Abstract
Objective. Very preterm newborns undergo multiple invasive procedures. Nonpharmacological interventions are valuable alternatives for pain relief during minor procedures in neonates. Oral sucrose analgesia has been widely studied in term and preterm neonates during painful procedures. The analgesic effect of oral glucose in very preterm infants has not yet been reported. The objectives of this study were to assess the analgesic effect of orally administered glucose and to determine the synergetic analgesic effect of glucose and pacifiers during subcutaneous injections in very preterm neonates using a validated behavioral acute pain rating scale.
Design. Two crossover trials.
Setting. One neonatal intensive care unit in a community-based general hospital.
Methods. A prospective study was conducted in 40 very preterm neonates. Each infant received 2 treatments in a crossover manner during 2 consecutive subcutaneous injections of erythropoietin. The first trial (25 infants) was intended to compare oral 30% glucose (0.3 mL) versus placebo (0.3 mL of sterile water); the second trial (15 infants) compared oral 30% glucose (0.3 mL) versus oral 30% glucose (0.3 mL) followed by sucking a pacifier. The primary outcome measure was the evaluation of pain induced by a subcutaneous injection of erythropoietin, using Douleur Aiguë Nouveau-né scale (0 no pain, 10 maximum pain).
Results. Twenty-four infants completed the study in the first trial and 15 in the second one. Mean (95% confidence interval [CI]) gestational age, birth weight, postnatal age, and weight at inclusion for neonates in the first and second trial were, respectively, 28.1 (95% CI: 27.3–29.0) and 29.1 (95% CI: 27.8–30.4) weeks, 1036 (95% CI: 944-1128) and 995 (95% CI: 848-1141) g, 26.4 (95% CI: 22.4–30.3) and 26 (95% CI: 22.0–29.9) days, and 1234 (95% CI: 1120–1348) and 1209 (95% CI: 1059–1359) g. In the first trial, median (interquartile) pain scores for placebo and 30% glucose, respectively, were 7 (2.5–9.75) and 4.5 (1–6). In the second trial, median (interquartile) pain scores for 30% glucose and for 30% glucose plus pacifier, respectively, were 4 (2–7) and 4 (1–6).
Conclusions. A small dose of 0.3 mL of 30% oral glucose has an analgesic effect in very preterm neonates during subcutaneous injections. This effect is clinically evident because it can be detected by a behavioral pain rating scale. The synergetic analgesic effect of glucose plus sucking a pacifier is less obvious in very preterm neonates as opposed to what other studies have showed in full-term infants.
The number of invasive procedures performed in newborns admitted to neonatal intensive care units (NICUs) is very high. Barker and Rutter1 recorded over 3000 procedures in 54 newborns admitted to a NICU; 74% of these procedures were performed in infants below 31 weeks’ gestation. Recent surveys still show that procedural pain management in the newborn remains below optimal levels.2,3 However, it has been shown that 1) the neurophysiological basis for pain perception are established by the end of the second trimester of gestation,4 2) even born preterm infants respond to pain and differentiate stimulus intensity,5 and 3) neonates exposed to numerous painful and noxious stimuli between postconceptual weeks 28 and 32 show different behavioral and physiologic responses to pain compared with neonates of a similar postconceptual age who had not had such experiences.6 There is now a growing body of evidence that multiple painful and stressful events undergone by infants born prematurely not only induce acute changes, but that permanent structural and functional changes may also result.7 Therefore, a proper management of analgesia in newborns who require medical procedures is mandatory.
Proven effective strategies to manage pain from surgery or major procedures do exist. However, strategies to manage pain from minor procedures such as venipunctures or heel pricks are less clear. Pharmacological treatments are rarely used for this type of procedure because of concerns about efficacy in the newborn (Emla cream8 [AstraZeneca, Ruiel-Malmaison, France] or paracetamol for heel pricks9) or adverse effects (central analgesics). Therefore, nonpharmacological interventions are valuable alternatives in these situations. Oral sucrose, with and without nonnutritive sucking (pacifiers), has been the most frequently studied nonpharmacological intervention for pain relief during minor procedures in neonates.10 Its analgesic effect has been shown in term10 and preterm11–14 neonates during heel pricks, venipunctures, and circumcision. The efficacy of oral glucose to reduce venipuncture pain in the term neonate has also been reported.15,16 To the best of our knowledge, the analgesic effect of oral glucose in very preterm infants has not yet been reported in the literature.
The objectives of this study were to: 1) assess the analgesic effect of orally administered glucose; 2) determine the synergetic analgesic effect of glucose and pacifiers during subcutaneous injections in very preterm neonates using a behavioral acute pain rating scale, Douleur Aiguë Nouveau-né (DAN) scale, which has shown initial validity in neonates.
METHODS
Protocol
This prospective, crossover clinical study was designed to include preterm newborns treated at the NICU of the Poissy-Saint Germain Hospital. The study protocol and the letter of permission addressed to parents were approved by the local Committee for the Protection of Human Subjects in Medical Research according to current law in France. Written informed consent was obtained from both parents of each newborn before the infant participated in the study. The inclusion criteria were as follows: neonate born ≤32 weeks’ gestation; aged ≥48 hours; first subcutaneous injection of erythropoietin as part of routine medical care in our unit; no feeding for the last 30 minutes or having continuous enteral feeding; APGAR scores >3 at 5 minutes, and availability of 1 investigator (R.L.) who performed all pain evaluations. Exclusion criteria were infant medical instability, naloxone administration during the last 24 hours, and the administration of a sedative or a major analgesic during the last 48 hours. Subcutaneous injections were performed by the nurse in charge of the infant. Injections were applied in the mid external aspect of the thigh according to a standard procedure with the infant lying supine. The primary outcome measure was the evaluation of pain induced by a subcutaneous injection of erythropoietin in preterm newborns, using DAN scale. The study was designed to include 2 separate crossover trials. Each infant was to receive 2 treatments in a crossover manner during 2 consecutive subcutaneous injections of erythropoietin. The 2 injections were performed at a 48-hour interval. The first trial was intended to compare oral 30% glucose (0.3 mL) versus placebo (0.3 mL of sterile water); the second trial compared oral 30% glucose (0.3 mL) versus oral 30% glucose (0.3 mL) followed by sucking a pacifier. An initial sample size calculation conducted with Minitab statistical package (Minitab, Inc) using means and a standard deviation of 3.1 yielded that to achieve 80% power and 5% significance level to detect a 2-point difference in DAN scale between glucose versus placebo administrations, 21 participants were required in the first trial. To detect a 3-point difference between glucose alone versus glucose plus sucking a pacifier, 11 infants were required in the second trial. These differences and standard deviation had been initially taken from data obtained in term neonates. Subsequently, a pilot study conducted in ten neonates born between 27 and 32 weeks’ gestation who were evaluated during 3 consecutive erythropoetin injections showed a mean (standard deviation) DAN score of 7 (1.7), 4.9 (2.9), and 1.7 (2.9) when sterile water, 30% glucose, and 30% glucose plus a pacifier were respectively used. The preliminary data of this pilot study was presented at the 5th International Symposium on Pediatric Pain.17 A sample calculation with PASS statistical software (NCSS Statistical Software) using this preliminary data and a nonparametric adjustment for 2-sided Wilcoxon test yielded that a sample size of 21 infants would achieve 89% power to detect a difference of 2 points between 30% glucose and sterile water with a significant level of 5% and that a sample size of 11 infants would achieve 92% power to detect a difference of 3 points when comparing 30% glucose versus 30% glucose plus pacifier with a significant level of 5%. Finally, we decided to include 25 infants in the first trial and 15 infants in the second one. Commercial vials of sterile water and 30% glucose were used; pacifiers were standard nipples stuffed with a gauze square for resistance (International Medical Ref 37089 [International Medical, Marche, Belgium]). The external diameter of pacifier was 6 mm.
DAN Scale
DAN scale is a behavioral scale developed to rate acute pain in term and preterm neonates.18 This scale scores pain from 0 to 10 where 0 is no pain and 10 maximum pain; it evaluates 3 items: facial expressions, limb movements, and vocal expression (Table 1). In the validation study of this scale,18 2 independent observers evaluated neonates, born between 25 and 41 weeks’ gestation, during both painful and dummy procedures. The scale showed a good sensitivity and specificity because all possible scores were obtained; these were ≥3 in 95% of painful procedures and ≤2 in 88% of dummy procedures. High intercorrelation of items (internal consistency) was confirmed by a Cronbach’s coefficient α of 0.88, and a good interrater agreement was showed by a Krippendorff’s r test of 91.2.
DAN: A Behavioral Acute Pain Rating Scale for Neonates (16)
Assignment
The 40 infants expected to be included in the study were randomized to 1 of the 2 trials, and each infant received the 2 treatments of the trial in a random order. Randomization was performed in advance using a random number table by an assistant not involved in the study, and treatment allocations were inserted in opaque sealed envelopes numbered 1 through 40; investigators were blind to these allocations. Codes of allocation were kept secret by the assistant who performed randomization and they were broken only after the inclusion of the last neonate.
Masking
Subcutaneous injections were performed in each neonate while she or he was in the incubator. The observer started newborn evaluations by an assessment of the arousal state using Prechtl’s observational rating system:19 1) eyes closed, regular respiration, no movements; 2) eyes closed, irregular respiration, gross movements; 3) eyes open, no gross movements; 4) eyes open, continual gross movements, no crying; and 5) eyes open or closed, fussing, or crying. Then, he momentarily quit the room and the infant was prepared for the procedure. A research assistant opened a consecutive numbered envelope, which contained the treatment assigned for each infant. Two minutes before the injection, the allocated solution was administered for 15 seconds by a sterile syringe into the infant’s mouth. Pacifier was also given 2 minutes before the injection and held gently in the infant’s mouth by an assistant throughout the procedure. Pain assessment started with the introduction of the needle and ended when the needle was removed. The observer had no indication to know which solution had been given to the neonate, but because pain evaluation was based on a behavioral scale, blinding to the pacifier was not possible. The nurse who performed the subcutaneous injection was naive as to the type of solution given to the newborn.
Statistical analysis was performed using NCSS 2001 software (NCSS Statistical Software). Median scores of two treatments in each trial were compared using the nonparametric Wilcoxon signed-rank test. A P value < .05 was considered statistically significant.
RESULTS
From June 2000 through August 2001, 55 newborn infants met the inclusion criteria. Thirteen neonates undergoing their first subcutaneous injection of erythropoietin and potentially eligible were not included in the study because of the nonavailability of the observer; parents refused their consent for 2 infants. Their perinatal characteristics were similar to those included in the study. As planned, 40 infants were included, 25 in the first trial comparing 30% glucose versus placebo, and 15 in the second trial comparing 30% glucose alone versus 30% glucose plus sucking a pacifier. In the first trial, 1 infant died of necrotizing enterocolitis before the second intervention (he had received sterile water during the first intervention), so the analysis of this group will concern 24 infants.
Ranges for gestational age, birth weight, postnatal age, and weight at inclusion for infants in the first and second trials, respectively, were 24.8 to 31.0 and 25.2 to 32.8 weeks, 700 to 1525 g and 595 to 1400 g, 12 to 46 and 17 to 45 days, and 760 to 1800 g and 800 to 1710 g. Birth weight, gestational age, APGAR scores, postnatal age, sex distribution, type of delivery, and arousal state are summarized in Table 2. Individual pain scores are presented in Figs 1 and 2. Pain scores were significantly lower in 30% glucose group as compared with placebo group. No statistically significant difference in pain scores was found between 30% glucose group and 30% glucose plus pacifier group. Mean and median scores for each intervention during subcutaneous injections are presented in Table 3. Slight (85%–88%) and transient oxygen desaturations were observed in 7 neonates during administration of interventions. In 5 neonates it happened during administration of glucose alone and in the other 2 during administration of glucose plus the pacifier. In other words, 7 of 54 glucose administrations elicited oxygen desaturations as compared with 0 of 24 placebo administrations; P = .09 by Fisher exact test. Three of these neonates were still receiving oxygen as part of their treatment. No other adverse effects were noted in any infant.
Individual pain evaluations with DAN scale (0 to 10) during two consecutive subcutaneous injections of erythropoietin in 24 preterm neonates. Each infant received sterile water and 30% glucose in a cross-over manner and in a random order. Overall, glucose gives lower scores than sterile water (p = 0.03); however, 8 infants did not show a reduction of pain scores. Solid lines indicate infants who had a lower pain score with 30% glucose. Dotted lines indicate infants who did not have a reduction in pain scores with 30% glucose as compared to sterile water.
Individual pain evaluations with DAN scale (0 to 10) during two consecutive subcutaneous injections of erythropoeitin in 15 preterm neonates. Each infant received 30% glucose and 30% glucose plus a pacifier in a cross-over manner and in a random order. Nine infants showed lower scores with glucose plus a pacifier but this difference did not reach a statistical significance (p = 0.4). Solid lines indicate infants who had a lower pain score with 30 % glucose plus a pacifier. Dotted lines indicate infants who did not have a reduction in pain scores with 30% glucose plus pacifier as compared to 30% glucose alone.
Perinatal Characteristics of 39 Preterm Newborns Who Completed the Study of Analgesic Effects of Glucose and Pacifiers
Mean and Median Pain Scores Obtained With Placebo, Glucose, and Glucose Plus Pacifier in 39 Preterm Neonates During Subcutaneous Injections
DISCUSSION
This study comprised 2 parallel trials. The first one has showed that a dose as small as 0.3 mL of 30% oral glucose has an analgesic effect in very preterm neonates during subcutaneous injections. To the best of our knowledge, oral glucose analgesic properties in this setting had not been previously described. The demonstration that this little dose (0.09 g of glucose) has analgesic properties in preterm neonates is consistent with the recent finding that oral sweet solutions have analgesic effects even when they are given in small doses.10,11 Furthermore, these analgesic effects are clinically obvious as proven by the fact that they were detected by a behavioral pain rating scale. In the second trial comparing 30% glucose versus 30% glucose plus sucking a pacifier, although scores tended to be slightly lower in the latter group, it was not possible to show a statistical difference between them. Actually, median scores were the same in both groups, 4, but the analysis of spread which can also be important for Wilcoxon-Mann-Whitney test, as stated by Hart,20 shows that interquartile ranges and mean values were, respectively, 1 to 6 and 3.8 with glucose plus pacifier versus 2 to 7 and 4.6 with glucose alone. The study lacked enough power to be able to show this slight difference because we had expected, as observed in term neonates and in a preliminary pilot study in preterm neonates, a 3-point difference in DAN scale between these 2 groups. Nevertheless, the data obtained revealed that sucking a pacifier adds, at best, little to the analgesic effect of oral glucose in the very preterm neonate during subcutaneous injections. This is different from what has been reported in term neonates.16,21 Different studies have showed that nonnutritive sucking of either a pacifier or a nonlactating nipple causes analgesia in human full-term newborns through stimulation of oropharyngeal tactile and mechanoreceptors.21,22 To our knowledge, only 1 study on the analgesic qualities of nonnutritive sucking in very low birth weight neonates has been previously reported.23 The authors who used the Premature Infant Pain Profile to assess pain in infants 27 to 31 weeks’ gestation during heel lance reported that a pacifier with sucrose and a pacifier with sterile water significantly reduced pain during consecutive heel lance procedures. They also found a trend toward lower Premature Infant Pain Profile scores in the pacifier with sucrose group compared with the pacifier with water group although statistical significance was not achieved. Our finding that nonnutritive sucking has little or no synergistic analgesic effect when combined with glucose in very preterm neonates is not fully understood. Several hypotheses may be given to explain these results. First, it is sometimes difficult to elicit sucking in preterm neonates as opposed to term newborns who easily suck a pacifier. It has been reported in term neonates that sucking a pacifier is analgesic (as reflected by lack of crying and facial grimacing) during heelstick only when the infant sucks at a rate that exceeds 32 sucks/min during the period that precedes heel lance.21 The authors suggested that central antinociceptive mechanisms are engaged above a certain sucking frequency. Second, pacifiers that were used might have been a little big for preterm infants whose mean weight at entry into the study was 1209 g. We did not use pacifiers specially designed for preterm infants because at the time of the study these were available only in latex. Latex is avoided in our institution. Recently, silicone pacifiers for preterms have become available and these might deserve to be studied. Third, we only assessed pain during the interval comprised between the introduction and removal of the needle. We did not evaluate pain during the immediate period that followed the subcutaneous injection. The inclusion of this period in the evaluation, as other authors have done in studies related to the analgesic properties of sweet solutions in newborns, could have modified the results.12,23,24 Anyway, the preliminary results of our pilot study were somehow misleading.
As for other sweet solutions studied in term and preterm neonates, the analgesic effect of 30% glucose noticed in these very preterm neonates had a rapid onset suggesting a mechanism activated by the presence of the solution in the mouth rather than a postingestive effect. Ramenghi et al25 reported that sucrose reduced the pain response of preterm infants exposed to heel prick blood samples only when it was administered into the mouth. Sucrose was ineffective when administered intragastrically. The pain relief elicited by sweet solutions is probably mediated by the activation of endogenous opioids mechanisms; this view is supported by the fact that the effect can be blocked by the administration of an opioid antagonist.26 Seven neonates presented a slight and brief oxygen desaturation during administration of 30% glucose. Although this did not reach statistical significance when compared with sterile water administration, the authors consider that staff should be aware of this potential minor and transient complication of oral concentrated glucose administration in very preterm neonates so that oral glucose is administered very slowly and that a close oxygen saturation monitoring is conducted when this sweet solution is given. Additional studies should look at this potential adverse effect of sugar solutions in very preterm neonates. No other complications were observed beyond the intervention interval.
Interpretation of the results of this study should acknowledge 2 limitations. First, the observer was completely blind to the type of solution administered to infants assigned to the first trial, but because the study was based on a behavioral pain scale he was not blind to the administration of a pacifier to newborns assigned to the second trial; it was impossible to avoid this potential bias. Second, although the validation study of DAN scale has showed that it discriminates pain in term and preterm newborns, no study has proved yet that this scale can grade the degree of pain perception. We assumed that the more pronounced the reactions were, the higher the pain in the newborn was.
Minor procedures are extremely common in very preterm newborns and effective analgesia must be used in this setting. Current pharmacological treatments are not appropriate for these infants during acute, repetitive, and short-lasting procedures. The oral administration of a small dose of 30% glucose seem to be a simple, non invasive and valuable intervention to improve analgesia in very preterm neonates. Nevertheless, we should notice that this pain relief is not constant. In our population, 8 of 24 neonates did not show a reduction in pain scores with glucose. And from the 16 who did have a pain reduction, only 11 had a DAN pain score of 4 or lower. All this means that although oral glucose can help to reduce pain in preterm infants, it is not yet the perfect analgesic in this setting. The association of concentrated glucose with the nonnutritive sucking of a pacifier did not show in very preterm neonates the analgesic synergism observed in term neonates in other studies. However, the authors consider that additional research is needed in this area to evaluate analgesic properties of nonnutritive sucking using specially designed pacifiers in very preterm neonates before concluding that these are ineffective and do not have synergetic analgesic effect with glucose in this population. It is all the more important, because the most potent analgesia that has been reported in both rat and human term newborns is obtained when nonnutritive sucking is associated with tasting a sweet solution.
Acknowledgments
We thank the nursing staff of the Neonatal Intensive Care Unit of the Poissy-Saint Germain Hospital for their help during the study.
Footnotes
- Received August 11, 2001.
- Accepted March 3, 2002.
- Address correspondence to Ricardo Carbajal, MD, Department of Pediatrics, Poissy-Saint Germain Hospital, 78300 Poissy, France. E-mail: carbajal{at}club-internet.fr
REFERENCES
- Copyright © 2002 by the American Academy of Pediatrics
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