Journal of Neonatal-Perinatal Medicine 3 (2010) 325–331 DOI 10.3233/NPM-2010-0132 IOS Press

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Sucrose as an analgesic in relieving procedural pain in neonates
Srijana Basnet∗, Laxman Shrestha and Prakash Sundar Shrestha
Department of Pediatrics, Institute of Medicine, Kathmandu, Nepal

Received 1 January 2010 Revised 29 June 2010 Accepted 27 July 2010

Abstract. Objective: This study was undertaken to study physiological and behavioral pain responses of neonates and to assess the analgesic effect of orally administered sucrose as assessed by the behavioral pain rating scale [DAN (Douleur Aigu¨ du e Nouveau-n´ ) score] during venepuncture in neonates. e Method: In 50 healthy neonates requiring bilirubin estimation, blood sugar was randomly assigned to receive 2ml of 30% sucrose two minutes before the venepuncture (intervention) in comparison to a group not receiving sucrose (control). During the procedure, pain was assessed by behavioral pain rating scale [Douleur Aigu¨ Nouveau-n´ (DAN) scale]. The heart rate, oxygen e e saturation before, during and after procedure as well as crying time was noted. Results: There was significantly lower pain (DAN) score in the intervention group compared to control group. Median (interquartile) DAN score in the group receiving sucrose was 3 (1.5–5.5) compared to 7 (5–9.5) in control group. The difference in median DAN score between two groups was statistically significant (p = 0.0001). There was a significant increase in heart rate in the control group whereas in group receiving sucrose, no significant change in heart rate was observed. Similarly, oxygen saturation was also significantly reduced in control group when compared to intervention group. Conclusion: The analgesic effect of 30% sucrose was large enough to be clinically significant and can thus be detected by behavioral rating scale for acute pain (DAN). Sucrose reduces the physiological alteration occurring during venipuncture. Keywords: Analgesia, venipuncture, sucrose

1. Introduction Neonates are sensitive to pain and vulnerable to both its short- and long-term effects. It is believed that learning about pain starts with the first painful experience and it may have effects on subsequent pain perception and response [1]. Apart from long-term negative effects; inadequately treated pain, particularly in the neonatal period, increases morbidity and mortality, creates hyperalgesia, and can have a negative impact on development [2]. Adequate pain management reduces newborn pain and may reduce parent anxiety

∗ Corresponding author: Srijana Basnet, MD, House nr 269/16, P.O. Box 5785, Chabahil, Kathmandu, Nepal. E-mail: drsrijanabasnet@yahoo.com.

and increase compliance and cooperate for the procedure. While newborns are frequently subjected to painful diagnostic and therapeutic procedures, the issue of analgesia remains largely neglected. This problem is even more apparent in a developing country like Nepal, where there are very few centers for neonatal care with limited number of trained medical staff who are always overworked. In most of the clinical settings of the country, it is a common practice to subject neonates to various painful procedures without giving analgesia. There is paucity of knowledge among medical staff that newborn baby undergoing any painful procedure need analgesia which is used only for major procedures but ignored while pricking neonates for blood sampling and peripheral intravenous canulation. Several therapeutic and preventive strategies, including systemic

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S. Basnet et al. / Sucrose as an analgesic in relieving procedural pain in neonates Table 1 Prechtl’s rating system for assessment of arousal state 1 2 3 4 5 Eyes closed, regular respiration, no movements Eyes closed, irregular respiration, gross movements Eyes open, no gross movements Eyes open, continual gross movements, no crying Eyes open or closed, fussing, or crying

and local pharmacological and non- pharamacological interventions, are reported to be effective in relieving pain in infants. Among all these interventions, sucrose is the cheapest, readily available and easy to prepare. Though the Cochrane review [3] has already concluded that sucrose is safe and effective for reducing procedural pain from single events, this simple intervention is still not practiced in our clinical setting. Thus this study was conducted to evaluate the physiological and behavioral response of neonates to pain and to assess the analgesic effect of sucrose. The study also aimed to disseminate message among medical staff regarding knowledge of existence of pain felt by newborn during any procedure which can be alleviated by the use of a simple, cost effective intervention like sucrose solution.

2.2. Sample size In the study done at Poissy hospital of France [4], when sucrose was used during venepuncture in newborns, there was a reduction in DAN score by 2. Therefore calculation of sample size was done to detect a mean difference of 2 point between intervention and control groups. To achieve 80% power and 5% significance, 25 newborns were required in each of the two groups. Sucrose, a pharmaceutical exipient, manufactured in Germany and packed in small pouches containing 3 gm at the local pharmaceutical industry on our request. 30% sucrose solution was prepared by dissolving 3 gm of sucrose in 10 ml of distilled water packed in disposable ampoules. All the nursing staff and doctors working in the neonatal unit were briefed about the methodology before initiation of the study by investigators. 2.3. Randomisation Using random numbers from 1 to 50 developed from a random number table, treatment allocations (intervention versus no intervention) were inserted in opaque sealed envelopes. The codes of allocation was kept secret with one of the faculty member not involved in the study and revealed only after enrollment of the last neonate. 2.4. Procedure For all neonates fulfilling inclusion criteria, written consent was obtained from the parents before they were involved in the study. All neonates had to be breast fed 30 minutes before venepuncture. Venepunctures were performed by experienced nurses using a 24 gauze needle or intravenous cannula. The clothed neonate was placed supine on the procedure table below a radiant warmer, with the lower limbs exposed to assess for movement. The pulse oximetry sensor attached to the monitor (Nihon Khonden BSM 2303, Japan) was placed either around fingers or toes, 10 min preceding the venepuncture, and the neonate’s

2. Methods 2.1. Protocol This study was a prospective randomized control trial conducted at neonatal ward of Tribhuvan University Teaching Hospital (TUTH), Kathmandu, Nepal. The study protocol was approved by the institutional review board. Term newborns between 12 hours to 8 days of life, with apgar score > 7 at 5 min undergoing venepuncture for estimation of blood glucose and bilirubin or intravenous cannulation for intravenous antibiotics for presumed sepsis were included. Preterm neonates or neonates with significant morbidity like birth asphyxia, major congenital malformations, neurological involvement, proven sepsis and babies whose mothers received general anesthesia during delivery were excluded from the study. Babies with abnormal results of blood glucose and bilirubin requiring exchange transfusion were also excluded from the study. The main aim of the study was to evaluate the analgesic effect of sucrose solution administered to newborns undergoing venepuncture. The study was based on the hypothesis that 2 ml of 30% sucrose solution when administered 2 minutes prior to venepuncture would result in a reduction of DAN score of pain by 2. The primary outcome was the evaluation of pain score using the DAN scale. The secondary outcome was the assessment of the impact of sucrose as an analgesic on crying time, heart rate and on oxygen saturation during venepuncture.

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heart rate and oxygen saturation was recorded. From a pre packed plastic pouch containing 3 gm of sucrose, 30% sucrose solution was then prepared using 10 ml of distilled water available in a disposable plastic ampoule and kept ready in a clean utensil by the newborn’s side. 2.5. Outcome measurement An assessment of the arousal state of the newborn was done by using Prechtl’s observational rating system [5] and recorded in the predesigned proforma with patient’s details. Components of the rating system are presented in Table 1. This was followed by noting physiological parameters stated above from the monitor. The nursing staff assigned to perform the venepuncture was briefed again about the study procedure and asked to randomly select one sealed envelope containing the treatment allocation for the particular neonate. The investigator left the room while the nursing staff carried out the assigned task. A neonate belonging to the study group was fed with the 2 ml of the recently prepared sucrose solution and the utensil used was removed from the procedure table. In those neonates assigned not to receive the treatment (control group), the sucrose solution was discarded. before the investigator came back into the room. After a waiting time lasting for no more than 2 minutes the investigator was called back into the room. The nurse then prepared the infant for the procedure. Venepuncture was performed with a 24-gauge needle or intravenous cannula. Blood was then taken out with gentle squeezing of the neonate’s hand or foot. Other soothing devices like pacifiers were not used for any of the neonates enrolled in the study. The investigator assessed pain felt by the newborn during venepuncture by the Douleur Aigu¨ Nouveaue n´ (DAN) [6] scale. This scale scores pain from 0 to e 10 and a composite score of the three items: facial expression, limb movements, and vocal expression was noted for each newborn (Table 2). The heart rate and oxygen saturation were noted by another doctor or nursing staff from the monitor. The same persons also recorded the duration the neonate cried using a stopwatch while the investigator was recording the response to pain. The heart rate and oxygen saturation was again recorded 10 minute after the procedure. Statistical analysis was performed with SPSS 1.5 software using Pearson Chi-Square and Fisher’s Exact Test

Table 2 Douleur Aigu¨ Nouveau-n´ (DAN) scale for pain assessment e e Score Facial expressions Calm 0 Snivels and alternates gentle eye opening and closing 1 Determine intensity of one or more of eye squeeze, brow bulge, nasolabial furrow Mild, intermittent with return to calm 2 Moderate 3 Very pronounced, continuous 4 Limb movements Calm or gentle movements 0 Determine intensity of one or more of the following signs: pedals, toes spread, legs tensed and pulled up, agitation of arms, withdrawal reaction Mild, intermittent with return to calm 1 Moderate 2 Very pronounced, continuous 3 Vocal expression 0 No complaints Moans briefly 1 Intermittent crying 2 Long-lasting crying, continuous howl 3

3. Results From February to August 2006, 50 neonates were studied in two equal sized groups. All parents of the eligible neonates gave consent for their infants to participate in the study. There were no withdrawals. The two groups were comparable in various perinatal characteristics like age of newborns at time of intervention, birth weight, sex distribution, type of delivery, duration of venepuncture and method used for venepuncture between intervention and control groups. Arousal state as measured by Prechtl’s observation rating before venepuncture in the two study groups was also comparable (Table 3). The pain score as measured by median DAN (interquartile) scale in the control and intervention group were 7 (5–9.5) and 3 (1.5–5.5) respectively reflecting that use of sucrose decreased the pain significantly (p value = 0.0001). (Fig. 1) Out of 25 babies in each group, 13 (52%) babies receiving sucrose did not cry at all during the entire procedure compared to 4 (16%) babies in the control group (p value = 0.001). Though less number of babies cried in the group receiving sucrose, the mean duration of cry among babies who cried was not significantly different in two groups (Table 4). In the group not receiving sucrose (control group), there was a significant increase in heart rate during the procedure (p = 0.008) followed by significant decrease after the procedure (p = 0.001) (Fig. 2A) whereas in the

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S. Basnet et al. / Sucrose as an analgesic in relieving procedural pain in neonates Table 3 Perinatal characteristics and procedures related variables in two groups Age at intervention (hours) Mean birth weight in (kg ) Number of female/male Mode of delivery (NVD/C.S) Method of venepuncture (needle/cannula) Mean duration of procedure (seconds) Median arousal state (range) *Data are expressed as mean ± SD. No sucrose 59.92 3.16 ± 0.54* 8/17 15/10 18/7 114 ± 62.47* 1 (1–5) sucrose 68.76 3.14 ± 0.37* 8/17 17/8 20/5 100 ± 63.1* 1 (1–5)

Fig. 1. Comparison of pain score (DAN score) between the intervention and control groups. Table 4 Comparison of duration of cry between two groups No sucrose Sucrose Duration of cry (Seconds) 115 ± 99.5 98.5 ± 98.6 p value 0.65

*Data are expressed as mean ± SD.

group receiving sucrose(intervention), change in heart rate was not significant (p = 0.39 and 0.41 respectively) There was a significant decrease in oxygen saturation during the procedure in control. (p = 0.001). The drop in the oxygen saturation was not significant in the group getting sucrose (p = 0.3). (Fig. 2B) 4. Discussion Venipuncture is a common procedure and is recognized to cause pain in patients able to report it. For neonates who cannot report the pain during the painful procedures like venepuncture, the assessment of pain is difficult.

Procedural pain assessment has been done by different validated pain assessment scales in various studies [4,6–16]. DAN score was used in few studies [4, 6,15,16]. All these studies concluded that neonates do feel pain and behavioral assessment of neonates during painful procedures helps to quantify the pain. Present study also supports the finding of above studies. In the present study, it was found that during venepuncture in newborns the analgesic effects of 30% sucrose is large enough to be clinically significant and can thus be detected by a behavioral rating scale (DAN) for acute pain. The median pain score was 7 & 3 for the control and intervention group respectively and it was statistically significant (p value = 0.0001). Similar results were observed in the study done by R. Carbajal [4] who found median (inter-quartile) pain scores during venepuncture were 7 (5–10) for no treatment; 5 (2–8) for 30% sucrose; and 1 (1–2) for 30% sucrose plus pacifier. p values for comparisons of 30% sucrose and 30% sucrose plus pacifier versus placebo (sterile water) were 0.01 and < 0.0001, respectively. The possible

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)

*

Fig. 2. Comparison of hemodynamic changes between the intervention and control groups. Panel A-Heart rate, Panel B-Oxygen saturation. Date are expressed in mean ± SEM. ∆ During = changes from baseline to during the procedure, ∆ After = changes from baseline to after the conclusion of the procedure.

reason for less significant effect of sucrose observed by R Carbajal compared to that observed in the present study is probably due to the synergistic analgesic effect of sucrose and pacifiers was also determined in R Carbajal’s study. Although the observer was blinded to the type of solution administered, blinding to the administration of a pacifier to newborns was not possible so there was possibility of potential bias as pain evaluation was based on a behavioural scale. Another study done by R. Carbajal [15] in preterm

neonates in which each infant received 2 treatments in a crossover manner during 2 consecutive subcutaneous injections of erythropoietin. He compared oral 30% glucose (0.3 ml) versus placebo (0.3 ml of sterile water) and he found that median (inter-quartile) pain scores for placebo and 30% glucose was 7 (2.5–9.75) and 4.5 (1–6) respectively, which was statistically significant (p = 0.03). He has shown less analgesic effect of sweet solution compared to the present study. This difference might have been due to the fact that in his study preterm

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S. Basnet et al. / Sucrose as an analgesic in relieving procedural pain in neonates

infants were included and glucose was used instead of sucrose. Cochrane Database of Systematic Review [3] 2010 on sucrose concluded that sucrose is safe and effective for reducing procedural pain from single events. Studies done by F. L. Porter [17], A. M. Taksande [18] and N. Mcintosh [19] that evaluated physiological changes occurring during painful procedures had shown that tachycardia and drop in oxygen saturation occurs during painful procedures. In the present study, there was significant increase in heart rate during the procedure (p value = 0.008) followed by significant decrease in the heart rate following procedure (p value = 0.001) and statistically significant fall in oxygen saturation during the procedure, followed by significant increase after the procedure (p value = 0.001) in the control group. However, these physiological changes were not significantly changed with use of sucrose. In the study done by J. Grabska [20], infants receiving sucrose (placebo) had a small but significant reduction in O2 saturation after dosing, which persisted during the exam of eye for retinopathy of prematurity but returned to baseline by 2 minutes postexam (p < 0.05) which support our finding. However, there has not been any study about the effect of sucrose on the heart rate and oxygen saturation during venepuncture. In the present study, out of 25 babies in each group, 13 (52%) babies receiving sucrose did not cried at all during the procedure compared to 4 (16%) babies in the control group which was statistically significantly (p value = 0.001). This finding is comparable to the finding of the study done by K. Bauer [21] who found that fifty percent of the neonates in the 2 mL glucose group did not cry at all in the first 5 min after venepuncture compared with only 10% in the control group. Among babies who cried, the median duration of cry in the control group was 100 seconds whereas in the control group, it was 80 seconds. Though significantly less number of babies receiving sucrose cried during the procedure, the mean duration of cry among babies who cried was not statistically significantly less compared to babies who did not received sucrose. Fifty percent of the neonates in the 2 mL glucose group did not cry at all in the first 5 min after venepuncture compared with only 10% in the control group. This finding support the similar observation by N. Hauri [22] who studied the effect of different concentration of sucrose in crying time of term neonates during heel prick and she found that median (interquartile) total duration of cry in seconds were 81 (12–150) , 45 (14–88) and 135 (100–155) with 25% sucrose, 50% sucrose and con-

trol respectively. There was a significant trend towards a reduction in crying time with greater concentrations (50%) of sucrose (P = 0.007) but the total duration cry was not reduced with the concentration lower than 50%. Compared to the above study, the duration of cry was shorter in the present study probably because the painful procedure in the present study was venepuncture whereas in study done by Nora Hauri, it was heel prick. The study done by A. B. Larson [7] has shown that venipuncture is more effective and less painful than heel lancing for blood tests in neonates.

5. Conclusion Sucrose has clinically significant analgesic effect which can be detected by behavioral rating scale for acute pain (DAN). Less number of babies cries when they are given sucrose during venepuncture. Sucrose also prevents significant alteration heart rate and prevent drop in oxygen saturation during venepuncture. Thus, sucrose could be simple, efficient and economical alternative analgesic for minor procedure in developing countries.

Acknowledgement We thank the staff of the neonatal unit for their help conducting this study. We also thank the institutional review board for approving this study. We would like to thank Mrs. Shova Basnet from S.R Drug laboratory for providing us sucrose and Dr. Sudha Basnet for helping us write this article. Last but not least, we would like to thank all the parents of the neonates who were involved in this study.

Financial disclosure The authors do not have any financial interest to disclose.

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