Materials and Methods
Research approval was obtained from the Institutional Review Board and Departments of Pediatrics and Obstetrics and Gynecology at the hospital where the study was conducted. Study procedures were in accordance with the ethical standards for human experimentation established by the revised Declaration of Helsinki (1983). All healthy male neonates born between October 1995 and September 1996 with no contraindications to circumcision were eligible. I planned to exclude infants with hypospadius or family histories of hemophilia A, but no infants presented with such conditions. One hundred forty-two neonates met the eligibility criteria. Written informed consent was obtained from the parents requesting circumcision for their sons. Sixty-one neonates met the selection criteria with parental consent.
The 61 infants were assigned to one of three groups using a computer-generated random list: 5% lidocaine-prilocaine (n = 20), 30% lidocaine (n = 20), and control (n = 21). The 30% lidocaine cream was formulated by the center's pharmacy and suspended in an acid-mantle base. The control treatment was a plain acid-mantle cream. Topical formulations were placed in identical vials and blindly labeled A (30% lidocaine), B (control), and C (5% lidocaine-prilocaine). The investigator was blinded to the contents of each vial until completion of statistical analysis.
Enrollment criteria were listed on an information sheet given to the parents of potential subjects. Study newborns were required to have had a gestational age between 37 and 42 weeks, an uncomplicated vaginal or cesarean delivery, a 5-minute Apgar score of 7 or more, and a birth weight greater than 2500 g. Postnatal age had to be between 6 and 72 hours, and parental request for circumcision was required.
All infants fasted for at least 1 hour before circumcision. After informed consent was obtained, 1 mL (approximately 1 g) of cream from one of the study groups was applied to the prepuce and covered with a small square of clear plastic wrap to form an occlusive bandage. The bandage was in place for 1 hour. Blood pressure was measured with a pediatric sphygmomanometer before the subjects were restrained and after the circumcisions were completed. A pulse oximeter (Nellcor Symphony 3000; Nellcor, Inc., Haywood, CA) was applied for continuous monitoring. Unrestrained, resting, baseline pulses and oxygen pressure (PO2) levels were measured. The infants were then strapped to a circumcision board (CIRCUMSTRAINT; Olympic Surgical Co., Seattle, WA) and prepared and draped in a sterile manner. Bell-shield clamps (Gomco Inc., St. Louis, MO) were used for circumcision. Pulse and PO2 were measured during each of seven stages of the circumcision: baseline restraint, initial clamping of the foreskin, adhesiolysis, dorsal clamp, application of the bell clamp, tightening of the bell clamp, and removal of the bell clamp. All procedures were videotaped for future analysis. All circumcisions were done by the same operator.
Pulse and PO2 measurements were recorded on videotape by the operator. For each step of the procedure, the pulse recorded was the peak heart rate sustained during or immediately after that step. Oxygen saturation recorded was the nadir sustained during or immediately after each interval. Crying recorded was the time spent crying during each step, timed if the facial characteristics of pain noted by Brazelton (brow bulge, eye squeeze, nasolabial furrow, open lips, horizontal and vertical mouth stretch, and taut tongue9) were present with or without audible cry. Timing ended the second crying ceased. All procedures were coded by the same operator, who was blinded to the analgesics. Time of each step recorded was the beginning of each step to the end of the objective measurements at the end of each step.
The data for pulse, oxygen saturation, time for each step, time spent crying, and BP were analyzed statistically using one-way analysis of variance. Differences were considered significant at two-tailed P < .05. Values were expressed as mean ± standard deviation (SD). A power analysis incorporated the anticipated difference of 10%, SD of 10, intermediate dispersion of means, and alpha of .05 for an effect size of 1 regarding heart rates and BPs. This resulted in a power of 0.79 with 20 subjects in each of the three groups. Isolated data points missed because of gaps in pulse oximeter readouts were excluded. Differences in physiologic outcomes among the groups were analyzed by one-way analysis of variance, and differences between before-and after-procedure data points were analyzed by dependent (matched) Student t test.
Sample characteristics were similar for each study group (Table 1). Differences before the procedure were controlled by randomization. The three groups were not significantly different in birth weight, age, baseline pulse, baseline PO2, baseline BP, time to complete the procedure, and type of delivery. Apgar scores at 1 and 5 minutes were similar across groups (P = .57).
There were no significant differences in oxygen saturation during any phase of the circumcision among the groups (Table 2). There was a uniform decrease in oxygen saturation for all groups during circumcision, with the nadir (average) at the same stage of circumcision (adhesiolysis) for each group.
Heart rate increased significantly in all groups during circumcision (P < .01). The 5% lidocaine-prilocaine group had the smallest increase in heart rate in each of four (of six) active phases of circumcision: placement of the dorsal clamp, application of the bell clamp, tightening of the bell clamp, and removal of the bell clamp (P < .01). Increases in heart rate for the 30% lidocaine group were significantly lower than for the placebo group during the same four phases. Table 3 presents the group means for each phase.
The mean peak heart rate occurred at different phases of circumcision for each group. The mean peak heart rate for the 5% lidocaine-prilocaine group occurred during the restraint phase (146 ± 16 beats per minute), for the 30% lidocaine group during placement of the dorsal clamp (157 ± 10 beats per minute), and for the control group during tightening of the bell clamp (164 ± 16 beats per minute).
Duration of crying was significantly different during tightening of the bell clamp (P < .001), but was statistically similar during the other phases of circumcision (Table 4). Although not statistically significant, both anesthetic groups uniformly showed fewer seconds of crying than the placebo group during each phase of circumcision. The 5% lidocaine-prilocaine and 30% lidocaine groups each produced less crying during three (of six) active phases of circumcision. There were no significant differences in BP across the three groups at baseline or after circumcision (P > .13 and P > .16, respectively).
There was insufficient power to conduct a two-way analysis of variance to compare BPs before and after the procedure. However, it was interesting to note the comparison using a matched Student t test (two-tailed significance). There remained a significant increase in systolic BP from baseline for the 30% lidocaine group (t = 4.8, P = .001) and the control group (t = 2.5, P = .023) after circumcision. There was also a significant difference over time in diastolic BP for the 30% lidocaine (t = 2.9, P = .009) and control (t = 2.3, P = .032) groups. After circumcision, systolic BP (t = 1.6, P = .12) and diastolic BP (t = 1.9, P = .067) in the 5% lidocaine-prilocaine group did not differ significantly from baseline.
Newborns who received 5% lidocaine-prilocaine or 30% lidocaine cream applied 60 minutes before circumcision showed attenuated pain responses, evidenced by smaller increases in heart rate and less crying associated with pain than newborns who received placebo. Newborns who received 5% lidocaine-prilocaine did not have significant increases in systolic and diastolic BPs, unlike the 30% lidocaine and placebo groups. Heart rate seemed to show the most consistent changes across study groups, hypothesized to be one of the most sensitive indicators of the pain response in newborns.2 Five percent lidocaine-prilocaine suppressed heart rate increases better than 30% lidocaine, which in turn was better than placebo (P < .01). Both anesthetics worked better than placebo.
Measured crying time was consistently lower in the anesthetic groups compared with placebo. Five percent lidocaine-prilocaine and 30% lidocaine were each more efficacious during three of six active phases of circumcision. However, infants cried for significantly fewer seconds during tightening of the bell clamp with 5% lidocaine-prilocaine than with 30% lidocaine, which in turn was better than placebo (P < .01). Placement of the bell clamp, as assessed by gross crying time (mean 61 ± 38 seconds) and percentage of time spent crying (mean 66.2%), was the most painful event during circumcision, but did not differ significantly across groups (P = .24). Crying time is a well-documented objective measure of infant pain response when used in conjunction with others.5,6
Increases in BP would be expected during a stressful procedure such as circumcision. One study found that local and general anesthetics blocked such increases.5 Comparing BPs before and after the circumcision, the 5% lidocaine-prilocaine group showed no significant systolic or diastolic increases, unlike the 30% lidocaine and placebo groups (P < .05). Although an interaction with time was possible, the study's sample size was too small to test such an interaction. The relative blockage of this physiologic indicator of pain in the 5% lidocaine-prilocaine group supports my contention of its efficacy.
Expected differences in oxygen saturation across groups were not seen. Mixed results have been shown before.2,7–10,12 In studies in which oxygen saturation was not significantly different, the anesthetic groups were small (n = 20, 15).2,8 The anesthetic groups in the present study were also small (n = 20), so there was a likely lack of power to detect significance for this characteristic. Differences in the partial pressure of oxygen might have been significant, although oxygen saturation was not. The neonatal oxygen-dissociation curve, on which oxygen saturation depends, had a small slope in this study because the data fell in the range of 96–99%.
A surprising result of the present study was the evidence that 5% lidocaine-prilocaine was more effective than 30% lidocaine. If the 5% lidocaine-prilocaine mixture was purely additive, or even moderately synergistic, I would still expect the serum levels of anesthetic to be higher in the 30% lidocaine group. However, the skin can function as a reservoir for lipophilic drugs, and because absorption of drugs applied topically to the skin is slow and incomplete,16 serum levels may not accurately parallel tissue drug levels. Tissue levels of lidocaine and prilocaine could be confirmed in future research by biopsy of anesthetized tissue.
Topical anesthetics for circumcision have several advantages over injectable preparations because they are easy to apply, well tolerated by patients, produce limited systemic absorption, and eliminate the potential vascular complications, stress, and pain associated with dorsal penile nerve block and local injection. A hospital formulation of 30% lidocaine cream has a low per-unit cost, but potential problems arise with homogeneity, shelf life, and standard concentration of each sample. A commercially available 5% lidocaine-prilocaine cream offers standardized dosing, and a long shelf life (36 months) in a prepackaged, premixed form.
The present study supports the use of 5% lidocaine-prilocaine for topical analgesia during neonatal circumcision. The standard dosing of 5–12 mg/kg for both lidocaine and prilocaine can be achieved with most neonates using 1–2 g of 5% lidocaine-prilocaine cream. Both anesthetics have proved safe and effective in previous studies and should not be withheld from neonates because of their perceived lack of pain sensation, memory of pain, or lasting effects. Application of topical anesthetics approximately 1 hour before circumcision can be done quickly and easily by medical or religious personnel with minimal training.
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