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. 2016 Jul 15;2016(7):CD001069. doi: 10.1002/14651858.CD001069.pub5

2. Trials assessing pain during venipunctures.

Study Participants Procedure Interventions Outcomes Metrics used Results  
Abad 1996 28 preterm, 29 to 36 weeks' PMA infants, PNA 1 to 26 days Venipuncture 2 min prior to venipuncture:

  1. 2 mL 12% sucrose via syringe (n = 8)

  2. 2 mL 24% sucrose via syringe (n = 8)

  3. 2 mL spring water via syringe (n = 12)

 Time crying for 3 min after venipuncture
HR: pre solution, post solution, 5 min after venipuncture
Mean SpO2 and respiratory rate pre solution, post solution, 5 min after venipuncture		 Median, IQR
Mean, SEM
Mean, SD		 Significant group effect noted, (F(2, 25) = 4.26; P = 0.0256) for cry duration 3 min after venipuncture. Cry duration was significantly reduced in 24% sucrose group (19.1 s) compared to 12% sucrose (63.1 s) and water (72.9 s) groups (P < 0.05)
Significant group effect for HR, F(2, 25) = 6.37, P = 0.006. Overall time effect, F(2, 50) = 14.15, P < 0.001. No significant interaction between treatment group and time. Post hoc Tukey test showed that group receiving 12% sucrose had lower HR compared to the 24% sucrose group or water group at all 3 time points (pre solution, P = 0.048; post solution, P = 0.010; 5 min after, P = 0.007)
No significant differences noted between groups over time for SpO2 and respiratory rates (no P values reported)
For time crying no SDs were reported by the authors
Differences in oxygen saturation, respiratory rate and HR between 24% sucrose and water were reported only at 5 min after venipuncture and therefore the findings were not included in RevMan‐analyses		  
Acharya 2004 39 preterm neonates, mean 30.5 weeks' PMA, mean PNA 27.2 days Venipuncture 4 min prior to venipuncture:

  1. 2 mL 25% (0.5 g) sucrose administered by syringe into front of infant's mouth over 2 min

  2. water


Cross‐over trial		 Duration of first cry (beginning to end of first cry); total duration of crying (onset of first cry to cessation of all crying)
Mean change in HR from pre procedure, procedure and postprocedure phase of venipuncture
Mean SpO2 (%) at pre procedure, procedure and postprocedure
NFCS changes across 3 phases of venipuncture		 Mean (SD)
Mean (95% CI)		 Mean duration of first cry lower in infants who received sucrose (18.6 s (24.4)) compared to infants who received water (52.3 s (56.2)) (estimated treatment effect = 33.7, P < 0.001). Mean total duration of crying was significantly lower in infants who received sucrose (31.9 s (41.9)) compared to infants who received water (72.5 s (66.7)) (estimated treatment effect = 40.6, P < 0.001)
Mean change in HR from pre procedure to procedure was lower in the infants receiving sucrose compared to water (estimated treatment effect = 7.5, P = 0.003). Mean change in HR from pre procedure to postprocedure was lower in the infants who received sucrose compared to water (estimated treatment effect = 4.16, P = 0.036)
No significant differences between groups with respect to changes in SpO2 from pre‐procedure to procedure phase (P = 0.17)
Changes in mean NFCS scores were significantly lower in the sucrose group compared to water group from pre procedure to procedure phase (estimated treatment effect = 1.08, P = 0.013) and between the pre procedure and postprocedure phase (estimated treatment effect = 2.39, P < 0.001)
Data prior to cross‐over for the two groups were not presented so we could not include the data in RevMan‐analyses		  
Basnet 2010 50 term infants between 12 h to 8 days old

  1. Non‐sucrose group: 59.92 h old

  2. Sucrose group: 68.76 h old

 Venipuncture

  1. No treatment group (n = 25)

  2. Sucrose group (n = 25): 2 mL 30% sucrose administered 2 min before the procedure


Method of administration (i.e. pacifier/syringe) was not reported		 Duration of cry, DAN scale, number of infants crying. HR and SpO2 were measured before, during and after the procedure Mean and SD for duration of cry, IQR for DAN scale 13 (52%) infants in sucrose group did not cry compared to 4 (16%) in no treatment group, P = 0.001, mean duration of cry was not significantly different between groups (P = 0.65)
HR increased during procedure (P = 0.008) followed by decrease postprocedure (P = 0.001) in no treatment group; no significant changes in sucrose group (P = 0.39). Decrease in SpO2 in the no treatment group (P = 0.001) during the procedure; no significant changes in sucrose group (P = 0.3)
Significantly lower DAN scores in the 30% sucrose group (score of 3 (1.5 to 5.5) compared to the no treatment group (score of 7 (5 to 9.5) (P = 0.0001)
Duration of cry could be used in RevMan‐analyses		  
Biran 2011 76 preterm infants, mean (SD) PMA:

  1. Sucrose group: 32.6 (2.33) weeks

  2. Sucrose + EMLA group): 32.3 (2.01) weeks

 Venipuncture

  1. Sucrose group: 0.5 mL 30% sucrose solution orally and placebo cream (0.5 g) (n = 37)

  2. Sucrose + EMLA group: 30% sucrose solution orally + EMLA (0.5 g) on the skin (n = 39)


The sucrose solution was given 2 min before the procedure via syringe.		 DAN scale, PIPP, crying time
Adverse effects		 Mean and SD Mean (SD) DAN pain scores for the sucrose group and the sucrose + EMLA group were 7.7 (2.1) and 6.4 (2.5), respectively, during venipuncture and 7.1 (2.8) and 5.7 (3.3) during the recovery period.
Significant time effect (P = 0.047) and treatment effect (P = 0.018) effect in favour of sucrose + EMLA group; no significant differences using PIPP
No adverse effects after sucrose administration were observed
Data used for meta‐analysis		  
Carbajal 1999 150 term newborn infants, 3 or 4 days old Venipuncture

  1. No treatment (n = 25)

  2. 2 mL sterile water via syringe over 30 s (n = 25)

  3. 2 mL 30% glucose via syringe (n = 25)

  4. 2 mL 30% sucrose via syringe (n = 25)

  5. Pacifier alone (n = 25)

  6. 2 mL 30% sucrose via syringe followed by sucking a pacifier (n = 25)


Sucrose was administered over 30 s 2 min prior to the procedure		 DAN scale Median, IQR Median pain scores with IQRs during venipuncture were: no treatment 7 (5 to 10); sterile water group 7 (6 to 10); 30% glucose group 5 (3 to 7); 30% sucrose (0.6 g) group 5 (2 to 8); pacifier alone group 2 (1 to 4); 30% sucrose with pacifier group 1 (1 to 2). All groups had significantly lower pain scores compared to sterile water group: 30% glucose (P = 0.005), 30% sucrose (P = 0.01), pacifier (P < 0.0001), 30% sucrose with pacifier (P < 0.0001). The pacifier alone group had significantly lower pain scores than infants receiving 30% glucose (P = 0.0001) or 30% sucrose (P = 0.001). Trend towards lower pain scores for infants receiving 30% sucrose with pacifier compared to pacifier alone (P < 0.06)
No data were used in RevMan‐analyses		  
Elserafy 2009 36 preterm infants, median (range): PMA 32 (27 to 36), mean (SD) PMA 32.4 (2.9)
Note: two different mean PMAs reported in the article		 Venipuncture Infants randomly allocated to 6 different regimens:

  1. 0.5 mL sterile water with pacifier

  2. 0.5 mL sterile water without pacifier

  3. 0.5 mL sucrose 24% with pacifier

  4. 0.5 mL sucrose 24% without pacifier

  5. pacifier alone

  6. control group


during a stay in intensive care of up to 15 days
For the sucrose and water solutions, the tip of a 1 mL syringe without the needle was placed in the infant’s mouth and the solution was instilled with gentle movements to stimulate sucking for 30 s. Each treatment was given 2 min prior to the procedure.
Every infant participating in the study received each of 6 different regimens during a maximum stay of 15 days from admission or the end of the NICU stay		 HR, SpO2, PIPP, respiratory rate, blood pressure, glucose check
Crying time was assessed at 0, 1, 3, 5, 10 min		 Range, mean PIPP score: significantly different between treatment groups P = 0.0005, over time P < 0.0005
24% sucrose + pacifier resulted in lowest pain scores (P < 0.05)
No difference in respiratory rate (P = 0.193), no difference in blood pressure (P = 0.246); no difference in glucose check (P = 0.227)
The sucrose groups had significantly shorter crying times compared to the other groups (P = 0.001)
This was a cross‐over study and each infant got all the 6 different interventions
No data that we could use in RevMan‐analyses		  
Montoya 2009 111 preterm and term neonates (55 in treatment group and 56 in control group) Venipuncture 5 min before venipuncture:

  1. 1 mL 12% sucrose

  2. Distilled water

 Overall NIPS score Means and SDs NIPS scores significantly lower for infants who received sucrose (2.9 (SD 2.3)) versus water (3.8 (SD 2.6)) (t = ‐2.063, P = 0.041)
Data used in RevMan‐analyses
(Article written in Spanish)		  
Taddio 2011 330 infants, mean PMA (SD) 39.5 (1.2):

  1. Liposomal lidocaine group: mean PMA (SD) 39.6 (1)

  2. Sucrose group: mean PMA (SD) 39.6 (1.3)

  3. Sucrose liposomal lidocaine group: mean PMA (SD) 39.6 (1.3)

 Venipuncture

  1. Liposomal lidocaine + water group (n = 110): 1 g liposomal lidocaine 4% cream to the dorsum of the hand, occluded by a dressing (Tegaderm) for 30 to 40 min, and oral water

  2. Sucrose + placebo group (n = 110): 2 mL 24% sucrose solution, administered by mouth using a syringe over 1 to 2 min, and placebo cream on back of hand

  3. Sucrose + liposomal lidocaine group (n = 110): both sucrose and liposomal lidocaine


Placebos were used for liposomal lidocaine and sucrose (i.e., double‐dummy design), so that all infants received a topically administered cream (liposomal lidocaine or placebo cream) and oral solution (sucrose or placebo water)
Non‐randomised group of healthy neonates undergoing venipuncture were administered water		 Facial grimacing, cry duration (s), Observer‐rated pain using a VAS (0 to 10 cm), HR (beats/min), oxygen saturation (%)
Safety/adverse events		 Means and 95% CI The mean facial grimacing score differed among the randomised groups (P < 0.001). Post hoc analyses demonstrated a significantly lower score for the sucrose group compared with liposomal lidocaine group (MD 27; 95% CI ‐36 to ‐19; P < 0.001) and for the sucrose plus liposomal lidocaine group compared with the liposomal lidocaine group (MD 23; 95% CI ‐31 to ‐14; P < 0.001). No evidence of difference between the sucrose and sucrose + liposomal lidocaine groups (P = 0.3)
Cry duration differed among groups (P < 0.001). Infants in the sucrose and sucrose + liposomal lidocaine groups cried less than infants in the liposomal lidocaine group (MD ‐38 s; 95% CI ‐52 to ‐25; P < 0.001; and MD 39 s; 95% CI ‐ 52 to ‐ 25; P < 0.001, respectively). There was no evidence of a difference in cry duration between the sucrose and sucrose + liposomal lidocaine group (MD 0 s; 95% CI ‐13 to 14; P = 0.95)
No difference in VAS, HR or oxygen saturation (%)
When compared with the non‐randomised placebo‐control group, the liposomal lidocaine group had significantly lower facial grimacing (mean difference ‐17; 95% CI ‐27 to ‐7; P < 0.001) and VAS scores (‐1.7 cm; 95% CI ‐2.5 to ‐0.9; P < 0.001). HR, oxygen saturation (%) and procedure duration were significantly higher in the liposomal lidocaine group compared to the control group. Cry duration and procedure success rate did not differ beyond chance
No significant adverse events reported
We transcribed 95% CI to SDs and included results in RevMan‐analyses		  

Abbreviations

CI = confidence interval
 DAN = Douleur Aigue du Nouveau‐ne
 EMLA = eutectic mixture of local anaesthetics
 HR = heart rate
 IQR = interquartile range
 MD = mean difference
 NFCS = Neonatal Facial Coding System
 NIPS = Neonatal Infant Pain Scale
 PIPP = Premature Infant Pain Profile
 PMA = postmenstrual age
 PNA = postnatal age
 SD = standard deviation
 SEM = standard error of the mean
 
 VAS = visual analogue scale