|Year : 2019 | Volume
| Issue : 4 | Page : 238-242
Effectiveness of oral glucose as analgesic for neonates undergoing retinopathy of prematurity screening – A randomized pilot study for a parallel randomized control trial
Praveen Ramar1, Prakash Vinayagam2, Arasar Seeralar2
1 Department of Neonatology, Institute of Child Health and Hospital for Children, Madras Medical College, Chennai, Tamil Nadu, India
2 Department of Neonatology, Institute of Obstetrics and Gynaecology, Madras Medical College, Chennai, Tamil Nadu, India
|Date of Submission||10-Jun-2018|
|Date of Decision||07-Dec-2018|
|Date of Acceptance||01-Sep-2019|
|Date of Web Publication||04-Oct-2019|
Dr. Praveen Ramar
Department of Neonatology, Institute of Child Health and Hospital for Children, Madras Medical College, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Eye examination is a painful procedure. Neonates exposed to painful stimuli have short- and long-term behavioral and sensory problems. To determine an analgesic for alleviating pain during this mandatory painful, medical procedure is of utmost importance, to have optimal outcomes in these vulnerable preterm babies. We analyzed the effectiveness of 25% dextrose solution as analgesic for retinopathy of prematurity (ROP) screening. Objective: The objective was to study the feasibility of conducting a Phase III randomized controlled trial, for oral analgesic during ROP screening in neonates and to utilize this pilot data for calculating sample size for Phase III trial. Place of the Study: The study was conducted in a tertiary care neonatal unit, Southern India. Type of Study: This was a randomized parallel group masked Phase I/2 external pilot study. Methods: Feasibility was defined a priori; the study population was inpatient babies undergoing ROP screening procedure for the first time as per unit protocol. All subsequent babies, after a written consent from parents/legal guardian, were randomized to oral glucose (25% dextrose solution) or placebo group (distilled water). Premature infant pain profile (PIPP) scores were assessed at basal and post procedure. Babies were observed for 24 h for predefined adverse events. Statistical analysis was done using Stata 11.2. Continuous data were expressed as median based on the skewness, and Mann–Whitney U-test was used for hypothesis testing. Results: Twenty-six inpatient neonates were randomized. The median pain scores (PIPP) at 1 min post procedure for the placebo group were 7 IQ (6, 8), and median pain scores of the oral glucose group were 4 IQ (3–5). Eighty-six percent of the eligible babies were randomized for the study. Eighty-five percent of the randomized babies where available for total observation period of 24 h. Inter-rater variability was assessed by interclass correlation (ICC) coefficient. No adverse events (predefined) were recorded in both groups. Conclusion: This randomized pilot trial is feasible to deliver. Oral glucose (25% dextrose) solution has a significant pain alleviation compared to placebo, in our pilot population. Pain scores assessed were validated by independent reviewer with high ICC of 0.89.
Keywords: Nursing, pain, premature infant pain profile score, prevention and control
|How to cite this article:|
Ramar P, Vinayagam P, Seeralar A. Effectiveness of oral glucose as analgesic for neonates undergoing retinopathy of prematurity screening – A randomized pilot study for a parallel randomized control trial. J Clin Neonatol 2019;8:238-42
|How to cite this URL:|
Ramar P, Vinayagam P, Seeralar A. Effectiveness of oral glucose as analgesic for neonates undergoing retinopathy of prematurity screening – A randomized pilot study for a parallel randomized control trial. J Clin Neonatol [serial online] 2019 [cited 2019 Dec 8];8:238-42. Available from: http://www.jcnonweb.com/text.asp?2019/8/4/238/268589
| Introduction|| |
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Neonates exposed to painful stimuli has long-term behavioral and sensory problems, more in preterm than term neonates. The International Evidence-Based Group for Neonatal Pain, has included eye examinations for retinopathy of prematurity (ROP) in the list of painful procedures performed in the neonatal intensive care unit. Pain prevention and alleviation in neonates and infants had been recognized and recommended by the American Academy of Pediatrics and other expert bodies, either by pharmacological or nonpharmacological means. Still this vulnerable population receive analgesia before or during procedure in only about 50% of painful exposures.
Existing evidence supports the use of glucose solutions (Sucrose) for pain alleviation in acute painful procedures. This pilot study was done in our population to analyze the effectiveness of oral glucose (25% dextrose) as analgesic for ROP screening. Existing evidence on glucose solutions for pain relief in eye examinations was inconclusive and nonsucrose solution was not studied for pain relief in ROP screening., The pilot study was done to analyze the feasibility of a phase III parallel group randomized control trial (RCT), in the same center and population.
The objectives were to study:
- Recruitment and retention rates
- Staff capacity to recruit and familiarity for randomization procedures
- Availability of equipments and backup
- Estimate of effect size and the use for sample size calculation in phase III trial.
| Methods|| |
We did a randomized parallel group masked phase I external pilot study, with 1:1 allocation ratio. The study was conducted at a tertiary care referral institute, in the same population where our phase III trial was planned. The study population was chosen with the same inclusion and exclusion criteria as our phase III trial. All babies were recruited after a written consent from the parents/legal guardian after explaining the feasibility nature of study. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional) and with the Helsinki Declaration of 1964, as revised in 2000. Institutional ethical committee (EC Reg. no. ECR/270/Inst./TN/2013) approval was obtained vide no. 27022018 dated February 6, 2018). The trial was registered with Clinical Trial Registry of India vide CTRI/2018/05/013639.
We decided a priori feasibility as:
- >70% recruitment of eligible babies and >80% of recruited babies available to record and analyze all the outcome measures at 24 h
- 100% available of equipments for recruited babies and at least 50% availability of backup
- To utilize the pilot data of effect size for calculation of sample size for phase III study.
Inclusion criteria: (As planned for phase III trial)
All inpatient babies satisfying the unit ROP screening protocol and undergoing the screening procedure for the first time, were included after getting a written consent from parents/legal guardian.
Exclusion criteria: (As planned for phase III trial)
- Babies on mechanical ventilator
- Babies already on study drugs for any other reason
- Breastfeeding mother in methadone or other analgesics
- Babies with ileostomy/colostomy
- Babies kept NPO for other medical/surgical illness
- Congenital anomalies.
All inpatient babies born <34 weeks of gestation and/or less than 1750 g, and babies born after this who required cardio-respiratory support, blood transfusion, poor weight gain, sepsis or treating physician felt baby is at high risk for ROP were subjected to ROP screening as per unit protocol.
Gestational age assessment was, done as per following, first, LMP, if not available first trimester ultrasonogram, if not available expanded new Ballard score. All subsequent babies, undergoing first ROP screening procedure, satisfying the inclusion criteria were randomized to either of the group, by serial numbered opaque sealed envelope method.
The interventional drugs were prepared in paired bottles numbered A and B. The pair of bottles were prepared in the department by a night duty nursing staff under aseptic precaution and label the same. The basic demographic details and initial clinical data of the participant were entered by the randomizing nursing staff after getting a written consent. All babies subjected to ROP screening were nursed under radiant warmer, with facilitated tuck and swaddling (nonpharmacological pain reduction for all babies) as per the unit protocol.
The paired bottle blinded to have oral glucose (25%-dextrose) contained placebo in bottle A and oral glucose in bottle B, and both bottles A and B had distilled water in the placebo group. Interventional drugs were given at a dose of 1 ml/kg orally by syringe under aseptic precaution. Babies subjected to ROP screening were administered eye drop tropicamide (0.5%–1%) every 15 min starting 1 h prior to the screening, first interventional drug was given along with first Tropicamide eye drop (placebo in either group). Eye drop phenylephrine (2.5%) was given 2 min before the examination, the second interventional drug was given along with this (placebo group had distilled water and oral glucose for glucose group). Baseline premature infant pain profile (PIPP) score was assessed 5 min before the procedure. Assessment of PIPP score was done, 1 min after the screening procedure by the treating clinical team masked for the group allocation, and labeled as 1st assessment in the recording sheet. Subsequent assessments were done at 5, 15, and 30 min, and the same was video recorded. The video recordings were reviewed by an independent clinician. All babies were monitored for 24 h for any adverse events (tachycardia, abdominal distension, apnea as per our study definitions). Babies were connected to multi para-monitor for continuous monitoring of vitals. The vitals were retrieved from instrument (pulse oximeter-Nihan Koden memory) and at least 20% of the data was reviewed by a second clinician.
Outcome measures: (As planned for phase III trial)
- To estimate and compare the change in mean pain scores in two interventional groups before and after the procedure at predetermined time points
- Basal – 5 min before first Tropicamide eye drop, post-randomization
- 1st – 1 min after the procedure
- 2nd – 5 min after the procedure
- 3rd –15 min after the procedure
- 4th – 30 min after the procedure.
- Adverse events were recorded in both the groups. Tachycardia >180/min, apnea, abdominal distention, feed intolerance, increase in respiratory support-increase in FiO2 increase by 20%, flow increase by 10%, increase in PEEP by 1, requiring new respiratory support or mechanical ventilation for 24 h.
We decided (convenient sample size) at least to study 10 babies in each group to study the feasibility goals and mean difference of pain scores between the groups.
Sequence generation was done by shuffling of sealed envelopes, and serially numbering the same for sequential allotment to specific group.
Allocation concealment and masking
The nurse involved in preparation of drug was not involved in drug administration and care of babies during the assessment period. The drug was administered by the clinical nurse detailed for ROP procedure for that day, who will open the sealed envelope at the time of first tropicamide drops after getting a written consent from parents and the patient details will be entered in the envelope, and master data sheet.
The babies will be assessed for PIPP score by a separate clinical team masked for group allocation.
Data were entered in excel format and statistical analysis was done using Stata 11.2. (StataCorp LLC, Texas, USA) Continuous data were expressed as mean (standard deviation) or median (interquartile range) based on the skewness, whereas categorical variables were expressed as proportions. Categorical variables were analyzed using Chi-square test or Fischer's exact test. Student's t-test/Mann–Whitney U-test was used for hypothesis testing based on the distribution of continuous variable. Shapiro–Wilk test of normalcy was applied. Intraclass correlation (ICC) was applied for inter-rater reliability. The recruitment and retention rates were expressed as percentage.
| Results|| |
The study was conducted from February 10, 2018 to March 3, 2018. One hundred and four babies were screened, 30 of them were eligible as per our inclusion criteria, out of this 26 babies were randomized [Figure 1].
Data were analyzed for 22 babies. The baseline demographic characteristics of study cohort in both groups were comparable [Table 1]. The median pain score (PIPP) at 1 min, for the placebo group was 7 IQ (6, 8) and the median pain score of the oral glucose group was 4 IQ (3, 4). Babies were monitored for 24 h. No adverse events were recorded during the study period as per our definitions. The mean gestational age of our study cohort was 32 weeks. Mean birth weight of our study population was 1344 g [Table 1].
The baseline PIPP scores were comparable between the groups; the PIPP scores were significantly low in oral glucose group at 1 min and 5 min post procedure. There was no significant difference in pain scores at 15 and 30 min post procedure [Table 2].
|Table 2: Premature infant pain profile scores at predefined time points (n=11)|
Click here to view
Eighty-six percent of the eligible babies were randomized for the study. Eighty-five percent of the randomized babies were available for a total observation period of 24 h. During study period post randomization, two babies were excluded because of the loss of blinding to clinical assessment, and one baby was discharged at parental request for social reasons before 24 h of observation period, one baby was transferred out to other institute for maternal indication. Availability of equipments was 100% throughout the study period. The video recordings were reviewed by an independent clinician not involved in primary assessment and masked for allocation. The ICC was 0.89 for PIPP scores at 1 min and 5 min post procedure.
| Discussion|| |
Pain in neonates is one of the important but least-addressed clinical entities. Neonatal painful experience has immediate and long-term implications. Infant receiving intensive care will experience an average of 10 painful procedures per day, Ophthalmologic examination during ROP screening is a painful procedure.
For children in higher-income countries, cerebral visual impairment and optic nerve anomalies remain the most common causes of severe visual impairment and blindness (SVI/BL), whereas ROP and cataract are now the most common avoidable causes. The constellation of causes of childhood blindness in lower-income settings is shifting from infective and nutritional corneal opacities and congenital anomalies to more resemble the patterns seen in higher-income settings. ROP examination has become mandatory in neonatal care. As more and more premature babies are being treated, the problem gets compounded. Pain is maximum during eye speculum placement and scleral indentation. Literature reveals various pharmacological with or without nonpharmacological interventions for reducing the procedural pain during ROP eye examination without stern conclusive evidence. The existing review on this topic, using sucrose analgesia was inconclusive on pain reduction during eye examination. Cochrane review on oral sucrose as analgesic for painful procedures showed high-quality evidence for pain reduction during heel lance, venipuncture, and intramuscular injection. There is conflicting evidence for other minor painful procedures and further research is needed to investigate these more thoroughly.
The effect of oral glucose (nonsucrose) for analgesia in newborns is known. Review of available data on nonsucrose solutions reported its effectiveness on heel lance and intramuscular injections.
In our pilot study, babies who were given oral glucose (25% dextrose) had a reduction of PIPP scores by 3 at 1 min post procedure, when compared to placebo. This study was conducted in population, and environment where our routine ROP screening procedure is carried out and our phase III RCT is planned.
| Conclusion|| |
This randomized pilot trial is feasible to deliver. There is a significant reduction of pain scores with oral glucose (25% dextrose) when used along with facilitated tuck and swaddling during ROP screening when compared to placebo at 1 min and 5 min post procedure in our pilot study population.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]