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Department of Anesthesia, National University Hospital, Singapore
To the Editor:
We read the case report by Bruun et al. (1) with great interest. We wish to raise the following concerns about this report.
The dose of rectal acetaminophen 175 mg/kg on the first day was larger than the suggested dosage i.e., 40 mg/kg followed by 20 mg/kg 6 hourly (2). The authors referred to the Anderson et al. (3) paper to justify this dose. Unfortunately, although the Anderson et al. (3) study suggests larger initial and subsequent dosing determined by computer simulation, this conclusion has not been examined in an actual clinical study. We find it difficult to translate this into a clinical scenario, especially in a sick patient. Also, the authors have failed to mention the formulations of the acetaminophen suppository. Lipid soluble drugs have higher absorption into systemic circulation and depending on the suppository formulations, the rectal bioavailability of acetaminophen varies between 6.5% and 92.2% (4).
In the presence of a fever, the absorption is more. If the suppository is inserted higher in the rectum, the drug gets into portal circulation. In this case we assume that the suppository was placed higher in the rectum leading to a large concentration in the liver. We agree with the authors that in the fasting patient, the glutathione levels are low.
The dose of thiopentonal administered 10 mg/kg in this child is twice the normal recommended dose especially in a sick and adequately premedicated patient. Thiopentonal induces cytochrome p450, which in a glutathione-depleted patient leads to a increased acetaminophen metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is hepatotoxic.
The usual dose of metronidazole is 7.5 mg/kg. In this case 25 mg/kg of metronidazole was administered which undergoes glucuronidation to its metabolites through the same pathway as acetaminophen leading to increased Phase I reaction of acetaminophen, which is normally <5%.
In conclusion, we think that hepatotoxicity in this child was caused mainly by acetaminophen contributed by other factors such as fever, fasting, and larger doses of thiopentonal and metronidazole, rather than sevoflurane. Is it good medical practice to administer such a large dose of acetaminophen to achieve analgesia because it is only a mild analgesic? Guidelines for pediatric analgesia are needed, especially for rectal administration of acetaminophen, and this may be the first reported case of therapeutic misadventure with rectal acetaminophen leading to hepatotoxicity.
References
Department of Pediatrics, Hellerød Hospital, DK-3400 Hillerød, Denmark
In Response:
We thank Drs. Reddy and Srinivas very much for the comment on our case report (1).
The acetaminophen suppositories given contained hard fat (adeps solidus) a mixture of mono-, di-, and triglycerides of saturated fatty acids. The bioavailability of acetaminophen is 60%–70% according to the manufacturer. We agree, however, that the dose of acetaminophen given to our patient on the first day was large.
As to the doses of thiopental and metronidazole, they were those recommended by the producers and approved by the Danish Medicines Agency. The recommended dose of thiopental in Denmark in children is 7–8 mg/kg body weight. Supplementary doses may be added until the ciliary reflex can no longer be elicited. Metronidazole was given IV during operation in a single dose of 25 mg/kg body weight for prophylaxis because infection with anaerobic bacteria was feared.
The comment points out some interesting possible interactions among the drugs administered to our patient. In support of their theories, it may be added that the clearance of a single oral dose of metronidazole at 30 mg/kg is much lower in malnourished children than in nourished controls (2).
We agree that the fasting state may have been crucial to the hepatic failure seen in our patient. However, we still think that the exact cause of the hepatotoxicity is uncertain and that sevoflurane may have been involved. We therefore suggest that similar patients be closely monitored.
References
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