SPECIAL ARTICLE |
A Cautionary Tale About Supplemental Oxygen: The Albatross of Neonatal Medicine
Abbreviations: FIO2, fraction of inspired oxygen • ROP, retinopathy of prematurity
"The chess-board is the world; the pieces are the phenomena of the universe; the rules of the game are what we call the laws of Nature. The player on the other side is hidden from us. We know that his play is always fair, just and patient. But we also know, to our cost, that he never overlooks a mistake, or makes the smallest allowance for ignorance." (T.H. Huxley1)
In 1774, an English clergyman and amateur chemist, Joseph Priestly, heated mercurius calcinatus (mercuric oxide) with a burning glass and liberated a remarkable life-giving gas.2 He demonstrated that, when compared with the ordinary atmosphere, mice live longer in a jar of this "eminently breathable [‘dephlogisticated’] air." However, Priestley warned, "the new air might not be proper for use in the healthy state of the body... the air which nature has provided us may be as good as we deserve." But the temptation to treat patients with the novel gaseous substance (named "oxygen" in 1777 by Lavoisier3) was irresistible: Physicians lost no time in prescribing inhalations of this "vital air" for an astonishing assortment of diseases not helped by "ordinary means."
In 1780, Chaussier experimented with the use of oxygen for newborn infants who failed to establish normal respiration.4 Over the next 150 years, the gas was administered by various techniques (eg, as intermittent "showers" through a funnel, by subcutaneous injection, piping the gas into the stomach, and exposure in an "oxygen bassinette") to prevent and treat recurrent cyanotic attacks in prematurely born infants. However, the modern era of treatment (routine prolonged exposure of small premature infants to high concentrations of oxygen) began in earnest after 2 sets of observations in 1942. In Detroit, Michigan, observers found that the typical form of respiration seen in premature infants while in room air (the regular-irregular pattern, known as "periodic breathing") could be converted to a regular ("normal") rhythm by increasing the fraction of inspired oxygen (FIO2) to high levels.5 Boston, Massachusetts investigators noted that the skin color of small neonates was an unreliable indicator of the state of oxygenation. The skin remained pink in small infants even when blood oxygen levels were relatively low; the term "subcyanotic anoxia" was coined as a label for the unusual circumstance.6
These 2 sets of observations were used to rationalize the liberal use of supplemental oxygen in the care of premature infants. Additionally, the arrival of newly designed incubators in the late 1940s (built with tightly fitting gaskets, sleeved access ports, and novel float valves in an oxygen-intake plenum) made it possible to maintain high concentrations of O2 for prolonged intervals. It took a number of years to recognize the causal connection between these changes in routine management and the appearance of a completely new kind of infantile blindness7: retinopathy of prematurity (ROP*).
The sudden appearance of ROP in Britain after implementation of the National Health Service in 1948 (when, for the first time, funds were available to buy the expensive American incubators and to pay for liberal use of the costly gas) led Mary Crosse of Birmingham, in 1951, to suspect excess exposure to oxygen.8 This conjecture soon reached Australia, where Kate Campbell surveyed 3 nurseries in Melbourne and found an association between liberal use of oxygen and the frequency of ROP.9
After these observations there was a sharp upsurge in attention to the possibility that supplemental oxygen was responsible for the alarming epidemic of blindness then spreading throughout the world, but the associations were not consistent. For example, one observer noted that early vascular abnormalities in the retina seemed to appear when supplemental oxygen was discontinued, and the changes returned to normal when oxygen treatment was resumed! An alternate-assignment, parallel-treatment trial of high versus low oxygen regimens was conducted in 1952, and the results implicated liberal use; however, this study had been unwittingly sabotaged (nurses surreptitiously increased the flow of oxygen in the low-oxygen arm of the trial because they were convinced restriction was threatening the lives of their patients). In Britain, the distinctive vascular changes of the unusual retinopathy were reproduced in newborn kittens placed in a high-oxygen chamber. However, the induced abnormalities in the animal model regressed spontaneously; the kittens did not become blind.
By early 1953, controversy about the causal role of supplemental oxygen rose to a fever pitch. Finally, the US Public Health Service convened a conference in Bethesda, Maryland in the hope of devising a plan that might put an end to the international disaster (by this time the strange disease had blinded 
10 000 infants throughout the world). It was immediately clear that there were 2 highly vocal opposing camps at the meeting. One side argued that a formal, randomized trial of oxygen restriction must be conducted without further delay, because there were 3 competing outcomes of interest: blindness, death, and brain damage. The opposition maintained that there was sufficient evidence extant to prove that oxygen was the cause of ROP blindness; a controlled trial was not only unnecessary, they argued, it was immoral! Finally, after an all-night debate, a compromise was hammered out.
Eighteen hospitals agreed to participate in a randomized clinical trial for 3 months, recording week-by-week mortality among enrolled infants weighing 
1.5 kg, under 2 policies: "routine oxygen" (FIO2 > 50% for 28 days) compared with "curtailed oxygen" (supplemental O2 administered only for cyanosis or respiratory difficulty, FIO2 < 50%, and the gas would be discontinued as soon as symptoms improved). If there was no appreciable increase in mortality at the end of this first stage of the cooperative study with the concurrent controls, the last 9 months would be used to carry out a prospective survey, solely under a policy of curtailed oxygen, to measure the size of an expected reduction in the frequency of cicatricial ROP. When this historic study began on July 1, 1953, all participants promised to remain silent about local results until the entire project was completed. September 1954 was the earliest date for an announcement of results (when the eyes of the last enrolled infant were to be examined at a scheduled 3-month follow up).
In May of 1954, to the complete surprise and consternation of all concerned, a report from one of the cooperating hospitals appeared in the Journal of the American Medical Association! After completion of a randomized trial of "routine versus restricted oxygen," the authors claimed that blindness was completely prevented in the "restricted" arm of the trial by using tanks of premixed oxygen and nitrogen to ensure that FIO2 never exceeded 40%. Needless to say, this preemptive publication caused great confusion (the authors made the dubious claim that they were reporting an independent trial, one which did not involve infants enrolled in the national cooperative study). Most observers, noting the small numbers of enrollees, complained that the mortality question hung in thin air. (Although the death rate in this single-center study was 50% higher under oxygen restriction, the difference was declared "not statistically significant"; but only 1 of 8 trials this small would be expected to detect a "true difference" of this size.) Additionally, the issue of brain damage in survivors was completely ignored in their early results. There had been so many mistaken pronouncements in the past, most pediatricians (the label "neonatologist" was not invented yet) decided to wait for the report of the large cooperative study before changing generally accepted practices of oxygen use.
Finally, on September 19, 1954, the preliminary results of the pioneering national study were presented in New York City.10 The outcomes appeared to be clear cut: There was no appreciable increase in mortality under oxygen curtailment, and the rate of cicatricial eye disease was reduced by two thirds. The findings seemed to provide a final answer after 12 years of bewilderment, and the cooperative study results were considered on par with the sensational announcement, 7 months later, about the successful outcome in the national trial of polio vaccine conducted in the summer of 1954.
Subgroup analysis of details in the cooperative study indicated that the risk of eye damage was associated with the duration of exposure to supplemental oxygen; no correlation was found with the level of FIO2. Nonetheless, pediatricians jumped to the conclusion that the national trial confirmed the claim made in the May 1954 report (ie, "blindness can be completely eliminated by strict efforts to keep the concentration of supplemental oxygen below 40%"). Unfortunately, all debate came to an end after 1954; "under 40% is safe" was repeated endlessly, and the simplistic mantra was accepted as gospel because ROP blindness virtually disappeared. Moreover, when a premature infant developed the eye disease after 1954, it was taken as proof positive that the 40% FIO2 limit had been exceeded. American juries began to award millions of dollars in judgments of malpractice if the hospital record indicated that concentration of oxygen in an incubator had been, even momentarily, >40%.
Incredible as it sounds in retrospect, it took 5 years to realize that the victory, proclaimed in 1954, was not as glorious as advertised. The initial jubilation obscured the fact that there were serious methodological problems with the national study. The defects surfaced in 1960, when a review of autopsies in Baltimore, Maryland revealed a sharp increase in the number of fatalities associated with hyaline membrane disease after curtailed use of oxygen. This was a belated reminder that infants had not been enrolled in the cooperative study until they were 48 hours old! (In the 1950s, before the use of ventilators, mortality was highest in the first 2 days of life. Because the earliest retinal abnormalities of ROP begin weeks after birth, it was argued that these early deaths could provide no evidence about the relationship between oxygen exposure and the risk of blindness. Thus, when the national study was planned, it was decided to enroll only infants who were alive at 48 hours of age.) As a result, the declaration in 1954 ("oxygen restriction does not increase mortality") was, in fact, only applicable after the second day of life. (Retrospective calculations performed several years later indicated a sizable increase in the number of first-day-of-life deaths after oxygen curtailment: "It would seem," the analysts noted, "each sighted infant gained may have cost some 16 deaths."11)
In an equally disturbing report of a British retrospective survey conducted in 1962, opposing trends in the prevalence of unfavorable outcomes were found. As exposure to supplemental oxygen decreased (after the shift in policy in 1954) the new practice was followed by a rise in the frequency of spastic diplegia and a fall in the numbers of the ROP blind. The look back was a painful reminder that the plan for long-term follow up of the neurologic status of survivors enrolled in the 1953–1954 cooperative study was never conducted. When blindness disappeared, the celebrators brushed aside their pretrial fears that oxygen restriction might increase the risk of brain damage. To make matters worse, increasingly intense efforts to rescue smaller and more immature infants in the late 1960s were followed by the reappearance of ROP blindness in ever-larger numbers.
In 1969, the National Society for the Prevention of Blindness convened a meeting of the principal protagonists to revisit the question of oxygen treatment, because newly invented techniques had shifted the focus from the level of FIO2 to that of partial pressure of arterial oxygen tension. The debate was as loud and fierce as it had been in the spring of 1953, but this time the outcome was different: Those opposed to a randomized trial now won their argument. Five centers agreed to conduct a joint observational survey of usual practice: Doctors were to use individual judgment in prescribing oxygen treatment, serial measurements of partial pressure of arterial oxygen tension were to be obtained, and these levels were to be correlated with outcome at 6 months old. This collaborative exploration might have served as a useful hypothesis-seeking exercise if it had been followed by a formal, randomized trial comparing 2 target levels of arterial oxygen. Instead, the posthoc findings in this weak investigation (finally published in 197712) were used to establish standard guidelines for oxygen treatment. Sadly, the failure to use rigorous methods of clinical research at that time resulted in confusion that has persisted to the present day.
In the 1970s, transcutaneous O2 electrodes arrived and were replaced in the 1980s by pulse oximeters, but these technologic advances provided a misleading sense of newly found accuracy. To put it bluntly, there has never been a shred of convincing evidence to guide limits for the rational use of supplemental oxygen in the care of extremely premature infants. For decades, the optimum range of oxygenation (to balance 4 competing risks: mortality, ROP blindness, chronic lung disease, and brain damage) was, and remains to this day, unknown. In the past few years, the findings in a number of studies have suggested that the long-accepted "physiologic" targets of O2 saturation may be too high.4,13–15 There is now considerable interest in exploring lower levels, and the belated concerns recall explorations conducted in Sweden a half-century ago.16
It is encouraging to see that neonatal medicine is beginning to wake up after years of dogmatic slumber.17 If the plans for an international oxygen-targeting trial (Pulse Oximeter Saturation Trial for Prevention of ROP) are conducted in the near future,18 there is reason to hope that uncritical acceptance of authoritative opinion about the most frequently prescribed "drug" in the care of small neonates will come to an end, at long last.
 |
FOOTNOTES |
|---|
Received for publication Sep 26, 2003; Accepted Sep 26, 2003.
Address correspondence to William A. Silverman, MD, 501 Via Casitas, Apt 421, Greenbrae, CA 94904-1947. E-mail: fumer{at}aol.com
* The disorder was originally called retrolental fibroplasia; I will use the modern terminology in this article. 
|
REFERENCES |
|---|
 TOP REFERENCES |
|---|
- Huxley TH. A liberal education. In Bibby C. The Essence of T. H. Huxley London, United Kingdom: Macmillan; 1967
- Priestly J. Experiments and Observations on Different Kinds of Air. Quoted by Gilbert Martin. Available at: http://www.mtsinai.org/pulmonary/papers/ox-hist/ox-hist1.html. Accessed August 22, 2003
- Silverman WA. Negative discovery. Paediatr Perinat Epidemiol. 2002;16:192–193
- Saugstad OD. Oxygen supplementation in the newborn period: Do we know the consequences? Yearbook of Neonatal and Perinatal Medicine.2002 :xv –xxii
- Wilson JL, Long SB, Howard PJ. Respiration of premature infants; response to variations of oxygen and to increased carbon dioxide in inspired air. Am J Dis Child.1942; 63 :1080 –1085
- Smith CA, Kaplan E. Adjustment of blood oxygen levels in neonatal life. Am J Dis Child.1942; 64 :843 –859
- Silverman WA. Retrolental Fibroplasia: A Modern Parable. New York, NY: Grune & Stratton, Inc; 1980. Available at: http://neonatology.org/classics/parable/default.html. Accessed August 6, 2002
- Crosse VM. The problem of retrolental fibroplasia in the City of Birmingham. Trans Ophthalmol Soc U K.1951; 71 :609 –612
- Campbell K. Intensive oxygen therapy as a possible cause of retrolental fibroplasia: a clinical approach. Med J Aust.1951; 2 :48 –50[Medline]
- Kinsey VE. Etiology of retrolental fibroplasia and preliminary report of the Cooperative Study of Retrolental Fibroplasia. Trans Am Acad Ophthalmol Otolaryngol.1955; 59 :15 –24[Medline]
- Bolton DPG, Cross KW. Further observations on the cost of preventing retrolental fibroplasia. Lancet.1974 :1 :445 –448[Web of Science][Medline]
- Kinsey VE, Arnold HJ, Kalina RE, et al. PaO2 levels and retrolental fibroplasia: a report of the cooperative study.
Pediatrics.1977; 60
:655
–668
[Abstract/Free Full Text] - The STOP-ROP Multicenter Study Group. Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes.
Pediatrics.2000; 105
:295
–310
[Abstract/Free Full Text] - Tin W, Milligan WA, Pennefather P, Hey E. Pulse oximetry, severe retinopathy, and outcome at one year in babies of less than 28 weeks gestation.
Arch Dis Child Fetal Neonatal Ed.2001; 84
:F106
–F110
[Abstract/Free Full Text] - Askie LM, Henderson-Smart DJ, Irwig L, Simpson JM. Oxygen-saturation targets and outcomes in extremely preterm infants.
N Engl J Med.2003; 349
:959
–967
[Abstract/Free Full Text] - Sjöstedt S, Rooth G. Low oxygen tension in the management of newborn infants. Arch Dis Child.1957; 32 :397 –400
- Tin W. Oxygen therapy: 50 years of uncertainty.
Pediatrics.2002; 110
:615
–616
[Free Full Text] - Cole CH, Wright KW, Phelps DL. Resolving our uncertainty about oxygen therapy.
Pediatrics.2003; 112
:1415
–1419
[Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Korvenranta, L. Lehtonen, M. Peltola, U. Hakkinen, S. Andersson, M. Gissler, M. Hallman, J. Leipala, L. Rautava, O. Tammela, et al. Morbidities and Hospital Resource Use During the First 3 Years of Life Among Very Preterm Infants Pediatrics, July 1, 2009; 124(1): 128 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-H. Nghiem, J. I. Hagadorn, N. Terrin, S. Syke, B. MacKinnon, and C. H. Cole Nurse Opinions and Pulse Oximeter Saturation Target Limits for Preterm Infants Pediatrics, May 1, 2008; 121(5): e1039 - e1046. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D A Todd, A Wright, J Smith, and the NICUS Group Severe retinopathy of prematurity in infants <30 weeks' gestation in New South Wales and the Australian Capital Territory from 1992 to 2002 Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2007; 92(4): F251 - F254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Clucas, L. W. Doyle, J. Dawson, S. Donath, and P. G. Davis Compliance With Alarm Limits for Pulse Oximetry in Very Preterm Infants Pediatrics, June 1, 2007; 119(6): 1056 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. van Wijngaarden, H. M. Brereton, D. J. Coster, and K. A. Williams Genetic Influences on Susceptibility to Oxygen-Induced Retinopathy Invest. Ophthalmol. Vis. Sci., April 1, 2007; 48(4): 1761 - 1766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W Tin and S Gupta Optimum oxygen therapy in preterm babies Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2007; 92(2): F143 - F147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Payne, M. LaCorte, S. Sun, P. Karna, M. Lewis-Hunstiger, J. P. Goldsmith, and on behalf of the Breathsavers Group Evaluation and Development of Potentially Better Practices to Reduce Bronchopulmonary Dysplasia in Very Low Birth Weight Infants Pediatrics, November 1, 2006; 118(Supplement_2): S65 - S72. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Hay Jr History of Pulse Oximetry in Neonatal Medicine NeoReviews, December 1, 2005; 6(12): e533 - e538. [Full Text] [PDF]
|
|
|
|
|
|
N. Ambalavanan, J. E. Tyson, K. A. Kennedy, N. I. Hansen, B. R. Vohr, L. L. Wright, W. A. Carlo, and and National Institute of Child Health and Human D Vitamin A Supplementation for Extremely Low Birth Weight Infants: Outcome at 18 to 22 Months Pediatrics, March 1, 2005; 115(3): e249 - e254. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
