renal


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FIGURE I. Effect of deoxycorticosterone (DOCA) prelreatmenlon renal sodium handling during water immersion to the neck(Nl). The shaded area represents the mean ± SE for control studies(C) following prelreatmenl with deoxycorlicosterone (control +DOC A). Although DOC A pretreatment blunted the natriuresisof immersion, the rate of sodium excretion (UNaV) was still 3-to 4-fold greater during immersion + DOC A than during the com-parable periods for control + DOCA (P < 0.01).

tubular reabsorption in response to extracellular fluid (ECF)volume expansion.143* The possibility of such a natriureticfactor is relevant to considerations of the mechanism(s) ofthe natriuresis of immersion. Studies during a recovery hourfollowing immersion revealed a continuing natriuresis thatoccurred despite the progressive volume contraction inducedby the earlier period of immersion." This delay in thedisappearance of the natriuresis suggests that a humoralfactor rather than more rapidly acting hemodynamic andneural mechanisms may contribute to the natriuresis.'4""The demonstration by Favre et al." that the humoral natri-uretic factor which was previously reported during renalfailure also is present in normal dogs during mineralocorti-coid escape suggests that such a humoral natriuretic factoralso may participate in the natriuresis of immersion.

Recent observations from our laboratory have disclosedthe presence of a natriuretic factor, as assessed by ratassay, in the urine of normal subjects undergoing immer-sion." Furthermore, a sodium transport inhibitor also hasbeen found in the serum of normal subjects undergoingimmersion (Fig. 2). When blood obtained during immersionwas fractionated and applied to toad hemibladder,*" therewas significant inhibition of short circuit current (SCC) (U.Michael and M. Epstein, unpublished observations). Ofinterest, blood similarly obtained and prepared from a nor-mal subject who did not manifest a natriuresis (subject 10in the study by Epstein et al.") did not alter SCC (Fig. 2,upper panel). These observations suggest that a humoral

factor may contribute to the natriuresis of immersion.Finally, it is possible that a decrease in sympathetic

nervous system activity may be responsible in part for thenatriuresis of immersion. Karim and co-workers" reportedthat left atrial distention results in a decrease in renalsympathetic nerve activity. Because several recent studieshave provided evidence for a direct effect of the renalsympathetic nerves on renal tubular sodium transport inthe absence of alterations in renal hemodynamics,40 it isconceivable that a decrease in renal sympathetic activitymay contribute to the encountered natriuresis.

The demonstration of a progressive kaliuresis duringimmersion"- " suggests that the natriuresis of immersion ismultifarious in nature and is mediated in part by an in-creased rejection of sodium proximal to the diluting site, inaddition to that component of the natriuresis which is sec-ondary to a decline in circulating aldosterone. This interpre-tation is supported by previous data from our laboratorywhich showed: (1) an augmented free water clearance at atime when sodium excretion was enhanced, suggesting an in-crease in sodium delivery to the diluting site;27- 2S and (2) animmersion-induced increase in bicarbonate excretion with aconcomitant increase in the urine to blood Pcos gradient,suggesting an increased proximal tubular rejection of so-dium bicarbonate."

CHANGES IN RENAL HEMODYNAMICS

Kaiser et al." determined inulin clearance (CIn) andp-aminohippuric acid clearance (CPAH) in normal subjectsundergoing 8 hours of immersion in the supine posture. Theyreported small but significant increases in both C|n and inCPAH (10% and 13%, respectively, compared to the 2 hourspreceding immersion). However, because a separate control

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MINUTESFIGURE 2 Effect of serum from normal subjects undergoingimmersion on the short circuit current (SCC) of toad hemibladder.Blood obtained during immersion from a subject who did notmanifest a natriuresis did not alter SCC (upper panel). In contrast,blood obtained from a subject who manifested a marked natriuresisduring immersion significantly inhibited SCC (lower panel).


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study bracketing the same time period as immersion was notcarried out, it is difficult to ascertain to what extent theconditions of the experiment may have contributed to therelatively minor changes reported. Similarly, Crane andHarris16 recently reported increments in creatinine clearanceCCr) (74 ± 6 1 % ) and urea clearance (230 ± 220%) duringwater immersion in "upright" subjects. Again, because ofthe lack of an appropriate control period, it is difficult todetermine to what extent the reported changes can beattributed to immersion per se. In an attempt to circumventthese difficulties, Davis and DuBois14 and Epstein etal."•"• " have examined CCr in a large group of normalsubjects undergoing both a control study and an immersionstudy using an identical seated position and conducted at theidentical time of day. Although these investigators notedoccasional small changes of CCr averaging 18-20%, thesesmall increments invariably were restricted to the initialhour of immersion, and a sustained increase in CCr duringimmersion never was detected in over 150 normal subjectsundergoing immersion. More recently, this group examinedthe effects of immersion on renal hemodynamics by assess-ing Cin and CPAH during a control study and during waterimmersion under identical conditions of posture and time ofday." Immersion did not alter Cin or CPAH from controldespite the occurrence of a marked and progressive natriure-sis. These data are consistent with the interpretation that thenatriuresis of water immersion is mediated independently ofalterations in renal hemodynamics.

III. Comparison of Water Immersion and Saline Infusion asVolume Determinants of Renal Sodium and Water Handling

While there are several potential advantages to thecapability of water immersion to provide a volume stimuluswithout the necessity of increasing absolute total bloodvolume, it was unclear whether the magnitude of thestimulus was comparable to that induced by standard saline-induced extracellular volume expansion. Thus, studies werecarried out on a group of normal subjects in an attempt tocompare the relative central hemodynamic and renal re-sponses to water immersion and to standard saline infu-sion.41 A noninvasive rebreathing method was used and theincrement in cardiac output induced by head-out waterimmersion was shown to be similar to that observed duringextracellular fluid volume expansion (ECVE) by acuteadministration of saline (2 liters/120 min) (M. Epstein andM.A. Sackner, unpublished observations). In a subsequentstudy, the increment in UN.V during immersion was indis-tinguishable from that noted after saline infusion in seatedsubjects.42 In addition, the kaliuretic response during immer-sion was similar to that induced by saline infusion in seatedsubjects. These data suggest that the "volume stimulus" ofimmersion is similar to that of standard saline-inducedECVE in normal, seated subjects. Furthermore, the abilityof immersion to induce a natriuresis without a concomitantincrease in total blood volume and with a decrease in bodyweight rather than the increase which attends saline infusionsuggests that immersion may be a preferred investigativetool to assess the effects of volume expansion on renal elec-trolyte homeostasis and renin-aldosterone responsiveness inedematous patients and patients with hypertension.

IV. Alterations in Renin-Aldosterone

CHANGES IN PLASMA RENIN ACTIVITY

Although the changes in renin-aldosterone responsivenessduring water immersion have been delineated only recently,several studies have suggested the possibility of suchchanges. Two decades ago, Bartter and Gann43 demon-strated that constriction of the supradiaphragmatic inferiorvena cava consistently increases aldosterone secretion, pre-sumably by producing a relative depletion of blood abovethe constriction. Subsequent studies have demonstrated asimilar increase in plasma renin activity (PRA) in the dogwith inferior vena cava constriction. Since immersion to theneck produces an opposite hemodynamic redistribution,characterized by an increase in intrathoracic volume,14- '•• "one would anticipate a decrease in both PRA and aldoster-one. Korz et al.44 were the first to report a suppression ofPRA during immersion. These authors reported a 28%decrease in PRA after water immersion for 6 hours,compared to preimmersion levels. Unfortunately, the ab-sence of a control study carried out at an identical time ofday complicates the interpretation of these findings, sincethe decrease may have been attributable in part to thenofmar diurnst variation; Subsequently; Epstein andSaruta33 studied the effect of water immersion for 6 hourson PRA in normal male subjects in balance on a diet con-taining 10 mEq of Na and 100 mEq of K. All subjects werestudied on three occasions: control, immersion to the levelof the umbilicus (waist immersion), and immersion to theneck. Waist immersion produced a decrease of one-third inPRA at 2 hours without any further depression at 4 or 6hours. Neck immersion produced a similar suppression ofPRA at 2 hours with a further suppression at 4 hours and 6hours. Crane and Harris28 studied the effect of head-outwater immersion on PRA in normal subjects maintained ina "near vertical position." Immersion caused a 51% de-crease in PRA after 2 hours of immersion, without a furthersuppression at the end of 4 hours of immersion. However,the interpretation of their findings is confounded by theabsence of dietary control of sodium and potassium intake,and the marked difference in posture and activity duringimmersion ("near vertical position") and control (2 hours ofambulation)."

Because the determination of PRA at 2-hour intervals inall the above studies precluded assessment of the rapidity ofchanges resulting from initiation or discontinuation ofimmersion, a study was undertaken recently to characterizethe temporal profile of the suppression of PRA duringimmersion. Blood was collected serially at 30-minute inter-vals for PRA determination. Immersion resulted in aprogressive suppression of PRA beginning within 30 min-utes of initiating immersion (Fig. 3). By 210 minutes, PRAwas suppressed maximally to 38% of the prestudy value.Cessation of immersion was associated with a prompt (in asearly as 30 minutes) return of PRA toward prestudy values.

MECHANISM OF PRA SUPPRESSION

Although the mechanism for the suppression of PRAremains to be established, recent studies by Mancia et al.48

are of interest. These investigators demonstrated that block-


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FIGURE 3 Comparison oflhe effects of immersion on plasma reninactivity and plasma aldosterone in subjects in balance on a diet con-taining 10 mEq of Na. Data are expressed in terms of percentchange from the preimmersion hour. As can be seen, the suppres-sion of plasma aldosterone paralleled the suppression of plasmarenin activity throughout the immersion period. Similarly, follow-ing cessation of immersion, the recovery of both plasma renin activ-ity and plasma aldosterone occurred in parallel. (From Epstein elal." Reproduced with permission.)

ing vagal traffic from the cardiopulmonary region causes amarked increase in renin release and that this effect isabolished after renal denervation. The authors interpretedtheir data to suggest that vagally innervated receptors in thecardiopulmonary region exert a tonic reflex inhibition ofrenin release by decreasing activity of sympathetic nerves tothe kidney. Although these studies do not permit discrimi-nation between atrial or pulmonary receptors, they suggestthe possibility that the central hypervolemia induced byimmersion may suppress renin release by affecting similarcardiac or pulmonary receptors, or both.

CHANGES IN ALDOSTERONE

The possibility that water immersion suppresses aldoster-one was suggested by several findings.8- "• 44 Several inves-tigators had reported an increase in urinary Na/K concen-tration ratio during immersion.8- " Gowenlock et a l . "reported that the increase in aldosterone excretion producedby a change in position from recumbency to the standingposition failed to occur during water immersion. In 1971Epstein and Saruta" demonstrated a two-thirds decrease inaldosterone excretion in sodium-restricted normal subjectsundergoing immersion. Additional studies undertaken toassess the effects of water immersion on both aldosteroneand 17-hydroxycorticosteroid (17-OHCS) release demon-strated that plasma 17-OHCS levels were not altered at atime when PRA and aldosterone were suppressed.4" Theseresults suggest that the suppression of the renin-aldosteronesystem is selective and not a manifestation of a generalizeddecrease in adrenocortical activity." More recently, Craneand Harris" reported a significant suppression of plasmaaldosterone (PA) after I hour of immersion in a group ofnormal subjects, with a subsequent decline of 71% and 74%at 2 and 4 hours of immersion. Qualitatively similar changes

were noted in the two normal subjects studied during dietarysodium restriction.

Epstein et a l ." recently assessed the temporal profile ofthe suppression of PA during immersion in a group ofnormal subjects studied during dietary sodium restriction.They demonstrated a progressive suppression of PA begin-ning as early as 60 minutes, with maximal suppression by210 minutes of immersion (Fig. 3). Cessation of immersionwas associated with a prompt return to prestudy values.

RELATIONSHIP OF PRA TO PA DURING IMMERSION

Crane and Harris" reported a 51% decrease in PRAduring immersion, compared to a 71-74% decrease in PA.In contrast, Epstein et a l . " recently characterized therelationship between PRA and PA during immersion andhave demonstrated that both the temporal and quantitativeresponse to immersion and the subsequent recovery follow-ing cessation of immersion occur in parallel (r = 0.993; P< 0.001) (Fig. 3).

V. Methodological Considerations

During immersion, there is a marked reduction in sweat-ing that minimizes fluid losses by this route.47 Furthermore,the subjects breathe approximately 5 cm above the surfaceof water at 34.5°C. Therefore the difference in water vaporsaturation between the inhaled and exhaled air is very small,hence respiratory water losses are minimal." The tempera-ture of the bath should be maintained constant within anextremely narrow range (±0.5°C) because an increase intemperature from 34.5°C to 36.5°C after 2 hours ofimmersion promptly reverses an established natriuresis (M.Epstein, unpublished data). It is possible that an increase intemperature results in peripheral vasodilation at a timewhen the absolute blood volume remains constant with aresultant abolition of the natriuresis. On the other hand,lowering the temperature of the bath significantly discom-forts the subject so that immersion cannot be extendedbeyond several hours.

VI. Other Experimental Maneuvers that Induce CentralHypervolemia

POSITIVE- AND NEGATIVE-PRESSURE BREATHING

Positive-pressure breathing decreases intrathoracic bloodvolume while negative-pressure breathing may increaseintrathoracic blood volume."-4"- " As one would anticipate,the increase in intrathoracic blood volume induced bynegative pressure breathing significantly alters renal func-tion and renin-aldosterone responsiveness as manifested by anatriuresis, diuresis, and a suppression of PRA.11- "•4"However, the spontaneous subsidence of the diuresis and thesubjective discomfort experienced by subjects during thismaneuver have precluded its use in investigation.

ANTI-G SUIT INFLATION

The anti-G suit is known to be an effective means ofincreasing tolerance to positive radial acceleration (+G,).80

Theoretical considerations have suggested that the anti-Gsuit would induce a redistribution of blood volume with anincrease in central blood volume analogous to that caused by


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water immersion. Indeed, it has been proposed that thisdevice might provide a means to normalize blood volumedistribution in patients with disease states associated withdecreased effective blood volume. Studies by Shubrooks etal.M have demonstrated that the standard Air Force anti-Gsuit (CSU-12/P) does not reverse the marked antinatriure-sis shown to occur with +G,, and that the initial increase incentral venous pressure that occurs after suit inflation in theseated position is not sustained.

Sackner and Dougherty" assessed the effects of anti-Gsuit inflation on pulmonary capillary blood flow using anoninvasive, nitrous oxide body plethysmographic methodand reported that inflation of the suit did not significantlyincrease stroke volume or cardiac output in either the seatedor supine position. The authors suggested these results maybe attributable to the tendency of the abdominal bladder topressurize slightly before the leg bladders, resulting in atourniquet effect on the lower extremities which cancelsthe increase of venous return produced by compression ofthe splanchnic and pelvic venous beds. It is apparenttherefore that the standard anti-G suit is ineffective inredistributing blood volume. Perhaps a modified suit de-signed for sequential inflation upward from the calf toabdominal bladders will succeed in inducing such a redistri-bution.

LOWER BODY POSITIVE PRESSURE

Lower body positive pressure has been used to redistributeblood volume.53 Essentially, the method consists of placing asubject in a box with the lower body enclosed to the level ofthe xiphoid and increasing the pressure around the lowerbody to levels exceeding 30 mm Hg. This results in a shiftof blood from the periphery into the upper parts of thebody." This maneuver has not been used widely and datadescribing its effect on renal function are not available.

HEAD-DOWN POSITION

Although orthostasis may be functionally comparable tohemorrhage in its ability to pool blood in the periphery andrtiereby reduce intrathoracic blood volume,64 the oppositemaneuver of head-down tilt does not result in significantexpansion in central blood volume. As a function of therelative distensibility of the capacitance vessels of the upperand lower halves of the body, the filling pressure of the rightand left atria may actually decrease."- " Hence a diuresishas been reported only sporadically in association withhead-down tilt."

VII. Physiological Studies in Normal Man

THE USE OF WATER IMMERSION AS AN ANALOG OFWEIGHTLESSNESS

Theoretical considerations have suggested that the expo-sure of astronauts to prolonged periods of a gravity-freeenvironment would result in the development of abnormali-ties of sodium and volume homeostasis.1- '• *' Recent reportson subjects of manned orbital space flights have indeedborne out this concept and demonstrated a significantnatriuresis and weight loss."- "° Because of the inherentdifficulties in performing in-flight physiological investiga-

tions, investigators have resorted to the use of the models ofabsolute bed rest and water immersion as analogs of the zerogravity state.1- •• " Both models are thought to exert theireffects on renal salt and water handling by producing aredistribution of blood volume with relative engorgement ofheart and intrathoracic vessels similar to that which hasbeen postulated to occur during the weightless state.2 Basedon these considerations, the water-immersion model cur-rently is being used in several laboratories in an attempt toexplore further the mechanism of the natriuresis associatedwith manned space flight, and possible countermeasures forits management.1- "

VIII. Studies in Disease States

STATES OF ABNORMAL VOLUME REGULATION

Several lines of evidence have suggested that the renin-aldosterone system plays an important role in the pathogen-esis of a number of clinical syndromes characterized bysecondary hyperaldosteronism, including congestive heartfailure, the nephrotic syndrome, and cirrhosis of the liver.Although the abnormal retention of sodium and water inone of these disease entities, Laennec's cirrhosis, has beenthe subject of intense-study, its precise pathogenesis remainsobscure. Although a diminished "effective" blood volumehas been postulated to mediate in large measure the sodiumand water retention,'2 this remains controversial." Despitethe demonstration of an improvement in renal sodium andwater handling after rapid volume expansion,*4-6S the lackof specificity of these maneuvers, which may increase thevolume of all fluid compartments, and the presumed con-comitant alterations in plasma composition have precludeddefinitive statements regarding the etiological role of adiminished effective plasma volume. While reinfusion ofascites approximates immersion more nearly, it also in-duces additional changes which may confound the interpre-tation of the results encountered. Thus, during reinfusion,fluid sequestered in a third space (peritoneal cavity) is addedto the circulating blood volume with a resultant expansion oftotal blood volume. In contrast, immersion redistributescirculating blood volume without significantly altering thetotal blood volume. The delineation of the immersion modeland the demonstration that it constitutes a potent "centralvolume stimulus" have permitted its application recently toan assessment of the role of "effective" volume in mediatingthe impairment of renal sodium and water handling incirrhosis." These studies have demonstrated that immersionresults in a marked natriuresis and kaliuresis in the majorityof patients with La2nnec's cirrhosis and avid renal sodiumretention. Furthermore, immersion induced a strikingimprovement in free water clearance in a majority of thesepatients. Additional studies during chronic administrationof spironolactone demonstrated a marked increase in so-dium excretion during immersion plus spironolactone ad-ministration, compared to a modest increase in sodiumexcretion after only spironolactone administration.'7 If theobserved sodium retention was due to elevated aldosteronelevels per se, one would have anticipated a significantnatriuresis with spironolactone administration alone. Takentogether, these data demonstrate that the renal sodium


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retention of cirrhosis is attributable only in part to hyperal-dosteronism and support the suggestion that a diminished"effective" blood volume is a major determinant of theabnormal renal sodium handling by cirrhotics.

HYPERTENSION

Many studies have indicated that hypertension is anextremely complex hemodynamic abnormality withderangements in a variety of cardiovascular and volumecontrol mechanisms. Included among these abnormalities isa redistribution of blood volume in borderline hypertension.Ulrych et a l . " and Safar et a l ." have reported that cardiacoutput is elevated in borderline hypertension despite the factthat blood volume per se is normal or low, and havedemonstrated a relative increase in central blood volumerelative to the total blood volume. Because the immersionmodel reproducibly induces a similar redistribution, it maylend itself to the further delineation of the role of thisvolume-regulatory abnormality in hypertension. As anexample, it might be anticipated that patients with border-line hypertension who already have an increased cardiopul-monary blood volume will manifest a much smaller bloodvolume redistribution during immersion and will thereforemanifest a blunted natriuretic and diuretic response and alessened suppression of plasma renin activity (PRA) andplasma aldosterone (PA) in comparison to patients withestablished hypertension. Indeed, a preliminary observationby Lange et a l . " lends support to this possibility. Theseworkers reported that one of 10 subjects undergoing head-out immersion failed to redistribute his blood volumesignificantly and manifested only a very small change incardiac blood volume in response to immersion; of interest,the subject had marked hypertension."

In addition, immersion may be used to delineate furtherthe responsiveness of the renin-aldosterone system in hyper-tension. Several investigators have assessed the relationshipbetween PRA and aldosterone in essential hypertension byinducing volume and/or postural manipulation, and havedemonstrated a striking dissociation characterized bydepressed aldosterone excretory response with an appropri-ate PRA response to dietary sodium restriction.70- " Simi-larly, a dissociation in renin-aldosterone responsiveness tosuppressive maneuvers such as oral salt loading also hasbeen reported.7* In view of the demonstrated ability ofimmersion to concomitantly suppress PRA and PA in aparallel manner, it may lend itself to the further elucidationof the relative autonomy of PRA and PA in hypertension.Finally, preliminary studies have suggested that immersioncarried out under standardized conditions of posture anddiet may constitute a more discriminating investigative toolthan saline infusine for delineating the wide spectrum of al-terations in sodium homeostasis characterizing essential hy-pertension.7'

Conclusion

Studies from several laboratories recently have succeededin delineating the circulatory, renal, and endocrine changesinduced in man by water immersion. These studies havedemonstrated that immersion in the seated posture results ina redistribution of blood volume with a relative central

hypervolemia. As a consequence, profound alterations influid and electrolyte homeostasis ensue, including a markednatriuresis, kaliuresis, and diuresis, as well as a suppressionof the renin-aldosterone system and of ADH release. Char-acterization of the immersion model and the demonstrationthat it constitutes a potent "central volume stimulus" thatdoes not necessitate infusing exogenous volume expandershave permitted its successful application in the investigationof abnormal sodium and water homeostasis in patients withdecompensated cirrhosis and, more recently, hypertension.Examples have been described of the successful applicationof the immersion model, commending its future use as an in-vestigative tool to assess dynamically the control mecha-nisms for the renin-aldosterone system in normal man and ina wide array of disease states characterized by a derangedvolume homeostasis. In an edematous or hypertensivesubject, water immersion constitutes a less hazardous meansto evaluate the effects of volume expansion than administra-tion of a saline load. In contrast to saline administration, (I)water immersion is associated with a decrease in bodyweight rather than with the increase which attends salineinfusion, (2) water immersion is associated with a signifi-cant, albeit slight, decrease in mean arterial blood pressurein contrast to the increase in blood pressure induced bysaline administration, and (3) the "volume stimulus" ofimmersion is promptly reversible after cessation of immer-sion in contrast to the relatively sustained hypervolemiawhich follows saline administration.

Acknowledgments

I am indebted to Dr. J. Ronald Oster for his advice and to Peggy DCumby for expert preparation of the manuscript.

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M Epsteinmodel in the assessment of volume homeostasis.

Cardiovascular and renal effects of head-out water immersion in man: application of the

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