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BRITISH MEDICAL JOURNAL 23 APR IL 1977

PAPERS ANDORIGINALS

D e a t h d u r i n g recovery f r o m severe m a l n u t r i t i o n and i t sp o s s i b l e r e l a t i o n s h i p t o s o d i u m pump a c t i v i t y in t h el e u c o c y t eJOHN PATRICK

B r i t i s h M e d i c a l J o u r n a l , 1 9 7 7 , 1 , 1 0 5 1 - 1 0 5 4

SummaryThe l e u c o c y t e d a t a on f o u r malnourished c h i l d r e n whod i e d s u d d e n l y when h i g h - e n e r g y f e e d i n g was s t a r t e dwere r e t r o s p e c t i v e l y a n a l y s e d . The pretreatment rateconstant f o r sodium e f f l u x i n l e u c o c y t e s was h i g h e r a n dt h e i n t r a c e l l u l a r sodium c o n c e n t r a t i o n lower i n t h i sgroup than i n 1 3 malnourished c h i l d r e n who recoveredu n e v e n t f u l l y w i t h f e e d i n g . Two o t h e r c h i l d r e n withunusual l e u c o c y t e e l e c t r o l y t e v a l u e s a n d sodium pumpa c t i v i t y were i d e n t i f i e d a n d c l o s e l y monitored whenh i g h - e n e r g y treatment was b e g u n . They r a p i d l yd e v e l o p e d t h e syndrome of e x t r a c e l l u l a r f l u i d o v e r l o a dbut were s u c c e s s f u l l y t r e a t e d with d i u r e t i c s a n d d i g o x i n .Though t h e p r e c i s e r e l a t i o n between t h e f i n d i n g s i n t h el e u c o c y t e s a n d t h e development o f t h i s overload syn-dro me i s n ot c l e a r , the pretreatment l e u c o c y t e v a l u e sare n e v e r t h e l e s s v a l u a b l e i n p r e d i c t i n g which m al-n o u r i s h e d c h i l d r e n are at r i s k o f sudden death whenr e f e e d i n g i s s t a r t e d .

I n t r o d u c t i o nL e u c o c y t e s f r o m m a l n o u r i s h e d c h i l d r e n h a v e s l o w sodiumpumps. Compared w i t h v a l u e s i n c h i l d r e n s h o w i n g c l i n i c a lrecovery, t h e r a t e constant f o r s o d i u m e f f l u x i s l o w, t he g l y c os i d e-s e n s i t i v e s o d i u m f l u x r a t e i s d i m i n i s h e d , t h e i n t r a c e l l u l a r sodiumc o n c e n t r a t i o n i s r a i s e d , a n d t h e i n t r a c e l l u l a r p o t a s s i u m concen-t r a t i o n i s d e c r e a s e d . ' 2 T h i s paper d e s c r i b e s s e v e r a l m a l n o u r i s h e dc h i l d r e n who d i d not show t h i s p a t t e r n . I n s t e a d t h e y h a d an

i n c r e a s e d r a t e constant f o r sodium e f f l u x a n d low i n t r a c e l l u l a rsodium v a l u e s . T h i s group i s a t r i s k o f sudden d e a t h d u r i n g t h es t a r t o f h i g h - e n e r g y f e e d i n g .

P a t i e n t s a n d methodsSodium pump a c t i v i t y i n l e u c o c y t e s was measured a l l t h e

m a l n o u r i s h e d c h i l d r e n when t h e y were on a maintenance d i e t .M e a s u r e m e n t s of s o d i u m p u mp a c t i v i t y - T h e l e u c o c y t e s werep r e p a r e d a n d t h e r a t e constant f o r sodium e f f l u x a nd i n t r a c e l l u l a rs o d i u m a n d p o t a s s i u m were measured as d e s c r i b e d . ' I n t r a c e l l u l a rs o d i u m a n d p o t a s s i u m c o n c e n t r a t i o n s ( m m o l / k g o f d r y s o l i d s ) can bem e a s u r e d more s i m p l y as f o l l o w s . L e u c o c y t e s s h o u l d be p r e p a r e d b yt h e d e x t r a n s e d i m e n t a t i o n m e t h o d . 3 The l e u c o c y t e s s h o u l d be washedw i t h i s o - o s m o l a r magnesium c h l o r i d e t o remove e x t r a c e l l u l a r sodiumand p o t a s s i u m and t h e c e l l p e l l e t d r i e d , w e i g h e d , e x t r a c t e d i n 0 1-Mn i t r i c a c i d , a n d t h e sodium and p o t a s s i u m c o n c e n t r a t i o n s m e a s u r e d .S i n c e t h e s o d i u m a n d p o t a s s i u m i o n s an d t h e d r y w ei g ht i n t h e f i n a ls p e c i m e n a re more t h a n 9 5 0 o i n t r a c e l l u l a r , an e x t r a c e l l u l a r f l u i dc o r r e c t i o n i s unnecessary. These a p p r o x i m a t i o n s l e a d t o v a l u e sw i t h i n 5 0 , , o f t h o s e o b t a i n e d w i t h an e x t r a c e l l u l a r f l u i d c o r r e c t i o n .

R e h a b i l i t a t i o n d i e t - T h i s c o n t a i n e d a r a c h i s o i l 5 5 m l / l and ap r o p r i e t a r y c o w s ' m i l k f o r m u l a , which p r o v i d e d 3 5 g p r o t e i n a n d5 6 MJ ( 1 3 5 0 k c a l ) per l i t r e o f f e e d . D u r i n g r e h a b i l i t a t i o n t h e c h i l d r e nwere f e d a d l i b i t u m a n d t o o k 0 - 5 - 1 - 2 5 M J / k g / 2 4 h ( 1 2 0 - 3 0 0 k c a l / k g / 2 4h ) .Four o f t h e c h i l d r e n d i e d when h i g h - e n e r g y f e e d i n g was s t a r t e d .T h e i r pretreatment d a t a were t h e r e f o r e a n a l y s e d , a n d two o t h e rc h i l d r e n w i t h t h e same p a t t e r n o f r a t e constants a n d sod iu m v a l u e swere i d e n t i f i e d . They were m o n i t o r e d c a r e f u l l y when f e e d i n g b e g a nan d s u c c e s s f u l l y t r e a t e d w i t h d i u r e t i c s an d d i g o x i n . The f o l l o w i n gcase r e p o r t s g i v e b r i e f d e t a i l s o f t h e f o u r c h i l d r e n wh o d i e d a f t e rt h e onset o f h i g h - e n e r g y f e e d i n g a nd more d e t a i l e d h i s t o r i e s oft h e two who showed t h e same s y n d r o m e b u t s u r v i v e d . Table I g i v e sd e t a i l s o f age, h e i g h t , w e i g h t , an d oedema r e c o r d e d on admission t oh o s p i t a l . The d i a g n o s t i c c a t e g o r i e s f o r t h e c h i l d r e n a re d e r i v e d fromt h e Wellcome c l a s s i f i c a t i o n . 5

CASE 1This c h i l d d i e d s u d d e n l y on h e r s i x t h d a y i n h o s p i t a l , when sheseemed t o b e r e c o v e r i n g . No c a us e o f d e a t h was found a t n e c r o p s y .

T r o p i c a l Metabolism Research U n i t , U n i v e r s i t y o f t h e West I n d i e s ,K i n g s t o n , J a m a i c aJOHN PATRICK, M D , M R C P , h on o r a ry c o n s u lt an t p h y s i c i an a n d W e l l c o m er e s e a r c h f e l l o w

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T A B L E I - A n t h r o p o m e t r i c d a t a a n d d i a g n o s t i c c ate g o r y o f s i x c h i l d r e n w h o d e v e l o p e d r e c o v e r y s y n d r o m eC a s e Age W e i g h t H e i g h t W e i g h t H e i g h t W e i g h tNo ( m o n t h s ) D i a g n o s i s ( k g ) ( c m ) ( U , , s t a n d a r d ( U , , s t a n d a r d ( , , s t a n d a r d Oedemaf o r a g e ) f o r a g e ) f o r h e i g h t )

1 1 1 K w a s h i o r k o r 6 - 8 5 70 5 7 1 9 6 7 7 + +2 2 0 Marasmic k w a s h i o r k o r 6 - 4 6 7 4 - 5 5 5 8 9 66 + +3 5 Marasmus 3 - 3 4 5 2 - 0 4 8 8 1 8 8 04 2 8 Marasmic k w a s h i o r k o r 6 0 0 7 9 - 0 0 4 6 8 8 5 6 + +5 1 7 M a r a s m i c k w a s h i o r k o r 6 - 3 5 7 2 - 0 0 5 8 8 9 6 9 + + +6 1 4 K w a s h i o r k o r 8 - 3 0 7 3 - 5 8 0 9 5 8 6 + +

CASE 2On t h e n i n t h d a y i n h o s p i t a l th i s c h i l d d i e d s u d d e n l y . B e f o r e s h ed i e d s h e h a d d e v e l o p e d t a c h y p n o e a , t a c h y c a r d i a g a l l o p r h y t h m , andd i a r r h o e a . N e c r o p s y showed a d i s t e n d e d b o w e l and no o t h e ra b n o r m a l i t i e s except t h o s e a s s o c i a t e d w i t h m a l n u t r i t i o n .

CASE 3On t h e e i g h t h d a y i n h o s p i t a l t h i s g i r l s u f f e r e d a sudden c a r d i a c

a r r e s t . I n r e t r o s p e c t a b r i e f a n t e c e d e n t t a c h y p n o e a was r e c o g n i s e d .

CASE 4T h i s c h i l d d i e d f r o m p e r s i s t e n t d i a r r h o e a w i t h gross a b d o m i n a ld i s t e n s i o n and g a s t r i c d i l a t a t i o n on h e r s e v e n t h d a y i n h o s p i t a l . Sheha d r e c e i v e d p o t a s s i u m s u p p l e m e n t s o f 3 0 m mo l ( m E q ) / d a y a ndmagnesium s u p p l e m e n t s o f 1 5 m m o l / d a y ( 3 0 m E q / d a y ) .

CASE 5T h i s 1 7 - m o n t h - o l d b o y ha d h a d marasmic k w a s h i o r k o r , d i a r r h o e a ,v o m i t i n g , and c o u g h f o r s e v e r a l m o n t h s . Oedema ha d b e e n p r e s e n tfor a w e e k . He h a d w e i g h e d 3 2 0 0 g a t b i r t h . S u b s e q u e n t l y h e ha dr e c e i v e d a very d i l u t e f o r m u l a t i o n o f a p r o p r i e t a r y m i l k s u p p l e m e n t e df r o m 3 months o f a ge w i t h d i l u t e c o r n m e a l p o r r i d g e from a b o t t l e ,o c c a s i o n a l c r u s h e d v e g e t a b l e s , and h e r b a l t e a s .On e x a m i n a t i o n t h e c h i l d was a p a t h e t i c w i t h r e d s c a n t y h a i r ,f l a k y d e r m a t i t i s , d y s p i g m e n t a t i o n , and a n g u l a r s t o m a t i t i s . He ha d

g e n e r a l i s e d o e d e m a . His l i v e r was n ot e n l a r g e d . He a l s o ha d a l e f to t i t i s media.T r e a t m e n t was s t a r t e d w i t h m i l k f e e d s p r o v i d i n g m a i n t e n a n c ea mounts o f p r o t e i n and energy a n d s u p p l e m e n t s o f p o t a s s i u m ,m a g n e s i u m , i r o n , f o l i c a c i d , and v i t a m i n s . A m p i c i l l i n was p r e s c r i b e df o r t h e o t i t i s m e d i a . F u r t h e r i n v e s t i g a t i o n s showed a u r i n a r y i n f e c t i o n ,p a t h o g e n i c E s c h e r i c h i a c o l i , an d s t r o n g y l o i d e s i n t h e s t o o l . A r i g h tupper l o b e p n e u m o n i a s u b s e q u e n t l y p r o v e d t o be t u b e r c u l o u s . Thep l a s m a a l b u m i n was 2 1 g / l . As t h e s e i n f e c t i o n s were d i a g n o s e ds t a n d a r d treatment was p r e s c r i b e d .D u r i n g t h e f i r s t week h i s c o n d i t i o n s l o w l y d e t e r i o r a t e d - i np a r t i c u l a r , h e became more a p a t h e t i c and r e q u i r e d f e e d i n g b y n aso-g a s t r i c t u b e . On t h e e i g h t h d a y i n h o s p i t a l h i s energy i n t a k e e x c e e d e dm a i n t e n a n c e r e q u i r e m e n t s a n d he was noted t o be s i t t i n g u p a n d morea l e r t . On e x a m i n a t i o n i n t h e l a t e a f t e r n o o n , h o w e v e r , he was d y s p n o e i cw i t h t a c h y c a r d i a , r a i s e d venous p r e s s u r e , a n d a g a l l o p r h y t h m . He

r a p i d l y b e c a m e m o r i b u n d , p a s s e d s e v e r a l watery s t o o l s i n q u i c ks u c c e s s i o n , w h i l e h i s abdomen b e c a m e d i s t e n d e d w i t h v i s i b l ep e r i s t a l s i s a n d a f e w h i g h p i t c h e d b o w e l s o u n d s . He was e x a m i n e do f t e n d u r i n g t h e d a y b u t b o w e l s o u n d s were never a b s e n t . Thed i a r r h o e a a n d a b d o m i n a l s i g n s were t h e most p r o m i n e n t f e a t u r e s ,b u t b e c a u s e o f t h e p r e v i o u s f a t a l cases h e was t r e a t e d w i t h a s i n g l ep a r e n t e r a l d o s e o f f r u s e m i d e ( 1 0 mg) a n d d i g o x i n ( 0 1 m g ) . Thet a c h y c a r d i a a n d t a c h y p n o e a s u b s i d e d over e i g h t h o u r s . I n t h i s acutee p i s o d e h e p a s s e d 1 3 watery s t o o l s i n e i g h t h o u r s a n d l o s t 1 6 0 g i nw e i g h t . T h e r e a f t e r t h e s t o o l s a g a i n b e c a m e n o r m a l i n f r e q u e n c y a n dc o n s i s t e n c y . H i s s u b s e q u e n t recovery was s l o w b u t c o m p l e t e .

CASE 6T h i s 1 4 - m o n t h - o l d g i r l p r e s e n t e d w i t h a h i s t o r y o f h a v i n g b e e nu n w el l w i t h i n t e r m i t t e n t d i a r r h o e a a n d c o l d s f o r t h r e e m o n t h s . O v e rt h e f e w d a y s b e f o r e a d m i s s i o n s h e h a d d e v e l o p e d o e d em a . S h e h adw ei g h ed 3 9 0 0 g a t b i r t h , a n d s h e h a d b e e n i n t e r m i t t e n t l y b r e a s t - f e dfor f i v e m o n t h s w i t h s u p p l e m e n t s o f d i l u t e p r o p r i e t a r y m i l k a n dd i l u t e c o r n m e a l p o r r i d g e .S h e l o o k e d e x t r e m e l y i l l a n d a p a t h e t i c w i t h sparse t h i n r e d h a i r ,g e n e r a l i s e d f l a k y d e r m a t i t i s , a n g u l a r s t o m a t i t i s , a n d u l c er a ti on o f t h ep e r i n e u m . The mucous membranes were d r y , y e t s h e h a d grossg e n e r a l i s e d o e d e m a . Her l i v e r was p a l p a b l e 4 cm b e l o w t h e c o s t a lm a r g i n . T h e r e was no e v i d e n c e o f i n f e c t i o n . A c h e s t r a d i o g r a p hs h o w e d n o t h i n g a b n o r m a l . H a e m o g l o b i n was 81 g / d l , w h i t e c e l l

count 8 - 9 x 1 0 9 / 1 , p l a s m a sodium 1 4 0 mmol ( m E q ) / l , p o t a s s i u m4 5 mmol ( m E q ) / l , a n d a l b u m i n 1 8 8 g / l .S h e was t r e a t e d i n i t i a l l y w i t h a d i e t p r o v i d i n g m a i n t e n a n c e a mo u n tso f energy a n d protein t o g e t h e r w i t h s u p p l e m e n t s o f p o t a s s i u m ,m a g n e s i u m , i r o n , f o l i c a c i d , a n d v i t a m i n s . On t h i s r e g i m e n s h e l o s t a l lh e r oedema-a w e i g h t l o s s o f 2 1 k g ( 2 5 3 0 , o f h er i n i t i a l w e i g h t ) - i ntwo w e e k s a n d h e r serum a l b u m i n rose t o 214 g / l ( a n amount com-p a t i b l e w i t h t h e c o n c e n t r a t i n g e f f e c t o f l o s s o f o e d e m a ) . Her energyi n t a k e was i n c r e a s e d a b ov e m ai n te n an c e l e v e l s on t h e 1 4t h d a y i nh o s p i t a l . F o r t y - e i g h t h o u r s l a t e r h e r r e s p i r a t o r y r a t e rose f r o m 3 0 to7 0 / m i n a n d h e r p u l s e r a t e f r o m 1 2 0 t o 1 6 0 / m i n . V e n o u s pressure wasa l s o r a i s e d . S h e was g i v e n a s i n g l e d o s e o f d i g o x i n a n d t h e r e s p i r a t o r yr a t e f e l l t o n o r m a l over 1 0 h o u r s . The treatment h a d t o b e r e p e a t e d4 8 h o u r s l a t e r , a f t e r w h i c h no f u r t h e r c a r d i o v a s c u l a r p r o b l e m so c c u r r e d . The c h i l d m a de a s t e a d y recovery t h e r e a f t e r apart f r o m ane p i s o d e o f m e a s l e s .

ResultsT a b l e I I s h o w s t h e r e s u l t s o f t h e l e u c o c y t e t e s t s p e r f o r m e d b e f o r e

T A B L E i I - L e u c o c y t e e l e c t r o l y t e s , r a t e c o n s t a n t f o r s o d i u m e f f l u x , a n d p l a s m a e l e c t r o l y t e s i n c h i l d r e n who d e v e l o p e d r e c o v e r y s y n d r o m eDay o f R a t e Sodium Sodium Sodium P o t a s s i u m P o t a s s i u m C e l l P l a s m a P l a s m aC a s e Day o f d e a t h o r c o n s t a n t e f f l u x c o n c e n t r a t i o n c o n t e n t c o n c e n t r a t i o n c o n t e n t w a t e r s o d i u m p o t a s s i u mNo s t u d y r e c o v e r y f o r s o d i u m r a t e ( m m o l / l c e l l ( m m o l l k g ( m m o l / l c e l l ( m r n o l / k g ( 1 / k g ( m m o l j 1 ) ( m m o l / l )s y n d r o m e e f f l u x ( m m o l / l / h ) w ate r ) d r y s o l i d s ) wa te r ) d r y s o l i d s ) d r y s o l i d s )

1 3 6 1 2 2 6 1 7 4 3 6 3 2 - 0 8 1 3 6 4 - 62 3 9 3 8 8 1 1 6 5 3 4 8 2 - 1 1 1 4 0 3 03 2 8 7 - 4 4 2 6 7 3 6 1 1 2 1 0 2 3 2 2 3 - 1 5 1 3 6 5 - 24 4 7 5 - 5 7 2 0 6 3 7 9 5 1 7 1 4 4 4 2 - 5 9 1 2 7 4 -61 8 2 - 5 8 6 2 2 4 6 3 1 4 1 3 6 4 2 - 5 8 1 3 0 4 - 15 7 3 7 5 1 5 2 4 1 9 1 1 6 9 3 7 3 2 - 2 1 1 3 0 4 - 59 * 2 3 1 1 8 5 8 0 1 7 5 1 6 8 3 9 4 2 6 0 1 3 1 3 -71 1 9 4 - 4 1 4 0 9 1 8 1 8 0 3 7 7 2 0 9 1 3 5 4 - 26 1 4 5 1 6 2 1 9 4 2 1 0 5 1 8 6 4 5 9 2 - 4 7 1 3 5 4 - 41 9 * 2 - 7 3 2 4 8 9 1 2 9 1 1 2 3 3 9 4 3 - 2 0 1 3 3 4 - 3* S t u d i e s a f t e r t r e a t m e n t w i t h d i g o x i n .C o n v e r s i o n : SI t o t r a d i t i o n a l u n i t s - S o d i u m : 1 m m o l / l 1 m E q / l . P o t a s s i u m : 1 m n m o l / l 1 m n E q / l .

1 0 5 2 BRITISH MEDICAL J O U R N A L 2 3 APRIL 1 9 7 7

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BRITISH MEDICAL JOURNAL 2 3 AP RI L 1977h i g h - e n e r g y f e e d i n g i n t h e s i x p a t i e n t s w i t h acute e x t r a c e l l u l a r f l u i do v e r l o a d .T a b l e I I I s h o w s t h e r e s u l t s i n t h i s group c o m p a r e d w i t h t h o s e i nt he c hi l d re n who r e c o v e r e d u n e v e n t f u l l y on h i g h - e n e r g y f e e d i n g . Thes i g n i f i c a n c e s o f t h e c h a n g e s were a s s e s s e d u s i n g b o t h t h e t t e s t a n d t h eMann-Whitney t e s t . T h e r e was a h i g h l y s i g n i f i c a n t d i f f e r e n c e i n thev a l u e s o b t a i n e d f o r t h e c h a n g e s i n t h e r a t e constant a n d i n t h e i n t r a -c e l l u l a r s o d i u m v a l u e s . I n t r a c e l l u l a r p o t a s s i u m c o n c e n t r a t i o n s weres i g n i f i c a n t l y d i f f e r e n t i n t h e tw o groups when m e a s u r e d per u n i t o fd r y s o l i d s b u t not when m e a s u r e d pe r u n i t o f c e l l water. T h i s wasl a r g e l y b e c a u s e on e o f t h e c h i l d r e n who d i e d ( c a s e 3 ) h a d a very h i g hc e l l water l e v e l f o r unknown reasons.

DiscussionT h i s group o f c h i l d r e n who d i d n ot show t h e s l o w s o d i u m

pump i n l e u c o c y t e s that i s u s u a l l y a s s o c i a t e d w i t h severem a l n u t r i t i o n were i d e n t i f i e d b y r e t r o s p e c t i v e a n a l y s i s o f pre-treatment s o d i u m transport measurements. A ft e r f i n d in gs i g n i f i c a n t d i f f e r e n c e s b e t w e e n t h e c h i l d r e n who d i e d a n d t h o s ewho s u r v i v e d we p r e d i c t e d f r o m t h e i r l e u c o c y t e s o d i u mt r a n s p o r t v a l u e s t h a t two o t h e r c h i l d r e n would d e v e l o p t h es y n d r o m e . We t h e r e f o r e m o n i t o r e d them c a r e f u l l y a n d t r e a t e dthem s u c c e s s f u l l y . Most c h i l d r e n who d i e i n h o s p i t a l w i t hp r o t e i n energy m a l n u t r i t i o n d i e w i t h i n t h e f i r s t 4 8 h ou r s , b e fo rer e f e e d i n g h a s s t a r t e d . T h e s e c h i l d r e n were a t r i s k o n l y a f t e rr e f e e d i n g h a d s t a r t e d .Once h i g h - e n e r g y f e e d i n g h a d b e g u n i t t o o k no l o n g e r t h a ntwo h o u r s f o r t h e c h i l d r e n ' s c o n d i t i o n t o c h a n g e f r o m apparentc a r d i o v a s c u l a r n o r m a l i t y t o d e f i n i t e a n d l i f e - t h r e a t e n i n gp u l m o n a r y c o n g e s t i o n , w i t h t he a dd i ti on al f e a t u r e s o f wateryd i a r r h o e a a n d a b d o mi n al d i s t e n s i o n . I t i s u n c l e a r w h e t h e r t h i ss y n d r o m e d e v e l o p s o n l y a f t e r treatment w i t h a n e n e r g y - d e n s eo i l - s u p p l e m e n t e d d i e t , b u t b o t h t h e c h i l d r e n who s u r v i v e dd e v e l o p e d t h e s y n d r o m e w i t h i n 4 8 h o u r s o f s t a r t i n g t h i sr e h a b i l i t a t i o n d i e t . The r e s p i r a t o r y a n d p u l s e r a t e o f t e n roset r a n s i e n t l y i n t h i s p e r i o d i n t h e o t h e r f o u r c h i l d r e n , e s p e c i a l l y i nt h o s e who p r e s e n t e d w i t h k w as h i or k or . Even t h o u g h marasmusi s t h e more common form o f m al n u t r it i on i n J a m a i c a , f i v e o f t hes i x c h i l d r e n ha d an i n i t i a l d i a g n o s i s o f k w a s h i o r k o r . I t i s p e r h a p sn ot s u r p r i s i n g t h a t p a t i e n t s who ha d b e e n o e d e m a t o u s were morel i k e l y t o d e v e l o p an " o v e r l o a d " s y n d r o m e .

C a r d i o v a s c u l a r p r o b l e m s d u r i n g r e f e e d i n g h a v e b e e n d e s c r i b e db e f o r e , t h o u g h some o f t h e f e a t u r e s d i f f e r f r o m t h e s y n d r o m ed e s c r i b e d h e r e . I n Uganda h e a r t f a i l u r e t e n d e d t o occur i nc h i l d r e n w i t h h a e m o g l o b i n v a l u e s b e l o w 7 - 0 g / d l who h a d b e e nr e c e i v i n g a b o u t 4 - 0 mmol o f s o d i u m / k g b o d y w e i g h t / d a y . 6 Ad i e t p r o v i d i n g 10 m m o l / k g / d a y was n ot a s s o c i a t e d w i t h h e a r tf a i l u r e . The - d i e t we u s e d p r o v i d e d a b o u t 1 - 0 - 1 - 5 m mol s o d i u m /k g / d a y , a n d severe a n a e m i a i s n ot as common i n J a m a i c a a s inU g a n d a . . I n some p a t i e n t s - f o r e x a m p l e , cases 2 and 4-wem i s s e d t h e p r e c e d i n g c a r d i o r e s p i r a t o r y symptoms b e c a u s e wef o c u s e d on t h e d i a r r h o e a , which we t r e a t e d w i t h c o n v e n t i o n a lf l u i d treatment f o r g a s t r o e n t e r i t i s . D i a r r h o e a o c c u r r e d i n s e v e r a lo f t h e s e c h i l d r e n , an d i n case 5 i t d i s a p p e a r e d as a b r u p t l y as i tha d b e g u n . T h i s a b r u p t onset and c e s s a t i o n r e m a i n s u n e x p l a i n e d .

B e f o r e wesaw t h e d e v e l o p m e n t o f t he s y n d r o m e i n cases 5 a n d6 we d i s c u s s e d w h e t h e r we s h o u l d d i g i t a l i s e t h e s e c h i l d r e n who

1 0 5 3were a t r i s k o f s u d d e n d e a t h . I t was a r g u e d t h a t s i n c e t h ep r o g n o s t i c f i n d i n g was a r e l a t i v e l y f a s t s o d i u m pump a n d n o r m a li n t r a c e l l u l a r e l e c t r o l y t e s , d i g o x i n w o u l d convert t h e c e l l s to amore " n o r m a l l y m a l n o u r i s h e d " s t a t e - t h a t i s w i t h a l o w e r r a t econstant f o r s o d i u m e f f l u x a n d a h i g h e r i n t r a c e l l u l a r s o d i u m . Wed e c i d e d , h o w e v e r , t h a t we s h o u l d f i r s t o b s e r v e c a r e f u l l y anda v o i d g i v i n g a p o t e n t i a l l y d a n g e r o u s d r u g for e n t i r e l y t h e o r e t i c a lreasons. Once i t was apparent t h a t t h e s y n d r o m e was one o fe x t r a c e l l u l a r f l u i d o v er l o ad d i g ox i n a n d d i u r e t i c s were g i v e n .U n f o r t u n a t e l y t h e y i e l d o f l e u c o c y t e s i n t h e l a s t two c h i l d r e nwas s m a l l a n d i t was t h e r e f o r e not p o s s i b l e t o measure t h eo u b a i n - i n s e n s i t i v e p r o p o r t i o n o f t r a n s p o r t . T h i s d o e s n oti n v a l i d a t e t h e p r o g n o s t i c v a l u e o f t h e measurements b u t i t d o e sm a ke i t d i f f i c u l t t o d i s c u s s t h e e f f e c t on t h e e n e r g y - c o n s u m i n gp o r t i o n of s o d i u m t r a n s p o r t . The e f f e c t i v e n e s s o f t h e treatmenta n d t h e r e d u c t i o n i n t h e r a t e constant for s o d i u m e f f l u x a f t e rd i g o x i n treatment suggest t h a t t h e i n i t i a l h i g h r a t e constants werei n f a c t l a r g e l y t h e g l y c o s i d e - s e n s i t i v e p o r t i o n .The p r e c i s e r e l a t i o n b e t w e e n t he fi n d i n g s i n t h e l e u c o c y t ea n d t h e d e v e l o p m e n t o f t h i s p a r t i c u l a r " r e c o v e r y s y n d r o m e " i sn ot c l e a r . M a l n o u r i s h e d c h i l d r e n a re a t r i s k o f p u l m o n a r yc o n g e s t i o n fo r s e v e r a l reasons. T h e i r c a r d i a c outputs a re l o wa n d r e n a l f u n c t i o n i s i m p a i r e d , 7 - 9 b u t b o t h t he s e d ef ec ts t e n dt o recover i n t h e f i r s t f e w d a y s . The p r o b l e m i s t o e x p l a i n t h eo r i g i n o f t h e sodium necessary t o e x p a n d t h e e x t r a c e l l u l a r spacea n d t h e s p e e d w i t h w h i c h t h e s y n d r o m e d e v e l o p s . What weo b s e r v e d i n t h e l e u c o c y t e s t u d i e s d u r i n g t h e m a i n t e n a n c ep e r i o d may h a v e b e e n t h e p o t e n t i a l f o r recovery. The l e u c o c y t es t u d i e s a re e s s e n t i a l l y i n v i t r o b e c a u s e i t t a k e s a b o u t 7 0 m i n u t e sf r o m c o l l e c t i o n b e f o r e t h e f i n a l measurements ca n b e m a d e .D u r i n g t h i s t i m e t h e c e l l s a re e x p o s e d t o p h y s i o l o g i c a l s a l i n e a n dn o r m a l g l u c o s e c o n c e n t r a t i o n s . I n t h i s p e r i o d l o w a d e n o s i n et r i p h o s p h a t e (ATP) l e v e l s m i g h t b e c o r r e c t e d . G a r a y a n dG a r r a h a n ' 5 h a v e shown i n t h e r e d c e l l t h a t l o w ATP l e v e l sd e p r e s s t h e a c t i v i t y o f t h e sodium pump, and ATP l e v e l s a reknown t o b e l o w i n l e u c o c y t e s o b t a i n e d f r o m m a l n o u r i s h e dc h i l d r e n . ' 1 The phenomenon we h a v e o b s er v ed i s u n l i k e l y t o b ea b a s i c c a r d i a c p r o b l e m , b e c a u s e t h e s y n d r o m e occurs as t h ec a r d i a c f e a t u r e s a re r e s o l v i n g a n d i t would n ot e x p l a i n t h e o t h e rf e a t u r e s o f t h e s y n d r o m e s u c h as t h e p r o f u s e d i a r r h o e a a n da b d o m i n a l d i s t e n s i o n .W h a t e v e r t h e p h y s i o l o g i c a l b a s i s , i t i s i m p o r t a n t t o b e awaret h a t t h e s e p r o b l e m s t e n d t o occur i n t h e f i r s t f e w d a y s o fr e h a b i l i t a t i o n w i t h a h i g h - e n e r g y i n t a k e . By c a r e f u l l y o b s e r v i n gp u l s e a n d r e s p i r a t i o n r a t e s i t s h o u l d b e p o s s i b l e t o s t a r t treatmenta p p r o p r i a t e l y . The s u d d e n onset o f watery d i a r r h o e a a t t h i s s t a g eo f recovery d o e s n ot n e c e s s a r i l y i n d i c a t e g a s t r o e n t e r i t i s . Thec l i n i c i a n s h o u l d t r y t o measure t h e j u g u l a r venous pressure, andh e s h ou l d l i s t e n t o t h e h e a r t a n d l u n g s a n d see w h e t h e r t h e l i v e ri s e n l a r g e d . I f t h e s e s i g n s suggest c i r c u l a t o r y o v e r l o a d treatments h o u l d b e s t a r t e d w i t h d i g o x i n and d i u r e t i c s . I t would b ei n t e r e s t i n g t o know w h e t h e r t h e same s y n d r o m e occurs w i t hp a r e n t e r a l f e e d i n g o f m a l n o u r i s h e d a d u l t s s e c o n d a r y t o o t h e rd i s e a s e s or p r o c e d u r e s . R e p o r t s o f severe m a l n u t r i t i o n i n c l u d eone e x a m p l e o f s u d d e n u n e x p e c t e d d e a t h d u r i n g r e f e e d i n g i n ana d u l t w i t h a n o r e x i a nervosat' a n d i n t h e M i n n e s o t a s t u d y o fs t a r v a t i o n i n i n i t i a l l y n o r m a l men one s u b j e c t d e v e l o p e d s u d d e ne n l a r g e m e n t o f t he h ea rt a n d i n c r e a s e d venous pressure, w h i c h

T A B L E I I I - S t a t i s t i c a l c o m p a r i s o n o f l e u c o c y t e e l e c t r o l y t e v a l u e s a n d r a t e c o n s t a n t f o r s o d i u m e f f l u x i n c h i l d r e n w h o r e c o v e r e d u n e v e n t f u l l y a n d t h o s e w h o d i e d o rd e v e l o p e d r e c o v e r y s y n d r o m e . R e s u l t s a r e e x p r e s s e d a s means SE o f meanNoofTotal I n t r a c e l l u l a r s o d i u m I n t r a c e l l u l a r p o t a s s i u mNo o f T o t a l r a t e c o n s t a n t .p a t i e n t s fo r s o d i u m e f f l u x m m o l / k g m m o l / l mmol/kg m m o l / ld r y s o l i d s c e l l w a t e r d r y s o l i d s c e l l w a t e r

S u r v i v o r s 1 3 3 - 7 2 0 - 2 6 1 6 3 + 2 0 6 6 - 8 X 6 - 7 3 3 6 +13 1 4 6 8 - 1C h i l d r e n who d i e d o r 4 5 4 8 t)76 8 5 1 2 3 4 - 3 4 - 6 3 8 4 i 2 2 1 6 1 1 2 - 2d e v e l o p e d t he r e c o v e r ys y n d r o m eP v a l u e :t t e s t

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10 54 BRITISH MEDICAL JOURNAL 23 APRIL 1977r e s p o n d e d t o b e d r e s t , d i u r e t i c s , a n d r e d u c e d f o o d i n t a k e .U n e x p e c t e d d e a t h i n m a l n o u r i s h e d c h i l d r e n d u r i n g r e f e e d i n gh a s b e e n r e p o r t e d m any t i m e s . 4 - ' 6

T h i s w o r k w a s s u p p o r t e d b y a g r a n t f r o m t h e W e l l c o m e T r u s t .

R e f e r e n c e sI P a t r i c k , J , Xth I n t e r n a t i o n a l C o n g r e s s o f N u t r i t i o n , K y o t o , J a p a n , 1 9 7 5 ,A b s t r a c t 3 1 1 5 .2 P a t r i c k , J , a n d G o l d e n , M N , A m e r i c a n J o u r n a l o f C l i n i c a l N u t r i t i o n . I np r e s s . -3 P a t r i c k , J , a n d H i l t o n , P J , C l i n i c a l S c i e n c e , 1 9 7 3 , 4 4 , 4 5 7 .4 H i l t o n , P J , a n d P a t r i c k , J , C l i n i c a l S c i e n c e , 1 9 7 3 , 4 4 , 4 3 9 .

W e l l c o m e C l a s s i f i c a t i o n , L an c et , 1 9 7 3, 2 , 8 7 .6 W h a r t o n , B A , H o w e l l s , G R , a n d M a c C a n c e , R A , L a n c e t , 1 9 6 7 , 2 , 3 8 4 .A l l e y n e , G A 0 , C l i n i c a l S c i e n c e , 1 9 6 6 , 3 0 , 5 5 3 .8 A l l e y n e , G A 0 , P e d i a t r i c s , 1 9 6 7 , 3 9 , 4 0 0 .9 K l a h r , S , a n d A l l e y n e , G A 0 , K i d n e y I n t e r n a t i o n a l , 1 9 7 5 , 3 , 1 2 9 .1 0 G a r a y , R P , a n d G a r a h a n , P J , J o u r n a l of P h y s i o l o g y , 1 9 75 , 2 49 , 5 1 .1 Y o s h i d a , T , e t a l , N a t u r e , 1 9 6 7 , 2 1 4 , 5 2 5 .1 2 B e r k m a n , J M, W e i r , J F , a n d K e p l e r , E J , G as t r oe n te r ol o gy , 1 9 4 7 , 3 5, 3 57 .1 3 S i m o n s o n , E , H en s c he l , A , a n d K ey s , A , A m e r i c a n H e a r t J 3 o u r n a l , 1 9 4 8 ,3 5 , 5 8 4 .1 4 V i t e r i , F , e t a l , i n M a m z m a l i a n P r o t e i n M e t a b o l i s m , e d H N Munro a n dJ B A l l i s o n , v ol I I , p 5 4 0 . Ne w Y o r k , A c a d e m i c P r e s s , 1 9 6 4 .1 S m i t h , R , MD T h e s i s , C a m b r i d g e , 1 9 6 0 .S m y t h e , P M, S w a n e p o e l , A , a n d C a m p b e l l , J A H , B r i t i s h M e d i c a lJ o u r n a l , 1 9 6 2 , 1 , 6 7 .( A c c e p t e d 1 1 F eb r u ar y 1 9 7 7 )

" M e t h i c i l l i n - r e s i s t a n t " S t a p h y l o c o c c u s a u r e u s :r e a s s e s s m e n t b y c o n t r o l l e d t r i a l i n b u r n s u n i tE J L LOWBURY, H A LILLY, A KIDSONB r i t i s h M e d i c a l J o u r n a l , 1 9 7 7 , 1 , 1 0 5 4 - 1 0 5 6

S u m m a r yA c o n t r o l l e d t r i a l o f o r a l f l u c l o x a c i l l i n ( 2 5 0 mg s i x - h o u r l yf o r f o u r d ay s ) was performed i n 3 4 p a t i e n t s t r e a t e d byt h e c o v e r e d method whose burns ha d y i e l d e d a heavyo r moderate growth o f S t a p h y l o c o c c u s aureus r e s i s t a n tt o m e t h i c i l l i n a t 3 0 C b u t moderately s e n s i t i v e a t 3 7 C .S t a p h aureus wa s e l i m i n a t e d i n n i n e o f t h e 1 7 p a t i e n t st r e a t e d w i t h f l u c l o x a c i l l i n b u t i n none o f t h e 1 7 c o n t r o l s ;t h e p r o p o r t i o n o f p a t i e n t s from whose burns s e n s i t i v eS t a p h aureus wa s e l i m i n a t e d i n a n e a r l i e r t r i a l o f c l o x a -c i l l i n wa s g r e a t e r t h a n t h i s . S t r a i n s o f S t a p h aureus com-monly d e s c r i b e d a s m e t h i c i l l i n - r e s i s t a n t a n d s h o w i n gh e t e r o g e n e o u s growth a t 3 7 C o f m a n y s e n s i t i v e a n d v e r yf e w r e s i s t a n t b a c t e r i a l c e l l s s h o u l d , i n t h e l i g h t o f t h e s ef i n d i n g s , b e c a l l e d m o d e r a t e l y s e n s i t i v e t o f l u c l o x a c i l l i n .Such " h e t e r o r e s i s t a n t " s t r a i n s showed c o n s i s t e n t moder-a t e s e n s i t i v i t y i n r e p l i c a t e d i f f u s i o n s e n s i t i v i t y t e s t s a t3 7 ' C , b u t v e r y i n c o n s i s t e n t r e s u l t s i n r e p l i c a t e d i l u t i o nt e s t s , e s p e c i a l l y w i t h f l u c l o x a c i l l i n . T h e s e s t u d i e s showedt h a t 1 8 - h o u r d i f f u s i o n s e n s i t i v i t y t e s t s i n d i c a t e t h ec l i n i c a l v a l u e o f treatment w i t h f l u c l o x a c i l l i n f o r s t a p h y -l o c oc c a l i n f ec t i on s o f moderate s e v e r i t y more c o r r e c t l ya t 3 7 C t h a n a t 3 0 C .

I n t r o d u c t i o nC u l t u r e s o f S t a p h y l o c o c c u s a u r e u s ar e u s u a l l y t e s t e d f o r s e n s i -t i v i t y t o m e t h i c i l l i n a t 3 0 C , b e c a u s e m any s t r a i n s t h a t a p p e a rs e n s i t i v e a t 3 7 C a r e f o u n d t o b e r e s i s t a n t a t 3 0 C . The r e s i s t a n tc u l t u r e s i n c l u d e a u s u a l l y v e r y l a r g e p r o p o r t i o n o f b a c t e r i a l c e l l st h a t a r e s e n s i t i v e t o m e t h i c i l l i n a t 3 7 C b u t r e s i s t a n t a t 3 0 C . Y - 6

MRC I n d u s t r i a l I n j u r i e s a n d Burns U n i t , Birmingham A c c i d e n tH o s p i t a l , Birmingham B1 5 1NAE J L LOWBURY, D M , F R C P A T H , b a c t e r i o l o g i s tH A LILLY, F I M L S , c h i e f r e s e a r c h o f f i c e rA KIDSON, F I M L S , c h i e f m e d i c a l l a b o r a t o r y s c i e n t i s t

A s t h e s i t e o f i n f e c t i o n i s u s u a l l y a t o r a b o v e t h e n o r m a l b o d yt e m p e r a t u r e , t h e u s e o f a t e s t a t a l o w e r t e m p e r a t u r e ( 3 0 - C ) i sa n o m a l o u s . M o r e o v e r , m a ny " h e t e r o r e s i s t a n t " s t r a i n s o f S t a p ha u r e u s , w h i c h a p p e a r s e n s i t i v e to m e t h i c i l l i n when t e s t e d a t3 7 ' C b u t r e s i s t a n t when t e s t e d a t 3 0 ; ' C , s e e m , o n d i f f u s i o n t e s t s ,t o b e s e n s i t i v e o r r e l a t i v e l y s e n s i t i v e t o c l o x a c i l l i n a n d f l u c l o x a -c i l l i n a t b o t h 3 0 C a n d 3 7 C . The i r r e g u l a r i t y o f r e s u l t s o nt e s t i n g s u c h s t r a i n s f o r s e n s i t i v i t y to c l o x a c i l l i n h a s l e d t o t h ef u r t h e r a n o m a l y o f u s i n g m e t h i c i l l i n a s t h e s e n s i t i v i t y t e s t a g e n twhen c l o x a c i l l i n o r f l u c l o x a c i l l i n a r e t h e a n t i b i o t i c s u s e d f o rt r e a t m e n t . 6I n c r e a s i n g p r o p o r t i o n s o f S t a p h a u r e u s i s o l a t e d f r o m b u r n si n o u r u n i t ( 5 7 " ' o i n 1 9 7 2 ) h a v e b e e n f ou n d t o b e r e s i s t a n t t om e t h i c i l l i n when t e s t e d b y a d i t c h p l a t e d i f f u s i o n t e s t a t 3 0 0 C . 7C o n t r o l l e d t r i a l s s o o n a f t e r t h e i n t r o d u c t i o n o f m e t h i c i l l i n a n dc l o x a c i l l i n s h o w e d t h a t i n a b o u t 8 0 % o o f p a t i e n t s s e n s i t i v es t r a i n s o f S t a p h a u r e u s w e r e e l i m i n a t e d f r o m b u r n s i t e s c o v e r e dw i t h d r e s s i n g s a f t e r a c o u r s e o f s u b c u t a n e o u s m e t h i c i l l i n 8 o rf i v e d a y s ' o r a l t r e a t m e n t w i t h c l o x a c i l l i n . 9 To a s s e s s t h e c l i n i c a ls e n s i t i v i t y o r r e s i s t a n c e o f s t r a i n s o f S t a p h a u r e u s d e s c r i b e d a sm e t h i c i l l i n - r e s i s t a n t b y s t a n d a r d t e s t s a t 3 0 C , we p e r f o r m e d ac o n t r o l l e d t r i a l o f o r a l f l u c l o x a c i l l i n i n p a t i e n t s w h o s e b u r n sw e r e c o l o n i s e d b y s u c h s t a p h y l o c o c c i a n d w e r e c o v e r e d w i t hd r e s s i n g s .

MethodThe b u r n s o f p a t i e n t s i n t h e b u r n s u n i t w e r e r o u t i n e l y e x a m i n e d ' 0f o r b a c t e r i a l f l o r a a t e v e r y c h a n g e o f d r e s s i n g . S t r a i n s o f S t a p h a u r e u sp i c k e d f r o m h o r s e b l o o d a g a r p l a t e s a n d i d e n t i f i e d b y a t u b e c o a g u l a s et e s t w e r e e x a m i n e d b y a d i t c h p l a t e t e s t f o r t h e i r s e n s i t i v i t y t o m e t h i -c i l l i n a t 3 0 ' C a n d 3 7 C , w i t h 2 5 f l g o f t h e a n t i b i o t i c p e r m l o f n u t r i e n ta g a r i n t h e d i t c h . A f e w s t r a i n s were a l s o t e s t e d b y a t u b e d i l u t i o nm e t h o d w i t h m e t h i c i l l i n a n d f l u c l o x a c i l l i n a t 3 0 ' C a n d 3 7 C ; 0 0 2 m lo f a 1 / 2 5 0 d i l u t i o n o f a n o v e r n i g h t b r o t h c u l t u r e w a s u s e d a s th ei n o c u l u m . T h e y w e r e a l s o t e s t e d b y a d i s c d i f f u s i o n t e s t , u s i n g M a s td i s c s o f m e t h i c i l l i n ( 1 0 j L g ) a n d f l u c l o x a c i l l i n ( 5 , u g ) a t 3 0 ' C a n d a t 3 7 ' Ca n d a 1 / 2 5 0 d i l u t i o n o f a n o v e r n i g h t b r o t h c u l t u r e a s t h e p l a t e i n o c u -l u m . The t e s t s w e r e r e a d a f t e r 1 8 h o u r s ' i n c u b a t i o n ; t e s t s a t 3 7 Cw e r e r e i n c u b a t e d a t 3 7 C a n d r e a d a g a i n a f t e r 4 2 h o u r s . The mediumu s e d f o r the t e s t s w a s h o r s e b l o o d a g a r .None o f t h e p a t i e n t s s t u d i e d h a d s i g n s o f c l i n i c a l i n f e c t i o n . T h e i rb u ms w e r e t r e a t e d w i t h d r e s s i n g s a n d w e r e f o u n d t o b e h e a v i l y o rm o d e r a t e l y c o l o n i s e d w i t h S t a p h a u r e u s t h a t was r e s i s t a n t to m e t h i -c i l l i n a t 3 0 ' C , a s s h o w n b y g r o w t h a c r o s s t h e d i t c h , a n d o f r e d u c e d o r