Can we treat retinopathy of prematurity under topical anesthesia?

Retinopathy of prematurity (ROP) is a retinal vasculature disease of preterm infants characterized by arrest of normal vascular development of retina and followed by a compensatory neovascularization process.

ROP is a leading cause of childhood blindness globally including Oman. A recent national hospital-based study concluded that the incidence of preterm infants in Oman is about 9.7% which is similar to international statistics reported at 10%.[1] ROP incidence is a population-based issue depending on the advances of care for surviving preterm infants in a certain population. In Sweden, for example, a prospective study in infants with gestational age of <27 weeks at birth, ROP was reported in 73% of them, while in Norway, ROP was reported in 33% of infants with gestational age of <28 weeks at birth.[2] In Oman, the incidence of ROP in preterm neonates was documented as 34% in 1994 and 25% in 2003, followed by a recent hospital-based study in 2017 showing that the incidence of ROP has increased to 40.4%.[3] The increase in ROP cases is explained by the younger age of surviving preterm infants as the neonatology care has been advancing worldwide as well as in Oman.

ROP develops in two phases, where the hyperoxia is an important driver for the arrest of vascular growth in phase one. Phase two is characterized by proliferation of new blood vessels largely in response to hypoxia-driven increase in vascular endothelial growth factor (VEGF) and erythropoietin. Those new blood vessels poorly perfuse the retina and are more permeable, which leads to fibrous scar formation, traction and retinal detachment. The disease is classified according to the International Classification of ROP to stages, zones and plus disease. The Early Treatment for ROP study further classified ROP into type 1 and type 2 for standardization of the treatment process as it is needed within 48 h in type 1, while follow up in type 2 cases is recommended.[4]

ROP treatment spectrum has changed over the years starting by cryo-therapy to the new modalities of laser photocoagulation and Anti-VEGF injections. The most used Anti VEGFs are Bevacizumab (Avastin), Ranibizumab (Lucentis) and Aflibercept (Eylea).[4] Anti-VEGF injections has been in favor due to a safer complications profile. However, the type of anesthesia needed while performing an anti-VEGF injection in preterm infants is not standardized. Depending on the institutional protocol it varies between doing it under general anesthesia (GA), bedside with some sedation, or with topical anesthetic drops alone. In Oman, GA remains to be the first choice by ophthalmologists treating ROP. In many cases, the sick and sometimes unstable preterm infant needs to be transferred to a tertiary care hospital to complete the procedure safely. This of course carries many disadvantages especially in this COVID-19 era where the risk of institutional transferring is at peak. Also, it is a financial burden on a not an intensive care unit patient which needs a full team of a physician, a nurse and a respiratory therapist to safely transfer the infant. In addition to needing oxygen supplements, sedation/medications, incubators, ambulance transportation and other specifics depending on the infant status. This will also cause unavoidable loss of personnel working hours on service that day in the transferring institute. Due to the high risk of this transfer, this usually needs to be arranged after several days of preparing and planning which can cause a delay in the treatment of ROP in a timely manner.

In the other hand, GA in preterm infants is associated with short-term complications like apnea and cardiorespiratory instability, as well as long-term complications related to neurodevelopment. There is a 30% chance for preterm infants below the age of 44 weeks to have postoperative apnea regardless of the type of procedure performed.[5]

In animal models the long-term neurotoxic effects of anesthetic exposure in developing brains are well established, including differences in learning, memory, motor activity, attention, and behavior during adulthood.[6] In a study done for long-term differences in language and cognitive functions after childhood exposure to anesthesia, it showed that children who were exposed to anesthesia for surgery or diagnostic testing before the age of 3, had an increased risk for long-term deficits in language and abstract reasoning at age 10. However, cognitive disability in children with anesthetic exposure, remains to be a controversial association.[7]

The main concern in treating ROP is the pain control while performing the procedure and many studies has established the effect of painful stimuli associated with ROP screening and treatment in preterm infants. It was found that the pain induced in the ROP infants who underwent treatment under topical anesthesia with the use of a pacifier and fructose as a soothing measure was minimal.[8] In another study assessing the pain with anti-VEGF injections using Tetracaine for topical anesthesia, most of the changes due to pain happened while applying the speculum due to the stretch on the eyelids rather than during the injection itself. A comparison of results from different studies concluded that for the preterm infant, the intravitreal injection was probably less painful than the ROP screening and examination process.[9]

A group of researchers in Harvard medical school suggested that anti VEGF injections can be done at bedside to maintain a normal feeding schedule of the infant and to avoid systemic complications of GA.[10] Sedation without intubation is a less complicated alternative method than GA. However, this is still not well studied in anti-VEGF injections, neither the choice of sedating agents.

The ultimate aim of every health system is to maintain an optimum standard of care management utilizing a lean approach. Shifting from doing anti-VEGF injections under GA to topical anesthesia at bedside in preterm infants is an expected advance in ROP management not only in Oman but worldwide. This will mean timely management of these ROP patients, reducing the complications associated with GA and the extended stay in the hospital due to risks of lengthy intubation. Financially, shorter hospital stay, no GA requirement and no operating theater time would be a major advantage to the health system.