 |
|
 |
|
 |
 |
|
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
a Center for Health Studies
b Preventive Care
d Pediatrics, Group Health Cooperative, Seattle, Washington
c Departments of Epidemiology
e Biostatistics, University of Washington, Seattle, Washington
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS. In this 3-group, randomized, blinded, controlled trial, 372 children were assigned randomly, in a 2:2:1 ratio, to receive 3 doses of acetaminophen, ibuprofen, or placebo. The first dose of study medication was administered within 2 hours before the fifth DTaP vaccination, and the remaining 2 doses were given at 6-hour intervals. The primary outcome measures included a local reaction with an area of redness or discoloration 
5 cm in diameter on the evening of or during the 2 days after vaccination, an increase in mid-limb circumference of 2 cm on the evening of or during the 2 days after vaccination, and a persistent local reaction, defined as an area of redness or discoloration present on the third day after vaccination.
RESULTS. Local reactions with a 5-cm area of redness or discoloration were reported for 35% of children in the placebo group, compared with 33% of children in the acetaminophen group and 37% of children in the ibuprofen group. There was also no significant difference between the placebo and treatment groups in the proportions of children with a 2-cm increase in mid-limb circumference or with a persistent local reaction.
CONCLUSIONS. We did not find evidence that prophylaxis with acetaminophen or ibuprofen offers a clinically significant benefit in prevention of local reactions to the fifth DTaP vaccination.
Key Words: vaccine • adverse reactions • pertussis vaccine • DTaP vaccine
Abbreviations: DTaP—diphtheria-tetanus toxoids-acellular pertussis
Acellular pertussis vaccines are associated with substantially lower rates of postvaccination fever than are older, whole-cell, pertussis vaccines.1–5 However, the frequency of local reactions increases with successive doses of diphtheria-tetanus toxoids-acellular pertussis (DTaP) vaccines, and these reactions are common after the fifth DTaP vaccination, given at 4 through 6 years of age.6–9 In a previous assessment, we found that approximately two thirds of children who receive their fifth DTaP vaccination have a local reaction, one third have a reaction with an area of erythema 5 cm in diameter, 1 in 10 have a reaction with an area of erythema 10 cm in diameter, and 1 in 50 have a reaction in which the erythema extends to the entire limb.10 Local reactions to the fifth DTaP vaccine are self-limited but may be associated with pain that restricts usual activities temporarily, and the larger reactions may be concerning to parents and physicians.
Interventions for the prevention of local reactions to DTaP vaccines have not been evaluated; therefore, it is not known whether prophylaxis with nonprescription medications can reduce the frequency or severity of these reactions. To determine whether prophylaxis with either acetaminophen or ibuprofen ameliorates local reactions after the fifth DTaP vaccination, we conducted a randomized, controlled trial.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Participants
The randomized, controlled trial was nested within a prospective, noncomparative, postlicensure study of the safety of the fifth consecutive dose of Tripedia DTaP vaccine (Sanofi Pasteur, Swiftwater, PA) at Group Health Cooperative, a health maintenance organization in Washington State. Children 4 to 6 years of age who had received 4 previous vaccinations with Tripedia DTaP at Group Health Cooperative were identified by using computerized immunization records, and their parents were contacted by telephone. Children were not eligible for enrollment in the trial if they had a history of hypersensitivity to aspirin, ibuprofen, or other antiinflammatory agents; known liver or renal dysfunction; a history of gastrointestinal ulceration, bleeding, or perforation; known coagulation defects; difficulty taking liquid medications; or a requirement for ongoing use of acetaminophen, ibuprofen, or any other antiinflammatory agent. Participants were enrolled from May 2003 through June 2004.
Randomization and Blinding
Eligible children whose parents consented to their participation were assigned randomly to receive acetaminophen, ibuprofen, or placebo, in a 2:2:1 ratio, according to a variable-permutated block-size randomization sequence that was generated by a study biostatistician not involved in participant recruitment or follow-up monitoring and was shared only with an off-site study pharmacist. After the parent returned the signed consent form by mail, study staff members assigned a study number, which the pharmacist used to identify the appropriate medication from the randomization list. The study medication was then dispensed by mail before the participant's scheduled vaccination visit. Children, parents, clinical staff members, investigators, and study monitors were unaware of the randomization assignments throughout the data-collection phase.
Study Medications
The study medications were formulated in a liquid suspension that was identical in appearance for all 3 formulations and was flavored to mask differences in taste. Parents were instructed to administer a medication volume, based on the child's weight, that would correspond to a dose of 15 mg/kg acetaminophen, up to a maximal dose of 450 mg, or 10 mg/kg ibuprofen, up to a maximal dose of 300 mg.
Parents were asked to administer the first dose 2 hours before the scheduled vaccination visit, with an allowable window of up to 30 minutes after vaccination. The second and third doses were to be given at 6-hour intervals, with an allowable window of up to 12 hours between consecutive doses.
Study Procedures and Data Collection
At the scheduled vaccination visit, study staff members instructed parents on data-collection methods and recorded the time of administration of the first dose of the study medication. The DTaP vaccine (Tripedia) was then administered, without concomitant vaccinations, by Group Health Cooperative clinical staff members according to their usual practice. This practice does not include the use of topical anesthetic treatments, such as lidocaine or prilocaine cream.
Parents recorded the timing of administration of the second and third doses of study medication in a study diary. On the evening of vaccination and for the next 6 days, parents recorded the oral temperature, the diameter of the vaccinated limb at the midpoint, and the maximal diameter of the area of redness or discoloration and localized swelling on the vaccinated limb. The areas of redness or discoloration and swelling were categorized as not present, present and <2.5 cm in maximal diameter; 2.5 and <5 cm in maximal diameter; 5 and <10 cm in maximal diameter; 10 cm and less than complete limb involvement; or complete thigh or upper arm involvement.
Parents also recorded daily symptoms of pain in the vaccinated limb, graded as none, mild (light reaction to touch), moderate (protesting in response to touch or pain with limb movement), or severe (child resists limb movement or keeps limb immobile), and itching of the vaccinated limb, graded as none, mild (child complains of itching or is noted to be scratching but no treatment is given), moderate (treatment with cold packs or topical nonprescription medications), or severe (interferes with daily activities or sleep, topical prescription medication is used, or any oral medication is used to treat itching). Study staff members contacted parents by telephone to collect the diary information.
Outcomes
The primary study outcomes included local reactions characterized by an area of redness or discoloration in the vaccinated limb of 5 cm on the evening of or during the 2 days after vaccination, increase in mid-limb circumference of 2 cm on the evening of or during the 2 days after vaccination, and a persistent reaction, defined as an area of redness or discoloration present on the third day after vaccination. For exploratory analyses, a series of secondary outcomes were defined, as described in Table 2.
|
The primary analysis was an intent-to-treat comparison of the risk of the primary outcomes between each of the 2 treatment groups and the placebo group. Secondary analyses included an intent-to-treat comparison of secondary outcomes and a per-protocol analysis of primary and secondary outcomes that included only children who received all 3 doses of the study medication within the specified time windows. Fisher's exact test was used for all comparisons of frequencies.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
1 dose of study medication, 359 (99%) received the first dose before vaccination and 350 (97%) received the first dose between 1 and 4 hours before vaccination.
|
2.5 cm, 49% reported some pain in the vaccinated limb, and 23% reported itching in the vaccinated limb on the evening of vaccination or in the next 2 days. In the intent-to-treat analyses, however, there were no significant differences in the proportions of participants with primary or secondary outcomes in either of the treatment groups, compared with the placebo group (Table 2). The results of the per-protocol analyses were similar to the results of the intent-to-treat analyses. Among children who received all 3 doses of study medication within the assigned windows, there were no significant differences in the proportions of participants with primary or secondary outcomes in either of the treatment groups, compared with the placebo group (data not shown).
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
50% for the primary outcome of a local reaction with an area of redness or discoloration of 5 cm. Although we cannot exclude the possibility that acetaminophen or ibuprofen treatment was associated with a smaller reduction in risk of local reactions, the frequencies of the primary outcomes in the treatment groups, compared with the placebo group, do not suggest a trend for a treatment effect. From these results, we conclude that prophylaxis with either acetaminophen or ibuprofen is not associated with a clinically significant reduction in risk of local reactions among children receiving the fifth DTaP vaccination. Two randomized trials of acetaminophen prophylaxis before whole-cell pertussis vaccination in the 1980s evaluated the effect of prophylaxis on the occurrence of local vaccination reactions.11, 12 Those studies enrolled primarily infants 2 through 6 months of age, and both studies reported significant reductions in the severity of pain in the vaccinated limb in the acetaminophen group compared with the placebo group. The observed effects of acetaminophen prophylaxis on signs of local reactions were not consistent between the 2 studies. In the study by Lewis et al,12 there was no difference in the frequencies of local redness, swelling, or induration between the acetaminophen and placebo groups, whereas Ipp et al11 reported a significant reduction in the frequency of local reactions with an area of redness of >2 cm in the acetaminophen group, compared with the placebo group, among infants 2 through 6 months of age. In contrast to those studies, we did not identify significant differences between the acetaminophen and placebo groups in the frequency or severity of postvaccination pain or in the frequency of local reactions characterized by redness in our study population of children receiving their fifth DTaP vaccination.
Our study included children enrolled in Group Health Cooperative whose parents had consented to their participation in a postlicensure assessment of the safety of the fifth dose of DTaP vaccine. The children enrolled in the postlicensure safety study represented 50% of Group Health Cooperative children eligible for participation in that study. Of the safety study participants recruited for the nested trial, 75% enrolled in the trial. Although it is possible that there were demographic differences between the children enrolled in the trial and other groups of children, it seems unlikely that such differences would be associated with variations in the effects of treatment; therefore, the results of this trial are likely generalizable to other groups of children receiving their fifth DTaP vaccination. Although it seems unlikely that effects of prophylactic acetaminophen or ibuprofen treatment would vary according to DTaP vaccine formulation, it is also worth noting that our study included only children who had received Tripedia DTaP vaccine for all 5 doses in the pertussis vaccination series. Lastly, in this study parents were instructed to administer the study medication every 6 hours, to yield a consistent dosing schedule across the study groups; therefore, acetaminophen was not administered at the minimal recommended dosing interval of 4 hours. Given our findings, however, it seems unlikely that more-frequent administration of acetaminophen would have been associated with a substantive reduction in risk of local reactions.
The cause of local reactions to the fifth DTaP vaccination is unclear. Although a single predisposing factor has not been implicated consistently, possible associations of reactions with higher antigen contents of 1 vaccine component7 and higher prevaccination antibody levels6 have been reported. These associations are consistent with the hypothesis that the local reactions are Arthus reactions, resulting from binding of circulating antibody to administered vaccine antigen. The results of this randomized, controlled trial suggest that the mechanisms leading to local reactions after the fifth DTaP vaccination are not modified substantially by administration of standard doses of either ibuprofen or acetaminophen.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
Address correspondence to Lisa A. Jackson, MD, MPH, Center for Health Studies, Group Health Cooperative, 1730 Minor Ave, Suite 1600, Seattle, WA 98101. E-mail: jackson.l{at}ghc.org
Financial Disclosure: Dr Jackson has served on the speakers bureau for Sanofi Pasteur. The other authors have no relevant financial relationships to disclose.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
 |
|
 |
|
  L. A. Jackson, P. Starkovich, M. Dunstan, O. Yu, J. Nelson, J. Dunn, T. Rees, A. Zavitkovsky, D. Maus, J. E. Froeschle, et al. Prospective Assessment of the Effect of Needle Length and Injection Site on the Risk of Local Reactions to the Fifth Diphtheria-Tetanus-Acellular Pertussis Vaccination Pediatrics, March 1, 2008; 121(3): e646 - e652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Hatfield, M. E. Gusic, A.-M. Dyer, and R. C. Polomano Analgesic Properties of Oral Sucrose During Routine Immunizations at 2 and 4 Months of Age Pediatrics, February 1, 2008; 121(2): e327 - e334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Taddio, J. Manley, L. Potash, M. Ipp, M. Sgro, and V. Shah Routine Immunization Practices: Use of Topical Anesthetics and Oral Analgesics Pediatrics, September 1, 2007; 120(3): e637 - e643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Manley and A. Taddio Acetaminophen and Ibuprofen for Prevention of Adverse Reactions Associated with Childhood Immunization Ann. Pharmacother., July 1, 2007; 41(7): 1227 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Neither paracetamol nor ibuprofen protects children against local reactions to the DTaP vaccine BMJ, April 1, 2006; 332(7544): . [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
||
|
||
Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2006 American Academy of Pediatrics. All rights reserved. |
||
|
||
