INDICATIONS
FOR
OXYGEN
THERAPY
IN THE
NEWBORN
J. P. M. Tizard, B.M., F.R.C.P.
Nuffield Neonatal Research Unit, Oxford
Institute of Child Health, Harnniersmith Hospital, London, W. 12
The Kenneth D. Blackfan Memorial Lecture, Children’s Hospital Medical Center, Boston, September
25, 1963.
PEDIATRICS, December 1964
771
I
T Is ALWAYS a difficult task to praisefamous men, the more difficult for me
in the case of Dr. Blackfan since this
par-ticuiar Blackfan Memorial Lecture is also
linked with the memory of Dr. Bronson
Crothers. Dr. Wilson’s’ admirable
bio-graphical memoir of Dr. Blackfan could
bring him to life for the reader if
any-thing could. Yet the fact is that I knew Dr.
Crothers: I mourned his death and he is
therefore as alive for me as if he was
sit-ting in the front row lighting and
relight-ing a much tortured pipe.
As you know, Dr. Crothers was to me a
hero, as evidently was Dr. Blackfan to his
students, yet in tile schoolboy sense of tile
word he lacked one conventional attribute
of heroism. I refer to tile olympian attitude
of mind which one is apt to expect from
the favorites of tile Gods and which was
so conspicuous a part of the therapeutic
armamentarium of the physicians of the
nineteentll century and indeed some of
them today. He was the antithesis of
Robert Louis Stevenson’s2 fasllionable
phy-sician, Sir Faraday Bond, who as you may
remember, would call you back even after
you had paid your fee, to say with
sten-torian emphasis “I had forgotten one
cau-tion: avoid kippered sturgeon as you would
the very devil.” In his gentle way, Dr.
Crothers spoke the truth to the parents of
his patients; if they found it too
uncom-fortable they might leave him but they
always came back eventually when they realized that it was on the basis of accept-ance of tile tragic fact of tile permanency
of brain damage that most could be done
to help their children. Dr. Crothers made
it clear to me, and it was far from clear
from the reading of the bewildering
hitera-ture on the subject, that the future was
likely to show more progress in tile
preven-tion rather than the cure of the cerebral
palsies. It is interesting that Dr. Crothers
was mucil more impressed by physical in-jury at birth rather than asphyxia as being
of etiological significance. In an early work
OIl the subject’ he said: “It is clear enough
that there is a limit to tile period that any
foetus can live without an adequate supply
of oxygen. I believe, however, that tilere
is nothing in the very voluminous literature
available on the subject which contains
valid evidence that suffocation is so
seri-ous a threat to the infant during delivery
that many of the radical procedures aimed
at rapid delivery are justified.” He went
on to discuss the work of Dr. Potter of
Buffalo, whose less successful imitators
sup-plied Dr. Crothers with many of his cases
of spinal cord injury and I cannot resist
quoting Dr. Crothers here because one
can almost hear him saying it: “The work
of Potter of Buffalo,” he says, “is
illumin-ating. Tilis obstetrician delivers almost all
his babies by version and extraction. I am
not sufficiently familiar with obstetrical
technique to follow his arguments on all
points.” Dr. Crothers was quite right in
his day in believing that injury was of
more importance than suffocation but now
the position is reversed and the decline in
neonatal deaths due to birth trauma is, I
believe, in no small part the result of Dr.
Crothers’ teaching. A study of fatal cases
of intracranial hemorrhage in newborn
Ham-(‘ES OF MASSIVE AND MODERATE INTRACRANIAL
hEMORRhAGE CAUSING OR CONTRIBUTING TO
NKONATAL I)EATH, HAMMER.SMITH HOSPITAL,
1954-1961
.)1ale Female Total Principle Site of hemorrhage
Intraventricular hemorrhage (±suharachnoi(I hemorrhage) Intact subependymal hemorrhage
Subdural hemorrhage
Suharachnoid hemorrhage ilone Intracerebral hemorrhage
10(81
53 (1)’
4(1(16) 18 (1)
U3 (18)
18 (7) 8(4)
4(1)
59 (11)
80 (1)
64 e23) 6 (5)
7(1)
18 (30)
Stillbirths in parentheses.
mersmith Hospital4 shows that cases of
subdural hemorrhage caused largely, but not I believe wholly by injury, are
out-numbered by the cases of intraventricular
hemorrhage which are clearly related to
asphyxia (Table I). I would like to point
out tvo other items of interest in tilis
sur-vey. It is commonly said that
intraventric-tilar hemorrhage is caused by anoxia but
I do not think that anoxia can be the
de-cisive factor. It is of interest that whereas
two-fifths of the cases of subdural
hemor-rhage were stillborn we only found
intra-ventricular hemorrhage in a stillborn baby
very exceptionally. It is possible that
hy-percapnoea is of greater importance than
anoxia in the etiology of intraventricular
hemorrhage. It is difficult to imagine that
gross hypercapnoea could occur in the
fetus, whereas we know that it does from
the work of Strang and MacLeish5 and
others in tile baby with respiratory distress
and we also know that high arterial CO2
tensions raise the cerebral blood flow in
adults. The other point to which I would
like to draw your attention is the very
great preponderance of male over female children, which alone fully accounts for the excess of male over female deaths in the neonatal period. Dr. Bronson Crothers’
knowledge of the extraordinary resistance
of the newborn to suffocation had, of
course, respectable antiquity. Dr. Robert
Boyle6 carried out his classic experiments
on newborn kitiings over 300 years ago,
TABLE I
and I have recently come across an
ac-count of a rather similar experiment in
Buffon’s7 celebrated natural history. He
arranged for a bitch to be delivered of the
first three of her litter of nine puppies into
a barrel filled with warm water;
immedi-ately after birth he removed the animals
and plunged them into a tub of warm milk
in case they felt in need of nourishment.
When, after half an hour, he removed
them, they started to breathe and
ap-peared perfectly well. He then re-immersed
them in milk for a further period of half
an hour following which he removed them
once more. Two were apparently in a good
state of health but the third he says
ap-peared in a somewhat languishing state
but revived on being returned to its
mother.
Nevertheless, it is quite clear, for
in-stance, from the work on monkeys by Dr.
Windle, Dr. Howard Jacobson, and their
colleagues8 that survivors of birth asphyxia may suffer brain damage. I know full well
the lecture I should have liked to have given on this occasion but which I am
incompetent to do. I would have liked to
have thrown some further light on the
cir-cumstances in which permanent brain
dam-age does result from asphyxia in the
hu-man infant. Instead, I propose to discuss
the more obvious and immediate effects of suffocation looked at from the standpoint
of the indications for oxygen therapy. It
is for me a sort of preliminary to the
lec-ture I would like to have been able to give
and in fact the subject of my lecture is
one that would have been of less interest
to Dr. Crothers than to Dr. Blackfan, whose
distinguished work on the control of the
environment of premature infants is well
known to you all. My audience vill
for-give me if I concentrate on the interesting
work being done at home rather than the
interesting work being clone in the United
States on these problems.
Although I am painfully aware that we haven’t taken full advantage of it,
RESUSCITATION AS REGARDS RESPIRATION, BLOOD PRESSURE & PULSE RATE
PLOTTED ON SEMI-LOGARITHMIC PAPER WITH TIME ALONG ABCISSA
N2 ACUTEANOXIA
INDUCED
FIG. 1. Schematic representation of the stages of experimental asphyxia of the newborn
rabbit. (J. A. Davis)
ARTICLES 773
outstanding physiologists, R.A. McCance,
Kenneth Cross, and Geoffrey Dawes and
much of the work to be reported here has
in some way or other derived from them.
There are three main sets of circumstances
in which one has to consider oxygen
ther-apy in the newborn baby: apnoea at birth,
respiratory distress, and recurrent apnoea
in small premature babies, and I propose
to discuss these three situations in turn.
APNOEA AT BIRTH
There is evidently growing unanimity
about the indications for intervention in
the apnoeic newborn baby but there is
still some confusion and this is, I think,
based on a failure to identify accurately
enough the varying physical states in birth
asphyxia. I would here like to report the
work of Dr. John Davis9 which throws
some light on this problem. Many of you
will remember John Davis; he now works
at the Hammersmith Hospital, but this
RABBIT AGED 2-4 DAYS.-50-lOOg.
PULSERATE PER MINUTE
MEAN ARTERIAL
BLOOD PRESSURE
mm Hg
INTRA-THORACIC
NEGATIVE PRESSURE mm Hg
work was carried out in the Nuffield
In-stitute for Medical Researcil at Oxford.
Davis was studying experimentally induced
asphyxia in newborn animals. He found
that whatever tile method used to produce
asphyxia the same sequence of events
fol-lowed. In the experiment illustrated (Fig.
1) a newborn rabbit was placed in an
atmosphere of nitrogen; this was
immedi-ately followed by dyspnoea which lasted
about half a minute ending in crisis in
which the animal became apnoeic and the
blood pressure and pulse fell precipitously,
rising shortly afterward but declining
grad-ually during the next several minutes.
After about three minutes, however, the
animal started to gasp spontaneously and
this gasping continued with gradually
de-creasing frequency for several minutes.
Fol-lowing the gasping there was a further
fall of pulse rate and blood pressure and
if steps had not been taken to revive the
animal he would have died without taking
Ajex beat l’ atIsethitatiohi
Respiration:
Inaudible Rate if PlseI1t: 1mm.
Absent Gasping or
irregular
Regular or shythmical
I)id the baby cry before the age of 1 minute?
Muscle tone and movement
YES/NO
Limp Normal muscle tone: no movement
None Grimace Cough
Grey or White Blue Pink
Is the baby brown skinned? YES/NO Signature
a further breath. There are, you notice,
two periods of apnoea, pre-gasping and
post-gasping. In the pre-gasping phase of
apnoea Davis found that he could
invaria-bly make the animal gasp by a variety of
different stimuli-pinching the skin,
injec-tions of various respiratory stimulants such
as lobeline, cardiozole, and so on. If at
this point the animal were exposed to an
atmosphere of room air it would recover,
as indeed it would if one waited for
spon-taneous gasping to take place. In contrast,
in the post-gasping phase of apnoea no
amount of stimulation could induce a gasp
and the only way in which the animal
could be revived was by artificial inflation
of the lungs with oxygen. This has a very obvious parallel with what is convention-ally known as the states of “blue” and “white” asphyxia at birth and it is
interest-ing to speculate on whether the
pre-gasp-ing phase of apnoea corresponds to the
state of “blue” asphyxia in the infant, and
the post-gasping to the state of “white”
asphyxia. Recording of the state of the
birth lacked plan and uniformity until Dr.
Virginia Apgar devised her now famous
rating.’#{176} When revising our neonatal
rec-ord (Table II) we did with considerable
hesitation make some alterations in the
Apgar rating, hesitation caused by the
use-fulness of the present system for the
pur-poses of comparison between hospitals. We
leave a blank for the time at which the
observations were made although we wish
them to be made at one minute. We have
introduced the question “Did the baby cry
before the age of 1 minute”-a point which
is of some interest. We have slightly
al-tered the sections on color and we have
introduced another question about the
pig-mentation of the baby. Only 40% of the
babies born at the Hammersmith Hospital
are born to parents each of whom was born
in England and whereas only a minority
of the remainder are brown skinned they
are a fairly substantial minority and I think
you will agree that it is more difficult to
assess tile presence or absence of cyanosis
in a colored baby. You will also note that
we do not produce a score. A single figure
score has not prevented the originator of
this plan from considering the individual
items separately,h1 but nevertheless we felt
that a single figure does really represent a
loss of information, whicil is undesirable.
Father Juniper’s sort of Apgar rating on
lliS controls for the victims of the Bridge
TABLE II
PART OF TIlE NEONATAL REC0IW SHEET UsED AT THE HAMMERSMITII HOSPITAL
CONDITION OF BABY AT MINUTE(S) AFTER BIRTh (at 1 minute whenever possible)
Please tick appropriate square:
Response to nasal or pharyngeal
catheter within first minute
Color of trunk
TABLE IV
B.snlEs AI’NoEIC AT ONE MINITE (RECoRDS Co%11’LETE), HAMMERSMITH HOSPITAL, MARCH,
196-FEmtv.snY, 1963
.\or,nqil .lhuor,nal D!irrre, I)el’cris
No. C
t1 100 65 100 loLl
heart rate Nil Less than 100 More than 100
11 14 0 17 9 0 LI LI 3.8 .3 33.8 0 65.3 31.6 0 46. 1 46. 1 7.8 11.5 80.7 7.8 45 19 4.5 it) 4 8 .55 1.5 69.2 29.3 35.4 69.2 1.5 64.6 23.3 3.1 12.3 84.6 3.1 (r’oodness
Alfonso C. 4
Nina
rslantiel B. 10
Alfonso \. -8
Vera N. 0
Piety Usefulness 4 10 5 10 10 0 -10 10 10 10 775 ARTICLES
of San Luis Rey12 would have lost its point
had the results been expressed as a single
figure (Table III).
Dr. Jagdish Gupta and I have analyzed
the results of our ratings for a
twelve-month period.13 Table IV relates to babies
who were apnoeic at 1 minute; you will
notice that less than a third of these
ha-bies had entirely normal deliveries, in the
remainder there had been abnormal
presentation, fetal distress, antepartum
hemorrhage, instrumental delivery or
caesarian section. It is fairly clear that this
slide does not support the idea of the neat
distinction between blue and white
as-phyxia. I would like to draw your
atten-tion to one other interesting point. You
will notice that none of the babies born
after a normal delivery who were apnoeic
at one millute had cried before the age of
one minute, on the other hand this was a
very common occurrence in babies born by abnormal delivery and in fact was
no-ticed in a third of them. The majority of these 23 babies were delivered by
caesar-ian section, the mother having had an in-halant anaesthetic. We think that this
fre-quently observed phenomenon of a cry
shortly after birth followed by apnoea may
be an example of the effect described by
Dr. Fink of New York as diffusion anoxia;”
the lungs expand but the alveoli are
rap-idly filled with the volatile inhalant gas
rf%,jJJ jj
PEIIII.sPs AN INTENTION
The thing was more difficult than he had foreseen. Almost every soul in a difficult frontier community turned out to be indispensable economically, and the third column was all but useless. (From The Bridge of San Lois !?ey by Thornton Wilder.
%Vith special lerluissiors of the author and Albert and Charles Boni, Inc.)
Cried before Iminute
Muscle tone Limp
Normal, no movement Spontaneous movement
Response to catheter stimulation Nil
Grimace Cough or sneeze
Color White
Blue
Pink
diffusing from the blood stream and these
babies consequently become anoxic. A
similar phenomenon is seen in divers when
on surfacing the alveoli filled with
nitro-gen. In Table V we have divided the
ba-bies apnoeic at one minute into the
con-ventional groups of blue and white
as-phyxia, but you will notice that it is only
a minority of babies who can be fitted into
one or other of these neat categories.
Davis’s belief is that response to
stimula-tion may well be the most important factor
in distinguishing between these two states
of apnoea. Kenneth Cross and his colleagues
in San Francisco showed the importance
of Head’s paradoxical reflex in the
initi-ation of respiration in the newborn baby,1
and it may be that it is the capacity to
initiate respiration in this way that
dis-tinguishes tile pre-gasping from the
post-gasping phases of apnoea in the
asphyxi-ated newborn animal. I had not intended
to deal with the practical aspects of
oxy-gen therapy in this lecture but I must add
TABLE V
BABIES APNOEIC AT ONE MINUTE (RECORDS
COMPLETE), IIAMMERSMITH HOSPITAL, MARCH,
196-FEBRUARY, 1963
Abnormal
Deliveries
Normal
Total
-:ienveraes
“White asphyxia’ (Limp, no response
to catheter. Heart
rate<100. White) 8
“Blue asphyxia” (Normal muscle tone -no movement. Grimace or cough to catheter. Heart rate
>100. Blue) 10 3
Other asphyxia 73 1
firm distinction between the more and less
serious types of apnoea we in practice
intubate the lot. We are well aware, of
Before I leave the subject of apnoea at
birth I would like to tell you about some
experiments carried out by John Davis and
Dr. Michael Moore1#{176}from the Obstetric
Department of Hammersmith Hospital
which throw some light on the aetiology
of birth asphyxia. It is commonly said that
there are three main causes of asphyxia
at birth-fetal hypoxia, head injury, and
drugs administered to the mother,
par-course, that we do it unnecessarily in the
majority of cases and it is also the case
that the application of a laryngoscope or
the mere threat of it is enough to make
many babies start breathing without the
benefits of positive pressure oxygen
ther-apy. One more word about the practical
aspects of treatment, we feel that too much
emphasis has in the past been laid on
the pressure at which oxygen or air should
he given. It is quite obvious from a
the-oretical basis that it is the volume which
is more important, but there are
consider-able practical difficulties in controlling
arti-ficial inflation of the lungs volumetrically
ratiler than barometrically and we are
studying these at the Hammersmith
Hos-pital.
ticularly morphia and pethidine
(Meperi-dine hydrochloride, Demerol). Yet we have
the paradoxical situation that whereas
morphia does undoubtedly depress
respi-ration in some newborn babies, as can
readily be seen from the occasional but
highly dramatic effect of the specific
an-tagonist, nalorphine, injected intravenously,
the vast majority of babies whose mothers
have been given pethidine or morphia
6 within a few hours of their births breathe
at once. Davis and Moore have studied the
effect of morphia on the respiration of the
newborn rabbit. In ordinary circumstances
astronomical doses of morphia are required
7 to stop the animal from breathing, but
Davis and Moore repeated the type of
experiment I showed you at the beginning
of the lecture with the following results.
You will remember that following acute
asphyxiation of a newborn animal there
were four periods, those of increasing
dyspnoea, the pre-gasping phase of apnoea,
the gasping and the post-gasping phase
of apnoea. Figure 2 shows you the effects
of morphia in small dosage on the
dura-tion of these stages. You will notice that
the total duration of life was not altered
by the administration of morphine but the
period of pre-gasping apnoea was very
greatly prolonged in the rabbits receiving
morphine compared with the controls. If
this is applicable to the human newborn
it would seem that morphine is only likely
to depress respiration when the baby has
also been hypoxic in utero and it is also
interesting to reflect that the
administra-tion of morphine might, in these
circum-stances, have a protective effect in
post-poning the time at which gasping and
therefore inhalation of amniotic fluid took
place.
I now leave the apnoeic newborn baby
and turn to the problem of respiratory
distress in the newborn.
RESPIRATORY DISTRESS IN THE NEWBORN
Tile discovery that retrolental fibroplasia
was associated with the administration of
effec-NO DRUG
AFTER
MORPHI NE
TIME MINUTES
ARTICLES 777
3 DAY OLD PABBI TS IMPEDANCE PNEUMOGRAPH TRACiNG
(/(
/7’I
I
Ii!
FIG. 2. The effects of morphia on the stages of experimental asphyxia in the newborn rabbit. (J. A. Davis and W. M. 0. Moore)
tively queered the pitch as far as a ra-tional oxygen therapy for newborn babies is concerned. It was an interesting
co-incidence that at the same time the
respir-atory physiologists were telling us that we
need not use more than 40% oxygen
be-cause that was sufficient to overcome all
possible diffusion defects. But it has
sub-sequently been shown by Leonard Strang
and others5 that the arterial hypoxemia
is in large part due to the pulmonary
shunts which develop in the respiratory
distress syndrome, and Douglas Gairdner
and A. M. Warleyl7 at Cambridge have
shown that concentrations of oxygen higher
than 40% will in fact increase the oxygen
saturation of arterial blood when lower
concentrations have failed to do so. This
is presumably brought about partly by
the solution of oxygen in plasma which
then becomes available for the red cells
of blood which has been shunted, and
partly due perhaps to a decrease in
pul-monary vascular resistance which has been
shown by Cook and colleagues’s to 1)e
related to the oxygen content of inspired
air. In connection with the shunts it is of
interest that even in tile healthy adult
gravitational forces cause ventilation
per-fusion inequalities between the uppermost
and lowermost parts of the lungs and tills
might become of importance when the
pulmonary arterial pressure is low as has
been shown to be the case by Dr. Smith,
Dr. Rudolph, and their colleagues in the
respiratory distress syndrome.#{176} Moreover,
it has always seemed very unlikely that
retrolental fibroplasia could be caused by
high ambient oxygen concentrations if the
arterial oxygen tension were normal or low.
Professor N. Ashton2#{176} has kindly allowed
me to report some unpublished
experi-ments of his which go a long way to
set-tling this point. He has shown that when
pure oxygen was administered by mask
or tracheostomy tube to a kitten kept in
air the retinal vessels completely closed
TABLE VI
SINGLE CHILDREN OF BIRTH WEIGhT NOT MORE ThAN
4 LB (1,800 GM) AND (;ESTATION PERIOD OF LESS THAN
33 WEEKS ACCORDING TO MEDIAN 1)uRATI0N OF
OXYGEN TREATMENT GIVEN AT CENTER OF BIRTh
(I)R.ALISON MCDONALD)
.1!edian I)uration Oxygen
Treat-meat (days)
0-1
5-8
10-17
Total
“,‘umnber
of
(‘hildren
51
207 129
Spastic Diplegia (%)
11.8 12.1 5.4
Deafness (%)
3.9 3.9 4.7
Retrolental Fibro-plasia (%)
3.9
12.4
TABLE VII
(juickly reversible when oxygen was
dis-continued. Conversely, he has shown that
when a kitten of susceptible age is kept
in air but had inserted between the lids of
one eye a small eyecup through which a
continuous flow of pure oxygen was
main-tamed for a period of 72 hours, no
abnorm-aiity in tile retinal vessels was observed
when compared with the other eye serving
as a control. Since this period of exposure
regularly and irreversibly injures tile retinal
vessels when the animal breathes oxygen,
it can be concluded that oxygen does not
pass through the eye in sufficient
quanti-ties to injure the retina within this period.
It was shown in 1960 by Dr. Mary Ellen
Avery and Dr. Ella Oppenheimer21 that
tile mortality among premature babies
fol-lowing tile institution of a rule limiting
tile maximum permitted oxygen
concentra-tion to 40% had risen significantly. Recently
Dr. Alison McDonald22 from the
Paedi-atric Research Unit at Guy’s Hospital ilas
studied surviving small premature infants
treated in hospitals before the dangers of
higil oxygen concentration were known and re-examined at the age of 7 or 8 years.
Table VI shows that when the duration of
oxygen therapy was long tile incidence of
retrolental fibroplasia was, as one might
expect, significantly higher, hut in
con-trast, the shorter the duration of oxygen therapy the higher the incidence of spastic
diplegia. You will notice that the incidence
of deafness was not significantly related
to tile duration of oxygen treatment. In
Table VII the babies are divided into
those in whom cyanotic attacks were and
were not reported. These were all single
children of a birth weight of not more than
4 lb (1.8 kg) and a gestation period of less
than 33 weeks. Those who were reported
as having had cyanotic attacks and for
whom oxygen therapy was not given or
given for a period of less than 10 days, tile
incidence of cerebral diplegia was no less
than 43%; whereas in a similar group for
whom oxygen was given for 11 days or more,
the incidence was only 3%. Tile numbers are
small but these are highly significant
dif-ferences. You vill notice that the incidence
of deafness was also higher in babies given
prolonged oxygen therapy, but Dr.
Mc-Donald has good collateral evidence that
deafness in surviving premature babies is
not related to oxygen therapy but is in
fact an indication of the severity of their
postnatal illness and it can therefore be
SINGLE ChILDREN OF BIRTH WEIGhT NOT MORE ThAN 4 LB (1,800 GM) AND GESTATION PERIOD OF LESs
THAN 33 WEEKS AccoitmNG TO CYANOTIC ATTACKS AND OXYGEN ThERAPY (Dn. ALISON MCDONALD)
Oxygen
(‘yanotic Attacks Reported No (yan otic Attack s Reported All
.
4t Risk Deaf Diplegia At Risk. Deaf Diplegia At Risk. Deaf Diplegia
None or less
thanlOdays 1 4.8 42.9 20 1.8 8.7 241 2.1 11.7
hldaysormore 34 14.7 2.9 99 6.1 8.0 133 8.3 6.8
AIR
20C 3OC 4DC
ENVIRONMENTAL TEMPERATURE
ARTICLES 779
said that tile babies who had the lowest
incidence of diplegia also happened to be
those who were most seriously affected by
premature birth.
What are then the indications for oxygen
therapy in the newborn baby with respir-atory distress? It is usually said that cyano-sis is an indication; most of us would agree
with this but it would, of course, be
re-garded as a complete failure of therapy in
the handling of say the case of pneumonia in an older child or adult if one waited for
cyanosis before administering oxygen. In
an older child or adult one can readily
de-tect the signs of cerebral hypoxia before
cyanosis becomes obvious and it is perhaps
yet another indication of the very limited role of the cerebral hemispheres in the
behavior of the newborn baby that hypoxia
even of a severe degree does not seem to
lead to restlessness. Moreover, skin color
in the newborn may be a very poor guide
to arterial oxygen saturation. I dare say
that many of you have shared my
experi-ence of seeing very small premature
ba-bies who appeared quite pink for about
three-quarters of an hour after they were
dead, and it seems likely that in the
thin-skinned immature infant with a reduced
peripheral circulation rate direct diffusion
of oxygen from the surrounding
atmos-phere may raise the oxygen saturation of
hemoglobin in stagnant skin capillaries.
Tilere is, of course, the question of tile
extent to which minor degrees of
hypoxe-mia are harmful to tile newborn and
pre-mature baby. It has been shown by
Geoff-rey Dawes and his colleagues23 that
as-phyxia reduces the glycogen content of
cardiac muscle in newborn animals.
Heath-er Shelly2 has recently examined the
glycogen content of various tissues
ob-tained postmortem, but only just
post-mortem, on stillbirths and neonatal deaths
from the Hammersmith and two otiler
Ilos-pitals and has shown that a constant
find-ing in babies dying after respiratory
dis-tress has been low, often negligible
con-tent of glycogen in the diaphragm, while
glycogen reserves in the heart and tissues
were still quite iligh. Tiiis finding fits in well witil tile Boston School’s studies on the work of respiration in tile respiratory dis-tressed infant in their suggestion that death
might ultimately be clue to fatigue of
res-piratory muscles.- It is reasonable to
Sup-pose that an adequate supply of oxygen
to the diaphragm would have a glycogen
sparing effect. We believe, however, that
an indication for tile need of added oxygen
may be available in the baby’s deep body
temperature.
To explain what I mean we shall have
to consider the effects of a cold environ-ment on the newborn animal’s or baby’s metabolism. Figure 3 is a schematic rep-resentation of the effect of environmental
temperature on the oxygen consumption
and deep body temperature of a newborn
baby or animal breathing air. You vill note that tilere is a range in the baby from about 32-35#{176}C of environmental
tempera-ture over which oxygen consumption is
minimal. If tile baby’s environmental
tem-perature is reduced below the lower end
of this range oxygen, consumption rises
and in doing so maintains the deep body
temperature at the normal level. But if
the newborn animal is given a mild
hy-poxic stimulus (e.g., 15% oxygen) oxygen
consumption and deep body temperature
DEEP BODY
TEMPERATURE
OXYGEN
CONSUMPTION
FIG. 3. Schematic representation of the changes in oxygen consumption and deep body temperature of newborn animals at varying environmental
mm Hg
120 E are maintaine(1 \vitilin the neutral thermal
cnvironment, whereas below tills ambient
temperature range oxygen consumption is
reduced to that which was present at a
neutral thermal environment and the deep
body
temperature consequently fails sinceileat loss is here in excess of heat
produc-tion. The effect of hypoxia on the
meta-bolic response to cold was demonstrated
(luite clearly by Kenneth Cross, David
Trythall, and me some years ago;26 only at
the time we thought we were
demonstrat-ing something else! But subsequently it has
been shown by Karlberg and Tim Oliver
in Stockholm27 and by Flynn and Hill28 in
Cross’s department at the London Hospital
that the newborn baby behaves no
differ-ently from other newborn animals in this
respect. The mechanism by which a rise in oxygen consumption in a relatively cool
en-vironment is achieved is a matter of
consid-erable interest. The older child or adult will
of course shiver but this is not at all
ob-vious in the newborn baby or animal. Bill
Moore at the Royal Free Hospital was the
first to suggest that the metabolic response
of a newborn animal to a cool
environ-ment might be mediated through secretion
of 29 He showed the large
increases in oxygen consumption which
oc-curred on injection of noradrenaline into
young animals and working with Karlberg
and Tim Oliver in Stockholm has also shown
that infusions of small concentrations of
noradrenaline into newborn babies will
have tile same effect.3#{176}This does not of
course prove that noradrenaline secretion is
the natural means by which a rise in
oxy-gen consumption occurs on exposure to a
cool environment, but there is some
col-lateral evidence which suggests that this
may be the case. The newborn animal has
a very large quantity of
noradrenaline-producing chromafin tissue for which no
explanation has hitherto been found, the
blood pressure has been shown to rise on
exposure to cold in newborn babies and,
tilird, the output of vanilyl mandelic
acid, a breakdown product of the
catechol-amines has been shown to be increased in
human infants on exposure to a cold
en-vironment by SandIer and his colleagues
at Queen Charlotte’s Hospital.31 Jon Scopes
and I studied this problem during a period
of sabbatical leave at the Nuffield Institute
for Medical Research.m2 Figure 4 shows
the effect of a continuous infusion of
nor-adrenaline at 1 p.g/kg of body weight per
minute into a newborn kitten. You will
notice that there is a considerable initial
rise of blood pressure which gradually falls
off, a rise in respiratory rate and in tidal
air and a very distinct rise in oxygen
con-sumption. Figure 5 is of results obtained
in newborn rabbits and shows that the
effect of noradrenaline infusions in raising
oxygen consumption very rapidly wanes
with advancing age and has practically
disappeared by the time the rabbits are
three weeks old, a point which interested
us because it is known that the
noradren-0
0
E
- 10
2 S
I-0
Infus
FIG. 4. Kymograph tracing showing the effects of
150
100
50 .1 0
I
0
I
FIG. 6. Effect of exposure to cold on oxygen con-sumption and temperature of mnterscapular fat i e organ, colon, and lumbar subcutaneous tissue in a
S 10 15 20 .
-Age (days) newborn rabbit. (Dawkins and Hull)
FIG. 5. The effect of intravenous infusions of
norad-renaline 2 tg/kg/min into unanesthetized rabbits of varying age. Each point refers to an individual
10-mm infusion. The inverse correlation between age and rise in 02 consumption is highly signfficant
statistically (r = -0.62, P < 0.001).
oxygen consumption but whereas the
sub-cutaneous temperature fell in the lumbar
region which is relatively free from fat and
fell slightly in the colon it was maintained
and even slightly raised in the interscapular
fat organ. Figure 7 shows the effect of an
intravenous infusion of noradrenaline in an
animal kept at a neutral thermal
environ-ment. The rise in temperature of tile
inter-scapular fat organ was far higher than tile
rise in temperature of other subcutaneous
tissues and the colon and in other
experi-ments they found temperature differences
p
0
E
F-0.
02:7
U E 20
cc
4
noradrenoline
40
0
mm.’
FIG. 7. Effect of an intravenous infusion of norad-renaline on the oxygen consumption and the tem-perature of the interscapular fat organ, colon, and lumbar subcutaneous tissue of a newborn rabbit.
(Dawkins and Hull)
ARTICLES 781
aline-producing tissue in the newborn
ani-mals rapidly disappears after birth. We
examined the effects of various drugs on
the metabolic response to infusions of
nor-adrenaline and found similar results to
those reported on the metabolic response
to cooling. Recent work by Doctors
Mi-chael Dawkins and David Hull33 at the
Nuffield Institute at Oxford has greatly
illuminated this problem. The
subcutane-ous fat of newborn animals, including
new-born infants, differs in structure and
com-position from the fat of older infants. It
is brown in color, contains many small fat
droplets and many more mitochondria; it
has a very rich nerve and blood supply
and contains large amounts of
noradren-aline. The oxygen consumption of isolated
brown fat from the newborn is ten times
higher than white fat and it is further
in-creased by the in vitro addition of
noradren-aline. Dr. Dawkins and Dr. Hull studied
the newborn rabbit because this animal
very conveniently has most of its brown
fat as a single organ, so to speak, between
the scapulae. Figure 6 shows the results of
one of their experiments in a newborn
rabbit exposed to a cold environment. You
will notice the very marked increase in
cold 25C
39 s.c. nterscapular
0. 3 colonic
35 - s.c. lumbar
C 0
.40
3j20 ‘Th
0 -Jo
0 Lu Lii
36
-35
34
60 /‘
\
.i__\
I
\
J
\..40 s-.
/
20-36 9 2 3 6 9 12 3
TIME
INCUBATOR TEMP. 33#{176}C
Fic. 8. Changes in deep rectal temperature of a premature newborn baby with changes in ambient oxygen concentration (environmental temperature
unaltered). of up to 4#{176}C.These results suggest that a
substantial component of the metabolic
re-sponse to cold ill the newborn rabbit may
he due to brown fat and it suggests that
the role of fat in the newborn animal is
not simply that of acting as insulating
ma-terial 1)ut also as a sort of electric blanket.
The brown fat is gradually replaced by
\Vilite fat in tile first 4 weeks of the rabbit’s
life, thus presumably accounting for Scopes’s
and my failure to produce a metabolic
re-sponse to noradrenaline after this age.
\Ve must now go back to consider how
tile known effects of a cool environment on
newborn babies might assist us in assessing
the need of added oxygen. It is
conven-tional to treat ill premature babies at an
environmental temperature of about 32#{176}or
33#{176}C,i.e., just at the lower end of the
neti-tral thermal environment and I think that
there are good and practical reasons for
doing it. \\Te vondered if what applies to
healthy newborn babies when ambient
oxygen is reduced to 15% might apply to
premature babies witil higher
concentra-tions. The hypothesis is that in the sick
pre-mature baby an atmosphere of air vill
contain insufficient oxygen to raise
metabo-lism when tile baby is nursed just below
tile neutral thermal range, but that the
addition of oxygen might allow metabo-lism to be raised and therefore deep body temperature to he maintained. Thirty years
ago Dr. Blackfan showed very clearly the
effects of prematurity and sickness in the
newborn infant on its body temperature.
We have taken to regarding a low or falling
deep body temperature in an ill newborn
baby as an indication for increasing the
concentration of ambient oxygen, in the
absence of cyanosis. Figure 8 is an example
of one of a number of cases in which tills
hypothesis has appeared to have validity.
Tills was a premature baby weighing under
800 gm who survived. You will notice that
at the age of 3 hours its deep rectal tern-perature was 34.5#{176}Cand that in the course
of a few hours it fell further. Without
alter-ing the incubator temperature we started
to increase the concentration of ambient
oxygen. When tile concentration was
in-creased from 30 to 40% there was a slight
rise in body temperature. When it was
in-creased to 60% there was a much steeper
rise. When the concentration was dropped
to 30% the rectal temperature leveled off
and started to fall, but tilere was a further
rise on again raising tile oxygen concentra-tion. \Vhen the baby was about 20 hours
old we again started to lower the
concen-tration of oxygen in the incubator, but this
time the deep body temperature did not fall
and the infant’s condition gave rise to no
further anxiety. We think that this may
prove to be a simple and useful way of
indicating the need for oxygen therapy in
sick newborn babies who have not reached
tile point of becoming visibly cyanosed.
Of course retrolental fibroplasia remains a
danger and frequent or even continuous
monitoring of the infant’s arterial P02 will
probably become a routine in premature
babies treated in high concentrations of
oxygen.
RECURRENT
APNOEA
I now turn to the third and last subject,
that of recurrent apnoea in small premature
z
w
PREMATURE BABY
re erence cottage
Ftc. 9. Circuit diagram of impedance pneumo-graph. (J.E. Pallett and
J.
W. Scopes)ARTICLES 783
babies. One encounters several rather
dif-ferent situations, very small babies with
rather frequent but brief periods of apnoea
but without otiler signs of respiratory
dis-tress; the onset of apnoeic attacks in the
ter-minal stages of the respiratory distress
syn-drome, and some babies who combine both
from the beginning. There is clearly a
rnui-tiple etiology for apnoeic attacks in the
pre-mature baby but the clinical picture of
in-creasing frequency and duration of attacks
leading to death is a familiar one. Twenty
years ago Dr.
J.
L. Wilson and hiscol-leagues5 showed that periodic respiration
in premature babies could be abolished by
high ambient oxygen concentrations. For many years the Sister Superintendent of the
premature baby unit at the Hammersmith
Hospital told me that she thought small
premature babies were less liable to get
prolonged apnoeic attacks if they were
given just a touch of oxygen, say 1 1/mm
into the incubator. Tills I resolutely refused
to believe thinking it was an old wives’
tale. However, one should listen to old
wives’ tales with respect. And this gives
me an opportunity of quoting from my
favorite textbook of medicine by vIaunsell and Evanson.” In discussing tile
manage-ment of a baby immediately after birth
Dr. Maunsell said: “The cord is then to be
drawn through a circular hole cut in a
piece of old linen about 4 to 5 inches in
diameter which is to be gently folded
round it. In tile preparation of this envelope
the nurses are particularly anxious to have it extremely dry and warm. It is always
held carefully to the fire and sometimes
even scorched before they vill permit its
application-a prejudice which is certainly
harmless and probably but one indication
of the general instinct that teaches them
that a newborn infant requires its heat to
he carefully husbanded.” Asterisk-footnote:
“As a curious instance of this dread of
extracting heat from a child we often find
tile peasants of this country carefully
warm-ing the scissors before division of the cord.
It is easy and no doubt appears scientific
to ridicule popular customs and
supersti-tions but would it not be more discreet and
philosophical to endeavor to discover their
origin from some instinct to which they may
generally be traced.” I think that was rather
an interesting observation of Dr. N’Iaunseil
since it was written many years before the
advent of Pasteur. But to return to the
Pre-mature Baby Unit of the Hammersmith
Hospital, I should have paid more attention
to an expert in tile newborn whose name
was Smith, and I have since become
con-vinced that her observations were correct.
Mr. Paliett and Dr. Scopes7 have recently
constructed an impedence pneumograph
for measuring respiratory rate in newborn
babies (Figs. 9 and 10). Figure 11 shows
the effect of slightly increasing tile ambient
oxygen concentration on the frequency and duration of spells of apnoea in a small pre-mature infant. You will notice that when
the incubator contained air there were 33
episodes of apnoea totaling 6.8 in 30
min-utes. When tile baby was treated in 30%
oxygen the numbers were reduced to 13
and 16 and the duration 3.5 and 4.3 minutes
per half hour. It is interesting in this
case-and we have not examined enough to know whether this is a general application-tilat
the durations of each period of apnoea were
slightly longer when the baby was in a
raised oxygen concentration although tile
total duration over a period of half an hour
was considerably less. \Vhether this is in
)4)__. .
S 307
Fic. 10. Impedance pneumograph in use. (J.E. Pallett and
J.
\V. Scopes)AIR
c
307.3OMIN
APNEA IN PERIOD I - 13 EPISODES TOTAL 35 MIN.
- 2 -33
I 3
6-8
4-3 V
I MIN
Fic. 11. Diagram to show frequency and duration of apnoeic spells over 3 half-hour periods in a pre-mature baby (svt 840 gm, age 48 hrs), breathing air or 30% oxygen. At the bottom of the figure are
ARTICLES 785
oxygen I cannot say but it is a possibility.
I have discussed some of the problems
connected with the indications for oxygen therapy in newborn babies. Obviously we
ilave a very great deal to learn and it is
equally obvious that anyone concerned with
oxygen must not lose his head. Just before
I left London John Davis reminded me that
Lavoisier himself lost his-on the guillotine.
REFERENCES
1. Wilson, J.: Kenneth D. Blackfan, 1883-1941.
In Pediatric Profiles, edited by B. S. Veeder. St. Louis, Missouri: Mosby, 1957, p. 211. 2. Stevenson, R. L., and Osborne, L. : The Wrong
Box. London: Longman and Co., Ltd., 1889. 3. Crothers, B. : Disorders of the nervous system in
childhood. Chapter 3 in Clinical Pediatrics, Vol. V. New York and London: D. Appleton and Company, 1930.
4. Claireaux, A. E., Mearman, S., and Tizard,
J.
P. M. : Intracranial haemorrhage in the newborn. In preparation, 1964.5. Strang, L. B., and MacLeish, M. H.: Ventila-tory failure and right to left shunt in new-born infants with respiratory distress.
PEDI-ATRICS, 28:17, 1961.
6. Boyle, R.: New pneumatical experiments about respiration. Phil. Trans. Roy. Soc., 5:2011, 1670.
7. Buffon, C. L. L.: In Barr’s Buffon’s Natural History, Vol. 3, Chap. 3, 1807.
8. Windle, W. F., Jacobson, H. N., Robert de
Ramirez de Arellano, M. I., and Combs, C. M.: Structural and functional sequeiae of asphyxia neonatorum in monkeys (Macaca mulatta). Res. Publ. Ass. Nerv. Ment. Dis., 39:169, 1962.
9. Davis, J.A.: The effect of anoxia in newborn rabbits. J.Physiol., 155:56P, 1961.
10. Apgar, V.: A proposal for a new method of evaluation of the newborn infant. Curr. Res. Anest. Anaig., 32:260, 1953.
11. Apgar, V., Holaday, D. A., James, L. S., Weis-brot, I. M., and Berrien, C.: Evaluation of the newborn infant-second report. J.A.M.A.,
168:1985, 1958.
12. Wilder, Thornton: The Bridge of San Luis Rey,
1927.
13. Gupta, J. M., and Tizard, J. P. M.: Recording the state of the newborn one minute after birth. In preparation, 1964.
14. Fink, B. R.: Diffusion anoxia in clinical anaes-thesia. Acta Anaesth. Belg., 5:42, 1954. 15. Cross, K. W., Klaus, M., Tooley, W. H., and
Weisser, K.: The response of the newborn baby to inflation of the lungs. J. Physiol.,
151:551, 1960.
16. Davis,
J.
A., and Moore, \V. M. 0. : The effect of narcotic (Irugs on the response of newborn rabbits to acute anoxia. In preparation, 1964.17. Varlev, M. A., and Cairdner, D.: Respirator distress syndronie of the newborn. Principles
ill Treatment. Arch. l)is. Child., 37:455,
1962.
18. Cook, C. D., Drinker, P. A., Jacobson, H. N., Levison, H., and Strang, L. B. : Factors deter-mining the increase in pulmonary blood flow on ventilation of the foetal lamb lung. J.
Physioi. (London), 166:9P, 1963. 19. Rudolph, A. M., Auld, P. A. M., Drorbaugh,
J.
E., Rudolph, A. J., Nadas, A. S., and Smith, C. A. : Studies on the circulation of infants with hyaimne membrane disease. J.Dis. Child., 98:630, 1959.
20. Ashton, N. : Retrolental fibroplasia in kittens. Personal communication, 1964.
21. Avery, M. E., and Oppenheimer, E. H. : Recent increase in mortality from hyalmne membrane disease. J. Pediat., 57:553, 1960.
22. McDonald, A. D. : Cerebral palsy in children of very low birth weight. Arch. Dis. Child., 38:579, 1963.
23. Dawes, C. S., Mott, J. C., Shelley, H. J.: The importance of cardiac glycogen for the main-tenance of life in foetal lambs and newborn animals during anoxia. J. Physioi. (London),
146:516, 1959.
24. Shelley, H. J.: Carbohydrate reserves in the newborn infant. Brit. Med. J., i:273, 1964.
25. Drorbaugh, J.E., Cherry, R. B., Lucey, J.F.
Segal, S., and Sutherland, J. P.: “Vital
ca-pacity” and lung compliance in normal
new-born infants and infants with hyalmne
mem-brane syndrome. J. Dis. Child., 94:434, 1957.
26. Cross, K. W., Tizard, J.P. M., and Trythall, D. A. H.: The gaseous metabolism of the newborn infant breathing 15% oxygen. Acta Paediat. 47:217, 1958.
27. Oliver, T. K., and Karlberg, P.: The effect of environmental temperature and 15 per cent oxygen on the gaseous metabolism of new-born infants. Acta Paediatr. (Stockholm) Suppl. 140, p. 51, 1963.
28. Flynn, D., and Hill, J.: Personal
communica-tion, 1963.
29. Moore, R. E., and Underwood, M. C.: Possible role of noradrenaline in control of heat pro-duction in the newborn mammal. Lancet,
278:1277, 1960.
30. Karlberg, P., Moore, R. E., and Oliver, T. K.: The thermogenic response of the newborn infant to noradrenaline. Acta Paediat., Scand., 51:284, 1962.
31. Sandler, M., Ruthven, C. R. J, Normand,
3-mthoxv-4-hdroxvmandelic acid in th new-born. Lancet, 280:485, 1961.
32. Scopes, J. W., and Tizard, J. P. M.: The effect of intravenous noradrenaline on the oxygen consumption of newborn mammals. J. Phys-iol., 165:305, 1963.
3:3. Dawkins, M. J.R., and Hull, D.: Brown fat
and the response of the newborn rabbit to cold. J.Physiol. (London), 169: 1O1P, 1963. 34. Blackfan, K. D., and Yaglou, C. P.: The
pre-mature infant: a study of effects of atmos-pheric conditions on growth and on (Ic-velopment. Amer. J.Dis. Child., 46:1175,
1933.
35. \Vilson, J. L., Long, S. B., and Howard, P.: Respiration of premature infants: response to variations of oxygen and to increased car-bon dioxide in inspired air. Amer. J. Dis.
Child., 63:1080, 1942.
36. Evanson, R. T., and Maunsell, H.: A Practical Treatise on the Management and Diseases
of Children. Dublin: Fannin and Co., 1838. 37. Pallett,
J.
E., Scopes,J.
W., and Campbell,E. J. M.: The monitoring of respiration of infants b recording electrical impedance of the chest. Proceedings of the 5th Interna-tional Conference on Medical Electronics, Desoer Ed. Liege, 1963.
CoEcTioN
