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Icterus neonatorum
ICTEI~US N E O N A T O R U M A ~TUDY OF THE ICTERUS INDEX IN I~ELATION TO THE FRAGILITY, HEMOGLOBIN CONTENT AND NUMBER OF I=~ED BLOOD CELLS MURR&Y B . GORDON, M . D . AND
MICHAEL C. KE~ELHOa, M.D. BROOKLYN, N. Y .
NY discussion of icterus n e o n a t o r u m must necessarily consider the genesis of bilirubin. The accepted opinion at present is that bilirubin is f o r m e d as an end-product from hemoglobin which is liberated upon destruction of the red blood cells. The various theories which have been a d v a n c e d are concerned with the factors involved in the formation of bilirubin f r o m hemoglobin and m a y be g r o u p e d u n d e r two main headings: the hepatogenous and extrahepatogenous. According to the hepatogenous theory, the f o r m a t i o n of bilirubin is one of the active functions of the hepatic polygonal cells, either independently or in conjunction with some other factor, such as increased e r y t h r o c y t i c destruction or the action of the reticuloendothelial sys~ tem. Icterus develops in one of two ways: (a) the bile pigment is f o r m e d normally, passes n o r m a l l y t h r o u g h the polygonal cells but is obstructed in the bile ducts; (b) the bile m a y be f o r m e d normally but is unable to pass t h r o u g h the liver because of c i r c u l a t o r y disturbance or damage to the polygonal cells themselves. The e x t r a h e p a t i c origin of bilimlbin is being stressed in recent studies. It is considered t h a t the cells of the reticuloendothelial system, especially those of the bone marrow, spleen and the K u p f f e r cells of the liver are concerned with the metabolism and f o r m a t i o n of bilirubin. The polygonal cells of the liver p l a y no p a r t in the f o r m a t i o n of bilirubin, t h e i r chief f u n c t i o n being the w i t h d r a w a l of this substance from the blood and its excretion in the bile. The hematogenous t h e o r y has f o r its basis an increased destruction of red blood cells and the excessive f o r m a t i o n of bilirubin in amounts above that which can be excreted b y the hepatic polygonal cells. The escape of l a r g e r amounts of hemoglobin m a y be due to an altered state of the e r y t h r o c y t e s themselves or to an increased fragility. The methods f o r the estimation of the a m o t m t of bi]irubin in the blood which are universally employed are the Van den B e r g h test 1 and the icterus index of Meulengracht. 2 The f o r m e r is the most accurate From the Pediatric Service of Israel-Zion Hospital, Brooklyn, N. Y. 685
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available m e t h o d f o r this d e t e r m i n a t i o n a n d also serves as a m e a n s of differentiation between h y p e r b i l i r u b i n e m i a due to o b s t r u c t i o n of the biliary p a s s a g e s a n d t h a t resulting f r o m excessive hemolysis or' hepathie disturbance. C o m p r e h e n s i v e reviews of the l i t e r a t u r e on ieterus n e o n a t o r u m h a v e been w r i t t e n r e c e n t l y b y V a n Creveld, 3 Mitchell 4 a n d Goldbloom and Gottlieb2 On the basis of a positive indirect V a n den B e r g h reaction in both cord a n d p e r i p h e r a l blood in the n e w b o r n , n u m e r o u s observers consider icterus n e o n a t o r u m to be of h e m a t o g e n o u s origin. (Rolleston, 6 Willia.mson, ~ K n o p f e l m a c h e r , 8 Cserna a n d L i e b m a n n , 9 Zamorani, 1~ K r a m e r , 11 Sehiff and F a t h e r , TM YlppS, 13 and H i r s e h 2 ~) The a m o u n t of bilirubin increases in the i n f a n t a f t e r birth, reaches the m a x i m u m b e t w e e n the first a n d s e v e n t h days a n d t h e n subsides. The degree of jaundice parallels the amount of bilirubin. The icterus i n d e x as originally described b y M e u l e n g r a e h t 2 and l a t e r modified b y Maue, 1~ Bernheim, 1G L a r r a b e e , ~ a n d Davis, ~s is a simpler a n d m o r e p r a c t i c a l but not as a c c u r a t e m e t h o d for' bilirubin estimation. The amount of bilirubin in the blood is fairly,constant 2or each individual u n d e r t h e same conditions, a n d ~in the a d u l t is considered to be between 4 a n d 6 or 5 a n d 7 units. Clinical j a u n d i c e is not recognizable, a n d p i g m e n t does not pass over into the urine w i t h an i n d e x lower t h a n ]5. L a t e n t jaundice is a h y p e r b i l i r u b i n e m i a with a content of 8 to 14 units w i t h o u t a n y clinical evidence of jaundice in t h e skin, sclera or urine. H i g h ieterus index values were f o u n d in the n e w b o r n b y Goldbloom a n d Gottlieb ~ who conclude t h a t icterus n e o n a t o r u m is a physiologic process a n d t h a t e v e r y n e w b o r n i n f a n t has jaundice irrespective of the presence or absence of its .clinical visibility. I e t e r ~ s was m a n i f e s t in all infants studied with an index of '~15 units or above. T h e y n o t e d a direct r e l a t i o n s h i p b e t w e e n the v a l u e of the ieterus i n d e x and the app e a r a n c e of jaundice. Closely associated w i t h the bilirubin content are the processes going on ia the r e d blood cells as evidenced b y t h e number, f r a g i l i t y a n d h e m o g l o b i n content of the e r y t h r o c y t e s . This has been studied recently b y Goldbloom and Gottlieb. The p r e s e n t r e p o r t is a s t u d y of this r e l a t i o n s h i p in icterus neonatorum. scoP~ oF STUDY D e t e r m i n a t i o n of e r y t h r o e y t e count, hemoglobin, icterus index and clinical jaundice were made on a group of 30 full-term, healthy newb o r ~ i n f a n t s in t h e N u r s e r y of th~ 1Vs W a r d of t h e Israel-Zion Hospital, r a n g i n g in age f r o m two to ten days. F i v e successive readings w e r e m a d e on the second, fourth, sixth, eighth and t e n t h days on
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each of these i n f a n t s d u r i n g its s t a y in the hospital. F r a g i l i t y tests were p e r f o r m e d u p o n t h e second a n d t e n t h d a y s on 14 of these. 2r The blood for examination was obtained by puncture of the external jugular vein. The ieterus index determinations were made by a comparison of diluted serum 1:4, with a standard 1:10,000 potassium biehromate solution in accordance with Bernheim's modification of the Moulengracht test.I6 Fragility tests were carried out with the use o5 graded saline solutions in 15 concentrations. Erythrocytes were counted in the usual manner with standardized pipettes. The Sahli method was employed for hemoglobin determination with standardized tubes and pipettes. Clinical jaundice was determined by yellowish discoloration of the skin, sclera and mucous membranes of the body, on a more or less arbitrary scale of 0, I plus, 2 plus, 3 plus and 4 plus. This grading is of course open to criticism as it is based upon personal equation but it is the most practical method for clinical application. Davis is points out that there are three sources of error in the determination of the ieterus index: (1) hemolysis, (2) lipemia, and (3) carotinemia. We noted early in the study t h a t there was a tendency to hemolysis, and to overcome this, all test tubes~ needles and syringes were scrupulously cleaned and dried. As a large degree of hemolysis still took place, it was decided to use only new glassware which had previously been soaked in distilled water for forty-eight hours. This last plan proved successful. All blood collected was immediately centrifuged and the serum separated. The second source of error was overcome to a great degree by drawing the blood before the 10 A.~t. nursing or feeding and the third by the fact that all the infants were obtaining either mother's or cow's milk. All determinations were made withirL twenty-four hours. RESULTS
Ieteruv I nde x . - - The icterns i n d e x d u r i n g the first ten d a y s shows h i g h e r v~Iues t h a n at a n y o t h e r period of life u n d e r n o r m a l conditions. A n o r m a l adult i n d e x of 4 to 6 units was not o b t a i n e d in a n y i n f a n t in this series. The lowest individual figure is 7 on the sixth d a y in an i n f a n t whose i n d e x r a n g e s f r o m 9 to 12 on the other days, a n d the highest is 60 in a child whose i n d e x on the other d a y s r a n g e s f r o m 27 to 48 units. The t r e n d of the i n d e x is to rise and t h e n fall as s h o w n b y tlle average figures of 21 units f o r the second day, 27 for the f o u r t h day, 28 f o r the sixth day, 25 f o r the eighth d a y a n d 21 f o r the t e n t h day. In s t u d y i n g the ieterus i n d e x of these respective days in each individual infant, we note t h a t in those w i t h m a n i f e s t jaundice, the figures on the t e n t h d a y are a b o v e the initial values in 11 instances a n d below these in 10. Of the l a t t e r t h e r e is the usual rise a n d subsequent fall in 8 and a continuous fall to below the initial values in 2. A rise followed by a fall to the original figures is n o t e d in 4 instances. The index c u r v e in i n f a n t s w i t h o u t discernible jaundice shows a r a n g e of f r o m 7 to i7 units w i t h only slight deviations f r o m the initial figures. Goldbloom a n d Gottlieb, ~ on the basis of d e t e r m i n a t i o n s m a d e by the Davis m e t h o d on p e r i p h e r M blood, repor~ values of 7 to 28 units at
688
THE JOURNAL OF PEDIATRICS TABLE I COMPLETE DA'rA OF STUDY
HE&X0(]LOBIN C]blNIGAL ICTERUS NO. AGE IN DAYSKEDBLOOD CELLS PERC~TAGB JAUNDICE INDEX 2 4 6 8 10
5,190,000 4 890,000 4,090,000 4,220,000 4,180,000
112 92 90 90 88
0 0 0 O 0
13 12 16 13 13
2 4 6 8 10
5,070,000 4,210,000 4,020,000 3,720,000 4,320,000
92 90 96 96 94
0 0 0 0 0
13 15 13 15 12
3.
2 4 6 8 10
6,410,000 6,190,000 5,980,000 4,970,000 5,350,000
104 102 98 98 98
1 1 2 2 I
plus plus plus plus plus
23 22 30 28 20
4.
2
5.
4 6 8 10 2 4 6 8 10
6,280,000 4,850,000 5,300,000 5,460,000 5,100,000 6,110,000 5,550,000 5,300,000 5,410,000 5,210,000
108 92 98 96 96 102 98 96 94 94
0 3 3 2 2 1 4 4 3 3
plus plus plus plus plus plus plus plus plus
14 30 32 26 24 18 45 52 40 36
6.
2 4 6 8 10
5,900,000 5,260,000 4,790,000 4,570,000 4,600,000
104 100 98 90 90
1 2 2 3 2
plus plus plus plus plus
20 32 32 48 34
7.
2 4 6 8 10
5,080,000 5,860,000 5,140,000 4,850,000 4,920,000
106 98 94 92 92
1 2 3 2 2
plus plus plus plus plus
19 32 48 28 24
8.
2 4 6 8 10
5,490,000 5,750,000 5,220,000 5,170,000 4,490,000
108 106 96 92 92
0 0 0 0 0
12 16 12 17 16
9.
2 4 6 8 10
5,390,000 5,230,000 4,270,000 4,710,000 4,560,000
104 94 94 92 90
0 2 plus 1 plus 1 plus 0
10 32 20 19 18
10.
2 4 6 8 10
5,560,000 5,770,000 4,690,000 4,810,000 4,900,000
106 104 98 98 90
1 plus 1 plus 1 plus 0 0
24 29 26 16 15
11.
2 4 6 8 10
4,580,000 4,120,000 4,140,000 4,530,000 4,600,000
94 92 92 82 84
0 0 0 0 0
10 12 7 10 9
FRAGILITY TEST
GORDON AND KEI~ELHOR:
ICTERUS I~EONAT0t~UM
689
TABLE I--CoNT'D NO.
12.
A G E I N D A Y S I%ED B L O O D CELLS
102 102
4 6 8 10
5,900,000 5,040,000 5,450,000 5,250,000 5,630,000
104 102 94 102 100
2 4 3 3 2
plus plus plus plus plus
30 50 40 34 28
14.
2 4 6 8 10
4,560,000 4,180,000 4,290,000 4,210,000 3,990,000
90 90 90 92 88
1 2 2 2 0
plus plus plus plus
24 32 35 30 18
15.
2 4 6 8 10
5,560,000 5,310,000 4,850,000 4,900,000 5,340~000
106 102 96 98 102
1 2 2 1 0
plus plus plus plus
24 27 23 20 18
16,
2 4 6 8 10
4,970,000 4,570,000 4,200,000 4,320,000 4,210,000
102 90 86 $8 88
0 1 plus 1 plus 1 plus 0
16 20 24 20 18
17.
2 4 6 8 10
5,310,000 5,200,000 4,450,000 4,500.000 4,730,000
104 102 90 90 94
2 2 3 2 1
plus plus plus plus plus
30 34 42 32 24
Begin .40 Complete .36
18.
2 4 6 8 10
4,520,000 4,430,000 4,600,000 4,790,000 4,820,000
96 90 92 94 92
1 plus 0 0 0 0
24 18 12 14 12
Begin .48 Complete .40
2 4 6 8 10
5,080,000 4,980,000 4,750,000 4,720,000 4,830;000
lO4
2 plus 1 plus
28
Begin .48 Complete .40
1 plus 0 0
20 22 17 18
Begin .40 Complete .36
20.
2 4 6 8 10
4,290,000 4,680,000 4,520,000 3,940,000 4,650,000
92 94 90 82 90
1 1 2 1 1
plus plus plus plus plus
20 23 26 26 22
Begin .48 Complete .40
21.
2 4 6 8 10
5,250,000 5,120,000 5,240,000 4,830,000 4,230,000
102 98 92 98 90
1 2 2 0 1
plus plus plus
Begin .52 Complete .40
plus
20 27 22 17 20
22.
2 4 6 8 10
6,170,000 6,220,000 5,790,000 5,860,000 5,460,000
112 108 104 98 98
1 1 3 2 1
plus plus plus plus plus
24 26 38 27 24
Begin .48 Complete .40
19.
112 102 I00
92 94 96 96
plus plus plus plus plus
30 34 30 32 26
I~RAGILIT~I T E S T
5,240,000
2
5,310,000 5,590,000 5,020,000 5,120,000
ICTEI~U S INDEX
2 2 2 2 2
13.
2 4 6 8 10
IIEM 0 G L O B I N C L I N I C A L PEI%OENTAGE JAUNDICE
Begin .40 Complete .36
Begin .40 Complete .36
Begin .48 Complete .36
Begin .48 Complete .36
Begin .44 Complete .40
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690
TABLE
NO. 23.
24.
I--CONT'D
R~D BLOOD ][IEIMOGL.ORINC'LINIOAL IC:TFA%US IVRAGIL~TYTEST D&YS ~ELLS PEE,C~ENT'AGE JAU~TDICE INDEX Begin .44 Complete 2 5,460,000 106 1 plus 27 4 4,320,000 86 4 plus 60 6 5,190,000 96 3 plus 48 8 4,890,000 92 3 plus 48 Begin .48 Complete 10 4,460,000 92 3 plus 35 Begin .52 Complete 2 4,690,000 96 1 plus 27 4 4,250,000 90 2 plus 30 6 4,010,000 86 1 plus 26 8 4,260,000 90 1 plus 20 Begin .48 Complete 10 4,390,000 90 0 17
A G E IN
18 30 35 30 28
Begin .60 Complete .48
0 2 2 1 1
Begin .48 Complete .44
plus plus plus plus
15 28 30 26 27
1 2 2 1 1
plus plus plus plus plus
24 32 34 30 27
Begin .52 Complete .44
108 102 96 98 98
0 1 plus 1 plus 1 plus 0
18 25 28 23 18
Begin .52 Complete .44
108 106 102 100 102
1 2 2 2 1
27 34 38 30 28
Begin .52 Complete .44
2 4 6 8 10
4,950,000 4,720,000 4,900,000 4,860,000 4,980,000
96 94 94 94 94
0 2 2 1 1
2 4 6 8 10
6,150,000 5,250,000 4,980,000 4,720,000 4,860,000
104 98 98 96 96
28.
2 4 6 8 10
5,650,000 5,210,000 4,860,000 4,960,000 4,890,000
96 94 92 92 94
29.
2 4 6 8 10
6,100,000 5,660~000 5,120,000 5,210,000 5,110,000
2 4 6 8 10
5,210,000 5,080,000 4,910,000 4,860,000 4,900,000
30.
.40
plus plus plus plus
10
0 0 0 0 0
27.
.44
Begin .52 Complete .44
94 88 94 90 92
26.
2 4 2 8
.40
12 11 11 10 14
4,430,000 3,650,000 4,240,000 3,940,000 3,890,000
25.
.40
plus plus plus plus plus
Begin .44 Complete .36
Begin .48 Complete .40
Begin .44 Complete .40
Begin .48 Complete. 40
Begin .44 Complete .40
Begin .44 Complete .40
b i r t h a n d o f 3 t o 30 u n i t s o n t h e t e n t h day. T h e y do n o t i n c l u d e figures noted in t h e i n t e r v e n i n g period. The values for the t e n t h day w e r e h i g h e r i n t h o s e i n f a n t s w h o h a d d e v e l o p e d j a u n d i c e a n d l o w e r in those who did not. t n the latter, t h e r e was a fall to n e a r l y the n o r m a l in about six days.
Erythrocytes.--There is an i n i t i a l p o l y c y t h e m i a (i.e., t a k e n on t h e s e c o n d d a y ) i n 22 of t h e 30 cases d i s t r i b u t e d as follows" Above 6 m i l l i o n , 6 ; b e t w e e n 5 a n d 6 m i l l i o n , 16 ; b e t w e e n 41/2 a n d 5 m i l l i o n , 6 ; a n d b e l o w 41/2 m i l l i o n , 2. T h e h i g h e s t i n i t i a l c o u n t is 6,410,000; t h e l o w e s t 4,290,000. a v e r a g e f o r t h e 30 i n f a n t s on t h e s e c o n d d a y is 5,354,000.
The
GORDON AND K E ~ [ E L H O R :
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ICTERUS NE01qATORUM
TABLE II
TItE AVEKAGE CUI~VES OF ]~ED BLOOD CELL, I~EMOSLOBIN, ICTEI~US, INDEX AND FI~AGII,ITY WITH THEIIr I~ELATIONSHIP TO ON~ ANOTttEI~
R.B.6. H.B.~ ,~OD,O00t 106 %
GRAPH I. AVERAGE
R.i).6. A.o
IK.B,~
4, ,~oo,oeol
4, ~'oo,o0oI .q~ %
30
~.
_GRAPH/'?'. AVERAGE ICTERU3/NDEX.
28
~2,f
"~" 2 0 /8
~
~
~
7o
DAYS
GRAPHI~. AVERAGEfRAG/Z/TYOFR.,B:C. .5O
.48
~ # / , r
G
. 4~ .42
~, .38 .36 _ _
The p o l y c y t h e m i a shows a d o w n w a r d t r e n d almost i m m e d i a t e l y as d e m o n s t r a t e d b y the difference b e t w e e n the samples t a k e n on the second and f o u r t h days. The fall in the total n u m b e r of erythrocytes is most m a r k e d in t h e first six days a n d was f o u n d in 25 ~nstances on the f o u r t h d a y followed b y f u r t h e r falls i n 20 on the sixth day, in 14 on the eighth d a y a n d in 13 on the last d a y of t h e s t u d y . F r o m the s i x t h d a y on there is a tendency to recompense for the e a r l y loss b y a g r a d u a l increase in the t o t a l number, but in spite of
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OF P E D I A T R I C S
this the final values are definitely l o w e r t h a n the initial ones as shown in 27 of the 30 cases. The r a n g e on the t e n t h d a y is f r o m 3,800,000 to 5,630,000 with an average of 4,761,000. Goldbloom a n d Gottlieb 5 r e p o r t erythrocyte values of f r o m 6,900,000 at b i r t h to 4,250,000 in 180 h o u r s (71/2 days) w i t h a subsequent rise to 4,500,000. L u c a s a n d c o w o r k e r s ~9 obtained a m a x i m u m of 6,700,000, a m i n i m u m of 4,500,000 and an a v e r a g e of 5,511,000. S a n f o r d 2~ f o u n d a count of 5,800,000 to 4,500,000. Others h a v e m a d e similar observations of an initial h i g h count and subsequent d r o p (Aitkin, 21 Perlin, 22 Williamson, 2~ Ziegelroth 2~ a n d Greil25).
HemogIobin.--Values above 100 p e r cent (Sahli) are p r e s e n t in 21 of the 30 cases on the second day. The initial values r a n g e f r o m 112 to 92 p e r cent. The h e m o g l o b i n curve simulates t h a t of the r e d b l o o d cells, showing a fall on the subsequent e x a m i n a t i o n s : in 28 cases on t h e f o u r t h day, a f u r t h e r f a l l in 19 on the sixth, in 16 on the eighth a n d in 7 o n the t e n t h day. T e n d e n c y to an increase is first n o t e d on the sixth day. The final figures are lower t h a n the initial in e v e r y i n f a n t r a n g i n g f r o m 84 to 10.2 p e r cent, w i t h 4 above 100. I n i t i a l h i g h r e a d i n g s at b i r t h which r a p i d l y fall to or below adult n o r m a l h a v e been r e p o r t e d by several (Schiff, 12 Williamson, 7 Fehrsen, 2G Lucas, 19 I t e i m a n n , 27 and TakasufS). Sanfor'd 2~ r e p o r t e d a h e m o g l o b i n r a n g e of f r o m 94 to 115 p e r cent. Goldbloom a n d Gottlieb ~ f o u n d initial values ranging from 114 to 98 with above i00 in 27 of 30. Final values at end of t h e w e e k were b e t w e e n 94 a n d 98 in e v e r y case b u t one which w a s 100. Fragility Test.--This was investigated in 14 consecutive cases, readings b e i n g m a d e on the second a n d t e n t h days. H e m o l y s i s b e g i n n i n g in dilutions of 0.48 p e r cent saline a n d over was considered as an increased f r a g i l i t y a n d a decreased resistance of t h e r e d blood ceils. A n increased f r a g i l i t y is n o t e d in 12 on the second day. A fall in f r a g i l i t y h a d o c c u r r e d b y the t e n t h d a y in 11 of the 14 cases; 8 show a f r a g i l i t y w i t h i n n o r m a l limits (0.40, to 0'.44 p e r cent) and 6 a slight increase (0.48 p e r cent). There is an increased f r a g i l i t y of the e r y t h r o c y t e s (a decreased resistance) w h i c h diminishes and tends to a p p r o a c h the n o r m a l figures on t h e t e n t h day. Goldbloom a n d Gottlieb 5 n o t e d an increased f r a g i l i t y in 19 of the 20 cases s t u d i e d b y t h e m at b i r t h a n d slightly g r e a t e r t h a n n o r m a l at the end of the w e e k in all but 2 instances. Clinical Jaundice.--Jaundice was discernible in 25 of the 30 infants. The onset is n o t e d on t h e second d a y in 19 instances a n d on t h e f o u r t h d a y in 6. The g r e a t e s t degree of jaundice is o b s e r v e d on t h e second d a y in 5, on the f o u r t h d a y in 15 a n d on the sixth d a y in 5 infants.
GOI~DON A N D K I g M E L H O R :
ICTEI~US N E O N A T O R U M
693
There was an entire absence or 1 plus degree of jaundice in 18 on the tenth day. B e r t h o n 29 n o t e d t h a t the highest point of cholemia in her series was on the t h i r d to f o u r t h days. CORt~ELATION BETWEEN THE VARIOUS COMPONENTS OF THE STUDY T h e r e is a definite relationship b e t w e e n t h e ieterus i n d e x values a n d t h e n u m b e r of r e d blood cells in the first six days. T h e r e is a simultaneous rise in the index and a fall in the erythr'oeytes in 20' instances on the second to the fourth days and in 12 on the fourth to the sixth days. This relationship is less apparent in the latter part of the week, being found in only 4 instances on the eighth day and in 3 on the tenth. The tendency of the icterus index is to fall after the sixth day irrespective of the rise or fall of the red blood cells. The hemoglobin values assume the same curve as the erythroeytes but with not as great variations. There seems to be a definite relationship in trend between the resistance of the red blood cells and the bilir]ibin content as shown by the coincidental occurrence of the highest point of fragility and the initial hyperbiliruhinemia with a subsequent drop in both fragility and icterus index values. E v e r y one of the i n f a n t s in this series showed a conc o m i t a n t high i n d e x a n d a n increased fragility, b u t there seems to be no f u r t h e r relation in v a r i a t i o n s in individual eases. T h a t is, high icterus index values are not always accompanied by high f r a g i l i t y figures or vice versa. There is a direct r e l a t i o n s h i p b e t w e e n the value of the icterus index a n d the i n t e n s i t y of clinical jaundice, as d e m o n s t r a t e d b y the following c o m p a r i s o n of the d e g r e e of discoloration a n d the a v e r a g e index values : 0 (no clinical jaundice), 14 units; 1 plus ja~mclice, 21 ~mits ; 2 plus jaundice, 31 units ; 3 plus jaundice, 42 units and 4 plus jaundice, 51 units. Clinical ~aundice was not noted until the icterus index reached 18. This was the lowest figure at which clinical jaundice was discernible a n d also the m a x i m u m at which no elinicaI m a n i f e s t a t i o n was present. The point r e a c h e d in our series is 3 units above t h a t r e p o r t e d b y Goldbloom a n d Gottlieb2 Manifest jaundice is m o s t intense d u r i n g the first six days, at a time w h e n t h e r e is the g r e a t e s t loss of e w t h r o c y t e s a n d d r o p in hemoglobin, increased f r a g i l i t y a n d highest ieter~s index. DIFFEaENC~S BETWEEN JAUNDmED AND NONJA~JNDIC~D INFANTS The icterus index values in the i n f a n t s who n e v e r developed jaundice are c o n s t a n t l y at a level which is t h e lowest in the series w i t h a r a n g e of f r o m 7 to 17 units. A n o t h e r i n f a n t with a 1 plus degree of jaundice on the second d a y h a d a n i n d e x of 24 b u t w i t h the d i s a p p e a r a n c e of jaundice on the n e x t day, the i n d e x d r o p p e d to 18, 12, 14 a n d 12 units on subsequent examinations.
694
THE
J O U R N A L OF P E D I A T R I C S
The hemoglobin figures in the n o n j a u n d i e e d infants are the lowest in the series, r a n g i n g from 92 to 82 p e r cent in 3 cases and f r o m t12 to 88 per cent in 2 others. There seems to be a more intimate relation between the hemoglobin content and the e r y t h r o c y t e values than t h a t between hemoglobin and jaundice as the higher hemoglobin figures are f o u n d in infants with counts above 5 million, irrespective of the degree of discoloration of the skin. The r e d blood cell count in n o n j a u n d i c e d infants does not show any p r o n o u n c e d variations from the general t r e n d even t h o u g h there seems to be a t e n d e n c y t o w a r d the lower range. Of the 5 cases, 3 had initial values of above 5 million cells. Lucas 19 did not observe a n y difference in the red blood cell count between the j a u n d i c e d and n o n j a u n d i c e d infants. SUMh~ARY A N D C O N C L U S I O N S
A study of the icterns index in relation to the number, hemoglobin content and f r a g i l i t y of the r e d blood cells in the p e r i p h e r a l blood of 30 n e w b o r n infants shows the following: 1. The i c t e r u s index d u r i n g the first ten days of life shows higher values t h a n at a n y other period u n d e r normal conditions. There is a rise and then a fall, the peak being reached on the sixth day. 2. The red blood cells show an initial po]ycythemia with a subsequent continuous drop in the first six days which is followed by an u p w a r d trend. The figures on the t e n t h day are below those of the second. 3. The hemoglobin content parallels the red blood cell count in both initial values and subsequent fall. 4. There is an initial increased f r a g i l i t y of the e r y t h r o c y t e s to saline which diminishes and tends to approach normal figures on the t e n t h day. 5. Manifest jaundice was present in 25 of 30 infants. The greatest degree of j a u n d i c e was observed in the first six days. There is a direct relationship between the degree of clinical jaundice and the icterus index values. E v e r y newborn i n f a n t has jaundice, either latent or manifest. 6. A definite relationship exists between the icterus index and the values of the e r y t h r o e y t e s and hemoglobin. The i n d e x rises and the other two components fall in the first six days, but the index falls in the l a t t e r p a r t of the week irrespective of a rise or fall in the other two elements. 7. Manifest jaundice is most intense at the time of greatest loss of e r y t h r o e y t e s and hemoglobin content, of increased f r a g i l i t y and of highest icter us index. 8. All of these conditions point to the hemolytic origin of icterus neonatorum.
GORDON AND KEI~IELHOR:
ICTERUS NEONATOlCUM
695
~EFERENCES
1. V a n den Bergh, H.: Presse m~d. l\lo. 45, 1921. 2. M e u l e n g r a c h t t E.: (a) Deutsches Arch. f. klin. Mad. 132: 285, 1920; (b) I d a m 137: 38, 1921. 3. V a n Croveld, S.: Am. J-. Dis. Child. 30, 240, 1925. 4. 1Y[itchell, J. 1VL: Am. J. Dis. Child. 36: 486, 1928. 5. Goldbloom, A., a n d Gottlieb~ 1%.: Am. 5. Dis. Child. 38: 57, 1929. 6. Rolleston, H.: P r a c t i t i o n e r 109: 1, 1922. 7. Williamson, A. C.: Surg. Gynec. & Obst. 37: 57, 1923. 8. Knopfelmaeher, W , a n d tt:ohn, C.: ]~[onatsehr. f. K i n d e r h . 22: 1~ 1921. 9. Cserna, S , a n d L i e b m a n n , S.: /~lin. Wchnschr. 2: 2122, 1923. 10. Zamora~li: Riv. di clin. pedlar. 21: 385, 1923. 11. Kramer, P . H . : Nederl. tijdschr, v. genaesk. 1: 249, 1926. 12. Schiff~ ~., and •arbar, E.: J a h r b . f. t(inderh. 97: 245, 1922. 13. u A.: Ztschr. f. Kinderh. 9: 208, 1913; Ergebn. d. ges. Mad. 5: 1924. 14. Hirsch~ A.: Ztschr. f. K i n d e r h . 9: 196, 1913. 15. ]~aue, H. P,: Surg. Gynee. & Obst. 34: 752~ 1923. 16. Bernhaim, Alice: 5. A. ~/I. A. 82: 291, 1924. 17. L a r r a b e e : Quoted b y Davis~ l~ef. 18. 18. Davis~ D.: Am. J. lYi. Sc. 172: 848, 1926. 19. Lueas, W. P., Dearing~ B. I%, Hoobler, H. R., Cox, A., Jones~ 1~. !~, and Smyth, F. S.: Am. 5. Dis. Child. 22: 525~ 1921. 20. Sanford, H . N . : Am. 5. Dis. Child. 35: 9, 1928. 21. Aitkin, 5.: 5. Obst. & Gynec. Brit. Emp. 1: 414, 1902. 22. P e r l i n : J a h r b . f. Kinderh. 58: 549, 1903. 23. Wiltiamson, C. S.: Arch. Int. ivied. 18: 505, 1916. 24. Ziegelroth, P.: ~/iiinchen. reed. Wchnschr. 73: 1440~ 1926. 25. Greil, A.: Ztschr. f. Geburtsh. u. Gyniik. 88: 628~ 1925. 26. Fekrsen, A. O.: 5. Physiol: 30: 322, 1903. 27. Heimann, 1%: Ztschr. f. Geburtsh. u. Gyn~k. 69: 165, 1911. 28. Takasu, K.: Arch. f. K i n d e r h . 39: 436, 1904. 29. Quoted b y Rocaz, C.: Am. 5. Dis. Child. 39: 1342, 1930.
MICHAEL C. KE~ELHOa, M.D. BROOKLYN, N. Y .
NY discussion of icterus n e o n a t o r u m must necessarily consider the genesis of bilirubin. The accepted opinion at present is that bilirubin is f o r m e d as an end-product from hemoglobin which is liberated upon destruction of the red blood cells. The various theories which have been a d v a n c e d are concerned with the factors involved in the formation of bilirubin f r o m hemoglobin and m a y be g r o u p e d u n d e r two main headings: the hepatogenous and extrahepatogenous. According to the hepatogenous theory, the f o r m a t i o n of bilirubin is one of the active functions of the hepatic polygonal cells, either independently or in conjunction with some other factor, such as increased e r y t h r o c y t i c destruction or the action of the reticuloendothelial sys~ tem. Icterus develops in one of two ways: (a) the bile pigment is f o r m e d normally, passes n o r m a l l y t h r o u g h the polygonal cells but is obstructed in the bile ducts; (b) the bile m a y be f o r m e d normally but is unable to pass t h r o u g h the liver because of c i r c u l a t o r y disturbance or damage to the polygonal cells themselves. The e x t r a h e p a t i c origin of bilimlbin is being stressed in recent studies. It is considered t h a t the cells of the reticuloendothelial system, especially those of the bone marrow, spleen and the K u p f f e r cells of the liver are concerned with the metabolism and f o r m a t i o n of bilirubin. The polygonal cells of the liver p l a y no p a r t in the f o r m a t i o n of bilirubin, t h e i r chief f u n c t i o n being the w i t h d r a w a l of this substance from the blood and its excretion in the bile. The hematogenous t h e o r y has f o r its basis an increased destruction of red blood cells and the excessive f o r m a t i o n of bilirubin in amounts above that which can be excreted b y the hepatic polygonal cells. The escape of l a r g e r amounts of hemoglobin m a y be due to an altered state of the e r y t h r o c y t e s themselves or to an increased fragility. The methods f o r the estimation of the a m o t m t of bi]irubin in the blood which are universally employed are the Van den B e r g h test 1 and the icterus index of Meulengracht. 2 The f o r m e r is the most accurate From the Pediatric Service of Israel-Zion Hospital, Brooklyn, N. Y. 685
686
TI4E
JOURNAL
O]~ P E D I A T R I C S
available m e t h o d f o r this d e t e r m i n a t i o n a n d also serves as a m e a n s of differentiation between h y p e r b i l i r u b i n e m i a due to o b s t r u c t i o n of the biliary p a s s a g e s a n d t h a t resulting f r o m excessive hemolysis or' hepathie disturbance. C o m p r e h e n s i v e reviews of the l i t e r a t u r e on ieterus n e o n a t o r u m h a v e been w r i t t e n r e c e n t l y b y V a n Creveld, 3 Mitchell 4 a n d Goldbloom and Gottlieb2 On the basis of a positive indirect V a n den B e r g h reaction in both cord a n d p e r i p h e r a l blood in the n e w b o r n , n u m e r o u s observers consider icterus n e o n a t o r u m to be of h e m a t o g e n o u s origin. (Rolleston, 6 Willia.mson, ~ K n o p f e l m a c h e r , 8 Cserna a n d L i e b m a n n , 9 Zamorani, 1~ K r a m e r , 11 Sehiff and F a t h e r , TM YlppS, 13 and H i r s e h 2 ~) The a m o u n t of bilirubin increases in the i n f a n t a f t e r birth, reaches the m a x i m u m b e t w e e n the first a n d s e v e n t h days a n d t h e n subsides. The degree of jaundice parallels the amount of bilirubin. The icterus i n d e x as originally described b y M e u l e n g r a e h t 2 and l a t e r modified b y Maue, 1~ Bernheim, 1G L a r r a b e e , ~ a n d Davis, ~s is a simpler a n d m o r e p r a c t i c a l but not as a c c u r a t e m e t h o d for' bilirubin estimation. The amount of bilirubin in the blood is fairly,constant 2or each individual u n d e r t h e same conditions, a n d ~in the a d u l t is considered to be between 4 a n d 6 or 5 a n d 7 units. Clinical j a u n d i c e is not recognizable, a n d p i g m e n t does not pass over into the urine w i t h an i n d e x lower t h a n ]5. L a t e n t jaundice is a h y p e r b i l i r u b i n e m i a with a content of 8 to 14 units w i t h o u t a n y clinical evidence of jaundice in t h e skin, sclera or urine. H i g h ieterus index values were f o u n d in the n e w b o r n b y Goldbloom a n d Gottlieb ~ who conclude t h a t icterus n e o n a t o r u m is a physiologic process a n d t h a t e v e r y n e w b o r n i n f a n t has jaundice irrespective of the presence or absence of its .clinical visibility. I e t e r ~ s was m a n i f e s t in all infants studied with an index of '~15 units or above. T h e y n o t e d a direct r e l a t i o n s h i p b e t w e e n the v a l u e of the ieterus i n d e x and the app e a r a n c e of jaundice. Closely associated w i t h the bilirubin content are the processes going on ia the r e d blood cells as evidenced b y t h e number, f r a g i l i t y a n d h e m o g l o b i n content of the e r y t h r o c y t e s . This has been studied recently b y Goldbloom and Gottlieb. The p r e s e n t r e p o r t is a s t u d y of this r e l a t i o n s h i p in icterus neonatorum. scoP~ oF STUDY D e t e r m i n a t i o n of e r y t h r o e y t e count, hemoglobin, icterus index and clinical jaundice were made on a group of 30 full-term, healthy newb o r ~ i n f a n t s in t h e N u r s e r y of th~ 1Vs W a r d of t h e Israel-Zion Hospital, r a n g i n g in age f r o m two to ten days. F i v e successive readings w e r e m a d e on the second, fourth, sixth, eighth and t e n t h days on
GORDON AND KlgMtSLHOR:
ICTEI~US NEON&TOI~UTM
687
each of these i n f a n t s d u r i n g its s t a y in the hospital. F r a g i l i t y tests were p e r f o r m e d u p o n t h e second a n d t e n t h d a y s on 14 of these. 2r The blood for examination was obtained by puncture of the external jugular vein. The ieterus index determinations were made by a comparison of diluted serum 1:4, with a standard 1:10,000 potassium biehromate solution in accordance with Bernheim's modification of the Moulengracht test.I6 Fragility tests were carried out with the use o5 graded saline solutions in 15 concentrations. Erythrocytes were counted in the usual manner with standardized pipettes. The Sahli method was employed for hemoglobin determination with standardized tubes and pipettes. Clinical jaundice was determined by yellowish discoloration of the skin, sclera and mucous membranes of the body, on a more or less arbitrary scale of 0, I plus, 2 plus, 3 plus and 4 plus. This grading is of course open to criticism as it is based upon personal equation but it is the most practical method for clinical application. Davis is points out that there are three sources of error in the determination of the ieterus index: (1) hemolysis, (2) lipemia, and (3) carotinemia. We noted early in the study t h a t there was a tendency to hemolysis, and to overcome this, all test tubes~ needles and syringes were scrupulously cleaned and dried. As a large degree of hemolysis still took place, it was decided to use only new glassware which had previously been soaked in distilled water for forty-eight hours. This last plan proved successful. All blood collected was immediately centrifuged and the serum separated. The second source of error was overcome to a great degree by drawing the blood before the 10 A.~t. nursing or feeding and the third by the fact that all the infants were obtaining either mother's or cow's milk. All determinations were made withirL twenty-four hours. RESULTS
Ieteruv I nde x . - - The icterns i n d e x d u r i n g the first ten d a y s shows h i g h e r v~Iues t h a n at a n y o t h e r period of life u n d e r n o r m a l conditions. A n o r m a l adult i n d e x of 4 to 6 units was not o b t a i n e d in a n y i n f a n t in this series. The lowest individual figure is 7 on the sixth d a y in an i n f a n t whose i n d e x r a n g e s f r o m 9 to 12 on the other days, a n d the highest is 60 in a child whose i n d e x on the other d a y s r a n g e s f r o m 27 to 48 units. The t r e n d of the i n d e x is to rise and t h e n fall as s h o w n b y tlle average figures of 21 units f o r the second day, 27 for the f o u r t h day, 28 f o r the sixth day, 25 f o r the eighth d a y a n d 21 f o r the t e n t h day. In s t u d y i n g the ieterus i n d e x of these respective days in each individual infant, we note t h a t in those w i t h m a n i f e s t jaundice, the figures on the t e n t h d a y are a b o v e the initial values in 11 instances a n d below these in 10. Of the l a t t e r t h e r e is the usual rise a n d subsequent fall in 8 and a continuous fall to below the initial values in 2. A rise followed by a fall to the original figures is n o t e d in 4 instances. The index c u r v e in i n f a n t s w i t h o u t discernible jaundice shows a r a n g e of f r o m 7 to i7 units w i t h only slight deviations f r o m the initial figures. Goldbloom a n d Gottlieb, ~ on the basis of d e t e r m i n a t i o n s m a d e by the Davis m e t h o d on p e r i p h e r M blood, repor~ values of 7 to 28 units at
688
THE JOURNAL OF PEDIATRICS TABLE I COMPLETE DA'rA OF STUDY
HE&X0(]LOBIN C]blNIGAL ICTERUS NO. AGE IN DAYSKEDBLOOD CELLS PERC~TAGB JAUNDICE INDEX 2 4 6 8 10
5,190,000 4 890,000 4,090,000 4,220,000 4,180,000
112 92 90 90 88
0 0 0 O 0
13 12 16 13 13
2 4 6 8 10
5,070,000 4,210,000 4,020,000 3,720,000 4,320,000
92 90 96 96 94
0 0 0 0 0
13 15 13 15 12
3.
2 4 6 8 10
6,410,000 6,190,000 5,980,000 4,970,000 5,350,000
104 102 98 98 98
1 1 2 2 I
plus plus plus plus plus
23 22 30 28 20
4.
2
5.
4 6 8 10 2 4 6 8 10
6,280,000 4,850,000 5,300,000 5,460,000 5,100,000 6,110,000 5,550,000 5,300,000 5,410,000 5,210,000
108 92 98 96 96 102 98 96 94 94
0 3 3 2 2 1 4 4 3 3
plus plus plus plus plus plus plus plus plus
14 30 32 26 24 18 45 52 40 36
6.
2 4 6 8 10
5,900,000 5,260,000 4,790,000 4,570,000 4,600,000
104 100 98 90 90
1 2 2 3 2
plus plus plus plus plus
20 32 32 48 34
7.
2 4 6 8 10
5,080,000 5,860,000 5,140,000 4,850,000 4,920,000
106 98 94 92 92
1 2 3 2 2
plus plus plus plus plus
19 32 48 28 24
8.
2 4 6 8 10
5,490,000 5,750,000 5,220,000 5,170,000 4,490,000
108 106 96 92 92
0 0 0 0 0
12 16 12 17 16
9.
2 4 6 8 10
5,390,000 5,230,000 4,270,000 4,710,000 4,560,000
104 94 94 92 90
0 2 plus 1 plus 1 plus 0
10 32 20 19 18
10.
2 4 6 8 10
5,560,000 5,770,000 4,690,000 4,810,000 4,900,000
106 104 98 98 90
1 plus 1 plus 1 plus 0 0
24 29 26 16 15
11.
2 4 6 8 10
4,580,000 4,120,000 4,140,000 4,530,000 4,600,000
94 92 92 82 84
0 0 0 0 0
10 12 7 10 9
FRAGILITY TEST
GORDON AND KEI~ELHOR:
ICTERUS I~EONAT0t~UM
689
TABLE I--CoNT'D NO.
12.
A G E I N D A Y S I%ED B L O O D CELLS
102 102
4 6 8 10
5,900,000 5,040,000 5,450,000 5,250,000 5,630,000
104 102 94 102 100
2 4 3 3 2
plus plus plus plus plus
30 50 40 34 28
14.
2 4 6 8 10
4,560,000 4,180,000 4,290,000 4,210,000 3,990,000
90 90 90 92 88
1 2 2 2 0
plus plus plus plus
24 32 35 30 18
15.
2 4 6 8 10
5,560,000 5,310,000 4,850,000 4,900,000 5,340~000
106 102 96 98 102
1 2 2 1 0
plus plus plus plus
24 27 23 20 18
16,
2 4 6 8 10
4,970,000 4,570,000 4,200,000 4,320,000 4,210,000
102 90 86 $8 88
0 1 plus 1 plus 1 plus 0
16 20 24 20 18
17.
2 4 6 8 10
5,310,000 5,200,000 4,450,000 4,500.000 4,730,000
104 102 90 90 94
2 2 3 2 1
plus plus plus plus plus
30 34 42 32 24
Begin .40 Complete .36
18.
2 4 6 8 10
4,520,000 4,430,000 4,600,000 4,790,000 4,820,000
96 90 92 94 92
1 plus 0 0 0 0
24 18 12 14 12
Begin .48 Complete .40
2 4 6 8 10
5,080,000 4,980,000 4,750,000 4,720,000 4,830;000
lO4
2 plus 1 plus
28
Begin .48 Complete .40
1 plus 0 0
20 22 17 18
Begin .40 Complete .36
20.
2 4 6 8 10
4,290,000 4,680,000 4,520,000 3,940,000 4,650,000
92 94 90 82 90
1 1 2 1 1
plus plus plus plus plus
20 23 26 26 22
Begin .48 Complete .40
21.
2 4 6 8 10
5,250,000 5,120,000 5,240,000 4,830,000 4,230,000
102 98 92 98 90
1 2 2 0 1
plus plus plus
Begin .52 Complete .40
plus
20 27 22 17 20
22.
2 4 6 8 10
6,170,000 6,220,000 5,790,000 5,860,000 5,460,000
112 108 104 98 98
1 1 3 2 1
plus plus plus plus plus
24 26 38 27 24
Begin .48 Complete .40
19.
112 102 I00
92 94 96 96
plus plus plus plus plus
30 34 30 32 26
I~RAGILIT~I T E S T
5,240,000
2
5,310,000 5,590,000 5,020,000 5,120,000
ICTEI~U S INDEX
2 2 2 2 2
13.
2 4 6 8 10
IIEM 0 G L O B I N C L I N I C A L PEI%OENTAGE JAUNDICE
Begin .40 Complete .36
Begin .40 Complete .36
Begin .48 Complete .36
Begin .48 Complete .36
Begin .44 Complete .40
THE JOURNAL OF PEDIATI%ICS
690
TABLE
NO. 23.
24.
I--CONT'D
R~D BLOOD ][IEIMOGL.ORINC'LINIOAL IC:TFA%US IVRAGIL~TYTEST D&YS ~ELLS PEE,C~ENT'AGE JAU~TDICE INDEX Begin .44 Complete 2 5,460,000 106 1 plus 27 4 4,320,000 86 4 plus 60 6 5,190,000 96 3 plus 48 8 4,890,000 92 3 plus 48 Begin .48 Complete 10 4,460,000 92 3 plus 35 Begin .52 Complete 2 4,690,000 96 1 plus 27 4 4,250,000 90 2 plus 30 6 4,010,000 86 1 plus 26 8 4,260,000 90 1 plus 20 Begin .48 Complete 10 4,390,000 90 0 17
A G E IN
18 30 35 30 28
Begin .60 Complete .48
0 2 2 1 1
Begin .48 Complete .44
plus plus plus plus
15 28 30 26 27
1 2 2 1 1
plus plus plus plus plus
24 32 34 30 27
Begin .52 Complete .44
108 102 96 98 98
0 1 plus 1 plus 1 plus 0
18 25 28 23 18
Begin .52 Complete .44
108 106 102 100 102
1 2 2 2 1
27 34 38 30 28
Begin .52 Complete .44
2 4 6 8 10
4,950,000 4,720,000 4,900,000 4,860,000 4,980,000
96 94 94 94 94
0 2 2 1 1
2 4 6 8 10
6,150,000 5,250,000 4,980,000 4,720,000 4,860,000
104 98 98 96 96
28.
2 4 6 8 10
5,650,000 5,210,000 4,860,000 4,960,000 4,890,000
96 94 92 92 94
29.
2 4 6 8 10
6,100,000 5,660~000 5,120,000 5,210,000 5,110,000
2 4 6 8 10
5,210,000 5,080,000 4,910,000 4,860,000 4,900,000
30.
.40
plus plus plus plus
10
0 0 0 0 0
27.
.44
Begin .52 Complete .44
94 88 94 90 92
26.
2 4 2 8
.40
12 11 11 10 14
4,430,000 3,650,000 4,240,000 3,940,000 3,890,000
25.
.40
plus plus plus plus plus
Begin .44 Complete .36
Begin .48 Complete .40
Begin .44 Complete .40
Begin .48 Complete. 40
Begin .44 Complete .40
Begin .44 Complete .40
b i r t h a n d o f 3 t o 30 u n i t s o n t h e t e n t h day. T h e y do n o t i n c l u d e figures noted in t h e i n t e r v e n i n g period. The values for the t e n t h day w e r e h i g h e r i n t h o s e i n f a n t s w h o h a d d e v e l o p e d j a u n d i c e a n d l o w e r in those who did not. t n the latter, t h e r e was a fall to n e a r l y the n o r m a l in about six days.
Erythrocytes.--There is an i n i t i a l p o l y c y t h e m i a (i.e., t a k e n on t h e s e c o n d d a y ) i n 22 of t h e 30 cases d i s t r i b u t e d as follows" Above 6 m i l l i o n , 6 ; b e t w e e n 5 a n d 6 m i l l i o n , 16 ; b e t w e e n 41/2 a n d 5 m i l l i o n , 6 ; a n d b e l o w 41/2 m i l l i o n , 2. T h e h i g h e s t i n i t i a l c o u n t is 6,410,000; t h e l o w e s t 4,290,000. a v e r a g e f o r t h e 30 i n f a n t s on t h e s e c o n d d a y is 5,354,000.
The
GORDON AND K E ~ [ E L H O R :
691
ICTERUS NE01qATORUM
TABLE II
TItE AVEKAGE CUI~VES OF ]~ED BLOOD CELL, I~EMOSLOBIN, ICTEI~US, INDEX AND FI~AGII,ITY WITH THEIIr I~ELATIONSHIP TO ON~ ANOTttEI~
R.B.6. H.B.~ ,~OD,O00t 106 %
GRAPH I. AVERAGE
R.i).6. A.o
IK.B,~
4, ,~oo,oeol
4, ~'oo,o0oI .q~ %
30
~.
_GRAPH/'?'. AVERAGE ICTERU3/NDEX.
28
~2,f
"~" 2 0 /8
~
~
~
7o
DAYS
GRAPHI~. AVERAGEfRAG/Z/TYOFR.,B:C. .5O
.48
~ # / , r
G
. 4~ .42
~, .38 .36 _ _
The p o l y c y t h e m i a shows a d o w n w a r d t r e n d almost i m m e d i a t e l y as d e m o n s t r a t e d b y the difference b e t w e e n the samples t a k e n on the second and f o u r t h days. The fall in the total n u m b e r of erythrocytes is most m a r k e d in t h e first six days a n d was f o u n d in 25 ~nstances on the f o u r t h d a y followed b y f u r t h e r falls i n 20 on the sixth day, in 14 on the eighth d a y a n d in 13 on the last d a y of t h e s t u d y . F r o m the s i x t h d a y on there is a tendency to recompense for the e a r l y loss b y a g r a d u a l increase in the t o t a l number, but in spite of
692
TI-IE J O U R N A L
OF P E D I A T R I C S
this the final values are definitely l o w e r t h a n the initial ones as shown in 27 of the 30 cases. The r a n g e on the t e n t h d a y is f r o m 3,800,000 to 5,630,000 with an average of 4,761,000. Goldbloom a n d Gottlieb 5 r e p o r t erythrocyte values of f r o m 6,900,000 at b i r t h to 4,250,000 in 180 h o u r s (71/2 days) w i t h a subsequent rise to 4,500,000. L u c a s a n d c o w o r k e r s ~9 obtained a m a x i m u m of 6,700,000, a m i n i m u m of 4,500,000 and an a v e r a g e of 5,511,000. S a n f o r d 2~ f o u n d a count of 5,800,000 to 4,500,000. Others h a v e m a d e similar observations of an initial h i g h count and subsequent d r o p (Aitkin, 21 Perlin, 22 Williamson, 2~ Ziegelroth 2~ a n d Greil25).
HemogIobin.--Values above 100 p e r cent (Sahli) are p r e s e n t in 21 of the 30 cases on the second day. The initial values r a n g e f r o m 112 to 92 p e r cent. The h e m o g l o b i n curve simulates t h a t of the r e d b l o o d cells, showing a fall on the subsequent e x a m i n a t i o n s : in 28 cases on t h e f o u r t h day, a f u r t h e r f a l l in 19 on the sixth, in 16 on the eighth a n d in 7 o n the t e n t h day. T e n d e n c y to an increase is first n o t e d on the sixth day. The final figures are lower t h a n the initial in e v e r y i n f a n t r a n g i n g f r o m 84 to 10.2 p e r cent, w i t h 4 above 100. I n i t i a l h i g h r e a d i n g s at b i r t h which r a p i d l y fall to or below adult n o r m a l h a v e been r e p o r t e d by several (Schiff, 12 Williamson, 7 Fehrsen, 2G Lucas, 19 I t e i m a n n , 27 and TakasufS). Sanfor'd 2~ r e p o r t e d a h e m o g l o b i n r a n g e of f r o m 94 to 115 p e r cent. Goldbloom a n d Gottlieb ~ f o u n d initial values ranging from 114 to 98 with above i00 in 27 of 30. Final values at end of t h e w e e k were b e t w e e n 94 a n d 98 in e v e r y case b u t one which w a s 100. Fragility Test.--This was investigated in 14 consecutive cases, readings b e i n g m a d e on the second a n d t e n t h days. H e m o l y s i s b e g i n n i n g in dilutions of 0.48 p e r cent saline a n d over was considered as an increased f r a g i l i t y a n d a decreased resistance of t h e r e d blood ceils. A n increased f r a g i l i t y is n o t e d in 12 on the second day. A fall in f r a g i l i t y h a d o c c u r r e d b y the t e n t h d a y in 11 of the 14 cases; 8 show a f r a g i l i t y w i t h i n n o r m a l limits (0.40, to 0'.44 p e r cent) and 6 a slight increase (0.48 p e r cent). There is an increased f r a g i l i t y of the e r y t h r o c y t e s (a decreased resistance) w h i c h diminishes and tends to a p p r o a c h the n o r m a l figures on t h e t e n t h day. Goldbloom a n d Gottlieb 5 n o t e d an increased f r a g i l i t y in 19 of the 20 cases s t u d i e d b y t h e m at b i r t h a n d slightly g r e a t e r t h a n n o r m a l at the end of the w e e k in all but 2 instances. Clinical Jaundice.--Jaundice was discernible in 25 of the 30 infants. The onset is n o t e d on t h e second d a y in 19 instances a n d on t h e f o u r t h d a y in 6. The g r e a t e s t degree of jaundice is o b s e r v e d on t h e second d a y in 5, on the f o u r t h d a y in 15 a n d on the sixth d a y in 5 infants.
GOI~DON A N D K I g M E L H O R :
ICTEI~US N E O N A T O R U M
693
There was an entire absence or 1 plus degree of jaundice in 18 on the tenth day. B e r t h o n 29 n o t e d t h a t the highest point of cholemia in her series was on the t h i r d to f o u r t h days. CORt~ELATION BETWEEN THE VARIOUS COMPONENTS OF THE STUDY T h e r e is a definite relationship b e t w e e n t h e ieterus i n d e x values a n d t h e n u m b e r of r e d blood cells in the first six days. T h e r e is a simultaneous rise in the index and a fall in the erythr'oeytes in 20' instances on the second to the fourth days and in 12 on the fourth to the sixth days. This relationship is less apparent in the latter part of the week, being found in only 4 instances on the eighth day and in 3 on the tenth. The tendency of the icterus index is to fall after the sixth day irrespective of the rise or fall of the red blood cells. The hemoglobin values assume the same curve as the erythroeytes but with not as great variations. There seems to be a definite relationship in trend between the resistance of the red blood cells and the bilir]ibin content as shown by the coincidental occurrence of the highest point of fragility and the initial hyperbiliruhinemia with a subsequent drop in both fragility and icterus index values. E v e r y one of the i n f a n t s in this series showed a conc o m i t a n t high i n d e x a n d a n increased fragility, b u t there seems to be no f u r t h e r relation in v a r i a t i o n s in individual eases. T h a t is, high icterus index values are not always accompanied by high f r a g i l i t y figures or vice versa. There is a direct r e l a t i o n s h i p b e t w e e n the value of the icterus index a n d the i n t e n s i t y of clinical jaundice, as d e m o n s t r a t e d b y the following c o m p a r i s o n of the d e g r e e of discoloration a n d the a v e r a g e index values : 0 (no clinical jaundice), 14 units; 1 plus ja~mclice, 21 ~mits ; 2 plus jaundice, 31 units ; 3 plus jaundice, 42 units and 4 plus jaundice, 51 units. Clinical ~aundice was not noted until the icterus index reached 18. This was the lowest figure at which clinical jaundice was discernible a n d also the m a x i m u m at which no elinicaI m a n i f e s t a t i o n was present. The point r e a c h e d in our series is 3 units above t h a t r e p o r t e d b y Goldbloom a n d Gottlieb2 Manifest jaundice is m o s t intense d u r i n g the first six days, at a time w h e n t h e r e is the g r e a t e s t loss of e w t h r o c y t e s a n d d r o p in hemoglobin, increased f r a g i l i t y a n d highest ieter~s index. DIFFEaENC~S BETWEEN JAUNDmED AND NONJA~JNDIC~D INFANTS The icterus index values in the i n f a n t s who n e v e r developed jaundice are c o n s t a n t l y at a level which is t h e lowest in the series w i t h a r a n g e of f r o m 7 to 17 units. A n o t h e r i n f a n t with a 1 plus degree of jaundice on the second d a y h a d a n i n d e x of 24 b u t w i t h the d i s a p p e a r a n c e of jaundice on the n e x t day, the i n d e x d r o p p e d to 18, 12, 14 a n d 12 units on subsequent examinations.
694
THE
J O U R N A L OF P E D I A T R I C S
The hemoglobin figures in the n o n j a u n d i e e d infants are the lowest in the series, r a n g i n g from 92 to 82 p e r cent in 3 cases and f r o m t12 to 88 per cent in 2 others. There seems to be a more intimate relation between the hemoglobin content and the e r y t h r o c y t e values than t h a t between hemoglobin and jaundice as the higher hemoglobin figures are f o u n d in infants with counts above 5 million, irrespective of the degree of discoloration of the skin. The r e d blood cell count in n o n j a u n d i c e d infants does not show any p r o n o u n c e d variations from the general t r e n d even t h o u g h there seems to be a t e n d e n c y t o w a r d the lower range. Of the 5 cases, 3 had initial values of above 5 million cells. Lucas 19 did not observe a n y difference in the red blood cell count between the j a u n d i c e d and n o n j a u n d i c e d infants. SUMh~ARY A N D C O N C L U S I O N S
A study of the icterns index in relation to the number, hemoglobin content and f r a g i l i t y of the r e d blood cells in the p e r i p h e r a l blood of 30 n e w b o r n infants shows the following: 1. The i c t e r u s index d u r i n g the first ten days of life shows higher values t h a n at a n y other period u n d e r normal conditions. There is a rise and then a fall, the peak being reached on the sixth day. 2. The red blood cells show an initial po]ycythemia with a subsequent continuous drop in the first six days which is followed by an u p w a r d trend. The figures on the t e n t h day are below those of the second. 3. The hemoglobin content parallels the red blood cell count in both initial values and subsequent fall. 4. There is an initial increased f r a g i l i t y of the e r y t h r o c y t e s to saline which diminishes and tends to approach normal figures on the t e n t h day. 5. Manifest jaundice was present in 25 of 30 infants. The greatest degree of j a u n d i c e was observed in the first six days. There is a direct relationship between the degree of clinical jaundice and the icterus index values. E v e r y newborn i n f a n t has jaundice, either latent or manifest. 6. A definite relationship exists between the icterus index and the values of the e r y t h r o e y t e s and hemoglobin. The i n d e x rises and the other two components fall in the first six days, but the index falls in the l a t t e r p a r t of the week irrespective of a rise or fall in the other two elements. 7. Manifest jaundice is most intense at the time of greatest loss of e r y t h r o e y t e s and hemoglobin content, of increased f r a g i l i t y and of highest icter us index. 8. All of these conditions point to the hemolytic origin of icterus neonatorum.
GORDON AND KEI~IELHOR:
ICTERUS NEONATOlCUM
695
~EFERENCES
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