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Oxygen for Preemies: Difficult Choices
Lowering oxygen saturation rates for extremely preterm infants in the neonatal ICU markedly decreases the risk of retinopathy of prematurity—but it does so at a risk of slightly increasing the mortality rate.
This trade-off of risks and benefits emerged from the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT), a 2x2 factorial randomized controlled trial of 1,316 infants born between 24 weeks/0 days and 27 weeks/6 days of gestation.
In the first arm of the trial, researchers compared two target ranges of oxygen saturation—85 to 89 percent vs. 91 to 95 percent. The primary outcome was a composite of severe ROP, death before discharge or both.1 The children were also randomly assigned to one of two ventilation approaches—standard intubation and surfactant vs. continuous positive airway pressure (CPAP) with a limited ventilatory strategy; the primary outcome was death or bronchopulmonary dysplasia.2
The news from the oxygen saturation arm was decidedly mixed: While the incidence of ROP was substantially lower (p < 0.001) in the lower-saturation group (8.6 percent) than in the higher-saturation group (17.9 percent), 19.9 percent of those in the lower-saturation group died before discharge, vs. 16.2 percent of those in the higher-saturation group (p = 0.04). “The data suggest that there is one additional death for approximately every two cases of severe retinopathy that are prevented,” the researchers state.
While infants randomized to receive CPAP had fewer complications, the use of CPAP did not substantially change the outcome of the ROP-mortality dilemma.
Where does this leave ophthalmologists? “We must consider the study design,” cautioned lead author Waldemar A. Carlo, MD, professor of pediatrics and director of neonatology and the newborn nurseries at the University of Alabama, Birmingham. “Essentially, we pushed the limits on both ends of the saturation ranges, beyond what many physicians would find acceptable. Now that we have this study, the optimal target may be somewhere in between, perhaps around 90 percent.”
Additional research is needed to confirm whether that is the case as well as to refine other treatment parameters such as patient selection. “We are now analyzing the data further to see whether we can determine up front who would do better with different oxygen targets,” Dr. Carlo said. “Right now, there seems to be no difference with regard to birth weight.” He also noted that many of the infants did not have resolution of their ROP at the time of discharge. Follow-up at around 2 years is under way.
In addition, Dr. Carlo hypothesized that, because the use of CPAP with a limited ventilatory strategy decreases an infant’s overall exposure to oxygen, it may eventually be found to reduce the risk of ROP. In the meantime, he said, “It’s extremely important for ophthalmologists to continue to work with neonatologists to solve these dilemmas.”
1 Carlo, W. A. et. al. N Engl J Med
2 Finer, N. N. et al. N Engl J Med
When to Treat Ocular Hypertensive Patients
If they were considering overall health care costs in the United States, would ophthalmologists treat everyone with ocular hypertension (OHT) or only some?
A new report from the Ocular Hypertension Study group (OHTS) comes down firmly on the side of considering age when offering treatment to patients with OHT.1 By age 65, treatment can only be justified for patients at a relatively high risk for glaucoma—a 5 percent or greater annual risk—and only when the most liberal standard of cost-effectiveness is applied. The finding was based on the relatively low risk of progression to glaucoma over time when combined with treatment cost and impact on quality of life.
The report is the latest spin-off from the OHTS, which in 2002 reported that treating a patient with OHT reduced his or her risk of developing primary open-angle glaucoma by 60 percent.
Steven M. Kymes, PhD, lead author of the new study, recalled his response to the initial OHTS report. Treating everyone in the United States with OHT would cost the health system more than $5 billion a year, said Dr. Kymes, director of the Center for Economic Evaluation in Medicine, Washington University in St. Louis.
So the OHTS group attempted to refine treatment guidelines using a risk stratification approach. In 2006, it reported that setting a population-wide treatment threshold at patients with a 2 percent or greater annual risk of developing glaucoma met most accepted standards for cost-effectiveness. The OHTS risk calculator followed, giving clinicians a handy tool for determining which patients had reached that threshold.
But many of Dr. Kymes’ clinical colleagues objected that the recommendation was still too broad. These ophthalmologists argued for factoring a patient’s lifetime risk of developing glaucoma into their treatment decisions. For example, they might not treat an 85-year-old with a 2 percent risk, yet they would treat a 40-year-old with a 1 percent risk. In a sense, the new study corroborates those clinicians’ instincts.
The study measured the cost-effectiveness of treatment at five thresholds, for simulated cohorts of people aged 45, 55 and 65 years old. The cost associated with treating patients with a risk of 2, 3, 4 or 5 percent or greater annual risk was compared with the cost of doing nothing until nerve damage occurred.
It found that by applying the 2 percent or greater annual risk standard, a 65-year-old must live another 21 to 26 years to justify treatment, while a 45-year-old need only have a life expectancy of 17 to 21 years. The difference is magnified at the 5 percent risk level. Then, a 45-year-old needs to live only nine more years, while a 65-year-old needs 21 extra years of life.
“I would not have been surprised to see that treatment was not cost-effective for people over the age of 75,” Dr. Kymes said. “I was really surprised to see the age threshold was as low as it was.”
While cost-effectiveness was the main outcome, the study acknowledged that a patient’s anxiety about developing a vision-threatening disease should factor into the treatment decision. Counseling low-risk patients to better understand their risk of progressing to glaucoma is more effective than treatment. Yet some patients are so risk averse that you may want to treat them anyway, said Dr. Kymes.
As for the price tag, Dr. Kymes estimates that use of the population-wide 2 percent or greater threshold would reduce the $5 billion societal burden by two-thirds. Incorporating age into the decision would bring down the cost by an additional half.
The bottom line, said Dr. Kymes, is that treatment needs to be personalized. “What the findings tell us is how important it is to understand the patient’s prognosis and the patient’s preferences.”
1 Kymes, S. M. et al Arch Ophthalmol
Eye Is a Window on Brain
Brain surgeons in Baltimore have reported using an upper-eyelid incision to gain acceto deep structures along the anterior skull base in order to repair cerebrospinal fluid leaks and to biopsy or remove tumors.1,2 The technique is called transpalpebral mini-craniotomy.
“This procedure combines the advantages of the standard open approach to craniotomy and of endoscopic brain and skull base surgery done through the nose,” said Kofi Boahene, MD, lead study investigator and assistant professor of otolaryngology head and neck surgery at Johns Hopkins University. He added that it spares patients from lengthy, traumatic brain manipulation, possible sensory losses and a disfiguring scar after standard orbitofrontal craniotomy.
Instead of a shaved head and an ear-to-ear incision, the patient has a hidden incision in the same upper eyelid crease that is used for blepharoplasty. And rather than folding back a large scalp section, removing the top half of the skull and then retracting outer sections of the brain, the surgeons removed skull sections of only 1 to 3 cm, the researchers report.
In their case series, the researchers found that minicraniotomy via an eyelid incision had several advantages over standard craniotomy, including:
- providing access to areas deep in the brain along the skull’s anterior base.
- allowing the use of bimanual instruments and a microscope. (The surgical range also can be extended by adding endoscopic illumination.)
- decreasing surgical times. Minicraniotomies took about 3 hours on average, compared with 4 to 8 hours for the standard procedure.
- speeding recuperation, without sensory losses or periorbital complications.
“The transpalpebral approach is a very viable and practical option for thousands of surgeries done each year in the United States that involve problems deeply seated behind the eyes or at the front of the brain,” said coinvestigator and neurosurgeon Alfredo Quinones-Hinojosa, MD.
1 Chu, E. A. et al. Otolaryngol Head Neck Surg
2 Boahene, K. et al. Skull Base
2010. In press.
Anti-Parkinson Drug May Damage Cornea
Long-term use of the drug amantadine hydrochloride, widely used to manage Parkinson disease, may adversely affect corneal endothelial cells.1
“The key finding of our study is that amantadine-associated corneal endothe- lial toxicity can be caused not only by drug hypersensitivity but also by dose-dependent effects,” said Won Ryang Wee, MD, PhD, professor and chair of ophthalmology at Seoul National University College of Medicine.
Dr. Wee and his associates studied 169 eyes of patients taking amantadine for Parkinson disease and compared them with an equal number of age-matched and gender-matched controls. They conducted slit-lamp biomicroscopy, specular microscopy and ultrasound pachymetry, and calculated endothelial cell density, coefficient of variation of cell area, and percentage of hexagonal cells.
Compared with the age-matched control group, the amantadine group’s cells had lower hexagonality and greater coefficient of variation, both of which, the researchers say, appear to be early indicators of pathology in the cornea preceding a decrease in cell density. The study also showed that endothelial cell density was significantly lower in the amantadine group than the control group, and that longer duration of use and higher cumulative drug intake led to greater reduction in endothelial cell density.
Keratopathy usually occurs soon after treatment begins with amantadine and disappears a few weeks after treatment ends, suggesting drug hypersensitivity, the researchers say. However, a previous study on irreversible corneal edema suggested that amantadine in the aqueous could be toxic to corneal endothelial cells.2 With this in mind, Dr. Wee said, “We encourage our colleagues to follow up regularly with Parkinson patients in order not to miss potential endothelial toxicity from long-term treatment with amantadine.”
1 Chang, K. C. et al. Ophthalmology
2 Jeng, B. H. et al. Ophthalmology
EyeNet thanks Susan B. Bressler, MD, K. David Epley, MD, Christopher Rapuano, MD, and Steven I. Rosenfeld, MD, for their help with this issue’s News in Review.