Routine Sucrose Analgesia During the First Week of Life in Neonates Younger Than 31 Weeks’ Postconceptional Age

Sample

Three level III university-affiliated NICUs in Canada were the sites for the study, and each site provided ethics approval by a constituted review board. The sites were similar in level of acuity of the infants and teaching programs. There were differences in level of developmental care: 1 site had completely implemented it, and the other 2 had some components (eg, unit darkened except for morning rounds). One unit treated with indomethacin more than the other units. Infants who were born between 25 and 31 completed weeks’ PCA, were expected to live according to the opinion of the attending neonatologist, were above the fifth percentile weight for gestational age, had intraventricular hemorrhage less than grade 3 and no periventricular leukomalacia, were free of major congenital anomalies, and did not require surgery and whose parents consented within 48 hours of birth were included in the study. Sample size estimates based on the primary outcomes of Neurobehavioral Assessment of the Preterm Infant (NAPI¹⁹; see below) were 35 per group for a power of 0.8 with statistical significance set at .05.

Intervention

Enrolled infants were randomly assigned to the sucrose or water group from a computer-generated schedule for each site. Only the project nurses in each site knew the group assignment; treating clinicians were blind to group assignment. Solutions of 0.1 mL of 24% sucrose or water were drawn up into sterile syringes and placed in the unit medicine refrigerator. Every time the infant was to undergo an invasive (eg, heel lance, intravenous cannulation, arterial puncture, injection) or noninvasive but presumably uncomfortable procedure (eg, endotracheal tube suctioning, tape/lead removal, gavage insertion for feeding), the solution in the syringe was administered into the infant’s mouth, at the beginning of the procedure, 2 minutes into the procedure, and another 2 minutes into the procedure. If the procedure was to last >15 minutes, up to another 3 0.1 doses were to be given 2 minutes apart.

In 1 site, there was videotaping of 1 infant at any point in time for the duration of the study week. A small wide-angle lens camera rested on top of the isolette and was connected to a mat on the floor next to the isolette such that stepping on the mat triggered 5-minute recording. The person who approached the infant was to identify his or her role (eg, nurse, mother) and the purpose of his or her approach (eg, suctioning, visiting). In this way, facial actions could be recorded during painful procedures to verify whether there was an immediate analgesic effect of the sucrose. Coding of faces was conducted in the laboratory according to the upper facial components of the Neonatal Facial Coding System.²⁰ Only the upper facial components were coded because many of the infants were intubated and these components have been shown to be specific to pain response in preterm infants.²¹

Outcomes

The primary outcome was neurobehavioral development assessed by the subscales of alertness and orientation (AO) and motor development and vigor (MDV) of the NAPI developed by Korner and colleagues.^{19, 22–24} The NAPI is appropriate for infants between 32 weeks’ PCA and term. It assesses the relative maturity of functioning of preterm infants, with higher scores reflecting higher maturity, and can differentiate 2 weeks’ PCA. Much of the examination consists of observational items, and the remainder rates the infant’s response to stimuli. This assessment takes approximately 30 minutes to administer and includes 7 clusters of single-item neurobehavioral dimensions: MDV, scarf sign, popliteal angle, AO, irritability, vigor of crying, and percentage asleep ratings. Test-retest reliability over 2 consecutive days ranged from 0.59 to 0.90. Original interobserver reliability ranged from 0.64 to 0.93.²³ The observers in this study were either occupational therapists (L.S., C.L.) or a psychologist (H.C.) with doctoral training and experience with this population. After the viewing of a detailed training tape provided with the NAPI kit, the interrater reliability using the intraclass correlation coefficient was >0.9. The clinical validity and sensitivity of the NAPI were established using an index of medical complications based on a 1 to 5 classification range of degrees of complications.²⁵ Functions that required strength and vigor were significantly related to medical complications, whereas items that assessed AO were not.^{25, 26} Assessments were conducted at 32, 36, and 40 weeks’ PCA if respirations were unassisted and the infant was available for assessment.

The secondary outcomes were measures of severity of illness during the course of the intervention and at discharge. These were assessed during the week of study by the Score for Neonatal Acute Physiology (SNAP)^{27, 28} for each 24-hour period and by the Neuro-Biological Risk Score (NBRS)²⁹ at 2 weeks’ postnatal age and at discharge. Background information, including PCA at birth (determined by ultrasound), birth weight, and Apgar, was obtained from the medical record, and the Clinical Risk Index for Infants (CRIB),^30–32 an index of severity of illness at birth, was calculated from information in the medical record. Serum glucose levels during the study time were obtained from the medical record when ordered clinically (not for purposes of the study).

Sample

Over the course of 27 months, 281 infants were admitted within the age category. Eighty-one (29.2%) were not evaluated for eligibility for the following reasons: mother too ill to consent within 48 hours, compassionate reasons (twin or triplet sibling had died), or unit difficulties when recruitment was temporarily stopped (Y2K problems, understaffing during holidays or ice storm). Thirty-two (16.3%) did not meet the selection criteria (died within 48 hours, deemed too ill by staff). Of the 168 remaining infants, 107 (63.7%) parents gave consent for the infant to participate. The reasons for the 63 refusals were as follows: the parents thought that the infant was too ill (5), were too stressed to consider study (4), did not want their infant to be in any research (10) or to receive sugar (4), or gave no reason (38). There were no significant differences between excluded infants, infants whose parents refused, and participating infants in the distribution of PCA or weight (Table 1).

Two infants were withdrawn from the study during the week of intervention. Two other infants died: 1 of grade 4 intraventricular hemorrhage and periventricular leukomalacia on the first day of the study after receiving 1 dose of water and the other infant of cardiac failure associated with patent ductus arteriosus at age 29 days. One infant was withdrawn on study day 4 for hyperglycemia after receiving 10, 6, and 12 doses of sucrose and serum glucose levels of 3.5, 16, and 12 on the respective study days. The infant became septic 48 hours after withdrawal from the study, which may be an alternative explanation for the glucose instability. The second infant was withdrawn from the study for suspected necrotizing enterocolitis. The infant did not develop necrotizing enterocolitis but did have Escherichia coli sepsis. At baseline, there were no group differences in birth PCA, birth weight, or CRIB score (see Table 1), and there were no differences between sites on age, CRIB score, or birth weight (see Table 1). There were differences in amount of indomethacin given to infants at 1 site.

Solutions

The total number of study doses given per infant during the week ranged from 24 to 125 with a mean of 58 in the water group and 63 in the sucrose group. An estimate of compliance in administering solutions was determined by dividing the number of procedures by the number of doses, which was an underestimate because an infant could potentially receive up to 3 doses per intervention. Overall, this estimate was only 69%, ranging widely between 27% and 185%, and was the same for both groups. One site accounted for the lack of compliance that became evident after the first 6 months of study, and this noncompliance persisted despite holding sessions with the nursing staff on the importance of adhering to the protocol. Serum glucose levels ranged from 1.8 to 13.5, but there were no group differences and there was no relationship between the number of solutions and the serum glucose level in either group.

The number of infants whose videotapes were able to be coded throughout the week was small (14) but indicated that the sucrose was effective as an analgesic during the immediate 60 seconds of initiation of the painful procedure, even on day 7.

NAPI

The NAPI was administered to infants who no longer required ventilatory assistance and were not discharged back to distant referring centers. At 32 weeks, 75 infants could be tested, 87 at 36 weeks, and 67 at 40 weeks, with only 53 infants having data at all 3 times. There were, however, at least 35 infants/group at each time, thus meeting the original sample size estimates. Multivariate analysis of covariance was therefore conducted at each age, to maintain the sample size estimates that would not have been met with repeated measures analyses, with covariates of PCA and number of invasive procedures on the 2 components of the NAPI that were tested, MDV and AO. No significant differences were found between the sucrose and water groups (MDV: sucrose at 32, 36, 40 weeks = 20.4, 48.6, 66.1; water at 32, 36, 40 weeks = 21.7, 49.7, 63.9; F(1,52) = 0.223, P = .64; AO: sucrose at 32, 36, 40 weeks = 16.0, 40.7, 54.3; water at weeks 32, 36, 40 = 19.5, 42.2, 55.5; F(1,52) = 2.016, P = .162).

Because compliance with administering solutions was generally low and there was a wide range of compliance, we were interested in determining whether number of doses of sucrose was related to outcomes while accounting for other factors that might be correlated with number of doses. Secondary analyses using standard multiple regressions were conducted by group on each of the NAPI components at each age to determine whether there were background factors, specifically age at birth, CRIB, or other factors related to the NICU experience, such as days on certain medications (sedatives, analgesics, caffeine, indomethacin), number of invasive procedures, or number of doses of sucrose that might have had an effect on the NAPI scores. So few infants received sedatives (4) or analgesics (3) that these medications were not able to be included in the analysis. After analyses of Pearson correlation coefficients, which fell below 0.5, thus satisfying lack of multicollinearity, the predictor variables for the 2 sets of standard regression analyses (ie, a set for sucrose group and a set for water group) on each NAPI outcome, were 1) age at birth, 2) CRIB, 3) days on caffeine, 4) days on indomethacin, 5) number of painful procedures, and 6) number of doses of sucrose or water. At 32 weeks, there were no significant predictive factors on the NAPI. Significant predictors were identified for only the sucrose group, with no factors reaching significance in the water group (Table 2). At 36 weeks, more developed MDV and more developed AO were predicted for the sucrose group by fewer days on indomethacin and fewer doses of sucrose. At 40 weeks, fewer doses of sucrose predicted more developed MDV and fewer days on indomethacin predicted more AO (Table 2). The only site differences were accounted for by days on indomethacin.

SNAP and NBRS

There were no group differences or factors associated with SNAP over each day, with day 7 being of interest because it was calculated on the final 24 hours of the intervention and would be most reflective of cumulative physiologic effects of the intervention (sucrose = 3.72 [3.33], water = 4.10 [3.18]; F(1,101) = 0.093, P = .761). On the basis of analysis of covariance with PCA at birth and number of invasive procedures as covariates, there were no group differences on any of the secondary outcomes of NBRS scores at 2 weeks’ postnatal age (sucrose = 1.42 [1.32], water = 1.68 [1.58]; F(1,101) = 0.640, P = .426) or at discharge (sucrose = 2.29 [2.68], water = 2.31 [2.47]; F(1,100) = 0.002, P = .965).

In the regression analysis to determine background and clinical factors that might have predicted higher (worse) physiologically based illness scores, multiple factors were identified (Table 3). Younger age was predictive of higher SNAP scores on study day 7 for the water group only. At 2 weeks’ postnatal age, younger PCA, fewer days on caffeine, and greater number of invasive procedures were predictive of higher NBRS for the water group, and fewer days on caffeine and greater number of doses of sucrose were predictive of higher NBRS for the sucrose group. For the NBRS at discharge, younger age, fewer days on caffeine, and greater number of invasive procedures were predictive of higher NBRS for the water group. However, fewer days on caffeine was predictive of higher NBRS at discharge for the sucrose group.