Shortened eutectic mixture of lidocaine and prilocaine plus skin cooling for pediatric vaccination pain: A randomized non-inferiority trial

Table 1 Baseline demographic and clinical characteristics of participants (intention-to-treat population, n = 150), n (%)/median (interquartile range)

Characteristic	Group A: EMLA 40 minutes (n = 74)	Group B: EMLA 20 minutes + cooling (n = 76)	P value
Child characteristics
Age (year)	8.50 (6.33-10.67)	8.46 (6.25-10.46)	0.870
Male sex	27 (36.5)	30 (39.5)	0.830
Weight (kg)	26.00 (20.62-42.75)	25.35 (20.00-39.25)	0.680
Height (cm)	127.50 (116.00-149.25)	128.25 (117.75-138.12)	0.970
BMI (kg/m2)	16.59 (14.49-19.62)	15.48 (14.18-18.26)	0.270
Overweight or obese	21 (28.4)	17 (22.4)	0.510
Obese	12 (16.2)	10 (13.2)	0.770
Allergy1	4 (5.4)	5 (6.6)	> 0.999
Underlying condition2	18 (24.3)	21 (27.6)	0.780
Fear of needles	26 (35.1)	31 (40.8)	0.590
Family characteristics
Parental report of fear of needles	8 (10.8)	11 (14.5)	0.670
Parent’s education ≥ Bachelor’s degree	67 (90.5)	63 (82.9)	0.260
Number of siblings	2.0 (2.0-2.0)	2.0 (1.0-2.0)	0.520
Caregiver present at injection	62 (83.8)	66 (86.8)	0.770

¹Allergy includes parental report of allergy to drug (e.g., cefaclor, amoxicillin), seafood, cow’s milk, egg, or mixed allergens.

²Underlying conditions include asthma, atopic dermatitis, chronic eczema, allergic rhinitis, congenital heart disease, attention-deficit/hyperactivity disorder, obstructive sleep apnoea, thalassaemia or single kidney.

P values are from Mann-Whitney U tests for continuous variables and Fisher’s exact tests for categorical variables. EMLA: Eutectic mixture of lidocaine and prilocaine; BMI: Body mass index.

Table 2 Wong-Baker FACES Pain Rating Scale scores and non-inferiority analysis at each assessment time point (linear mixed-effects model, intention-to-treat population, n = 150), mean ± SD

Time point	Group A	Group B	Adjusted difference (B-A)	95%CI	Non-inferiority
Before injection	0.89 ± 1.37	0.95 ± 2.08	+0.07	-0.70 to +0.80	Met
Immediately after injection (primary)	2.73 ± 2.66	2.42 ± 3.03	-0.30	-1.00 to +0.50	Met
5 minutes after injection	2.00 ± 2.20	1.76 ± 2.29	-0.22	-1.00 to +0.50	Met

Adjusted mean differences are presented as group B minus group A; because lower Wong-Baker FACES scores indicate less pain, negative values favour group B. Non-inferiority was concluded if the upper bound of the two-sided 95% confidence interval lay below the prespecified margin of Δ = +1.4 points (equivalent to a one-sided α of 0.025). The model included a random intercept per participant and fixed effects for group, time point and their interaction. CI: Confidence interval.

Table 3 Adverse events at 5 minutes and 15 minutes after vaccination (intention-to-treat population), n (%)

Adverse event (CTCAE v5.0, grade 1 unless noted)	Group A	Group B	Risk ratio (B/A), 95%CI	P value
At 5 minutes after injection
Pain	42 (56.8)	39 (51.3)	0.90 (0.67-1.22)	0.517
Swelling	0 (0.0)	1 (1.3)	Not estimable	> 0.999
Bruising/ecchymosis	0 (0.0)	0 (0.0)	Not estimable	> 0.999
Erythema	9 (12.2)	4 (5.3)	0.43 (0.14-1.34)	0.156
Pruritus	13 (17.6)	6 (7.9)	0.45 (0.18-1.12)	0.089
Anaphylaxis	0 (0.0)	0 (0.0)	Not estimable	> 0.999
Any event	52 (70.3)	43 (56.6)	0.81 (0.63-1.03)	0.092
At 15 minutes after injection
Pain	23 (31.1)	13 (17.1)	0.55 (0.30-1.00)	0.056
Swelling	1 (1.4)	2 (2.6)	1.95 (0.18-21.02)	> 0.999
Bruising/ecchymosis	1 (1.4)	1 (1.3)	0.97 (0.06-15.28)	> 0.999
Erythema	12 (16.2)	7 (9.2)	0.57 (0.24-1.36)	0.227
Pruritus	7 (9.5)	3 (3.9)	0.42 (0.11-1.55)	0.206
Anaphylaxis	0 (0.0)	0 (0.0)	Not estimable	> 0.999
Swelling and erythema combined	1 (1.4)	2 (2.6)	1.95 (0.18-21.02)	> 0.999
Any event	34 (45.9)	19 (25.0)	0.54 (0.34-0.86)	0.010

P values from Fisher’s exact tests. Risk ratios are presented as group B/group A with 95% confidence intervals calculated by the log-normal approximation; values below 1.00 indicate a lower risk in group B. Risk ratios are not estimable when one or both cells contain zero events. All adverse events were Common Terminology Criteria for Adverse Events grade 1 (mild) and self-resolving. CTCAE: Common Terminology Criteria for Adverse Events; CI: Confidence interval.

Table 4 Univariable and multivariable analyses of factors associated with any pain (Wong-Baker score ≥ 1) immediately after injection and at 5 minutes after injection

Time point	Variable	Univariable P value	Multivariable OR (95%CI)	Multivariable P value
Immediately after injection	Younger age (per 1-year decrease)	0.020	1.10 (0.96-1.26)	0.180
	Fear of needles (not afraid vs afraid)	0.010	0.39 (0.19-0.82)	0.012
5 minutes after injection	BMI z-score -1.5 to -3 (underweight)	0.050	0.38 (0.12-1.19)	0.100
	Parental education = high school (vs Bachelor)	0.040	0.37 (0.09-1.48)	0.160
	Number of siblings (greater)	0.030	0.61 (0.32-1.16)	0.130

Logistic regression of any pain (Wong-Baker score ≥ 1) vs no pain (score 0). Variables with univariable P < 0.20 were entered into the multivariable model. OR: Odds ratio; CI: Confidence interval; BMI: Body mass index.