Rheumatic fever is the most serious nonsuppurative complication of group A beta-hemolytic streptococcal infection. Despite the overall decrease in the incidence and severity of acute rheumatic fever in developed countries, interest in the disease has been renewed in response to reports of several outbreaks during the last decade.1, 2 Because recurrent attacks are a frequent complication of streptococcal infection, affected patients required continuous prophylaxis against group A beta-hemolytic streptococci. A recommended regimen is a monthly intramuscular injection of benzathine penicillin G (BPG). However, the local pain and discomfort associated with the injection tend to decrease compliance with prolonged treatment of BPG especially in children and adolescents.
BPG in combination with aqueous procaine penicillin has been used in the treatment of acute streptococcal pharyngitis because it results in a higher blood concentration of penicillin and is better tolerated than BPG diluted in sterile water.3 Lidocaine is used as a diluent for ceftriaxone to reduce the pain of the intramuscular injection.4 As a local anesthetic, lidocaine produces faster, stronger, longer lasting and more extensive anesthesia than an equal dose of procaine.
The aim of the present study was to compare the administration of BPG in two diluents, sterile water or lidocaine hydrochloride 1% for drug penicillin concentrations and pain of injection.
PATIENTS AND METHODS
Design. The study was designed as a randomized double blind, crossover trial. It was carried out from November, 1995, to March, 1996, in the pediatric ambulatory unit of Hasharon Hospital, Petah Tikva, Israel. The protocol was approved by the institution's Ethics Committee and written informed consent was obtained from each patient's parent before enrollment.
The study population consisted of all children >9 years old who were receiving monthly prophylactic BPG for rheumatic fever in the pediatric ambulatory unit. Children with known hypersensitivity to penicillin or lidocaine were excluded.
During the 2 months of the study each child was given two injections of BPG, 1 200 000 units. The patients were randomly divided into two groups. One received penicillin diluted with 3.2 ml of sterile water the first month and followed by penicillin diluted with 3.2 ml of 1% lidocaine hydrochloride in the second month. The second group received the same regimen in reverse order. All injections were administered intramuscularly in the gluteus muscle by one of two nurses. Only the attending nurses were aware of the group assignments.
Penicillin concentrations. Venous blood was obtained from all patients before and 24 h after each injection and then once a week for 4 weeks, for a total of 11 samples from every patient. The serum was separated and samples were immediately frozen at −70°C. Sera were kept frozen for 60 to 90 days. A urine sample was also obtained 4 weeks after each injection and immediately frozen at −70°C. These samples were sent frozen on dry ice for measurement of penicillin in these body fluids.
Penicillin values were measured by agar well diffusion with Bacillus subtilis 6633, as previously described.5, 6 The minimal concentration detected by this method is 0.02 μg/ml. Samples with undetectable levels were given a value of 0.01 μg/ml. All samples were tested in duplicate, using code numbers.
Pain sensation. Pain was measured 24 h after each injection on a visual "smile" face scale, of 1 to 5 (1 = no pain, 5 = terrible pain). Children were asked to rate their pain at the time of injection, 2 to 4 h later and at the time of the questionnaire. After the second injection they were also asked to compare the pain with that of the first injection on a scale of 1 to 5: 1 = significantly less; 2 = less; 3 = the same; 4 = worse; 5 = significantly worse.
Statistical analysis. Paired t test and unbalanced repeated measure models7 were used to analyze the data of the penicillin serum and urine concentrations with the two diluents. The assessment of the pain reported after the injections was evaluated by an analysis of variance and covariance with repeated measure. Differences in values were considered significant at P ≤ 0.05.
Eighteen patients, 10 male (56%) and 8 female (44%), participated in the study. Median age was 14.9 years (range, 11 to 19 years) and median weight 48 kg (range 32 to 65 kg). All had received an injection of BPG (1 200 000 units) diluted in sterile water 1 month before enrollment. For this study 10 patients received penicillin diluted in sterile water first and 8 received penicillin diluted in lidocaine first. Altogether 180 (91%) serum samples and 36 (100%) urine samples were available. Measurable serum penicillin levels (≥0.02 μg/ml) were noted in 35% of the children before the first injection; there was no difference in the serum values between the 2 groups, 0.023 ± 0.16 and 0.016 ± 0.011 μg/ml, respectively. After the injections, peak serum concentrations were similar in the two groups at 24 h and throughout the month (Table 1). We examined the percentage of serum samples containing ≥0.02 μg/ml penicillin. Through 21 days after the injection, 72 and 61% of the serum samples contained ≥0.02 μg/ml (P = 0.2). However, on Day 28, detectable serum of penicillin were found in 44% of the subjects who received the sterile water dilution and in 29% of those who received the lidocaine dilution (P = 0.4). Urine penicillin concentrations on Day 28 were 1.81 ± 0.25 and 2.31 ± 0.25 μg/ml, respectively (P = 0.09).
The postinjection pain ratings are shown in Figure 1. The children receiving BPG diluted with lidocaine hydrochloride reported significantly less pain immediately after the injection than those receiving the water dilution (1.7 vs. 3.7 points, P = 0.0002). There were no significant differences in the pain score at 2 to 4 h (1.9 vs. 2.4 points) or at 24 h (Fig. 1). After the second injection 70.6% of the children reported feeling less pain with the lidocaine dilution than with the water dilution (58.8% significantly less pain and 11.8% less pain); 29.4% did not find any difference between the injections.
This study suggests that the pharmacokinetics of BPG were no different with the lidocaine or sterile water diluent. The serum penicillin after intramuscular injection of BPG 1 200 000 units diluted with either sterile water or lidocaine hydrochloride 1% was undetected in >50% of the children in the fourth week after injection. This agrees with earlier findings8, 9 and has been shown to have clinical significance, given that more recurrences of rheumatic fever were noted after administration of 1 200 000 units of BPG every 4 weeks then after the same dose given every 3 weeks.10 However, because the injection of this formulation of penicillin is very painful, its administration every 3 weeks, despite the better protection provided, must be weighed against the pain to the patient, which can be so disturbing that it leads to noncompliance.
The bioassay for serum penicillin used in this study is not very sensitive (sensitivity of ≥0.02 μg/ml) and it is possible that smaller concentrations of penicillin below the detected threshold may provide some protection. Other assays which use different microorganisms such as Sarcina lutea8 or Micrococcus luteus9 have a better sensitivity of ≥0.008 and ≥0.014 μg/ml, respectively. Measurements of urine penicillin at 28 days after injection have indicated here and in other works11 that some penicillin remains in the body even when it is undetected in the blood. The peak serum of 0.10 μg/ml in the present study was lower than that in other studies (0.15 and 0.17 μg/ml).8, 9 Statistically significantly lower serum penicillin levels were demonstrated in patients younger than 18 years of age than in adults.9 Variable sensitivity of the bioassays used may explain this difference. Weight is an important factor in determining serum penicillin levels. However, because of the small number of patients included in this study, it is not possible to relate penicillin concentrations to body weight. The significance of urine concentrations at 28 days or the penicillin peak serum in determining protection from recurrent streptococcal infection is not known.
This study also demonstrated that the children experienced less pain when BPG was diluted with lidocaine. Although pain score at 2 to 4 h was similar to that at 24 h for each type of injection, at both time points it was low. We assume that the reduction in pain associated with the use of lidocaine will improve the compliance of children and adolescents with rheumatic fever when long term prophylaxis is needed.
A possible limitation of the use of lidocaine as a diluent for BPG is its potential toxicity. We used 3.2 ml of 1% lidocaine, which contains 32 mg of lidocaine, significantly less than the recommended maximum dose for local anesthetic without epinephrine of 4.5 mg/kg.12
In summary we found that the use of lidocaine hydrochloride as a diluent for benzathine penicillin G did not change the serum concentrations of the drug whereas it significantly reduced the pain associated with its intramuscular injection.
We are indebted to Galia Zaicaner, R.N., nurse of the day-care center, for her dedication and technical assistance.
1. Veasy LG, Wiedmeir SE, Orsmond GS, et al. Resurgence of acute rheumatic fever
in the intermountain area of the United States. N Engl J Med 1987;316:421-7.
2. Wallace MR, Garst PD, Popodimos TJ, et al. The return of acute rheumatic fever
in young adults. JAMA 1989;262:255-61.
3. Bass JW, Crast FW, Knowels CR, et al. Streptococcal pharyngitis in children: a comparison of four treatment schedules with intramuscular penicillin G benzathine. JAMA 1976;235:1112-15.
4. Schichor A, Bernstein B, Weinerman H, Fitzgerald J, Yordan E, Schechter N. Lidocaine is a diluent for ceftriaxone in the treatment of gonorrhea: does it reduce the pain of injection? Arch Pediatr Adolesc Med 1994;148:72-5.
5. Young P, Barza M, Kane A, Baum J. Radioactive and bioassay of intraocular antibiotics. Arch Ophthalmol 1979;97:717-20.
6. Grynne B. Identification of small amounts of antibiotics by electrophoresis and bioautography. Acta Pathol Microbiol Scand B Microbiol Immunol 1973;81:583-8.
7. Dixon WJ, ed. BMDP Statistical Software. University of California Press, 1990.
8. Ginsburg CM, McCracken GH Jr, Zweighaft TC. Serum penicillin concentration after intramuscular administration of benzathine penicillin G in children. Pediatrics 1982;69:452-4.
9. Kaplan EL, Berrios X, Speth J, Siefferman T, Guzman B, Quessy F. Pharmacokinetics of benzathine penicillin G, serum levels during the 28 days after intramuscular injection of 1 200 00 units. J Pediatr 1989;115:146-50.
10. Lue HC, Wu MH, Hsieh KH, et al. Rheumatic fever
recurrences: controlled study of 3 weeks versus
4 weeks of benzathine penicillin prevention program. J Pediatr 1986;108:299-309.
11. Wright WW, Welch H, Wilner J, Roberts EF. Body fluid concentration of penicillin following intramuscular injection of single doses of benzathine penicillin G and/or procain penicillin G. Antibiot Med Clin Ther 1959;6:232-41.
12. Physicians' Desk Reference. 46th ed. Montvale, NJ: Medical Economics Data, 1992:639.