ADJUSTMENT
OF VENTILATION,
INTRAPULMONARY
GAS
EXCHANGE,
AND
ACID-BASE
BALANCE
DURING
THE
FIRST
DAY
OF
LIFE
Normal
Values
in Well
Infants
of
Diabetic
Mothers
1. Samuel Prod’hom, Henry Levison, Ruth B. Cherry, James E. Drorbaugh,
John P. Hubbell, Jr., and Clement A. Smith
Department of Pediatrics, Harvard Medical School, Children’s Hospital Medical Center,
and Boston Lying-in Hospital, Boston, Massachusetts
(Submitted August 1; accepted for publication November 21, 1963.)
Work supported by grants from the National Institutes of Arthritis and Metabolic Discases and
Neurological Diseases and Blindness, and the Association for the Aid of Crippled Children.
Dr. Prod’hom was a Fellow of the Acad#{233}mieSuisse des Sciences M#{233}dicales.
PRESENT ADDRESSES: (L.S.P.) Clinique infantile, H#{244}pital Cantonal, Lausanne, Switzerland; (H.L. Hospital for Sick Children, Toronto 2, Ontario, Canada. (R.B.C., J.E.D., J.P.l1., and C.A.S.) Boston
Lying-in Hospital, 221 Longwood Avenue, Boston 15, Massachusetts.
PEDIATRICS. May 1964
ARTICLES
682
T
HE etiology and pathogenesis ofhya-line membrane disease are still poorly understood.’ It is well known that the in-fant of the diabetic mother (1DM) is
par-ticularly susceptible, but the connection
be-tween the disease of the mother and the
high pulmonary morbidity of the neonate
is still a complete mystery.
An unselected series of IDM’s was
sys-tematically studied at 1, 4, and 24 hours of age in order to reveal and describe the
early phase of the respiratory distress
syn-drome in physiological terms. Cord blood
was also analyzed for information at age
0. Ventilation, gaseous metabolism, func-tional residual capacity, intrapulmonary gas
exchange (alveolar-arterial Po2 difference in room air and after 100% 0: breathing, arterial-alveolar Pco2 difference), and
acid-base balance were measured by the
tech-niques described by Nelson Ct al.2’ In
all, 30 IDM’s were studied. Three devel-oped respiratory distress and are described
with a series of distressed newborn infants
in a subsequent paper. Two others had
severe malformations. Of the remaining
25, the 20 delivered by section are the
sub-jects of this paper. The five born vaginally
are too small a group to be compared with these 20.
INFANTS
The most important clinical (lata are
given in Table I. These 20 IDM’s constitute
a reasonably uniform population of white infants, delivered by cesarean section
usu-ally with spinal anesthesia (Nos. 23, 25, and 34 after unsuccessful induction), 18 of them at 36-37 weeks, without any sign of fetal distress. Condition at birth was good ex-cept that Nos. 7, 11, 24, 34, and 36 had in-itial Apgar scores of 4 or 5. All recovered rapidly, to scores of & or above at 5
min-utes. No infant had clinical signs of
res-piratory distress, except for occasional iso-lated high rates of respiration (Table I),
not considered significant (see Comment).
METHODS
During the first 20 minutes of life a soft
polyvinyl feeding catheter (size No. 5
French) was placed in one of the umbilical arteries and left for 24 hours. Between studies the catheter was filled with heparin solution, diluted 1:10 with saline.
Umbilical cords were isolated between
two simultaneously applied clamps at birth
and blood was then removed from the
vein and artery with a 10 ml syringe, whose
Infant Sex vumoer
2 “SE
3 “51
5
7 M
8 M
9 F
11 M
12 “51
14 F
16 M
18 M
‘10 F
23 M
24 F
‘15 M
26 F
Birth
Class of Weight Diabetes3’
(kg)
2.72 F
3.52 F
3.09 1)
2.96 F
3.97 I)
2.48 D
3.29 B
2.84 B
3.66 D
3.42 1)
4.31 C
3.46 C
3.09 1)
3.09 D
2.99 D
2.48 1)
3.35 C
I) F
I)
Apgar Score Respiratory Rate*
Gest.
(nun) (age-hr)
Age _____________________________
_______
_1.
LL_L±J_
36 8 S 8 47 29 31
36 8 8 8 42 49 70
36 8 8 9 72 78 70
36 5 8 9 60 70 57
36 8 10 10 40 42 32
36 8 8 9 35 35 32
36 5 6 8 60 45 50
37 8 8 9 54 69 56
36 8 8 8 42 37 42
37 8 8 i 9 69 72 39
37 8 8 8 56 42 40
37 8 8 9 46 32 37
37 8 10 10 39 39 44
36 4 7 9 70 96
37 I 9 9 9 46 44 44
37 8 8 9 47 38 34
36 4 6 9 61 66 45
36 8 8 9 67 50 47
35 4 5 8 49 48 51
39 6 8 51 58
immediately before study.
X-Ray
negative
negative negative infilt.right lung negative negative hyperinfi. lungs negative negative negative negative negative negative negative negative negative fhyperinfl.
lungs-interst. markings
negative
fat 1hr: diffuse
granu-)larity;at24hr:normal
negative .11
35 ‘SE 3.94
36 M 2.27
48 iSI 2.72
* f counted while infant was in incubator or bassinet
TABLE I
CLINICAL DATA FOR 0 INFANTS OF DIABETIC MOTHERS
until analysis (in the next 30 minutes). All blood was similarly handled, except that 5
ml syringes were used in the collection of
2-3 ml of blood from the umbilical cathe-ter. The dilution of the blood by the
solu-tion filling the dead-space was taken into account for the final calculations of the results.
Expired gas was collected through a one-way ball valve in a spirometer. Alveolar
gas was obtained with a micro-modified
Rahn sampler. The complete open circuit
is described at length by Nelson et al.2
Functional residual capacity (FHC) was
determined with the classical open-circuit N2-washout method of Darling et al.,
modi-fied by Nelson and co-workers.
During each study the infant was
wrapped in a swaddling blanket, and at
the end of each study, the environmental
and rectal temperatures were measured by
thermocouple.
Protocol of Studies Subsequent to
Cord Blood Collection at 0 Time
1. 20 minutes: Sampling of arterial blood
(determinatien of blood gases, pH, CO2
content of plasma).
2. 1 hour (actual time: 1.46 ± .26 hours): (a) Simultaneous collection of expired and
alveolar gas and arterial blood during room-air breathing (measurement of ventilation, gaseous metabolism, alveolar-arterial Po2
and Pco2 differences, acid-base balance); (h) collection of expired gas during 100%
02 breathing (determination of FRC); (c)
hyperoxia-test (breathing of 100% 02 given
by funnel at a flow of over 8 L/min for
30 minutes), after which blood (1 ml) was again taken for determination of arterial
Po2 (measurement of true right to left
shunt).
3. 4 hours (actual time: 4.41 ± .25 hours):
as in (2) above.
lkr 4/jr 24k,
n mean SD range n mean SD range n mean SD range
f-breatha/min Vx-mi/min BTPS YE/Kg-mi/mm/Kg VT-mi BTPS VAtml/min BTPS VAanat/Kgml/mifl/Kg VDanatml BTPS VD,,/VT VAphysInl/mifl BTPS VAphy,/KgInh/min/Kg Vophy,ml BTPS VDphy,/VT Vo,-ml/min STPD Yo,/Kg-mi/min/Kg Vco,-mI/min STPD 02/Kg.m’,’mmn/7g both VO1L VAphy,/VO,11h1/mifl STPD FRC-ml BTPS FRC/Kg-ml/Kg VT/FRC 17 17 17 17 15 15 15 15 17 17 17 17 17 17 17 17 17 17 14 14 13 53 670 212 13.0 407 127 3.7 28 345 109 5.0 .37 21. 8.8 ‘19.51 0.92 13.8t 71 22.5 .20 12 171 40 2.9 110 27 1.4 .07 89 20 1.5 .10 6.1 1.5 5.0 1.3 0.13 3.4 4.0 .04 34-72 391-949 124-256 6. 6-18. 9
248-598 75-165 1.0-6.4 .15-44 206-465 67-146 1.9-7.6 .14-52 10.3-31.6 4.5-9. 1
10. 9-29. 1
3. 8-8.5 0. 74-1. 21
8.3-21.1 49-92 15.0-29.4 12-. 26 17 17 17 17 17 17 17 17 16 16 16 16 17 17 17 17 17 16 13 13 13 49 616 I 99 13.2 373 120 3.8 320 100 5.0 .39’ 17.7t 5.61 15.91 5.1’ 0.89 14.7 76 24.0 .20 17 160 44 3.0 76 24 1.3 .07 88 24 1.2 .09 3.8 1.0 3.6 1.0 0.09 2.6 30 9.5 .06 29-96 329-893 121-289 9. 1-17.8 235-490 82-164 1.9-6.5 .17-38 188-523 74-149 3.0-8.0 .27-52
9. 9-24 .3
4.0-8.0 8.4-22.7 3.7-6.7
0.79-1.10
10. 9-2 1. 0
39-140 14.3-46.8 .11-28 15 15 15 15 15 15 15 15 14 14 14 14 15 15 15 15 14 11 Ii 9 45 599 192 13.7 397 128 3.1 .221 372 118 3.71 .27’ 18.7 6.0 15.1’ 4.
0.821
16.31 77 24.4 .19 12 178 48 3.5 99 28 1.4 .08 106 30 1.7 .10 4.4 1.0 3.9 1.0 0.13 2.7 16 5.7 .06 29-70 327-1017 114-289 8. 9-19.8 241-606 86-181 1. 1-5.6 .11-59 23 -555 74-185 1.8-6.0 .16-41
10. 4-25. 0 4.2-8. 1
10.3-21.8
3.3-6.5 0. 61-1. 00
I I .3-20.0
52-110
13.2-32.3
.10-.28
TABLE II
VENTILATION, GASEOUS METABOLISM, AND FUNCrIONAL RESIDUAL CAPACITY
‘and t. P<.O1; , .05>P>.O1.
hours): as in (2) and (3) above.
From the nature of these investigations, it can be understood that in occasional in-fants one or more determinations were for
various reasons omitted. The number of
satisfactory studies of each parameter at
each age period is included in Tables II
and III.
Determinations
02 and CO2 concentrations in expired
and alveolar air were measured with the
0.5 ml Scholander gas analyzer. In some
cases CO2 concentration in the expired gas
was determined with a Beckman infrared
rapid CO2 analyzer (Spinco Model LB-i
Medical Gas Analyzer).
Po2 and Pco2 in blood were directly meas-ured in micro-cuvettes at a temperature
of 37#{176}C with Clark-type and Severinghaus-type electrodes (Instrumentation Labora-tory, Inc., Boston, Model 113 system). In
duplicate measurements the maximum
dif-ference for Po2 at low level was 3 mm and
at more than 200 mm, 20 mm; maximum
difference for Pco2, 2 mm. In some cases
Po2 and Pco2 were determined by
micro-modification6 of Riley’s bubble technique. The agreement between these two methods is good. CO2 content in plasma and oxygen capacity of whole blood were determined with the Kopp-Natelson Microgasometer (Model 600, Scientific Industries, Inc.).
Duplicate analysis within 0.2 mM/L was
required for CO2 content and within 0.3
volume % for 02 content.
The pH was determined directly at 37#{176}
C, at first with a glass-electrode (0.5 ml
whole blood) of the Model 113 system,
later with the Astrup-micro pH-electrode (Radiometer Type E5020 micro-electrode) connected to the Instrumentation Labora-tory’s Model 113 pH meter. Duplicate
anal-yses within .01 pH unit were required.
pH was also calculated from CO2 content and Pco2 by the Henderson-Hasselbalch
equation, assuming a pK’ factor of 6.093
co-NP =
* Standard symbols for respiratory variables used.’#{176}
efficient of CO2 in plasma at 37#{176}C of .5i34. The average difference between
cal-culated and actually determined pH in 150
different blood samples was .01 with a
maximum difference of .06. The pH values
presented are the calculated ones; the
actual determinations were used only as
checks.
Calculations
All gas volumes are given in BTPS with
the exception of oxygen consumption, CO2
production, and ventilation equivalent which are in STPD.
The raw data of respiratory rate (f),
minute volume (7)* and 02 and CO2
con-centration in inspired, expired, and alveolar air were used for the calculation of anatomic dead space (VDanat) , anatomic alveolar venti-lation (VAanat) , oxygen consumption (Vo2), and CO2 production (jTco2). Physiologic dead-space (VD0hy,) and physiologic alveolar ventilation (VAph,) were calculated by re-placing the fractional CO2 concentration of alveolar (end-tidal) gas (FAC02) by arterial Fao2, or Pao2/(PB-47).
These different volumes have been inter-related below as follows:
VD/VT = dead space-tidalvolume ratio
co2/Vo2 = respiratory quotient (RQ) or
respiratory exchange ratio (R)
VA/V02 = ventilation equivalent (in this
case, physiologic alveolar ven-tilation, VAPLYS, was used as
VA).
FRC was calculated in the usual way.
Tidal volume and alveolar tidal volume were
related to FRC (VT/FRC and VT-VD/FRC).
The (A-a)Po2 gradient in room air was ex-pressed as venous admixture (VA), by use of the classical shunt formula:
Sc’-Sa
___--Sc’-S
and by the 02 hemoglobin dissociation curve for fetal blood.” In all cases alveolar
Po2 (PA02) was calculated from the alveolar gas formula:
/ 1-Fi02
PAeffo2 = Pi0. - Pao2
(
Fi02+-R
The true right to left shunt (s/T) was
calculated, according to Berggren,’2 from data obtained during the hyperoxia-test:
Qs/QT =
(PA02 - Pa02) X .00302
(PA02-Pa02) X .00302+CapO2Xav Sat.diff. in which .00302 is the solubility factor for 02 in plasma at 370 C. The oxygen-binding
capacity for whole blood (CapO2) was
ac-tually determined after equilibrating the
blood with room air during 20 minutes.
An arterial-venous saturation difference
(a Sat.diff.) of 0.15 is assumed from the
work of Rudolph and his associates.’3
Julian’s formula’4 was used to express per-centage of alveoli which are ventilated but not perfused (NP):
Paco2 - PACO2
Paco2 - PACO2+PECO2
This fraction, like those for VA and true
shunt above, was converted to a #{231}ercentage by appropriate multiplication.
Finally, in an attempt to quantitate the degree of metabolic acidosis, the amounts of nonvolatile acid
(
= fixed acid) were deter-mined by plotting CO2 content and Paco2 Ona modified Davenport-diagram (see below).”
RESULTS
The results in Tables II and III are best presented under separate headings.t
t Original data used for these tables have been de-posited as Document number 7881 with the ADI Auxili-ary Publications Project, Photoduplication Service, Library of Congress, Washington ‘15, D.C. A copy may be secured by citing the Document number and by re-mitting $1.25 for photoprints, or $1.25 for 35 mm microfilm. Advance payment is required. Make checks
TABLE
Po2 AND Pco GRADIENTS
Umbilical Vein Umbilical Arlay 20 mm
n mean SD range n mean SD range vi mean SD ranye
Body temprature-’C -
-5-24 - --16 16 I 6 16 .59 97 38 33 17 11 13 16 29-94 78-113 13-37 7-72 Pao,in room air-mmHg
PAeo,_mm Hg (A#{176}.a)Po,-mm Hg VA-% 18 -25 -. -4 -17-31 -17 . -15 -6
-Pao, in 100% 0,-mm JIg
(A#{176}-a)Po,-mm Hg ,/T-%
--
- - --Faco, at 37’C-mm hg
Paco, at body temp-mm Hg
PAco,atbodytemp.-mmllg
(a-A) Pco, at body temp. -mmHg NP-% 15 -46 -6 -36-60 -15 -58
-9 -44-81 -16 -47 -8 -35-66 -C0,plasma-mM/L pH-ealculated-atS7#{176}C pH-ealculated-atbodytemp. FixedAcid-wM/L 20 15 -20 24.1 7.31 1.2 3.0 0.09 5. 17.8-28.7 7.08-7.46 -7.5--’I2.7 19 15 19 26.4 7.24 1.! ‘2.5 0.09 4.7 21.2-29.1 6.99-7.26
--4.3-*13.6
16 21.9 , 3.2
16 , 7.26 1 0.09
- -
-16 1.5 5.0
17.4-16.7
7.11-7.39
-2.5--’12.3
‘andt,P<.Ol; I..05>P>.01.
Ventilation (Table II)
No change was found in minute volume
(YE and YE/Kg), in tidal volume (VT),
anatomic dead-space (VDanat), and anatomic
alveolar ventilation (VAanat and VAan,t/Kg),
during the first day of life. Physiologic
alveo-lar ventilation (TA9h, and TA,,/Kg)
showed a slight, but statistically not signifi-cant, increase during the same time, whereas
VDPbYS/VT ratio decreased significantly
be-tween 4 and 24 hours (t=3.4, P<0.01). At 24 hours of life anatomic and physiologic
dead-space, and therefore also anatomic and physiologic alveolar ventilation, were in the same range.
Gaseous Metabolism (Table II)
Oxygen consumption (o2/Kg) fell from
6.8 ml/min/Kg at 1 hour to 5.6 ml/min/Kg
(t = 2.5, P = .02) at 4 hours and 6.0
mi/mm/Kg at 24 hours. These values agree well with the 6.7 ml/min/Kg of Nelson’s
nonIDM’s2 and with the 6.2 ml/min/Kg
oh-tamed in Karlberg’s’6 very careful investi-gation with rigorous control of the body
temperature. The observed decrease in 02
consumption could be related to a change in environmental or body temperature.
[low-ever, there are no significant changes in
eu-vironmental temperatures at 1, 4, and 24
hours (21.6±2.3#{176}C, 22.0± 1.9#{176}C and 22.3
± 2.0#{176}C, respectively) and, although the
body temperature of these IDM’s was low
(35.2±0.6#{176}C) at 1 hour, it (lid not change between 1 and 4 hours (35.5 ± 0.9#{176}C)as the
02 consumption decreased. Thus, the
(Ic-crease in \02 does not appear to be related to these tenhl)eratures. CO2 l)rodUetiOI1
(
\‘co2/Kg) decreased significantly froiui 6.2nil/nun/Kg at 1 hour to 5.1 iiil/miii/Kg at
4 hours (t=2.8, P<.01) and 4.9 mi/mm/Kg
at 24 hours (t=3.2, P<.005).
With these changes in 02 consumption and
CO2 production, the respiratory exchange
ratio (RE), based on expired gas sample, fell
from 92 ± .13 at 1 hour to .82 ± .13 at 24
hours (t=2.3, P=.02), in agreement with
observations of others. 7
The ventilation equivalent (VA9b,/ \“02,
1hr 4 hr
n mean SD
24 hr
range n mean SD ranga
‘5 20 17 17 17 20 20 20 18 13 13 ‘3 13 18 18 18 20 mean 35.2 61’ 9.5. 36 368 299 22 461 42’ 4 11 23.2 7.27’ 7.311 f2.3’ SD 0.6 12 14 90 90 6 9 8 7 10 3. 1 0.08 0.08 4.5 37.1 71 107* 36 20 0.5 10 7 9 7 range
34. 0-36. 0
36-86 6(1-115 18-67 12-60 222-523 140-452 11-29 34-69 37-63 3 1-58
- 4-.9 0-28
17. 6-30.6 7.02 7.39 7. 08-7. 41 -3.5--.14.9 1.5 ‘9 16 16 16 17 ‘7 16 12 12 12 12 16 16 14 18 35.5 72’ l01 29 386 285 21 140’ 37 3 24.7 7.35* 17.37’ -1. Ot 0.9 10 7 13 10 97 92 3 6 14 2.1 0.05 0.01 2. 9
33. 3-37. 0
46-93 84-118 12-55 8-46 157-5 13 160-478 13 30 37-56 35-48 26-46 -5--’ll 0-35 20.4-27.8 7.27-7.42 7.31-7.45 -5. 9-4.5 5 ‘4 ‘4 14 ‘4 13 13 13 ‘5 14 14 ‘4 14 15 14 15 35.6-37.8 55-88 9,-I’S I7-51 9-34 304-483 197-374 I 7-32 49-Il 29-11 25-39 -4--’13 0-42
20. 5-26. 8 7.34-7.49
7. 33-7.49
-5 .0-’3. 6
388 56 289 56 24 4 36’ 3 36’ 3 133’ 3 3 5 II 12 23.8 1.7 7.43’ 0.04 7.43* 0.04 -2.0’ 2.2
AND ACID-BASE BALANCE
equivalent at 1 hour of age was 13.8 ± 3.4
and rose to 14.7±2.6 at 4 hours and 16.5
± 2.7 at 24 hours (t, between 1 and 24 hours,
=2.4, P= .02).
Functional Residual Capacity (Table II)
The average FRC/Kg varied between
22.5 ± 4.0 inl/Kg and 24.4 ± 5.7 ml/Kg,
values which are in agreement with the first
24-hour data in tWo j)apers on nonIDM’s: Klaus et al.,’8 means between 21.3 and 26.3
obtained by plethysmography, and Geubelle
et a!.,” iiiean of 27.7 by helium (lilUtiOll. Nelson et al.’ obtained a mean of 40.6 ± 13.1
by plethysmography in nonll)M’s of 10-day average age. The absence of statistically
sig-nificant change in FRC and FRC/Kg be
tween 1, 4, and 24 hours of life is also in agreement with Geubelle et al.’9 and Klaus et al.2#{176}
To evaluate FRC in its physiologic
con-text, this volume may be usefully correlated
with VT or with alveolar-tidal volume
(VT-VD0h38). The V’r/FRC ratio in adults is 0.21, and-as reported by Karlberg21-in
nonIDM’s, 0.18; the VT-VDh,/FRC is 0.13
in adults and in the nonIDM. These ratios are in the same range for the IDI’l : VT/FRC
being 0.20 and VT-VD/FRC 0.14 without
changes from 1 to 24 hours.
Alveolar-arterial P02 Difference (Table Ill)
Arterial Po2 in room air increased from
59± 17mm Hg at 20 minutes to 61 ± 15 at I
hour, and to 72±10 at 4 hours (t=2.6,
.02>P>.OI), and remained at 71 ± 10 at
24 hours. At 20 minutes and 1 hour, the
values were in the same range as those of Oliver’s22 cesarean-section i ufan ts.
The niean Pao2 values in the 1DM
throughout the first 24 hours were not
systematically (hiferent from nonIDM re-suits4’ 23, 24 The alveolar-arterial Po2
dif-ference varied from 38 mm Hg at 20
minutes to 29 at 4 hours and 36 at 24 hours, but the calculated venous admixture (virtual plus true right to left shunt) fell from 33%
at 20 minutes and 31% at 1 hour, to 20 at
both 4 and 24 hours (t, between 1 and 4
hours, =2.6, .02>P>.01).
The mean Pao2 after 30 minutes of 100%
at 4, and 388 at 24 hours. The calculated true right to left shunt of 22% at 1 hour remained
essentially unchanged at 4 and 24 hours. Nelson et al.4 have demonstrated that the larger (A-a)Po2 gradient of the newborn as compared to the adult is mainly due to an over-all true right to left shunt whose exact localization cannot be defined by the
deter-minations used. Although certain assump-tions were necessarily involved, calculations
from the current study suggest a similar con-elusion. At 4 and 24 hours, at least, the venous admixture in room air had essentially the same value as that in 100% 02. In the latter environment the (A-a)Po2 difference
due to diffusion impairment and uneven
ventilation/perfusion ratio disappears so that the remaining (A-a)Po2 gradient will be due entirely to a true right to left shunt. The significant difference between venous
admixture and true right to left shunt
(t=2.5, .02>P>.01) at 1 hour indicates some degree of virtual shunting in the lungs, probably from uneven ventilation/perfusion ratio. Between I and 4 hours the fine adjust-ment between alveolar ventilation (A) and
pulmonary blood flow (Qc) appears to have been completed.
Arterial-alveolar Pco2 Difference (Table Ill)
Mean arterial Pco2 remained between 47
and 49 mm Hg at 20 minutes and 1 hour of
life. It fell to 44 at 4 hours (t=2.0, P=.05),
and between 4 and 24 hours to 36 (t = 5.4, P<.001). Except for that at 24 hours, these values are higher than the age-equivalent values reported by Weisbrot et al.,2’ Reardon
et aL,24 or Oliver et al.2’ All the foregoing
figures are adjusted for a body temperature
of 37#{176}C. If mean Pco2 is converted for the actual body temperature at sampling, by the
factors of Severinghaus,’6 the actual Pco,
becomes reduced (significantly) to 46 mm
Hg at 1 hour, 40 at 4 hours, and is unchanged
at 24 hours when body temperatures were
37#{176}C. Even with this correction the 1 and 4 hour values are significantly higher than those reported by Reardon.
The mean alveolar (end-tidal) Pco, simi-larly decreased from 42 mm Hg at 1 hour to 33 at 24 hours. Since the assumption that
end-tidal gas is representative of mixed al-veolar gas in adults has been found also valid in newborn infants,3 an (a-A)Pco, difference will reflect the presence of alveolar dead-space. Iii this series of IDM’s the locals (a-A)Pco, gradient, at body temperature,
was 4±4 mm hg at 1 hour, 3±5 ‘ii” hg
at 4 hours, and 3±5 inni Hg at 24 hours. Statistically there is no difference at any tiiiic between Paco2 and PAco2. The calculated dif-ferences are of the same order of magnitude
as the (a-A)Pco, difference of 1 .8 ± 3.8 inns
Hg obtained by Nelson et al.’ in a series of well nonIDM’s and IDI%I’s. From these data
it can reasonably be concluded that no sig-n ificasig-nt (a-A)Pco, difference is detectable during the first day of extrauterine life. Ad-justment of perfusion of the capillaries to alveolar ventilation is adequate.
Acid-base Balance (Table Ill)
Despite the many reported
detern1ina-tions, exact measurement of acid-base
bal-ance during the newborn period is not en-tirely satisfactory. The biology of fetal and neonatal blood is still not well known. Weisbrot et al.” and Reardon et al.’4 assuiiied
that the Singer-Hastings diagram can be
used without introducing too many errors.
For several reasons we cannot agree, and
prefer, with Oliver,” a modified Davenport”
diagram with two assumptions. Until the
buffer line of neonatal blood is knowii, it must be assumed that the slope of the line for adult blood can be used.” At 24 hours of age
the blood has a pH of 7.40, a Pco, of 35, and
a plasma CO, content of 22.5 inM/L. For
this reason, it is assumed that the line niay be drawn through this point, and the acid-base balance estimated from a diagram thus modified.
Table III indicates, in umbilical veiti
blood, an average pH (at 37#{176}C)of 7.31, Pco, of 46, CO2 content in plasnsa of 24.1
mM/L, and fixed acid of 1.2 mM/L.
Cor-responding averages for umbilical artery
blood were: pH, 7.24; Pco,, 58 iiiiii Hg; CO,
content in plasma, 26.4 muM 1; and fixed
acid, 1.1 mM/L. Both umbilical vein and
artery blood thus reflect acidosis, mainly
Hg
40
35
30
rM/L 70 65 60 55 50
700 7.10 720 730
pH at 37CC
74#{212} 750
FIG. 1. Adjustment of acid-base balance in new-born infants without respiratory distress during
the first 24 hours after birth.
Time:
O Birth (umbilical artery)
#{149}5-10 minutes
El 20 minutes
z 1 hour
x 4 hours
+ 24 hours
KEY
Infants: Of diabetic
moth-ers; cesarean. (Pres-ent study)
Of
nondiabeticmoth-ers; vaginal.22’ .
-
-Ofnondiabeticmoth-ers; ccsarean.22
The values are in agreement with those of
nonIDM’s,2427’28 although not with the other published data on IDM’s.28 29 Unlike those
figures, only 3 of the 20 IDM’s here reported had an important metabolic acidosis
(non-volatile acid: 13.6, 7.9, 6.4 mM/L). The
reason for the more “normal” values in this
series is not known. The mean pH reported
for a temperature of 37#{176}Cwas relatively low at 1 hour (7.27) and at 4 hours (7.35), but adjusted to the body temperature of the in-fant became 7.31 and 7.37 respectively. These values are well within the range of
those reported in normal infants by Weis-brot,2’ Oliver,” and Reardon.’4
The Paco2 at 1 and 4 hours indicates per-sistence of some respiratory acidosis, but less netabolic acidosis than in infants of
lion-diabetic mothers (Fig. 1). At 24 hours, there
is a stage of respiratory alkalosis. No data
from other laboratories could be found for
comparison except those for capillary blood of 7 IDM’s without respiratory distress re-ported by Lowry.’#{176} For those 7 infants our calculations indicate average pH and Pco2 at 4 hours of 7.36 and 40, and at 24 hours, 7.38 and 35, lying entirely within the range ob-served here.
COMMENT
The high incidence of respiratory distress
syndrome and hyaline membrane disease in
IDM’s is well known.3’ For this reason the
adjustment of ventilation, gaseous
metabo-lism, FRC, intrapulmonary gas exchange, or
acid-base balance during the first day of
extrauterine life might have been expected
to behave differently in such an infant as
compared to the infant of a nondiabetic
mother. No fundamental difference has been found to characterize the adaptation of these functions in the 1DM’s. This statement needs brief discussion under several headings.
1. VOLUMES: Compared on a body-weight basis there is no significant difference
be-tween the VT, VD, YE, and VA of these
IDM’s and the 24-hour data of Nelson et at.’
from infants of nondiabetic mothers. 2. CHANGES IN R: Oxygen consumptioii
related to body weight is in the same range as in the nonlDM’s. The decrease in
respira-(S) ‘
(L) ‘#{176}
tory gas exchange ratio (R) is also that ex-pected. A widespread of values in R can be due to change in ventilation or to changes in metabolism. Only in the steady state is R
equal to RQ. From theventilation equivalent
(
\TAh/VO,) and R, one can easily evaluateR as a function of VA/Vo, (Fig. 2). As cx-pected, there is a good relationship between
these two ratios. Thus, for a ventilation
equivalent of 16, there is a highly significant
decrease in R from 1.0 at 1 hour to 0.8 at
24 hours (t = 8.5 ;P < .001). This change must represent altered metabolism, and it is in-teresting to see that abnormally low and
ah-normally high values of R are related to
hypoventilation and hyperventilation, re-spectively.
As found by Nelson,2 the drop in R is ac-cornplished by a highly significant fall in CO2 production with a steady 02 consumption
between 1 and 24 hours. On the other hand,
Cross’7 observed a rise in 02 consumption with steady CO2 production in the first day of life. This difference may well be related to
oh-Li
1.10
.80
.60 .70
.60
4 hr
24 hr
Ihr-o
r..79
a 4hr.x
r 81
24 hr - a
r.79
fo, (both 60tumes STPD)
Fic. 2. Relation of respiratory gas exchange ratio (R) to ventilation equivalent (V.sPh}$/V2) at 1, 4.
and 24 hours.
Regression lines: 1 hr, R = .487 .032
“yr .06; 4 hr, R = .452 + .029 V/V9, ay =
.07; 24 hr, R = .125 + .042 V./V9, ayx .06. Significance: At V.%I)hyS/Vo 16 nornial ventilation, R changes significantly: between 1 and 4 hr, P < .01; between 4 and 24 hr, P <
.001; between 1 and 24 hr, P < .001.
The widespread of R during the first day of life is due not only to changes in ventilation but also to metabolic changes.
served in this study was almost completed at 4 hours of age, when Cross was just
be-ginning his determinations. Fromii his
regres-sion line, R at 24 hours should be 0.77 which is not too far from the 0.82 of Table II. Further studies of ventilation and gaseous metabolism in very early life are needed.
3. HYPERVENTILATION
(?)
AT 24 Houns:At 24 hours, the low arterial Pco2 usually
found is commonly thought24” to result from
hyperventilation. This should be reflected in a high ventilation equivalent. In these
in-fants at 24 hours, the ventilation equivalent
was 16.5 (normal for young adults) when
arterial Pco2 was 36 mm Hg. As postulated by Nelson et al.,2 this result rules out hyper-ventilation, though no other reason for the low Paco2 is immediately apparent. Possibly the threshold of excitability of the respira-tory center is “set” for an in utero biological
“milieu int#{233}rieur” different from that of
I hr adult life.
4. RAPIDITY OF ADJUSTMENT OF
INTRAPUL-MONARY GAS EXCHANGE: With Karlberg’s
first-breath analysis’4’ it becamiie evident that
the inflation of the lung is rapidly achieved.
The determinations of FRC by Geubelle
et at.,’9 Klaus et al.,’8 and in this series have
confirmed this finding. Analyses of the (us-tribution of ventilation4” have also demon-strated how complete is the adjustment of ventilation during the first and second day
of life. As an indication of intrapulmonary
2c2 2zc gas exchange, Graham 23 found a relatively
low value of 74 mm Jig for arterial Po, on
the first day comnj)ared to 95 in adults. He
postulated pulmonary shun ting through
ateleetatic lung areas. Nelson et al.4”7 have more directly evaluated the gas exchange in the lungs of normal newborn infants by
con-sidering diffusion, distribution, and shunt as the three components leading to reduced Pa02. The conclusion was reached that, after
the age of 12-24 hours, the observed
(A-a) Po2 difference was entirely due to a
true right to left shunt. The exact
localiza-tion of this shunt is still a matter of
specu-lation.
With this same method of analysis at 1
hour after birth the results from these infants of diabetic mothers indicate a larger venous
admixture in room air than could he
ac-counted for by true right to left shunt. The difference (virtual shunt) is (Ille to imbalance between alveolar i-en tilation and pulmonar’
capillary blood flow (A,/’Qc less than
normal).
The larger part of the (A-a) Po, difference, however, is due to true right to left shunt
(approximately 20-25% of total cardiac
output) which does not change during the
first day of life. It is unlikely that this shunt
is larger in IDM’s thami in infants of normal
mothers; the arterial Po, (in room air) and
(A-a) Po2 difference are essentially the sante
in 1)0th groups.4”3”4 In no,ihi)M’s, venti-lation is ideally tlistr,buted.4 In nonhl)M’s and IDM’s, the diffusion capacity of the lung
Infants Whose
f= .() or
VE/Kg 240±34(4)* 186±40(13)* 0.05
VT/Kg
o/Kg
\Ai3,/\o3
3,3±0.5(4)
95,0±16.0(4)
5.6±0.6(4) 14.1 ± 1. (4)
4.5±0.6(18)
10-2±27(1)
5.7±1.(13) 14.9±3.0 (li)
.93 0.45
0.13 0.54
0.01 <0.70
0.90 0.60
0.48±0.04(1) 0.36±0.O9(1) .50 0.0
l’aco. (temp. 370C) 46±4 6) 4±5 (10) 1.40 0.O
1)11 calc 7.34±0.04(6) 7.34±0.05(10) 0.5 0.80
* Figure in( ) indicates number of infants so studied at 4 hours.
5. HYPOVENTILATION AT 1 AND 4 Houns:
The arterial Pco2 of these infants of diabetic
mothers is high at 1 and 4 hours; both
Reardon’4 and Oliver” reported lower values
from full-term babies, whereas those reported here are prematures of 36-37 weeks
gesta-tion. Identical studies with premature babies of 36-37 weeks gestational age horn also by
cesarean section are necessary to evaluate the effect of prematurity or of cesarean see-tion in the genesis of this slight CO2 reten-tion. At 24 hours the arterial Pco, is in the
range of the nonIDM.
6. SIGNIFICANCE OF RESPIRATORY RATE
OVER 60: Rates can be measured without
complicated instruments. sIiller’8 in
non-IDM’s and Haddad’9 in I1)M’s have
con-eluded that rate indicates presemiceor absence of respiratory distress, an(l Gellis and IIsia3’
reported a respiratory rate exceeding 60 per
minute in 55% of 172 infants of diabetic
mothers. Nevertheless, the assillliption that disturbance of respiratory rate necessarily means lung disease is not always right. Since
YE VTf an increase in minute volume is
often associated ith an increase in f alone, but a normal minute volume may occur with
a high f providing VT is correspondingly de-creased. For a given alveolar ventilation the optimum respiratory frequency is usually
that at which work4#{176}or average force of the respiratory muscles4’ will be minimal. Cook4’
has found this rule to explain the relatively
high respiratory rate associated with the
particular mechanical properties of the lung
ill the newborn period.
Six of the 17 IDM’s studied at 4 hours had
a respiratory frequency higher than 60.
Several parameters were analyzed separately in these 6 infants and compared with those of the others with respiratory rates of 60 or
less. The results are summarized in Table IV. It appears quite clearly that the most
im-j)Ortaflt difference is the size of the tidal
volume per unit of body weight (P= .01). To keep alveolar ventilation normal,
respira-tory frequency is increased. As the frequency of breathing rises, there is an increase in
physiologic dead-space, so that the
organ-ismn must still further increase minute volume to obtain adequate alveolar ventilation. In fact, there are no significant differences in
VA/Kg, VA/VO,, and Paco,. The observed
change in VDh8/VT ratio is that expected. I1)I1’s who breathed at a rate over 60 (with-out other clinical signs of respiratory distress) miiay rej)reseflt only the upper extreme of a
population with average f= 49 with 2 S.I).
± 17=34. A “normal” limit of f=60 may he
not only statistically but clinically erroneous. The reason for change in VT is not yet
known. 1)isturbance of some physical
prop-erty of the lungs may be shown by further
studies of compliance and resistance. Fromii
the reported data, a high respiratory
fre-uency alone is not believed to establish the clinical diagnosis of respiratory distress
syndrome.
TABLE IV
EFFECT OF RESPIRATORY FREQVENCY
Signfieance of Difference
between Means
SUMMARY
Determinations of blood gases and of
acid-base balance were done in umbilical vein and artery blood at birth and in arterial blood at the age of 0 minutes in 0 infants of diabetic
mothers. All were born by cesarean section,
18 of them between 36 and 37 weeks
gesta-tion. None showed respiratory distress at any time.
Ventilation, gaseous metabolism ,
func-tional residual capacity, intrapulmonary gas exchange, and acid-base balance were deter-mined at the age of 1, 4, and 24 hours in these
o
infants.The results indicate the following conclu-sions with regard to infants of diabetic
mothers.
1. Adjustment of ventilation to
per-fusion in the lung appears to be complete at
4 hours of life.
2. Throughout the first 24 hours there is
a persistence of an over-all true right to left shunt of approximately 0-25% of the total cardiac output. The exact localization of this shunt is unknown.
3. Acid-base balance in cord blood and in
arterial blood during the first day of life in
infants of diabetic mothers differs only slightly from that of infants of nondiabetic
mothers. At 1 and 4 hours of age there is some persistence of a slight respiratory acidosis.
4. At 24 hours infants of diabetic mothers have the usual low arterial Pco2 of other
new-born infants, but a ventilation equivalent of 16.5, which is normal for adults.
5. Although 6 of the 17 infants studied at
4 hours have shown a respiratory rate above
60 without other signs of respiratory distress, these infants with high rates had small tidal
volumes, high physiologic dead-space/tidal
volume ratios, and relatively little increase
in minute volume. It is suggested that such
rates in some otherwise well infants of dia-betic mothers are probably at or near the
extreme upper values in a population whose
average rate is slightly higher than that of a normal population.
6. It seems reasonable to assume that the
infant of a diabetic mother has much the
same adjustment of ventilation, gaseous metabolism, functional residual capacity,
intrapulmonary gas exchange, and acid-base balance as does the infant of a nondiabetic
mother.
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