THE
RESPIRATORY
DISTRESS
SYNDROME
OF
PREMATURITY
I. Changes
in Potassium inthe
Serum
and
the
Electrocardiogram
and
Effects
of
Therapy
Robert Usher, M.D.
Departments of Obstetrics and Pediatrics, Royal Victoria Hospital, Montreal
(Accepted May 7, 1959; submitted October 22, 1958.)
These studies were carried out with the aid of a National Health Grant (Canada). ADDRESS: Montreal 2, Canada.
PnrATiucs, October 1959
562
T
HE MORTALITY rate for prematurein-fants during the first 5 days of life is
the same today1 as it was in Yllpo’s large
series2 40 years ago. Most premature infants
who die within this period show pathologic findings restricted to the lungs. The post-mortem picture has been called congestive
pulmonary failure (resorption atelectasis with hyaline-like membrane) by Potter.3 The
clinical course, usually 1 to 3 days in
dura-tion, is marked by respiratory distress and
is sufficiently constant to be termed the
respiratory distress syndrome.’
A detailed clinical and laboratory
inves-tigation of premature infants with
respira-tory distress syndrome has been in progress
at this hospital since July, 1957. Serial
ob-servations have been made over the 3-day
course with the main emphasis on the
respir-atory, cardiovascular and metabolic aspects
of the disease process.
The following is the first of a series of
reports on the findings obtained in this
study. This report presents data on the
concentrations of potassium in the serum
and
the
electrocardiograms
both
in infants
with respiratory distress syndrome and
con-trol infants. The effect of parenteral fluid
therapy in some of the affected subjects is
described.
There have been few previous clinical
studies of this syndrome. In the absence of
an adequate specffic clinical description in
the literature, the following definition of the respiratory distress syndrome of prematurity has been used in this study:
Infants weighing 500 to 2,500 gm who for
hours or days after birth have retraction of the
chest, expiratory grunting, and decreased entry of air on auscultation, without evidence of other
coexisting disease.
This working definition excludes other
causes of neonatal respiratory distress such
as pneumonia, meconium aspiration
syn-drome, or congenital heart disease. In fatal
cases of this syndrome, the postmortem
examination revealed only pulmonary
atel-ectasis with hyaline membrane formation, pulmonary congestion, and occasional sub-arachnoid hemorrhages.
SUBJECTS AND METHODS
Fifty-nine premature infants with respiratory
distress syndrome, 45 premature infants
with-out respiratory distress syndrome and 13
nor-mal full-term infants were studied (Table I).
The 59 infants with respiratory distress syn-drome included 47 available for study at this
hospital (of 57 premature infants who
devel-oped the syndrome during the past 18 months), and 12 seen at other hospitals. Of the total
69 patients with respiratory distress syndrome,
38 died, a mortality rate of 55%.
The premature infants without respiratory
distress syndrome were selected solely on the basis of absence of chest retraction and grunt-ing after birth. They followed a normal course for premature infants, all but three surviving. The three deaths occurred at 3 to 9 days of age
in infants weighing 1,100 to 1,300 gm. There
were no diagnostic postmortem findings on
two of these infants; the third showed severe bronchopneumonia.
All premature infants were given high
hu-midity without supersaturation, and
environ-mental temperatures of 29 to 32#{176}C.Feedings
were started at 12 to 24 hours of age in
TABLE I
.
Procedures Electrocardwgrams Concentration. of in Serum
Polassiurn
Num- Mean Num- Num- 1!ean
Num-ber Weight ber ber Weight ber
Case.s (gm) EKG’s Cases (gm) Tests
26
66
Is
105
ARTICLES 563
Premature infants without respiratory (listress syndrome
Premature infants with respiratory distress syndrome
Normal full-term infants
Total 117
45 1,750 143 11 1,810
59 1,50 195 40 1,660
13 3,190 13 13 3,19()
351 64
respiratory distress syndrome. The patients with
respiratory distress syndrome were given
sup-plemental oxygen for cyanosis.
Serial physical examinations were done by the author at 6- to 12-hour intervals during the first 4 days of life. Roentgenograms of the
chests of 15 of the patients with respiratory
dis-tress syndrome were made to help verify the
diagnosis; all showed the typical
reticulogranu-lar pattern.4’ Repeated electrocardiograms
were made and occasional blood samples taken.
There were 351 electrocardiograms and 105
determinations of the concentration of
potas-sium in the serum made in all, on 117 infants.
In 24 patients with respiratory distress
syn-drome during the latter half of the study, the
effect of parenteral fluid therapy on the electro-cardiogram and the concentration of
potas-sium in the serum was evaluated.
Determinations of the concentration of
potas-sium in the serum were done in duplicate on
a flame photometer. The blood was usually obtained from the umbilical or femoral vein
amid in sonic cases from heel prick. There was
ho significant difference (p greater than 0.500)
between the means of results obtained from venous (6.08 meq/1) and capillary blood (6.20
meq/l) in controls. In all samples the serum was separated from the cells within 2 hours
(usually within 1 hour) of blood drawing;
hemolyzed specimens were rejected.
The electrocardiograms were made with a Sanborn direct-writing Viso-Cardiette#{174}
ma-chine, using both standard and chest leads. The PR interval was measured in lead II and
the QRS interval in the chest lead with the largest QRS duration-usually V4.
In addition, serial electrocardiograms were
made on abnormal controls who had other
forms of neonatal respiratory insufficiency. Five
300- to 800-gm fetuses who died within 12
hours of birth were studied. They were cyanotic
and had recurrent apneic spells, but did not show the retraction and grunting seen with the respiratory distress syndrome. Serial electro-cardiograms were also made of three full-term
infants with meconium aspiration syndrome and two with pneumonia.
RESU LTS
Electrocardiograms
Early in the study it became apparent
that electrocardiographic abnormalities
ap-peared after 12 hours of age in infants with
respiratory distress syndrome, but not in
control infants.
EicmocuirnocnMs OF CONTROLS: In
premature infants without respiratory
dis-tress syndrome the duration of PR and
QRS showed no change with age (Figs. 1
and 2). In only 3 of 143 electrocardiograms
made of these infants were the PR and QRS prolonged beyond 0.11 and 0.04 seconds, respectively. There was characteristically a
flat or absent T wave at birth which
be-came larger after the second day, and right axis deviation with right ventricular
pre-ponderance in the chest leads. Thirteen
full-term controls had PR and QRS durations
which did not exceed values found in the
premature infants. A more complete
de-scription of
the
serial
electrocardiographicchanges with age in the normal will be
pre-sented
in a
later report.se-.16] S. S.
-5]
.14] 5 5
.13] #{149}5.SS
.12} ...
I
SECONDS.11 #{149}
J,$.
5#{149} S #{149}#{149}#{149}S.I0
bc?
00 !8.. .s: . S 00 0 0
0 8 4%oO 0 0 0 O08
#{149}O7]o.oOo o o
1
S .
0 0
#{149}0 S
0 0
AGE (hr)
- U_I,.,. U
yO 50 90 100 110
564 RESPIRATORY DISTRESS SYNDROME
.J ,-,-..I.I. U
0 tO 20 30 40 50 60
. .
S ‘ DISTRESS
C S NORMAL
FIG. 1. Duration of PR interval at different ages in the first 5 days of life
nicas-ured on 147 electrocardiograms made from 52 premature infants with respiratory
distress syndrome and 102 electrocardiograms made from 42 premature infants without respiratory distress syndrome. The mean PR duration between 12 and 60 hours of age was 0.086 seconds in control infants and 0. 1 12 seconds in infants with respiratory distress syndrome. This difference is statistically significant
(t :9.41;pless than 0.001).
vere respiratory distress from other causes) showed electrocardiographic conduction times similar to the normals. Hourly trac-ings on dying fetuses, in spite of marked
bradycardia, always showed normal
conduc-tion up to the moment of death (Fig. 3).
Serial tracings of all five full-term infants
with pneumonia or meconium aspiration
syndrome were also normal.
ELECTROCARDIOGRAM OF INFANTS WITH
RESPIRATORY DISTRESS SYNDROME : Although
similar to those in controls at birth, the
electrocardiograms in premature infants
with respiratory distress syndrome devel-oped the following abnormalities between
12 and 60 hours of age:
1. Prolongation of the PR interval over
0.11 seconds.
2. Prolongation of the QRS interval over
0.04 seconds.
3. Decreased QRS voltage in the
stand-ard leads.
4. Prolongation of the QT interval.
5. Broadening andi flattening of the P
wave.
6. Left axis deviation and left ventricular
preponderance.
7. Absence of P waves.
8. Peaked T waves.
9. Two-to-one atrioventricu lar heart
block.
The first six disturbances appeared in
most cases. Peaked T waves were less
fre-quent, and absence of P waves and
two-to-one atrioventricular block each appeared in
ap-155 5 5
S S S
S ‘ DISTRESS
0
#{149}
NORMALS 8
OS S
S
0 SO
#{149}5 S
. U11’
70 SO 90. 100 110
AGE (hr)
lm(;. 2. Duration of QRS interval at different ages in the first 5 days of life measured on
147 electrocardiograms miade from 52 premature infants with respiratory distress
syn-(Ironic and 102 electrocardiogranis made from 42 premature infants without respiratory
(listress syn(lrOmiie. The mean QRS duration between 12 and 60 hours of age was 0.035
S(COflds in control infants and 0.052 seconds in infants with respiratory distress syndrome. This difference is statistically significant (t :4.84; p less than 0.001).
II
hrs.
45mm.
II
hrs.
55 mm.
1I(;. .3. Terminal
electrocardio-grams ( lead II) on a very
imma-tore fetus weighing 610 gm who
died at age 12 hours after a cya-notic course with repeated apneic spells. Electrocardiographic con-duction was normal on serial
frac-ings up to minutes before death.
200 40
20 120
‘I 00] ‘095
J
.090] 5 .
‘085]
080] S
075]
‘070]
.06 5]
1.060J SSSSS I S
I
SECONDSI.055j S1#{149} S S.050)D SSS4 S S S 55 5
045) IS $) . j
:
oc4k#{149}035 .‘ 0 SO 050
.O300S% #{243}0 5 00 SO 0
.025&5cS 8. o
.02OJo0S 0.
I-’ I ‘ I ‘ I ‘ #{149}I ‘
0 10 20 30 40 50 50
peared after 12 hours of age. They increased until death in fatal cases and disappeared
with recovery in survivors. Examples of the
electrocardiographic changes in three cases
___________________________ are presented in Figures 4 to 6.
The most constant and easily recognized
changes were in the durations of the PR
and QRS intervals. These intervals are
com-_____________________ pared in Figures 1 and 2 with those found
_____
in premature infants without respiratorydis-_________________________
tress syndrome. The mean durations of PRand QRS intervals were both significantly
longer in patients with respiratory distress
syndrome than in the infants without
respir-atory distress syndrome between 12 and 60
hours of age (p less than 0.001
),
though notbefore or after this period. These conduc-tion differences were unrelated to rate; the
566 RESPIRATORY DISTRESS SYNDROME
AGE
I’hrs
3lhrs
43hrs
69hrs
I
rtr
+*+
]I
______________
__oVR
VL
aVF
__
_
v4R
_
- .
_
vi
v2
V
__
__
__
v6_
_
FIG. 4. Serial electrocardiograms made from a 1,200-gm infant with respiratory distress syndrome who survived. At 1 hours of age there was retraction of the
chest and grunting and electrocardiogram showed normal axis and conduction.
At 31 hours of age there was marked flaccidity and duskiness and
electro-cardiogram showed prolonged PR, QRS and QT with left axis deviation and
left ventricular preponderance. At 43 hours of age there was improved tone and color and electrocardiogram was returning to normal. At 69 hours of age there was continued clinical improvement and electrocardiogram had returned
to normal.
distress syndrome was 138/mm and for
controls was 144/mm.
The incidence of PR and QRS
prolonga-tion in respiratory distress syndrome is
pre-sented in Figure 7 for different time periods
during the first 4 days of life. While only
8% of the tracings made of infants with
____
33
hrs
132
hrs
LA& 14
________
__________
-1--f -1- 1 1 11t . #{149} .:. #{149} .#{149}:ii:
__
___
1ff
..1_ ta
V R
_____
aVL_
aVF
_
v4R
__
VI
_
_
ILALM J.i.
____
I
I ‘#{149}-i I . :#{149}.:.iiiii
F ___
____
V
4 __________
___
1v!vVt’
Lll jJJ______
V
6
___FIG. 5. Serial electrocardiograms made from a 1,100-gm infant with respiratory distress syndrome who survived. At 21 hours of age there was retraction of the chest, grunting and edema and the QRS interval was prolonged. At 223k hours of
age there was two-to-one atrioventricular block with shorter QRS, left axis
devia-tion and left ventricular preponderance. At 33 hours of age there was clinical
improvement and the electrocardiogram was returning to normal but left
yen-tricular preponderance remained. At 132 hours of age there was no respiratory distress but apneic spells were frequent. Electrocardiogram was normal.
ARTICLES 567
AGE
21
hrs
22
hrs
I
#{149}:::.#{149}‘#{149}#{149}#{149}‘ ‘r1nTr,
.--tf.::t...A.i. :I-L.l Li 1
..
first 6 hours of life showed prolonged
con-duction, 75% of those made between 12 and
48 hours were abnormal. Thirty-six of 37
infants with respiratory distress syndrome
who had more than one tracing between
12 and 60 hours of age showed these
abnor-malities in conduction at some time. All but four of the infants who died with
respira-tory distress syndrome showed
35
hrs
v4
568 RESPIRATORY DISTRESS SYN l)RONI E
AGE
13hrs
18
hrs
I
j4
=
‘Ii
ciVR
rv
aVL
4-+*
aVF
V
4 R
tr
V
IJ(JftJ
4rr--1
i- _p! I,
_
‘:-.V
2
NjIJ
;drrAInr
ti:
t1”’
-r-I4
v6_
_
Fic. 6. Serial electrocardiogramiis made from a 1,500-gin infant with
r-spiratory distress syndrome who died at agc 40 hours. At 1:3 hours of agc
there was retraction, grunting, and edenut with prolonged PR and QRS
intervals. At 18 hours of age electrocardiographic conduction was
worsen-ing with left axis deviation and left ventricular preponderance. At :35 hours of age there was flaccidity, sclerema, bradycardia and absence of P waves, peaked T wave, disruption of QES complex. The concentration of potassium
in the serum at this time was 10.7 meq/l.
last 12 hours of life; three of the four who Concentration of Potassium in Serum
did
not
develop abnormalities died before The resemblance of theseelectrocardio-12 hours of age. The average duration of graphic changes to those reported in
hyper-the electrocardiographic disturbance in the kalemic states (see Discussion
)
prompted anindividual case was 36 hours in both dying investigation of the associated concentration
TABLE II
(oNcENTItATIoNs 01? PoTAssIuo IN SEuuM oF
MATURE INFANTS “,%!TIIOUT REsPIRATORY
1)msrmsF:ss SYNDROME
Birth (‘oncenira- Age
Jl7eight lratwrm
----(get) (rneq/l) (days) (ler)
0 6 2 6 24 36 48 96
13
ii
Si
G’)
‘24
13 16
4
1
a iz
6
5 1
7
54
1 1
was present when the concentration of
p0-tassiurn was below 7.0 meq/l and that
con-duction was prolonged with concentrations
of potassium over 7.0 meq/l.
The mean concentration of potassium in
the serum rose from 5.1 meq/1 in the first
6 hours of life to 9.0 meq/1 at 18 to 24
hours of age, and fell again after 48 hours
of age. A curve of the incidence of
“abnor-mal” electrocardiograms at different ages in
infants with respiratory distress syndrome is
superimilpose(l 011 the curve of niean
concen-FIG. 7. Incidence of prolonged conduction (solid
columns) at different ages during the first 4 days of life in 149 electrocardiograms niade from
prc-mature infants with respiratory distress syndrome.
Conduction was considered prolonged if PR
in-terval was more than 0.11 seconds or QRS interval
more than 0.04 seconds.
CONCENTRATION OF POTASSIUM IN
CON-TROLS : Thirty-nine determinations of the concentration of potassium in the serum
were performed on 11 premature infants
without respiratory distress syndrome
(Table II) and 13 normal full-term infants.
Twenty-four of these determinations were
made during the important 12- to 60-hour
age period, and were associated with
“nor-mal” electrocardiograms made
simultane-ously. The concentration of potassium
dur-ing this period ranged from 4.2 to 7.0 meq/l
(
mean 6.09) for the premature, and 5.1 to6.8 meq/1 (mean 6.01) for the full-term
in-fants.
CONCENTRATION OF POTASSIUM IN INFANTS WITH RESPIRATORY DISTRESS SYNDROME : The
concentrations of potassium found in infants
with respiratory distress syndrome are
re-ported in Table III. The individual
concen-trations of potassium are plotted against age
in the scattergram (Fig. 8
)
. Theconduc-tion times on simultaneously made
electro-cardiograms are indicated as normal or
pro-longed by open and solid circles,
respec-tively. It is evident that normal conduction
10.
ARTICLES 569
1. 1,100 6.0 1
). 1,110 6.8 1
3. 1,300 7.4
6.9 1
4. 1,510 .5.3
6.4 10
o:i so
:5. 1,590 4.4
6.1
6.7 6
6. 1,690 6.1)
7.3 7.1
7. ‘2,044) 6.7
7.0 1
6. 8
8. 2,240 4.1
4.2 1
6.3 9
9. 2,410 5.7
6.6
2,470 6.2
5.’2 6.2
11. 6.1
Birth Concen- Age at
Weight tratwn Age (hr) Death
(gm) (meq/l) (hr)
Birth Concen- Age at
Weight tration Age (hr) Death
(gm) (meq/l) (hr)
1. 1,800 6.4 14 64
. 1,800 10.5 16 144
23. 1,860 7.5
9.7
W
29
Lived
24. 1,860 4.8 3 Lived
25. 1,860 8.9
11.7 9.1 12 25 43 52
26. 1,870 6.0 6 45
27. 1,880 7.4
6.4
36
312
Lived
28. 1,930 10.7 32 52
29. 1,950 5.6 34 Lived
30. 2,090 7.9 33 345
31. 2,090 8.5 38 Lived
32. 2,130 7.4
10.3
15
26
47
83. 2,140 4.4 96 Lived
34. 2,160 6.7 34 44
35. 2,240 5.2
7.7 6.5 3 20 .53 Lived 36. 2,250 87. 2,330
1. 740 5.3 13 30
8.2 20
2. 900 9.3 99 113
3. 1,000 8.2 17 23
4. 1,110 9.0 18 26
5. 1,180 7.1 26 27
6. 1,240 8.9 12 Lived
7. 1,250 5.3 4 Lived
3.3 216
8. 1
,
270 6.3 60 Lived9. 1,300 5.4 2 28
7.0 8.9
25 26
10. 1,340 4.4 5 105
8.6 104
11. 1,370 5.9
10.6
34
14
18
12. 1,390 5.2 14 34
13. 1,400 6.2 4 144
6.2 15
14. 1,500 6.0 5
7.9
9.5
26
27
15. 1,500 10.7 36 40
16. 1,520 5.6 13 Lived
17. 1,600 12.7 18 80
18. 1,670 6.1 26 Lived
6.5 48
19. 1,690 4.0
6.6 6.2 4.6 7 26 120 Lived
20. 1,750 4.6 2 Lived
4.5 44 4.5 44 8.2 16 Lived 19 Lived 41
38. 2,350 7.7 25
7.9 33
8.2 49
39. 2,S9() 7.0 15
10.0 27
40. 2,430 9.9 120 120
570 RESPIRATORY DISTRESS SYNDROME
TABLE Ill
1 3 12
II#{149}
I0
9.
8
ARTICLES 571
S
S
5,
P100 9O ‘80
70
‘60
50
40
‘30
‘20
‘IO
0
0 I’2 18 24 36 48 72 96
AGE (hr)
FIG. 8. The scattergram represents the distribution with age of 69 determinations of concentration of potassium in serum of 39 premature infants with respiratory distress syndrome (Table III). Open circles represent determinations associated
with normal electrocardiograms; solid circles are associated with
electrocardio-grams showing prolonged conduction; dots represent concentrations of potassium with no associated electrocardiogram made. The solid line represents the mean concentration of potassium in the serum and the interrupted line represents the percentage of electrocardiograms which were abnormal during each age interval
(Fig. 7).
S. #{149}55
S.
.s
‘I
v_.#_._v S I
/ll, 55 #{149} S
/,
0 SS 50 9 0 00 % V.4 V0 cs .4
00 S
:
.4.40 9
0 Vs #{149} S
I
OS
19
0
trations of potassium
(Fig.
8). These curvesclosely parallel each other.
The mean concentration of potassium in
serum of infants with respiratory distress
syndrome was markedly elevated when
compared to that found in control
prema-ture infants between 12 and 60 hours of
age, though not before or after this period.
Although none of the control infants had
concentrations over 7.0 meq/l between 12
and 60 hours of age, 18 of 29 (62%) of the
infants with respiratory distress syndrome
tested during this period had concentrations
over 8.0 meq/l.
Of 23 infants who died who had
potas-sium determinations, 17 had concentrations
at some time over 8.0 meq/l, 3 had
concentrations from 6.7 to 8.0 meq/l, and
3 others had lower concentrations but
were not tested during the last 12 hours of life. There was a surprising degree of
cor-relation between concentration of potassium and the mortality rate considering the small numbers and the sporadic nature of the
de-terminations. It can be seen from Table III
that while none of the eight infants with
concentrations of potassium over 10.0 meq/l lived, one of four with concentrations
be-tween 9.0 and 10.0 meq/l, three of eight
with concentrations between 8.0 and 9.0
meq/l, and 6 of 11 who had concentrations
less than 8.0 meq/l survived.
Examples of electrocardiograms with
si-multaneously determined concentrations of
potassium in serum of two premature
concen-CASE
AGE
K
AGE
K
AGE
K
IH
4.1
24H
4.2
9D
6.2
I
__
IH
.22H
5.3
100
6.4
2
_
IH
4.5
18H
8.2
3
4
5
4H
6.0
3H 6.1
24H
7.9
36H
8.3
2TH
9.5
6
9H5.3
18H
8.2
FIG. 9. in serum
Serial of six
electrocardiograms (lead II) awl concentration of potassium
infants:
Case
1.
. . Clmnmcal Condition
Normal
Birth Weight (gm)
Age at Death
(hr)
2,240 Lived
2. Normal 1,520 Lived
.3. R.D.S. 2,330 19
4. R.D.S. 1,500 29
5. R.D.S. 800 62
6. R.D.S. 740 30
572 RESPIRATORY DISTRESS SYNDROME
tration of potassium and a deterioration of
the electrocardiogram with age in the
in-fants with respiratory distress syndrome, which did not occur in the control infants.
Effects of Therapy
A
solution of glucose, insulin andbicar-bonate was given intravenously to 24
in-fants with respiratory distress syndrome at
the stage when they appeared to be dying. In almost all of the cases there was
immedi-ate decrease in concentration of potassium
in the serum amid correction of the
abnor-mal electrocardiographic conduction .
Ex-amples are illustrated in Figure 10.
When the fluid was administered
inter-mittently, an electrocardiographic effect was
noted within 10 minutes, which persisted for 1 to 2 hours. There was usually an asso-ciated strengthening of the heart sounds,
improvement in the gray mottled skin color,
increased responsiveness, and sometimes a
rise in blood pressure.
Eighteen of the 24 infants went oil to
die although they seemed to live longer
1500 GM
AGE K
9.3 16TH 8.3
GLUCOSE
INSU
26
H27 H
1900 GM
AGE K
35H
7.4
ITED AT
37 H
31 H
48H
5.8.
27H 1.3
ttt1r1T11TTTTn1r11mm1 h-rt
30
H
5.1-
. #{149}UDIED
101 H
DIED 115K DIEDSIH
LIVEDARTICLES 573
terventli)n. Iiie Iiiean duration of life in
in-fants who died without therapy was 37
hours, and the mean age at death with
ther-apy was 58 hours. The average age at
initia-tion of therapy was 26 hours.
With the sustained administration of fluid to the dying infants, the electrocardiogram never again showed prolonged conduction
time. The usually (lied after a course
marked by progressively severe apneic
spells. Six infants lived, but in the absence of an alternate control group of infants, it
is not possible to say that their survival was
due to the treatment.
The intravenous solution used contained
15 gni glucose, 5 Ifl((l sodium l)icarhonate,
and 7.5 units of regular insulin per 100 ml
for the initial correction of the
electrocardi-ogram. Subsequent maintenance fluids to
prevent recurrence of the hyperkalemia
con-sisted of 10% solution of glucose with 40
meq/l sodium bicarbonate. The fluid was
administered at the rate of 60 mI/kg of body
weight per day. The intravenous therapy
was continued until adequate oral intake
had been established as it was found that
the infants did very poorly if all fluid and
caloric intake were suddenly stopped.
Al-though intravenous or even gastric
adminis-tration of glucose or glucose-saline was
sometimes effective in correcting the
hyper-kalemia, the above solution seemed to act
1090 GM
4ic
26H 8.6
UN
BICARBONATE
STA99H
6TH
___________
#{149}7H
6.1____
_______
7’H
IOOH 69
101 H
so. H
FIG. 10. Four examples of the correction of hyperkalemic electrocardiographic
con-(luction defects in premature infants with respiratory distress syndrome after intra-venous infusion of fluid containing 15 gin of glucose, 5 meq of sodium bicarbonate, and 7.5 units of insulin per 100 ml. In the first two cases, as the two-to-one
574 RESPiRATORY DISTRESS SYNDROME
more rapidly and occasionally was found to
be effective after there had been no
re-sponse to glucose alone.
DISCUSSION
Previous clinical studies of this syndrome
have been mainly related to respiratory function. They have found a typical
retic-ulogranular pattern on roentgenograms of
the decreased lung compliance and
vital capacity,7 and anoxemia with
respira-toly and metabolic acidosis.
The importance of the disease as the
prime cause of neonatal death, the striking
pathologic picture, and the lack of clinical
knowledge pertaining to etiology and
path-ogenesis have resulted in a prolific
litera-ture full of conjecture.8 The many different
hypotheses agree on only one point: that
the cause of death is respiratory
insuffi-ciency. This is felt by some to be due to
primary disease of the lung, and by others
to be secondary to pulmonary congestion
from left heart failure or from patent ductus
arteriosus.
The results obtained in this study
indi-cate that premature infants with the
respir-atory distress syndrome develop hyperkal-emia with consequent electrocardiographic
disturbances
of conduction.
There is no previous evidence in the
literature associating hyperkalemia or
ab-normalities in the electrocardiogram with
the respiratory distress syndrome of
prema-turity. However, several workers have
de-scribed changes which probably represented
the same pathologic processes observed
here.
Two articles from Germany have reported
the finding of similar electrocardiograms in
premature infants who were sick with signs
which might here have been called respira-tory distress yndr91#{176} McCance and Widdowson11 mentioned several premature
infants with respiratory distress syndrome
who had elevated concentrations of potas-sium in the serum; they believed such levels were a normal concomitant of prematurity
and were innocuous;12 electrocardiograms
were not obtained. Lynch et al.’ has
de-scribed a metabolic disturbance with
hyper-kalemia in experimental animals dying with induced hyaline membrane syndrome.
Rose’4 found hyperkalemia in infants with
respiratory distress syndrome born to
dia-belie mothers. There have been no previous
reports of autointoxication with potassium
in a newborn infant with any disease,
al-though hyperkalemia in an infant from
ex-cessive
administration
of
potassium hasbeen described.15
Concentrations of potassium in serum of
premature and full-term infants without
respiratory distress syndrome have been
found by many workers’’9 to be within
the upper half of the normal adult range,
usually 4 to 7 meq/l. Asphyxiated
new-borns have been shown to have high
con-centrations of potassium in serum at birth2#{176}
and
premature infants recently were shownto have normal adult levels unless fed a
high potassium intake.21 The findings of
the present study would indicate that
fu-ture
investigations of the concentration of potassium in the serum of prematurein-fants should carefully distinguish between
infants with, and those without respiratory distress syndrome.
The causative role of hyperkalemia in pro-ducing electrocardiographic disturbance was
borne out by the correlation with the con-centration of potassium in the serum, the re-versal with glucose and insulin, and the
sim-ilarity of the tracings to those seen in adults
with hyperkalemia.22 The absence of peaked
T waves might possibly be attributed to an
intracellular deficit of potassium instead of an extracellular excess as the primary cause of the abnormal electrocardiograms. It
would seem, however, more probable that the absence of peaked T waves in the
pres-ence of hyperkalemia is somehow related
to the phenomenon of low or absent T
waves during the first days of life in healthy premature infants.
Bjorklund,23 . the basis of slight T wave
changes, has suggested that infants born to
ARTICLES 575
The parenteral administration of potassium
which he advises would appear to be not
without danger.
There is some evidence from this study
that hyperkalemia might be a cause of
death in infants with respiratory distress
syndrome. There was a direct correlation between the concentration of potassium and mortality rate, and there was a longer life
span when hyperkalemia was treated.
How-ever, most of the treated infants died after
the concentration of potassium had been
lowered to normal, and it has yet to be
proved that treatment directed against hy-perkalemia can effectively lower the
mor-tality rate.
Parenteral fluid therapy might well be
more effective if given from birth as rou-tine prophylactic therapy to infants with
respiratory distress syndrome, as it has been shown here that almost all such infants will develop hyperkalemia after 12 hours of age. The lower mortality of infants born to
dia-betic mothers which Reardon et al.24 have reported after administration of a solution of glucose and saline from birth might be attributed to the prevention of
hyperkale-mia.
The cause of hyperkalemia during
respir-atory distress syndrome is uncertain.
Possi-ble factors which might increase the
re-lease of intracellular potassium are
respir-atory acidosis, dehydration, and starvation.
Alternative or additional factors which
might decrease excretion of potassium are
shock, adrenocortical exhaustion, and the
known inability of the neonatal kidney to
handle large solute loads.
Anoxia, immaturity, and terminal change
might be considered as causes of the
hy-perkalemia and/or the abnormal electro-cardiograms during respiratory distress syn-drome. The development of the
abnormali-ties in surviving infants, and long before
death in those who die, and the normal
tracings obtained from anoxic dying fetuses
would, however, all seem to indicate that
anoxia, immaturity and death itself are not the direct causative factors.
Sources of error in such a clinical study
of an indefinite disease entity will always
include the difficulty of diagnosis. The
sub-jective error was in this study at least made
uniform by having all cases evaluated by
one observer. The clinical signs,
roentgeno-graphic findings and postmortem findings in
these infants with respiratory distress syn-drome were typical of those reported else-where.
SUMMARY
A study of 59 premature infants with respiratory distress syndrome has revealed the presence of severe increase in
concentra-tion of potassium with electrocardiographc
changes. Thirty-six of 37 of these infants
examined
serially between 12 and 60 hoursof age developed electrocardiographic
ab-normalities. Concentrations of potassium in
serum of over 7.0 meq/l were associated
with these prolonged conduction times.
Concentrations of over 9.0 meq/l occurred
in 12 infants, 11 of whom died. Parenteral administration of glucose, insulin, and
bicar-bonate produced a fall in the concentration
of potassium in the serum and a correction
of the electrocardiogram.
Control premature and full-term infants
had concentrations of potassium between
4 and 7 meq/l and never showed
electro-cardiographic disturbances.
Evidence is produced that premature
in-fants with the respiratory distress syndrome
develop a toxic degree of hyperkalemia
which is reversible.
Acknowledgment
The aid received from Dr. George Maughan, Dr. Aubrey Geddes, Dr. Alan Ross, Miss
Fran-ces MacLean, R.N., Miss Arlene Maximchuk,
M.Sc., and from the nursing staff of the Pre-mature Nursery is gratefully acknowledged.
REFERENCES
1. Dunham, E. : Premature Infants, 2nd Ed. New York, Hoeber, 1955, p. 70.
2. Hess,
J. :
Premature and Congenitally Dis-eased Children. Philadelphia, Lea, 1922,576 RESPIRATORY DISTRESS SYNDROME
3. Potter, E. L. : Pathology of the Fetus and
the Newborn. Chicago, Yr. Bk. Pub.,
1952, p. 249.
4. Bauman, W., and Nadelhaft,
J. :
Radiog-raphy of prematures : a practical tech-nique of correlation with respiratory distress. PEDIATRICS, 21:813, 1958. 5. Blystad, W. : Blood gas determinations ofpremature infants. II. Investigations of
premature infants with early neonatal
dyspnoea (the hyaline membrane
syn-drome). Acta paediat., 45: 103, 1956. 6. Peterson, H., amid Pendleton, M. :
Con-trasting roentgenographic pulmonary
patterns of the hyaline membrane and the fetal aspiration syndromes. Am.
J.
Roentgenol., 74:800, 1955.7. Drorbaugh, J., et a!.: “Vital capacity” and lung compliance in normal newborns, amid infants with “hyaline membrane
syndrome.” A.M.A. J. Dis. Child.,
94:434, 1957.
8. Brown, R. : Respiratory difficulties at birth.
Brit. M.
J.,
1:404, 1959.9. Kottgen, H., and Feverabend, H. :
St#{246}run-germ der Reizbildung und
Erregungslei-tung im Herzen bei fruhgeborenen
Kindern. Monatsschr. Kinderh., 100:244, 1952.
10. Joppich, G., and Stoermer,
J. :
Das EKGbei unterkuhlten Fruhgeborenen.
Mon-atsschr. Kinderh., 105:264, 1957.
1 1. McCance, R., and Widdowson, E. : Pro-tein catabolism and renal function in the first two days of life in premature in-fants and multiple births. Arch. Dis. Childhood, 30:405, 1955.
12. Widdowson, E., and McCance, R. : The
effect of development on the composition
of the serum and extracellular fluids.
Chin. Sc., 15:361, 1956.
13. Lynch, M., Mellor, L., and Badgery, A.: Hyaline membrane disease; its nature and etiology. The poisonous metabolic
effects of excess oxygen. Neural control
of electrolytes.
J.
Pediat., 48:602, 1956. 14. Rose, V. : Problems of the infants ofdia-betic mothers. Bull. Hosp. for Sick Chil-dren, Toronto, 7:110, 1958.
15. Govan, C., and Weiseth, W. : Potassium intoxication; report of an infant
surviv-ing a serum potassium level of 12.27 millimoles per liter.
J.
Pediat., 28:550,1946.
16. Hansen,
J.,
and Smith, C. : Effects ofwith-holding fluid in the immediate postnatal period. PEDIATRICS, 12:99, 1953. 17. Earle, D., Bakwin, H., and Hirsch, D.:
The plasma potassium level in the new-born. Proc. Soc. Exper. Biol. & Med., 76:756, 1951.
18. Spivek, M. : Microchemical blood
stand-ards for normal five-day-old newborn
in-fants.
J.
Pediat., 48:581, 1956.19. Pincus,
J.,
et al.: A study of plasma valuesof sodium, potassium, chloride, carbon
dioxide, carbon dioxide tension, sugar, urea, and the protein base-binding
power, pH and hematocrit in prematures
on the first day of life. PEDIATRICS,
18:39, 1956.
20. James, L. : Changes in acid-base balance
and blood electrolytes in vigorous and
depressed newborn infants (Abstract). A.M.A.
J.
Dis. Child., to be published. 21. Keitel, H. C. : The concentration ofpotas-sium in the plasma (of premature
in-fants). A.M.A.
J.
Dis. Child., 97:583, 1959.22. Levine, H. : Electrolyte imbalance and the
electrocardiogram. Mod. Concepts
Car-diovas. Dis., 23:246, 1954.
23. Bjorklund, S. : Children of diabetic
moth-ers : electrocardiographic studies in the newborn. Acta paediat., 42:526, 1953.
24. Reardon, H., et a!. : Treatment of acute
respiratory distress in newborn infants of diabetic and “prediabetic” mothers
(Abstract). A.M.A.
