Acetaminophen is a popular non-narcotic analgesic drug that is widely used in the perioperative period for the management of pain in pediatric patients. The drug has been extensively studied for its efficacy and safety. However, controversy still surrounds the use of the acetaminophen suppository in pediatric patients. Our study compares the perceptions of pediatric anesthesiologists concerning the composition and clinical use of acetaminophen suppositories with laboratory findings.
After obtaining IRB approval, the research was divided into three parts. First, 50 survey forms were nonrandomly distributed to anesthesiologists at a national anesthesia conference to determine their understanding of the uniformity of rectal acetaminophen and their opinion of physically altering acetaminophen suppositories.
Second, 3 sets of 1 each of 80 mg (FeverAll®; ALPHARMA, Baltimore, MD), 120 mg (Goldline®; Goldline Laboratories, Inc., Miami, FL) and 325 mg (Goldline®) acetaminophen suppositories were selected. Each set contained two samples of each dose. All samples were divided by the same laboratory person. The first set was divided into two portions along the longitudinal axis, the second set was divided along the vertical axis, resulting in a head portion and tail portion, and the third set was divided into three parts along the longitudinal axis, resulting in head, middle, and tail portions (Fig. 1). Finally, 10 pediatric anesthesiologists were asked to physically alter acetaminophen suppositories to achieve one half and two thirds doses of the 80 mg, 120 mg, and 325 mg suppositories. Each pediatric anesthesiologist was given 2 sets of 3 samples each of 80 mg, 120 mg, and 325 mg rectal acetaminophen. The only stipulation during the trial was to alter the drug according to their clinical practice; otherwise there were no restrictions to the method used for altering the rectal acetaminophen.
All samples were stored in a plastic bag at room temperature and later analyzed using a modified high-performance liquid chromatographic procedure as described by Ou and Frawley (1). Each portion of a single suppository was weighed and completely dissolved in 10 mL of chloroform/isopropanol mixture (95%:5% by volume). After further diluting 100-fold with the same chloroform/isopropanol mixture, 200 μL of the sample, standard, or control was mixed with 200 μL of internal standard and dried under a stream of air. The residue was redissolved in 250 μL of mobile phase, and 75 μL aliquots of this solution were injected onto the column. The interassay and intra-assay coefficients of variation were determined to be <11.1% for various doses of 80, 120, and 325 mg acetaminophen suppositories.
Evaluation for uniformity was achieved by having each portion of a single suppository weighed and converted to a percentage of the whole. Next, each portion was analyzed for acetaminophen content and the dose converted to a percentage of the total dose. Accuracy in alteration was evaluated in the same manner as uniformity.
Twenty-nine of 50 surveys were completed and returned. Ninety-four percent of the respondents used rectal acetaminophen on a daily or weekly basis in their practice. Fifteen of 29 anesthesiologists believed there was uniform distribution of acetaminophen. Eleven of 29 anesthesiologists considered alteration of suppositories to be accurate. However, the majority of anesthesiologists (18 of 29) felt that alterations are inaccurate and therefore do not alter the suppositories in their clinical practice. In addition, among the 18 anesthesiologists who did not alter the suppository, 11 believed there was an uneven distribution of acetaminophen (Table 1).
The laboratory evaluation of rectal acetaminophen in 80 mg, 120 mg, and 325 mg doses supports the concept of a uniform distribution of acetaminophen. The percentages of weight versus concentration of acetaminophen were compared and found to be similar in all sets of the various doses. The alteration of rectal acetaminophen by the pediatric anesthesiologists resulted in a wide range of values (Fig. 2). The summation of the individual parts to the whole suppository resulted in values within the tolerance of the 11.1% coefficient of variation.
The alteration of rectal acetaminophen is a common practice. Although much has been published about acetaminophen, information concerning the actual clinical use of rectal acetaminophen is lacking. The survey of pediatric anesthesiologists illustrates that rectal acetaminophen is commonly used, but there was an even split among those who alter the suppository and those who do not. In addition, among those anesthesiologists who chose not to alter the suppository, it may have been related to their perception of the dispersion of acetaminophen.
This study demonstrates that acetaminophen is uniformly distributed in the vegetable oil matrix. We restricted our observations to those manufacturers of the acetaminophen suppositories and recognize the limitations of our sample size. However, the notion of an uneven distribution of acetaminophen has never been independently verified and has only been cited from a personal communication (2).
The alteration of rectal suppositories resulted in a wide range of dosages. In particular, there were 2 values of 89 and 83 for the 80 mg acetaminophen suppository in the two-thirds category of alteration. Although their measured weights were less than an intact sample, their values were felt to reflect the technical difficulties working with organic solvents and minute measurements. Therefore, the two values were classified as outliers and not included in the data analysis.
In general, children seem more resistant to the hepatotoxic effects of acetaminophen because of the immaturity of their metabolic pathways (3–5). However, there is a small subset of children who may be more predisposed to the toxic effects of the acetaminophen metabolite, N-acetyl-p-benzoquinone, because of low glutathione levels or the induction of their cytochrome P-450 system (3–5). In addition, insertion of a suppository in a newborn or infant may result in a high placement in the rectum, which may allow for a significant first-pass effect on the liver (3,4,6).
We conclude that the lack of accuracy and precision of the pediatric anesthesiologists in altering the suppositories makes a compelling reason to restrict the delivery of rectal acetaminophen to unaltered suppositories. Theoretically, it may be possible to improve accuracy by weighing the portion of rectal acetaminophen to be administered, based on the assumption of a uniform dispersion of acetaminophen. We find this impractical. If the hospital pharmacy is providing nonstandardized doses of rectal acetaminophen, it is very important to understand the techniques used to customize the suppository and verify the accuracy of formulation. Numerous studies support the concept that children are less susceptible to the hepatotoxic effects of acetaminophen and characterize the absorption of rectal acetaminophen to be erratic and subtherapeutic. Therefore, children are more prone to be underdosed than overdosed. However, this does not mitigate the possibility that some children are at risk for hepatotoxicity. Various factors, including underlying medical condition, such as malnutrition, induction of the cytochrome P-450 system, and the cumulative dose of acetaminophen, may predispose to a toxic buildup of the metabolite N-acetyl-p-benzoquinone.
The authors would like to thank Stephen A. Stayer, MD and Barbara S. Skjonsby, R.N., B.S.N for their assistance in the preparation of this manuscript.
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