ARVO (Association for Research in Vision and Ophthalmology) presentation - May 2002
Strict Oxygen Management is Associated with Decreased Incidence of Severe Retinopathy of Prematurity
Paula Hong, MD; Kenneth W. Wright, MD; Cedars-Sinai Medical Center, Los Angeles, California
Purpose: To determine whether strict curtailment of oxygen in the neonatal intensive care unit (NICU) is associated with decreased levels of severe retinopathy of prematurity (ROP).
Methods: This was a retrospective longitudinal study of the incidence of severe ROP in infants less than 1501g birth weight before and after implementation in April 1998 of a new clinical practice of oxygen management in a large level III NICU. Data was collected in real time in a local database. A separate phase of the study included a retrospective chart review of the incidence of myopia and strabismus in infants less than 1251g birth weight who underwent strict oxygen monitoring.
Results: The incidence of stage III-IV ROP significantly decreased from 12.0% in 1997 (n=217) to 2.3% in 2000 (n=260) (p < 0.01). The need for ROP laser treatment decreased from 4.6% in 1997 to 0% from 1999-2000 (p<0.01). The incidence of stage III-IV ROP and ROP laser as reported by the Vermont Oxford Network had not changed significantly over the same time period. The prevalence of -0.25 D or greater myopia was 7.5% (6/80) in eyes with 3-12 months post-term follow-up and 25.8% (16/62) in eyes with 1-3 years post-term follow-up. The prevalence of strabismus was 10.0% (4/40) in patients with 3-12 months post-term follow-up and 19.4% (6/31) in patients with 1-2 years post-term follow-up.
Conclusions: Severe ROP in very low birth weight infants has decreased significantly in association with the implementation of a strict bedside practice of oxygen management. The prevalence of myopia and strabismus in our study group was similar to previous reports for very low birth weight infants at other centers. CR: None Support: The Discovery Fund for Eye Research, The Henry L. Guenther Foundation, The Pfeiffer Foundation, Ruth and Harry Roman Chair in Neonatology-Cedars-Sinai Medical Center.
WASHINGTON, Sept. 22 (UPI) -- Doctors can save the sight of very premature babies without endangering their lives by reducing oxygen levels in the neonatal intensive care unit, researchers said Sunday. "Every year 500 to 700 premature babies are blinded by retinopathy of prematurity," said Kenneth Wright of Cedars-Sinai Medical Center in Los Angeles. "We struggle so hard to keep these babies alive and then they lose their sight. It is really a tragedy." Wright, director of pediatric ophthalmology research and education, said since the hospital instituted a new protocol that maintains reduced oxygen saturation levels in the babies -- a level 5 to 15 percent lower that what would be considered normal for a healthy person -- the number of cases of severe vision problems has dropped dramatically. The protocol, which went into effect in 1998, has resulted in a complete lack of the need for stopgap laser surgery in the eyes of the tiny babies in the years 1999-2001.
At a Washington symposium sponsored by Research to Prevent Blindness, of New York City, Wright explained when very early premature babies are delivered the blood vessels in their retinas and other areas of the body are not fully developed. Sudden exposure to the world of oxygen aborts the normal growth of those blood vessels. After a while, retinal tissue that has no blood vessel sends out molecular signals demanding blood vessel growth. Instead of normal growth, however, fragile blood vessels sprout inappropriately, starting a cascade of events that can lead to retinal detachment and blindness. "Once you lose sight in this process, you don't get it back," Wright said, noting doctors often increase oxygen to premature babies in hopes it will help keep them alive and prevent other related problems such as cerebral palsy. Attempting to recreate oxygen conditions in the womb may prove more beneficial to the children, said Lois Smith, associate professor of ophthalmology at Children's Hospital/Harvard Medical School in Cambridge, Mass.
"Although this protocol is counterintuitive," said William Mathers, professor of ophthalmology at Oregon Health Sciences University in Portland, "it is very exciting, and fascinating. The data is spectacular." Wright said in 1997 about 12.5 percent of premature babies at Cedars Sinai developed severe retinopathy of prematurity. After the protocol was established, the cases dropped to 3.7 percent. Compared to a national registry, the Cedars-Sinai neonatal intensive care unit had one-third the cases of the blinding disorder in 1999-2001. The most common way to treat retinopathy of prematurity was by using a laser to destroy the retinal tissue clamoring molecularly for blood, Wright said. But the results of that treatment are less than satisfactory, he said, because about half of the babies end up legally blind, although they retain some vision. In 1997, Wright said, about 7.5 percent of the babies at Cedars-Sinai needed laser therapy. After initiation of the low oxygen protocol, none of the babies treated under those provision required laser treatment from 1999-2001. In fact, the only case of laser surgery for the condition occurred in one baby whose doctor insisted the child be given full oxygen therapy. There were no statistically significant differences in mortality or in cerebral palsy among the children getting low oxygen compared with those babies treated prior to the protocol going into effect, Wright said, noting there appeared to be a trend showing fewer deaths and fewer cases of CP.
"While on the surface, the protocol appears to be counterintuitive," Smith told United Press International," because we are thinking of how we treat adults. Premature babies are not miniature adults." She said the babies have physiological differences that permit them to use low levels of oxygen more efficiently. "These really aren't babies," Wright said, "they are fetuses out of the womb." He said that by trying to recreate womb-like oxygen levels, more appropriate growth can take place. The researchers said prospective clinical trials in which groups of premature babies treated conventionally and treated under a protocol similar to what Wright used in Los Angeles is needed to convince doctors that bright pink babies - given supplemental oxygen - might not be the best for these premature children.
In 1997, the level III neonatal intensive care unit at Cedars-Sinai Medical Center in Los Angeles, California recognized it had a problem. It had elevated rates of retinopathy of prematurity (ROP) and an increased need for laser treatment of the condition. So, in 1998 it initiated a strict protocol to curtail oxygen in all very low birth weight infants (500g to 1,500g). In utero, babies are in a lower oxygen environment with a blood PaO2 of 22 mm Hg to 24 mm Hg. In full term infants, the level ranges from 70 mm Hg to 90 mm Hg. High oxygen levels suppress VEGF in the retina and vessels do not grow properly. Ischaemic retina eventually over-stimulates VEGF production and abnormal neovascularisation results. “When a baby is born prematurely, it enters this environment of oxygen and it’s too much for them. It’s not normal,” pediatric ophthalmologist Kenneth Wright MD said. By curtailing oxygen at every step for premature infants, the medical center has been successful in reducing the incidence of severe ROP. The protocol maintains low oxygen levels and keeps tight control over fluctuations, alarm settings on monitors, clinical responses to alarms and bedside care after increasing oxygen doses. It stipulates careful regulation of oxygen levels in the delivery room, during transport and throughout the infant’s hospital course. Oxygen saturation levels are kept at 83% to 90% (by pulse oximetry) for infants weighing less than 100g.
Before 1998, Cedars-Sinai’s incidence of severe ROP was 12.5% of at-risk infants and laser treatment was 7.5%. After instituting the protocol, Dr. Wright said the incidence of severe ROP dropped to 3.72%. In the following three years, only one out of 300 premature infants needed laser treatment. “There were no cases in 1999 and 2000. Now in 2002, we had one which required laser surgery. And guess what? That child had a heart defect and the cardiologist put a note on the isolette saying ‘Keep the oxygen high – 95 to 100’. And that’s the only baby that we have treated now in four years,” Dr. Wright stressed. The center has seen a significant decrease in severe ROP. At the same time, infant survival improved slightly from 80.43% in 1997 to 89.47% between 1999 and 2001. (p=0.03). This suggests that normal vessel growth is occurring, simulating the in utero environment by lowering the oxygen, he said.
Future studies will be needed on cognitive development among premature infants to ensure that solving one problem does not cause another.
Pediatrics Article - February 2003
Pediatrics; February 2003; volume 111; number 2; pages 339-345
Presented at Annual Ophthalmology Meetings in 2006
AAPOS - American Academy of Pediatric Ophthalmology and Strabismus 2006
AOS - American Ophthalmological Society 2006
A Physiologic Reduced Oxygen Protocol Decreases the Incidence of Threshold Retinopathy of Prematurity
Kenneth W. Wright, MD and David Sami, MD: Cedars-Sinai Medical Center, Los Angeles, CA; Lisa Thompson, MD: Stroger Hospital of Cook County, Chicago, Il; Rangasamy Ramanathan, MD: Division of Neonatal Medicine,
USC Keck School of Medicine, Los Angeles, CA; Roy Joseph, MMed, FRCPCH, Department of Neonatal Medicine, National University Hospital of Singapore and Sonal Farzavandi, MD, Singapore National Eye Centre: National University of Singapore, Singapore
Purpose: To report the incidence of threshold retinopathy of prematurity (ROP) in very low birth weight (VLBW) premature infants from 3 neonatal intensive care units (NICUs) before and after implementation of a physiologic reduced oxygen protocol (PROP).
Methods: Prospective, observational study of data from 3 NICUs: Cedars-Sinai Medical Center (CSMC), Los Angeles, Good Samaritan Hospital (GSH), Los Angeles and National University Hospital (NUH), Singapore. PROP was implemented to keep oxygen saturation values by pulse oximeter (SpO2) between 83-93% (as described in Pediatrics 2003; 111:339-345). The incidence of threshold ROP in the year before and the year after implementation of PROP was compared. Data from the transition year was not included in the analysis.
Results: The incidence of threshold ROP decreased in each center: CSMC - 3.3% to 0.0% (3/92 to 0/88); GSH -14.8% to 4.9% (8/54 to 2/41); NUH - 6.7% to 0.0% (3/45 to 0/30). Overall, the incidence of threshold ROP decreased from 7.3% to 1.3%. (P < .05). The 95 % confidence interval for the pre–PROP group was 4.3% to 12% and for the post-PROP group it was 0.05% to 4.76%.
Conclusions: Physiologic hypoxia is the normal fetal state. Exposure of new born premature infants to hyperoxia downregulates retinal VEGF. This arrests the normal retinal vascular migration and causes vaso-obliteration, the first phase of ROP. The hypothesis is maintaining SpO2 values between 83-93% in the immediate post gestation life, combined with strict control of oxygen fluctuations prevents the early vaso-obliterative phase and subsequent development of severe ROP. Significant reduction of threshold disease after implementation of PROP in all 3 centers supports the hypothesis.