The role of sodium, potassium and water in the hypo-osmotic states of heart failure

The

Role

Potassium a- ! ~d W a t e r rates o f H e a r t F a i l u r e

in

the

By R o y H . MAF*FLV AND l. S. E~ELMA'~,~ Y P O N A T I ~ E M I A is a f r e q u e n t c o m p l i c a t i o n of p r o f o u n d or r e f r a c t o r y chronic c o n g e s t i v e h e a r t failure. T h i s c h e m i c a l a b n o r m a l i t y , w h e n severe, is a s s o c i a t e d with u n r e s p o n s i v e n e s s to d i u r e t i c t h e r a p y , m e n t a l confusion, a n o r e x i a a n d i n c r e a s i n g e d e m a . H V t h e n first r e c o g n i z e d , h y p ~ m a t r e m i a was a s s u m e d to r e p r e s e n t s i m p l e d e p l e t i o n of I)o(lv s o d i u m , w h i c h c o u l d b e t r e a t e d b y a d m i n i s t r a t i o n o f s o d i u m chloride. <~ Bu't a d m i n i s t r a t i o n of h y p e r tonic saline to t h e h y p o n a t r e m i e , e d e m a t o u s p a t i e n t in heart f a i l u r e (fitch I l l a ( l e nlatters w o r s e : in s o m e inslanees it p r e c i p i t a t e d a c u t e l)~dmonarv e d e m a : in ~thers it i n c r e a s e d the e d e m a but effected little or rm c h a n g e in the s e r u m s o d i u m e(meentration, mr M o r e o v e r , Ni¢~()re a n d c o - w o r k e r s s s h o w e d t h a t hvp o n a t r e m i a m a y coexist w i t h an a b n o r m a l l y high b o d y s o d i m n eontenl as m e a s u r e d l)y the isotope dilution m e t h o d . In s o ( t i t a n - d e p l e t e d p a t i e n t s the ~¢a m a n f f e s t d t m n s , w h i c h a r e attribut~d~le p r i m a r i l y to d e h y d r a t i o n a n d h,)imw)lemia, differ in g e n e r a l from those p r e s e n t in edemata)us, hyp~matremie patients. S o d m m d e p l e t m n i n v a r i a b l y lt, ad:" 1o c o n l r a e t i o n of the p l a s m a interstitial tluid v o l u m e , b u t n e e d not result in h y p o n a t r e m i a , w h e r e a s hv-. p o n a t r e m i a r (-p r t s, ' e,n t ,s a faih~re to m a i n t a i n n o r m a l osmolalitv. Ira! ~,,ed nol indicate s o d i u m d e p l e t i o n . T h e reali~u~tion that h y p o n a t r e m i a is a d e f e c t in osmolalilv led to lhe eouce "')I I thud it could Im understood solely in terms of the relative am~mnts of body sodimn and water. (',onseq~mnlly. lwo lypes of hyponatremia were recognized: water excess, generally desigm~led as "dilutional hyponatremia.'" and sodium depletion, often designated by the obscure aud indefinite term. "'low sodium syudrome. TM Recently. however, il l)eeame dear lhat body potassium content is also an important factor in determining sermn sodimn e O l l ~ r t t r a t i o n . Io. i

A m a i n p r e m i s e of this r e v i e w is t h a t h y p o n a t r e m i n is best m~derstood in temps o f t h e c o n s t i t u e n t s c o n t r i b u t i n g to the osmolalitv of the b o d y fluids. E v i d e n c e will be p r e s e n t e d in s u p p o r t ol: t h e two concepts u p o n w h i c h tl~is thesis rests: ( a ) t h a t t h e b o d y fluids a r e iso-osmotie, and ( h ) that t h e prim a r y d e t e r m i n a n t s of bo w osmolality, a n d h e n c e o f s e r u m s o d i u m c o n e e n l r a tion, a r e t h e total a m o u n t s of osm,~tieallv active salts ~md w a t e r , i n the l>odv. Os~nolality a n d l l y p ( ~,osmotic "" States q h e o r e t m a l l ) , the m a i o r fi)rces w h i c h m i g h t m o v e w a t e r across cell m e m b r a n e s a r t h y d r o s t a t i c p r e s s u r e g r a d i e n t s , osmt~tie p r t . s m gradieuts and From lhe (.nrdtotas~:uh~r Ilexeatth hlslttut~ and ttie l)~'parlment o] M4"di~inr~, Uniretslty o/Califi~rnhJ Scfiool ~,1 ,~h,dictn~, S~tn Frantqw'o. (~Stli[. I J~s wt~rk tvas ~hnl~, durbJg tile t,~nUre ot ~ltl Advart~:~d l{~,sf'ar~qj F,'lloushlp o[ the American il~srt A , ~ J c i a t t ~ (Dr. l ~ l a ~ L

88

?'CA, K A N D H~O IN H Y N ~ t O ~ C

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active transport o f water. Since. t h e first , o f t h e s e . a l t e r n a t i v e s e~m be dismissed i n animal c e l l s ; a iltil~[~er of investigators songh! ,a means to di.~tingi~ish patss i r e d i ~ r i b u t i o n o £ : w a t e r . ( L e , distrilmtion Of~ v+ater in prop~,~ion to soh~te cm-~tent:) , from .active transport of water:~a-~+ W h e n :tWo aquecms. Solutions Oare separated by :a m e m b r a n e p e r m e a b l e tO w a t e r b u t i m p e r m e a b l e ,to:soh~t~, ~water.will move f~m* the Solution"~f hm ~.~ solt~te<,oneentrat~on t0 din: solution 0f t n"g h e r", s~flt~to t~neentration.;". TIlls nlow+int~nt eali l?e. p r e v e n t e d b y the application of,,a hydrostatic |lr(~2"sllre,:Oll tim solid,on of h i g h e r "solule eoncentrationY T h e h y d r o s t a t i c pressure, nc~,essara; to redtlee ,let. water lnooem0nt to zero can be,ct~nce**-;:"0cd to be tamnter2 aet)ng a=i e
-graM!clotS iS n o t tcelmieally feasible, but fl'm ~;e~moladitv ~f i~t:racelhdar and " extraeelltdur fluids c a n " b e inferred from tim mea.surenlent n[ .the o t h e r . . e o l [igativ"e properties; nnrnely, the " ' ~ ' Iris, zing lmird ~. vapor t~t..s..~rc. ",'s* ~* be0ili=~g point, am! m e l t i n g p o i ~ t . . T h e Colligative p ~p~ h~e¢ tlepe;Jd ~ m "t}~- ¢u)~ea:,i~le,atiorL or .more r~orous],~, the ehenlleal aet~v~t~ of w a t e r i~ the, so|,.~th)~ ~lt is rt'a~s~nable to.cor~clude t h a t Water is passiv¢'Jy~dls~rlb|aed~ birtween.!l',e t~|{raeellul~r-

osmotic tO phlsma~ current evidencx: sup|~$rts strtmg|y t h ( ! ~:xm(~pt t|,at cx:lls ~irc in osmotic e q u i l i b r i u m ~v~~th, . their fluid env~ronmi~nt~ " " :C""c m w ' a y' and..IM0= C o r m a c k slmwed that v,~en correction t,cas ,iiade f o r auto|ysjx, lhe: fse:e:,:in~ p~.~int of ti.sstms d i d not d j ! b r sigm:Rm=mtly f r o m t h a t Of sermn. Th~vae regultx w e r e confirmed by Appell}oom al~d assoeiali~7~ ~ w*h o d e t e r m i"n e d t h e ft ng poh~t of. boi|ed tlssims.: aitd |~V ~da~/ly: al~d I.¢+~E~Y Who~ measur~n| the me]linR p o i n t e r r a p i d l y frozen ti~stles. Known ~excepti0~j~ to tim: rule o f omnotie eqttMity i h r o u g h o u t t!ie b o d y w a t e r a r e the,i renal m e d n I | a a n d e X o e ~ n e glands d u r i n g the secretiml o f h y p o t o n i c f l u k ~ i n t h e w h o l e animat~ howe~mr, the osmotic e o n t f b u l i o n of these tissuc~ is qum~titntively tTlsigntfiCant O n the basis of these studies: it can b e S t a t t ~ t t { a t : ¢

where r,:e, ~ e a n d =~r~ d e n o t e t h e o s m o h d i W o f t|m extracetinlur fluid, l"l t t r ;"~ ,cellular fluid a n d total l~_~dv water; r~p,:-etivdy, '*~m ~ormaI extrac, rl|t~lar fluid osmolality i~ man, i n f e ~ e i l from mea~t=rement of t h e fn:x~ing point o f " x a t c r, . ~z " C;,h t r n i m d : ~ t l a | v s e ~ ,Of l m n n a l sermn, is a l ~ m t 2 9 0 m O s m p e r Kg. ~f x-. |~|a~ma. indicate that e t e c t r o l y t ~ provide" ab,.mt a , mOsn~ p e r "Kg. o f ,~vatet, ant! ghteo~c and oonprolein ~/!trogen ilm remahiing~ |0, ,~xl'lum ac,'cv-~nts h,r ahnost half tilt" electrolyte t~mttil)ution to o.~molalilv, cve~ wil|~ w i d e V~tlr|a" liOItS ill |)|ilSllla clectrt~lvte ~ , , o n c e ~ ¢ r a t l "o l l s . ~-. (+ons~|ueltl . . . |y, .lj~e "¢lUa~tt . tlat~'~., ' =Z g~* re|alien |u.-Iweel~ s+~rmn s¢-_|ium t~t}ll~'t*tt|r;~l{ol| [n t | t l ; q , h~, ¢~[ x~,ater { ~ ' ~ a , ) a n d exlrlicellnlar osmolltlity ~vi|t |m,: ,

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where A repres(mts osmo]alitv due to.glucose and nonprotein nitrogen and a is an e m p i r i c a l c'oel|icient r e l a t i n g N a . to rv,> "~Vhen N a . a n d =~:~- a r e exp r e s s e d p e r Kg. o f wader, r, s h o u l d h a v e a v a l u e o f : q ) p r o x i m a t e l y 0.9. T h u s

E q u a t i o n 3 h a s l i n e n e x p e r i m e n t a l l y v e r i f i e d in m a n . TM T o d e v e l o p t h e r e l a t i o n s h i p b e t w e e n N a . a n d b o d y c,¢mlposition w e n e e d t o k n o w t h e o s m o t i c COml)osition o f tl~e i n t r a c e ] h d a r thlid, as w e l l as t h a t of t h e e x t r a c e l h d a r fluid. In a l m o s t all c e l l s p o t a s s i , im c o n s t i t u t e s t h e m a j o r i n t r a c e l l u l a r c a t i o n ) s I n s k e l e t a l musc, l~. W h i c h c o n s t i t u t e s a b o ~ t 4 0 p e r c e n t o f / h e b o d y w e i g h t , t h e total i o n i c e q u i v a l e n c e at a 1)171 o f 7.0 is e s t i m a t e d Io b e 4 7 5 n a E q . p e r Kg. o f w a t e r . *'~''-'~' T h e c o n e e n t r a t i ( m o f p o t a s s i u m is a p p r o x i m a l e l y 150 ml~( t. p e r Kg. of w a t e r , w h i c h r e p r e s e n t s 75 p e r c e n t o f t h e t o t a l c a t i o n i c e q u i v a l e n t s : t h e b a l a n c e is m a d e u p p r i m a r i l y o f m a g n e s i u m and a n s e r i n e , a e e o r d i n g to C o l ) w a y . a " l n t r a c e l l u l a r a n i o n s it~ m u s c l e consist of o r g a n i c p h o s p h a t e s ( 5 0 p e r c e n t ) , p r o t e i n s ( 35 p e r c e n t ). a n d o t h e r s { 15 p e r c e n t ) . In t h e p l l r a n g e of t h e cell, t h e a v e r a g e i o n i c v a l e n c y of t h e o r g a n i c p h o s p h a t e s is d o s e to 2 a n d t h a i o f t h e p r o t e i n s p r o l m b l y a l ) o n t 30. As a c o n s e q u e n c e n f t h e i r m n l t i v a l e n c v , t h e o s m o t i c e t l u i v a l e n e e of t h e i n t r a c e l l u l a r a n i o n s is less t h a n h a l f o f t h e i r c h e m i c a l e~luivadence. A c c o r d i n g l y . in t h e a b s e n c e o f a p p r e c i a b l e b i n d i n g , p o t a s s i u m s h o u l d y i e l d al:mut 5 0 p e r c e n t o f l h e o s m o t i c a l l y a c t i v e s o l u t e in t h e m ) r m a l cell. o t h e r e l e c t r o l y t e s 10 p e r c e n t . ~}rga~tic a n i o n s 20 p e r c e n t . a n d r e m a i n i n g c o m p o u n d s ( p r i m a r i l y a m i n o a c i d s a n d a n s e r i n e ) ~0 p e r cx~nt, h l t r a c e l l u l a r o s m n l a l i t v t h e r e f ~ r e c a n 1)e expressed by:

w h e r e Ku. d e n o t e s t h e i n t r a t - e l l n l a r c o n c e n t r a t i o n o f p o t a s s i u m a n d B d e n o t e s t h e o s m o l a l i t v o f d i f f u s i b l e s o l u t e , p r i m a r i l y n o n p r o t e i n n i t r o g e n (i.e~, u r e a . c r e a t i n i n e ) a n d to s o m e e x t e n t f r e e h e x o s e s . T h e e m p i r i c a l c o e ~ e i e n t relates K~e to =m w h e n b o t h a r e e x p r e s s e d p e r Kg. of w a t e r . S i n c e t h e osm o l a l i t i e s o f t h e e.xtracellular a n d i n t r a e c l l u l a r f l u i d s a r e e q u a l , a n d s o d i u m a n d p o t a s s i u m c o n s t i t u t e a p p r o x i m a t e l y h a l f t h e o s m o l a l i t v in t h e t w o fluids r e s l m c t i v e | y , B s h o u l d h a v e a b o u t t h e s a m e v a h m as ,, of e q l m t i o n 2. i.e.. --0.9. T h e r e f o r e e q u a t i o n 4 beet}rues: ¢

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It is Imssible, h o w e v e r , t h a t in d i s e a s e s t a t e s t h e r e l a t i v e t a m t r i l m t i o n of pot a s s i u m t o i n t r a c e l l u l a r osm¢~lalitv m a y c h a n g e , h e n c e t h e c~~lficient 1.S in e q u a t i t m ;S m a y n o t !~_, a e o n s t a n l . Situati~ms w h e r e s u e h d e v i a t i o n s m i g h t b e suspected include (a) lmtassium depletion. (b) acid-base distHrbances. (c) c h a n ~ e s in t h e o s m o t i c a c t i v i t y t~f c e l l u l a r o r g a n i c a n i o n s a n d (tl I c h r o n i c tletlcits in c,,ilular e n e r g y . "FOr 1,e.'iltel¢ io~. ~)t~r calculali~,m~ inehule truly the net e~cvs~ ~1 ¢barRe e~limaled hy

N A . K A N D !1.~O IN | t Y P e - o s M o T I C

Potassium d e p h , t i o n . - - T h e

STATIGS O F IIF.AI/T F ~ I | , ; I I I I E

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l o s s o f K * f r o m c e i l s m a y h a v e t h r e e c(,msequences: K may. l e a v e t h e c e i l a c c x ) m p a n i e d b y a n e q u i v a l e n t a m o u n t o f a n i o n : it m a y , e x c h a n g e f o r N a * : c r it m a y e x c h a n g e , f o r I! ~. g h c first o f t h e s e is d i s c u s s e d n n d e r s i t u : a i o n ( c ) . T h e s e c o n d a l t e r n a h ~.: foss o f K ~ a n d g a i n o f N a ~' , w o u l d p r o d u c e n o c h a n g e in o s m o l a l i t v simx~ t h e o s m o t i c c ( } e f f i c i e n t s o f K ~ a n d N a ~ in t l w c e l l a r e s n n ~ l a r . - C o n s t ~ l u ( n t l y . if it ix t o h e a c c u r a t e in t h i s c l r c m n s t a n e e , {~lnation 5 n~ust b e m o d i f i e d t o i n c l n d e Na T i m t h i r d p o s s i b i l i t y , K * -- H * e x c h a n g e , is n o t e a s y t o e v a h m t e . G o o k e e t al. :~ p r e s e n t e d e v i d e n c e t h a t o n e [1~ ent{ws t h e c e l l f o r e v e r y tlirex.~ K + lost. A l m o s t a l l t h e n e w i t ~ w o u l d b e b u f f e r e d b y t h e f o r m a t i o n o f w e a k a c i d s , l e a d i n g t o a n e t l o s s o f o n e o s m o l f o r e a c h K " r e p l a c e d b y II -~. Q t ~ a n t i t a t l v e | y , h o w e v e r , l o s s o f a s m u c h a s ~') l ~ r c e n t o f c e l l K ~ w 0 t d d m e a n a n e r r o r o f o n l y 5 p e r c e n t in e q u a t i o n 5. Acid-basv disturbanves.--The quantitative contribntion of C02 to cellular o s m c h ' d i t ) - ~s . x c , x x h n g l > s m a l l , e v e n in r e s p i r a t o , ~ " a c i d - b a s e d i s t t l r | ) a n c e s w h v r e v a r i a t i o n s in | )( 2 "0 2 a r e e x t r e m e . 2° I n m e t a b o l i ( - a c i d - b a s e d i s t u r b a n ( ~ s , the exchange of I I' across the cell membrane may be coupled with K*. as i n d i c a t e d in t h e p r e c e d i r | g s e c t i o n , trot c l u a n t i t a t i v e l v s h o u l d l)ro(tu(_~ o n l y s m a l l d e v i a t i o n s f r o m l i n e a r i t v in th(: i(.i,ltlotl "'' : ! )etx * ' ¢~' e .~t =ra a n d Ktr. I n e x p e r t m e n t a l c o n f i r m a t i o n t h e c h a n g e in ~,,. p r o d u c ~ , d l)y i n ~ c e t i o n o f I I C I i n t o nephrectcmized th)Ks 2"*~ I)y o u r c a l c u l a t i o n s wits .qttributabh? simply to tile i n c r e m e n t i n t o t a l l ~ ( l v ,,'~,,tt(r.," C h a n g e s in o s m o t i c a c t i e i t y of celhdar or~,m~ic,~ a n i o n s , - S i n e e s e v e n - e i g h t h s o f t h e a n i o n i c c o n s t i t u e n t s o f c e l l s s n p p l y o n l y one-fiftt~ o f t h e o s m o t i c a c t i v i t y . C | i l l l t g t ' s ill t|lt~ v a l e n c y ~r o r m o l v c u l a r c o t { / i ~ , s i t i o n o f t h e s e ( ~ t ) | l l l l o l l e n ' s may h~|htence osmolality cm~siderablv. If organic phosl)hates or proteins break d o w n t o s m a l l e r u n i t s , a r i s e in ((]lnla-", r o s m o l a l i t v w i l l r e s u l t . T h i s m i g h t o c c u r d u r i n g a n o x i a , s t a r v a t i o n o r t r a u m a . S n o b a n elftx*t i n : i v il~x'N)llllt ft,r t h e o b s e r v a t i o n s o f W e l t et aL. 2~ w h o o b s e r v e d s h a r p r i s e n i n s e r u m s o d i u m and potassiunl concentrations ( N i t . a n d K. ) in o n e n l i n l i t e d u r i n g e l e c t r o shock cnnvulsions. They calculated that the transient increase in total ~:ly m i l l i o s m o l s ,~vas o,0-" t o 1 ~ - 0 . I n t i m e , h o w e v e r , t h e o r g a n i c s u b c o n s t i t u e n t a might be cleared by diffusion from the cell or by resynthesis el new coinpounds. Each organic anion lost from the cell would lm aec-ompanied on the average by about two K-. In the extreme ~tse. a selective loss of one-half the organic phosphate and protein would lower the contribution of K 4 to c e l h i l a r o s m o l a i i t ) - f r o m t h e n o r l n a t v a l u e o f 5() p e r a , n t t o 3 7 l~,r c ~ n t . I n o f 1,8 w h i c h r e l a t e s K w t o c e r t a i n e i r e t l n l s t a n t x . - s , t h e r e f o r e , t h e c,ot.lllc~ent ' " :,,- might b e s n b s t a n t i a l l v , a l t e r e d . It r e t n a i n s t O };~; d e m o n s t r a t t x l t h a t s i g n i f i c a n t c h a n g e s in t i l e f r a c t i o n a l c o n t r i l ) u t l o n o f K " tO c e l l o s n l o l a l i t v a c t u a l l y ~:ccnr in r i v e f o r m o r e i l i o n a v e r q s h o r t p e r i o d o f t i m e . C h r o n i c ~h'ficils in c e l h d a r ~,nt:rgy.---The s o l n t c c x m t e n t of t h e o , ll d e p t , n d s otl t l u , int,*grit-,, , o f i o n p u m p s a n d t h e c ~ m q ~ ) s i t i o n o f t h e o r g a l ) i e a n i o n s . . I ~ t t l c,f x v i f i c h in t u r n d e p e n d o n a ( ~ n t i n l l o t l s SUpllly o f m c l a l m l i e e n e r g y ' . T h e c h a n g c : ~ t h a t m i g h t (~.~L-tlr ill t h e e s t h e t i c a c t i v i t y o f t h e o r g a l l i c a n i o n s i n a c u t e a n t i c h r o n i c c e l l d a m a g e w e r e b r t e l t y d i s c u s s e d i n t h e llre~.'itms s e c t i o n . A failure by the cell to provide snlBeient em-rgv to sitstain No" r*xtruston res u i t s i n a c c u m n l a t i o n o f N a ' . a n d s o m e C i - as w e l l . a n d a ios~ otr K " .2~.~a P~

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93

N A , K A N D 11.20 I N i | Y P O - O S N | O T I C $ FATFLS O F E i ~ A B T F A I L U ~

hexost\,;. A s s u n ) i n g i|la! A a n d B :ire a p l ) r o x i m a t t ' l y e(lual in all e|ii)icai t4rcumstauccs, except possil)lv in ac)ito hyperglycemia, then: till 4. lJ)' a d d i n ~ obtain:

Oir t)(illittiOll

t h o lltlll/(wator~ ;iItd d e i i o n / i l i a l o r s

---'}:c •

~ "

l.S

.......................................................................................

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arid 9. We

(lt

or

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w h e r e Na~.)~ a n d K-r)~ d e n o t ( ~ t h e toted | m d v q l m n t i t y ~| o.~motica|lv a~tiv~ sod i m n a n d [-mtassimn rt,spcctiw, ly. 5. By slzbstittding t|m qzmniiti(,s Na.. a n d K.. w h i c h ;ir(" m e a s u r a b | e isotopically, for the imn-measimtbh, quantities, llie rehditmship between ~.'~,:,. and

Na,~. K, aim TBVV can be fornmhited: ~.'~:(: ~.~ 1+8

('<% + K,,) TBXV

D

-~ 1.~ . . . . . . TB%V

(13

w h e r e O is t h e (~sn!otically inactive but ( ' x c h a n g e a | d e s o d h u n a n d p o t a s s i u m . 1;:quatiort 1.3 w a s tested ill otir ] a l m r a t o D" b y nteastiring Na,.. K.., T B \ V a n d l)hisma osnlola|itv ( = . ) ill D8 I~;ltients wit|l a v-,lrlct~ ' " " of ilhtesses. ~2 An e s t i m a l e o f -'- t:(" w a s o|~tairwd by. s u b t r a c t i n g plasil~a n o n p r o t e i n n i t r o g e n (Nit ,Ni,), a n d g|ucx)se ((.i,) f r o m ::'... These data, d e p i c t e d in figuro 1, d e m o n s t r a t e a h i g h tlogree of c o r r e l a t i o n ( r :: 0.82) b e t w e e n ~' a n d the ratio of ( N i l . @ K . ) / TB~A ". ( = ' . which is expressed ill lit(|Sill per l., of serum water, is virtually i( critic lI with .. ~:,.. expressed in niOsin per Kg. of w a t e r ) . T h e empirical regression eqtmtion proved to be: "

=. ~ ~

.J'~3 It

TBXV

)

lit view of the asstunptions required to derive t~ttuatio)i t 3 and the itiherent errors of tneasurezneitt, the agreement between theory and ex!~-rimezi* is veD' g o o d . Morcov('r, this 5t", rl¢. ",s i n c l u d e d l~aticnts- w i t h ;1 w i d e v a r i e t y of c h e m i cal a n d l)|tvsi°l°gicaI, d i s t u r b a n c e s , i n c l u d i n g acidosis, alkalosis, c h r o n i c a n o x i a , e i l d o c r i n e d i s o r d e r s , p o t a s s i u m d e p l e t i o n a u d v a r y i n g d e g r ( ~ of ( a l e m a . " F h e ~ r(,sttlts, iher(fforc, SUl)port t h e l)ritil;zr;,' ;~ssumptions made in derivil)g e t | u a tiott 13 thai body wat(-r is passively distril)uted it) pr~)F,orli()l) to sohtte cot)sine)tic tent, that the t~" "" coelficients
9t

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{Nu.* Kt } / r . o . ~ f~[q/t} Fig. l . ~ T h e relation between the corrected serum osmolarity {~'~) and the ratio of the sum of exchangeable sodium (Na,.) nn¢l potassium (K,) per tot;al body water (TB~'} in 98 p~ttlents w i t h a variety of illnesses. ~'~, which is expressed in mOsm per L. of senlm water, is virtually identical with w'~w, expressed in mOsm per Kg. of water, used in the text. Taken from Edelman et al. 1:

agreement with the predicted value. The intercept value of - ~ 5 . 6 is a measure of the exchangeable sodium and potassium that is osmotically inactive. Exchangeable txme sodium accounts for most of this quantity, which provides independent evidence that there is little or no binding of intracellnlar potassium. *u This is in agreement with the evidencx~ summarized by Ussing. z* who concluded that under ph).siological circumstances chemical binding of potassium probably involves only a small fraction o f cellular potassium. Two fltetors which conceivably could modify the relationship between Na. and the ratio ( N a . + K..)/TBXV are acid-base disturbances and the accumulation of osmotically active nonelectrolytes, such as glucose or urea. In patients with an arterial p! I > 7 4 8 or < 7.36. no deviation was found in the dependence of Na. on the ratio ( N a . + K.)/TB'~V. Nor was there any significant variation in this dependence in patients with 130 < Gp < and ~') < N P N p < ~3,S expressed in rag. per 1C~3ml. ta

Phystoh)gical Control oI" Sodium. Potassi,m and Water In view of the quantitative dependence of ~'~:.- and Na. on the ratio ( N a . 4- K. )~'B~A'. the I)hysiological mechanisms txmtrolling the body content of these t~tmstituents also determine tile osmolality of the l ~ d y fluids. Because of the large variation in intake of sails and water, control of body

NA, K :ANI~:ll.:,O I~':-~tIYI'O-OS~IOTIC ~F.~,'t':I~ OF tlEAItT FAII.I:;}H~:

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F i g . ~ . - - T h e r e | a l i e n |v-~tween s e r u m s o d [ . m e o n c e n t r n t i o n { N ~ . } a n d t h e r a t i o of tile s u m o t e x c h a n g e a b l e s o d i u m (Na,,) nntl p o t a s s | u m { K . } p e r total b o d y ~v0ter (TB'~V) i . 9 8 p a t i e n t s w i t h a v a r i e t y of i | | n e s s e s . N a ' . , w h i c h is e x p r e s s e d in m E q . p e r L. of s e r t t m winter, is v i r t u a l l y i d e n t i c a l w i t | t Na~, e x p r e s s e d i n m ~ q . p e r Kg. n | w a t e r , u s e d in t h e text. T a k e l l [ r o m E d e l r n n r t et a l J 2

composition d e p e n d s primarily on excretory p a t h w a y s . In tilt: absence of diarrhea a n d act~,~t, " " " ' ~: sweating, the kidney t~mstitutes the main excretory route. T h e pathw~-tys for regttlation of salt a n d w a t e r conlent ~la), | ~ convet~tently classi~ed as: ( a ) "receptors," which sense tile need for m o r e or less of a g i v e n substance in the body: ( b ) "transmitters." which relay t h e information; a n d ( c ) °effectors." w h i c h carry Out the r e q u i r e d adjustment, qMble I s u m m a r i z e s some e l the c u r r e n t c mcepts of these p a l h ~ v a y s . "File kith~ey a p p e a r s a|,le to respond directly to elevations e l K, ~md N.,t, x~'itll an ftlcrease ill excretion of these electrolytes, m e d h d e d b)" an increase in the tttbtllar secretion el r potassium a n d an increase ill t h e filtered load of s~# ,.lit lit/. ~2~*

V o h t m e receptors provide a llnk betw4a,n sodittm balanc-e a n d ahh,sttrrone secretion; e~mtraction of tile blood vohune Stitllt|]nt(~S *llld tYXp;tllS|otl ill]li|~[tS ahlosterone secretion. ~:' "File right atrittm and the carotid arteries have | ~ n S t l ~ e s t e l | ~|S V~ISCIII;IF reeel)tor -: ..... a r. a,t Ak:iosterone p r o m o t ~ N a ' * c(mscrva~ lioll nn(l K * excretion, presunlably b)" stimulating Na " - K " a l l t | N a ~ ~- } | "~ t.xehatlge in the distal c~mvoltdt.d tubules o[ the k i d n e y : tx A l t h o u g h no lmtas-

90

?~iA,FFLY ~A N D EL)EL.%f~N"

T~tbte l.~Paihwa~s:for the Reg.iatlon of Sodium, : P o t ~ h o ~ a n d IVater

Vohi~ sl,,roid~ ?l lit~tlil t ~ l i b i t l l ~ t + f , - t l t ~ o t e p l i i l n flllfhtt-lie~] 1,1 l~,i~e~ll~,¢

~teroM. ~i

LI i l l s 1 1

I~tl f l t l t i l I~ tl~,l~ t ~ l i t l l r l

lion

(ll~81ierteOt h)-

n ~ e 8~HI l~Oxin~al liibulttl~

leellbS¢lleDl i l ~ l l )

siuin-sel~sitive r e c e p t o r s lmvc beet! kltmtificd, i t has b e e n s h o w n that p o t a s s i u m lowers a n d pot~Issium l o a d i n g miiscs the mite of al(losterone s~:ere~ a t c r b a l a n c e appe~trs to I)~: reguhltt.,d b y t h e co~tevritr~tio~ of w a t e r (t>sm o l a l i t y ) arid b y e x t n i c e l h t h i r volume. E l e v a t i o n of the osmolality, of tl~e b l o o d in t h e i n t e r n a l c a r o t i d ~ r t e ~ ' stimulatt, s 0~e release el ~ ;lilt|diuretic h o r m o n e ( A D I I ) f n J m t|te nellrt)hypt)p|lysis a n d p r o l ) a b l y s i i m u h i t v s thirst as wello m e t l i ; d e d ILv reee)tors, [ . ht the hypothLlhmlus. :l"`*':' Ilt ildtlition, alltidiuresis occurs w l i e n the effective eircuh~tlng b l o o d v o l u m e is reth~ctrd. ~ l l e n r v et ;d. ~e p r e s e n t e d evidt~nc.e tlmt a v o l u m e rt:ceptor site is l o c a t e d in the left at'rial wall. Antidh~relic h o r m o n e acts on the distal t u b u l e s a n d c o l l e c t i n g d u e t s o( t h e kidney t{) f a e i f i i . t e the reubsorr~tioli o f water. ~:~ l . o e a l r e n a l t u b u l a r faet~trs m a y also a ~ e c t the n~tes of ~.xcrctio~l of Na -5 " K +, a n d wlitt;r. TI,ic btllk of tht~ filtered Na* liter! w a t e r l i n d / ) r o b : l b l y all eft the K ~ tire reat>sort)ed in the p r o x i m a l e ( m v o l u l e d tid)ldes, p r c s u m i l h l y inde" " o[ hor~loltal in|lilctlc'~zs.I~.i~ If tile ;li~totint:~ o f Nil*" arid w a t e r (|c.I 11c" I ! d~llt|~ l i v e n a l to t h e d i s t a l t u b u l e s a r e reduc~(l, the ma:dml~m rode of e x c r e t i o n of t h e s e s u b s t a l i c e s im~st also b e r e d u c e d . A d d i t i o n a l l y . since K + is secrcle(l in exc| ,!ilge h)r N a ~, a decre~tse in t h e a m o u n t of N ~ re~chii~g t h e dist;d h d ~ d e w i l l ( I n m m s l the i n ; ) x i m u m rate of e x c r e t i o n of K ~".'~~ In d i s e a s e statc~ c h a r a c t e r i z e d b y s ~ t i u m :rod w a t e r ~-elentiou, twt~ [i~ctors h a v e I~_'en p r o p o s e d Its col~tributiitg to i, r e d u c t i o n in the r;Ite o f d e l i v e r y oir s o d i u m a n d w a t e r to t h e d i s t i i l ,s;. (gm~:~nt. • . - ( a ) a d e c r e i l s e in the n d e of g l o m e r u Iltr filtration p e r r!epliron; c~nd ( b ) it p r i m a r y i n c r e a s e in p r o x i m a l rciibsorption of slllt aitd ~vitler. t~,l'l 1111) Sigllificiiilct: Ot" thes¢~ mecharlisms ill hyl~o-osnlotio slatt~ wiU be discilsst, d i~ il l i l l e r sl~,~lJl)il.

llyl~o,~o.~ttotic Statc~" in Patictits frith ColJg~!it~e lh,art F.ilurc Evidency." has b e e n presenlt'd t h n l b o d y ostnohlliiy ;rod scnmt sodi~un t ~ , l c e i t l m l i o n s ~lre a fi~jietion of b o d y ,-;odium, potassium and water, \Vt, art" ltware of no fllciors in t.,oxigrstivc t/eart'faihln~ w h i c h w o u l d ~ller t h e s e rellllit)nshiFlS, ltl t h e five hTt)tinlllreInlc l);dir~lls w i t h heart dise;l~-(, r('porh:d b y Hdelm a n el M., ~: who, re N a , vtirivd from J i¢4, Io I~0 m E q . p e r Kg. t}f water, g r . ) d

NA, K AND

II20

IN ItYPO'OSS|O~C

STATF4-; O F

97

litEART FAtLUBE

a g r ~ . r n e n t w a s n o t e d in t h e d e p e n d e n c e o f = ' . a n d N a , o n ( N a , + ~ ) / ~ F B X V . O n the basis of p r e s e n t e v i d e n c e , therefore, h y p o - o s m o l a l i t y in c o n g ~ t i v e h e a r t f a i l u r e c a n b e i n t e r p r e t e d as a r e d u c t i o n in t h e r a t i o o f t h e s u m o f o s m o t i ¢ ~ d l v a c t i v e s o d i u m a n d p o t a s s i u m to total l x ) d y w a t e r . A ingly, three m~hanisrns for t h e p r o d u c t i o n o f h y p o n a t r e m i a J n a y l:,0 e n v i s i o n e d : ( a ) s o d i u m d e p l e t i o n , ( b ) p o t a s s i u m d e p l e t i o n , a n d ( e ) w a t e r e x c e s s . In a n y o n e e a s e t h e r e t h a n o n e o f t h e a h n o r ~ n a l i t i e s m a y acc~0unt f o r t h e h y p o n a t r e m i a . A n e x a m p l e o f t h e c o r a l ) ! n e d e f f e c t s o f pota~usium loss a n d w a t e r g a i n is shoxvll in r u b l e 0. ~-~ c l a r i f y t h e i r role~ in t h e g e n e s i s of | a t ~ m i a in ct~i tire heart failure. however, the three mechanisms may be ~nsidered separately. S o d i u m d e p l e t i o n . - : T h L ~ h a s o f t e n b e e n b l a m e d as t h e e a t | s t e l l i y ~ n a t r e m i a in e d e m a t o u s c~lr(liacs i n w h o m Na~ falls d u r i n g t r e a t m e n t w i t h a l o w salt diet and (litireti~. In the patient with generalized edeloa, however, total l~dv s o d i t i m is r a r e l y if e v e r d e c r e a s e d , i n t h e s t u d y b y E d e l m a n 7 ( s u m m a r i z e d in table 3). the av N a . in e d e m a t a ! i s , h y p o n a t r ~ 2 m i e sub~ects ( N a , < 130 m E q . p e r L. ) a n d in e d e m a t o u s , e u n a t r e m i e s u b j e c t s (lid tint difl'er s i g n i f i c a n t l y ; in n o i n s t a n c e in t h e h y p o n a t r e m i c g r o t t p w a s t h e Na., less t h a n o n e s t a n d a r d d e ~ ' i a t i o n b e l o w t h e n o r m a l m e a n v a l u e . E v e n in t h e c a r d i a c w h o h a s b e e n r e n d e r e d e d e m a f r e e |~" t ~ : a t m ~ t , t h e N a . t e n d s to b e p e r s i s t e n t l y h i g h . *z-*~ T h e o h s e r ~ , a t i o n t h a t h y p o n a t r e m i a in e d e m a t o u s c a r d i a c s ~ l n at time.,; Fm reversed by vigorous diuresis of sodium and water also speaks against sodium d e p l e t i o n as t h e c a u s e o f t h e h y p o n a ~ e m i a . 'r' T h e a d m i n i s t r a t i o n o f s o d i u m salts t o t h e e d e m a ! e r r s , h y p o n a t r e m i c c a r d i a c , w h i l e o c c a s i o n a l l y h e l p f n l , u s u a l l y Ls o f n o b e n e f i t . *~-r"*-~i In t h e first r e l m r t to call a t t e n t i o n t o t h e p h e n o m e n o n ' o f h y p o n ~ d r e m i a in c o u g e s t i v e h e a r t f a i l u r e . r e l i e f o f t h e a z o t e m i a a n d o f t h e c e n t r a l nervot~s s y s t e m s ~ n p t o m s w a s a c h i e v e d w i t h h y p e r t o n i e s a l i n e . * A t h e r a p e t l t i e r e s p o n s e to s a l i n e , h o w e v e r , d o e s n o t prove the existence of sodium depletion, since the sx'mptoms of pure water i n t o x i c a t i o n ( n a u s e a . v o m i t i n g , c o n v u l s i o n s a n d c o m a ) also r e s p o n d p r o m p t l y t o this ~ t r e a t m e n t . z X'~iglat g a i n p r e c e d e d t h e o n s e t o f s y m p t o m s in S e h r o e d e r ' ~ cases¢* s u g g e s t i n g t h a t w a t e r r e t e n t i o n e o n t r i b t i t e d t o t h e d e v e l o p m e n t o f t h e In e s s e n c e , t h e mcx5t r e l i a b l e i n d i c e s o f s o d i u m n e ~ t in a p a t i e n t a r e t h e ysiea] a n d e h e m i ~ t l s i ~ s o f h y p o v o l e m i a ;anti d e h y d r a t i o n r a t h e r t h a n T a b l e 2 . - - S e r k ~ l C h a n g e s in S e r u m S o d i u m Concentration a n d B o d y C o m p o ~ t on tn a P a t i e n t with Hypertet,slon a n d Chronic C o n g e s t i v e H e a r t F n i i u m e |

Dat~

8 .~30L56

CIinteaI ~tat~t~

Weight

K~,

m~%

o

v mF2Q.

T|tV¢ L.

7 B ~'~ mlv~./L

a m Ir~./I,.

. t mtr~tm.~,.

2¢-

48.B

?~t~6

17~

31.B

I5 ! .9

l ~.5

~5~.4

,19,8

37M

1211

,37.8

131.6

117.8

~,0

~cma

10/1956

2-~edema

Differences: ~ i .2 4 " ~ . - 8 --5~) ~6.0 --5~,3 "Data taken frt)m Edelman et a|, t2 ~Coneentration in last ,3 cohmms expresse~| !~'r liter el ~mter.

"~.9

--48,4

t)8

NfAI"I,'I/~'. A N D t;;l~)l.;t,~iAN

"F~lb|e a . ~ T h e Relag&~n.~hip Bctwee)) Edc)na and Excha))geabI~'~ i)ody Sodiuna (Na,)*.

No~)l);tl .|;:lh:',l~llit~nlS

,~.14 ~'3.:)

/> 1 ~ [~5 135

4 t,4:4z *|.E G f L 8 "A:; 8. I

h y p o m l t r e m i a per se. it few wvl!-clocumer)ted cases o[ sodi~)m-del:)|el ion -hv:)mmlremla iJti patt~,.ts 'IviOi heart /aih.-e hay(. been ri:l:),~rted." 1 . (:mr exper: ie)w(*, lmwt?,:er, 0f.t|le t h r e e mail) factors determiIfi~)g Na~, isohlted sodium l()ss i s l)~ far ihe.h?ast fre~ ui;))t calls(.-(ff hy|lOi)i~{TetI)ili; I t has also l)(.,en. Woposed t|)a! hypo'mtlr('mia m a y develop as n d i r e e l ; ¢ o n . seq~tence j~t" h)tr~le~l|ulat mi~ra|ion or si.'qu(!,.'stratio)~ of s0dimn. :,~,~'a This poxtui ) late, lmwe.ver, lacks a d e q i m t e ¢×per)melltlit "tlslt))t)rt, 7sin(~¢ , t|)(: '~vii|(,'r (_:()lltt~l)| ()f isoh~|t,~d tiss))es is pr()l)ortior)ate t(-, s()lul(: c()))t,r)it am! more. specifically to the conhm! of sodh.))' plus pot.lssiuin.-., "" "~':'~ S l l d i l i r i l c o . l d (mi(.')" " the cell hi two l i ~ . ( a ) with a i ) ( x l i i i v a l e l ) i q~iil))iity '(.)f alliOi), ill which ease water, wol)Id [O|low. Ic~)ving ))o )mr elmr)gt, J)) Na.; or ( b ) i)) (vichang(., f,)r l?)()h:~ssii)m, which v,'onh:l rvq).)ire (,,|tiler u rise i~) K. cquld to !he fall in Na.~. m~ vve,)t w|)ieh is 1}ever rcli|iz¢'t| ¢-]l)l)(ail'). " " ' ' ' ¢,x~.reiio)) of |)OtasSiUln ill lhe )irine. ' ' . . .Of. l Iie ~l):al)tllalJ~,,(: I)) the h a t e r i¢~sta~m(,, the |iyp~malron)ia womb! correlate x~ql|) the loss of potassi,m. l ) o t a ~ x i u n l d e / ) h : t i o t t ; , . - . - A s in m)) oihfyr mi~jor illness, chroi~ic e¢mgestive | w a r t faih~re iS i-itlt~)~ii~d I~'~ It fall h') body. |)otitssi)ml lind a rise i,~ l)odv sodium a n d water2 <*" |i) c'ardiaes, the n l i l g l l i i i l l I e Of |he" Nil,, izll(| ;I'B\V correiat(:s with Ihe m a g u i t i M e of the t.dema. )~, *" T h e (|lu,slion., ~,,a b~st,~e, tlmre[ore, is w h e t | m r s,dee,five loss of p~)tassium is a p r i m a r y factor in the d e v e l o p m e n t of h y p o n a t r e m i a in cardiacs. In congestive h e a r t Milure, se eral factors might c o n t r i b u t e to potassium loss of a kind w h i c h evokes a s u s t a i n e d h y p o - o s m o l a l i t y : nnorexia a n d the att e n d a n t failure'~ of potassium intake, sometimes complicated by vomiting or d m ~ l m a : secotl¢l~lD: Iu¢perahlosteronism; and. in particular, u s e of diuretics. l l y p o n a t r e m i a e f t e n ~W,l)ears after t)rolongc(t diuretic therapy, usually in as.aoc),dmn'. " ,,,-ill) a fail, ire to di,lr, e'~.~,":":'~"~* AI)untl'a)-)t (,vidence mcheales" " that most effective dmretm, s incrvase t)rimu T excr(.ti(m of pota.,~s))im; iu refravtory patients kaiiiiresis n)av. Ix"e e e d ))atrl,rv resziltx from .loss of Iml~)ssi)im, lleeause l)ota:4simn depletion m a y ( I c v d o p i n s i d i o t l s l v llll(| tvit}lOllt II el)llt'onli~il)l| fa 1 ill K . , its p a r t i c i p ; i t i ( ) ) ) it) t h e p a t h Og(', rl ('S iS 1-)f l )y l)~)l )a I r(,'! l') ill is (),as i I.v ( )v erlo(')k ('( I.

A mm~|)er of insla))ces .of l)Otltssi)))!)-d,'ph'tio)) hy|)o))iilr(.mia have l)(..en .d°e'. till|I'll|eel. Th(? (lilIil ¢))1 o l w Silt*h eIls(:. ~tr(" ~Ili)l,¢n ill I l l | l i e E: a i l i | j t i o ) ) i i l i?xlillil)]~.-;

hlv¢(" l)('('*) g i v e . l)'v ~Vilson (:t al: ~" It i.~ i))lvresli~L"g Ih:it ih =)),)st of these eases

S A , K A N D I ! ~ O IN I I £ 1 ~ O - ( ; ' S h l O I ' ! C SI'A'II~.S O F

| I E A H T I;'All.lJtll~;

~-~)

w a t e r r e t e n t i o n a e t ~ m l ~ a n i e d p o t a s s h m l loss. r a i s i n g the p o s s i b i l i t y tim! t | J e s e e v e n t s a r e p h y s i o l o g i c a l l y i n t e r d e l ~ e n d t , nt. P o t a s s i , u n loss m a y b e m a n i f ~ ' s t e d b y a n y o f t h r e e s e p a r a t e c h e m i c a l a b n o r m a l i t i e s , iw... h y p o n a t r e n a i a , h y p o k a l e l n i a or met~d)olie a l k a l o s i s , a n d in s o m e instan¢~es b y all thr(a~ s i m u l l a m ~ ) u s l v . T h e d e v e l o p m e n t o f m e t a b o l i c a l k a l o s i s as a c o n s t ~ l U e n c e o f p o t a s s i m n loss s e e m s to d e p e n d oil w h e t h e r s o t l i m n is r e t a i n e d sinudtimet)~lslv. :'~.'~ E v i d e n c ~ h a s alsc~ b e e n p r e s e n t e d t h a t in p o t a s s i m n d e f i c i e n c y , c h a n g e s in K. dtq~end strol~gly o n t h e a s s o c i a t e d c h a n g e s in e x t r a c e l l u l a r p l l ; n t e t a b o l i e a l k a i o s i s a g g r a v a t e s t h e t e n d e n c y o f K. to fall, w h i l e m e t a t > o l i e a c i d o s i s t e n d s to r~~ise In e x p e r i m e n t a l p o t a s s i u m d e f i c i e n c y , h y p o n a l r e m i a has i~ot bcx, n observk~l. p o s s i b l y b e c a u s e rec'iproeal s o d i m n r e t e n t i t m maid,rains i s o - o s m o t i c c o n d i t i o n s ? v-'.'m i n cardiac's, h o w e v e r , a l o w s o d i u m d i e t xvo~dd prt~'elud~, rete~atit~c~ of s o d i u m in p r o p o r t i o n to loss o f p o t a s s i m n . ( ; o n s e q u c n t l y . h y F ~ o n a t r e m i a w o u l d r e s u l t m f l e s s a n i s ~ - o s m ~ t i c q u a n t i t y o f w a t t w were' lost w i t h l)Otassimn. O b v i o u s | v . w e n e e d to k n o w c o n s i d e r a b l y m o r e a b o u t t h e r o l e of p t : t t l s s i u m i~ t h e p a t h o g e n t - s i s of h y p o ~ m t r e m i a in h e a r t f a i l t l r e ill,it the; p a t h w l t y s i~w¢flved. Water r~ffctlliotl.--A w~,alth o f p , b l i s h e d d a t a h a s s h o w n t h a t w a t e r r e t c h lion, o f t e n in the-. a b s e n c e o f f r a n k e d e m a , is a ,~rt'~l,ent c a u s e o f lLvl)~matremia.~-r'".n~ F r a n k g e ~ e r a l i z e d e(le~na a t , e o m p a n ) ' i ~ g h y l ) ~ m a t r e m i a constit~/tes prima [acie evi(lenc~r o f a n ex~-ess o f w a t e r . ~ T h e role. of w a t e r in the p l d h o g c - n e s i s o f h y p o n ~ t r e m i a i~, p a t i e n t s in h e a r t f a i l u r e h a s bee,~ e h ~ c i ( l a t e d b y a n m u l > e r o f stutlit,s. T h e e×perim~,~flal produc-tion o f p o s i t i v e w a t e r b a l a n c e in patterers in ht:,art fi~ilure b y w a t e r l o a d i n g ~,~d b y a d m i n i s t r a t i o n o f p i t r e s s i n r e s u l t e d in t | ~ q ) o n a t r e m i a ? ~**;'~ C o n v e r s e l y . thor ind u c t i o n ~ff n e g a t i v e w a t e r t)ahu~re i , exc-trss el r ~adion loss in h y p ~ ; n : , t r e m i c c a r d i a c s b y rt.strictio~a ~ f w a t e r i n t a k e , v i g o r o u s m e r c ~ r i i f l t h e r a p y or osn~t~tie o r a l c o h o l d i u r e s i s r a i s e d Nit,. d e s p i t e a n e g a t i v e sodi~|m b a l a n c e . *~''~°-*~7 A d t l i t i o n a l l y , p a t i e n t s in h e a r t f a i l u r e e x c r e t e a w;~ter l o a d s l o w l v f i " i n clinitud confirmation of t h e s e e x p e r i m e n t a l o b s e r v a t i o n s , V~'eston e t al. e~sd o c u m e n t e d t h a t h y p o n a t r e m i a w h i c h b e c a m e m a n i f e s t d u r i n g a w o r s e n i n g o f heart failure w a s c o i n c i d e n t w i t h a s p o n t a n e o u s r e t e n t i o n of water: w i t h i m p r o v e m e n t in cardiac f u n c t i o n , u r i n e o u t p u t i n c r e a s e d and N a , r o s e t o w a r d normal. T h e m e c h a n i s m s l ~ d i n g to a c c u m u l a t i o n o f w a t e r i n e x c e s s o f s o d i u m a n d p o t a s s i u m h a v e rec-eived c o n s i d e r a b l e a t t e n t i o n r e c e n t l y . I n c r e a s e d A D I 1 a c t i v i t v h a s b e e n i n f e r r e d f r o m a s s a y s of u r i n e a n d s e r m n a n d f r o m t h e d i u r c t i c r e s p o n s e to e t h y l a l c o h o l . ';~'-'~-r*~ A s s a y s for A I ) t t . h o w e v e r , havre b e / ' n eritieiz,_~l o n t e c h n i c a l g r o u n d s , a n d altx~hol, a n i n h i b i t o r o{ A 1 ) I I . h a s n o t c ~ m s i s t e ~ t l v i n d u c e d a w a t e r d i u r e s i s i n h y p o n a t r e m i c c a r d i a c s , r~-7~ B u c h l ~ ) r n . 7z u s i n g t o a d a s s a y , f o u n d n o r m a l A D H a c t i v i t y in t h e s e r u m o f p a t i e n t s w i t h d ~ r o n i e h e a r t fail'ure, l n i l w h e t h e r h i s s e r i e s i n c l u d e d h y p o n a t r t ; m i c p a t i i . n t s is n o t ell'at. T h e i s s u e o f thor p a r t i c i p a t i o n e l A I ) l l in ,,vati~r-ex~x'.,~s h y l ~ n m t r e m i a is t h e r e f o r e sttb/tulhr¢" at t h e m o m e n t : its r e s o l u t i o n a w a i t s h ~ r t h e r a n d m o r e r e fined s t u d i e s . t l e m o d v n a m i t " o r h~.'ai r~,n:zl f~lclors m a y l~" iml~rt,z~d in t h e p a t h o g e n e s i s o~ dih~tionll'l" l|yl~o~idremi;! i~ h,.itrl |aih~r~,. As m t . n t i o n e d l ) ~ ' v i o t l s l y , rt-d~,ction

![£~

'~tAFFLY AND EDI~;L:~I[A2-N"

p r 0 p o g e d as t h e basis f o r ' t t i e retention Of Wate r in hypomitremie cardiacs. 7. T h e mfirked increase w,~ter excretion after administraticmlof osmotic dire:reties to s . e h patients provides Sdme support f o r this~. postulate. ~ l " h e r a p e u t w P r i m zO~les i n t h e ~ t a n a g e m e n t o f Patte h's tvith H~v~ol~alremia a n d C o n g c s t w" e t l e a" r t F"allure " '

I n t!~e preceding sections arguments t!ave been Offered to Show that hyponatrcmia arises heeausc qf a: d e c r e a s e in,the ratio o f osrnotieally active ~sodium p l u s p o t a s s i u m to total b o d y , w a t e r . I n : m 0 s t patients with congestive heart f,dh,re )sodium i s pr6sent in excess s o that t h e strate, gy, o f thera!D' should be directed toward reduci1ig/b0dy water and s0diml~ a n d increasing b o d y potassium. U n d e r the following circumstances, however, h)l~ertonie s a l i n e often is needed Or is o f s o m e benefit: ( it ) circulatory. t.oI • Iapse manifested by hypotensio~i, taehvCardia., and peripheral ~ , a n o s i s , presumably reflecting hypoVotemia,or ei'trdiogenie Shock; ( b ) d e l i r i | i m , dOIIVII|SiOIiS, or fi-ank coma re: sulting~from, severe0 hvDo-~v~molalitv,... , ~ since d e a t h may. ensue, in. a. few hours; and ( e ) sodium and water tie letion, w h i c h occ,|.lonally appears in heart failure Owing tO dimThca, vomiting~, excessive sweating or renal salt wasting. In almost all other ~ r e u m s h m c e s saline is.of no awdl and tisuatb¢ is harmful. T h e tactics of therapy must take cognizance of the clinical status and the ancillary disturbances in the individual patient, and, of course, every effort must tm m a d e to improve c a r d i a c function. If hyponatremia is mild ( i . e . Na, > 130 m E q . per I , ) and asymplomatie, im specific thenlpy need 1:-2 employed. For pntients refractory to odiuretics, as well as for those with symptomatic hyponatremia, a therapeutie program designed to rc.duce body water , nd raise body potassinm should be initiated. Bedm:tiot~ ~ b e d b, w a t e r . ......q lie simplest m e t h y l of producing a negative wltter balance is to r e d . c e water intake to less ? h a n o n e liter per (lay. Also. a water diur,mis may b e prodneed b y administenng osmotic dmretlcs, r" These agents have the disadvantage of tending to expand pla. nm volume, but they may prove useful after further study. A limiting factor in the use of water deprivation it, tim treatn|ent of h)l)onatremia is tha! some patients become thirsty when Na. is sti!! low. In some eases, however, even a modest n.'s,., in N a . will restore sensitivity to diuretics; following a succe.~sful diuresis the c~rd ae stattts m a y improve stt~ciently to obviate the need for further restriction of A d m i n i s t r a t i o n ~q p o ~ M u m . ~ l f K, ix low, administration of potassit, m at a rate of I00 to ~41 m E q . per day, often rat. • 's es Nil. ns well as K. and m a y re~tore sensitivity to dluretic:~. E v e n ill patie~tts who are not hypok;demie, potassimn therapy may be of substantial benefit, ~.'~r,a~ ~ e major contraindi~,dions to per l,, and the presence of p o t a s s i u m s u p p l e m ~ t t a t t o n are a K. > 6.0 n aLq. : recta|relic acittosis. ~t Since potassilm~ deficiency may contribute to reduced t~rinarv olttptlt, ~,*~ w e consider oliguria a relatt~r rntiter t|mn an absohtte eor~t r a l n d t e t t l t o t l | 0 Sllpplt~'lnelltilt|(~n ~.vJth I-~ota. Sllttll.

;,;A. K AND } l v O iX !iYPo-o~2~i0Tlc Wr;J'l't~2~ {)V I I E A l r i ~ F ^ liA~aE

101

A t prcsetlt:addl~ona] d a t a lift-~ ll~,cded to {leOne the ((xtelit and role o f potassi(ml d e p i c t i o n ill tile hyi>onatren.lm o f h e a r t failure. Particillarly£ w e ile(;~{f tO knOw in w h i c h l};{tientS....W(~ eali confi(l{,,lltly l}rUdictiin, provement;,, f o l l o w;i n,'g a
t}y the potential t}eliofiis of p{}tassiunl therapy; REFERENCES 1. Welt> L. G.: Edema and hylmilatreinia[ Arch. liti. Meal.:89:931, 1952. dmnges ~Of r~|a~ma-ok~trotytc levds "2~ MVynn, V., and. t/oh, C, (.,~.; Water* iaioMeation: Differential {ttagl]o~i~ of 1957. ilic liyDolonic sylil|rOliiCs> ]~iillC[,I I: , 12. E d d m a n , 1. ~8o. Leiblnan, J., @Mearlt, 5 8 7 , 19,~l. M- P-, arid Birken|cld, L. XV;; Inter3, %V~,ston, ] L E., ~seli¢.r, l ) , j . %V., G r o s s relations lJ¢.iwc,-n .~t.rmn ~ l i u m ~ n . iililn, J., a l l d Leficr, L.: }t|qt~hilrlj$11lS {:enlr>ltion. sertmt oslnoladty and tolaI cont~l}uting to llnr¢~t}olisiVclles$ tO c.xehal~g~lblP sc~linm, total c x c h a n l l ~ niercutiat diliretlcs iit cxlngeslilm failable p{}tasMtltn and tolM l~dy walex. ure. j. Clln. lnvt~st. 31:{Nil, 1952, ]. Ctiit£ hivcst. 37:1~36, 19519+ 4, Schnieder, }I. A.: Renal failure ass{>. 13. l h l r v t ~ ' , E. N,: Tcllsion a t the tx,ll slltciated ~+vithli}tv exli~acelhilar ~)dililii fact,, l'a}iophisnmto|{~gia ( Vielma } chloride, qtte Iow salt syndrillile, J. 2(155 } :1, I95,I. ,A..%I.A. 141:117, 1949. 14. Robi~soth J. R.: ~lt.lab0|isin O[ liitTa¢~l5. Ci(riin, t).. lh'rcil, B+, Lt'lniiil't, llo. lular wal(% P h y M l i L llt,v. 40:112, and Massie. E x Conge~t!ve ticarl f;iil1.gf~}. IS. {2oliwity, E, J+, an{t Mcl2oInlaek, J. I.: ltrc aild hyponatretnia: Uillo~,l~trd effects o f mercurial diur{$is. Alln, lnl, Tli~k total inlract.|hilar {lincentrtttlon Mcd. 34:872. 195I. l}f tittinllil;ili;tn li~$tic~ ¢~}mi}an~i ~ t t l t 6, Uricdlitt, J. F., and CMell{ta. I), G.; thai i l l tile exlt~{~-llillar ~llhl. iT h e futlure iff hypt;rtonic saline ill the Phy~i{tl. J : 0 : l , 1!}$3. Irt:iitlilent ill h)'pi)nlltrt-iliia illld ¢~iiPlll;t IlL J l l t i<~lil,/,nn, J. XV., tir{~t>ky. W. A,, Tu{hi ci)ngt, sli~;{~ ttt~tll liiilila,. AIili. llil, it,-, V& S., aim I}ialtmnd. I.: 11t~Mt, d. 39:1~'18, 1:d53. fft~{~zing lW~iiil dcpre~it}n of tllalli7. EdlJnliiii, I. S.: ~ t e 1)aihol~eilesil of |i)T}Oliilltt'llii;!; PIIyMoloNic lilid tlwralmtling di.
]02

~,.[AFFLY A N D EDEL~tAN J: Physi01. I94:3(~3, 1958.

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84. ~Vl~son, L - ( ; L J r , , m,d Anslow, ~V, [L; Jr,; ]leIationship o f c h a n g e s in .glomeiolar filtrat!0n:,plasma ehkwide a n d b i c a r b o n u t c cbneen{rati0ns a n d . u r i - . nnQ¢ osmotic load to renal excretion tff chloride, fAn,.: J , Physiol. 180;237, L955, 35. Bartter, F. C . , x.lills, I. t.L. B i g l i e r i / E . G . al]d I)ele;i, (L: Studies on the conof aldostrol a n d i}hysiol{}gic a{Amn " "" t¢~rol}e. R e c c n l Progr. 1l o r m o n e Res,. 15:3 ] 1 , 1959. 86. lrarr¢ll, G.: q ' h c 1}tWs!ologica[ factors w h i c h infl,,enee t h e / s e c r e t i o n of a l ¢lost{.~rone. Recent Progr. H o r m o n e Rcs. 15:275, 1959. 37, Bartt!-r, IV. C.: Th{~ role of aldostcrone in n o r m a l homeostasis a n d i,} ct;rtain disease state-'~. Metabolistu 5:369. 1956. 38, J o h n s o n , |L B., L i e b e r m a n , A. H., a n d Mulrow, IL J.: AIdosterone excretion in normal suhjects deplete{t of so{litm} a n d p{~tassimn. J. Clin. Invest, 36: 757, 1957. 89. Vet~my~ E. tL: T h e untidiuretic horm{mc ~m¢l t h e factors "w h i c h {h,lermine its rolvase. Proc. Roy. Sow,, L o n d o n . s.]] t,]S:x~), 1947. •l(I, Ander:~s(m, B.: Polydipsia, antidiuresis ;rod milk vjcx:tion eaus{,d by hypoIhalamic sthn, datiom in T h e NeurohypophyM-~, i lelIer, I I., ed. N e w York. Atvt(temie l'r~ss Inc., I957, t]. 181. 4I. la:~If, A., a~,d 3 I m n b y , A. R.: A n anti(Iittrctic mecbar, ism not r e g n l a l e d b y t~xtgtcellular fluid tonieity. J. Clin. Invest. 31:61), 1952. •12, Ih,nB... J. p., Gauer, O, II.. aml Reew~, J, L.: E v i d e n c e o[ the atrial location eft receptors inl[uencing urine flow. Circldation lies. 4:8,5, 1956. -t3. Cottselmlk, C. "~'., a n d XlyIle, M.: Micropnnet~tre s t u d y of t h e m a m m a l i a n urinary concentrating medmnism: E v i d e n c e for t h e ¢ot mlercurrent hyl~)lht~sxs. Anl. J. Physiol. 196:927, 1-959, 4"I. Ih'rltn(,r, R, "~V.: Ion exchange m e c h a nisms in t h e n e p h r o n , Cirenlatiou 21: 892, 1960. 45. Berliz~er, R. ~V, a n d i)avi~[~nn, l}. C,.: t'rodllction Of h ) ~ c r t o n i e tit/tie h | t h e |~bscnee ol l}iluilary an|klharetitr }u]rnlone, J. Clin. Invest. 36:1,110, 1957,

NA, K.:tNt} i,i,~o j ~ t I Y P o - o s M o T t { " STATi'~ OI: liEAitT I~A.li.t~ilE

46. SctiedI, 1L P,. and B a r t t ? r , F - C . : Ati exi>lanati0ii f o r itItd experimental correcti0n {ff theL~tblionxm| water distr,:Ms in cirrhosis. J. Ciin. I,lvest. 39:2-t8. 47, 1;'arber, S j & ' a n d Sol~m,mli, R- J.: Total b M y ~ t t e i and "total exehangeablt} s o d l . m in' edeltlaa}t|} .~iates title [o cardiac, rcbal or h o p a t i e disease, J. .Clin. htvest. " " "t8. Birken~ek|, L; w . , , L d b m a n , J.,~.O" Me;ira, AL IL, ' a n d l~deinmn, I . S.: Total exchange;ible sodlmn, total exdi!mgeali]e l~tlts~im~] .im{t total b o d y w a t e r ill e d e n / a t o u s patter, ix with Ci~llO'SiS Of tile liver and "cotigestive heart fai|ure+ J . Ctim Invest, ¢:~a~, 1958. 49. Itnbin, A. L., a n d 'Bravetnml~ %V: S.: T r e a t m e n t of the low-salt s y n d r o m e in congestive h ~ r t failure by tile colttrolled u s e of mercurial dinretk~% Cir{ ~ culati,.m 13:655, 19a6. 50. ~%,fls{.n, {;. :xl., Edehtm,i, I. S.. Brooks. I.., Myrden, J. A., ilarken. 1). E., and ~xloore, F. 1).: hletabiflie changes a s s¢~qated x~Sth mitrid valvuloplasty. Circulation 9: 199, I.{J~54. 51. Bruce, R. A., 51cr,endino, K, A., l)mlning, M. F., Scri|mer, B. i l., I)olt0h u e , I).. (,urb'cn, E. R., a n d C t m w rnins, J.: {}l>servalions Oltl ll)?tloltiltretnia f,dlowing mitral valve nnrgery. Sitrg, C,y:/cc, & (}bst. 100:293, |,t}88, 5~.. LlqlPr. I,., ~Vestt}lt, R. 1:2, an(1 (~ro~sIllttIl. J.; "l~le Io~a" si}dJlliII sylldrolile; tt5 origirts an{l varieties, lh,ll. N e w York Aca{I. Med. z9:STL 1953. 53. Jaenike, J+ II., and XVaierhoilse. C.: Brady ~uid alterations d u l i n g the kh-.'e|op~nleitt of and rt'eoveo" fr, mi hypoIlatrelliia ill ht
2.8:862. 1959. 54. jaife, It. L , Master. A- XI., and t.~rran¢¢}~ %V,: T h e salt depleti{}l~ s)'ftl irollle folleBvili~

tlllfrt*urial

distil,sis ill

elderly Ilt.'r~{lliS, Ant, J. ;%I. Sl;. ~ 0 : 611, 1950. 85. Sctm;trtz, %V. B., and %Vallaee. %%'. M.; E l e c l ~ l ) ' t e e q , i l i b f i u l n d n r i n g ili{*reiirial ditir{~t~, J, Clili, ln,¢e~l, ;DT): io8,% i.{}5i, 56. l:riedbt:rg. C. K,: T h e use of diurelies tit hearl disease+ Ill Diiire.~e IL [)i* lirvlira, illt¢}lbotn, I{. and ltfmk, K.

]03

D , c d s ~ ~Berlin, SprB~ge.r~\:eHag, 1959,.

57. C~rL ~J . l I,. a ~ d Matlh¢:ws, ! L L : Pma~sim~ d61icibiU:w In Congc~,~ltve |i~nmfailure. ' ' ~as~.. irlik+n{ia, i n d n d i n g resttltg o f pota~-dtmt repla~.~tmlenb0 ~ll On0 ease. Laiu:et •J: 1202,, 195,1. ,58.. Laragh, J. !I[.' T i m eil{x:t [of |~mlSSim-l~ chlorid}~ mI' |iyDo|tatrpll~ia. J~-{[;lit{, l a ves}. 33:8(7, 195~1, 59. Mmltw) h.~r, F Grdf " ' i it, (k t:., .0 "rout. laeo; bellis,' M.: E f f e a t of ~ d i i , m ; .ehi6risle. a n d llOtasailitlt sltDplellWnti/lion; v¢i!l~ it|Ill %vit}lOitt !}iilll}Ol , 0i} /lltlsele_. colllpOSition' and renal' e l e c t r o t y l e exc're--i lion ] n eleCtr,/Iyte~depleled rats. AIIt2 J. Piivsit}l,~ 19S:347, 1,'L58. ~ ." 60. l l u t h , E , J.. S q u i r e s , It. 0I)., atid EI-kh!tott, J. !t.; Experillic'|ltnl " " F¢~iilssiIilii {leplcti0n in normal h m n a n st, t,jtxl:,,, II. Renat anti h i m n 0 n a l f a c t . r ~ h : r Ill(-. developmel}t tff extracellular Mkatosis during d e p l e t i o n . . L Ctim lnvi:st. 38: 1149, 1959. ~I. Lvibman, J.~ a n d l{delmim, I. S.: lllierrelations ~i{ Dlilsllla l~i|ilssilli:tl con-; c{*lllralioil, tilasnla Nt~Ii/Itll: ttllltl'lltrdIiOil, arlv~riltl DII a , d total ex{']ian~{:~ al]le potit,';siiitl}, J~ Clitl, Irtve.,~t. ,218: °ITO, 1959. 62. l}h,ek, t.'}; A. K.. iiittl Milne., M. 1}.: Exl!erhltvltlal lmtit~shint depl¢.lltm in ClIFf. St:. I1:397, {~3. Sqlfires, It. 13., a n d l l u t h , E. J.; Exp,~"imental p o t a s s i u m dH}let!o n it~ nor,nal h u m a n sut)joets. L Relation o f i{mic i n t a k e . 1o the renal conservation O~ i~¢)tas~ilIlll, J. C]itl. I n v ~ t . ~ : I l F M , 1959. 64. Ariel. I. M.: E l i , - I s o f a %~ier Mad atl2 miiiister~M to pat:ients d u r i n g the in}mtxliale t~StOl~rntive l~fi~.~t. ~ l n h ) ~ } t o n i e sylll]ronle. Atetl. S~,rg. ~'2: ?XI3, 1951. 65. %Veston, IL E.. t lane~r~o., L IL. Bonm. .H. R,, (,IX}Sstt an, J2, ttnd %V}}lftm~tn, M.: Pr~Mtletitm of w a t ~ retentl~m and ;i{'ll|e ]l}'l~lliatYelliiil l['it||OlJt ~,{lium loss by admln|stralion of l~tr-c:.~.~sin Tanna te tO patienls ~ i a ~nge.~fi~-e . h e a ~ failmre. J. Ciin{ l n v ~ t , 31:tt712, +

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1952. 88. ltane/istm. I. IL, Golul~fff, IL, Grabsman, J.> %Ve~,ton} R. F;{, a n d L~terr.

104

IAI: FLY AND EDEL~IAN L;: Shtdtc~s ~m Water excre~on following tn{ravemms: hydration and the ~idzMrdstratj0n pttress:in or nico: tine ffl" congestive heart f,'~i|iire. Ci'v Cu|atlm~ 13:24~, 195a, ~rd~ugi~, tL V.~ :Jr.: ~d~m~on of ditir¢*sis i n hypona|remie edematous states ~ith a!¢~h0L J..Clin. lnv~t:

hormone. :Ph~iol, Rev. 38:169, 1958. 72. Lamdiu, E;,Kleeman, C; R., Rubini, M~..

diuresis. ]IL T h e to "ethyl Mcohol-in certain d i ~ t s e ~tates ehav act byi~filired water tolerance. J: Clin; Invest. 35:386, 1956. 7& Buehb~,'n, E.:? Vas0pressin .and Odem~tstehmag. Dedtsche me
ROy 1t, M , M.D., ttesearch Fellow it~ Medwme and Clinical l~mtnwtor i~ Medwme, umve ~nty t~f California School c4 Medicine. I. S. Ldcl na 3, M.D., Professor of Medwme and Physiology, Universily of Cah'[ornia School o/Medk'ine.