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Newborns are subject to pain during routine invasive procedures. Pain caused by immunization injections is preventable, but remains untreated in neonates.
The purpose of the study was to compare the effectiveness of three nonpharmacological pain relief strategies on newborns’ pain, physiological parameters, and cry duration before, during, and after hepatitis B intramuscular (IM) injection.
In this prospective, randomized clinical trial, we enrolled 165 newborns (gestational age, ≥36 weeks). The infants received IM injections and were randomized to three treatment groups: nonnutritive sucking (NNS), 20% oral sucrose, or routine care. Pain was measured by the Neonatal Facial Coding System, physiological signals by electrocardiogram monitors, and cry duration using a stopwatch.
Pain was significantly lower among infants in the NNS (B=−11.27, P<0.001) and sucrose (B=−11.75, P<0.001) groups than that in controls after adjusting for time effects, infant sleep/wake state, number of prior painful experiences, and baseline pain scores. Infants in the NNS and sucrose groups also had significantly lower mean heart and respiratory rates than the controls. Cry duration of infants receiving sucrose was significantly shorter than those in the NNS (Z=−3.36, P<0.001) and control groups (Z=−7.80, P<0.001).
NNS and oral sucrose can provide analgesic effects and need to be given before painful procedures as brief as a one-minute IM injection. Sucrose orally administered two minutes before injection more effectively reduced newborns’ pain during injection than NNS. Both nonpharmacological methods more effectively relieved newborns’ pain, stabilized physiological parameters, and shortened cry duration during IM hepatitis injection than routine care.
To promote newborns’ well-being and development, clinicians are obliged to offer them pain relief.
Pain can be managed by pharmacological and nonpharmacological interventions. Using analgesics to relieve short-term procedural pain in newborns is questionable because of these agents’ poor effectiveness and potential side effects.
Nonpharmacological pain relief strategies are not only convenient, inexpensive, and can be used without prescriptions, but also are well tolerated by infants. Procedural pain in newborns has been relieved by nonpharmacological interventions, such as nonnutritive sucking (NNS),
Most of these studies examined effects on pain caused by heel sticks, venipuncture, eye examination, and circumcision. Only two studies have examined the effects of oral sucrose and kangaroo care on newborn pain during intramuscular (IM) injection.
Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).
Thus, promoting infant health requires considering and treating the pain caused by injecting hepatitis B vaccine soon after birth. Neonatal clinicians also need to consider which strategies better relieve pain caused by routine injections.
Among nonpharmacological pain relief strategies for newborns, the most appropriate for use during thigh IM injections are NNS and oral sucrose because they do not impede the procedures. NNS is hypothesized to produce analgesia by stimulating orotactile and mechanoreceptors in the mouth, thus modulating transmission or processing of nociception by the endogenous nonopioid system.
Thus, it remains unknown whether NNS or sucrose can effectively relieve newborn pain caused by IM injection of hepatitis B vaccine around 48 hours after birth and which pain relief strategy better relieves pain.
To address these gaps in knowledge, this study offered newborns receiving their first IM injection for hepatitis B three nonpharmacological pain relief strategies: routine care measures, NNS, or sucrose. The purpose of the study was to compare the efficacy of these three strategies on newborns’ pain, physiological parameters, and cry duration, before, during, and after their first IM injection of hepatitis B vaccine. We hypothesized that pain caused by IM injection would be better managed in infants receiving NNS and sucrose than in those receiving routine care. We also hypothesized that sucrose would be more effective than NNS in relieving newborns’ pain, stabilizing physiological parameters, and in reducing cry duration during injection procedures.
Infants were recruited by convenience sampling from the neonatal nursery at a medical center in Taipei, Taiwan. Healthy newborns were included if they met these criteria: 1) gestational age (GA) greater than or equal to 36 weeks; 2) birth weight greater than or equal to 2200 g; 3) Apgar score greater than or equal to 7 at the first and fifth minute after birth; 4) underwent IM injection for hepatitis B; and 5) mothers healthy without substance abuse. Newborns were excluded by these criteria: 1) congenital anomalies; 2) neurological impairment; 3) documented congenital or nosocomial sepsis; 4) surgery; 5) substance-abusing mother; 6) had been administered sedatives, analgesics, or naloxone; and 7) no need for injection against hepatitis B. Parents of infants who met the study criteria received a pamphlet that briefly introduced the study. Interested parents returned the response sheet to the research nurse, who then explained the study in more detail and obtained parental consent. This study was approved by the study site's institutional review board.
Of 220 newborn infants screened for participation from 2007 to 2008, 193 infants met the study criteria (Fig. 1). Twenty-eight parents refused participation because they did not want their infants to be filmed during data collection, leaving 165 newborn infants who received IM injection. Infants who did and did not participate in the study were not significantly different in terms of sex, GA, age (days since birth), and birth weight. The sample size was sufficient to power the study, based on estimates using G∗Power (Heinrich Heine University, Dussëldorf, Germany).
The effect size of outcome variables, according to differences in means and standard deviations (SDs) of pain scores within each study group, was 0.54. For this effect size, 98.95% actual power, and a significance level of 0.05, a sample of 55 newborn infants was required. Each infant enrolled in the study was randomly assigned to one of three pain relief methods by a statistician blind to the study purpose and using random allocation software.
The software generated a permutated three-block randomization list, which was used to assign each qualified subject to one of the three pain relief measures.
A randomized clinical trial was used to compare the efficacy of NNS, oral sucrose, and routine care on newborn infant pain, physiological parameters (heart rate [HR] and respiratory rate [RR]), and cry duration associated with IM injection.
Pain Relief Interventions
All newborn infants were placed in a side-lying position. The injection procedures included nine steps: 1) prepare the materials needed and select the site for injection; 2) stabilize the infant’s leg; 3) cleanse the injection site with alcohol cotton balls; 4) pinch up the infant’s muscle between the thumb and forefinger; 5) insert the needle into the vastus lateralis at a 90° angle; 6) release the muscle and gently withdraw the syringe plunger; 7) if no blood is aspirated in Step 6, inject the hepatitis vaccine; 8) after injection, quickly withdraw the needle; and 9) press the site with gauze and cover with an adhesive bandage.
During injection procedures, infants in the routine care group (control group) received gentle touch and verbal comfort, whereas infants in the experimental group received NNS or sucrose two minutes before the injection procedures. Infants in the NNS group (one experimental group) were given a standard silicone newborn pacifier manufactured with natural scent (Super Soothie, Natural Scent; Philips Children’s Medical Ventures, Monroeville, PA) to stimulate sucking two minutes before touching the thigh to initiate the injection procedures. Infants in the sucrose group (the other experimental group) were fed 2 mL of 20% sucrose through a syringe two minutes before the injection procedures.
Outcome variables included newborn infants’ pain, physiological responses (HR and RR), and cry duration.
Procedural pain, the major outcome, was assessed by a research assistant (RA) trained to use the Neonatal Facial Coding System (NFCS), which has been successfully used with preterm and full-term infants between 25- and 42-week GAs.
The NFCS scores the presence (1) or absence (0) of 10 discrete facial expressions: brow bulge, eye squeeze, nasolabial furrow, open lips, vertical mouth stretch, horizontal mouth stretch, lip purse, taut tongue, tongue protrusion, and chin quiver. Because infants receiving NNS had a pacifier in their mouths, it was difficult to observe the actions of their lips, mouth, and tongue. Thus, measurement of facial expressions focused only on actions that could be clearly and consistently observed in all infants, that is, brow bulge, eye squeeze, nasolabial furrow, and chin quiver. Facial actions were measured by time-triggered coding. Infants’ facial actions were coded at 10-second intervals during the baseline, IM injection, and recovery phases by the blinded RA, who typed the facial codes in Word files. Each code was scored and summed for every minute of each injection phase (see Data Collection).
Each facial action is scored from 0 to 2 (0=face relaxed; 1=slight facial actions; 2=intense/continuous facial actions).
For each 10-second interval, the possible score is 0–8; scores are then summed over one minute for a total possible score of 0–48. A higher total score indicates more intense pain. To ensure fidelity of behavioral measurements, videotapes were coded in random order. All infant facial actions on the videotapes were coded and scored in a quiet room to maintain consistency and accuracy of data analysis. The NFCS interrater reliability (between the RA and first author [J.- J. L.]) was 0.88–0.92, and the intrarater reliability was 0.93–0.96.
HR and RR were continuously monitored (HP M1166A Monitor; Hewlett-Packard, Palo Alto, CA) and recorded by custom software. Electrocardiogram (ECG) monitors were regularly calibrated by certified technicians, and computer function was checked before data collection. HR and RR were recorded from ECG leads attached to the infant’s chest and digitally sampled at 15-second intervals by computer. The mean HR and RR values were calculated and compared among the control, NNS, and sucrose groups across the seven phases of the injection procedures (see Data Collection).
The RA who was trained to code infants’ facial expressions watched the video of each injection a second time and measured the infant’s cry duration in seconds using a stopwatch. The interrater reliability for measuring cry duration (between the RA and J.- J. L.) was 96% for a random sample of 33 newborns.
Data were collected on newborn infants’ pain, HR, RR, and cry duration (see Measures for details). Data collection procedures were based on the first author’s preliminary observations that newborns who received IM injections in the nursery took almost five minutes to completely recover from pain. Therefore, all data were collected for five minutes without stimuli (mean baseline, T1); during injection procedures (T2); and after injection procedures (five minutes of recovery starting from when the nurse finished the IM injection and lifted her hands). Pain scores, HR, and RR were measured every minute during baseline (T1) and injection procedures (T2), and during recovery at the first (T3), second (T4), third (T5), fourth (T6), and fifth (T7) minutes. The duration of crying was measured in seconds from the video recording using a stopwatch from the start of the injection procedures to the fifth minute of recovery.
Data were collected by two trained RAs. One RA, who was informed about the research purpose and plans, was trained to select participants and collect infants’ background data and prior painful experiences by reviewing medical and nursing charts. A painful experience was defined as an invasive, tissue-damaging cutaneous procedure, including heel stick, intravenous or arterial line insertion, and IM injection in this study. The other RA, blinded to the study purpose and the infants’ clinical information and intervention group, was trained to code facial actions, to score pain using the NFCS (see Measures), and to measure cry duration.
Two neonatal research nurses also were trained to conduct experimental procedures on newborns. The senior research nurse was trained to skillfully follow the nursery’s standard procedures for IM injections of hepatitis vaccine. The IM injection procedures were controlled to be administered within one minute in all newborns of the three groups. The other research nurse was trained to adeptly offer NNS or oral sucrose to infants in the experimental groups before the IM injection procedures. All personnel were trained separately by J.- J. L.
Study fidelity was established by weekly meetings between the authors and senior research nurse to review the exact procedures and discuss any problems. The other research nurse worked regularly with one author (T. Y.) to confirm that NNS and sucrose oral administration were consistently provided to each newborn and to discuss any problems. As described earlier, infants were placed in a side-lying position, with the video camera (Sony DCR-DV42, Sony Taiwan Limited) lens focused on the infant’s entire face to record facial actions. Facial actions and cry duration were recorded using a real-time color video recorder. Video signals were directly transmitted to a computer, and a time code was recorded and entered into videotapes by software (Ulead Videostudio, Tapei, Taiwan).
Data were analyzed using SPSS for Windows, Version 15.0.0 (IBM SPSS Inc., Ardsley, NY). Background data of infants in the three groups (routine care, NNS, and sucrose) were compared by nonparametric Kruskal-Wallis tests. Data were described using means (SDs) for continuous variables and frequencies for categorical variables. NFCS pain scores, HR, and RR of infants in the three groups were compared by the generalized estimating equation method’s generalized linear models.
number of prior pain experiences, phase of the injection procedure, and lag time to prior pain exposure or feeding (breast or bottle), were not significantly related to infants’ pain responses. Cry durations among the three groups were compared by Kruskal-Wallis tests and Mann-Whitney U tests. NFCS inter- and intrarater reliabilities were measured by intraclass correlation coefficients. P-values less than 0.05 were considered statistically significant.
The study participants were 28 male and 27 female newborn infants in each of the three groups (n=55), for a total sample of 165. Infants’ basic characteristics did not differ significantly among the three groups (Table 1).
Table 1Characteristics of Newborn Infants in Control, Nonnutritive Sucking, and Sucrose Groups (n=165)
Infants in the NNS and sucrose groups had significantly lower NFCS pain scores (B=−11.27, P<0.001 and B=−11.75, P<0.001, respectively) than controls after adjusting for the effects of time, infant sleep/wake state before injection, number of prior painful experiences, and baseline NFCS pain scores (Table 2). The NFCS pain scores of infants receiving NNS and sucrose were significantly lower than those of infants in the control group at all seven phases of IM injection procedures (Fig. 2). Infants’ pain scores increased during and in the first minute after IM injection procedures and significantly decreased afterward (Table 2). The pain scores in newborn infants were significantly related to their sleep/wake state before injection and baseline pain score. Infants’ facial expressions of pain during injection procedures were not significantly influenced by the number of prior painful experiences.
Table 2Changes in NFCS Pain Scores of Control, Nonnutritive Sucking, and Sucrose Groups, Predicted by Generalized Estimating Equation Method Multiple Regression Model (n=165)
Infants in the NNS and sucrose groups had significantly lower mean HR (B=−13.28, P<0.001 and B=−17.01, P<0.001, respectively) than those in the control group after adjusting for the effects of time, infant sleep/wake state before injection, number of prior painful experiences, and baseline HR (Table 3). Infants’ mean HR significantly increased over time during the IM injection procedures and gradually decreased thereafter. The infants’ mean HR was significantly related to their state before injection except the state of fussing or crying. Furthermore, infants’ mean HR was only significantly influenced by the number of prior painful experiences when they had experienced six painful events (B=−14.84, P<0.001).
Table 3Changes in Heart Rates of Control, Nonnutritive Sucking, and Sucrose Groups, Predicted by Generalized Estimating Equation Method Multiple Regression Model (n=165)
Infants in the NNS and sucrose groups had a significantly lower RR (B=−2.76, P=0.005 and B=−3.47, P<0.001, respectively) than those of the control group after adjusting for the effects of time, infant sleep/wake state before injection, number of prior painful experiences, and baseline RR (Table 4). Infants’ mean RR significantly increased during the IM injection procedures and decreased thereafter, but not significantly. Infants’ mean RR was not significantly related to their state before injection and number of prior painful experiences.
Table 4Changes in Respiratory Rates of Control, Nonnutritive Sucking, and Sucrose Groups, Predicted by Generalized Estimating Equation Method Multiple Regression Model (n=165)
The average cry duration in the three groups was shown by Kruskal-Wallis test to be significantly different (χ2=79.22, P<0.001). Multiple comparisons showed that the cry durations of the infants in the NNS and sucrose groups were significantly shorter (Z=−66.8, P<0.001 and Z=−7.80, P<0.001, respectively) than the cry durations of the infants in the control group (Table 5). The cry duration of infants receiving sucrose was significantly shorter (Z=−3.36, P<0.001) than the cry duration of infants in the NNS group.
Table 5Comparison of Cry Duration During and After Immunization Injection in Control, Nonnutritive Sucking, and Sucrose Groups (n=165)
Our study demonstrated that both NNS and sucrose are effective pain management methods during IM injection of hepatitis B vaccine. These findings support our hypothesis that pain because of IM injection would be relieved better in infants receiving NNS and sucrose than in those receiving routine care. Indeed, we found that oral sucrose and NNS reduced newborns’ pain scores, HR, RR, and cry duration during IM hepatitis injection. In contrast, sucrose was previously reported to be ineffective in reducing pain during IM vitamin K injection in the first hour after birth.
For newborns younger than one day, NNS is the best choice to relieve pain. Others have reported that sucrose can reduce pain associated with immunization beyond the neonatal period, that is, in two- to six-month-old infants.
However, the use of oral sucrose to relieve pain is still controversial in some infants. For example, preterm infants who received more than 10 doses of sucrose over 24 hours were found to be at risk of poorer neurodevelopmental scores than infants who received less than 10 doses in 24 hours.
These findings indicate the need to avoid overuse of sucrose in preterm infants and guide clinicians to avoid the complications of using sucrose by alternating its use with NNS in infants who have received more than 10 painful procedures.
In this study, sucrose was more efficacious than NNS in relieving pain during IM hepatitis injection, in contrast to previous reports that NNS relieves procedural pain better than sucrose.
These different results might be because of the different types of stimuli, sucrose concentrations, ways of administering sucrose, and infants’ GAs. Another reason for the different findings might be the pain measurement used. Most previous studies have measured infant pain using the Premature Infant Pain Profile,
Choosing NNS or sucrose to relieve procedural pain depends on the infant’s condition, the type of pain, clinical situation, and availability of materials. Although using multiple doses of sucrose or repeated use of NNS has not been found to lead to any adverse events, such as hyperglycemia,
great care must still be taken in using oral sucrose and NNS, especially in newborns of diabetic mothers, with necrotizing enterocolitis, gastrointestinal disorders, or after surgery. Furthermore, for extremely painful procedures, such as eye examination or circumcision, NNS or sucrose may need to be combined with a pharmacological strategy. For infants receiving suctioning, clinicians can provide facilitated tucking. In addition, some investigators have reported that combining sucrose with NNS has an additive analgesic effect
Our findings that NNS and sucrose significantly stabilized newborns’ HR and RR are comparable with reports that the HR of newborns receiving NNS, sucrose, facilitated tucking, swaddling, or kangaroo care increased less than that of infants not receiving such interventions during painful procedures.
During IM hepatitis injection in our study, newborns’ HR and RR decreased and returned to baseline when they received sucrose and NNS compared with those of routine care, in contrast to a report that newborns’ HR was not affected by NNS during circumcision.
Pain-related crying in newborns increases HR, blood pressure, and diaphragmatic splinting that might lead to greater blood volume and lower vagal tone, possibly resulting in intraventricular hemorrhage in fragile and immature infants.
Such neurological impairment in newborns can be avoided during invasive painful procedures by using sucrose and NNS.
Considering the consequences of pain in newborns, pain relief should be offered for all painful procedures. NNS and oral sucrose must be given before painful procedures begin, even a one-minute IM injection. In general, neonatal clinicians need to become familiar with the mechanisms of the nonpharmacological pain-relief strategies and the methods for administering them, and should wisely select the one that is available and appropriate for the infant and the clinical situation or combine the appropriate strategies to enhance their analgesic effects.
Our findings suggest that newborns who had received six painful stimuli before the IM injection had significantly lower HR than those with fewer prior pain experiences. In contrast, newborns repeatedly exposed to pain were found to develop hyperalgesia and lower thresholds to pain.
These different findings might be the result of the different numbers of newborns’ prior painful experiences and the observational contexts of the two studies. In our study, infants’ facial responses to pain and HR were also significantly influenced by their sleep/wake state before IM injections. Regardless of whether the infants were asleep or awake, they perceived pain as indicated by significant increases in NFCS pain scores and HR.
Furthermore, the study time effects suggest that newborns’ HR and RR significantly increased during hepatitis injection, but NFCS pain scores did not increase significantly. This lack of effect on pain scores might be explained by newborn infants having insufficient time to express facial responses to pain during the very short IM injection. Although grimace is a very sensitive pain indicator, it is not the only one. Thus, infant pain should be assessed by multiple pain dimensions, such as HR, RR, and cry duration.
Despite the contributions of this study, it had some limitations. Infant behavioral responses to injection procedures varied greatly at each observation. Infant facial responses to pain as well as physiological responses and cry duration might have been influenced by multiple confounding factors, such as infant hunger or discomfort, temperament, sleep/wake state, and prior painful experiences. Although some of these variables were controlled in our analyses, future studies should consider these factors in selecting newborns and in data analysis. Although outcome assessors and interveners were different, they could not be completely blind to all research processes because they could clearly distinguish among routine care, NNS, and oral sucrose administration. The effects of NNS and sucrose were examined separately during injection procedures. Thus, we do not know whether the combination of NNS and sucrose can additively relieve pain in painful procedures. This study selected only the four items of the NFCS that could be observed clearly and consistently. These items might not capture the full expression of neonatal pain. Future studies should include more pain indicators. The outcome variables of this study focused on pain, cry duration, and physiological changes. Future research should examine the effectiveness of sucrose, NNS, or other nonpharmacological interventions on other outcomes, such as sleep, or neurodevelopmental indicators. The pain relief effectiveness of NNS and sucrose plus other supportive or pharmacological interventions could also be examined during different invasive procedures.
Pain caused by IM injection procedures, as brief as one minute, was lower after administering NNS or 20% oral sucrose than that after routine care. Using NNS and sucrose also enhanced infants’ physiological stability and shortened their cry duration during injections. Furthermore, administering sucrose two minutes before the injection more effectively reduced newborns’ pain during injection than NNS. Clinicians should incorporate NNS and sucrose into caregiving while newborns undergo painful procedures. These study results add to evidence supporting the use of NNS and sucrose for pain relief in newborns during immunization injection.
Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).
The recent study by Liaw et al.1 in the December 2011 issue showed that sucrose effectively reduced pain in newborn infants during a single, short-lasting, painful procedure. This is now the 145th published study of sweet solutions for infants and the 131st study where a placebo or no treatment group has been used (Harrison et al., unpublished data).