To compare the efficacy of 25% dextrose with 24% sucrose for heel-lance analgesia in preterm infants admitted to the NICU.
In this noninferiority, double-blind, randomized controlled trial, preterm infants born at 28 weeks and 0 days to 35 weeks and 6 days of gestation who were due for a scheduled heel-lance procedure were enrolled. Infants randomly assigned to the intervention arm received 0.5 mL 25% dextrose, whereas infants in the active control group received 0.5 mL 24% sucrose orally just 2 minutes before the heel-lance procedure. The primary outcome was Premature Infant Pain Profile (PIPP) score 30 seconds after the procedure. Secondary outcomes included PIPP scores at 60 and 120 seconds, PIPP-Revised scores at 30, 60, and 120 seconds, and any adverse events.
Sixty-four infants were enrolled (32 in each group). The mean (SD) PIPP score at 30 seconds was 6.41 (2.56) in the dextrose group and 7.03 (2.23) in the sucrose group (mean difference, −0.63 (95% confidence interval, −1.85 to 0.60; P = .31). The upper margin of the confidence interval did not cross the predefined noninferiority margin of 2. The mean PIPP scores at 60 (5.03 [2.18] vs 5.39 [1.48]) and 120 (4.75 [1.97] vs 4.94 [1.46]) seconds were also similar. The PIPP-Revised scores between the 2 groups at all time intervals were comparable. One infant in the intervention group had a transient coughing episode.
In preterm infants under intensive care, 25% dextrose is noninferior to 24% sucrose for heel-lance analgesia as assessed by PIPP score.
Twenty-four percent sucrose is often used for relieving pain while doing heel lancing in preterm neonates admitted to the NICU. However, it is expensive and sparingly available in resource-limited settings.
Twenty-five percent dextrose is noninferior to 24% sucrose for heel-lance analgesia in preterm infants requiring intensive care.
Neonates in general and preterm infants in particular are highly vulnerable to pain because of their immature nervous systems, causing hypersensitivity to painful stimuli complemented with the multiple procedures they are subjected to in the NICU.1 In fact, the reported median number of painful procedures in neonates requiring intensive care can be as high as 7.5 to 43 per day.2,3 Repetitive painful stimuli early in life can result in neurodevelopmental, behavioral, and cognitive deficits later in childhood.4–6 Despite this association, many painful procedures are carried out without adequate analgesia, more so in low- and middle-income countries.2,7–11
Heel lancing is one of the most common painful procedures performed among infants admitted to the NICU.2 Oral sweet solutions effectively alleviate procedural pain in infants, including the pain during heel lancing, and 24% sucrose is the most commonly used solution.12–14 Despite their remarkable safety profile, sucrose solutions have been constrained by unavailability and cost, especially in resource-limited settings.15–20 Alternatively, oral glucose solutions of varying strengths (10%–50%) have been explored for procedural analgesia and found to be effective.15–21 Only 1 study has given a direct comparison of the analgesic effect of sucrose with glucose among preterm infants in an intensive care setting.22 However, the researchers evaluated infants at a mean postnatal age of 21 days. In reality, most painful interventions in preterm infants are usually performed within the first 2 weeks of life.2 In addition, the researchers used 20% solutions that are not commercially available.2,23 Therefore, in the current study, we planned to evaluate if 25% dextrose solution is not inferior to 24% sucrose for heel-lance analgesia in preterm infants requiring intensive care.
Methods
We performed this noninferiority, double-blind, randomized controlled trial over a 12-month period from August 2019 to July 2020 in a level III NICU in western India. Infants admitted to the NICU who were born at a gestational age of 28 weeks and 0 days to 35 weeks and 6 days, age >12 hours, and due for a scheduled heel lance for blood glucose monitoring were eligible. Infants with perinatal asphyxia (5-minute Apgar score <3); birth trauma; major congenital anomalies; neurologic abnormality; seizures; receipt of mechanical ventilation, inotropes, or sedation-analgesic medications within the past 48 hours; or a history of substance abuse or exposure to opioids/general anesthesia in the mother were excluded. The institutional ethics committee approved the study protocol, and the trial was registered at Clinical Trial Registry–India (CTRI/2019/02/017383). Infants were enrolled after obtaining written informed consent from the parents or legally authorized representative.
Random assignment was done using permuted blocks of randomly varying sizes and a 1:1 allocation ratio. Assignment was stratified for gestational age at birth (28 weeks and 0 days–31 weeks and 6 days and 32 weeks and 0 days–35 weeks and 6 days). An investigator (K.S.) generated the randomization sequence using https://www.randomization.com. Sequentially numbered, opaque, sealed envelopes were used to ensure allocation concealment.
The infants were randomly assigned to receive orally either 0.5 mL of 25% dextrose (intervention) or 24% sucrose (control) solution 2 minutes before a scheduled heel lance. These solutions were given to each infant only once per their study group allocation and administered at the next scheduled heel lance after enrollment. Both solutions were available in the hospital supply as 100-mL bottles for 25% dextrose (Fresenius Kabi) and 2-mL ampules for 24% sucrose (StayHappi; Delcure Lifesciences Limited). They are indistinguishable by physical appearance and appear as colorless, transparent liquids when loaded into a syringe.
After an infant was enrolled and due for a scheduled heel lance, a nurse from the NICU who was neither part of the research team nor involved in the care of that particular infant loaded 0.5 mL of either test solution in a 1-mL syringe. The test solution was loaded as per the allocated intervention in a separate fluid preparation room within the NICU complex. Subsequently, this syringe was handed to the nurse taking care of the enrolled infant without revealing its contents. The nurse who loaded the syringe did not participate in any further aspects of the study.
Before initiating the study, a 7-minute prerecorded voice command with clear instructions for each procedure step was developed, tested, and validated by the principal investigator. The principal investigator also trained a group of experienced nurses to synchronize the various steps of the heel-lance procedure with this voice command. These trained nurses performed all heel lances for the study by using an automated lancet (BD Microtainer Quikheel Preemie Lancet). The entire procedure was standardized into 5 phases: (a) baseline (2 minutes), (b) intervention (30 seconds), (c) wait period (2 minutes), (d) lance (0 seconds), and (e) return to baseline (2.5 minutes) (Fig 1).
At the beginning of the procedure, the principal investigator played the voice command from a laptop computer. During the initial 2 minutes (phase a), the infants were allowed to settle. The baseline vital signs and behavioral states were calculated from a window of 15 seconds before handling the infants for the intervention (from 1 minute 30 seconds to 1 minute 45 seconds) (Supplemental Table 3). The maximum heart rate and the minimum oxygen saturation levels during this period were noted as the baseline vitals.24 The predominant behavioral state was defined as the state in which the infants spent the maximum time during this period. The infants were then held in a semireclined position, and the treating team nurse administered the test solution over the anterior portion of the tongue during the next 30 seconds directly from the syringe (phase b). Afterward, the infants were laid back on the warmer for the next 2 minutes (phase c) with their faces slightly turned toward the side to allow the digital camera to capture facial expressions. The heel lance (phase d) was performed similarly for all infants using an automated lancet to ensure uniform delivery of pain-inducing stimulus. After the heel lance (phase e), the blood was allowed to flow freely, and care was taken not to squeeze the heel after lancing to avoid any additional pain. Blood sugar was checked using a glucometer (SD Codefree, SD Biosensor, Inc., Gyeonggi-do, Republic of Korea). The infants were monitored for another 2.5 minutes after the procedure. The entire 7 minutes of the procedure were recorded by the principal investigator by using 2 dedicated camera recording systems. One mobile camera system (Xiaomi Mi Max 2) was set up to focus on the multiparameter monitor screen (Infinity C700 with Masimo SET; Drager Medical Systems, Inc.) for recording the infant’s vital signs. The other digital camera system (EOS 1300 D; Canon) mounted on a tripod stand was set up for recording the infant’s facial expressions (Supplemental Fig 5). The vital signs were continuously recorded with a saturation probe attached to the infants’ hands or feet. The principal investigator ensured that both cameras were started simultaneously as instructed in the voice command.
For infants who received nasal continuous positive airway pressure at the time of heel lancing, their head cap was loosened slightly to expose the entire forehead without compromising the delivered pressures. The principal investigator recorded the video from the front to capture the forehead, both eyes, and the nasolabial region.
The primary outcome was Premature Infant Pain Profile (PIPP) score at 30 seconds after the procedure.25 PIPP includes 3 behavioral (brow bulge, eye squeeze, and nasolabial furrow), 2 physiologic (heart rate and oxygen saturation), and 2 contextual (gestational age and behavioral state) parameters. Each item is numerically scaled and scored on an empirically based 4-point scale (0, 1, 2, or 3), reflecting increasing changes in each variable from baseline values. The scores obtained for the 7 items are added for a total pain intensity score. PIPP-Revised (PIPP-R) is the latest scoring system.24 In PIPP-R, the 2 contextual variables gestational age and behavioral state are scored only if there are changes in any of the physiologic and/or behavioral variables in response to the painful stimulus (Supplemental Table 4, Supplemental Fig 6).
Secondary outcomes were PIPP scores at 60 and 120 seconds, PIPP-R scores at 30, 60, and 120 seconds, the correlation between PIPP and PIPP-R scores, and any adverse events. The various adverse events recorded were as follows: choking, coughing, or vomiting; sustained tachycardia (heart rate >200 beats/minute) or bradycardia (heart rate <80 beats/minute) for >15 seconds; sustained tachypnea (respiratory rate >80 breaths/minute) or bradypnea (respiratory rate <20 breaths/minute) for >15 seconds; or sustained oxygen desaturation <80% for >15 seconds.26
For each infant, the 2 7-minute videos were checked for technical errors by the principal investigator, and 4 pairs of video segments were edited out separately (Supplemental Table 3). Two outcome adjudicators blinded to the intervention (2 senior neonatology fellows including the principal investigator) independently calculated the pain scores from these videos using the second-by-second stop frame method.26 Because the intraclass coefficient (ICC) between the 2 examiners was 0.91 (excellent), the outcomes were analyzed using the scores assigned by the principal investigator himself, who was not involved in the generation of the randomization sequence and was blinded to group allocation.
The SD of PIPP scores in the 24% sucrose group was found to be 3 from a study by Simonse et al.27 With an α error of 5%, power of 80%, and an absolute noninferiority margin of 2 points in the PIPP scale, the number of infants required to reveal noninferiority of 25% dextrose was 56.16,28 We took a noninferiority margin of 2 based on the study by Gao et al,29 where they observed a mean reduction of PIPP score by 3.2 (95% confidence interval [CI], 2.6 to 3.8) among preterm infants (30–34 weeks) who received 20% sucrose compared with routine care for heel lancing. Assuming an attrition rate of 15% because of a technical error, the total sample size calculated was 64 infants (32 in each arm).
Data were analyzed using Stata release 12 statistical software (StataCorp LP, College Station, TX). Categorical variables were compared using the χ2 test or Fisher’s exact test and continuous variables by Student’s t test or Mann–Whitney U test, as applicable. The correlation coefficient (r) was calculated between PIPP and PIPP-R, and agreement was checked using a Bland-Altmann plot. Pain scores of the 2 outcome assessors were compared using ICC. P < .05 was considered significant. Being a noninferiority study, per-protocol analysis was planned for the primary analysis. Because all neonates received the assigned intervention and outcome information was available in all but 1 infant (because of corrupted video recording), per-protocol and intention-to-treat analyses are identical.
Results
We enrolled 64 infants (32 in each group). Video recordings were complete for all infants except 1 in the sucrose group because of an inadvertent error in the recording (Fig 2).
The baseline characteristics, including medications received, vital signs, and behavioral state, were comparable (Table 1). However, the dextrose group had a significantly higher proportion of male infants and older maternal age. The median (interquartile range) age at intervention in the dextrose group was older than in the sucrose group, although this finding was not statistically significant. One-fifth of the infants were receiving nasal continuous positive airway pressure at the time of intervention.e m
Characteristic . | 25% Dextrose (n = 32) . | 24% Sucrose (n = 32) . |
---|---|---|
Before intervention | ||
Gestational age, wk, mean (SD) | 32.6 (1.9) | 32.8 (1.6) |
28–31 wk, stratum 1 | 10 (31) | 7 (22) |
32–35 wk, stratum 2 | 22 (69) | 25 (78) |
Birth wt, g, mean (SD) | 1596 (452) | 1651 (350) |
Birth wt <1500 g | 12 (38) | 10 (31) |
Small for gestational age | 14 (44) | 11 (34) |
Male sexa | 24 (75) | 14 (44) |
Maternal age, y, median (IQR)a | 26 (24.25–29) | 24.5 (23–27) |
Primipara | 9 (28) | 7 (22) |
Pregnancy-induced hypertension | 12 (38) | 8 (25) |
Gestational diabetes mellitus | 6 (19) | 7 (22) |
Antenatal steroids received (n = 37)b | 16 (89) | 17 (90) |
Cesarean delivery | 23 (72) | 20 (63) |
Apgar 1 min, median (IQR) | 7 (5–8) | 8 (7–8) |
Apgar 5 min, median (IQR) | 8 (8–9) | 9 (8–9) |
48 h before enrollment | ||
Invasive ventilation | 4 (13) | 3 (9) |
Inotropic support | 1 (3) | 1 (3) |
Hydrocortisone | 1 (3) | 1 (3) |
Paracetamol | 2 (6) | 1 (3) |
Fentanyl | 1 (3) | 1 (3) |
At time of intervention | ||
Age at intervention, h, median (IQR) | 62 (25.5–87.5) | 36 (24–72) |
No. of previous heel lances | ||
1–5 | 12 (38) | 17 (53) |
6–10 | 13 (41) | 10 (31) |
>10 | 7 (22) | 5 (16) |
Grade I or II IVH | 1 (3) | 2 (6) |
On CPAP | 7 (22) | 6 (19) |
Receiving IV fluids | 6 (19) | 5 (16) |
Orogastric feeds | 25 (78) | 20 (63) |
Paladai feeds | 12 (38) | 13 (41) |
Baseline physiologic parameters and behavioral state | ||
Maximum heart rate, beats/min, mean (SD) | 144 (15) | 138 (15) |
Minimum Spo2, %, mean (SD) | 96 (2) | 96 (2) |
Predominant behavioral score, median (IQR) | 3 (2–3) | 3 (2–3) |
Characteristic . | 25% Dextrose (n = 32) . | 24% Sucrose (n = 32) . |
---|---|---|
Before intervention | ||
Gestational age, wk, mean (SD) | 32.6 (1.9) | 32.8 (1.6) |
28–31 wk, stratum 1 | 10 (31) | 7 (22) |
32–35 wk, stratum 2 | 22 (69) | 25 (78) |
Birth wt, g, mean (SD) | 1596 (452) | 1651 (350) |
Birth wt <1500 g | 12 (38) | 10 (31) |
Small for gestational age | 14 (44) | 11 (34) |
Male sexa | 24 (75) | 14 (44) |
Maternal age, y, median (IQR)a | 26 (24.25–29) | 24.5 (23–27) |
Primipara | 9 (28) | 7 (22) |
Pregnancy-induced hypertension | 12 (38) | 8 (25) |
Gestational diabetes mellitus | 6 (19) | 7 (22) |
Antenatal steroids received (n = 37)b | 16 (89) | 17 (90) |
Cesarean delivery | 23 (72) | 20 (63) |
Apgar 1 min, median (IQR) | 7 (5–8) | 8 (7–8) |
Apgar 5 min, median (IQR) | 8 (8–9) | 9 (8–9) |
48 h before enrollment | ||
Invasive ventilation | 4 (13) | 3 (9) |
Inotropic support | 1 (3) | 1 (3) |
Hydrocortisone | 1 (3) | 1 (3) |
Paracetamol | 2 (6) | 1 (3) |
Fentanyl | 1 (3) | 1 (3) |
At time of intervention | ||
Age at intervention, h, median (IQR) | 62 (25.5–87.5) | 36 (24–72) |
No. of previous heel lances | ||
1–5 | 12 (38) | 17 (53) |
6–10 | 13 (41) | 10 (31) |
>10 | 7 (22) | 5 (16) |
Grade I or II IVH | 1 (3) | 2 (6) |
On CPAP | 7 (22) | 6 (19) |
Receiving IV fluids | 6 (19) | 5 (16) |
Orogastric feeds | 25 (78) | 20 (63) |
Paladai feeds | 12 (38) | 13 (41) |
Baseline physiologic parameters and behavioral state | ||
Maximum heart rate, beats/min, mean (SD) | 144 (15) | 138 (15) |
Minimum Spo2, %, mean (SD) | 96 (2) | 96 (2) |
Predominant behavioral score, median (IQR) | 3 (2–3) | 3 (2–3) |
Data are presented as No. (%) unless otherwise indicated. Coding for predominant behavioral score: 0 = active awake, eyes open, facial movements positive; 1 = quiet awake, eyes open, no facial movements; 2 = active sleep, eyes closed, facial movements positive; 3 = quiet asleep, eyes closed, no facial movements. CPAP, continuous positive airway pressure; IQR, interquartile range; IV, intravenous; IVH, intraventricular hemorrhage; Spo2, pulse oxygen saturation.
Baseline difference significant (P < .05).
Eligible mother of infant with gestational age <34 wk.
The mean (SD) PIPP score at 30 seconds was comparable between the 2 groups (6.41 [2.56] vs. 7.03 [2.23] in the dextrose versus sucrose groups, respectively; mean difference, −0.63; 95% CI, −1.85 to 0.60; P = .311) (Table 2). The upper margin of the CI was below the predefined noninferiority margin of 2 (Fig 3). Results did not change on adjusting for sex and maternal age (adjusted PIPP score at 30 seconds, 6.41 [0.73] vs 7.00 [0.85]). However, male sex was independently associated with a lower PIPP score at 30 seconds.
Pain Score . | 25% Dextrose (n = 32) . | 24% Sucrose (n = 31) . | Mean Difference (95% CI) . | P . |
---|---|---|---|---|
PIPP at 30 s | 6.41 (2.56) | 7.03 (2.23 | −0.63 (−1.85 to 0.60) | .311 |
PIPP at 60 s | 5.03 (2.18) | 5.39 (1.48) | −0.36 (−1.30 to 0.59) | .454 |
PIPP at 120 s | 4.75 (1.97) | 4.94 (1.46) | −0.19 (−1.06 to 0.69) | .672 |
PIPP-R at 30 s | 6.28 (3.01) | 7.03 (2.27) | −0.75 (−2.10 to 0.59) | .269 |
PIPP-R at 60 s, median (IQR) | 5 (4–6) | 5 (5–7) | −0.53 (−1.85 to 0.79) | .425 |
PIPP-R at 120 s, median (IQR) | 5 (0–6) | 5 (4–5) | −0.51 (−1.88 to 0.86) | .460 |
Pain Score . | 25% Dextrose (n = 32) . | 24% Sucrose (n = 31) . | Mean Difference (95% CI) . | P . |
---|---|---|---|---|
PIPP at 30 s | 6.41 (2.56) | 7.03 (2.23 | −0.63 (−1.85 to 0.60) | .311 |
PIPP at 60 s | 5.03 (2.18) | 5.39 (1.48) | −0.36 (−1.30 to 0.59) | .454 |
PIPP at 120 s | 4.75 (1.97) | 4.94 (1.46) | −0.19 (−1.06 to 0.69) | .672 |
PIPP-R at 30 s | 6.28 (3.01) | 7.03 (2.27) | −0.75 (−2.10 to 0.59) | .269 |
PIPP-R at 60 s, median (IQR) | 5 (4–6) | 5 (5–7) | −0.53 (−1.85 to 0.79) | .425 |
PIPP-R at 120 s, median (IQR) | 5 (0–6) | 5 (4–5) | −0.51 (−1.88 to 0.86) | .460 |
Data are presented as mean (SD) unless otherwise indicated. IQR, interquartile range.
The mean PIPP scores at 60 and 120 seconds were also not different (Table 2). Similarly, there were no significant differences in the PIPP-R scores between the 2 groups at 30, 60, and 120 seconds after the procedure (Table 2). On subgroup analysis (28 weeks and 0 days–31 weeks and 6 days and 32 weeks and 0 days–35 weeks and 6 days), the PIPP scores were not significantly different in both the strata across all 3 time intervals (P > .05) (Supplemental Table 5).
There was a very strong positive correlation between PIPP and PIPP-R at 30, 60, and 120 seconds after the procedure, with the Spearman ρ (r) values being 0.998, 0.993, and 0.966, respectively (P = .001). On Bland-Altman plot, the mean difference between the 2 scores across all time points was between the clinically acceptable limits of agreement of 1 to −1 except for those situations where the PIPP-R score was automatically assigned a value of 0 when the infants showed no response to pain (Fig 4). One infant in the dextrose group had a transient adverse event (coughing episode), with no adverse event observed in the sucrose group.
Discussion
We did not find a statistically significant difference in the mean PIPP score at 30 seconds, with the upper 95% CI margin of 0.60 very well within the set noninferiority margin of 2. Moreover, the mean PIPP scores at 30 seconds in both the dextrose and sucrose groups were similar to those reported in individual studies that have evaluated these test solutions separately.27,30,31
Even if a noninferiority trial reveals that the intervention being tested is not inferior to the active control, researchers still need to prove assay sensitivity (ie, the active control worked with similar efficacy). The first supporting evidence of assay sensitivity in our study is the high adherence rate to the allocated intervention. All neonates received the assigned intervention, outcomes were measured objectively, and the outcome assessors were blinded to the study group allocation. The second evidence of assay sensitivity is provided by the historical evidence of sensitivity to the drug effect. A Cochrane systematic review included 2 studies in which researchers compared sucrose with water (placebo) for pain relief during heel lancing.32 The mean PIPP score at 30 seconds in the water group ranged from 8.5 to 9.62. The PIPP score in the sucrose group was lower by −1.42 (95% CI, −2.86 to 0.01). This reduction is similar to the PIPP score observed in our active control group (mean [SD], 7.03 [2.23]), indicating that sucrose was associated with a successful reduction of pain in our study compared with a historical placebo group.
Few researchers have found no discernible difference between the 2 solutions in agreement with our results. Kumari et al18 found comparable mean PIPP scores between 24% sucrose and 25% dextrose, although they included stable late preterm infants only. Okan et al22 concluded similar efficacy of both solutions, although they used 2 mL each of 20% sucrose and dextrose and a different pain scale for outcome assessment. A recent review and meta-analysis by Wade et al11 for neonatal procedural analgesia guidelines for low- and middle-income countries also revealed similar analgesic efficacy among various sugar solutions. On the other hand, Işik et al33 reported that 30% sucrose was associated with the least duration of cry compared with 30% glucose in term infants with 2 mL of either solution, but the physiologic parameters were comparable. Leng et al34 reported a similar conclusion among term healthy infants using the Neonatal Facial Coding System. Guala et al35 reported that higher strengths of glucose solution (>30%) were associated with the least increase in heart rate from baseline at 3 minutes compared with similar strengths of sucrose, although the finding was not statistically significant and no validated pain scales were used.
Among the secondary outcomes, there were no significant differences in the pain scores at 60 and 120 seconds between the groups, irrespective of the pain scale used.
PIPP-R is more user friendly and reliable in extremely preterm infants.24 Although PIPP-R has been extensively validated, no studies have compared the 2 scoring systems.36–38 In our research, we found a strong positive correlation between PIPP and PIPP-R at all time intervals.
The strengths of our study lie in its robust methodology. We ensured that all the steps involved in the heel lancing were standardized, and only trained and selected nursing staff performed the heel-lance procedure. We also used a prerecorded voice command for providing instructions for the heel-lance procedure and an automated heel lancet to ensure a uniform single noxious stimulus for all infants. The entire procedure was video recorded using 2 dedicated camera systems. Blinding of the participants (enrolled neonates), investigators, caregivers, outcome assessors, and statisticians was also done. There was only 1 loss to follow-up in which the video recording was corrupted, thereby minimizing the attrition bias. The outcome assessed (PIPP score) is a highly validated and objective scale derived from the recorded videos by 2 blinded assessors, with the ICC for the primary outcome being excellent (0.91). All these measures were associated with high internal validity for our study.
Our study also had a few limitations. Although we enrolled preterm infants from age 28 weeks and 0 days to 35 weeks and 6 days, only one-fourth of the study population was age <32 weeks. We also did not specifically investigate the effect of the time of day on the pain response. Although all heel lances were performed for the prefeeding blood sugar monitoring at least 1 hour after the last feed, we did not document the exact timing of the last feed before the study intervention. However, we expect it to be similar in both groups by random assignment. Moreover, in the literature on oral sweet solutions for analgesia, researchers have suggested that the onset of action is immediate, with the effect lasting only for 5 to 10 minutes.12 Blood glucose levels may become altered with the use of these solutions; however, we did not explicitly compare the incidence of hyperglycemia in either group. Use of these solutions once within the recommended doses, with no case of hyperglycemia being reported (even with higher doses of 2 mL of 50% sucrose) in the published literature, points toward the rarity of this adverse event.14,39 Moreover, the various other concurrent interventions and overall clinical condition of the infants would have a bearing on blood sugar levels.
A dearth of data exists on the continued efficacy of repeated doses of sweet solutions during the NICU stay, as well as on their long-term neurodevelopmental safety. Interestingly, with the upcoming data, researchers have raised a controversy about oral sucrose solutions and point out that their use may not be completely harmless. Asmerom et al40 and Angeles et al41 reported that oral sucrose decreased the behavioral markers of pain but was associated with an increase in the biochemical markers of adenosine triphosphate degradation and oxidative stress, more so in preterm infants with respiratory distress. However, Angeles et al42 more recently showed that dextrose solution alone or with facilitated tucking was not associated with an increase in these markers among preterm infants. Therefore, it is equally important to study the analgesic properties of these sweet solutions in combination with other nonpharmacologic measures, including breast milk, swaddling, facilitated tucking, and kangaroo mother care. All these can be achieved by involving families through family-centered care, which notably is being promoted widely in the field of neonatology. Moreover, it would be prudent to generate long-term data of this oxidative stress on various diseases, including the metabolic syndrome, when using these sweet solutions.
Conclusions
Oral 25% dextrose can be used as an effective alternative to 24% sucrose for heel-lance analgesia in preterm infants requiring intensive care in resource-limited settings without any major immediate adverse events.
Dr Sasidharan conceptualized and designed the study, recruited participants, compiled the data, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Gupta conceptualized and planned the study, supervised the data collection, analyzed and interpreted the data, and critically revised and finalized the manuscript; Dr Yadav contributed to designing the study, coordinated the data collection, contributed to the initial analysis, and critically reviewed the manuscript for important intellectual content; Dr Chawla contributed to the data analysis and critically reviewed and revised the manuscript for important intellectual content; Dr K. Singh supervised the design of the study and recruitment of patients and critically revised the manuscript for important intellectual content; Dr A. Singh supervised the recruitment of patients and critically revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
This trial has been registered with the Clinical Trials Registry–India (http://ctri.nic.in/Clinicaltrials/login.php) (identifier CTRI/2019/02/017383).
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.
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