Pain relief for neonatal circumcision

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Authors

Brady-Fryer B, Wiebe N, Lander JA

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


Dates

Date edited: 23/08/2005
Date of last substantive update: 01/05/2004
Date of last minor update: 03/08/2005
Date next stage expected / /
Protocol first published: Issue 2, 2003
Review first published: Issue 3, 2004

Contact reviewer

Ms Barbara Brady-Fryer, RN, PhD (c)

Director
Child Health - Critical Care
Capital Health
Royal Alexandra Hospital
10240 Kingsway, Room 5027-10 DTC
Edmonton
Alberta CANADA
T5H 3V9
Telephone 1: 780-491-5537
Facsimile: 780-477-4072

E-mail: barbbradyfryer@cha.ab.ca

Contribution of reviewers

Brady-Fryer - protocol development; study selection; data extraction; contact authors;data preparation & analysis; write report
Wiebe - data extraction; data preparation & analysis; write report
Lander - protocol development and review; review draft and final report
Brankston - study selection; data extraction

Sources of Support

Internal sources of support

Capital Health, CANADA
Faculty of Nursing, University of Alberta, CANADA

External sources of support

Alberta Association of Registered Nurses, CANADA
Canadian Nurses Association, CANADA
Canadian Health Services Research Foundation, CANADA

What's new

Thisreview updates the existing review "Pain relief for neonatal circumcision"which was published in The Cochrane Library Issue 3, 2004 (Brady-Fryer 2004).

The review has been updated to correct the numbers reported for totalpatients randomized for the included trials. Results of meta-analyses werenot effected except in one case, comparison 03.02 where the effect size changedfrom [WMD = 15.8%, 95% CI -20.8 to -6.8] to [WMD = 15.22%; 95% CI 21.08to 9.36].

Abstract was changed to note that data from three (not four) trials of DPNB versus EMLA including 133 patients were subjected to meta-analysis.

No new trials were identified as a result of the most recent search.

Dates

Date review re-formatted: / /
Date new studies sought but none found: 03/08/2005
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Synopsis

  • Synopsis pending

Abstract

Background

Circumcision is a painful procedure that many newborn males undergo inthe first few days after birth. Interventions are available to reduce painat circumcision; however, many newborns are circumcised without pain management.

Objectives

The objective of this review was to assess the effectiveness and safetyof interventions for reducing pain at neonatal circumcision.

Search strategy

We searched Cochrane Central Register of Controlled Trials (CENTRAL, TheCochrane Library, Issue 2, 2004), MEDLINE (1966 - April 2004), EMBASE (1988- 2004 week 19), CINAHL (1982 - May week 1 2004), Dissertation Abstracts(1986 - May 2004), Proceedings of the World Congress on Pain (1993 - 1999), and reference lists of articles. Language restrictions were not imposed.

Selection criteria

Randomised controlled trials comparing pain interventions with placeboor no treatment or comparing two active pain interventions in male term orpreterm infants undergoing circumcision.

Data collection & analysis

Two independent reviewers assessed trial quality and extracted data. Tenauthors were contacted for additional information. Adverse effects informationwas obtained from the trial reports. For meta-analysis, data on a continuousscale were reported as weighted mean difference (WMD) or, when the unitswere not compatible, as standardized mean difference.

Main results

Thirty-five trials involving 1, 997 newborns were included. Thirty-threetrials enrolled healthy, full term neonates, and two enrolled infants bornpreterm.

Fourteen trials involving 592 newborns compared dorsal penile nerve block(DPNB) with placebo or no treatment. Compared to placebo/no treatment, DPNBdemonstrated significantly lower heart rate [WMD -35 bpm, 95% CI -41 to -30], decreased time crying [WMD -54 %, 95% CI -64 to -44], and increased oxygensaturation [WMD 3.7 %, 95% CI 2.7 to 3.7]. Six trials involving 200 newbornscompared eutectic mixture of analgesics (EMLA) with placebo. EMLA demonstratedsignificantly lower facial action scores [WMD -46.5, 95% CI -80.4 to -12.6], decreased time crying [WMD - 15.2 %, 95% CI -21 to -9.3] and lower heartrate [WMD -15 bpm, 95% CI -19 to -10]. DPNB, compared with EMLA in threetrials involving 139 newborns (133 of whom were included in the analysis), demonstrated significantly lower heart rate [WMD -17 bpm, 95% CI -23 to -11]and pain scores. When compared with sucrose in two trials involving 127 newborns, DPNB demonstrated less time crying [MD -166 s, 95% CI -211 to -121], andlower heart rate [WMD -27 bpm, 95% CI -33 to -20]. Results obtained for trialscomparing oral sucrose and oral analgesics to placebo, and trials of environmentalmodification were either inconsistent or were not significantly different.

Adverse effects included gagging, choking, and emesis in placebo/untreatedgroups. Minor bleeding, swelling and hematoma were reported with DPNB. Erythemaand mild skin pallor were observed with the use of EMLA. Methaemoglobin levelswere evaluated in two trials of EMLA, and results were within normal limits.

Reviewers' conclusions

DPNB was the most frequently studied intervention and was the most effectivefor circumcision pain. Compared to placebo, EMLA was also effective, butwas not as effective as DPNB. Both interventions appear to be safe for usein newborns. None of the studied interventions completely eliminated thepain response to circumcision.

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Background

Neither the American Academy of Pediatrics nor the Canadian PaediatricSociety recommends routine or elective circumcision of the male newborn.Nevertheless, elective circumcision of male newborns is commonly performedin the first few days after birth. Approximately 1.2 million newborn malesare circumcised in the United States annually at a cost of 150 to 270 milliondollars (AAP 1999). Precise Canadian data are notavailable because the procedure has been delisted in many provinces, butit is estimated that 48% of male neonates born in Canada are circumcised(CPS 1996). The practice of male neonatal circumcisionis not limited to North America; it is performed worldwide for religiousand cultural reasons.

As an invasive, painful procedure, unanaesthetized circumcision elicitssystemic stress responses in the vulnerable newborn which negatively affectmajor body systems. Documented physiological and behavioral responses includeincreased output of adrenal corticoids (Gunnar 1981; Talbert 1976), increased heart rate and respiratory rate, decreased arterial oxygen (Rawlings 1980), skin flushing, vomiting and cyanosis (Poma 1980), changes in sleep/wake state, increased crying (Anders 1974; Gunnar 1981), and diminished responsiveness to parents (Dixon 1984). Unanaesthetized circumcision has also been linked with complications such as apnea and choking (Lander 1997), gastric rupture (Connelly 1992), and recurrence of pneumothorax (Auerbach 1978).Infants circumcised without anaesthesia exhibit stronger pain responses toroutine immunizations during the first six months of life than infants whowere not circumcised (Taddio 1997b), suggesting that circumcision pain may exert long term effects on infant behavior.

INTERVENTIONS FOR CIRCUMCISION PAIN

Numerous interventions to prevent or reduce circumcision pain havebeen examined. These include penile blocks, topical anaesthetics, oral analgesiaand sucrose administration, non-nutritive sucking, music and other environmentalinterventions.

The technique of dorsal penile nerve block (DPNB) for newborn circumcision was first described in 1978 (Kirya 1978), and it has since been extensively evaluated. More recently, subpubic (Dalens 1989) and penile ring block techniques (Hardwick Smith 1998; Lander 1997) have been examined. Adverse effects of penile blocks appear to be limitedto bruising and slight bleeding at the injection site (Snellman 1995).Of note, the rapidity of onset of the anaesthetic used for penile blocks(generally 1% lidocaine without epinephrine) is intermediate and a "waittime" of 5 minutes is recommended to achieve anaesthesia (Taddio 2001).Wait time is a concern for clinicians because it increases the total timerequired for the circumcision surgery; however, inadequate "wait time" influencesanaesthetic effect (Kharasch 2003).

Several types of topical anaesthetics have been used for neonatalcircumcision, including eutectic mixture of local anaesthetics (EMLA) and4 to 30% lidocaine creams. EMLA is a water-based cream that contains 2.5%lidocaine and 2.5% prilocaine. Compared with placebo, EMLA attenuates thepain responses of increased heart rate, facial activity and crying, and decreasedoxygen saturation (Lander 1997; Taddio 1997).A meta-analysis of three studies examining this intervention indicated thatthe use of EMLA results in a significantly lower increase in heart rate (frombaseline) and less crying during the various phases of circumcision surgerycompared to placebo. In two of the included studies, lower facial actionscores suggested less pain in the EMLA treated groups compared to placebo(Taddio 2002).

Potential difficulties with drug administration and the presurgicalwait time may limit the feasibility of topical anaesthesia as a pain interventionfor circumcision in many settings (Lander 1997).Considerable technical skill is required to apply the drug, and to securethe occlusive dressing needed to keep it in place. For adequate absorption, EMLA must be applied for at least 60 minutes prior to surgery (Taddio 1998), and must be reapplied if the infant voids during the wait time.

Methaemoglobinaemia (MetHb), caused by oxidation of haemoglobin bythe metabolites of prilocaine, is a serious but relatively rare risk associatedwith EMLA use in infants less than 12 months of age. A recent systematicreview of the use of EMLA for acute pain in infants demonstrated that therisk of significant MetHb is low with single dose applications of 0.5 to2g applied for 10 - 180 minutes for full term neonates, and 0.5 to 1.25gapplied for 3 to 180 minutes for preterm neonates (Taddio 1998).Local skin reactions, such as blanching, erythema, and edema of the skinhave been reported with the use of EMLA, but these are usually transientand not considered serious.

Sucrose or other sugar solutions alone or in combination with non-nutritivesucking have recently been recommended as interventions for procedural painmanagement (Mitchell 2000). Oral sucrose isthought to activate central endogenous pathways, and may stimulate releaseof endorphins from the hypothalamus. Non nutritive sucking (NNS) is alsothought to have an analgesic-like effect through stimulation of orotactileand mechanoreceptor mechanisms (Gibbons 2001; Mitchell 2003).The sensations created by NNS may deflect attention away from pain and facilitateself regulation because the infant is in control of the sucking. Sucroseand NNS appear to operate synergistically when offered in combination, andmay provide more effective pain relief (Carbajal 1999; Gibbons 2001; Gibbons 2002). The analgesic effect of sucrose is activated within two minutes, and lasts for three to five minutes (Haouari 1999; Mitchell 2003).Although sucrose in a wide variety of dosages (concentrations from 12 to24%, and volumes from 0.05 to 2.0 ml) has generally been found to decreaseacute, procedural pain responses in neonates (Mitchell 2000; Stevens 1997), the optimal dose has not yet been identified. Meta-analyses results indicatethat a 0.24g dose is effective to reduce pain responses in term infants, and higher doses do not appear to increase effectiveness (Stevens 1997). In comparison, relatively small doses (0.01 to 0.02g) appear to be effective for preterm infants (Johnston 1997).Interest in sucrose or other sugar solutions as a single or adjunctive interventionfor circumcision pain is reflected in the design of recent research (e.g. Kass 2001; Kaufman 2002).

Acetaminophen is the most frequently prescribed non-opioid oral analgesicused to treat mild to moderate pain in pediatric populations (Berde 2002; McGrath 1990). Acetaminophen is safe and effective for neonates and can be administered orally or rectally (Stevens 1999). Acetaminophen has been used as an intervention for circumcision pain (Howard 1994).

A variety of non-pharmacological interventions have been evaluated fortreatment of acute procedural pain in neonates. In theory, these interventionsprovide nonpainful stimuli that compete with painful stimuli for the neonate'sattention, and thus may blunt the perception of pain (Bellieni 2002). Interventions such as rocking, massage, facilitated tucking, and cuddling reduce pain responses during invasive procedures (Campos 1994; Corff 1995; Gray 2000).Music and other sounds (intrauterine, heartbeat) provide an auditory stimuluswhich may modulate pain perception and these have been evaluated as interventionsfor circumcision pain (Marchette 1989; Marchette 1991).

NEONATAL PAIN RESPONSES

It is difficult to evaluate the effectiveness of interventions forcircumcision pain because newborns are non-verbal and display stereotypicresponses to a variety of painful and non-painful stimuli. To maximize thevalidity of pain assessment in newborn populations three classes of painindicators or outcomes, biochemical, physiological, and behavioural, aregenerally employed for research. Salivary and serum cortisol, the most frequentlymeasured biochemical indicators, serve as markers of the stress responseto pain because hormones of the hypothalamic-pituitary-adrenal axis are assayed.Physiological indicators include heart rate, respiratory rate, blood pressure, transcutaneous oxygen saturation (Tc pO2), transcutaneous carbon dioxide(Tc pCO2), oxygen saturation (SaO2), palmar sweat, intracranial pressure(ICP) and vagal tone. In newborn populations, heart rate is the most frequentlystudied physiological indicator (Sweet 1998).Behavioral indicators include facial expression, cry, gross motor movement, and changes in behavioral state. Facial expression (Grunau 1987) is the most comprehensively studied behavioral indicator for neonatal pain.

Multidimensional measurement tools that employ more than one parameterusually contain physiological and behavioral indicators, and occasionallyadd contextual information to obtain an overall pain score. The NeonatalInfant Pain Scale (NIPS) (Lawrence 1993) and the Premature Infant Pain Profile (PIPP) (Stevens 1996) are multidimensional tools frequently utilized as outcome measures for investigationof acute procedural pain in term and preterm neonates. Although a numberof pain measures are available for use with neonatal populations, no singlemeasure has proven to be the best for all situations. Accordingly, all outcomesevaluated in the included studies as measures of neonatal pain were includedin this review.

SUMMARY

The substantial amount of research conducted to date suggests a willingnessto address the problem of circumcision pain. However, the majority of neonatesare circumcised without interventions for pain (Myron 1991; Ryan 1994; Snellman 1995; Wellington 1993).This situation persists despite growing awareness that newborns may perceivepain more intensely than older children or adults (Anand 2001; Fitzgerald 1993) and can be significantly compromised by it.

It has been suggested that training to manage circumcision pain isinadequate to promote consistent use of available interventions (Howard 1998).Recent surveys indicate that significant numbers of obstetricians (75%), family practitioners (44%), and pediatricians (29%) do not use analgesia/anaesthesiafor circumcision because of concerns about adverse drug effects or becausethey believe that the procedure does not require pain management (Maxwell 1999; Stang 1991; Stang 1998).

Although a wide variety of interventions for circumcision pain havebeen examined, the individual and relative effectiveness of each has notbeen systematically assessed. Thus, the apparent reluctance of practitionersto adopt the regular use of pain interventions for circumcision may reflectbeliefs that the findings of research conducted to date are collectivelyun-interpretable. At the same time, negative perceptions of the technicaland practical difficulties associated with pain interventions may diminishclinician motivation to implement their regular use.

A systematic review of the research in this area was needed to summarizeand identify implications arising from the existing evidence, and to providean informed basis for practice and to identify gaps in knowledge which requirefurther investigation. This review adds to knowledge gained from a previoussystematic review which examined the efficacy of a single intervention forcircumcision pain (Taddio 2002) by evaluating the efficacy and safety of all interventions for reducing pain at neonatal circumcision.

Objectives

To determine the safety and effectiveness of interventions to relievepain associated with neonatal circumcision. Subgroup analyses were prespecifiedaccording to wait time (after anaesthetic administration and prior to startof surgery) for penile blocks, and for dose delivered for sucrose interventions.

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs). Studies reported only as abstracts were included if relevant.

Types of participants

Male term or preterm neonates undergoing circumcision during the neonatalperiod (with postnatal age maximum of 28 days after reaching 40 weeks correctedgestational age).

Types of interventions

Any intervention intended to relieve pain during the circumcision procedure, for example, penile blocks, topical anaesthetics, oral sucrose administration, oral analgesics, surgical devices or techniques, or environmental manipulationsuch as music therapy or special restraints. This review included trialsof interventions for circumcision pain in which any intervention was comparedwith placebo, no treatment, or with another active intervention.

Types of outcome measures

The primary outcome was pain as assessed by:
  1. Physiological variables, such as heart rate (HR), respiratory rate(RR), oxygen saturation, or blood pressure (whether reported as change in, mean or absolute values)
  2. Biochemical variables, such as salivary or serum cortisol levels(whether reported as pre- and post- measures or as change from baseline values)
  3. Cry variables, for example, latency and duration of first cry, totalcry duration, and/or percentage of time crying during the circumcision procedure
  4. Validated pain measures, for example:
Secondary outcomes:

Complications of pain interventions were assessed as secondary outcomes. The outcomes included but were not limited to:

  1. occurrence/incidence of methaemoglobinaemia (topical anaesthesia)
  2. blanching and local skin irritations (topical anaesthesia)
  3. bleeding, bruising and hematoma formation (penile blocks)
  4. behavioral responses such a choking, spitting up, etc. during circumcision (all interventions)

Difficulties encountered in implementation of pain interventions, as reported by researchers, were noted.

Search strategy for identification of studies

Standard methods as per the guidelines of the Cochrane Neonatal Review Group (CNRG) were utilized.

  1. CIRCUMCISION/exp
  2. circumcision surgery.mp
  3. newborn circumcision.mp
  4. 1 OR 2 OR 3
  5. local anaesthes*
  6. penile block.mp/exp
  7. dorsal penile nerve block.mp/exp
  8. ring block.mp/exp
  9. 5 OR 6 OR 7 OR 8
  10. eutectic mixture of local anaesthetics.mp/exp
  11. EMLA.mp/exp
  12. LIDOCAINE.mp/exp
  13. 10 OR 11 OR 12
  14. acetaminophen.mp/ OR paracetamol.mp/exp
  15. sucrose.mp
  16. pacifiers.mp
  17. music therapy.mp
  18. Gomco clamp.mp
  19. Mogen clamp.mp
  20. 9 OR 13 OR 14 OR 15 OR 16 OR 17 OR 18 OR 19
  21. 4 AND 20
  22. HUMAN
  23. MALE
  24. 22 and 23
  25. infant, newborn
  26. neonat*
  27. 25 OR 26
  28. 24 AND 27
  29. 21 AND 28
  30. clinical trial
  31. 29 AND 30

Databases searched included: Cochrane Central Register of ControlledTrials (CENTRAL, The Cochrane Library, Issue 2, 2004; MEDLINE 1966 - April2004; EMBASE 1988 - 2004 week 19; CINAHL 1982 - May week 1 2004; PubMed 1966- May 2004; Web of Science 1975 - May 2004; Dissertation Abstracts 1986 -May 2004. Keywords and (MeSH) terms included infant/newborn, male, circumcision, penile blocks, sucrose, lidocaine, EMLA, acetaminophen. Abstracts of theWorld Congress on Pain were searched for the years 1993 - 1999 inclusive.Reference lists of all articles were screened to identify any additionalstudies. Language restrictions were not imposed.

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Methods of the review

Study Selection

The titles and abstracts of all reports identified through the electronicand other searches were scanned independently by two reviewers and full studyreports were obtained for those that appeared to meet the inclusion criteria.Study reports were then evaluated independently by two reviewers for possibleinclusion in the review. Disagreements were resolved by consensus. Studiesrejected at this stage were included in the Table of Excluded Studies.

Quality Assessment

Assessment of the quality of all included studies was undertaken independentlyby two reviewers as a component of the data extraction process. Standardmethods of the CNRG were used to assess: 1) the randomisation procedure, 2) concealment of allocation/blinding of randomisation, 3) blinding of intervention, 4) subject attrition and follow-up, and 5) blinding of outcome measurement.As per the CNRG guidelines, an overall quality score was not assigned. Reviewerswere not blind to trial authors or institutions during the study selectionor quality assessment processes.

Data Extraction

Data were extracted from included studies by two independent reviewersusing a data extraction form designed specifically for this review. The dataextraction form was developed in a draft format and piloted on several studiesand modified as required before use. The reviewers abstracted data independently, compared results and resolved differences.

Sixteen trials included in this review either did not report outcomedata, or did not report data in a format that could be analysed in this review(Arnett 1990; Benini 1993; Blass 1991 A; Holliday 1999; Holve 1983, Joyce 2001; Kass 2001; Marchette 1989; Marchette 1991; Maxwell 1987; Mohan 1998; Mudge 1989; Spencer 1992; Williamson 1997; Zahorodny 1998; Zahorodny 1999).Additional information was sought from ten authors and means and standarddeviations were subsequently obtained for three trials (Benini 1993; Joyce 2001; Kass 2001). Where means and standard deviations were not available, data were imputed or derived from graphs contained in the reports (Arnett 1990; Benini 1993; Blass 1991 A; Holliday 1999; Maxwell 1987; Mohan 1998; Mudge 1989; Taddio 1997).Missing standard deviations were either calculated from other summary statisticsor imputed using singular or mean standard deviations from similar trials.

Several authors reported total sample size only and information aboutthe number of subjects per group was obtained from the authors (Benini 1993; Joyce 2001).When additional information about sample size could not be obtained fromthe authors, we assumed equal distribution to study groups in our data analyses(Blass 1991 A; Zahorodny 1998; Zahorodny 1999).

Data Analysis

The outcomes presented in this review were reported as results obtainedduring the whole circumcision procedure. Usually, the circumcision surgerywas described as commencing with application of forceps to the dorsal foreskinof the penis (referred to as dorsal or lateral clamping) and ending withremoval of the surgical clamp (the Gomco, Mogen, or Plastibell surgical device, also referred to as a clamp). Some authors reported a single numerical outcomeresult for the entire circumcision procedure (e.g. Butler O'Hara 1998; Howard 1999; Maxwell 1987; Taddio 1997).Others reported numerical results by procedure phase or step (e.g. dorsalforeskin grasped with forceps, adhesion lysis, dorsal incision, surgicalclamp application, foreskin amputation, surgical clamp removal) (Benini 1993; Lander 1997; Woodman 1999).For the latter studies, depending on the outcome, we calculated either thearithmetic mean (e.g. heart rate) or total (e.g. time crying) across thephases or steps of the circumcision (as defined by the authors), and didnot include the baseline or recovery phase data. Variance formulae for thesearithmetic means and these totals were derived according to the general formulafor linear combinations of variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y)).We assumed a correlation of 0.5 as proposed by Follmann 1992. Additional Tables 1 - 7 provide specific details on summary estimate extractions from the included studies.

Data were analysed using the statistical package (RevMan 4.2) providedby the Cochrane Collaboration. When two or more studies were identified thatexamined the same comparison and clinically similar outcomes, data were pooledusing fixed effects. Random effects accounting for inter-study heterogeneitywere considered in sensitivity analyses. Studies that compared an activeintervention with placebo were analysed separately from those that comparedthe same active intervention with no treatment.

Continuous data summaries are reported as weighted mean differences(WMD) when the units provided were compatible. When the units were not compatible, the standardized mean difference (SMD) is reported. The SMD describes thedifference between the treatments in terms of units of standard deviations(SDs). To improve interpretability, we also report estimates of WMDs derivedfrom the estimated SMDs. To derive the WMDs from the SMDs, we selected eitherthe unit used in the majority of the trials or the most clinically relevantunit under a particular comparison and pooled the available SDs from thetrials that used that unit. We then multiplied this pooled SD by the SMDto obtain an estimate of the WMD. The WMDs thus derived are reported alongside the SMDs in the results. An example of how a SMD was converted to aWMD is provided in Figure 1.

Individual study outcomes were reported as both final values (FVs) and change from baseline values (CVs). It is appropriate to combine FVs andCVs when combining mean differences to calculate a WMD. However, it is notappropriate, generally, to combine FVs and CVs when combining SMD to calculatean overall SMD. CVs often have smaller standard errors (SEs) than FVs sincesome of the intra-patient variation is removed from their SEs. Thus the individualstudy CV SMD tend to be in smaller SD units than the individual study FVSMD. However, in this systematic review, many of the SEs for CVs were eitherwithin the range of the FV SEs or they were larger, which is counterintuitiveto the argument presented here. Hence, some of the SMD calculated in thisreview do combine CVs and FVs (Metagraphs 01.03; 01.08; 01.09; 03.02). AdditionalTables 1 - 7 provide specific details on summary estimate extractions fromthe included studies.

Heterogeneity was assessed quantitatively with the I-squared statistic (Higgins 2003).The I-squared statistic indicates the percent variability due to betweenstudy (or inter-study) variability as opposed to within study (or intra-study) variability. An I-squared greater than 50% may be considered large. Onlynon-null heterogeneity statistics are presented here. Too few studies undera single comparison did not allow for any assessment of publication biasnor extensive sub-group or sensitivity analyses. However, post-hoc, we selectedheart rate (the most frequently reported outcome) for between-study subgroupanalyses using a chi-square method proposed by Deeks 2001.We selected the following subgroup analyses a priori: for penile block interventions, "wait time" from anaesthesia administration to start of the circumcisionprocedure were considered by the following three categories: no wait timereported, wait time less than/or equal to 5 minutes, wait time greater than/or equal to 5 minutes; for sucroseadministration interventions, dose of sucrose administered was to be consideredbut could not be due to the lack of information provided in the reports.Surgical clamp type, use of pacifiers as a co-intervention, and choice ofcontrol group were selected for consideration post-hoc.

Description of studies

210 unique references were identified through search of the electronicdatabases. The full text of forty-two potentially relevant articles wereobtained and reviewed for possible inclusion in this review. Six studieswere excluded (see Table - Characteristics of Excluded Studies). In two excludedstudies, subjects were not randomised and the intervention was chosen bythe attending physician (Malnory 2003; Olson 1998). Two of the excluded studies had no comparison group (Mintz 1989, Russell 1996). One study was a cohort design and the outcome data for the control group was obtained from a previously conducted trial (Taddio 2000), and one (Taeusch 2002) was a head to head comparison of surgical clamps used for the circumcisionprocedure rather than a direct comparison of interventions for pain relief.

Thirty-five studies (thirty-six reports) were included in this systematicreview. Details of each are given in the Table - Characteristics of Included Studies. Two reports outlined different outcome data from the same trial(Dixon 1984, Holve 1983). Two trials were reported as abstracts only (Zahorodny 1998, Zahorodny 1999) and we were unable to obtain additional information from the authors. Oneunpublished report of Master's thesis research was included (Zolnoski 1993).

Thirty-three of the thirty-five included studies enrolled healthy, full term neonates. One trial included infants born preterm (and less than28 days age after reaching 40 weeks corrected gestational age) who were readyfor discharge from the neonatal intensive care unit (NICU) at the time ofcircumcision (Butler O'Hara 1998), and one trial enrolled infants born preterm and weighing 1600 - 2500g at the time of circumcision (Holliday 1999).

Nineteen trials examined the effectiveness of penile blocks (Arnett 1990; Butler O'Hara 1998; Hardwick Smith 1998; Herschel 1998; Holliday 1999; Holve 1983; Howard 1999; Kass 2001; Kurtis 1999 A; Lander 1997; Masciello 1990; Maxwell 1987; Newton 1999; Spencer 1992; Stang 1988 A; Stang 1997; Williamson 1983; Williamson 1986; Williamson 1997). Twelve trials assessed topical anaesthetics (EMLA, lidocaine creams) (Benini 1993; Butler O'Hara 1998; Holliday 1999; Howard 1999; Joyce 2001; Lander 1997; Mohan 1998; Mudge 1989; Taddio 1997; Weatherstone 1993; Woodman 1999; Zahorodny 1998), and nine evaluated oral sucrose in a variety of concentrations and doses (Blass 1991 A; Herschel 1998; Kass 2001; Kaufman 2002; Mohan 1998; Stang 1997; Zahorodny 1998; Zahorodny 1999; Zolnoski 1993). In two trials, subjects received an oral analgesic (acetaminophen) (Howard 1994; Macke 2001). Three trials evaluated forms of environmental manipulation (e.g. music, intrauterine sounds) (Joyce 2001; Marchette 1989; Marchette 1991). For trial details see Table - Characteristics of Included Studies.

In the trials, the interventions were compared with placebo/sham treatments(e.g. saline penile block or inactive topical cream), no treatment, or withother active interventions. In several trials, all subjects received an activebaseline intervention (e.g. EMLA cream or DPNB) prior to administration ofthe study intervention (Butler O'Hara 1998; Kaufman 2002; Stang 1997).

Methodological quality of included studies

All of the studies included in this systematic review were described asRCTs. However, fifteen of the study reports provided insufficient informationor described inadequate procedures for assurance of blinding of randomisation(see Table - Characteristics of Included Studies). Nine were double-blindfor delivery of all interventions (Howard 1994; Howard 1999; Joyce 2001; Macke 2001; Mudge 1989; Taddio 1997; Weatherstone 1993; Woodman 1999; Zolnoski 1993). Some studies compared interventions which could not be masked, for example, block techniques (Masciello 1990; Newton 1999; Spencer 1992). Partial blinding was achieved in several trials through inclusion of a sham or placebo group (Arnett 1990; Blass 1991 A; Holve 1983; Kass 2001; Kaufman 2002; Lander 1997; Stang 1988 A; Stang 1997). Blinding was occasionally achieved on a temporary basis during baseline assessments (Butler O'Hara 1998; Holliday 1999).

There was considerable methodologic diversity between the included studies.For example, there was variation between all of the trials as to what constitutedthe circumcision "procedure". In one trial (Williamson 1983), outcome data were reported for an undefined three minute "dissection period".In other trials, data were reported for each of multiple steps of a standardizedprocedure (Benini 1993; Hardwick Smith 1998; Herschel 1998; Lander 1997; Woodman 1999), or reported as a single summary statistic for the entire procedure (Taddio 1997). Other authors did not describe any details of the circumcision procedure followed for the trial (Blass 1991 A; Holliday 1999; Maxwell 1987; Stang 1988 A; Weatherstone 1993).In general, not enough information was provided by authors to be certainthat outcome results were directly comparable across studies, as the eventsthat constituted the procedure may not have been equivalent.

There were differences within the group of trials of DPNB (the mostfrequently studied intervention) in length of time fasting prior to surgery, anaesthetic dose, wait time after anaesthetic administration, and in typeof surgical clamp used. In some cases, a single operator performed all circumcisions(Butler O'Hara 1998; Hardwick Smith 1998; Howard 1994), in others, the circumcisions were performed by a number of different operators (Howard 1999; Macke 2001; Stang 1997).Differences in operator technique or in the circumcision procedure couldhave effected outcome results. For most of the trials, subjects were requiredto fast prior to the surgery, however, the fasting period varied betweentrials from 30 - 90 minutes (Arnett 1990; Blass 1991 A; Herschel 1998; Kurtis 1999 A; Maxwell 1987) to 2 - 4 hours (Butler O'Hara 1998; Howard 1994; Kaufman 2002; Masciello 1990).Hunger could have influenced outcomes such as duration of infant crying orother behavioral responses. In a number of studies, subjects were offeredpacifiers (Holliday 1999; Howard 1994; Howard 1999; Kurtis 1999 A; Mohan 1998; Spencer 1992; Stang 1997) although pacifiers were not the study intervention. In one trial, all subjects were offered sugar pacifiers (Butler O'Hara 1998). The potential effect of NNS on the outcomes measured in the trials providing pacifiers was not addressed in the reports.

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Results

ACTIVE VERSUS PLACEBO OR NO TREATMENT COMPARISONS

Penile block interventions

Dorsal penile nerve block

Fourteen trials compared dorsal penile nerve block (DPNB) to no treatmentor placebo (sham injection). A total of 592 infants were included. Threetrials employed pain scores (Metagraph 01.01) as an outcome measure (Arnett 1990; Holliday 1999; Kass 2001).These trials were not combined for meta-analysis of effect on pain becausethe scores used are not similar in conceptual development or measurementtechnique. However, outcomes significantly favoured DPNB using all four scoresreported: infant irritability score [MD -1.8, 95% CI -2.4 to -1.2], modifiedbehavioral pain scale (MBPS) [MD -3.2, 95% CI -4.5 to -1.9], Holliday'sbehaviour score [MD -8.8, 95% CI -11.1 to -6.5], and the crying componentof the same behavioral score [MD -9.8, 95% CI -13 to -6.6]. Another behavioralmeasure, time crying, also significantly favoured the DPNB group [WMD -54%, 95% CI -64 to -44; SMD -1.74, 95% CI -2.1 to -1.4; Metagraph 01.02; SMDdisplayed, WMD derived from SMD; data not shown].

Among the physiological measures, heart rate significantly favouredDPNB [WMD - 35 bpm, 95% CI -41 to -30; SMD -1.6, 95% CI -1.8 to -1.3; I2 = 73%; Metagraph 01.03; ; SMD displayed, WMD derived from SMD; data not shown].Oxygen saturation results also significantly favoured DPNB [WMD 3.2 %, 95%CI 2.7 to 3.7; I2 = 97%; Metagraph 01.06]. Results were heterogeneous, and one author reported the loss of large amounts of data (Herschel 1998). A single trial (Williamson 1983) reported results for transcutaneous oxygen saturation that also significantlyfavoured DPNB [MD 9.3 torr, 95% CI 1.8 to 16.9; Metagraph 01.07].

Respiratory rate (Metagraph 01.08) and serum B-endorphin (Metagraph01.12) were not significantly different. Systolic blood pressure was reportedin two studies. The combined result was significant and favoured DPNB [WMD-9 mmHg, 95% CI -16 to - 2; SMD -0.66, 95% CI -1.18 to -0.13; I2=92%;Metagraph 01.09; SMD displayed, WMD derived from SMD; data not shown] butthe effect was not significant in the random effects model or when Maxwell 1987 was removed. The populations for these two trials were different. Maxwell 1987 recruited healthy newborns in the first few days of life, while Holliday 1999 enrolled low birthweight preterm infants. The preterm infants were caredfor NICU and experience with other invasive procedures prior to circumcisionmay have affected their pain responses.

Serum cortisol (Metagraph 01.10) outcomes were reported in mg/dL, ug/dL and nmol/dL. Results were converted to nmol/dL using standard conversionfactors and the outcomes expressed in these units were combined but werenot significantly different. A single study (Kurtis 1999 A) reported salivary cortisol results and these were not significantly different.

In two studies (comparing DPNB to no treatment), authors did not report means and SDs. Williamson 1997 found significantly lower oxygen saturation and higher heart rates in theno treatment group during adhesion lysis and application of the surgicalclamp (p < 0.001). There was a significant difference in duration of cryingbetween the groups (p < 0.001) with the DPNB group crying less. The secondstudy found that the mean increase in heart rate and percent of time cryingduring circumcision was 50% less for infants in the DPNB group (p < 0.01) (Holve 1983). The DPNB group infants were moreattentive to stimuli following circumcision, and were better able to quietthemselves when disturbed (Dixon 1984).

Ring block

Two trials compared ring block to no treatment and included 65 subjects (Hardwick Smith 1998; Lander 1997).Percent time crying was significantly reduced in the ring block group [WMD-26.3%, 95% CI -38 to -15, SMD -1.25, 95% CI -1.82 to -0.69; I2 = 68%; Metagraph 02.01; SMD displayed, WMD derived from SMD; data not shown].Only single studies reported other measures. In one (Lander 1997) heart rate significantly favoured the ring block group [MD -29 bpm, 95% CI-52 to - 7; Metagraph 02.02]. Oxygen saturation (Metagraph 02.03) and respiratoryrate (Metagraph 02.04) were reported by Hardwick Smith 1998 and were not significantly different.

Topical anaesthetics

EMLA

Six studies compared EMLA to placebo for a total 200 patients (Benini 1993; Joyce 2001; Lander 1997; Taddio 1997; Woodman 1999; Zahorodny 1998). Two studies measured infant behavioral responses using the same pain score, the Neonatal Facial Coding System (Grunau 1987). The trials used the same measure, but the researchers scored a different set of facial actions (see Additional Table 01), and calculated the summary pain score differently. In both summation techniques, a lower score indicated less facial action and less pain. When combined, the results significantly favoured EMLA [WMD -46.5, 95% CI -80.4 to -12.6; SMD -0.6, 95% CI -1.0 to -0.2; Metagraph 03.01; SMD displayed, WMD derived from SMD; data not shown].

Cry time was also significantly decreased with EMLA treatment [WMD- 15.2 %, 95% CI -21 to - 9.3; SMD -0.78, 95% CI -1.08 to - 0.48; Metagraph03.02; SMD displayed, WMD derived from SMD; data not shown]. One study (Joyce 2001) did not favour the EMLA treatment, but for this study cry time was measuredfrom the start of circumcision until crying stopped or until 30 minutes elapsed.The other studies measured cry time by phases of the procedure or gave asummary value for the procedure and thus only time spent crying during circumcisionsurgery could be calculated.

Heart rate was significantly decreased for infants treated with EMLA [WMD -15bpm, 95% CI -19 to -10; Metagraph 03.03]. The effect on oxygen saturationwas not significant [WMD 0.9%, 95% CI -0.2 to 2.0; Metagraph 03.04], andheterogeneity was large (I2= 86%). Respiratory rate, systolicand diastolic blood pressure (Metagraphs 03.05, 03.06, 03.07) were not significantlydifferent.

Lidocaine cream

Three trials compared topical lidocaine to placebo and included 115 patients (Mudge 1989; Weatherstone 1993; Woodman 1999). One study measured percentage of time spent in Brazelton behavioral state 6 (full cry) as a proxy for pain (Weatherstone 1993) and the results were insignificant [MD -8, 95% CI -23 to 7; Metagraph 04.01].Cry time was significantly reduced [WMD -60 s, 95% CI -99 to -20; Metagraph04.02] and favoured lidocaine. Heart rate was also significantly reduced[WMD -9 bpm, 95% CI -14 to - 4; I2=12%; Metagraph 04.03]. A single study examined B-endorphinlevels, and these were significantly reduced for the group treated with lidocaine[MD -49 pg/mL, 95% CI -89 to -9; Metagraph 04.06]. One study (Mudge 1989) did not report standard deviations for oxygen saturation (Metagraph 04.04) and respiratory rate (Metagraph 04.05) andthese could not be calculated from the information available. However, thedirection of results favoured treatment with lidocaine. Oxygen saturationresults for another study (Woodman 1999) were not significantly different.

Oral sucrose/dextrose

Eight trials compared sugar solutions to water and/or no treatment and included 360 subjects (Blass 1991 A; Herschel 1998; Kass 2001; Kaufman 2002; Stang 1997; Zahorodny 1998; Zahorodny 1999; Zolnoski 1993).A variety of concentrations (24 to 50%) and volumes (1.5 to 10 ml) of sucroseor dextrose were tested. Two studies measured pain scores (Kass 2001; Stang 1997).The results were not combined because the measures are not similar in conceptualdevelopment or measurement technique. For example, distress scores (Stang 1997) ranging from 0 to 3 indicated no crying to sustained cry respectively. The modified behavioral pain scale (MBPS) scores (Kass 2001) ranged from 0 to 10 and incorporated ratings for facial expression, cryingand body movements. Results using the behavioral distress score significantlyfavoured sucrose [MD -0.7 units, 95% CI -1.1 to -0.3], while the MBPS resultswere not significantly different (Metagraph 05.01).

Cry time results were not significantly different overall [WMD - 1.3 %, 95% CI -5.8 to -8.3; SMD 0.07, 95% CI -0.31 to 0.44; I2 = 78%; Metagraph 05.02; SMD displayed, WMD derived from SMD; data not shown].Individual results from five trials were inconsistent in direction. Zahorodny 1998 reported means only and SDs were substituted from another study using thesame intervention and same outcome measure. One study (Kaufman 2002) reported a different measure of cry time. They averaged time spent cryingin 10 second intervals, then took the cumulative average of that for eachgroup. In this study, cry time was statistically significant and favouredthe sucrose group (56 vs 86 s; P=0.0001). Zahorodny 1999 did not report means or standard deviations, but did report that both thesucrose and the water group cried much less than the no treatment group (p < 0.001), and that subjects receiving the sucrose pacifier cried the least (p < .03).The sucrose and water groups in this trial also had smaller increases inheart rate compared to those receiving no intervention (p < .017). Theseauthors did not comment on any differences between the sucrose group andthe water group.

The effect on heart rate was not significant [WMD -4 bpm, 95% CI-9 to 2; Metagraph 05.03] overall in three trials. Heterogeneity was large(I2=55%) with two trials favouring the water treatment and one trial favouring the sucrose treatment. In two trials (Herschel 1998; Kass 2001) oxygen saturation was significantly greater in the sucrose group [WMD 1.8%, 95% CI 0.5 to 3.1; Metagraph 05.04] although heterogeneity was again large(I2=88%) and the random effects estimate was not significant [WMD1.3%, 95% CI -2.7 to 5.2]. Serum cortisol (Metagraph 05.05) was measuredin a single study (Stang 1997) and results were not significant.

The inconsistent results in these trials may be related to the volumeand concentration of sucrose provided and to the sucrose delivery method.For example, in two studies the treatment group received a dose of 10 mlof 50% sucrose as the treatment intervention (Herschel 1998; Zahorodny 1999), while in two other studies, the treatment group received 2 ml of 50% sucrose (Kass 2001; Zahorodny 1998). The treatment groups in the other trials received 1.5 ml (Blass 1991 A), 2.3 ml (Zolnoski 1993) or an unspecified volume of 24% sucrose (Kaufman 2002; Stang 1997) respectively. The delivery method for the sugar solution also varied betweenstudies. Five administered the sugar/water solution via a nipple/pacifier(Blass 1991 A; Herschel 1998; Kaufman 2002; Stang 1997; Zahorodny 1999) thus providing the opportunity for non-nutritive sucking. In one trial (Herschel 1998), the sucrose group had a nipple (and the opportunity for non-nutritive suckingthroughout the circumcision procedure), while the no treatment control groupdid not receive a pacifier at all. In two studies, the sugar solution wasdelivered using oral syringes (Kass 2001; Zolnoski 1993). In one trial, the method of delivery was not specified (Zahorodny 1998).

Oral analgesics

Acetaminophen

Two trials compared acetaminophen to placebo with a total of 104 patients (Howard 1994; Macke 2001).The studies employed two different pain scales, and the results were notcombined because the measures are not similar in conceptual development ormeasurement technique. Howard 1994 used a comfortscore that measures 10 behaviours (sleep, facial expression, motor activity, tone, etc.) to arrive at a composite score of 0 to 20. The lower the score, the more uncomfortable the infant. Macke 2001 used the Nursing Child Assessment Feeding Scale (NCAFS) which measures mother-infantfeeding interactions using 76 behavioral items based on the concepts of synchronismand adaptation. Lower scores on the NCAFS indicate less positive responseson the part of the infant. Results using the post-operative comfort scorewere not significant, but the total infant scores on the NCAFS were significantand favoured acetaminophen [MD 4.0, 95% CI 1.0 to 7.1; Metagraph 06.01].All other outcomes (cry time, heart rate, respiratory rate Metagraphs 06.02, 06.03, 06.04) were not statistically significant.

ACTIVE VERSUS ACTIVE TREATMENT COMPARISONS

DPNB versus EMLA

Three studies compared DPNB to EMLA for a total of 139 patients (Butler O'Hara 1998; Howard 1999; Lander 1997).Two studies measured different pain scores (Metagraph 07.01). The resultswere not combined because of conceptual and measurement differences betweenthe scales. The Neonatal Infant Pain Scale (NIPS) consists of 6 behavioralcomponents with a composite score of 0 to 6 based on facial expression, crying, breathing pattern, body movement and arousal. The behavioral distress scoremeasures crying on a scale of 0 (no crying) to 3 (sustained crying). Lowerscores indicate less pain for both measures. Results using both scales werestatistically significant and favoured DPNB; NIPS [MD -2.5, 95% CI -3.3 to-1.7]; behavioral distress score [MD -0.3, 95% CI -0.5 to -0.03].

Cry time was measured in a single study and was not significantly different [MD -10%, 95% CI -30 to 10; Metagraph 07.02]. Heart rate was significantly reducedfor the DPNB group [WMD -17 bpm, 95% CI -23 to -11; Metagraph 07.03] butheterogeneity was large (I2=93%). The random effects estimate was not statistically significant. Butler O'Hara 1998 had a large mean difference [MD -40 bpm, 95% CI -51 to -29 ]; when this studywas removed, heterogeneity was absent and the overall fixed effects WMD wasno longer significant [WMD -7 bpm, 95% CI -14 to 0.5]. The large heterogeneitymay be related to differences in the characteristics of the study subjects.Infants enrolled in the Butler O'Hara 1998 trial were born prematurely and hospitalised in the neonatal intensive careunit (NICU). Postnatal age was 3 - 105 days by the time of circumcision (butless than 28 days after reaching 40 weeks corrected gestational age). Exposureto invasive treatments during their NICU stay may have caused the infantsto become sensitized and thus respond differently than infants in the othertwo trials who were healthy newborns in the first few days of life. Respiratoryrate (Metagraph 07.05), measured by a single study, was not significantlydifferent.

DPNB versus sucrose

Two trials compared DPNB to sucrose for 127 patients. In onetrial, pain was measured using the modified behavioral pain scale (MPBS) (Kass 2001) and the results significantly favoured DPNB [MD -3.2, 95% CI -4.7 to -1.8;Metagraph 08.01]. Cry time was measured in one trial and significantly favouredthe DPNB group [MD -166 s, 95% CI -211 to -121; Metagraph 08.02]. Heartrate also significantly favoured DPNB [WMD -27 bpm, 95% CI -33 to -20; Metagraph08.03]. Heterogeneity was large (I2=94%) however, both trialsmeasuring heart rate favoured the DPNB group. The effect on oxygen saturation(Metagraph 08.04) was not significant, heterogeneity was large (I2=96%), and the individual trial estimates were not consistent in direction of effect. The authors of one study (Herschel 1998) reported that a significant amount of oxygen saturation data (measured usingpulse oximetry) was lost due to excessive motion. Also of note, the doseand delivery method of the sugar solution differed between the two studies.In one study (Kass 2001) subjects received 2 ml of 50% dextrose by oral syringe. In the other (Herschel 1998), subjects received up to 10 ml of 50% sucrose by nipple and had a pacifier throughout the procedure.

DPNB versus ring block

One trial compared DPNB to ring block (Lander 1997) and included 27 patients. Results for cry time and heart rate were not significantlydifferent between the groups (Metagraphs 09.01, 09.02).

DPNB versus local block

A single trial compared DPNB to local block using 1% lidocaine (Masciello 1990) and included 20 patients. Local block was performed by injecting lidocainesubcutaneously into the foreskin at the 10 and 2 o'clock positions at thelevel of the corona. Results for serum cortisol significantly favoured thelocal block administration group [MD 306 nmol/dL, 95% CI 141 to 471; Metagraph10.01].

Ring block versus EMLA

Ring block was compared to EMLA in a single trial that included 28 patients (Lander 1997). Results for heart rate [MD -3 bpm, 95% CI -20 to 14; Metagraph 11.01] and cry time [MD -16 %, CI -36 to 3; Metagraph 11.02] were not significantly different between the groups.

Buffered lidocaine DPNB versus lidocaine DPNB

Two trials compared buffered lidocaine DPNB to lidocaine DPNB and included 234 patients (Newton 1999; Stang 1997).In clinical trials with adult subjects, buffering lidocaine with sodium bicarbonatehad shown potential to decrease the burning sensation of injection, and enhancethe speed of anaesthesia. The results for all outcomes measured (behavioraldistress score, cry time, heart rate, oxygen saturation and serum cortisol;Metagraphs 12.01, 12.02, 12.03, 12.04, 12.05) were not significantly differentbetween the groups.

EMLA versus topical lidocaine

One trial compared EMLA to 30% topical lidocaine, and included 40 patients (Woodman 1999).Cry time and oxygen saturation (Metagraphs 13.01, 13.03) were not significantlydifferent. Heart rate was significant and favoured EMLA [MD -12 bpm, 95%CI -19 to -4; Metagraph 13.02].

EMLA versus sucrose

Two studies (Mohan 1998; Zahorodny 1998) compared EMLA to sucrose (67 patients). Cry time, heart rate, oxygen saturation(Metagraphs 14.01, 14.02, 14.03) were not significant. Systolic and diastolicblood pressures mean differences could not be calculated because no standarddeviations were provided (Metagraphs 14.04, 14.05), but both means were largerin the sucrose group, indicating higher mean blood pressure.

EMLA versus music

A small pilot study (Joyce 2001) compared EMLA to music, and included 12 patients. None of the outcome results(cry time, heart rate, oxygen saturation, respiratory rate; Metagraphs 15.01, 15.02, 15.03, 15.04) were significantly different.

ENVIRONMENTAL COMPARISONS

Music versus no treatment

Three studies compared the provision of music or other soothing sounds during the circumcision procedure (Joyce 2001; Marchette 1989; Marchette 1991). In one trial that included 12 patients (Joyce 2001) the effect of the intervention on the outcomes of cry time, heart rate, oxygensaturation and respiratory rate (Metagraphs 16.01, 16.02, 16.03, 16.04) was not significant. In a second study, music was compared with intrauterine sounds and no treatment (Marchette 1989).Although 103 infants were randomised, 45 records were deleted from analysisdue to missing data or prolonged circumcisions related to physician training.The researchers did not report standard deviations, but they did report thatduring all steps of the circumcision procedure in which infants were touchedwith surgical instruments the interventions did not offset pain as indicatedby heart rate, systolic blood pressure, facial expression, and behavioralstate outcomes. In the third study (Marchette 1991) 121 infants were randomised to six groups and received either classical music, intrauterine sounds, a pacifier, music and a pacifier, intrauterine soundsand a pacifier, or no treatment. The researchers did not report means andstandard deviations but they did state that the interventions tested didnot greatly reduce circumcision pain as assessed by heart rate, blood pressure, transcutaneous oxygen saturation, and time crying.

COMPLICATIONS/ADVERSE EFFECTS

Ten studies reported adverse effects (see Additional Tables - Table 08).Adverse effects including gagging, choking, and emesis were reported in untreatedgroups, while DPNB groups exhibited minor bleeding, swelling and hematomaat the block injection site post-circumcision. EMLA use was associated witherythema and minor skin pallor. In one study (Holliday 1999), two subjects who received EMLA had redness and blistering of the foreskin, leading to closure of the EMLA arm of the study. Methaemoglobin levels weremeasured in two trials of EMLA and found to be within normal limits (Lander 1997; Taddio 1997).All adverse effects of pain interventions were reported to be transient innature and were not considered serious. Several authors reported on the questionableclinical utility of topical anaesthetic interventions (Herschel 1998; Howard 1999; Lander 1997) given the dexterity required to apply the creams properly and the lengthy application time.

SUBGROUP AND SENSITIVITY ANALYSES

We examined two subgroups: length of wait time after penile blockinterventions (a priori) and choice of clamp for all procedures (post-hoc) on the most frequently reported outcome heart rate. One study compared differentlengths of wait time and two anaesthetics (Spencer 1992) but did not report means and SDs. The authors did report that DPNB groupsthat received either anaesthetic exhibited decreased pain responses comparedto the control group. We made indirect (or between study) comparisons. Sixtrials comparing DPNB to no treatment prescribed and reported wait times.The trials with the longer wait time (>5 minutes) did not perform significantlybetter than short wait time trials (less than/or equal to 5 minutes) [Metagraph 01.04]. Infact, the probability under the null hypothesis was close to significant(P=0.09 vs P=0.65) when Maxwell 1987 was removedand favoured shorter wait times. A similar and statistically significantresult was calculated when comparing wait times in DPNB vs EMLA (P=0.04;Metagraph 07.04). Using an indirect comparison, the Mogen clamp trial performedsignificantly better on reducing heart rate compared to the Gomco clamp trialswhen Maxwell 1987 was again removed (P=0.05vs P=0.07) under the DPNB versus no treatment comparison (Metagraph 01.05).Sucrose dose (a priori) was not analysed because there were too few studiesunder the same comparison and not enough information was provided.

Post-hoc, we considered two other potential treatment effect size modifiers: control intervention and choice of pacifiers. Forethical considerations, use of saline DPNB in pain research was generallyabandoned since the early 1990's. Among the included studies for this review, three used both saline DPNB treatment (sham) and no treatment control arms(Arnett 1990, Holve 1983, Stang 1988 A). In one study saline DPNB was used to blind comparison of lidocaine DPNB with another active intervention (Howard 1999).The researchers wanted to control for the effects of the injection and fluidvolume compression on penile sensation. None of the studies found statisticaldifferences between these control arms. In our review, the two control armswere displayed separately in the metagraphs when the data were reported separatelyin the referenced study (Stang 1988 A). Visually, we also see no difference. Other concerns for blinding involve placebo creams. One study (Mohan 1998) did not use a placebo cream and one study (Benini 1993) reported using petroleum jelly as a placebo for EMLA cream.

In nine trials pacifiers were made available to all patients (Butler O'Hara 1998; Holliday 1999; Howard 1994; Howard 1999; Kurtis 1999 A; Mohan 1998; Spencer 1992; Stang 1988 A; Stang 1997). In one (Butler O'Hara 1998) all infants were provided with sugar pacifiers although sucrose was not theintervention under study and its use may have affected results obtained onoutcome measures. In another (Herschel 1998) only one out of the three study groups received a pacifier because it wasused to deliver a sucrose intervention. At least two studies (Kass 2001; Zolnoski 1993) strictly prohibited the use of pacifiers and used oral syringes to deliverthe sucrose intervention. The remaining studies did not report pacifier use.There were too few studies to compare within outcomes, and we could not identifyobvious deviations with use or non-use of pacifiers. Of mention, Blass 1991 A and Zahorodny 1999 both found that in a water via pacifier group, cry time was significantlyreduced compared with the no treatment control group (P < 0.001; P < 0.001).

Discussion

This systematic review incorporates data from 35 trials enrolling 1997neonates to examine a variety of interventions for circumcision pain relief.Although the results are generally applicable to current practice, the reviewidentified a number of important limitations of the primary studies includedin the review and thus the results should be interpreted with some caution.Sample size in the majority of the trials was small (total sample size was less than/or equal to to 80 in 32 out of 35 trials), and there were some differencesin the characteristics of the study subjects. Butler O'Hara 1998 enrolled neonates from an NICU that were between 3 and 105 days postnatalage at the time of circumcision (although still less than 28 days after reaching40 weeks corrected gestational age). Holliday 1999 enrolled low birthweight neonates aged 25 - 27 days at circumcision. Eachof these groups of subjects could have experienced numerous painful or invasivetreatments during their stay in NICU prior to circumcision. Accordingly, their responses during circumcision, regardless of the intervention, couldhave been different from those of the healthy newborns that were recruitedfor the remainder of the trials.

All of the studies included in this review were described as randomised, but 15 of the trial reports did not include sufficient information or describeadequate procedures for assurance of blinding of randomisation. Nine of thetrials were double-blind for all interventions, but some interventions suchas block technique could not be blinded. In six trials of DPNB, a standardizedapproach to the circumcision procedure was not described in the reports, making it impossible to tell whether every infant underwent exactly the samesurgical process. The impact of this could be intensified within individualtrials where more than one operator performed the circumcisions (e.g. Howard 1999, Macke 2001).Other differences that may have affected outcome results between trials ofthe same comparison include the variability in wait time after block administration, length of fasting prior to circumcision, provision of pacifiers or othernon-study interventions, and use of different surgical clamps. Finally, differencesbetween trials in the structure of pain interventions were evident, especiallyin trials of oral sucrose where the dose and method of delivery varied substantially.

The studies included in this review reported on measurement of avariety of pain outcomes (physiological, behavioral, biochemical). Techniquesand methods for measurement of outcomes were more dissimilar than similaracross the trials, even within a single outcome variable (e.g. heart rate), and this presented significant challenges to combining outcome results. Inparticular, the dissimilarity in outcome measures severely limited the feasibilityof combining pain scores across the included studies. None of the reportsincluded in this review offered a definition of pain, and in general, thereports did not differentiate between the painful versus the distressing/stressfulaspects of the circumcision procedure (e.g. removal of foreskin versus applicationof restraints). Reasons for selection of pain scores as outcome measureswere not articulated in most cases, and among the included studies, a varietywere used that differed in conceptual development and in measurement technique.Some pain scores were author-devised measures with no reported psychometrictesting (Arnett 1990; Holliday 1999; Weatherstone 1993), while others measured behavioral indicators that were not conceptually linked to the neonate's experience of pain (Dixon 1984; Macke 2001; Newton 1999; Stang 1988 A). Others were subjective in their measurement technique (Howard 1999; Stang 1997). In six trials, researchers employed validated pain scales developed specifically to measure neonatal pain (Benini 1993; Butler O'Hara 1998; Howard 1994; Joyce 2001; Kass 2001; Taddio 1997).

Sixteen trials included in this review either did not report outcomedata, or did not report data in a format that could be analysed in this review.One of the strengths of this review was that we were able to obtain additionalinformation for three trials. Where means and standard deviations were notavailable, data were imputed or derived from graphs contained in the reports, and missing standard deviations were either calculated from other summarystatistics or substituted with singular or mean standard deviations fromsimilar trials allowing us to maximize the data included under each comparison.

DPNB was identified as the most effective intervention and demonstrateddecreases in time crying and heart rate that were statistically and clinicallysignificant (time crying 54% less, heart rate 30 beats per minute less) whencompared with placebo or no treatment. EMLA also reduced pain responses whencompared with placebo but the differences in time crying (15% less) and heartrate (15 beats per minutes less) were not as large as those observed withDPNB. Topical lidocaine demonstrated statistically significant decreasesin time crying (60 seconds less), heart rate (9 beats per minute less) andserum B-endorphin levels (49 pg/ml less) compared to placebo. The issue ofthe statistical versus clinical significance of the outcome results was notdiscussed in any of the study reports, and no author identified a thresholdfor clinically significant (as opposed to statistically significant) interventioneffects. It should be emphasized that none of the interventions examinedin these trials completely eliminated pain responses to circumcision.

Ease of administration of the pain interventions will influence theapplicability of the results of this review to current clinical practice.The relative ease of establishing the different penile blocks was not systematicallyevaluated, but it was suggested that the ring block technique is easier andsafer because it eliminates the risk of injection of lidocaine into the dorsalvessels (Hardwick Smith 1998). A single study reported on use of local penile block (Masciello 1990) which appears to be similar in technique to ring block. Few adverse effectswere reported with use of any of the penile blocks. EMLA and lidocaine topicalanaesthetics are effective for circumcision pain when compared with placeboor no treatment, but their use may be precluded because of difficulties inapplication and the time required for maximum anaesthetic effect. Adverseeffects such as transient skin reactions were reported but not consideredserious, and methaemoglobin levels, when measured, were within normal range.

Reviewers' conclusions

Implications for practice

Circumcision is a painful procedure and routine or elective newborn circumcisionis not recommended by either the American Academy of Pediatrics or the CanadianPaediatric Society. However, if circumcision is performed, the results ofthis review show that DPNB, RB and the topical anaesthetics EMLA and lidocainecream can be recommended over no treatment for attenuation of circumcisionpain. DPNB demonstrated the most consistent results, has been the most comprehensivelystudied, and was the most effective in terms of clinically significant reductionsin pain responses. RB is also effective to reduce circumcision pain comparedwith placebo. The RB technique may be easier and safer to use because iteliminates the risk of injection of lidocaine into the dorsal vessels.

EMLA and lidocaine topical anaesthetics are effective for circumcisionpain when compared with placebo or no treatment, but their use may be precludedbecause of difficulties in application and the time required for maximumanaesthetic effect. Adverse effects with EMLA use such as transient skinreactions were reported but not considered serious, and methaemoglobin levels, when measured, were within normal range. Topical anaesthetics are a lesseffective alternative to no treatment when expertise with penile blocks isnot readily available.

Results for oral sucrose, oral analgesics and environmental modificationinterventions were either inconsistent or did not produce significantly differentoutcome results. These therapies cannot be recommended as treatments forcircumcision pain.

None of the studied interventions completely eliminated the pain response to circumcision.

Circumcisions performed using the Mogen clamp take less time thanis required using Gomco clamps. Shorter procedure time may reduce the totalamount of pain experienced during circumcision, and may be important in termsof practitioner time to do the surgery.

Implications for research

Future studies should compare two or more active interventions for painrelief - a placebo or no-treatment control group is no longer acceptable.The impact of different "wait times" on the effectiveness of penile blocksand the relative acceptability and ease of administration of DPNB versusRB for practitioners should be systematically investigated. Use of the Mogenclamp in combination DPNB and RB should be investigated further to identifyan optimal target time for circumcision surgery and to maximize anaestheticeffect. Although sucrose cannot be recommended as an intervention for circumcisionpain at this time, research to determine the optimal dose and delivery methodand the effect of combining oral sucrose with other interventions and comfortmeasures (e.g. nonnutritive sucking) should be pursued.

Lidocaine block and topical anaesthetic interventions could be usefulin other situations where neonates undergo acute procedural pain. The painassociated with chest tube insertion, lumbar puncture, insertion of percutaneouscentral lines and other procedures commonly performed on high risk neonatesmay be significantly reduced with use of an appropriately adapted lidocaineblock technique or topical anaesthetics. Further research should be pursuedto identify situations where this potential can be examined.

Acknowledgements

We are grateful to Dr. J. R Holman, Dr. C Johnston, and Dr. J. F. Keckfor their willingness to provide us with additional data from their studies.

Potential conflict of interest

Two of the reviewers, Brady-Fryer and Lander, were authors of a trial, Lander 1997, included in this review.

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Arnett 1990 RCT
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - no
Blinding of outcome measurement - can't tell
52 male NB; FT; BW > 2000 g; 5 min Apgar scores greater than/or equal to 6 0.4 ml lidocaine DPNB (n=23)
0.4 ml saline DPNB (n=22)
no treatment control (n=7)
WT not reported; mean length for entire procedure was 4.4 minutes
HR, infant irritability, O2sat
  • no treatment control group added after study start; results for saline DPNBgroup and no treatment group were combined for analysis (n=29)
  • data missing for 3 subjects (1 in each group) and cases deleted from analysis
  • procedure not standardized
  • lower dose lidocaine used (0.4 ml total)
  • subjects fasted 90 minutes prior to circumcision
  • Gomco clamp
  • adverse effects reported
A
Benini 1993 RCT
Blinding of randomization - can't tell
Blinding of intervention - no
Complete follow-up - no
Blinding of outcome measurement - yes
28 male NB; FT; BW > 2500g; 5 min Apgar > 7; < 7 d age 0.5 ml (0.5g) LP cream (n=14)
0.5 ml (0.5 g) petroleum jelly (n=14)
applied and covered with occlusive dressing 45 - 60 min prior
HR, O2sat, % time crying, facial action
  • 1 withdrawal from placebo group because infant not FT
  • procedure standardized to 9 phases
  • Gomco clamp
  • no adverse effects reported
B
Blass 1991 A RCT
Blinding of randomization - can't tell
Blinding of intervention - partial
Complete follow-up - can't tell
Blinding of outcome measurement - yes
30 male NB, FT; 28 - 54 h age; Apgars > 8 1.5 ml 24% sucrose by nipple
1.5 ml water by nipple
no treatment control
*comparison is sucrose versus water (placebo)
number subjects per group not specified
3 min WT after intervention
% time crying
  • assumed distribution was equal (10/group) for data analysis
  • procedure not standardized
  • infants fasted for at least 1 hr prior
  • Gomco clamp
B
Blass 1991 B see Blass A see Blass A * comparison is sucrose versus no treatment B
Butler O'Hara 1998 RCT
Blinding of randomization - yes
Blinding of intervention - no
Complete follow-up - no
Blinding of outcome measurement - yes
50 male infants in NICU; greater than/or equal to 34.5 weeks (post-menstrual) at time of circumcision and stable for discharge
participants were 3 -105 days age at time of circumcision
0.5 ml (0.5g) LP cream (n=25)
0.7 - 1.0 ml lidocaine DPNB + placebo cream (n=25)
creams applied 60 min prior and covered with occlusive dressing
3 min WT after DPNB
HR; RR; NIPS score (primary outcome)
  • non-randomized, no treatment group (n=20) also had data collected
  • outcome data for 6 subjects (4 LP cream, 2 DPNB) lost due to technical difficulties
  • infants fasted for 2 to 3 hours before circumcision
  • all subjects had sugar pacifiers during procedure
  • procedure standardized
  • Plastibell clamp
  • adverse effects reported
A
Dixon 1984 RCT
Blinding of randomization - yes
Blinding of intervention - can't tell
Complete follow-up - yes
Blinding of outcome measurement - partial
31 male NB, FT, AGA, < 7 days age, > 2500 gm, 5 min Apgar > 7 0.8 ml lidocaine DPNB (n=15)
0.8 ml saline DPNB (n=8)
no treatment control (n=8)
4 - 5 min WT
Brazelton Neonatal Assessment Scale
  • Holve 1983 is primary study report
  • circumcision procedure not standardized
  • all circumcisions performed by single physician
  • Gomco clamp
  • adverse effects reported
A
Hardwick Smith 1998 RCT
Blinding of randomization - yes
Blinding of intervention - no
Complete follow-up - can't tell
Blinding of outcome measurement - no
40 male NB; FT; Apgar greater than/or equal to 7; 6 hr - 5 days age; fasting 30 -120 min prior; normal exam 1.0 ml 5% lidocaine RB (n=20)
no treatment control (n=20)
3 min WT
HR; RR; O2sat; behavioral state; cry time
  • O2sat not recorded in up to 50% of infants
  • single operator performed all circumcisions
  • Gomco clamp
  • no adverse effects reported
A
Herschel 1998 RCT
Blinding of randomization - yes
Blinding of intervention - no
Complete follow-up - no
Blinding of outcome measurement - yes
120 male NB; FT; > 2500g; Apgar greater than/or equal to 8 at 5 min; greater than/or equal to 12 hr age 0.8 ml 1% lidocaine DPNB (n=40)
10 ml 50% oral sucrose via nipple (n=40)
no treatment control (n=40)
3 min WT for DPNB; 2 min WT for sucrose group
HR; O2sat (%)
  • 1 withdrawal from sucrose group, circumcision contraindicated
  • O2 sat data missing - 31% intervals control, 10% intervals DPNB, 8% sucrose
  • infants fasted 30 min prior to circumcision
  • sucrose group had nipple throughout procedure, other groups did not have pacifier
  • Gomco clamp
A
Holliday 1999 RCT
Blinding of randomization - yes
Blinding of intervention - no
Complete follow-up - no
Blinding of outcome measurement - can't tell
50 male preterm/low birthweight NICU patients,
subjects weighed 1600 to 2500g at time of circumcision
25-27 days age, 36 week GA at circumcision
0.8 ml 1% lidocaine DPNB + placebo cream (n= 19)
LP cream (n=12) (group enrollment stopped, excluded from data analyses)
placebo cream (n=19)
DPNB 5 min WT
cream applied 1 hr prior and covered with occlusive dressing
HR, RR, O2sat, systolic BP, behavioral score, serum B-endorphin
  • LP cream group discontinued due to redness and blistering of foreskin in 2 infants
  • procedure not standardized
  • all circumcisions performed by single operator
  • pacifiers provided
  • Gomco clamp
  • no adverse effects reported for DPNB group
A
Holve 1983 RCT
Blinding of randomization - yes
Blinding of intervention - partial
Complete follow-up - yes
Blinding of outcome measurement - can't tell
31 male NB; FT, < 7 days age, > 2500 gm, 5 min Apgar > 7 0.8 ml 1% lidocaine DPNB (n=15)
0.8 ml saline DPNB (n=8)
no treatment control (n=8)
4-5 min WT
HR; % time crying per interval; clinical observation of anesthesia effectiveness (good, fair, poor)
  • procedure standardized
  • Gomco clamp
  • adverse effects reported
A
Howard 1994 RCT
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - yes
Blinding of outcome measurement - yes
44 male NB, healthy, AGA, FT, Apgars > 7, greater than/or equal to 24 h age acetaminophen 15 mg/kg/dose (n= 23)
placebo (n= 21)
given 2 hr prior and q 6H X 24 hr following
HR; RR; cry time; post-operative comfort score; feeding behavior pre/post
  • infants fasted 2 - 3 h prior to circumcision
  • all had pacifiers
  • procedure standardized
  • single operator performed all circumcisions
  • Gomco clamp
  • no adverse effects reported
A
Howard 1999 RCT
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - unclear
Blinding of outcome measurement - yes
62 male NB; healthy; AGA; FT 1g LP cream + 0.8 ml saline DPNB (n=31)
0.8 ml 1% lidocaine DPNB + 1g placebo cream (n=31)
4 min WT for DPNB
creams applied 1 hr prior and covered with occlusive dressing
HR; RR; behavioral distress score
  • 2 infants withdrawn (1 tachypnea, 1 parents withdrew consent)
  • procedure standardized
  • 3 operators performed the circumcisions
  • all subjects had pacifiers
  • Gomco clamp
  • no adverse effects reported
A
Joyce 2001 RCT;
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - yes
Blinding of outcome measurement - yes
23 male NB, FT; 5 min Apgar > 7; BW > 2500 g; age < 7 d LP cream (1 - 2 g) + music (n=6)
LP cream + no music (n=5)
placebo cream + music (n=7)
placebo cream + no music (n=5)
cream applied 1 hr prior and covered with occlusive dressing
music started just prior to procedure and continued to 10 min post procedure
HR, O2sat, cry duration; RR, Riley Infant pain scale, salivary cortisol, infant state
  • pilot study
  • no adverse effects reported
A
Kass 2001 RCT
Blinding of randomization - can't tell
Blinding of intervention - no
Complete follow-up - yes
Blinding of outcome measurement - can't tell
71 healthy male NB lidocaine DPNB (n=24)
2ml D50W orally (n=23)
2 ml H2O orally (n=24)
WT 2 to 6 min
time cry (primary outcome) ; HR; O2sat ; modified behavioral pain scale
  • additional data obtained from authors
  • no pacifiers used
  • Gomco clamp
B
Kaufman 2002 RCT
Blinding of randomization - can't tell
Blinding of intervention - partial
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
57 NB; healthy; male; FT; Apgar > 7 at 5 min Mogen + water pacifier (15)
Mogen + 24% sucrose pacifier (n=14)
Gomco+ water pacifier (n=14)
Gomco + 24% sucrose pacifier (n=14)
time crying; grimacing, procedure length
  • all subjects had EMLA cream applied between 1 and 3 hr before procedure
  • single operator performed all circumcisions
  • procedure standardized
  • infants fasted from 15 min to 4 hr before procedure
  • no adverse effects reported
B
Kurtis 1999 A RCT
Blinding of randomization - can't tell
Blinding of intervention - no
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
48 male NB; FT; 5 min Apgar greater than/or equal to 7 Mogen clamp and 0.8 ml 1% lidocaine DPNB (n=16)
Mogen clamp and no DPNB (n=16)
Gomco clamp and 0.8 mL 1% lidocaine DPNB (n=8)
Gomco clamp and no DPNB (n=8)
5 minute WT
time crying, HR, O2sat, salivary cortisol, RR
  • all subjects had pacifiers
  • infants fasted 1 - 2 hr before procedure
  • Mogen = 8 procedural steps; Gomco = 13 procedural steps
B
Kurtis 1999 B see Kurtis 1999 A see Kurtis 1999 A comparison is Mogen versus Gomco for patients receiving no DPNB D
Lander 1997 RCT
Blinding of randomization - yes
Blinding of intervention - partial
Complete follow-up - no
Blinding of outcome measurement - yes
54 male NB; FT; AGA; 1-3 d age 2g LP cream (n=15)
placebo cream (n=12)
0.8 ml 1% lidocaine DPNB (n=14)
0.8 ml 1% lidocaine RB (n=13)
- penile blocks 8 min WT; creams applied 90 min prior and covered with occlusive dressing
HR; time cry; O2 sat, RR, palmar sweat, metHgb level
  • 2 withdrawals, 1 in placebo group, 1 in RB group (1 parents unable to remain in hospital, 1 required phototherapy)
  • procedure standardized
  • Gomco clamp
  • adverse effects reported
A
Macke 2001 RCT
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - yes
Blinding of outcome measurement - yes
60 male NB; FT; Apgar greater than/or equal to 8 acetaminophen 10 mg/kg (n=29)
placebo (n=31)
given 1 hr prior to circumcision
HR, Nursing Child Assessment Feeding Scale, cry time, infant state
  • 12 operators performed circumcisions in analgesia group, 21 performed circumcisions in placebo group
  • Gomco clamp
A
Marchette 1989 RCT
Blinding of randomization - can't tell
Blinding of intervention - can't tell
Complete follow-up - no
Blinding of outcome measurement - can't tell
103 male NB; Apgar greater than/or equal to 8 classical music (n=25)
intrauterine sounds (n=15)
control (no nurse present) (n=18)
HR; heart rhythm; BP; TcpO2; MDFMCS; BNAS
  • 103 subjects randomized, 45 cases deleted due to missing data or prolonged circumcisions
  • procedure standardized
  • Gomco clamp
B
Marchette 1991 RCT
Blinding of randomization - can't tell
Blinding of intervention - can't tell
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
121 male NB; Apgar =/> 6; normal delivery; 2 - 9 days age taped music (n=20)
intrauterine sounds (n=20)
pacifier (n=20)
music and pacifier (n=20)
intrauterine sounds and pacifier (n=20)
control - no treatment (n=21)
HR, rhythm, BP; tcPO2; rate pressure product, BNAS; crying
  • cases excluded if circumcision longer than 15 min or if bleeding
  • Gomco clamp
B
Masciello 1990 RCT
Blinding of randomization - can't tell
Blinding of intervention - no
Complete follow-up - no
Blinding of outcome measurement - can't tell
30 male NB, healthy, FT 0.8 ml 1% lidocaine DPNB (n=10)
0.8 ml 1% lidocaine local block (n=10)
no treatment control (n=10)
5 min WT
plasma cortisol, HR, O2sat, cry
  • cortisol levels obtained for first 3 cases lost (1 in each group)
  • all fasted for at least 3 hours prior
  • procedure standardized
  • single operator performed all circumcisions
  • Gomco clamp
B
Maxwell 1987 RCT;
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - yes
Blinding of outcome measurement - can't tell
30 male NB; FT; healthy 0.8 ml 1% lidocaine DPNB (n=20)
no treatment control (n=10)
5 min WT
HR, O2sat, BP, plasma lidocaine
  • subjects fasted for 2 hr prior
  • procedure not standardized
  • Gomco clamp
  • no adverse effects observed
A
Mohan 1998 RCT
Blinding of randomization - can't tell
Blinding of intervention - can't tell
Complete follow-up - yes
Blinding of outcome measurement - can't tell
60 male NB; FT; BW greater than/or equal to 2500 g; 5 min Apgar greater than/or equal to 7; < 5 days age 5 g LP cream + 2 ml 24% sucrose via pacifier (n=19)
5 g LP cream + water via pacifier (n=20)
2 ml 24% sucrose via pacifier (n=21)
water via pacifier (n=19) - non-randomized control
- cream applied 45-60 min prior, covered with occlusive dressing
HR; O2sat; BP; cry duration
  • control group not randomized
  • all received pacifiers
  • procedure standardized
  • Gomco clamp
  • no adverse effects reported
B
Mudge 1989 RCT
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - yes
Blinding of outcome measurement - can't tell
44 male NB; 5 min Apgar > 7; BW 2.5 - 4.5 kg; FT; age 12 - 72 h 4% lidocaine cream (n=20)
placebo cream (n=24)
cream applied 2 hr prior covered with occlusive dressing
HR, RR, O2sat, cry time, behavior
  • Gomco clamp
  • procedure standardized
A
Newton 1999 RCT
Blinding of randomization - yes
Blinding of intervention - no
Complete follow-up - no
Blinding of outcome measurement - can't tell
194 male NB; healthy 0.8 ml 1% lidocaine DPNB (n=92)
0.8 ml 1% buffered lidocaine (n=102)
HR (primary outcome variable) ; O2sat; number crying/phase; modified BNAS
  • complete data on crying for 165 subjects; complete data on BNAS for 194
  • complete data on HR, O2 sat for 143 subjects due to technical difficulties
  • procedure standardized
  • Mogen clamp
  • adverse effects reported
A
Spencer 1992 RCT
Blinding of randomization - can't tell
Blinding of intervention - can't tell
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
75 male NB; BW 2500 - 4500 g; >12 hr age; 5 min Apgar > 6; normal exam lidocaine DPNB - 5 min WT (n=15)
lidocaine DPNB with 2 min WT (n=15)
1% chloroprocaine DPNB with 3 min WT (n=15)
1% chloroprocaine DPNB with 5 min WT (n=15)
no treatment control (n=15)
cry duration, O2Sat, HR, BNAS
  • all received pacifiers
  • fed 60 to 90 min prior to circumcision
  • procedure standardized
  • Gomco clamp
B
Stang 1988 A RCT
Blinding of randomization - can't tell
Blinding of intervention - partial
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
60 male NB; > 24 hr age; BW > 3000 g; 5 min Apgar > 7; uncomplicated delivery 0.8 ml 1% lidocaine DPNB (n=20)
saline DPNB (n=20)
no treatment control (n=20)
5 min WT
*comparison is DPNB versus no treatment
% time cry, modal behavior state, plasma cortisol
  • all handling avoided for 2 hr prior
  • 1/2 had blood sample for cortisol at 30 min, 1/2 at 90 min
  • all received pacifiers and continuously soothed
  • procedure standardized to 3 periods
  • Gomco and Plastibell used at operator's discretion
  • adverse effects reported
B
Stang 1988 B see Stang A see Stang A *comparison is DPNB versus sham (saline) treatment see Stang A see Stang A B
Stang 1997 RCT
Blinding of randomization - can't tell
Blinding of intervention - partial
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
83 male NB, > 20 hr age; BW 3000 - 4000 gm; 5 min Apgar greater than/or equal to 8; FT group 1 = 0.8 ml 1% lidocaine DPNB, padded restraint, water via pacifier (n=20)
group 2 = 0.8 ml 1% lidocaine DPNB, regular restraint, 24% sucrose via pacifier (n=20)
group 3 = 0.8 ml 1% buffered lidocaine DPNB, regular restraint, water via pacifier (n=20)
group 4 = 0.8 ml 1% lidocaine DPNB, regular restraint, water via pacifier (n=20) (control)
5 min WT
behavioral distress scale, plasma cortisol 30 min post-circ
  • 5th arm of study (24% sucrose only) abandoned due to high behavioral distress scores
  • no forced preoperative fasting period
  • all handling avoided for 1 hr prior
  • procedure standardized
  • all given pacifiers
  • Gomco and Plastibell methods used
B
Taddio 1997 RCT
Blinding of randomization - can't tell
Blinding of intervention - yes
Complete follow-up - no
Blinding of outcome measurement - yes
68 male NB, BW greater than/or equal to 2500 g; FT; no jaundice or metHgb 1 g (1ml) LP cream (n=38)
1 g (1ml) placebo cream (n=30)
creams covered with occlusive dressing for 60 - 80 min prior
HR, time cry, NFCS, systolic/diastolic BP, metHgb
  • 68 subjects randomized, 8 in the LP group included in safety analysis only, 59 subjects in the efficacy analysis
  • 1 withdrawal
  • procedure standardized
  • Gomco clamp
  • adverse effects reported
B
Weatherstone 1993 RCT
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - yes
Blinding of outcome measurement - yes
30 male NB; BW greater than/or equal to 2500 g; FT; Apgar greater than/or equal to 7; 6-72 hr age 0.5 g 30% lidocaine cream (n=15)
placebo cream (n=15)
applied 20 min prior to circumcision and covered with occlusive dressing
HR, RR, O2 sat, BP, Newborn Pain Behavior Scale, serum B-endophin (15 min post), serum lidocaine
  • procedure not standardized
  • Gomco and Plastibell clamps
  • no adverse effects reported
A
Williamson 1983 RCT
Blinding of randomization - yes
Blinding of intervention - no
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
30 male NB; BW = 2500 - 4000 g; 24 - 72 hr age; FT; Apgar score > 7; systolic BP > 40 mm Hg 0.6 to 0.8 1% ml lidocaine DPNB (n=20)
no treatment control (n=10)
4 min WT
TcpO2, time cry; HR, RR
  • fasted at least 2 hr prior
  • PI performed all circumcisions
  • Gomco clamp
C
Williamson 1986 RCT
Blinding of randomization - yes
Blinding of intervention - no
Complete follow-up - yes
Blinding of outcome measurement - can't tell
24 male NB; Apgar > 7; BW 2500 - 4500 g; FT; 24 - 72 hr age; normal physical exam lidocaine DPNB (n= 11)
no treatment control (n=13)
5 min WT
plasma cortisol pre and 30 min post circumcision
  • 6 additional infants circumcised after study completed to serve as controls for blood sampling/injections
  • all circumcisions done by PI
  • Gomco clamp
A
Williamson 1997 RCT
Blinding of randomization - yes
Blinding of intervention - no
Complete follow-up - yes
Blinding of outcome measurement - yes
30 male NB; FT; greater than/or equal to 24 hr age; BW 2500- 4500g; Apgar > 7 lidocaine DPNB (n=20)
no treatment control (n=10)
TcPO2, RR, HR, cardiac rhythm, cry time and type
  • procedure standardized
  • fasting at least 2 hr prior
  • Gomco clamp
  • adverse effects reported
A
Woodman 1999 RCT
Blinding of randomization - yes
Blinding of intervention - yes
Complete follow-up - yes
Blinding of outcome measurement - can't tell
61 male NB; Apgar > 7; FT; BW > 2500 g; 6-72 hr age 1 g (1 ml) LP cream (n=20)
30% lidocaine cream (n=20)
placebo cream (n=21)
creams applied 1 hr prior and covered with occlusive dressing
HR; time crying; O2sat
  • all subjects fasted for at least 1 hr prior
  • procedure standardized
  • all circumcisions performed by same operator
  • Gomco clamp
A
Zahorodny 1998 RCT
Blinding of randomization - can't tell
Blinding of intervention - yes
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
53 healthy male NB 1g LP cream + 2 ml 50% sucrose
1g LP cream + 2 ml H2O
1g placebo cream + 2 ml 50% sucrose
1g placebo cream + 2mL H2O
creams applied 1 hr prior; sucrose or H2O oral 2 min prior
total n=53, allocation not clear
time cry
  • abstract only, number of subjects per group not reported
  • assumed equal distribution to groups
    unable to obtain additional data
B
Zahorodny 1999 RCT
Blinding of randomization - can't tell
Blinding of intervention - yes
Complete follow-up - can't tell
Blinding of outcome measurement - can't tell
61; healthy male NB 10 ml 50% sucrose via pacifier
10 ml H2O via pacifier
no treatment control
total n=61, allocation not clear
HR, time cry
  • abstract only, unable to obtain additional data
  • assumed equal distribution to groups
B
Zolnoski 1993 RCT
Blinding of randomization - yes
Blinding of intervention - can't tell
Complete follow-up - yes
Blinding of outcome measurement - yes
20 male NB, 8 - 120 hr age, FT; no maternal medication, BW > 2700 g, 5 min Apgar greater than/or equal to 7 2.4 ml 24% sucrose (n=10)
2.4 ml water via syringe (n=10)
given 3 min prior
cry time, HR
  • pilot study - Master's thesis
  • procedure standardized
  • Gomco clamp
A

ParticipantCharacteristics: NB = newborn; AGA = growth appropriate for gestational age; BW = birthweight; FT = full-term greater than/or equal to 37 weeks gestation; NICU - neonatalintensive care unit;
Interventions: DPNB = dorsal penile nerve blockas described in Kirya (1978) using 1% lidocaine without epinephrine; RB= ring block following the procedure outlined by Broadman (1987) ; local block= local anesthesia performed by injecting 0.4 ml of 1% lidocaine withoutepinephrine subcutaneously into two positions on the foreskin at the levelof the corona; LP cream = a lidocaine-prilocaine cream commonly known asEMLA (eutectic mixture of local anesthetics) ; D50W = 50% dextrose oral solution;control/no treatment group = group receiving no intervention for pain; placebogroup = group receiving sham intervention which mimics active interventions;WT = the time from completion of administration of pain relief interventionto the start of circumcision procedure;
Scales: NIPS = Neonatal InfantPain Scale consisting of six behavioral components with a composite scoreof 0 to 7 (Lawrence, 1993) ; NFCS score = evaluates the presence or absenceof 10 discrete facial actions at outlined in Grunau (1987), scored from videotapein 2 sec intervals for the first 20 sec of each circumcision phase; BNAS= Brazelton Neonatal Behavioral Assessment Scale; MDFMCS = Maximally DiscriminativeFacial Movement Coding System for coding facial movements of three facialregions to determine emotions demonstrated; NCAFS = Nursing Child AssessmentFeeding Scale measures mother-infant interaction using 76 behavioral itemsgrouped into six subscales based on concepts of adaptation and synchronism- mother and infant are observed during natural feeding session; MBPS =modified behavioral pain scale;
Physiological measures: HR = heart ratein beats/minute (bpm) ; TcpO2 = transcutaneous oxygen saturation; O2sat =% oxygen saturation in the blood; BP = blood pressure; RR = respiratory ratein breaths/minute;

Biochemical measures: [PC] = plasma cortisol concentration; metHgb = methemoglobin

Characteristics of excluded studies

Study Reason for exclusion
Malnory 2003 Study subjects not randomized to treatment groups, intervention chosen by physician
Mintz 1989 Not a clinical trial, no comparison between groups
Olson 1998 Study subjects not randomized to treatment groups, intervention chosen by physician
Russell 1996 Not a clinical trial, all subjects received EMLA, Plastibell technique
Taddio 2000 Cohortdesign with two study groups; all recruited subjects assigned to Group 1;Group 2 data obtained from previously conducted RCT
Taeusch 2002 Trialof head to head comparison of surgical devices (clamps) used for circumcisionprocedure, procedural differences have indirect effect on circumcision pain

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References to studies

Included studies

Arnett 1990

{published data only}

ArnettRM, Jones JS, Horger EO. Effectiveness of 1% lidocaine dorsal penile nerveblock in infant circumcision. Americal Journal of Obstetrics and Gynecology1990;163:1074-80.

Benini 1993

{published data only}

Benini F, Johnston CC, Faucher D, Aranda J V. Topical anesthesia during circumcision in newborn infants. JAMA 1993;270:850-3.

Blass 1991 A

{published data only}

Blass EM, Hoffmeyer LB. Sucrose as an analgesic for newborn infants. Pediatrics 1991;87:215-18.

Blass 1991 B

{published data only}

Blass EM, Hoffmeyer LB. Sucrose as an analgesic for newborn infants. Pediatrics 1991;87:215-18.

Butler O'Hara 1998

{published data only}

Butler-O'HaraM, LeMoine C, Guillet R. Analgesia for neonatal circumcision: A randomizedcontrolled trial of EMLA cream versus dorsal penile nerve block. Pediatrics1998;101:e5.

Dixon 1984

{published data only}

DixonS, Snyder J, Holve R, Bromberger P. Behavioral effects of circumcision withand without anesthesia. Journal of Developmental and Behavioral Pediatrics1984;5:246-50.

Hardwick Smith 1998

{published data only}

Hardwick-SmithS, Mastrobattista JM, Wallace PA, Ritchey ML. Ring block for neonatal circumcision.Obstetrics and Gynecology 1998;91:930-4.

Herschel 1998

{published data only}

HerschelM, Khoshnood B, Ellman C, Maydew N, Mittendorf R. Randomized trial of a sucrosepacifier for pain control. Archives of Pediatrics & Adolescent Medicine1998;152:279-84.

Holliday 1999

{published data only}

HollidayMA, Pinckert TL, Kiernan SC, Kunos I, Angelus P, Keszler M. Dorsal penilenerve block vs topical placebo for circumcision in low-birth-weight neonates.Archives of Pediatrics & Adolescent Medicine 1999;153:476-80.

Holve 1983

{published data only}

HolveRL, Bromberger PJ, Groveman HD, Klauber MR, Dixon SD, Snyder JM. Regionalanesthesia during newborn circumcision. Clinical Pediatrics 1983;22:813-8.

Howard 1994

{published data only}

HowardCR, Howard FM, Weitzman ML. Acetaminophen analgesia in neonatal circumcision: the effect on pain. Pediatrics 1994;93:641-6.

Howard 1999

{published data only}

HowardCR, Howard FM, Fortune K, Generelli P, Zolnoun D, tenHoopen C et al. A randomized, controlled trial of a eutectic mixture of local anesthetic cream (lidocaineand prilocaine) versus penile block for pain relief during circumcision.American Journal of Obstetrics and Gynecology 1999;181:1506-11.

Joyce 2001

{published data only}

JoyceBA, Keck JF, Gerkensmeyer J. Evaluation of pain management interventionsfor neonatal circumcision pain. Journal of Pediatric Health Care 2001;15:105-14.

Kass 2001

{published data only}

Kass FC, Holman JR. Oral glucose solution for analgesia in infant circumcision. Journal of Family Practice 2001;50:785-8.

Kaufman 2002

{published data only}

KaufmanGE, Cimo S, Miller LW, Blass EM. An evaluation of the effects of sucroseon neonatal pain with 2 commonly used circumcision methods. American Journalof Obstetrics and Gynecology 2002;186:564-8.

Kurtis 1999 A

{published data only}

KurtisPS, DeSilva HN, Bernstein BA, Malakh L, Schechter NL. A comparison of theMogen and Gomco clamps in combination with dorsal penile nerve block in minimizingthe pain of neonatal circumcision. Pediatrics 1999;103:e23.

Kurtis 1999 B

{published data only}

KurtisPS, DeSilva HN, Bernstein BA, Malakh L, Schechter NL. A comparison of theMogen and Gomco clamps in combination with dorsal penile nerve block in minimizingthe pain of neonatal circumcision. Pediatrics 1999;103:e23.

Lander 1997

{published data only}

LanderJ, Brady-Fryer B, Metcalfe J, Nazarali S, Muttitt S. A comparison of ringblock, dorsal penile nerve block, and topical anesthesia for neonatal circumcision.JAMA 1997;278:2157-62.

Macke 2001

{published data only}

MackeJK. Analgesia for circumcision: Effects on newborn behavior and mother/infantinteraction. Journal of Obstetric, Gynecologic, and Neonatal Nursing 2001;30:507-14.

Marchette 1989

{published data only}

Marchette L, Main R, Redick E. Pain reduction during neonatal circumcision. Pediatric Nursing 1989;15:207-10.

Marchette 1991

{published data only}

MarchetteL, Main R, Redick E, Bagg A, Leatherland J. Pain reduction interventionsduring neonatal circumcision. Nursing Research 1991;40:241-4.

Masciello 1990

{published data only}

MascielloA L. Anesthesia for neonatal circumcision: Local anesthesia is better thandorsal penile block. Obstetrics and Gynecology 1990;75:834-8.

Maxwell 1987

{published data only}

MaxwellLG, Yaster M, Wetzel RC, Niebyl JR. Penile nerve block for newborn circumcision.Obstetrics and Gynecology 1987;70:415-19.

Mohan 1998

{published data only}

MohanCG, Risucci DA, Casimir M, Gulrajani-LaCorte, M. Comparison of analgesicsin ameliorating the pain of circumcision. Journal of Perinatology 1998;18:13-9.

Mudge 1989

{published data only}

MudgeD, Younger J B. The effects of topical lidocaine on infant response to circumcision.Journal of Nurse-Midwifery 1989;34:335-40.

Newton 1999

{published data only}

NewtonCW, Mulnix N, Baer L, Bovee T. Plain and buffered lidocaine for neonatalcircumcision. Obstetrics and Gynecology 1999;93:350-2.

Spencer 1992

{published data only}

SpencerDM, Miller K A, O'Quin M, Tomsovic J P, Anderson B, Wong D et al. Dorsalpenile nerve block in neonatal circumcision: Chloroprocaine versus lidocaine.American Journal of Perinatology 1992;9:214-8.

Stang 1988 A

{published data only}

StangH J, Gunnar M R, Snellman L, Condon L M, Kestenbaum R. Local anesthesia forneonatal circumcision - Effects on distress and cortisol response. JAMA 1988;259:1507-11.

Stang 1988 B

{published data only}

StangHJ, Gunnar MR, Snellman L, Condon LM, Kestenbaum R. Local anesthesia forneonatal circumcision - Effects on distress and cortisol response. JAMA 1988;259:1507-11.

Stang 1997

{published data only}

StangHJ, Snellman LW, Condon LM, Conroy MM, Liebo R, Brodersen L et al. Beyonddorsal penile nerve block: A more humane circumcision. Pediatrics 1997;100:e3.

Taddio 1997

{published data only}

TaddioA, Stevens B, Craig K, Rastogi P, Ben-David S, Shennan A et al. Efficacyand safety of lidocaine-prilocaine cream for pain during circumcision. NewEngland Journal of Medicine 1997;336:1197-1201.

Weatherstone 1993

{published data only}

WeatherstoneKB, Rasmussen LB, Erenberg A, Jackson EM, Claflin KS, Leff RD. Safety andefficacy of a topical anesthetic for neonatal circumcision. Pediatrics 1993;92:710-4.

Williamson 1983

{published data only}

WilliamsonPS, Williamson ML. Physiologic stress reduction by a local anesthetic duringnewborn circumcision. Pediatrics 1983;71:36-40.

Williamson 1986

{published data only}

Williamson PS, Evans ND. Neonatal cortisol response to circumcision with anesthesia. Clinical Pediatrics 1986;25:412-5.

Williamson 1997

{published data only}

WilliamsonML. Circumcision anesthesia: A study of nursing implications for dorsal penilenerve block. Pediatric Nursing 1997;23:59-63.

Woodman 1999

{published data only}

WoodmanPJ. Topical lidocaine-prilocaine versus lidocaine for neonatal circumcision:A randomized controlled trial. Obstetrics and Gynecology 1999;93:775-9.

Zahorodny 1998

{published data only}

ZahorodnyW, Surez Y, Marshall R, Regan M, Holland B, Brendel D. Efficacy of EMLA andsucrose for crying associated with circumcision. In: Pediatrric Research.Vol. 43 Supplement 2. 1998:204.

Zahorodny 1999

{published data only}

ZahorodnyW, David ES, Estrada P, Co J, Marshall R. Efficacy of a sucrose pacifierfor newborn pain. In: Pediatric Research. Vol. 45 PART 2 of 2. 1999:17A.

Zolnoski 1993

{unpublished data only}

Zolnoski BAP. Effect of sucrose ingestion on pain during newborn circumcision [Masters thesis]. Univ. of Florida, 1993.

Excluded studies

Malnory 2003

{published data only}

MalnoryM, Johnson TS, Kirby RS. Newborn behavioral and physiological responses tocircumcision. MCN. The American Journal of Maternal Child Nursing 2003;28:313-7.

Mintz 1989

{published data only}

Mintz MR, Grillo R. Dorsal penile nerve block for circumcision. Clinical Pediatrics 1989;28:590-1.

Olson 1998

{published data only}

OlsonT, Wessman Downey V. Infant physiological responses to noxious stimuli ofcircumcision with anesthesia and analgesia. Pediatric Nursing 1998;24:385-9.

Russell 1996

{published data only}

RussellCT, Chaseling J. Topical anesthesia in neonatal circumcision: a study of208 consecutive cases. Australian Family Physician 1996;25:530-4.

Taddio 2000

{published data only}

TaddioA, Pollock N, Gilbert-MacLeod C, Ohlsson K, Koren G. Combined analgesia andlocal anesthesia to minimize pain during circumcision. Archives of Pediatrics& Adolescent Medicine 2000;154:620-3.

Taeusch 2002

{published data only}

TaeuschHW, Martinez AM, Partridge JC, Sniderman S, Armstrong-Wells J, Fuentes-AfflickE. Pain during Mogen or Plastibell circumcision. Journal of Perinatology2002;22:214-8.

* indicates the primary reference for the study

Other references

Additional references

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American Academy of Pediatrics Task Force on Circumcision. Circumcision Policy Statement. Pediatrics 1999;103:686-93.

Abu-Saad 1998

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Anand 2001

AnandKJS. Consensus statement for the prevention and management of pain in thenewborn. Archives of Pediatrics & Adolescent Medicine 2001;155:173-80.

Anders 1974

AndersTF, Chalemian RJ. The effects of circumcision on sleep-wake states in humanneonates. Psychosomatic Medicine 1974;36:174-9.

Auerbach 1978

AuerbachMR, Scanlon JW. Recurrence of pneumothroax as a possible complicationof circumcision. American Journal of Obstetrics and Gynecology 1978;132:583.

Bellieni 2002

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Berde 2002

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Brazelton 1973

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Brazelton 1984

Brazelton TB. Neonatal behavioral assessment scale. Philadelphia: J B Lippincott, 1984.

Campos 1994

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Carbajal 1999

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Connelly 1992

ConnellyKP, Shropshire LC, Salzberg A. Gastric rupture associated with prolongedcrying in a newborn undergoing circumcision. Clinical Pediatrics 1992;31:560-1.

Corff 1995

CorffKE, Seideman R, Venkataraman PS, Lutes L, Yates B. Facilitated tucking: anonpharmacologic comfort measure for pain in preterm neonates. Journal ofObstetric, Gynecologic, and Neonatal Nursing 1995;24:143-7.

CPS 1996

Canadian Pediatric Society Fetus and Newborn Committee. Neonatal circumcision revisited. CMAJ 1996;154:769-80.

Dalens 1989

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Fitzgerald 1993

FitzgeraldM, Anand KJS. Developmental neuroanatomy and neurophysiology of pain. In:Schecter N L, Berde C B, Yaster M, editor(s). Pain in infants, children andadolescents. Baltimore: Williams & Wilkins, 1993:11-31.

Follmann 1992

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Frank 1997

FrankLS, Miaskowski C. Measurement of neonatal responses to painful stimuli:A research review. Journal of Pain and Symptom Management 1997;14:343-78.

Gibbons 2001

GibbonsS, Stevens B. Mechanisms of sucrose and non-nutritive sucking in proceduralpain management in infants. Pain Research & Management 2001;6:21-8.

Gibbons 2002

GibbonnsS, Stevens B, Hodnett E, Pinelli J, Ohlsson A, Darlington G. Efficiacy andsafety of sucrose for procedural pain relief in preterm and term neonates.Nursing Research 2002;51:375-82.

Gray 2000

Gray L, Watt L, Blass EM. Skin-to-skin contact is analgesic in healthy newborns. Pediatrics 2000;105:e14.

Grunau 1987

Grunau RVE, Craig KD. Pain expression in neonates: facial action and cry. Pain 1987;28:395-410.

Gunnar 1981

GunnarMR, Fisch RO, Korsvik S, Donhowe JM. The effects of circumcision on serumcortisol and behavior. Psychoneuroendocrinology 1981;6:269-75.

Haouari 1999

HaouriN, Wood C, Griffiths G, Levene M. The analgesic effect of sucrose in fullterm infants: a randomized controlled trial. BMJ 1999;310:1498-1500.

Higgins 2003

Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.

Howard 1998

HowardCR, Howard FM, Garfunkel LC, de Blieck EA, Weitzman M. Neonatal circumcisionand pain relief: Current training practices. Pediatrics 1998;101:423-8.

Johnston 1997

JohnstonC, Stremler R, Stevens B, Horton L. Effectiveness of oral sucrose and simulatedrocking on pain response in preterm neonates. Pain 1997;72:193-9.

Kharasch 2003

KharaschS, Saxe G, Zuckerman B. Pain treatment: opportunities and challenges. Archivesof Pediatrics & Adolescent Medicine 2003;157:1054-6.

Kirya 1978

KiryaC, Werthmann MW. Neonatal circumcision and penile dorsal nerve block - apainless procedure. Journal of Pediatrics 1978;92:998-1000.

Lawrence 1993

LawrenceJ, Alcock D, McGrath P, Kay J, MacMurray SB, Dulberg C. The developmentof a tool to assess neonatal pain. Neonatal Network 1993;12:59-66.

Maxwell 1999

MaxwellLG, Yaster M. Analgesia for neonatal circumcision: No more studies, justdo it. Archives of Pediatrics & Adolescent Medicine 1999;153:444-5.

McGrath 1990

McGrath PA. Pain in children. New York: The Guilford Press, 1990.

Mitchell 2000

Mitchell A, Brooks S, Roane D. The premature infant and painful procedures. Pain Management Nursing 2000;1:58-65.

Mitchell 2003

Mitchell A, Waltman P A. Oral sucrose and pain relief for preterm infants. Pain Management Nursing 2003;4:62-9.

Myron 1991

MyronAV, Maguire DP. Pain perception in the neonate: Implications for circumcision.Journal of Professional Nursing 1991;7:188-95.

Poma 1980

Poma PA. Painless neonatal circumcision. International Journal of Gynaecology and Obstetrics 1980;18:308-9.

Rawlings 1980

RawlingsDJ, Miller A, Engel RR. The effect of circumcision on transcutaneous pO2in term infants. American journal of diseases of children 1980;134:676-8.

Ross 1988

Ross DM, Ross SA. Childhood pain. Baltimore: Urban & Schwarzenberg, 1988.

Ryan 1994

RyanCA, Finer NN. Changing attitudes and practices regarding local anesthesiafor newborn circumcision. Pediatrics 1994;94:230-3.

Snellman 1995

SnellmanLW, Stang HJ. Prospective evaluation of complications of dorsal penile blockfor neonatal circumcision. Pediatrics 1995;95:705-8.

Stang 1991

StangHJ. Response to : Pain perception in the neonate: Implications for circumcision.Journal of Professional Nursing 2001;7:194-5.

Stang 1998

Stang HJ, Snellman LW. Circumcision practice patterns in the United States. Pediatrics 1998;101:e5.

Stevens 1996

StevensB, Johnston CC, Petryshun P, Taddio A. Premature infant pain profile:Development and initial validation. Clinical Journal of Pain 1996;12:13-22.

Stevens 1997

StevensB, Taddio A, Ohlsson A, Einarson T. The efficacy of sucrose for relievingprocedural pain in neonates - a systematic review and meta-analysis. ActaPaediatrica 1997;86:837-42.

Stevens 1999

StevensB. Pain in infants. In: McCaffery M, Pasero C, editor(s). Pain Clinical Manual.2nd edition. St. Louis: Mosby, 1999:626-673.

Sweet 1998

SweetSD, McGrath PJ. Physiological measures of pain. In: Finley G A, McGrath PJ, editor(s). Measurement of pain in infants and children. Seattle: IASPPress, 1998:59 - 81.

Taddio 1997b

TaddioA, Katz J, Ilersich A L, Koren G. Effect of neonatal circumcision on painresponse during subsequent routine vaccination. Lancet 1997;349:599-603.

Taddio 1998

TaddioA, Ohlsson A, Einarson TR, Stevens B, Koren G. A systematic review of lidocaine-prilocainecream (EMLA) in the treatment of acute pain in neonates. Pediatrics 1998;101:e1.

Taddio 2001

Taddio A. Pain management for neonatal circumcision. Paediatric Drugs 2001;3:101-11.

Taddio 2002

TaddioA, Ohlsson K, Ohlsson A. Lidocaine-prilocaine cream for analgesia duringcircumcision in newborn boys (Cochrane Review). In: The Cochrane Library, Issue 4, 2002. Oxford: Update Software.

Talbert 1976

TalbertLM, Kraybill EN, Potter HD. Adrenal cortical response to circumcision inthe neonate. Obstetrics and Gynecology 1976;48:208-10.

Wellington 1993

Wellington N, Rieder MJ. Attitudes and practices regarding analgesia for neonatal circumcision. Pediatrics 1993;92:541-54.

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Other published versions of this review

Brady-Fryer 2004

Brady-FryerB, Wiebe N, Lander JA. Pain relief for neonatal circumcision. In: The CochraneDatabase of Systematic Reviews, Issue 4, 2004.

[top]

Data and analyses

01 DPNB versus no treatment or sham

Comparison or outcome Studies Participants Statistical method Effect size
01.01 Pain score WMD (fixed), 95% CI Subtotals only
01.02 Cry time (by unit) 6 211 SMD (fixed), 95% CI -1.73 [-2.06, -1.40]
01.03 Heart rate (by unit) 8 348 SMD (fixed), 95% CI -1.64 [-1.89, -1.38]
01.04 Heart rate (by wait time) SMD (fixed), 95% CI Subtotals only
01.05 Heart rate (by clamp) SMD (fixed), 95% CI Subtotals only
01.06 Oxygen saturation (by unit) 6 293 WMD (fixed), 95% CI 3.21 [2.69, 3.73]
01.07 Transcutaneous oxygen saturation - change from baseline 1 30 WMD (fixed), 95% CI 9.30 [1.75, 16.85]
01.08 Respiratory rate (by unit) 3 86 SMD (fixed), 95% CI -0.07 [-0.50, 0.36]
01.09 Systolic blood pressure (by unit) 2 68 SMD (fixed), 95% CI -0.66 [-1.18, -0.13]
01.10 Serum cortisol (nmol/dL) 30 min post 4 102 WMD (fixed), 95% CI -70.11 [-142.12, 1.91]
01.11 Salivary cortisol increase (ug/dL) from baseline to 30 min post 1 48 WMD (fixed), 95% CI -0.54 [-1.08, 0.00]
01.12 B-endorphin (pmol/L) 1 38 WMD (fixed), 95% CI 21.00 [-73.45, 115.45]

02 Ring block versus no treatment

Comparison or outcome Studies Participants Statistical method Effect size
02.01 Cry time (by unit) 2 63 SMD (fixed), 95% CI -1.25 [-1.80, -0.69]
02.02 Heart rate (bpm) change-from-baseline 1 23 WMD (fixed), 95% CI -29.27 [-52.94, -5.60]
02.03 Oxygen saturation (%) change-from-baseline 1 40 WMD (fixed), 95% CI 3.84 [-0.94, 8.62]
02.04 Respiratory rate (rpm) change-from-baseline 1 40 WMD (fixed), 95% CI -5.69 [-16.02, 4.64]

03 EMLA versus placebo or no treatment

Comparison or outcome Studies Participants Statistical method Effect size
03.01 Pain score 2 86 SMD (fixed), 95% CI -0.59 [-1.02, -0.16]
03.02 Cry time (by unit) 6 189 SMD (fixed), 95% CI -0.78 [-1.08, -0.48]
03.03 Heart rate (by unit) 5 143 WMD (fixed), 95% CI -14.59 [-19.34, -9.84]
03.04 Oxygen saturation (%) 3 78 WMD (fixed), 95% CI 0.90 [-0.19, 2.00]
03.05 Respiratory rate (rpm) 1 10 WMD (fixed), 95% CI -4.31 [-20.79, 12.17]
03.06 Systolic blood pressure (mmHg) change-from-baseline 1 38 WMD (fixed), 95% CI -3.00 [-15.50, 9.50]
03.07 Diastolic blood pressure (mmHg) change-from-baseline 1 38 WMD (fixed), 95% CI -5.00 [-23.60, 13.60]

04 Topical lidocaine versus placebo

Comparison or outcome Studies Participants Statistical method Effect size
04.01 Pain score WMD (fixed), 95% CI Subtotals only
04.02 Cry time (s) 2 85 WMD (fixed), 95% CI -59.75 [-99.14, -20.36]
04.03 Heart rate (bpm) 2 85 WMD (fixed), 95% CI -9.20 [-14.32, -4.07]
04.04 Oxygen saturation (%) 1 85 WMD (fixed), 95% CI -0.50 [-1.75, 0.75]
04.05 Respiratory rate (rpm) WMD (fixed), 95% CI No numeric data
04.06 B-endorphin (pg/mL) 1 30 WMD (fixed), 95% CI -49.00 [-88.73, -9.27]

05 Sucrose versus water or no treatment

Comparison or outcome Studies Participants Statistical method Effect size
05.01 Pain score WMD (fixed), 95% CI Subtotals only
05.02 Cry time (by unit) 5 123 SMD (fixed), 95% CI 0.07 [-0.31, 0.44]
05.03 Heart rate (by unit) 3 146 WMD (fixed), 95% CI -3.46 [-8.98, 2.07]
05.04 Oxygen saturation (by unit) 2 126 WMD (fixed), 95% CI 1.82 [0.51, 3.13]
05.05 Serum cortisol (nmol/dL) 30 min post 1 40 WMD (fixed), 95% CI 68.90 [-53.93, 191.73]

06 Acetaminophen versus placebo

Comparison or outcome Studies Participants Statistical method Effect size
06.01 Pain / behavior score WMD (fixed), 95% CI Subtotals only
06.02 Cry time (%) 2 104 WMD (fixed), 95% CI -1.76 [-8.26, 4.74]
06.03 Heart rate (bpm) 2 104 WMD (fixed), 95% CI 2.27 [-2.89, 7.44]
06.04 Respiratory rate (rpm) 1 44 WMD (fixed), 95% CI -3.73 [-11.00, 3.54]

07 DPNB versus EMLA

Comparison or outcome Studies Participants Statistical method Effect size
07.01 Pain WMD (fixed), 95% CI Subtotals only
07.02 Cry time (%) 1 29 WMD (fixed), 95% CI -10.00 [-29.74, 9.74]
07.03 Heart rate (by unit) 3 133 WMD (fixed), 95% CI -16.85 [-22.69, -11.00]
07.04 Heart rate by wait time SMD (fixed), 95% CI Subtotals only
07.05 Respiratory rate (rpm) 1 60 WMD (fixed), 95% CI -2.90 [-7.47, 1.67]

08 DPNB versus sucrose

Comparison or outcome Studies Participants Statistical method Effect size
08.01 Pain score 1 47 WMD (fixed), 95% CI -3.23 [-4.65, -1.81]
08.02 Cry time (s) 1 47 WMD (fixed), 95% CI -166.00 [-210.54, -121.46]
08.03 Heart rate (by unit) 2 126 WMD (fixed), 95% CI -26.56 [-33.36, -19.76]
08.04 Oxygen saturation (by unit) 2 126 WMD (fixed), 95% CI 0.25 [-0.78, 1.27]

09 DPNB versus ring block

Comparison or outcome Studies Participants Statistical method Effect size
09.01 Cry time (%) 1 26 WMD (fixed), 95% CI 6.33 [-15.94, 28.60]
09.02 Heart rate (bpm) change-from-baseline 1 26 WMD (fixed), 95% CI 4.43 [-14.42, 23.28]

10 DPNB versus local block

Comparison or outcome Studies Participants Statistical method Effect size
10.01 Serum cortisol (nmol/dL) 30 min post 1 18 WMD (fixed), 95% CI 306.27 [141.33, 471.21]

11 Ring block versus EMLA

Comparison or outcome Studies Participants Statistical method Effect size
11.01 Heart rate (bpm) change-from-baseline 1 27 WMD (fixed), 95% CI -3.17 [-20.84, 14.50]
11.02 Cry time (%) 1 27 WMD (fixed), 95% CI -16.33 [-36.15, 3.49]

12 Buffered lidocaine DPNB versus plain lidocaine DPNB

Comparison or outcome Studies Participants Statistical method Effect size
12.01 Pain score WMD (fixed), 95% CI Subtotals only
12.02 Cry time (%) 1 194 WMD (fixed), 95% CI 9.00 [-11.71, 29.71]
12.03 Heart rate (bpm) 1 194 WMD (fixed), 95% CI -4.20 [-10.51, 2.11]
12.04 Oxygen saturation (%) 1 194 WMD (fixed), 95% CI 0.50 [-0.87, 1.87]
12.05 Serum cortisol (nmol/dL) 30 min post 1 40 WMD (fixed), 95% CI 35.80 [-105.62, 177.22]

13 EMLA versus 30% topical lidocaine

Comparison or outcome Studies Participants Statistical method Effect size
13.01 Cry time (s) 1 40 WMD (fixed), 95% CI -17.00 [-75.00, 41.00]
13.02 Heart (bpm) 1 40 WMD (fixed), 95% CI -11.88 [-19.40, -4.36]
13.03 Oxygen saturation (%) 1 40 WMD (fixed), 95% CI -0.17 [-1.44, 1.10]

14 EMLA versus sucrose

Comparison or outcome Studies Participants Statistical method Effect size
14.01 Cry time (%) 1 26 WMD (fixed), 95% CI -10.00 [-26.74, 6.74]
14.02 Heart rate (bpm) 1 41 WMD (fixed), 95% CI -9.35 [-20.08, 1.38]
14.03 Oxygen saturation (%) 1 41 WMD (fixed), 95% CI -0.82 [-2.63, 0.99]
14.04 Systolic blood pressure (mmHg) 0 0 WMD (fixed), 95% CI No numeric data
14.05 Diastolic blood pressure (mmHg) 0 0 WMD (fixed), 95% CI No numeric data

15 EMLA versus music

Comparison or outcome Studies Participants Statistical method Effect size
15.01 Cry time (min) 1 12 WMD (fixed), 95% CI 0.38 [-3.68, 4.44]
15.02 Heart rate (bpm) 1 12 WMD (fixed), 95% CI 2.31 [-15.99, 20.61]
15.03 Oxygen saturation (%) 1 12 WMD (fixed), 95% CI 0.19 [-3.56, 3.94]
15.04 Respiratory rate (rpm) 1 12 WMD (fixed), 95% CI 1.52 [-13.60, 16.64]

16 Music versus no treatment

Comparison or outcome Studies Participants Statistical method Effect size
16.01 Cry time (min) 1 12 WMD (fixed), 95% CI -1.58 [-5.81, 2.65]
16.02 Heart rate (bpm) 1 12 WMD (fixed), 95% CI -7.89 [-41.37, 25.59]
16.03 Oxygen saturation (%) 1 12 WMD (fixed), 95% CI 2.51 [-0.62, 5.64]
16.04 Respiratory rate (rpm) 1 12 WMD (fixed), 95% CI -5.83 [-21.41, 9.75]

Additional tables

01 Trials assessing pain/behavior scores

Study ID scale measurement method data reported data preparation
Arnett 1990 infant irritability
irritabilify graded subjectively on a scale of 1 to 6 with 1 representing the least crying/agitation and 6 the most
nurse and physician rating of infant irritability graded before, during and 1 hour after circumsion mean/SD of assessment during procedure data entered into meta-analysis as reported
Benini 1993 Neonatal Facial Action Coding System
(Grunau, 1990b)
10facial actions scored, 7 (brow bulge, eye squeeze, nasolabial furrow, openmouth, vertical stretching of mouth, horizontal stretching of mouth, tauttongue) entered into analysis
facial actions videotaped continuously, second by analysis of facial actions
10 facial actions scored, 7 facial actions entered into analysis
total score computed by summing 7 categories
outcome data (means/SDs) obtained from authors calculate arithmetic mean of scores across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure"= [application of dorsal clamp, incision, adhesion lysis, Gomco clamp on, foreskin excision, Gomco clamp off, restraints removed]
Butler-O'Hara 1998 Neonatal Infant Pain Scale (NIPS)
consists fo 6 behavioral components with a composite score of 0 to 6
5 components used - facial expression, cry, breathing pattern, arm movements, state of arousal
(Lawrence, 1993)
procedure videotaped
NIPSscores assigned for each of 6 events (clamping of foreskin, adhesion lysis, dorsal cut, adhesion lysis, tying of Plastibell, foreskin excision)
mean NIPS score calculated for each infant
mean(SD) NIPS score/group data entered into meta-analysis as reported
Dixon 1984
(Holve 1983 is primary study report)
Brazelton Neonatal Assessment Scale (BNAS)
consists of 27 behavioral items, each scored on scale of 1 to 9, and 20 reflexes scored on 3 point scale
scale examines organization and integration of behavior in response to positive and adversive situations
examinations conducted prior to (exam 1), following the circumcision (exam 2), and 1 day after circumcision (exam 3) mean scores/item for 3 exam times states "variation in item scores precluded determination of statistically significant differences between groups'
not included in meta-analysis
Hardwick-Smith 1998 behavioral state (Stang et al 1988) score 1 - 6 in order of increasing arousal scored at baseline, 10 intervals during procedure, and 2 hr post-circumcision p values not included in meta-analysis
Holliday 1999 behavioralscale - includes 8 behavior state variables (sleep state, cry, facial expression, torso movement, soothability, response to distress, need for tactile stimulation, environmental noise)
each variable scored 1 to 6, scores totaled for each infant
assessed 20 min before, during and after circumcision means scores/group reported in graph format graph extractions to obtain mean/SD
Howard 1994 Postoperative Comfort Score
(Attia 1987)
10 behaviors, each scored 0, 1, or 2, possible scores 0 to 20, lower score = less comfortable
assessed baseline, and postcircumcision at 30, 60, 90, 120, 360 min mean/SD scores/group/interval
mean/SD change from baseline scores/group/interval
data entered into meta-analysis as reported for 30 min post-circumcision scores
Howard 1999 behavioral distress scale (from Stang et al 1997) score 0 - 3 based on Brazelton statte assessment
score 0 = neutral to 3 = sustained cry
videotape of procedure assessed and scores assigned every 30 s of the procedure mean/SE scores / group for stages 2 to 6 of procedure data entered into meta-analysis as reported
"procedure" = [block administration to recovery; includes 4 min WT and Gomco clamp left on for 5 min]
Joyce 2001 Riley Infant Pain Scale
6 categories of behavior (vocal, facial expression, body movement, sleep, consolability, response to touch)
rates on scale of 0 (no pain) to 3 (severe pain)
videotapeof procedure assessed at baseline, undressing, restraints, cleanse, clamping, cutting, end of procedure, 15 min post and 30 min post RIPS score / group / phase presented in graphic format
p values
not included in meta-analysis
Kass 2001 MBPS - modified behavioral pain scale
(Taddio et al, 1995)
rates facial expression, crying, and body movements to obtain a score of 0 to 10
scored at 30 s intervals mean/SD for baseline and procedure MBPS / group obtained from authors mean/SD procedure scores entered into meta-analysis
Macke 2001 Nursing Child Assessment Feeding Scale (NCAFS)
76 behavioral binary items (yes, no) grouped into 6 subscales based on concepts of adaptation and synchronism
scored during feeding interaction before and after circumcision mean/SD score pre/post circumcision data included as reported
Newton 1999 Brazelton Neonatal Assessment Scale -
scale categorized to 6 level\s - (deep sleep (1), light sleep (2) drowsy (3), quiet alert (4) active alert (5) crying (6)
(Brazelton, 1984)
3 evaluations - baseline, injection, clamp application modal state/group data not included
Stang 1988 behavioral state
6 levels = quiet sleep (1), active sleep (2), drowsy (3), alert (4), active awake (5), crying (6) (Brazelton, 1973)
assessed at baseline, during injection, during circumcision, and 30 min from the start of the circumcision modal response / group / time period data not included
Stang 1997 behavioral state scale and behavioral distress scale
4 levels - neutral (0), minimal fuss (1), moderate fuss (2), sustained cry (3)
(Brazelton, 1973)
behavioral state and distress scored every 30 s beginning 2 min before circumcision
scores averaged for 5 periods - preinjection, injection, 2 min post-injection, 4 min post-injection, circumcision
mean/SD /group / study period mean/SD for circumcision period included
Taddio 1997 Neonatal Facial Coding System (Grunau et al, 1987; 1990)
codespresence or absence of 10 discrete facial actions (brow bulge, eye squeeze, nasolabial furrow, open mouth, vertical stretching of mouth, horizontal stretchingof mouth, lip pursing, taut tongue, chin quiver, tongue protrusion)
higher score = more pain
facial actions continuously recorded on videotape
facial actions scored from videotape in 2 s intervals for first 20 s of each phase
rawscores of each facial action expressed as proportion of time observed/phase;poorly correlated facial actions deleted leaving 6 facial actions; the sixscores were weighted and totaled to arrive at overal score for facial action
mean/95% confidence intervals for facial activity score / group / 13 phases reported in graph format
data extracted from graphs
data extraction to obtain mean/SD facial score for circumcision phases
circumcision (7 phases) = [application of forceps to foreskin excision]
calculate arithmetic mean/group across phases of circumcision
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
SE = ((high CI - low CI) /2) /1.96
SD = SE (sqrt(n))
Weatherstone 1993 newborn pain behavior scale
adapted from 3 other scales (Brazelton 1973; Yarrow 1975; Ross 1988)
scoreincludes assessment of behavioral state, leg and arm movement, facial expression, torso movement, respiratory pattern, soothability, response to distress bycaregivers, tactile stimulation
videotape of procedure scored in 30 s intervals increase in mean/SD % of time behavior observed post-cirucmcision compared to pre- circumcision/group data not included

02 Trials assessing heart rate outcome variables

Study ID measurement method data reported preparation of data
Arnett 1990 HR measured by pulse oximetry at baseline, every min for 4 min, and 5 min post-circumcision mean HR/group/phase reported in graph format graph extraction for means
graph extraction for SDs (averaged over 4 phases of the circumcision procedure)
"procedure" = [min 1 to min 4]; steps not described or standardized
Benini 1993 HR measured continuously by pulse oximeter outcome data (mean/SDs) obtained from authors calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure"= [application of dorsal clamp, incision, adhesion lysis, Gomco clamp on, foreskin excision, Gomco clamp off, restraints removed]
Butler-O'Hara
1998
HR monitored continuously using cardiac monitor mean/SD heart rate (bpm) at completion of circumcision by group
mean/SD heart rate (bpm) change from baseline at completion of circumcision by group
data entered into meta-analysis as reported
Joyce 2001 HR monitored continuously using cardiac monitor data (bpm) obtained from authors calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure" = [cut, end of procedure]
Hardwick-Smith 1998 HR monitored continuously using cardiac monitor
highest HR recorded at start of each interval
increase in HR from baseline per group for operative interval reported in graph format graphsdid not depict SDs (whiskers) ; researchers reported control infants had signifcantlygreater increase over baseline during 7 out 10 operative intervals; theydid not comment on differences between the groups/interval
Herschel 1998 HR monitored continuously using cardiac monitor mean/SD HR (bpm) change from baseline during procedure by group data entered into meta-analysis as reported
"procedure" = lateral clamp of foreskin to foreskin excision
Holliday 1999 HR monitored continuously using cardiac monitor
HR recorded every 5 min before, during, 5 and 20 min after circumcision
mean/SD HR (bpm) /group reported in graph format for 4 time points (before, during, 5 min after, 20 min after) graph extraction to obtain mean/SD during procedure
Holve 1983 HR continuously recorded using monitor mean change in HR from baseline (bpm) weighted averages/group for 6 phases reported in graphic format no SDs, SEs depicted on graphs
Howard 1994 HR counted via auscultation every 30 s mean/SD HR (bpm) / group / phase
mean/SD HR (bpm) change from baseline by group/phase
calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure" = [dissection, clamp on, excision, clamp off]
Howard 1999 HR recorded every 60 s using cardiac monitor - mean/SE HR (bpm) during procedure by group means included as reported
convert SE to SD using formula:
SD = SE (sqrt (n))
"procedure" = [block administration to recovery; includes 4 min WT and Gomco clamp left on for 5 min]
Kass 2001 HR monitored at 1 min intervals during procedure mean/SD HR (bpm) during procedure by group obtained from authors mean/SD entered into meta-analysis
Kurtis 1999 HR monitored continuously using cardiac monitor mean/SD % HR change from baseline during procedure by clamp used (Mogen, Gomco) and by penile block status (block, no block) data entered into meta-analysis as reported
"procedure" = [lysing adhesions to 60 sec after closing clamp]
Lander 1997 HR monitored continuously using cardiac monitor mean/SD HR (bpm) change from baseline by phase by group calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure" = [separation, clamp on, clamp off]
Macke 2001 HR recorded every 15 s using cardiac monitor mean/SD HR (bpm) during circumcision by group data included as reported
Marchette 1989 HR monitored mean HR /phase / group
no SDs reported
not included
Marchette 1991 HR monitored and data collected during 14 cirumcision steps RMANOVA over 14 steps not included
Masciello 1990 HR monitored continuously using cardiac monitor
peak HR during each step recorded
mean HR as a percent of baseline HR reported in graphic format not included
Maxwell 1987 HR monitored continuously by pulse oximeter
peak HR during each period recorded
mean/SD HR change / group / period as a % of control (baseline) reported in graph format graph extraction to obtain mean/SD during circumcision procedure
Mohan 1998 HR monitored continuously by pulse oximeter
HR recorded at each of 9 steps
mean HR / group / procedure step reported in graph format graph extraction to obtain mean HR / group / procedure step
substitutedweighted average treatment-specific SDs from 5 studies: Benini 1993, Joyce2001, Lander 1997, Taddio 1997, Woodman 1999 for EMLA and from 3 studies:Herschel 1998, Kass 2001, Zolnoski 1993 for sucrose
Mudge 1989 HR measured by monitor at 5 time points during circumcision mean HR / group / event reported in graph format
RMANOVA for 4 events (adhesion breakdown to clamp off)
graph extraction to obtain mean HR/group for events 2 - 5
calculate arithmetic mean HR / group across 4 phases of the procedure
(adhesion breakdown, clamp on, tighten clamp, clamp off)
substitute SDs from Woodman 1999 who applies same outcome to same comparison
Newton 1999 HR monitored continuouslly by pulse oximeter
HR recorded at 10 s intervals
mean/SD HR / group at baseline, injection, clamp application included as reported
Spencer 1992 HR monitored by pulse oximeter
recorded highest HR for each of 6 events
mean change in HR (bpm) from baseline / group / event no SDs, not included
Taddio 1997 HR continuously monitored by cardiac monitor mean/SD HR (bpm) change from baseline during procedure data included as reported
"procedure"= [forcep application, lysis of adhesions, dorsal incision, clamp application, pull foreskin through clamp, tighten clamp, cut foreskin]
procedure does not include clamp removal at 5 min after cut foreskin
Weatherstone 1993 HR monitored at 5 min intervals for 20 min none not included
Williamson 1983 HR monitored continuously mean/SD HR (bpm) change from baseline for 3 min "dissection" period mean/SD data included as reported
dissection does not include clamp application
Woodman 1999 HR monitored continuously using pulse oximeter
recorded peak heart rate during or immediately following 7 stages of circumcision procedure
mean/SD peak HR (bpm) / group calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure" = [clamp, adhesionlysis, dorsal clamp, bell on, clamp tightening, bell off]
Zolnoski 1993 HR monitored continuously using cardiac monitor
HR (bpm) recorded at beginning of 7 procedure steps
- mean/SD HR (bpm) /group for 4 procedure steps calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))

03 Trials assessing cry outcome variables

Study ID measurement method data reported data preparation
Benini 1993 cry tape recorded % time crying/phase (duration of time crying) reported in graph format means, SEs (assumed) extracted from graph; calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure" = [dorsal clamp, incision, lysis, clamp on, foreskin cut, clamp off, unrestrained]
Blass 1991 cry tape recorded mean % time crying (duration of time crying) during entire procedure reported in graph format - graph extraction of group mean/SE;
- SD calulated using formula:
SD = SE (sqrt (n))
Holve 1983 cry tape recorded mean % time crying /interval reported in graphic format no SDs, not included
Hardwick-
Smith 1998
cry tape recorded mean/SD minutes crying/group during operative interval (lateral clamping to clamp removal) convert reported time to seconds
data included in meta-analysis
Howard 1994 used stopwatch to time crying during each phase mean/SD % time crying by group/phase
mean/SD % time crying change from baseline/group/phase
calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure" = [dissection, clamp on, excision, clamp off]
Joyce 2001 behavior videotaped
calculated total time crying from start of foreskin cut until crying ceased or 30 min elapsed
cry time (min) for each subject obtained from authors calculate mean/SD time crying in min and sec/group
Kass 2001 primary outcome variable
behavior videotaped
mean/SD time crying (s) /group during procedure obtained from authors mean/SD included in meta-analysis
Kurtis 1999 behavior videotaped
calculated time crying using stopwatch
mean/SD % time crying during procedure
reported by clamp used (Mogen, Gomco) and by penile block status (block, no block)
mean/SD included as reported
Lander 1997 behavior videotaped
proportion of time crying calculated/subject
mean/SD % time crying/interval calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y)) - "procedure" =[separation, clamp on, clamp off)
Macke 2001 continuous vocalizations of 15 s or more classified as crying and tape recorded
total s used to calculate % time crying
mean/SD % time crying during circumcision period by group data included as reported
Mohan 1998 stopwatch used to measure duration of crying mean % time crying / group during entire procedure not included
Mudge 1989 crying time tape recorded during procedure
measured by stop watch
mean total crying time (s) /group for entire procedure
t-statistic, p value
mean crying time included as reported
SD imputed from t statistic
procedure includes 5 events (baseline, adhesion breakdown, clamp on, tighten clamp, clamp off)
Spencer 1992 cry duration measured by modified Brazelton Neonatal behavioral Scale (Stang et al, 1988)
6 behavioral states
recorded for each of 6 events
mean % change from baseline / group no SDs, not included
Stang 1988 not described mean/SEM % time crying during circumcision period/group means included as reported
SEM converted to SD using formula:
SD = SEM (sqrt (n))
Taddio 1997 behavior videotaped
calculated % of time crying during each phase
mean/SD % increase from baseline in time crying during procedure data included as reported
"procedure"= [forcep application, lysis of adhesions, dorsal incision, clamp application, pull foreskin through clamp, tighten clamp, cut foreskin]
does not include clamp removal at 5 min after foreskin cut
Williamson 1983 time crying recorded using event marker mean/SD % time crying change from baseline during 3 min dissection period mean/SD data included as reported
Woodman 1999 behavior videotaped
recorded time crying based on facial actions with or without audible cry
mean/SD time crying (s) for 6 phases by group addtime crying for 6 of 8 stages (clamp, adhesionlysis, dorsal clamp, clampon, clamp tightening, clamp off) to obtain total time crying during procedure
add SD to obtain total SD for group
Zahorodny 1998 not reported mean % time crying/group substitutedweighted average treatment-specific SDs from three other studies: Benini1993, Lander 1997, Taddio 1997 for EMLA vs placebo/ no treatment
substituted treatment-specific SDs from Blass 1991 A (also versus water) for sucrose vs placebo/ no treatment
substituted with the SDs used in the two above comparisons for EMLA vs sucrose
Zolnoski 1993 cry tape recorded, measured using stopwatch time cry (s) /infant mean/SD cry time (s) /group calculated

04 Trials assessing oxygen saturation outcome variables

Study ID measurement method data reported data preparation
Arnett 1990 measured by pulse oximetry at baseline, every min for 4 min during procedure, and 5 min postcircumcision mean oxygen saturation (%) / group / phase and SDs presented graphically graph extraction of means, graph extraction of SDs, averaged over 4 phases
Benini 1997 O2sat continuously monitored using pulse oximeter outcome data (mean/SD) obtained from authors calculate arithmetic mean/group across phases of the procedure
calculatevariance for arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
procedure =[application of dorsal clamp, incision, adhesion lysis, Gomco clamp on, foreskinexcision, Gomco clamp off, restraints removed]
Hardwick-Smith 1998 O2sat monitored continuously by pulse oximeter, lowest O2sat recorded at the start of each interval
during some intervals of procedure, O2sat not recorded in up to 50% of infants
mean/SD of O2sat (%) /group for operative intervals data included in meta-analysis as reported
"operativeinterval" = [llateral clamp, blunt dissection, dorsal clamp, adhesion takedown, Gomco bell on, Gomco clamp applied, Gomco clamp removed]
Herschel 1998 O2sat continuously monitored via pulse oximetry
substantial proportion of data lost due to excessive motion (31% control, 10% DPNB, 8% sucrose)
mean/SD O2sat (%) change from baseline during operative procedure by group data included in meta-analysis as reported
"operativeprocedure" = [lateral clamp of foreskin, adhesion lysis, dorsal clamp, dorsalcut, foreskin retraction, Gomco application, Gomco tightened, foreskin excision]
Holliday 1999 O2sat continuously monitored, recorded every 5 min before, during, 5min and 20 min after circumcision mean/SD O2sat (%) /group reported in graph format for 4 time points (before, during, 5 min after, 20 min after) graph extraction for mean/SD during procedure
Joyce 2001 O2sat monitored continuously using pulse oximeter
recorded O2sat (%) at each of 6 data collection points
raw data per subject per 6 phases obtained from authors calculate mean/SD by group/phase
calculate arithmetic mean/group across phases of the procedure
calculatevariance for arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
procedure = [cut, end]
Kass 2001 monitored O2sat at 1 min intervals during procedure mean/SD O2sat during procedure by group data obtained from authors mean/SD included in meta-analysis
Kurtis 1999 O2sat (%) monitored continuously and transferred to computer -mean/SD % change from baseline during procedure reported by clamp used (Mogen, Gomco) and by penile block status (block, no block) data included in meta-analysis as reported
procedure = [lysing adhesions to 60 sec after closing clamp]
Marchette 1991 tcpO2 monitored and recorded during 14 circumcision steps RMANOVA over 14 steps not included
Masciello 1990 O2sat monitored continuously by pulse oximeter
lowest level during each interval recorded
mean O2sat / group / interval reported in graphic format not included
Maxwell 1987 O2sat monitored continuously
using pulse oximeter
peak value during period recorded
mean/SD O2sat /group / period reported in graph format graph extraction to obtain mean/SD during circumcision period
Mohan 1998 O2sat monitored continuously
using pulse oximeter
recorded at each of 9 procedure steps
mean O2sat / group / procedure step reported in graph format graph extraction to obtain mean O2sat / group / step
substitutedweighted average treatment-specific SDs from 3 trials: Benini 1993, Joyce2001, Woodman 1999 for EMLA and from 2 trials: Herschel 1998, Kass 2001for sucrose
Mudge 1989 O2sat measured by pulse oximeter and recorded at five time points during circumcision mean O2sat (%) /group/event reported in graph format graph extraction to obtain mean O2sat/group for events 2 - 5
calculate arithmetic mean O2sat / group across 4 phases of the procedure
(adhesion breakdown, clamp on, tighten clamp, clamp off)
Spencer 1992 O2sat monitored by pulse oximeter
recorded lowest level for each of 6 events
mean O2sat % change from baseline / group / event no SDs, not included
Weatherstone 1993 O2sat monitored at 5 min intervals for 20 min none not included
Williamson 1983 O2sat measured using transcutaneous electrode (tcpO2) mean/SD O2sat (torr) change from baseline for 3 min dissection period data included in meta-analysis as reported
dissection does not include clamp application
Woodman 1999 O2sat monitored continuously using pulse oximeter
recorded peak/nadir during or immediately following 7 stages of circumcision procedure
- mean/SD peak/nadir O2sat / stage / group calculate arithmetic mean/group across phases of the procedure
calculatevariance for arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
procedure = [clamp, adhesiolysis, dorsal clamp, clamp on, clamp tightening, clamp off)

05 Trials assessing respiratory rate outcome variables

Study ID measurement method data reported preparation of data
Butler-OHara 1998 RR monitored continuously starting after anesthetic administration, and 1 and 4 hr after procedure RR variable and difficult to evaluate
not reported
not included in meta-analysis
Hardwick-Smith 1998 highestRR recorded at start of each interval (anesthesia/restraint, 3 min post restraint/anesthesia, lateral clamp, blunt dissection, dorsal clamp, adhesion breakdown, Gomcobell on, Gomco clamp on, Gomco clamp removed) mean/SD increase from baseline RR/group for operative intervals (lateral clamping to Gomco clamp removal) data included in meta-analysis as reported
Holliday 1999 RR monitored continuously using cardiac monitor
HR recorded every 5 min before, during, 5 and 20 min after circumcision
mean/SD RR (bpm) /group reported in graph format for 4 time points (before, during, 5 min after, 20 min after) graph extraction for mean/SD during procedure
Howard 1994 RR assessed by visual observation every 30 s mean/SD RR (rpm) / group / phase
mean/SD RR (rpm) change from baseline by group/phase
calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure" = [dissection, clamp on, excision, clamp off]
Howard 1999 RR counted and recorded every 60 s mean/SE RR (rpm) by group for procedure means included as reported
convert SE to SD using formula: SD = SE (sqrt (n))
"procedure" = [block administration to recovery; includes 4 min WT and Gomco clamp left on for 5 min]
Joyce 2001 RR monitored continuously, recorded at 6 data collection points raw data obtained from authors calculate arithmetic mean/group across phases of the procedure
calculatevariance for the arithmetic mean using general formula for linear combinationsof variance (i.e. Var (X+Y) = Var(x) + Var(Y) + 2Cov(X, Y))
"procedure" = [cut, end of procedure]
Kurtis 1999 RR monitored continuously using physiologic monitor mean/SD% change from baseline during procedure reported by clamp used (Mogen, Gomco) and by penile block status (block, no block) data entered into meta-analysis as reported
"procedure" = [lysing adhesions to 60 sec after closing clamp]
Mudge 1989 RR measured by pneumography monitor at 5 time points mean RR / group / event reported in graph format
RMANOVA for 4 events (adhesion breakdown to clamp off)
graph extraction to obtain mean RR/group for events 2 - 5
calculate arithmetic mean RR / group across 4 phases of the procedure
(adhesion breakdown, clamp on, tighten clamp, clamp off)
Weatherstone 1993 RR monitored at 5 min intervals for 20 min none not included

06 Trials assessing biochemical outcome variables

Study ID measurement method data reported data preparation
Masciello 1990 blood drawn via heel stick 30 minutes post-circumcision mean/SD plasma cortisol levels in mg/dL mg/dL multiplied by 27.59 = nmol/L
nmol/L included in meta-analysis
Stang 1988 blood drawn via heel stick for 1/2 subjects at 30 min post-circumcision, and 90 min for remaining 1/2 subjects mean/SEM plasma cortisol levels in nmol/L and ug/dL means (nmol/L) included in meta-analysis
SEM converted to SD using formula:
SD = SEM (sqrt(n))
Williamson 1986 blood drawn by heel stick at baseline and 30 min post-circumcision mean/SEM plasma cortisol levels in ug/dL SEM converted to SD using formula:
SD = SEM (sqrt(n))
ug/dL
Holliday 1999 serum B-endorphin levels - blood sample taken before and 20 min post-circumcision mean/SD / group in pmol/L data included as reported
Joyce 2001 salivary cortisol samples collected at baseline abd 30 min after procedure mean/SD before/after
no units of measurement
results not broken down by group
not included
Kurtis 1999 salivary cortisol collected sample at baseline and 30 min post-circumcision mean/SD included as reported
Stang 1997 plasma cortisol 30 min after beginning of circumcision mean/SD / group
nmol/dL and ug/dL
mean /SD (nmol/dL) included as reported
Weatherstone 1993 serum B-endorphin level taken pre-operatively and 15 min after circumcision mean/SD B-endorphin level (pg/mL) for pre and post circumcision period/group mean/SD level for post-circumcision period included as reported
Williamson 1986 plasma cortisol obtained at baseline and 30 min after Gomco clamp applied mean/SEM plasma cortisol levels (ug/dL) /group ug/dL multiplied by 27.59 = nmol/L
SEM converted to SD using formula:
SD = SEM (sqrt(n))

07 Trials assessing blood pressure outcome variables

Study ID measurement method data reported data preparation
Holliday 1999 systolic BP monitored continuously using cardiac monitor
HR recorded every 5 min before, during, 5 and 20 min after circumcision
mean/SD BP (mmHg) /group reported in graph format for 4 time points (before, during, 5 min after, 20 min after) graph extraction for mean/SD during procedure
Marchette 1991 systolic and diastolic BP monitored and recorded during 14 steps of the cirumcision procedure RMANOVA over 14 steps not included
Maxwell 1987 BP measured by Doppler every 5 min mean/SD systolic BP change as a % of control / group / period reported in graph format graph extraction to obtain mean/SD during circumcision period
Mohan 1998 systolic and diastolic BP measured over upper arm at each of 9 procedural steps mean systolic and diastolic BP (mm Hg) reported in graph format graph extraction to obtain mean / group / step
substituted treatment-specific SDs from Taddio 1997 for EMLA; no SDs available for sucrose
Taddio 1997 systolic and diastolic BP measured at baseline and during lysis of adhesions mean/SD increase mm Hg in systolic and diastolic BP data included as reported
Weatherstone 1993 BP monitored at 5 min intervals for 20 min none not included

08 Trials reporting adverse effects

Study ID intervention(s) adverse effects
Arnett 1990 0.4 ml lidocaine DPNB (n=23)
0.4 ml saline DPNB (n=22)
control (n=7)
lidocaine group - 1 emesis treated with suction
saline group - 2 bleeding post-procedure, 1 required suture
control - 1 bleeding post-procedure controlled with pressure
Butler-O'Hara
1998
0.5 ml LP cream (n=21)
0.7 ml - 1.0 ml lidocaine DPNB + placebo cream (n=23)
DPNB group - 10 hematoma; 1 penile edema on day 5
LP cream group - 3 erythema
Holve 1983 & (primary study) Dixon 1984 0.8 ml lidocaine DPNB (n=15)
0.8 ml saline DPNB (n=8)
control (n=8)
lidocaine group - 1 small unilateral hematoma
Holliday 1999 0.8 ml lidocaine DPNB + placebo cream (n=19)
placebo cream (n=19)
original protocol included LP cream group (n=12)
LP cream group - 2 redness and blistering of foreskin, LP cream group discontinued
Lander 1997 2 g LP cream (n=15)
placebo cream (n=12)
0.8 ml lidocaine DPNB (n=14)
0.8 ml lidocaine RB (n=13)
placebo group - 1 apnea and emesis, 1 choking and apnea
Newton 1999 0.8 ml lidocaine DPNB (n=92)
0.8 ml buffered lidocaine DPNB (n=102)
lidocaine group - 4 had minor bleeding
buffered lidocaine group - 6 had minor bleeding
Stang 1988 0.8 ml lidocaine DPNB (n=20)
0.8 ml saline DPNB (n=20)
control (n=20)
occasional insignificant bleeding - groups and numbers not specified
Taddio 1997 1 g LP cream (n=29)
1 g placebo cream (n=30)
LP cream group - 12 minor foreskin pallor, 1 mild edema
placebo group - 4 minor foreskin pallor
Williamson 1997 lidocaine DPNB (n=20)
control (n=10)
DPNB group - 9 bleeding, 12 swelling, 1 erythema
control group - 5 bleeding, 5 swelling, 1 hematoma, 3 erythema
Zolnoski 1993 2.4 ml 24% sucrose (n=10)
2.4 ml water (n=10)
sucrose group - 1 gagging
water group - 2 regurgitation after circumcision

Additional figures

Figure 01

Refer to figure 1 caption below.

DPNB versus Placebo. Cry time in %

Additional tables

  • None noted.

Contact details for co-reviewers

Ms Gabrielle Brankston

Research Assistant
University of Alberta
Faculty of Nursing, University of Alberta
3rd Floor Clinical Sciences Building
Edmonton
Alberta CANADA
T6G 2G3
Telephone 1: 780-492-6317

Dr Janice A Lander, PhD

Professor
Faculty of Nursing
University of Alberta
5-120A Clinical Sciences Building
University of Alberta
Edmonton
Alberta CANADA
T6G-2G3
Telephone 1: 780-492-6317
Facsimile: 780-492-9954

E-mail: jlander@ualberta.ca

Ms Natasha Wiebe, M Math

Statistician
Alberta Research Centre for Child Health Evidence
University of Alberta - Department of Pediatrics
Room 9417 ABC
11402 University Avenue
Edmonton
Alberta CANADA
T6G 2J3
Telephone 1: 780-482-1273
Facsimile: 780-407-6435

E-mail: nwiebe@ualberta.ca

Secondary contact person's name: Natasha Wiebe


The review is published as a Cochrane review in The Cochrane Library, Issue 4, 2005 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emergesand in response to comments and criticisms, and The Cochrane Libary shouldbe consulted for the most recent version of the review.