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The Placebo Response in Studies of Acute Migraine

RICARDO FERNANDES, MD, JOAQUIM J. FERREIRA, MD, AND CRISTINA SAMPAIO, MD, PHD

bjectives To characterize the magnitude of the placebo response in trials of migraine therapy in children and adolescents,nd to identify its determinants.

tudy design MEDLINE and CENTRAL were searched through November 2006 for randomized controlled trials orontrolled clinical trials of pediatric acute migraine pharmacologic treatment that included a placebo comparator group. Theain outcomes were headache relief and pain-free response, and effect estimates for risk differences were calculated wheneverossible. The influence of placebo response determinants was studied using subgroup analysis. A total of 13 trials (1324articipants in the placebo groups) were included in the analysis.

esults The pooled placebo responses for pain relief and pain-free at 2 hours were 46% (range, 38% to 53%) and 21%range, 17% to 26%). Parallel studies conducted in North American centers demonstrated a significantly higher placeboesponse, as did trials that used 4-point pain scales. Other placebo determinants did not influence the effect estimate, althoughnsufficient data were available to study some of them.

onclusions There is a widely variable placebo response in pediatric migraine trials, supporting the continued use oflacebo groups and suggesting the need for more research into the placebo effect in the pediatric population.J Pediatr 2008;152:527-33)

igraine is common in children and adolescents, with an estimated prevalence ranging from 3% to 19% and increasingwith age.1 The clinical presentation of pediatric migraine can be similar to that of adults, characterized by attacks ofintense, throbbing, unilateral head pain often accompanied by nausea, vomiting, photophobia, and phonophobia. 2,3 In

hildren, however, the pain is often bilateral and may be of shorter duration than in adults.3-5

The mainstay of acute migraine treatment in children is the use of symptomatic medication, including analgesics, triptans,nd antiemetics in oral, nasal, or subcutaneous formulations. Recent systematic reviews have recommended the use of oralbuprofen and acetaminophen or nasal sumatriptan as safe and effective first-line treatments.6,7 However, the evidenceupporting these recommendations is limited by the paucity of controlled data due to the reduced number of trials for eachedication.6,7 The need for well-designed clinical trials research in this field of pediatric therapeutics is widely recognized.8

A key issue in pediatric migraine trials has been the frequently reported high placebo responder rate. 9-11 This can poseignificant challenges to the design of studies, as differences in outcomes between thective intervention and the placebo are statistically harder to detect.10 The use of placeboontrol groups in clinical trials is also coming under increasing question, particularly inhildren, by both physicians and parents.12-15 The magnitude and determinants of thelacebo response have been studied in adult migraine trials, with the results used tomprove study design, suggesting a rationale for the continued use of placebo controls.11,16

he placebo response in pediatric migraine trials has been addressed but not studiedystematically.10,11 Furthermore, despite the ongoing controversy regarding the nature ofhe placebo effect,17,18 few studies have analyzed the placebo response in other types ofediatric clinical trials.

Consequently, we undertook a systematic review of the placebo response in mi-raine trials of children and adolescents to characterize its magnitude and identify itseterminants.

CT Controlled clinical trialCHD International Classification of Headache

ITT Intent to treatRCT Randomized controlled trial

From the Pediatrics Department, SantaMaria Hospital, Lisbon, Portugal (R.F.) andthe Neurological Clinical Research Unit, In-stitute of Molecular Medicine, LisbonSchool of Medicine, Lisbon, Portugal (J.F.,C.S.).

No reprints are available from the authors.

Submitted for publication May 3, 2007; lastrevision received Jun 26, 2007; acceptedSep 11, 2007.

Correspondence: Ricardo Fernandes, Bib-lioteca de Pediatria, Clínica Universitáriade Pediatria, Faculdade de Medicina de Lis-boa, Av. Prof. Egas Moniz, 1649-028 Lisboa,Portugal. E-mail: ricardocunhafernandes@clix.pt.

0022-3476/$ - see front matter

Copyright © 2008 Mosby Inc. All rightsreserved.

Disorders RD Risk difference

10.1016/j.jpeds.2007.09.024

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METHODSWe searched the Cochrane Central Register of Con-

rolled Trials (CENTRAL; Cochrane Library, Issue 4, 2006)sing the terms “headache,” “migraine,” “cephalgia,” “cepha-algia,” “p(a)ediatric,” “infan,*” “child*,” “teenage,*” and “ad-lescent*.” We also searched MEDLINE from 1966 throughovember 2006 using these same terms, along with the

earch strategy for identifying randomized controlled trialsRCTs) described by Dickersin et al.19 Additional strategiesor identifying trials included hand searching the referenceists of systematic and descriptive review articles and studies,nd consulting experts in the field. We attempted to identifyll relevant published trials irrespective of language, and ac-epted abstracts and other presentation formats. We includedrospective, double-blind RCTs or controlled clinical trialsCCTs) of pharmacologic interventions for the symptomaticelief of acute migraine attacks.

Study participants were required to be children or ad-lescents (under age 18 years) with migraine with or withoutura, as defined by the 1988 International Classification ofeadache Disorders (ICHD) diagnostic criteria or the revised

004 ICHD criteria for children.2,3 Secondary headache dis-rders were excluded using clinical or imaging criteria. Noestrictions regarding the frequency, duration, or intensity ofigraine headaches, and the use of preventive medication

eyond those imposed by the ICHD criteria were placed onhe studies. Trials composed primarily of adults but includingarticipants under age 18 years also were accepted, providinghat they fulfilled the diagnostic criteria and that the out-omes for this age group were reported separately.

Only pharmacologic interventions were included, andll studies were required to have at least 1 arm in which alacebo comparator group was used, irrespective of the activentervention for symptomatic treatment of an acute migrainettack. Both active drugs and placebo could be administeredn oral, nasal, subcutaneous, or intravenous formulations.

Reviewers collected trial data on short-term symptom-tic outcomes related to head pain and associated symptomsf migraine, as well as data on headache recurrence, rescueedication, and adverse events. Trials were included if the

ata were adequately reported, and, in the case of multiple-ttack trials, only if separate data for the first attack treatedere available, to minimize carry over effects.

Our main outcome measures of interest were headacheelief and pain-free response at various time points postint-rvention. Headache relief was defined as pain reductionreater than 50%, regardless of the type of scale used tovaluate pain, and pain-free meant a complete resolution ofeadache pain. We used 0.5, 1, 2, and 4 hours or more as time

ntervals for the analysis. Associated symptoms, includingausea, vomiting, photophobia, and phonophobia, also werenalyzed at these time points. Headache recurrence includedatients who suffered again from migraine for up to 24 hours,nd rescue medication was defined as additional medications

other than study medications) permitted in nonresponders. e

28 Fernandes, Ferreira, and Sampaio

hen a protocol allowed the use of rescue medication beforeutcome measurement, the latest outcome assessment notonfounded by the use of rescue medication was extracted.he analysis of data reported on adverse events considered theverall number of patients reporting at least 1 adverse event.

Based on previous works and hypothetical assumptions,e defined a number of clinical and methodological factors

hat could affect the outcome results.10,11,16,18 These includedatient age, baseline frequency of migraine headaches, studyesign, study center, sample size (n � 50 or �50), type andumber of active interventions, route of administration, typef pain scale and who fills it (parent or child), time toreatment, and day of the week on which treatment wasnstituted.

ethods of ReviewTwo independent reviewers (R.F. and J.J.F.) screened

he titles and abstracts of the studies identified by the litera-ure search for eligibility. A complete article was obtained forach article deemed eligible, for further analysis. Disagree-ents regarding eligibility were resolved through discussion.he reviewers were not blinded to the authors’ names and

nstitutions, journal of publication, or study results at this orny stage of the review.

Data extraction was performed by 1 author (R.F.) andverread by a second author (J.J.F.), using previously preparedlectronic forms. Disagreements were resolved by consensus.xtracted information included patient characteristics, alongith the previously described outcomes and possible placebo

esponse determinants. We used dichotomous outcomes,onverting ordinal and continuous scale data when necessary,ccording to the definitions stated above.

Two reviewers independently assessed the internal validityf individual trials using the scale devised by Jadad et al 20 tovaluate the quality of clinical trials describing pain treatmentrange, 0 to 5). Disagreements between reviewers were resolvedhrough consensus.

ata AnalysisDichotomous outcome data meeting our definition of

linical response were used to calculate risk differences (RDs),ith 95% confidence intervals. The analysis aimed to deter-ine the placebo response, calculated as the difference in the

ercentage of patients who achieved the main outcomes in thelacebo group and in a virtual group (“0% group”) in which itas assumed that no patients had achieved these outcomes.or the outcomes “associated symptoms” and “recurrence,”nly patients with the symptom at the beginning of the studyr those patients who had improved, respectively, were con-idered.

Consistency of RD results from multiple studies wasested using Cochran’s Q statistic and quantified using the I2

alue.21 Any study estimates that were homogeneous wereombined using a fixed-effects model. When significant het-

rogeneity was present, a random-effects model was chosen.

The Journal of Pediatrics • April 2008

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n attempt was made to explain the differences based on theossible placebo response clinical and methodological deter-inants described earlier, with pooling of RDs from different

ubgroups of studies and further consistency testing (sub-roup analysis). The analysis of the responses rates was basedn the intent-to-treat (ITT) population whenever possible. Avalue �.05, using a 2-tailed test, was defined as significant.he meta-analysis was performed using Review Manager,

ersion 4 (Cochrane Collaboration, Oxford, UK; available atttp://www.cc-ims.net/RevMan).

RESULTSA total of 5416 potential relevant articles were identified

fter the first search, aimed at sensitivity. Most were discardedfter title or abstract analysis because they were not acute mi-raine treatment RCTs or CCTs, they did not include childrenr adolescent groups, or they did not include a placebo compar-tor group. Only 16 trials remained, of which a further 3 trialsere excluded, 2 because the abstracts did not report adequatelacebo group data22,23 and the third because it was an RCT thatncluded both adult and adolescent participants but did notiscriminate the latter group results.24 Consequently, 13 trialsere included in the final review.9,25-33,35-37

The main study characteristics are summarized in Table Iavailable at www.jpeds.com). The eligible studies were pub-ished between 1997 and 2006, all of them in English language.

Only 6 trials reported separate age and sex results forhe placebo group,9,29-32,35 and the data were heterogeneouslyummarized as either mean or median age. Twelve trials usedhe 1988 International Headache Society migraine headacheriteria,9,25-33,35-37 and 1 trial used the latest 2004 revision.36

leven trials included only participants with a baseline mi-raine frequency of �1 episode/month.9,25-30,32,33,35,37 In 6tudies, resistance to previous acute migraine therapy wasequired,25,27-29,33,37 and in another 6 trials, migraine prophy-axis was not allowed.25-28,33,37

Data regarding interventions are shown in Table I. Inhe 4 trials that defined a maximum time to treatment, thisime was within 1 hour of migraine onset.30,32,34,35 Two trialsompared weekend versus weekday treatments, 1 of themsing a post hoc analysis.30,32

All studies used headache diaries to assess outcomes andain scales to evaluate pain. Nine trials used 4-point validatedating scales9,26,28-32,35,36 (1 of which was a faces scale), and

able II. Placebo response for different study outcom

OutcomeNumber of trials/

participantsR

[9

ain relief at 2 hours 13/1324ain-free at 2 hours 13/1284escue medication 11/912eadache recurrence 9/430*dverse events 12/1290

Primary responders.

he remaining 4 trials used 5-faces scales.25,27,33,37 In 2 stud- a

he Placebo Response in Studies of Acute Migraine

es, a continuous visual analog scale was also used if the childhose it, and results were later transformed into a 5-pointategorical scale.25,27 Only 1 trial specifically stated the diariesere filled in by parents according to the child’s

nput.28Although in other trials diaries were supposedly pa-ient-filled, authors of 1 study indicated that parents usuallylled their children’s diaries.31 ITT analysis was used in 9rials for efficacy results.9,25,29,30,32,33,35-37

lacebo ResponseAll studies assessed pain outcomes, at time points rang-

ng from 0.25 to 24 hours. Results at 2 hours are summarizedn Table II and plotted in Figure 1. Eight trials also presentedesults at 1 hour.25,29,31,33-37 The effect estimate for pain reliefn � 889) was 33% (range, 23% to 43%) (heterogeneity: �2 �5.71; P � .01; I2 � 91%), and that for the pain-free outcomeas 14% (9% to 18%) (�2 � 8.77; P � .07; I2 � 54%) (n �48). Results for later time points were presented in only 3rials.30,33,37

Data comparison was limited by unclear time limits orollow-up intervals, both in 8 trials for rescue medicationse,25-28,33,35,36,37 and in 5 trials for headache recur-ence.25,28,33,36,37 Both effect estimates are shown in Table II.

Associated symptoms outcomes were included in therotocol of 7 trials, at time points ranging from 0.5 to 24ours.28-32,35,36 However, only 3 trials reported completeata, the remainder either failing to report baseline symptomrevalence, or presenting partial and heterogeneous informa-ion.28-30 This did not allow a correct effect estimate.

All trials except 1 reported adverse events data, most usingafety population analysis.9,25-30,32,33,35-37 Seven of them did notlearly identify the time intervals for occurrence of this out-ome,25-28,30,33,37 with the remainder defining it as less than 24ours.9,29,31,32,35,36 It was sometimes unclear whether reportedausea and vomiting were true adverse events or pain-associatedymptoms, particularly in trials that did not distinguish associ-ted symptoms. Results are shown in Table II.

lacebo Response DeterminantsThe influence of all previously described potential pla-

ebo response determinants on all outcomes was evaluated.nly pain relief and adverse events outcomes are shown, due

o the small number of trials and heterogeneous data, whichimited analysis of other outcomes. Data on pain relief are

ifference estimateonfidence interval] Heterogeneity: �2, P, I2

% [38% to 53%] �2 � 86.02; P � .01; I2 � 86%% [17% to 26%] �2 � 41.7; P � .01; I2 � 71%% [32% to 45%] �2 � 36.03; P � .01; I2 � 72%% [13% to 46%] �2 � 123.9; P � .01; I2 � 93%% [8% to 25%] �2 � 234.84; P � .01; I2 � 95%

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igure 1. Pooled RDs of the placebo response for headache relief (A) and headache-free at 2 hours (B).

able III. Placebo response for pain outcomes according to study design, study center, and paincale determinants

DeterminantNumber of trials/

participantsRisk difference estimate

[95% confidence interval] Heterogeneity: �2, P, I2

ain relief at 2 hoursStudy design

Cross-over 7/348 35% [30% to 40%] �2 � 5.85, P � .44, I2 � 0Parallel 6/976 58% [52% to 64%] �2 � 16.18, P � .01, I2 � 69%

Study centerEurope 8/523 37% [28% to 45%] �2 � 21.87, P � .01, I2 � 68%US 6/976 58% [52% to 64%] �2 � 16.18, P � .01, I2 � 69%

Pain scale4-point 9/1030 52% [44% to 59%] �2 � 39.44, P � .01, I2 � 80%5-point 4/294 36% [31% to 42%] �2 � 2.94, P � .4, I2 � 0

ain free at 2 hoursStudy design

Cross-over 7/313 15% [8% to 21%] �2 � 12.78, P � .05, I2 � 53%Parallel 6/971 27% [23% to 31%] �2 � 8.69, P � .12, I2 � 43%

Study centerEurope 8/488 16% [11% to 21%] �2 � 13.95, P � .05, I2 � 50%US 6/971 27% [23% to 31%] �2 � 8.69, P � .12, I2 � 43%

Pain scale4-point 9/1025 22% [16% to 28%] �2 � 32.73, P � .01, I2 � 76%

2 2

5-point 4/259 19% [13% to 25%] � � 4.2, P � .24, I � 29%

30 Fernandes, Ferreira, and Sampaio The Journal of Pediatrics • April 2008

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All parallel studies were performed in North Americanenters, all cross-over studies were performed in Europe, andof the parallel studies was carried out in both.

For the adverse events outcome, the effect estimate inross-over studies (7 trials; n � 351) was 9% (range, 3% to4%), and 25% (range, 11% to 39%) in parallel studies (5rials; n � 939). This difference was not statistically signifi-ant. The effect estimate was 9% (range, 4% to 15%) inuropean center studies (8 trials; n � 527) and 25% (range,1% to 39%) in American center studies (5 trials; n � 939),statistically nonsignificant difference. Finally, the effect es-

imate was 21% (range, 10% to 32%) in 4-point scale studies8 trials; n � 993) and 7% (range, 1% to 14%) in 5-scaletudies (4 trials; n � 297). Again, this difference was nottatistically significant.

There were overlapping effect estimates for the placeboesponse in partial and complete pain relief and adverse eventsutcomes when comparing studies according to mean patientge (under age 12 vs over age 12), sample size (n �50 or n � 50),nd number of active interventions (1 or more than 1). In-omplete data and the small number of trials did not allow thenalysis of other determinants.

DISCUSSIONOur systematic review has demonstrated a high and

ariable placebo response rate in pediatric migraine trials.here are only a limited number of studies in this age group

igure 2. Pooled RDs of the placebo response for the headache relief (A)nd headache-free at 2-hour (B) outcomes, comparing pediatric trials fromhe current systematic review and adult trials from a previous study.

s opposed to adults, in whom more than 100 trials with d

he Placebo Response in Studies of Acute Migraine

vailable placebo data have been reported.16 Although therere few variations in design, quality scores, and migraineefinition among these studies, some criteria used for inclu-ion and the reporting of participant characteristics and out-omes vary sufficiently to make data pooling and subgroupnalysis difficult for both placebo and active interventionesponses.

The placebo response estimates for pain reductionutcomes are of considerable magnitude in the pediatricge group, confirming suggestions from previousorks.10,11 The estimate is larger than that of a recenteta-analysis of adult migraine treatment trials that used

imilar outcome definitions, the results of which are shownor comparison in Figure 2.16 We also identified a significanttatistical heterogeneity in the placebo response for theseutcomes. Taken together, these results represent a strongethodological argument for the continued use of placebo

roups in pediatric migraine trials, in accordance with whatas been suggested for adult migraine trials.11 Indeed, the usef placebo versus active comparator groups in clinical trialsemains a subject of ethical and scientific controversy, partic-larly in trials of new treatments for disorders for whichroven effective treatments exist.12,40 Nevertheless, there ap-ears to be a middle ground that allows the use of placeboontrols in children given certain conditions.38,41,42,43 Thesenclude a waxing-and-waning course of a disease that is noterious and a high placebo responder rate, both of which areresent in cases of pediatric migraine.38,43

The analysis of possible placebo response determi-ants identified only study design, center, and type of paincale used as influencing the placebo responder rate in painutcomes. The influence of the first 2 variables in thelacebo response has been previously observed in adultigraine trials and in other disease states, although in this

articular study, the contribution of each 1 cannot bessessed individually.16,34 Cultural aspects may explain dif-erences between centers, and this variability is a furtherrgument for the use of a placebo control group to comparerials from different populations. Four-point pain scalestudies had a greater placebo response for the pain reliefutcome than studies with 5-point or faces scales. Theseast scales, particularly analog faces scales, may be moreensitive for distinguishing the level of pain in children,nd their use may reduce the placebo response in futurelinical trials, as has been suggested previously.10

We did not confirm a greater placebo response inounger children, as suggested in previous works, but ade-uate age category data reporting in future studies shouldddress this relevant issue.10 The number of interventionsrandomization ratio) did not affect the response rate. Scantlyata kept us from studying other relevant determinants, in-luding the route of administration, which has been shown tonfluence the placebo response in adults.16,44

Other factors have been identified that may explain thelacebo response.18,45 Migraine is known to have a shorter

uration in children and adolescents than in adults, possibly

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ith a greater response for the same time points. Therefore,significant time delay before treatment may inflate both

ctive intervention and placebo responders.10 In most trials,he influence of this variable was not analyzed due to incom-lete data; the inclusion of both time to treat criteria andndpoints at shorter time points may benefit future trials.10

he differences in placebo response between weekdays andeekends suggested in 2 trials also may be related to this

actor; we can speculate that the delay before treatment isonsiderably longer in attacks occurring on a schoolay.10,30,32 Trial design and type of scale were both shown toffect the placebo response; however, neither could fully ex-lain the response’s magnitude or variability. Although thexistence of a true placebo effect has been repeatedly ques-ioned, clinical and neuroimaging data support its presence,articularly in pain conditions, including migraine.17,18,46

his effect has been linked to the expectation of benefit by theatient, but to date no studies have addressed this issue inhildren.18

Several limitations of this study should be considered.e included only studies with fully published data, and thusay have excluded studies in abstract form and others thatay have remained unpublished due to undesired efficacy

esults. But these studies were probably more likely to havead a higher placebo response rate, thus biasing this analysisoward a reduced magnitude of the placebo response.11 Inddition, most of the participants in those trials had a signif-cant history of moderate to severe migraine attacks, some-imes previously resistant to therapy or under prophylaxis, andome subjects had previous trial experience as well,25-27 whichay have affected the expectation of benefit in these patients

nd thereby the external validity of this observed placeboesponse. The small number of trials implies that the effectizes of the random-effects models should be interpreted withaution and limits the investigation of heterogeneity by sub-roup analyses. For some variables (eg, age), there was also aonsiderable aggregation or ecological bias, because we couldse only a mean or median for analysis, with only scantynowledge of the distribution of individual data.39

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9. Winner P, Rothner AD, Saper J, Nett R, Asgharnejad M, Laurenza A, et al. Aandomized, double-blind, placebo-controlled study of sumatriptan nasal spray in thereatment of acute migraine in adolescents. Pediatrics 2000;106:989-97.0. Winner P, Lewis D, Visser WH, Jiang K, Ahrens S, Evans JK. Rizatriptan 5 mgor the acute treatment of migraine in adolescents: a randomized, double-blind, placebo-ontrolled study. Headache 2002;42:49-55.1. Lewis DW, Kellstein D, Dahl G, Burke B, Frank LM, Toor S, et al. Children’sbuprofen suspension for the acute treatment of pediatric migraine. Headache 2002;2:780-6.2. Visser WH, Winner P, Strohmaier K, Klipfel M, Peng Y, McCarroll K, et al.izatriptan 5 mg for the acute treatment of migraine in adolescents: results from aouble-blind, single-attack study and two open-label, multiple-attack studies. Headache004;44:891-9.3. Ahonen K, Hamalainen ML, Rantala H, Hoppu K. Nasal sumatriptan is effective inreatment of migraine attacks in children: a randomized trial. Neurology 2004;62:883-7.4. Moerman DE. Cultural variations in the placebo effect: ulcers, anxiety, and bloodressure. Med Anthropol Q 2000;14:51-72.5. Winner P, Rothner AD, Wooten JD, Webster C, Ames M. Sumatriptan nasalpray in adolescent migraineurs: a randomized, double-blind, placebo-controlled, acutetudy. Headache 2006;46:212-22.6. Evers S, Rahmann A, Kraemer C, Kurlemann G, Debus O, Husstedt IW, et al.reatment of childhood migraine attacks with oral zolmitriptan and ibuprofen. Neu-

ology 2006;67:497-9.

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7. Ahonen K, Hamalainen ML, Eerola M, Hoppu K. A randomized trial ofizatriptan in migraine attacks in children. Neurology 2006;67:1135-40.8. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials: a middle ground.

Engl J Med 2001;345:915-9.9. Berlin JA, Santanna J, Schmid CH, Szczech LA, Feldman HI. Individual patient-ersus group-level data meta-regressions for the investigation of treatment effect mod-fiers: ecological bias rears its ugly head. Stat Med 2002;21:371-87.0. Freedman B, Glass KC, Weijer C. Placebo orthodoxy in clinical research. II:thical, legal, and regulatory myths. J Law Med Ethics 1996;24:252-9.1. Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the

valuation of new treatments. Part 2: practical issues and specific cases. Ann Intern Med000;133:464-70. o

he Placebo Response in Studies of Acute Migraine

2. Lewis JA, Jonsson B, Kreutz G, Sampaio C, van Zwieten-Boot B. Placebo-ontrolled trials and the Declaration of Helsinki. Lancet 2002;359:1337-40.

3. Miller FG, Wendler D, Wilfond B. When do the federal regulations allowlacebo-controlled trials in children? J Pediatr 2003;142:102-7.

4. de Craen AJ, Tijssen JG, de Gans J, Kleijnen J. Placebo effect in the acutereatment of migraine: subcutaneous placebos are better than oral placebos. J Neurol000;247:183-8.

5. Macedo A, Sampaio C. Influence of placebo effect on planning and analysis oflinical trials. Rev Port Cardiol 2001;20:313-9 [in Portuguese].

6. Turner JA, Deyo RA, Loeser JD, Von Korff M, Fordyce WE. The importance

f placebo effects in pain treatment and research. JAMA 1994;271:1609-14.

50 Years Ago in The Journal of PediatricsACID-BASE HOMEOSTASIS OF THE NEWBORN INFANT DURING THE FIRST 24 HOURS OF LIFE

Weisbrot IM, James LS, Prince CE, Holiday DA, and Apgar V. J Pediatr 1958;52:395-403

Umbilical arterial blood was sampled from a clamped segment of umbilical cord in 21 newborns with Apgar scoresof 6 or higher. Twelve of these infants were delivered by cesarean section. Left atrial samples were drawn through anumbilical venous catheter from the infants during the first hour after birth or at the third hour and again at approximately24 hours after birth. Each analysis took about 5 mL of blood; informed consent was not even a consideration. These wereheady times. James, Holiday, and Apgar were luminaries in the field, and this was a bold new undertaking to use fetalinformation. The mean pH of 7.23 and partial pressure of carbon dioxide (pCO2) of 58 compare favorably with the meanvalues of 7.28 and 49 subsequently found in other, larger studies. This occurred despite the small sample size, absenceof fetal monitoring to help rule out fetal distress, absence of uniformly normal Apgar scores, and absence of pairedumbilical venous and arterial samples to ensure that arterial blood had indeed been sampled.

Over the last 50 years, much has been learned about interpreting umbilical cord blood gas data, as well as the manypotentially misleading pitfalls. For example, almost 20% of paired specimens come from the same vessel;1 almost always,both are venous. Unless both umbilical venous and arterial samples are obtained, one cannot be certain that a singlesample represents arterial blood. Frequently, specimens are mislabeled. If an umbilical vessel is occluded, the blood gasvalues reflect only the status before occlusion, or the cessation of blood flow associated with severe bradycardia andhypotension.2

Wide differences between venous and arterial pH (�0.10; differences as large as 0.6 have been observed), pCO2

values, and sometimes base deficits suggest cord compression and anticipate neonatal hypovolemia secondary to occlusionof the umbilical vein while the umbilical arteries remain patent.2 Far less often, it may signify chronic fetal heart failure.3

On the other hand, similar derangements in the venous and arterial samples (not widened) suggest uteroplacentalinsufficiency.4 This information may be of help both to obstetricians in gaining insight into the mechanism of neonataldepression and to clinicians caring for newborns, because newborns with severe cord compression will likely respond wellto volume expansion.

Fifty years ago, umbilical cord blood gas analysis was in its neonatalcy. Baby, you’ve come a long way!

Jeffrey Pomerance, MD, MPHProfessor Emeritus

Department of PediatricsDavid Geffen School of Medicine at UCLA

Los Angeles, California10.1016/j.jpeds.2007.10.039

1. Westgate J, Garibaldi JM, Greene KR. Umbilical cord blood gas analysis at delivery: a time for quality data. Br J Obstet Gynaecol 1994;101:1054-63.2. Pomerance JJ. Interpreting umbilical cord blood gases. Pasadena, BNMG, Inc 2004, 54-7, www.cordgases.com.3. Pomerance JJ. Interpreting umbilical cord blood gases. Pasadena, BNMG, Inc 2004, 77-84, www.cordgases.com.4. Pomerance JJ. Interpreting umbilical cord blood gases. Pasadena, BNMG, Inc 2004, 45-9, www.cordgases.com.

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able I. Characteristics of studies evaluated

tudy design (number of trials)Cross-over 725-28,33,36,37

Parallel 629-32,35,39

tudy centers (number of trials)Europe 825-28,33,36,37,39

US 629-32,35,39

adad score �4 (all trials)articipantsPlacebo group size n � 1324 (total); range:

11 to 244 per trialAge (years)* Mean: 13.9 � 1.7; range:

4 to 18Female 50% (range, 42% to 82%)

ype of active interventions (numberof trials)

Triptan 1027-30,32,33,35-37,39

NSAID/acetaminophen 325,31,36

DHE 126

umber of active interventions(number of trials)

1 826-28,30-33,37

�1 525,29,35,36,39

dministration of active interventions(number of trials)

Oral 925-27,30-32,36,37,39

Nasal 428,29,33,35

Assuming placebo or whole population mean age values when reported.HE, dihydroergotamine; NSAID, non-steroidal anti-inflammatory drug.

33.e1 Fernandes, Ferreira, and Sampaio The Journal of Pediatrics • April 2008