CHANGING
RECOMMENDATIONS
AND
PRACTICE
IN THE
USE OF OXYGEN
Impact
of the Controlled
Studies
on Mortality
and Morbidity
On completion of the Cooperative Study of
RLF, three controlled clinical trials conducted in
20 premature nurseries had unequivocally related
oxygen therapy to RLF. This resulted in new recommendations to limit the use of oxygen. Although the studies of both Lanman and co-workers (1954) and Kinsey and Hemphill (1955)
had not demonstrated any increase in mortality with restricted use of oxygen, many physicians were skeptical, partly because of their early training and the previous long-standing clinical experience and partly because of their fear of producing hypoxic brain damage. Nevertheless, notable changes in practice took place, and the use of oxygen was severely curtailed. The first increase in perinatal mortality in the United States occurred in 1955. At first this increase could not be ascribed to the restricted use of
oxygen. However, recent analysis of subsequent mortality trends, both in the United States and
Great Britain, over the next ten years of limited
oxygen use (Cross 1973) has suggested that the increased mortality was indeed associated with the decreased use of oxygen.
RECOMMENDATIONS
Prior to 1955, the recognized textbooks of
pediatrics available to pediatricians advised that oxygen be used liberally. The 12th edition of
Pediatrics (Holt and McIntosh, 1953)
recom-mended: “... as a rule the oxygen content of the incubator need not exceed 60%, although higher
concentrations appear to do no harm and may
serve to tide the patient over a spell of anoxia.”
In 1954 the Textbook of Pediatrics (Nelson)
stated: “For the small premature infant just admitted to the nursery, observation in an atmo-sphere of 40 to 60 percent oxygen for a few hours or days, followed
Not until 1959 did the Textbook of Pediatrics
(
Nelson) urge caution with: “ . . . moist oxygenshould be used only in quantities sufficient to
relieve cyanosis when it is present and
“ . . . adoption of the practice of administering
oxygen only in such amounts and at such times as are absolutely necessary for respiratory distress has practically eradicated retrolental
fibropla-Sm.
The second revised Academy manual, Hospital
Care of Newborn Infants, published in 1954 “to
define optimum standards for those procedures which will safeguard the physical well-being of the newly-born infant and foster wholesome and normal relationships between him and his envi-ronment, ‘ ‘ had the following recommendations:
Particularly feeble premature infants and those with actual or threatened respiratory distress or cyanosis, require atmospheric oxygen concentrations of 40-50%, as determined
by direct analysis. The use of oxygen at higher concentra-tions, the duration of its use, and, in the last analysis, its use or non-use depend upon observed clinical effects and should not be routine matters.
Any oxygen concentration above 40% should be given with at least 65% humidity as a protection against the possibility of oxygen poisoning. In tents or incubators inca-pable of providing a saturated atmosphere, this elevated humidity can be best attained by passing the oxygen through a nebulizer containing sterile water” (pp. 62-63).
The instructions were amplified:
Particularly feeble infants and those with actual or threat-ened respiratory distress or cyanosis require atmospheric
oxygen concentrations of 40-50%. The oxygen analyzer should be used to determine the concentration. Use of oxygen should depend upon observed clinical effects and should not be a routine matter. The use of higher concentra-tion and the duration should likewise be a similar decision.
When an infant is to be removed from oxygen, the
concen-tration should be gradually reduced over several days to that of room air” (p. 89).
With the completion of the study of Lanman
et a!., (1954), the New York City Health
Depart-ment issued an alert in April 1954, warning
against the routine use of oxygen in nurseries
(Appendix II). The bulletin caused some concern
because not all pediatricians were convinced of
the safety of limiting oxygen and preferred to
wait for the report of the large Cooperative Study
which was coming to a close.
The results of the Cooperative Study were
announced on September 19, 1954. Five days
prior to this, the Air Shields Company, having
received prior notification of the findings of the
Collaborative Study implicating oxygen as a
major factor in the development of RLF, sent a
telegram to every hospital in the world known to
have an Isolette: “Recommendation-removal of the small float in the air-oxygen intake assembly.”
This small float was responsible for the
“efficien-cy” of the incubator in maintaining high
concen-trations of oxygen.
After publication of the Academy’s manual,
Hospital Care of Newborn Infants, in 1954, the
November 1954 issue of Pediatrics carried an
editorial comment, “Oxygen Administration and
Retrolental Fibroplasia,” by Gordon; his
com-ments summarized the clinical and laboratory evidence to that time associating the
administra-tion of oxygen with RLF. He reported that, at the
Colorado General Hospital, limitation of
environ-mental oxygen to concentrations not to exceed
40% by regular analyses resulted in a sharp drop
in incidence of RLF over a two-year period. He
added: “Because the absolute risk of extensive
retinal disease is now small, it is important, on the
other hand, that oxygen not be discontinued when
close supervision of the small infant is not avail-able. We therefore do not start to discontinue
oxygen at the 24-hour mark if this comes during a
nursing shift when the physician cannot be sure of
supervision.”
Dr. Gordon ended by advising: “Optimal use of
oxygen requires that we balance possible harm for
the eyes against possible benefit for respiratory function.”
In the same year Karlberg and co-workers
demonstrated in infants with the respiratory
distress syndrome (RDS) that alveolar ventilation was increased in a higher oxygen environment. This emphasized the continued need for oxygen in infants suffering from respiratory difficulties.
The second edition of Dunham’s Premature
Infants, published in 1955, recommended that
oxygen be administered as follows:
For premature infants that have respiratory difficulties or cyanosis at any time in the neonatal period oxygen adminis-tration is always indicated. Some authorities advocate giving oxygen to all very small premature infants . . .(p. 110).
Another possible danger from oxygen therapy is that there may be a relationship between relatively high concentrations of oxygen and the occurrence of retrolental fibropla-sia .. .(see p. 325).
For premature infants, recommended concentrations of oxygen vary considerably. There is a tendency at the present time to use relatively low concentrations of oxygen, about 40 to 50 percent, and to use oxygen for the shortest period necessary to relieve symptoms. If higher concentrations are used they should be used for short periods only.
And under RLF (p. 324), Dr. Dunham
summar-izes the various causes of RLF and quotes both
the report of Lelong et a!. (1952) and the
prelim-mary report presented by Kinsey at the annual
meeting of the American Academy of
Ophthal-mology and Otolaryngology (1954). From Lelong
et a!., she quotes: “The data, they maintain, point
rather to the danger of anoxia than to that of
oxygenation,” and from Kinsey and Hemphill
(1955): “ . . . it was concluded that pediatricians
should restrict the use of oxygen to those minimal
amounts which on the basis of frank clinical need
are required for the survival of the infant.”
There was no attempt to reconcile these two
opposite views and no firm recommendation was
made.
In June 1955, the California State Department
of Health strongly recommended that physicians
give oxygen only for specific reasons, and then
only on the written order of a physician and in a concentration not to exceed 40%. Concentrations
over 40% were said to be needed rarely, if ever,
and then only for short periods of time.
In the fall of 1955, the Chairman of the
Academy’s Committee on Fetus and Newborn
Committee statement on the use of oxygen in the treatment of premature infants. This statement was approved by the Board at its October
meet-ing, and published in January 1956 under News
and Announcements (which is not retrievable in
the Cumulative Index):
The accumulated evidence definitely incriminates the excessive use of oxygen as a major factor in the cause of retrolental fibroplasia in premature infants. “Excessive use” implies concentrations of more than 40 per cent or the prolongation of administration after the indication for its use has passed. It is possible that even short periods of
adminis-tration of higher concentration may be harmful.
On the other hand, the intelligent use of oxygen can be the means of saving the lives of hypoxic, dyspneic, and cyanotic babies. It would be unwise to arbitrarily deny adequate therapy (and perhaps life) to those babies because of possible injury to the eyes of some.
Accordingly, the following recommendations are made: 1. Oxygen should be prescribed only on medical order the same as any drug or treatment (except in emergency).
2. Oxygen should not be administered routinely but only upon specific medical indication.
3. Oxygen concentration should be kept at the lowest possible level that will relieve the symptoms for which it is given, if possible not over 40 per cent.
4. Oxygen therapy should be discontinued as soon as the indication for it has passed.
5. Ordinarily, the indications for supplemental oxygen are general cyanosis (not acrocyanosis) and dyspnea.
“The Possibility of Total Elimination of Retro-lental Fibroplasia by Oxygen Restriction,” by
Guy, Lanman, and Dancis was published in
Pediatrics in February 1956. The authors
concluded: “We believe that retolental fibro-plasia can be either completely or almost com-pletely eliminated by administering oxygen only
at times of clinical need, and then for as brief periods as possible and at concentrations less than 40 per cent.”
The authors also pointed out that mortality
among infants given restricted oxygen therapy was higher than among those receiving intensive
oxygen therapy-32% as against 20%, although
the difference was not statistically significant
(P slightly less than .2).
Publication of this paper prompted a letter to
the editor by Kinsey (published in Pediatrics,
September 1956) which emphasized the impor-tance of the duration of oxygen therapy: “In view of . . . the paucity of evidence that there is any
critical concentration below which RLF is
markedly reduced in incidence, I believe that merely restricting the concentration of oxygen, without stringently reducing the duration in
oxygen, may result in unnecessary cases of RLF.
Certainly the emphasis should be placed on
restricting the duration in oxygen to an absolute
minimum consistent with the clinical indications
of anoxia irrespective of the concentration of oxygen administered.”
However, the notion of a “critical
concentra-tion” of oxygen (40%) had become fixed in the minds of pediatricians and, despite all evidence to the contrary, the misconception persisted.
Patz presented the E. Mead Johnson Award
Address in October 1956, and his paper, which was printed in Pediatrics in March 1957, concluded: “The results of a controlled nursery study, supported by observations of others in both uncontrolled and controlled studies, clearly
estab-lished the overuse of oxygen in the premature
nursery as an important and probably the
prin-cipal factor in the development of retrolental
fibroplasia.”
The revised Academy manual on Hospital Care
of Newborn Infants was published in 1957. It
contained the announcement printed in Pediatrics
in January 1956, and added the following recommendations:
5. (Continued) The urgency of treating general cyanosis and dyspnea must rest with the clinical judgment of the attending physician.
6. Oxygen concentration must be determined by means of an oxygen analyzer as often as necessary to keep it properly stabilized but at least every four hours.
7. A source which does not contain or deliver more than 40% oxygen will insure against exceeding that concentration but may not be adequate in those occasional instances where higher concentration is desired. If such a restricted source of oxygen is employed, additional oxygen should be available for those special instances where it is indicated.
8. There are no apparent contra-indications to the use of supplemental oxygen in infants weighing more than five pounds.
Later in the manual it is recommended:
“Ox-ygen, preferably piped along walls by a manifold
system, and apparatus for its administration and
control of its concentration [should be
availa-ble].”
The following statement concerning
examina-tion schedules is given under “Medical Service for
Premature Infant Care:” “A complete physical
examination should be performed and recorded as soon as the infant’s condition allows, weekly thereafter, and at discharge (see forms in
Appen-dix). The discharge examination should include
funduscopy” (p. 53).
In the 1962 edition of Pediatrics (Holt,
McIn-tosh, and Barnett) the recommendations were more specific and specified that no more than
40% oxygen should be given under any
Routine use of oxygen therapy has been eliminated since the recognition of its relation to retrolental fibroplasia. The only indication for administration of oxygen to premature infants is respiratory distress, particularly when cyanosis is present. The oxygen concentration is carefully controlled so
as not to exceed 40% .. . . The suggestion has been offered
that oxygen saturation may be safely raised above 40% if
cyanosis is not relieved, since the oxygen saturation of the
blood would still be below toxic levels. There is no evidence on this point, and the subjective factor in the evaluation of cyanosis makes it a hazardous approach.
These restrictions on oxygen use were made
without knowing whether it was an increase in
oxygen in the ambient air or in the blood which
caused RLF. Later, when oxygen tension in
arterial blood was shown to be the critical factor,
there were no data on the arterial oxygen tension
necessary to cause vasoconstriction in the
imma-ture retina.
The 1962 recommendations in Pediatrics (Holt
et a!., 1962) reflected the growing fear of oxygen
use which prevailed from 1956 to the mid-1960’s.
Many physicians supervising the care of small,
prematurely born infants shifted precipitously
from administering liberal amounts of oxygen to
all preterm infants for the prevention of apnea to
providing no more than 40% oxygen, and then
only to infants who had cardiopulmonary symp-toms. In some institutions there was a reluctance
to use more than 40% oxygen under any
circum-stances, even in the presence of cyanosis.
At the same time that restriction of oxygen use
was being recommended in textbooks and
manu-als, a number of state health departments were
also issuing cautionary or restrictive directives.
The American Academy of Pediatrics has
recent-ly requested the Health Departments of all states
to send a copy of regulations issued between 1950
and 1970 which relate to the use of oxygen for
newborn infants. Forty-eight replies were
received, and telephone responses were received
from the other states. Thirty-three of these states
had issued no directives. Five had issued
regula-tions between 1954 and 1963 which were
cautionary or restrictive with regard to the use of
oxygen (Appendix IV). The remainder sent out
educational material or recommendations.
RISK VERSUS BENEFIT
Despite the recommendations for restricted use
of oxygen, pediatricians continued to remain
concerned over risk versus benefit in their
approach to oxygen therapy. This was
empha-sized in a letter to the editor in Pediatrics
(Gor-don, 1957):
The recent publication (Pediatrics, 18:51 1, 1956) of a caution on the use of oxygen in the care of premature infants prompts this letter.
Although the Cooperative Study of Retrolental Fibro-plasia confirmed, beyond question of even the most skeptical, previously published reports of investigators from
many countries that excessive use of oxygen caused
retro-lental fibroplasia, the conclusions reached concerning the relation of oxygen restriction to survival rate of the infants are not clear. In the text of the report (Arch. Ophth., 56:481, 1956) it is pointed out that infants were admitted to the study only if they had survived 48 hours, and that the mortality figures refer to infants who had already survived the first 2 days of life (Ibid., p. 489). An italicized conclusion (Ibid., p. 490) omits this qualification, and it is stated that “reducing the length of stay in oxygen to that deemed necessary to meet acute clinical needs of the infant is without effect on mortality.” Although the 48-hour reservation is again stated
in an early part of the summary, in the Conclusions the
statement is again made: “Limiting the duration in oxygen to that deemed necessary to meet frank clinical emergency was shown to be without effect on the survival rate of the premature infant.” Since the risk of dying from anoxia is greatest for premature infants during the first 48 hours, it is obvious that a conclusion such as the one stated may be misleading.
The wide distribution of reprints of the report, the recent publications of the summary and conclusions without the text (Am. J. Dis. Child., 92:395, 1956) and of an abstract (J.A.M.A., 163:77, 1957) warrant emphasizing that no one has collected any controlled data on the value or lack of value of oxygen during the first 12, 24 or 48 hours of life when risks of death are highest. The need for study in this
period has been pointed out. (Pediatrics, 16:427, 1955; Obst.
& Gynec., 8:459, 1956). The danger of cicatricial retrolental fibroplasia has been reduced so markedly that this writer still is of the opinion that all newly born premature infants under
1500 gm should be placed in environmental oxygen not to
exceed 30 and 40% for 24 hours with removal as soon thereafter as the infant’s condition permits (Pediatrics,
14:543, 1956). It may well be that future studies will prove this recommendation erroneous; these studies have not yet been made.
Miller (1957) writing on respiratory
insuffi-ciency and the need for oxygen concluded:
The results suggest that oxygen therapy can be withheld with some confidence in the case of infants with birth weights from 1,001 to 1,750 gm, provided the infants (1) are free of cyanosis within a few minutes of birth, (2) initiate sustained, spontaneous respirations within 2 minutes of birth, (3) attain a respiratory rate of 40/mm or more during the
first hour, and (4) do not have a significant increase in
respiratory rates after the first hour . . . . The incidence of
oxygen therapy, and of deaths, was high among infants with birth weights from 1,001 to 1,750 gm who did not fulfill the above criteria ....
The indications for discontinuing oxygen therapy were difficult to determine for infants with birth weights less than 1,751 gm . . . .The criteria for discontinuing oxygen therapy
in small premature infants will continue to be indefinite until some means is found for predicting the occurrence of late severe bradypnea and apnea with greater accuracy than is at present available.
Continued concern over the dangers of hypoxia
Resusci-tation of the Newborn Infant, which was
prepared by the Academy’s Committee on Fetus
and Newborn with the cooperation of the
Amer-ican College of Obstetricians and Gynecologists,
American Society of Anesthesiologists, American
Hospital Association, and the American Public
Health Association. It was published in 1958:
“Some babies who survive asphyxia are left with
permanent injury to the brain. The brain does not
receive enough oxygen during serious asphyxia,
and some of the cells are damaged. Some cases of
cerebral palsy, epilepsy and mental deficiency
may be related to this type of lesion.”
Asphyxia is defined in the booklet as including
the various forms of impaired gaseous exchange,
i.e., anoxia, hypercapnia, oxygen lack, and so
forth. The booklet recommends that infants with
Apgar scores of 0 to 4 should be ventilated with
oxygen after the airway is cleared. It might be
necessary to aid inflation of the lungs by use of a
snuggly fitting mask and administration of oxygen under controlled intermittent pressure.
Despite the fear of RLF, the recognition of the
value of oxygen remained. This is clearly stated in
Schaffer’s The Diseases of the Newborn, the
principal published text on the clinical practice of
neonatology in 1960. It reflects standards of
practice throughout the 1950’s even after oxygen
was finally recognized as the major cause of RLF.
From the introduction to Chapter 77: “Yet the
damage it [asphyxia neonatarum] inflicts upon
the lower centers of the brain is responsible for its first and most distressing sign, apnea; damage inflicted upon the higher centers is responsible for
the less immediate but equally disturbing
sequelae which may follow in its wake.”
From the section on treatment comes: “It is
now recognized that he needs but one medicine,
and that medicine is oxygen.”
From the section on prognosis the following
sentences are relevant:
A few [infants] will demonstrate the neurological sequelae attributable to asphyxial cerebral damage. The majority of these will clear up in several days or weeks but in a minority it will become evident that the damage done to the brain has been profound and permanent .. . . Careful rereading of the
abundant literature on this subject leaves us with the strong feeling that severe asphyxia does indeed damage the central nervous system irreparably in many instances. It may lead to death, to permanent severe mental and motor deficit, to lesser degrees of mental deficiency, to epilepsy, to cerebral palsy or to deviations from normal behavior.
From Chapter 82 comes the comment (in
reference to the cause of cerebral palsy): “The
pendulum appears to have swung back to the
belief that the diffuse damage caused by cerebral
asphyxia is the most important etiologic agent.”
Although the sequence of events leading to
various degrees of cerebral damage or death were
poorly understood, there is little doubt that
unre-lieved asphyxia was thought to have an adverse
effect on the newborn nervous system leading to
permanent damage.
INCREASED MORTALITY AND MORBIDITY
WITH RESTRICTIVE OXYGEN THERAPY
Reexamination of neonatal mortality data of
the past few decades suggests that the severe
oxygen restriction which followed acceptance of
the role of oxygen in RLF was associated with
increased number of deaths among premature
infants (Cross, 1973; Bolton and Cross, 1974).
There are a number of reasons which may
explain why the three controlled studies failed to
reveal this influence on survival. First, the studies
of Patz et a!. (1952) and of Lanman et al. (1954)
dealt with small numbers of infants. Though each
showed a trend towards a higher mortality in the
restricted-oxygen group, the increase was not
statistically significant. Second, infants were not
enrolled in the Cooperative Study and assigned to
contrasting oxygen treatment groups until they
were 48 hours of age. Thus, the effect of oxygen
restriction on survival during ‘the first 48 hours
after premature birth was not evaluated. Some
indication of the magnitude of the risk of dying in
the first 48 hours of life in 1953 and 1954 among
infants 1,500 gm can be appreciated from this
statement in the report of the Cooperative Study:
“There were 634 additional premature infants in
this birthweight category born in or brought to
these hospital nurseries during this period [one year]. All of these were reported to have died before 48 hours.”
Of the 786 infants who survived the first two
days of life and were enrolled in the program, 166
died prior to 40 days of age.
Disturbing results were reported from Johns
Hopkins Hospital in 1960 (Avery and
Oppen-heimer); there was an increase in the number of
deaths associated with hyaline membrane disease
in the five-year period 1954 through 1958 when
oxygen use was restricted.
More recently, the survival experiences in the
United States and in England and Wales during
years before and after 1954 have been reviewed.
When deaths on the day of birth per 1,000 live
births were plotted for the years 1935 to 1970
(Cross, 1973) and later extended to 1974 (Bolton
USA
8
7
6
5
1965
1975
Deaths
on day of birth/l000
live births
NO.
15
14
13
12
11
10
9
England
and Wales
I
I
I
I
I
I
I
I
I
1935
1945
1955
YEAR
FIG. 4. Mortality on the first day of life in the United States and in England and Wales, before
(open circles and squares) and after (closed circles and squares) oxygen restriction. The general policy change toward restriction of oxygen use for premature infants took place somewhat
earlier in Great Britain than in the United States. (Redrawn from Bolton and Cross, 1974).
(
Figure 4) which corresponded to the years of“ . . . a policy of uncritical oxygen restriction.”
Cross (1973) has estimated that the cost of
pre-venting RLF may have been 16 deaths for each
sighted infant gained during the years after the
RLF epidemic. However, this charge must
remain speculative because there were other
relevant events in the years immediately after
1954, notably a number of drug-associated deaths attributable in particular to use of sulfisoxazole
and chloramphenicol before their hazards for
premature infants were understood, and at least
one influenza pandemic (1957). These events
confound a single-factor interpretation of the
survival experience during this period.
With regard to morbidity, McDonald (1963
and 1967) found that there was an inverse
rela-tionship between an incidence of spastic diplegia
and RLF. A relationship with duration of oxygen
gesta-tion period of less than 31 weeks, 19 (19.2%) of 99
children given oxygen for less than 1 1 days had
diplegia; this was compared to 4 (4.6%) of 87
given oxygen for 1 1 days or more (P < .0 1).
However, this difference was almost restricted to
children who had cyanotic attacks; of 14 children
with a gestation period of less than 31 weeks who
had cyanotic attacks and were given oxygen for
less than 1 1 days, eight (57%) had spastic diplegia,
compared with none of 24 comparable children
given oxygen for a longer time. Among the
children with no reported cyanotic attacks, 11
(13%) of 85 children given oxygen for not more
than 10 days and 4 (6%) of 63 children given
oxygen for 1 1 or more days had diplegia.
Long-term follow-up of the survivors of the
Cooperative Study (1956), or indeed any of the
earlier trials, has not been undertaken. The
possi-bility of additional “lesions,” especially in the
central nervous system, has been virtually
unexplored (Chase, 1972).
OXYGEN THERAPY FOR RESPIRATORY
DISTRESS OR APNEA IN THE IMMATURE
INFANT
At the same time that the association between
oxygen and RLF was suspected and being
investi-gated, idiopathic RDS was being recognized as
the clinical, premortem expression of what had
been only an autopsy diagnosis-hyaline
mem-brane disease. Hyaline membranes were first
described in the lungs of infants dying shortly
after birth by Hocheim in 1903. Further
descrip-tions of these membranes and atelectasis in lungs
of preterm infants dying shortly after birth were
given by Farber and his colleagues (1931, 1932,
1933). The hyaline membranes and a
character-istic set of clinical signs of respiratory distress were not clearly associated until the mid-1950’s. Before then, apnea was the sign usually associated
with respiratory failure and imminent death in
preterm infants. From the mid-1950’s, the more
complete clinical picture of increasing
respira-tory failure with tachypnea, intercostal
retrac-tions, expiratory grunting, and cyanosis was
stressed (James, 1959). When these were
estab-lished as the clinical manifestations of hyaline
membrane disease, investigations into the
cardio-pulmonary causes of death increased. Between
1954 and 1965, various investigators contributed
to a better understanding of the biophysical basis
(Avery and Mead, 1959), and the biochemical
(Reardon, 1957) and physiological consequences
(Karlberg and co-workers, 1954) of RDS.
Further-more, RDS was shown to be the principal cause of
death during the first 28 days after birth. The
estimated number of infants suffering from RDS
in 1965 was 50,000, of whom approximately
25,000 died. For infants with a birthweight of less
than 1,750 gm, the mortality rate was nearly 70%,
even when they were given oxygen. Dyspnea and
cyanosis, secondary to progressive pulmonary
atelectasis, were the principal signs of RDS and
often could not be relieved by 40% oxygen.
Therefore, in the early 1960’s, physicians treating
infants with the syndrome began again to use
higher concentrations of oxygen with caution,
even though this practice was discouraged by
textbooks, state health departments, and the
American Academy of Pediatrics.
MONITORING OF ARTERIAL OXYGEN
TENSION
From 1955 to 1960, there was a reluctance to
use high concentrations of inspired oxygen, not
only because of the fear of RLF but also because
of the inability to measure oxygen tension in the
blood other than as a research procedure. Direct
measurements of arterial oxygen tension were rarely made, although there was increasing
recog-nition of the unreliability of clinical judgment of
the amount of oxygen needed. Until the late
1950’s, measurement of the oxygen tension (Po2)
in blood was laborious and was done by one of
two methods: (1) the measurement of oxygen
content and capacity, the calculation of oxygen
saturation, and the determination of oxygen
tension from the oxyhemoglobin dissociation
curve (Roughton et a!., 1944); or (2) by
equili-brating the blood for five minutes or more with a small bubble of alveolar air at 37 C and
deter-mining the Po of the bubble by microanalysis of
the percentage of oxygen therein (Riley et al.,
1945). Both methods required meticulous care to
avoid errors and required a skilled technician
about an hour to perform. Serial measurements of
Po became possible only after the oxygen
elec-trode was developed (Clark, 1956) and became
available for clinical research in a few hospitals in
the early 1960’s. However, a large volume of
blood was necessary for the determination (2 ml).
Consequently, the technique could not be used
for multiple serial measurements with requisite
duplicate analyses, particularly in small infants.
Reliable microtechniques for measuring Po2 were
not available until the late 1960’s; even in 1969,
there were, by reliable estimates, less than 50
such machines in pediatric departments in the
United States. Most of these machines were used
in cardiopulmonary diagnostic laboratories where
the patients were larger, hence the degree of
problem. Thus, control of oxygen administration
by blood analysis was possible only in a few
institutions and almost entirely on a research
basis.
Even today, arterial oxygen tension cannot
always be followed safely with serial samples in
small infants. At times the umbilical artery is too
constricted to allow passage of the catheter, and
at other times the catheter has to be removed
because of risk. Obtaining serial arterial samples
by arterial puncture is extremely difficult and
may be dangerous; it may be impossible even in the most skilled hands. Furthermore, the
intro-duction of a catheter into the umbilical artery is
not an innocuous procedure, and its presence is
potentially dangerous.
With the development of intravascular and
especially of surface electrodes, it may soon be
possible to measure arterial Po2 continuously. The
development of this technology should allow
optimum treatment of RDS with minimum risk.
However, until these devices are thoroughly
tested, proven safe, and generally available, some
instances of RLF are the inevitable consequence
of the successful treatment of RDS.
VENTILATORY ASSISTANCE FOR RDS
AND NEW RECOMMENDATIONS
The first attempts to treat small infants with
RDS with assisted ventilation were made in the
early 1960’s (Stahlman et a!., 1962 and 1970;
Delivoria-Papadopoulos and Swyer, 1964).
Pedi-atricians began to use higher concentrations of
inspired oxygen and to regulate the artificial
ventilation and ambient oxygen levels by
moni-toring the arterial Po2 with arterial blood from
umbilical artery catheters (James, 1960), although
it was not known what level of arterial Po was
“safe.”
Recognizing that the restrictions on oxygen
delivery were now too severe, the State of Cali-fornia Department of Public Health (1968)
revised its recommendations and the health code
in April 1968 so concentrations of inspired oxygen
above 40% were permissible if arterial oxygen
tensions were measured and the need
docu-mented. The American Academy of Pediatrics’
Standards and Recommendations for Hospital
Care of Newborn Infants, published in 1971,
made similar recommendations (Appendix I):
“... the oxygen tension of arterial blood [should]
be kept close to this normal range” (60 to 100 mg
Hg).
It was also pointed out:
The upper limit of arterial oxygen tension and its duration
which are safe for these infants is not known. It is probable that even concentrations of 40% oxygen in inspired air .. .could be dangerous for some infants.
. .. The infant born before 34 weeks’ gestation or
weighing less than 2,000 gm . . .who requires an inspired
oxygen concentration greater than 40% for more than brief periods should be treated, where feasible, in a hospital at which the inspired oxygen concentration can be regulated on the basis of blood gas measurements.
The Committee was fully aware that this
represented an optimal standard of care. They
pointed out in the introduction to the manual:
“This manual is meant to set general guidelines
for future development rather than strict
oper-ating rules for currently operating nurseries and
newborn intensive care units. Moreover, a
delib-erate attempt has been made to recommend
idealized facilities, rather than minimal
stan-dards
Continuous positive airway pressure (CPAP)
for the treatment of RDS was introduced by Gregory et al. in 1971. With the introduction of this simple method for assisting respiration, mortality from RDS in small infants appeared to
fall dramatically. At the Moffitt Hospital at the
University of California, it fell from more than
90% to 35% in infants with RDS who weighed
between 750 and 1,500 gm at birth (Gregory
et al., 1971). However, as ventilation became
more efficient, the regulation of inspired oxygen
to prevent hyperoxemia became more important,
even though arterial oxygen tensions were
measured frequently. Some small, prematurely
born infants who were ventilated continuously at
constant inspired oxygen concentrations,
ventila-tory pressures, and respiratory frequencies could
lower their arterial oxygen tensions abruptly from
100 to 20 mm Hg with straining and fussing; Po2
may return promptly to the previous level as soon
as the infant is calm. Because of the rapidity with
which arterial oxygen tension may change, even
the most frequent sampling of arterial blood does
not guarantee against the development of
exces-sively high or low oxygen tensions.
It is not unusual in infants with severe RDS on
CPAP to have oxygen tensions of 100 mm Hg
while breathing 30% oxygen or for arterial Po2 to
rise from 40 to 200 or 300 mm Hg within minutes
of applying positive pressure to the airway. As a
consequence, arterial oxygen tensions, which theoretically could cause retinal vessel injury,
may be obtained while infants breathe 30% to
40% oxygen. The regulation of the inspired
oxygen to keep the arterial Po,, within the normal
range (60 to 90 mm Hg), as recommended by the
American Academy of Pediatrics, is not always
Even measurements of arterial Po2 every hour
(
which requires an enormous amount of blood: 0.3x
24 = 7.2 nil or 10% of the blood volumeper day for a 1,000 gm infant) may not prevent
transient periods of hyperoxemia.
In 1976, apparently as a consequence of
improved supportive measures (including CPAP), an increasing number of extremely immature
infants and those with severe forms of RDS, all at
high risk of developing RLF, are surviving.
Increased survival also appears to be associated
with an increase in RLF because CPAP increases
arterial oxygen tension so effectively. The current
technique of using the indirect ophthalmoscope
enables the far periphery of the retina to be visualized, permitting identification of early
stages of RLF. Although both moderate and even
severe cicatricial RLF is still seen occasionally,
the overall incidence of RLF reflects to some
extent our ability to recognize low-grade disease,
most of which will regress completely.
COLLABORATIVE STUDY TO DETERMINE
“SAFE” ARTERIAL OXYGEN TENSION
Between 1969 and 1972, a collaborative study #{182}co-chaired by Patz and Kmnsey was
con-ducted on premature infants, both inborn and
outborn, who were cared for at the university hospitals associated with Columbia, Johns
Hop-kins, McGill, Vanderbilt, and Washington
(Seat-tie). The study was aimed at preventing blindness in premature infants by establishing a more definitive relationship between arterial oxygen tensions and the development of RLF. Hopefully,
this will enable the formulation of guidelines for
prescribing oxygen to relieve anoxia based on arterial levels of oxygen.
Results obtained from 719 infants, most of
whoiii were being treated for RDS, showed that
there was no significant difference in average arterial oxygen tensions in infants with some
cicatricial grade of RLF (mostly nonbiinding) and those whose eyes were normal. These infants were all carefully monitored, and their arterial oxygen
tensions were almost exclusively in the range of
60 to 100 mm Hg by intermittent sampling.
The authors emphasize: “Because the infants in
this selected population had special need of
oxygen for survival, it ‘would be misleading to
extrapolate these results to premature infants in general. Accordingly, it is unwarranted to make recommendations regarding either the ideal
#{182}Paper in preparation.
range of arterial oxygenation or the ambient
oxygen levels that would prevent CNS damage
from hypoxia as well as blindness from too much
oxygen.”
RETROLENTAL FIBROPLASIA IN THE
ABSENCE OF SUPPLEMENTAL OXYGEN
OR HYPEROXIA
The claim that RLF is seen occasionally in
infants who have never received supplemental
oxygen, or is already present at birth, was
regarded with doubt and suspicion for many
years. Disbelief was reinforced when the
relation-ship between oxygen therapy and RLF was
clearly demonstrated. However, now that the
pathology and clinical signs have been clearly
defined, a number of such instances have been
verified without question.
Bruckner (1968) described an infant born near
term who was never given supplemental oxygen
but developed grade V cicatricial RLF in both eyes; the diagnosis was verified by Reese.
Brock-hurst and Chrishti (1975) reported six adult
patients who had never received oxygen but had
typical signs of moderate to severe late cicatricial
RLF. Three of these patients had been born
prematurely at home, and three were born at term. RLF has also been found at birth, albeit in
conjunction with other congenital anomalies such
as hydrocephalus or anencephaly. Therefore, the
condition can develop in utero in a relatively low oxygen environment (Reese and Blodi, 1952;
Addison et a!., 1972; Karlsberg et a!., 1973; Foos,
1975). RLF has been found in otherwise normal
infants shortly after birth and in whom the duration of oxygen therapy has been too brief to
account for the lesions (Roberton et a!., 1968;
Johnson et al., 1974). Finally, RLF has been seen
in a premature infant (940 gm) with tetralogy of
Fallout (Kaiina et al., 1972).
RLF by definition refers to abnormal
vasopro-liferation rather than to the preceding vasocon-striction phase. Local retinal anoxia appears to stimulate the abnormal proliferation. On these
grounds, local retinal anoxia, caused by factors other than vasoconstriction of the retinal arteries in response to hyperoxia, could also result in the lesions of RLF. As noted earlier, Ashton and
Henkind (1965) have produced RLF
experimen-tally by local retinal anoxia. Thus, the foregoing
cases do not conflict with current concepts of
RLF because hypoxia of the retina, following
vasoconstriction of the retinal arteries, is
consid-ered the basic mechanism.
reex-amine the mechanism by which oxygen causes
RLF and to undertake a renewed search for
additional possible causes or for factors which
might increase or reduce individual susceptibility. That such factors exist has long been evident from
the observation of the Cooperative Study (Kmnsey,
1956) that the incidence of severe cicatricial RLF
in infants of single birth was approximately one
third that in infants of multiple birth (P < .001).
Similarly, among the 53 infants in the routine
(h igh)-oxygen group who survived for more than
40 days after having received an average of 30
days of 50% to 60% oxygen, 15 did not develop
any degree of RLF as judged by serial
examina-tion by direct ophthalmoscopy. This evidence of
biological variation is supported by the difference
in severity of lesions in the two eyes of an
