Oral Sucrose Improves Analgesia During Retinopathy of Prematurity Screening

Purpose To determine whether sucrose provides signicant analgesia during Retinopathy of Prematurity (ROP) screening Methods This was a prospective, randomized, sinlge masked audit. The examinations were performed by a single examiner. Forty-ve (45) neonates were separated into two groups; Group 1 received oral sucrose while Group 2 received oral sucrose and non-nutritive suckling (NNS) at the discretion of the attending nurse. Pain was assessed using the Premature Infant Pain Prole (PIPP) score and recorded at baseline, immediately following lid speculum, at 3 minutes and 6 minutes following lid speculum insertion. Results The mean baseline PIPP score was 0.5. Fifteen (15) neonates (33%) received NNS. The mean PIPP scores at speculum insertion in both groups (Group 1: 7.24, Group 2: 5.50) were observed to be higher than at baseline and lower in Group 2 than in Group 1. In both groups, the scores at 3 minutes (Group 1: 4.70, Group 2: 4.20) and 6 minutes (Group 1 4.50, Group 2: 4.70) were observed to be higher than at baseline, lower than at speculum insertion, but not signicantly different to each other. ROP examinations should for greatest


Introduction
Worldwide, about 10% of births occur preterm (before gestational age 37 full weeks). [1] Preterm birth is the most common cause of neonatal death, [2] and the second most common cause of death in children younger than 5 years. 3 [3] Prematurity also has associated comorbidities, one of which is Retinopathy of prematurity (ROP).
ROP is a leading cause of childhood preventable blindness in middle-income countries [4].
Ophthalmologic examination with binocular indirect ophthalmoscopy is considered to be the gold standard to detect ROP. This has been shown to be a painful procedure which causes stress and physical debilitation. It is thought that this can occur during use of the eyelid speculum or scleral indentation during ophthalmoscopic examination [5][6][7][8][9] In the United Kingdom, the Royal College of Ophthalmologists guidelines state that all babies less than thirty two weeks gestational age or less than 1,501g birthweight should be screened, while all babies less than thirty-one weeks gestational age or less than 1,251g birthweight must be screened for ROP. [10] The use of local anesthetic eye drops before an eye examination is a partially effective therapeutic procedure. [11] Our study set out to measure the effect of pain relieving measures during ROP examinations at the East and North Hertfordshire NHS Trust. The aim was to determine the e cacy of our most frequently used pain relieving procedure; titrated oral sucrose combined with non-nutritive sucking (NNS). The effect of any additional pain relieving intervention such as swaddling was also measured. We used the Premature Infant Pain Pro le (PIPP) score to measure this in our study.
The Premature Infant Pain Pro le is a validated pain scale used for infants of gestational age 37 weeks or less. [12] (Figure 1) Based on a tiered approach to analgesia in the neonate, examination of ROP falls between Tiers 1 and 2 on the 5-tiered scale, suggesting that non-pharmacologic and topical anaesthesia should be used. [13] (Figure 2) [14] Sucrose, along with non-nutritive suckling (NNS) and swaddling has been found to be effective in some studies reducing pain in Retinopathy of Prematurity examination, [15] although others showed no adjunctive effect of sucrose with NNS and swaddling. [16] Patients And Methods The Principles of the Declaration of Helsinki were adhered to. Ethical approval was sought from the East and North Hertfordshire NHS Trust but was deemed to not be required. This was a prospective, randomized, single masked audit which recruited patients for 3 consecutive months. The inclusion criteria were all infants born at < 32 weeks gestation or <1501g birth weight who underwent screening examinations for ROP.
Exclusion criteria were sucrose intolerance, sucrase-isomaltase de ciency, fructose intolerance, glucosegalactose malabsorption and muscle relaxed neonates. Forty-ve patients met the study criteria and were all included in the study.
Pain assessment was completed by a neonatal nurse experienced in assessing neonatal pain scores.
This nurse was blinded to the examination and any pain relieving measure employed during the procedure. The examination technique was standardised and carried out by a single examiner with 10 years' experience in ROP examinations. The technique included instillation of topical anaesthetic, insertion of a lid speculum and scleral indentation. Pain was assessed by the Premature Infant Pain Pro le (PIPP) by an experienced neonatal nurse blinded during the pain relieving and comforting measures that were employed during the examination. The PIPP score was recorded at baseline and immediately following speculum insertion, at 3 minutes and 6 minutes respectively. This time frame was chosen because the analgesic effect of sucrose lasts 6-8 minutes. Oral Sucrose 0.5 ml was administered 2 minutes prior to the insertion of the lid speculum.
NNS was administered at the discretion of the attending nurse if the neonate demonstrated increasing signs of distress during the examination more than 1 minute after the sucrose bolus. To minimise bias from the systemic analgesic effect of sucrose, only pain scores from the rst eye examined were included in the study data.
We divided the patients into two groups. Group 1 received only sucrose and Group 2 received sucrose and NNS. In both the sucrose only group (Group 1) and the sucrose and NNS group (Group 2), we compared the PIPP scores at baseline, speculum insertion, and 3 and 6 minutes post sucrose administration. Data was compared within each group and then we compared the groups to each other.

Results
The mean baseline pain score in both groups was 0.5. The mean length of examination was 7 minutes.
The average range was 5 -9 minutes. The median length of the examination was 6 minutes. Nonnutritive sucking (NNS) was applied to 33 % (n= 15) of neonates.

Group 1 (n=30)
In Group 1 (sucrose only); the mean speculum insertion PIPP score was observed to be 7.24 compared to baseline (0.50).
At three minutes, the mean PIPP score was 4.70 compared to base line (0.5).
Comparing the speculum insertion (7.24) and three-minute (4.70) scores, a large, and likely signi cant difference was observed.
At six minutes, the mean PIPP score was 4.50 compared to baseline (0.50), but did not appear to be signi cantly different from the three-minute score (4.70). (Figure 3) In Group 2 (sucrose and NNS); the mean speculum insertion PIPP was 5.50 compared to baseline (0.50).
At three minutes, the mean PIPP score was 4.20 compared to base line (0.50). Comparing the speculum insertion (5.50) to three-minute (4.20) score, a likely signi cant difference exists.
At six minutes, the mean PIPP was 4.70 compared to baseline but not likely to be signi cantly different from the three-minute (4.20) score. (Figure 4) Group 1 and Group 2 comparison.
When comparing Group 1 (sucrose only) with Group 2 (sucrose and NNS), the mean PIPP scores at speculum insertion were observed to be 7.24 vs 5.50 respectively.
At three minutes, the Group 1 mean PIPP was 4.70 vs Group 2 mean PIPP score of 4.20.

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The six-minute mean PIPP scores were 4.50 in Group 1 and 4.70 in Group 2. The differences in the threeminute and six-minute scores were not likely to be statistically signi cant. At ten minutes post examination, the mean pain score was 1.32 for the sucrose-only group and 1.25 for the group with adjunctive NNS. (Table 1 and Figure 5) Table 1.
Oxygen desaturation was reported in 20% of the neonates. This was self-resolving. No other adverse events were documented during the examination.

Discussion
Our results strongly suggests that insertion of the lid speculum is a signi cantly painful stimulus during the screening examination because pain scores were maximum at that point in both groups. We do not think that the pain score was confounded by scleral indentation as scleral indentation was not performed until after the rst minute of the examination. Scleral indentation was started by the second or third minute of the examination as this was the standard method used by the examiner.
The three-minute pain scores were similar in both groups; 4.70 without NNS and 4.20 with NNS. In both groups, pain scores were likely signi cantly lower at three minutes compared to speculum insertion and we attribute this to the analgesic effect of the sucrose. In both groups, oral sucrose with and without NNS appear to signi cantly reduce pain scores at three and six minutes. However, the PIPP scores appeared to be signi cantly higher at speculum insertion, without NNS. Our results suggest that during the period of scleral indentation from minute-two to minute-six, additional NNS did not have any effect on the three and six-minute PIPP scores. Further evaluation is required to determine the precise cause or causes of this, and these may be addressed following publication of the recently concluded stressROP clinical trial. [17] No untoward effects of the administration of sucrose were observed. Our study has shown that the combination of sucrose and NNS is more effective than either method alone and we now use both measures in our screening examinations. We feel this provides signi cantly reduced pain as measured in our PIPP scores, which is better for the neonates being examined. Single and repeated doses of sucrose have not been found to have adverse effects on the neonate, [18,19] and it is our recommendation that ROP examinations should be conducted with a combination of Tier 2 (topical) and Tier 1 (Sucrose and NNS) analgesia for the greatest pain relieving effect.  At six minutes, the mean PIPP score was 4.50 compared to baseline (0.50), but did not appear to be signi cantly different from the three-minute score (4.70).

Figure 4
At six minutes, the mean PIPP was 4.70 compared to baseline but not likely to be signi cantly different from the three-minute (4.20) score.