Effect on Pain of Oral Sucrose Versus Placebo in Children 1 to 3 Months Old Needing Venipuncture
Condition: Pain
Study type: Interventional
Phase: Phase 4

Summary: 
      Background : Previous studies suggest that early recognition and treatment of pain among
      children is important for their cognitive development and their future response to pain
      throughout their life. Oral sweet solutions have been accepted as effective pain reducing
      agents for procedures in the neonatal population. To date, there have been a limited number
      of published clinical trials in an emergency setting studying this type of intervention among
      infants and these studies have shown conflicting results.

      Objective : To compare the efficacy of an oral sucrose solution versus placebo in reducing
      pain in children 1 to 3 months of age during venipuncture in the Emergency Department (ED).

      Methods : A single-center, randomized, double-blind, placebo controlled clinical trial will
      be conducted in an urban tertiary care pediatric university-affiliated hospital ED. The study
      population is all infants from 1 to 3 months of age requiring venipuncture as part of their
      planned ED management. Study participants will be randomly allocated to receive 2 ml of a 88%
      sucrose solution or 2 ml of a placebo solution. The primary outcome measure is the difference
      in pain levels during the venipuncture in the study population as assessed by the Face, Legs,
      Activity, Cry and Consolability Pain Scale (FLACC). Secondary outcome measures will evaluate
      differences of pain levels using the Neonatal Infant Pain Scale (NIPS). Crying time and
      changes in heart rate during the procedure will be recorded. Side effects and adverse events
      will also be noted. The investigators will also measure the number of successful
      venipunctures at the first attempt. Based on previously reported data, using an alpha value
      of 0,05, a power of 90% and using a 2-point difference in mean FLACC scores as clinically
      significant difference, approximately 41 patients per group will be needed considering a
      drop-off value of 25%. Patients' characteristics and outcomes will be compared using the
      Pearson Chi-square test for categorical variables and the Student's T test for continuous
      variables. A intention to treat analysis will be performed.
    

Detailed description: 
      INTRODUCTION AND JUSTIFICATION

      Acute pain is one of the most common adverse stimuli experienced by children, occurring as a
      result of injury, illness, and necessary medical procedures[1]. The American Academy of
      Pediatrics (AAP) and the American Pain Society (APS) have jointly issued a statement
      promoting the responsibility of paediatricians as leaders and advocates to ensure the humane
      and competent treatment of pain and suffering in all infants, children, and adolescents[1].
      In Emergency Departments (ED), children undergo many painful procedures, such as bladder
      catheterization, capillary blood tests, venipuncture and lumbar puncture. All these
      procedures are associated with increased anxiety, avoidance, somatic symptoms, and increased
      parental distress[1]. Numerous myths, insufficient knowledge among caregivers, and inadequate
      application of knowledge contribute to a lack of effective pain management among infants[1].

      Long-term effects of unmanaged pain in human infants have been shown to include permanent
      impairment of elements of cognitive development, such as learning, memory, and behaviour[2],
      and increased somatisation in childhood[3]. The plasticity of the developing brain and the
      changes that occur in response to painful stimuli[4] also contribute to altered perceptions
      of pain later in life[5-6]. Early painful experiences affect children's future responses to
      analgesia. Weisman et al[7] found that inadequate analgesia in young children during
      procedures diminished the effects of adequate analgesia during subsequent procedures. Many
      studies have suggested that the prompt and accurate recognition and treatment of pain in
      young infants is important for their immediate comfort and for their best possible lifelong
      development[8]. Despite the recent interest in paediatric pain assessment, prevention and
      treatment, many children do not receive adequate management to alleviate pain[1, 8-9]. The
      ideal pre-procedural analgesic for minor invasive procedures would be a cost-effective,
      inexpensive, short-acting agent with few associated risks[10].

      The use of sucrose has been well studied for certain procedures in the patients of the
      neonatal intensive care unit and in the newborn nursery settings, particularly for venous
      blood draws, capillary blood tests and circumcision[11-13]. In these studies[11-13], infants
      receiving oral sucrose solutions before procedures cried less and had overall decreased
      behavioural pain responses when compared with those receiving placebo. Furthermore, sucrose
      has been shown to be a safe intervention with no serious life-threatening adverse events and
      only few reported side effects consisting of minimal coughing with administration[14].
      Sucrose is inexpensive, short acting, non-sedating, easily administered and non-invasive.
      Administration of sucrose does not require additional training and does not expose the infant
      to risks greater than those associated with breast or bottle feeding.

      Summaries of randomized controlled trials among hospitalized neonates of 32 to 40 weeks of
      gestation suggest that a single dose of 0,5 to 2 mL of 12% to 50% sucrose delivered by
      non-nutritive sucking via a pacifier for 2 minutes before a painful event is safe[15] and
      effective in decreasing physiologic (heart rate, respiratory rate and oxygen
      saturation)[16-17]. It is also effective in minimizing behavioural pain indicators (crying,
      facial expression and motor activity)[16, 18] and in reducing overall composite pain scale
      scores[16]. A Cochrane systematic review concluded that sucrose is safe and effective in
      reducing procedural pain from single short procedural events in neonates, but an optimal dose
      could not be identified due to inconsistency in effective sucrose dosage among studies[19]. A
      review of published studies reported that sucrose or glucose in healthy term or preterm
      infants during single episodes of heel lancing, venipuncture or intramuscular injection is
      effective[20]. However, uncertainties remain beyond the neonatal period, given the limited
      number of published studies [20].

      A growing number of studies looking at infants undergoing immunizations suggest that this
      analgesic effect may extend past the neonatal period and into infancy[21-26]. Nevertheless,
      the upper limit of this effect is unknown in terms of age and appropriate sucrose dosage. Two
      studies have examined the effectiveness of sweet solutions as an analgesic in the paediatric
      ED. A randomized controlled trial in an emergency setting of sucrose and/or pacifier for
      infants receiving venipuncture conducted by Curtis and al[27] among infants of 0 to 6 months
      demonstrated a trend in reducing pain among the sub-group of infants of 0 to 3 months.
      However, this study showed no difference in pain scales after 3 months of age. Also, in a
      study examining the effect of sucrose during bladder catheterization, the subgroup of infants
      1 to 30 days old who received a sweet solution showed smaller changes in pain scores, were
      less likely to cry during catheterization and returned to baseline more quickly, in
      comparison with the placebo group[14]. However, among children of 31 to 90 days, there was no
      statistically significant difference.[14].

      Also, studies have used varieties of concentrations of sucrose (e.g. Rogers had used sucrose
      24%[14], Curtis had used sucrose 44%[27] and Lewindon had used sucrose 75%[24]). Systematic
      reviews of the current literature have been unable to demonstrate superiority of one
      concentration of a sweet solution over another[28], but many studies suggest that higher
      concentrations of sweet solutions seem more effective[25, 29-32]. Therefore, the
      investigators chose to study the effect of a sweet solution named syrup B.P. (product by
      Laboratoire Atlas inc.) which contains 88% of sucrose. This solution is already commonly used
      in the population of infants up to 3 months of age and it is safe (e.g. prednisone syrup or
      codeine syrup are made using this syrup). A 2 ml dose of 88% sucrose contains the same amount
      of carbohydrates as 25 ml of infant milk formulas which contain approximately 7,5g/100
      ml[33]. Also, 88% sucrose has the same concentration of sugar as many other medications which
      are commonly used in infants, such as oral antibiotics, oral steroid solutions and other pain
      medications (e.g. codeine syrup). This syrup is of particular interest as it is of low cost
      ($9,58 for a bottle of 2000 ml), universally available, stable and viable for approximately
      three months. Therefore, the procedure studied here would be easy to apply in most clinical
      settings.

      Finally, the painful procedure chosen for our study is venipuncture (indwelling catheter with
      or without drawing of blood samples). Venipunctures are frequently performed in the ED in
      this age group. In fact, in our study center, the CHU Ste-Justine, approximately 15 patients
      of 1 to 3 months require venipuncture as a part of their investigation each month.

      To date, there are no pain scales which have been validated precisely for the age group
      studied in our project. However, the Face, Legs, Activity, Cry and Consolability (FLACC)
      scale is recommended by the IMMPACT group (Initiative on Methods, Measurement and Pain
      Assessment in Clinical Trials)[34]. FLACC is an easily applicable pain scale in which the
      observer scores a patient for 5 categories, from 0 to 2 points, for a total score of maximum
      10 points (Table 1). The validity and reliability of this pain scale has been established in
      the past for children from 2 months to 7 years[35]. Validity was evaluated by comparing the
      FLACC scale with the Objective Pain Scale and demonstrated that both tools showed similar
      behaviours (r=0.80; p<0.001)[35]. The interrater reliability between 2 observers was
      considered good (r[87]=0.94; p<0.001) with a kappa value greater than 0,50 for each
      category[35]. Therefore, this pain scale was chosen as the measure of our primary outcome, in
      our population of infants from 1 to 3 months old. Furthermore, the Neonatal Infant Pain Scale
      (NIPS)[36] (Table 2) is a well validated pain scale for newborns up to 1 month of age[37].
      This pain scale was chosen as a secondary outcome. The investigators hypothesize that using
      one pain scale validated in infants up to 1 month of age and another validated in infants
      older than 2 months of age will allow us to assess pain in infants from 1 to 3 months of age
      best, given current available tools. Furthermore, several other patient parameters will be
      used to corroborate findings.

      HYPOTHESIS The investigators believe that providing an oral sucrose solution during
      venipuncture will decrease pain levels in infants 1 to 3 months of age.

      OBJECTIVES Our primary objective is to compare the efficacy an oral 88% sucrose solution to a
      placebo solution in reducing pain as assessed by the Face, Legs, Activity, Cry and
      Consolability scale in children of 1 to 3 months during venipuncture in the Emergency
      Department (ED). Our secondary objectives are to asses changes in pain levels as per the NIPS
      scores. The investigators will also measure variations of heart rate and crying time. Any
      side effects will also be reported. The investigators will also measure the number of
      successful venipunctures at the first attempt.
    

Intervention name(s): 88% sucrose po solution; placebo po
Intervention type(s): Drug; Drug
Intervention description(s): 88% sucrose solution (Syrup B.P.) The pharmacy will provide 2 syringes labeled "sucrose study" calculated to provide a 2 ml dose of a 88% sucrose solution or a color, consistency- and odor-matched placebo in identical packagings (2 syringes per patient in the case the dose needs to be repeated).; The pharmacy will provide 2 syringes labeled "sucrose study" calculated to provide a 2 ml dose of a solution or a color, consistency- and odor-matched placebo to the sucrose solution in identical packagings (2 syringes per patient in the case the dose needs to be repeated).
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment