The effect of combined non-pharmacological interventions on venous blood sampling pain in preterm infants: a clinical trial study

Abstract

Background

Using non-pharmacological methods to reduce the pain of hospitalized infants is one of the most important priorities in the health of newborns. Pain relief during painful procedures can help prevent unwanted physical and psychological effects. This study was conducted with the aim of investigating the effect of combined non-pharmacological interventions on venous blood sampling pain in preterm infants.

Methods

In this clinical trial study, 88 preterm infants admitted to the Neonatal Intensive Care Unit of Rouhani Hospital was randomly assigned to four groups of sucrose (S), the combined group of sucrose and non-nutritive sucking (NS), the combined group of swaddle and sucrose (SS) and the combined group of sucrose, non-nutritive sucking and swaddling (NSS). In order to collect information, were used the premature Infant Pain Profile Scale (PIPP) and demographic characteristics questionnaire.

Results

This study showed that during blood sampling, the difference in the mean pain score of two groups of S and NS was equal to 3.54 (95% CI = 1.85, 5.24) and in two groups S and NSS was equal to 4.68 (95% CI = 2.99, 6.38), and these differences were significant (P < 0.001). In addition, the mean pain difference in all study groups was significant in two time periods before-during and during-after blood sampling (P < 0.001). Also, the mean pain difference in the two time periods before-during and during-after in NS and NSS groups was significant compared to the control group (sucrose) (P < 0.001).

Conclusions

Based on the results of this study, the use of combined non-pharmacological interventions of NSS has been more effective in reducing the pain caused by venous blood sampling than other conditions where two or one non-pharmacological intervention were used.

Introduction

Infants who need special medical care are often admitted to the neonatal intensive care unit (NICU). Most infants admitted to the NICU are preterm (born before 37 weeks of gestation), or with low birth weight (less than 2500 g), or in a medical condition that requires special care [1].

For preterm Infants, painful procedures are considered part of medical care. Research has shown that almost 7% of infants are admitted to the hospital after birth and face painful procedures. Infants who are hospitalized in NICU, are in contact with these painful procedures for an average of 7.5 to 17.3 days. Almost 70% of medical procedures performed in the NICU are painful [2].

It was believed that infants do not feel pain [3], but now research has shown that this belief is wrong. It can even be said that pain threshold in premature infants is lower compare to term infants and children [4].

According to the studies, many painful procedures are performed without any kind of analgesia by the multidisciplinary team and may contribute to the mid-term and long-term complications for their neurobehavioral and cognitive development [5, 6]. Studies show that there is a gap between the knowledge and practice of health professionals for the management of pain in infants and, in general, the use of analgesic measures is poor or insufficient [7].

Pharmacologic methods are the most common methods used to relief or prevent pain in infants. However, many pain relievers have adverse effects. For example, the use of drugs such as fentanyl has side effects including miosis, pruritus, respiratory depression, constipation, urinary retention, and hypotension [8]. Based on these outcomes, an alternative to drug treatments is needed. Although there are various reasons for using non-pharmacological analgesic methods, these strategies are not widely used. Some of the non-pharmacological analgesic methods are: non-nutritive sucking (NNS), breastfeeding, oral sucrose/glucose solution, skin-to-skin contact care, swaddling, massage therapy and music therapy [9]. Even, some studies have shown that combined non-pharmacological interventions provide better pain relief than single non-pharmacological interventions [7, 10]. On the other hand, other studies also showed that there is no difference between some combined and single non-pharmacological interventions [11, 12], Most of the previous studies were about the effects of single non-pharmacological interventions on pain control in hospitalized infants, and there have been fewer studies on the combined use of non-pharmacological interventions in pain control. In most of these interventions, the effect of using two non-pharmacological intervention methods to reduce pain was assessed, and a study that used three combined intervention methods at the same time was very rarely done. In Iran, no study has been found that simultaneously uses three non-pharmacological methods to control the pain of preterm infants during painful procedures. Also, venous blood sampling is one of the most common [13, 14] and most painful [15] procedures in infants. Because nurses, due to their special position in the care of newborns, should be aware of the research conducted on non-pharmacological methods of pain control and always start pain relief with the use of non-pharmacological methods [16] and considering that swaddling, feeding sucrose and non-nutritive sucking are safe, low-cost and easy methods, this study was conducted to determine the effect of combined non-pharmacological interventions in relieving pain caused by venous blood sampling in preterm infants.

Materials and methods

This clinical trial study was conducted in 2023 on 88 infants hospitalized in the NICU of Rouhani Hospital in Babol (Northern Iran) who met the inclusion criteria after obtaining the permission of the ethics committee with code IR.MUBABOL.REC.1401.167 and informed consent. The initial sampling was done by the convenience method, and then the infants were divided into four groups of 22 oral sucrose (routine care, group S), the combined group of oral sucrose and non-nutritive sucking (NS), the combined group of swaddle and oral sucrose (SS) and the combined group of oral sucrose, non-nutritive sucking and swaddling (NSS) based on random allocation method.

Inclusion criteria in this study included: premature infants with a gestational age of 32 to 36 weeks, Apgar above 7 in 5 min, no receiving anesthetic drugs, no intubation, no painful procedure at least 6 h before blood sampling, sampling should be done when the infant is awake and active and in between feedings. Also, the exclusion criteria include premature infants with congenital problems, infants who had intraventricular hemorrhage more than grade II, not being able to draw blood from the hand, a pacifier or swaddle should be used before oral sucrose, infants who cannot tolerate pacifier, instability of vital signs during blood sampling, candidate for surgery and transfer to another center. The present study was registered in Iran’s clinical trial site under the number IRCT20200913048704N3 on 25.03.2023.

The sample size was determined by the formula of comparing two means, taking into account the confidence level and study power of 95%, the first type error of 5%, the mean and standard deviation of 13.3 ± 1.6 for the control group and 10.1 ± 2.0 for the intervention group, based on the previous study [17], (effect size 1.76), using GPower version 3 software, assuming two-sided, at least 10 samples was required for each group in the first stage. However, due to the fact that we had 4 groups and double comparisons were to be made, the sample size was modified by taking the square root of the number of groups multiplied by the initial sample size, so the number of 20 samples in each group was considered in this study. Taking into account the 10% attrition, 88 sample (22 sample in each group) were determined as the final volume (Fig. 1).

Fig. 1

Selection of the study participants

The initial sampling was in a convenience method, and then the infants were placed in each of the four control groups of sucrose, the combined group of sucrose and non-nutritive sucking, the combined group of sucrose and swaddle, and the combined group of sucrose and non-nutritive sucking and swaddle were based on the random allocation method. The infants under study were not included in the study at the same time, and the placement of the infants in any of the groups could not be predicted. In order to assign the infants of the target group to one of the four study groups (A, B, C and D), block randomization method was used. According to the block randomization protocol (generated by random assignment software), infants were assigned to one of four groups: 1- Sucrose (control) 2- Combination of sucrose and non-nutritive sucking 3- Combination of swaddling and sucrose 4- Combination of non-nutritive sucking, swaddling and sucrose were divided.

In order to concealment the list of random assignment, a special code was assigned to each of the groups, which only the main researcher of the project (supervisor) was aware of it. These codes were written on a piece of paper and placed inside a sealed envelope. A unique code for each person was written on this paper as well as its envelope. All envelopes were placed in a larger box in random order and sealed in the box. At the beginning of sampling, the researcher after checking the criteria for entering the study and obtaining informed consent, as well as registering the patient’s profile in a special form, contacted the statistical consultant and he gave her a special code for each sample for blinding and considering the type of intervention, the study evaluator did not know about the type of intervention. Also, the data was provided to a statistician for statistical analysis in a blind manner and with a group randomization code.

In this study, the primary outcome was “pain intensity during venous blood sampling in preterm infants”, and the secondary outcome was “changes in physiological parameters of preterm infants during and after venous blood sampling”.

Sucrose feeding was done as follows: 0.2 ml/kg of the standard 20% sucrose available in the department was poured into the infant’s mouth 2 min before venous blood sampling with a 1 ml syringe without a needle [7]. Also, the nurse was reminded not to use sucrose, pacifier or other intervention to calm the child beforehand.

Swaddling the neonate was done as follows: the neonate was laid on a triangular cloth on a flat surface without clothes and only with a diaper. At first, one side of the sheet was folded up over the neonate, then the bottom, and finally, the other side was folded up over the neonate. In this method, called Frog Flexible, the neonate is able to move the pelvic joints easily, the arms are bent and placed along the line under the chin, and it is similar to the neonate’s position in the mother’s uterine. Checking the time on a stopwatch, 10 min after the end of swaddling, the neonate’s hand was taken out of the swaddling, and intravenous sampling was performed for all neonates by a nurse who had more than 18 years of experience in the neonatal ward with one insertion of the needle No. 24–24 in the direction of blood flow, and the blood was collected dropwise without using a syringe. After placing a small dressing on the blood collection site, the neonate’s hand was placed in the swaddle again, and the swaddle was maintained for up to 2 min after the blood collection [7].

In this study, a small, short, standard pacifier, made of latex and soft, with the Babyland brand and for babies from 0 to 6 months (code 383), was used 2 min before the venous blood sampling.

Blood sampling was part of the diagnostic and treatment process of the infant and no additional invasive intervention was performed. From the moment of blood sampling to 2 min after that, the infant’s face was filmed in a closed view by a camera, by a trained research assistant. Physiological parameters of heart rate and arterial blood oxygen saturation were measured using a cardiorespiratory monitoring device. These parameters were measured and recorded 2 min before, during and after blood sampling (within 30 s). Then the videos were coded. The interpretation of the film and scoring was done by two trained research assistants (nurses working in the NICU with at least one year of work experience) who were not aware of groupings and statistical analysis [7, 10].

The data collection tools include: demographic profile questionnaire and PIPP. The demographic characteristics questionnaire included questions to check the demographic characteristics of the infant such as the infant’s gestational age, sex, weight, age after birth, hospitalization date, disease diagnosis, mother’s type of delivery, etc., which was completed by the researcher before taking blood from each infant. Infant pain was assessed using PIPP, which has a score between 0 and 21. This tool is generally used to assess pain from heel lancets and venous or arterial punctures and to assess pain after surgery. This tool contains Seven four-choice items include heart rate, oxygen saturation, brow bulge, eyes squeeze, and the nasolabial furrow are taken into consideration together with gestational age and behavioral state that are used for both groups of term and preterm infants. Each item includes scores from 0 to 3. As a result, the total score of the tool is 0–21 (minimum score = 0, maximum score = 21). A score of 0–6 indicates minimal pain or no pain. A score of 7–12 indicates mild to moderate pain that requires non-pharmacological interventions, and scores above 12 indicate moderate to severe pain that requires pharmacological intervention and providing comfort. The validity and reliability of this tool has been shown in many studies and it has a favorable validity and reliability of 0.96 − 0.93 [18, 19].

To check the desired results in the groups, in order to check the relationship between a quantitative variable in two dependent situations, the Paired Samples T Test was used and in the two independent situations, the Independent Samples T Test was used. Also, in order to check the relationship between two qualitative variables, the chi-square test was used, and if the conditions of the chi-square test were not met, the Fisher’s exact test was used. One Way ANOVA and proportional post hoc tests were used to compare the equality of means in the categories of qualitative variables. Repeated Measures ANOVA test was used to compare the mean of a quantitative variable in more than two dependent situations. Also, mean difference and 95% confidence interval as effect size was reported in all analyses. All analyzes were done by SPSS software version 20. A significant level was considered for all analyzes (P < 0.05).

Results

In the present study, 88 infants were examined in 4 groups, and there was no significant difference in terms of demographic and clinical characteristics in the study groups. (p > 0.05) (Table 1).

Table 1 Demographic and clinical characteristics of premature infants by groups

The findings of the study showed that the mean difference between the two groups of S and NS during the intervention was 3.54 (95% CI: 1.85, 5.24), which was significant (P ≤ 0.001). During the intervention, the mean difference between the S group and the NSS group was 4.68 (95% CI: 2.99, 6.38), which was significant (P ≤ 0.001). But after the intervention, the Pain score difference in two groups of S and SS was equal to -0.182 (95% CI: -1.03, 0.66), and this difference was not significant (P = 0.943). Also, after the intervention, the Pain score difference in two groups of S and NS and two groups of S and NSS was not significant (P = 0.498) (Table 2).

Table 2 Mean and difference of mean pain score in three intervention and control groups in three time periods investigated in the study

The findings of this study showed that the average pain score difference in the four study groups was significant in the before-during and during-after periods (P ≤ 0.001) (Table 3).

Table 3 Examining the difference in mean pain score in three different time periods in the intervention and control groups

Based on the obtained results, mean pain score in the before-during time period in the four investigated groups was significantly different (P ≤ 0.001). But in the before-after period, the mean difference between the four groups was not statistically significant (P = 0.278). The mean difference in the time period during-after in groups was significant (P ≤ 0.001) (Table 4).

Table 4 Comparison of the average pain score difference in three time periods of each of the intervention groups with the control group

Fig. 2

Mean pain score in the intervention and control groups in the three time periods examined in the study

Figure 2 shows the increase in pain score during the intervention compared to before and after the intervention in the intervention groups compared to the control group.

The results showed that the percentage of blood oxygen saturation during venous blood sampling compared to the other two times (before and after blood sampling) is lower, so that the percentage of oxygen saturation in the SS group was the lowest, but in the NS group and then the NSS was higher than other groups. The results showed that the heart rate during blood sampling was higher than the other two times, so that it was the highest in the SS group, and it was lower in the NS group than the rest of the groups.

Discussion

The results of the present study showed that the pain during venous blood sampling was greater than the other two times before and after venous blood sampling, and in the four investigated groups, the combined group of NSS showed less pain than the other groups. In the study of Thakkar et al., the results showed that the combined intervention of sucrose and non-nutritive sucking was more effective in producing analgesia in term infants undergoing heel-stick procedures. The group that received the combined intervention had a significant decrease in the average pain score compared to the other groups that received the intervention alone or did not receive any intervention [20]. The results of a systematic review by Shayani et al. showed that mostly single non-pharmacological interventions were used to control pain in newborns. These interventions included massage, swaddling or wrapping, gentle touch and kinesthetic stimulation, and the combined non-pharmacological interventions were non-nutritive sucking and swaddling, oral sucrose and swaddling, sensory stimulation and familiar odors, and sensory saturation. They concluded that combined non-pharmacological techniques lead to better outcomes in neonatal pain control compared to single non-pharmacological techniques and they recommended the use of these interventions as a simple, safe and economical method. In addition, such supportive treatments that provide stress and pain control for premature and full-term infants help neuro-psychomotor development [21]. Also, in another study, the use of combined non-pharmacological interventions such as sweet tasting solutions, swaddling, non-nutritive sucking, breastfeeding and skin-to skin care, during painful procedures in infants is recommended to reduce pain [22].

The results of Shen et al.‘s study showed that interventions such as facilitated tucking, kangaroo care, sweet solutions, familiar odour or combined non-pharmacological interventions, such as a combination of sucrose and non-nutritive sucking, were effective and safe in reducing pain from medical procedures in neonates, however, the use of sucrose alone has been less effective in reducing pain during medical procedures [23].

Other studies have shown that the use of facilitated tucking interventions, skin-to-skin care or sucrose (20–33%) was more effective in reducing pain caused by heel-stick compared to usual care [24,25,26]. Also, the use of sucrose (24–30%) has been effective in reducing pain during venipuncture, retinopathy of prematurity examination and intramuscular injection [26]. The facilitated tucking position can lead to a significant reduction of pain during endotracheal suction [24], while the use of sucrose 24% showed benefits in improving pain scores during gastric tube insertion, bladder catheterization, and echocardiography [26]. Combined non-pharmacological interventions such as sucrose combined with non-nutritive sucking or combined with swaddling were more beneficial than the methods used alone [27, 28].

In the study of Youssef et al., the results showed that although the use of oral sucrose or pacifier alone reduces pain in preterm infants during painful procedures, the combined use of pacifier and oral sucrose leads to greater improvement in the reduction of pain [29]. In general, sucrose with a concentration of 24–25% has an analgesic effect on the infant, and its mechanism of action involves the activation of the endogenous opioid system through taste, which acts as an opioid analgesic [30]. Also, among the ways to relieve pain, we can mention 1-distraction of thought (by sleeping) 2-warming, 3-touching (stimulating the sense of touch) and since the swaddling has multidimensional effects and by stimulating the sense of touch, warming and distraction improves the child’s sleep, may control pain optimally [31]. Also, the non-nutritive sucking activates the tactile receptors and reduces pain through gait control mechanism of inhibition of pain. As both sucrose and non-nutritive sucking are supposed to act through both the pathways, they are supposed to reduce the pain more than the individual intervention [20]. Therefore, the combined use of these interventions during blood sampling can intensify the analgesic and sedative effects. One of the advantages of the interventions used in the present study is that parents and health care givers can easily learn and implement them. They can also be used for infants who are unable to transfer from the incubator or bed. In general, according to the findings of the present study and other studies, the results of this study can be interpreted as follows, since the palliative effects of the combined interventions of using sucrose, swaddling and non-nutritive sucking are more than using them alone, and considering since the use of these interventions is a convenient and cost-free care method, it is recommended to use these interventions at the simultaneous to make preterm infants more comfortable during painful procedures. In addition, this issue is especially important for parents and families of preterm infants who experience a lot of pressure and stress and want to have a better treatment experience for their infant.

The results of this study showed that the percentage of blood oxygen saturation during venous blood sampling intervention was lower than the other two times before and after blood sampling. The percentage of oxygen saturation was lower in the SS group, but in the combined NS group and then the combined intervention of NSS was higher than other groups. Therefore, in the NS group, the percentage of oxygen saturation during blood sampling was higher than in other groups. This helps to improve the respiratory condition of infants and reduce the risks associated with respiratory failure. This result will help clinicians and treatment teams to consider ways to improve the care of preterm infants and promote their health. In another study, it was observed that the use of non-nutritive sucking in neonates under the Nasal Continuous Positive Airway Pressure (CPAP) can significantly improve oxygenation [32]. But in another study, it was shown that oral stimulation is effective in improving the feeding skills of preterm infants and has no positive effect on parameters such as breathing rate, oxygen saturation percentage, and weight [33].

This study showed that the heart rate during blood sampling was higher than the other two times (before and after), and it was higher in the SS group than the other groups and lower in the NS group. In a study by Viana et al., infants who received simultaneous music and swaddling interventions experienced less pain and heart rate changes during blood sampling [34]. Also, Talebi et al. reported in their study that there was a significant difference in heart rate changes during blood sampling between the studied groups, and the number of heart rates of infants in the combined sucrose- swaddling group was significantly reduced compared to the control group. In 2 min after blood sampling, infant’s heart rate changes decreased and gradually returned to the state before blood sampling [28]. This may be because the changes in heart rate caused by painful procedures are short-lived. This means that the pain is at its peak in the first moments of venous blood sampling, and then 2 min after the needling, the perception of pain decreases. Therefore, it seems that preventing pain in painful procedures and increasing the heart rate at the moment of needling can be the main key in reducing heart rate fluctuations in infants. The effect of reducing infant heart rate by combined non-pharmacological interventions should be considered as an important outcome of the study. A lower heart rate means less stress and anxiety in infants, and this can help improve their quality and comfort in the early stages of life.

Strengths, limitations, and future research

One of the strengths of the present study is the design of the study as a randomized clinical trial with a control group and the approach of using combined non-pharmacological pain management (combination of two or three non-pharmacological interventions) in infants, which is rarely done. Since infants who had some medical or congenital problems were not included in the study, the results of the present study cannot be used for such infants, so it is suggested that premature infants with the mentioned problems should also be studied in this regard. In addition, in order to more accurately understand the effect of pain management with combined non-pharmacological interventions, more research with a larger sample size and using other pain measurement tools is needed.

Conclusion

Although more studies with a larger sample size are needed to more fully understand the effect of combined non-pharmacological pain management, the present study provides clinical evidence that the effectiveness of combined non-pharmacological pain management in pain control is greater than the use of single interventions when performing painful procedures. This issue is especially important for parents and families of preterm infants who experience a lot of pressure and stress and want to have a better treatment experience for their infants. Therefore, for better pain management during venous blood sampling in the NICU, it is recommended to use combined non-pharmacological pain control methods instead of routine methods such as sucrose alone or without non-pharmacological intervention.