Paracetamol is the most frequently used analgesic drug in the world. It is widely available and is sold over-the-counter under different brands and in different concentrations. Not surprisingly, paracetamol overdose is the major cause of acute liver toxicity and failure in many countries.1 Anaesthesiologists routinely prescribe paracetamol alone or in drug combinations via different routes of administration, to control and prevent postoperative pain. Its use in children has attracted much interest, and because its pharmacokinetic profile has been extensively studied, there is currently a significant feeling of safety in this context.2–4 However, recent studies and reviews highlight the potential of paracetamol to increase the susceptibility of children to develop an allergic disease such as eczema or asthma,5–9 or in the case of prenatal exposure, even neuro-developmental problems.10 The mechanism responsible for this causative role of paracetamol in asthma lies in a paracetamol-induced reduction in glutathione levels, which results in an increased oxidant-induced inflammation and subsequent enhancement in T-helper type 2 immunological responses.11,12 However, whether the decrease in glutathione leads to airway mucosa damage and/or an increase in airway inflammation is still not completely understood. Recently, some evidence of the role of certain antioxidant genes in enhancing the association between paracetamol and asthma has been suggested, implying a higher risk in genetically susceptible children.13
The first randomised controlled trial to point out the potential relationship between paracetamol and exacerbation of asthmatic symptoms was designed in febrile asthmatic children receiving either ibuprofen or paracetamol as antipyretic treatment. The relative risk for an exacerbation of asthma was greater in the children receiving paracetamol.14 The impact of this on the anaesthesia community was wider perioperative prescription in asthmatic children of NSAIDs, particularly ibuprofen. Parallel to the incrimination of paracetamol, systematic reviews and meta-analyses revealed weak evidence for an association between the use of antibiotics and early childhood asthma.15–17 Very recently, it has been pointed out there is an additional confounding factor associated with these two treatments, paracetamol and antibiotics: the presence of respiratory infection, which has a well established causative role in the development of asthma.18 Taken together, the ongoing randomised controlled trials, the potential bias of cross-sectional studies and the conflicting results of the systematic reviews and meta-analyses have brought about uncertainty in the scientific community. As a result, some authorities have started discouraging the use of paracetamol, particularly in infancy.19,20
The question is whether anaesthesiologists should take this seriously and reduce their prescription of paracetamol in children. To help answer this question, we should re-examine the role of glutathione in the perioperative setting. Oxygen is the basis of our aerobic metabolic system and almost all oxygen metabolism is controlled by the cytochrome oxidase system in the mitochondria.21 Incomplete reduction of oxygen leads to reactive oxygen metabolites (ROMs) that include superoxide and hydroxyl radicals, as well as hydrogen peroxide. These ROMs are responsible for the oxidative stress that can damage DNA and directly impair mitochondrial function and the lung parenchyma.22 Hence, glutathione, an important antioxidant and cofactor of the enzyme glutathione peroxidase, plays a major role particularly in eliminating hydrogen peroxide. Any intervention that makes antioxidants such as glutathione less efficient will imbalance their relationship with the liberation of ROM and will lead to oxidative stress. This, in turn, contributes significantly to various inflammatory diseases.21 In the perioperative context, although surgery and ischaemia-reperfusion lead to inflammation and enhancement of oxidative stress, the much more variable role of anaesthetic drugs may lead to aggravation,23 reduction24 or absence of protection against ROM.25
As anaesthesiologists, we are sometimes faced with patients with reduced glutathione levels in our routine practice. This reduction can be observed in different situations such as in malnutrition (anorexia, eating disorders, failure to thrive) and in children with cystic fibrosis or liver failure.1 More commonly, glutathione levels may fall following a fasting period lasting more than a day. If we attach importance to the presence of oxidative stress in the perioperative period, we should question any behaviour that adds to that stress. So do we really need paracetamol in the perioperative setting? And should we go so far as to consider giving some N-acetylcysteine perioperatively to restore depleted glutathione stores?
The beneficial effect of adding paracetamol as part of a multimodal analgesia strategy in children remains a subject of debate in the scientific press. This debate arises in part from confusion about the opioid-sparing effect of paracetamol and its analgesic efficacy when administered alone or with other analgesic drugs. The pros and cons of postoperative paracetamol were addressed recently in a well conducted systematic review, which, in conclusion, supported the addition of paracetamol to systemic opioid for perioperative pain management in children.26 This was despite evidence that indicated that its effectiveness was less obvious than that of NSAIDs with regard to both analgesic efficacy,26 and reduction of opioid-related side effects.27 Moreover, in the rare paediatric studies comparing paracetamol with placebo,28,29 or with other mild analgesics,30,31 no evidence of a beneficial effect of paracetamol was apparent.
This Editorial is not intended to question the usefulness of paracetamol in routine clinical practice, but to question the Trivialisation of our most frequent medical prescription in the perioperative setting. We hope it will act as a timely reminder to clinicians about the potential short and long-term adverse effects of unthinking, repetitive medical prescription. Accordingly, both the scientific community and the health authorities are once more drawing attention to the maximal paracetamol dosage. It is noteworthy that the new recommended maximum doses of paracetamol are age-dependent but lower than those in the published guidelines of the paediatric anaesthesia community.1 The recent update on intravenous dosage has the merit of preventing drug errors and securing better paracetamol use in neonates and infants.32 However, no limit on duration has been advocated, despite early reports that warned clinicians about the risk of toxicity following use of paracetamol for more than 3 to 5 days.33–35 This aspect of paracetamol prescription is often overlooked by anaesthesiologists and paediatricians alike, and should be borne in mind. Thus, we are left with an additional uncertainty, with potential for another form of distress.
Acknowledgements relating to this article
Assistance with the Editorial: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Comment from the editor: this Editorial was checked by the editors but was not sent for external peer review. WH is a Deputy Editor-in-Chief and FV is an Associate Editor of the European Journal of Anaesthesiology.
1. Ferner RE, Dear JW, Bateman DN. Management of paracetamol poisoning. BMJ
2. Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child
3. Palmer GM, Atkins M, Anderson BJ, et al. I.V. acetaminophen pharmacokinetics in neonates after multiple doses. Br J Anaesth
4. Anderson BJ. Pharmacology in the very young: anaesthetic implications. Eur J Anaesthesiol
5. Wickens K, Beasley R, Town I, et al. The effects of early and late paracetamol exposure on asthma and atopy: a birth cohort. Clin Exp Allergy
6. Beasley RW, Clayton TO, Crane J, et al. Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International Study of Asthma and Allergies in Childhood Phase Three. Am J Respir Crit Care Med
7. Beasley R, Clayton T, Crane J, et al. Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6-7 years: analysis from Phase Three of the ISAAC programme. Lancet
8. Amberbir A, Medhin G, Alem A, et al. The role of acetaminophen and geohelminth infection on the incidence of wheeze and eczema: a longitudinal birth-cohort study. Am J Respir Crit Care Med
9. Etminan M, Sadatsafavi M, Jafari S, et al. Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis. Chest
10. Liew Z, Ritz B, Rebordosa C, et al. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr
2014; [Epub ahead of print].
11. Dimova S, Hoet PH, Dinsdale D, Nemery B. Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro. Int J Biochem Cell Biol
12. Veldhuijzen N, Kamphuis S, van den Bergh F, et al. Madam, why are you so sour? Cause, diagnosis and complication of 5-oxoprolinemia. Eur J Anaesthesiol
13. Kang SH, Jung YH, Kim HY, et al. Effect of paracetamol use on the modification of the development of asthma by reactive oxygen species genes. Ann Allergy Asthma Immunol
14. Lesko SM, Louik C, Vezina RM, Mitchell AA. Asthma morbidity after the short-term use of ibuprofen in children. Pediatrics
15. Penders J, Kummeling I, Thijs C. Infant antibiotic use and wheeze and asthma risk: a systematic review and meta-analysis. Eur Respir J
16. Murk W, Risnes KR, Bracken MB. Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review. Pediatrics
17. Marra F, Lynd L, Coombes M, et al. Does antibiotic exposure during infancy lead to development of asthma? A systematic review and metaanalysis. Chest
18. Heintze K, Petersen KU. The case of drug causation of childhood asthma: antibiotics and paracetamol. Eur J Clin Pharmacol
19. McBride JT. The association of acetaminophen and asthma prevalence and severity. Pediatrics
20. Muc M, Padez C, Pinto AM. Exposure to paracetamol and antibiotics in early life and elevated risk of asthma in childhood. Adv Exp Med Biol
21. McCord JM. The evolution of free radicals and oxidative stress. Am J Med
22. Andreoli TE. Free radicals and oxidative stress. Am J Med
23. Allaouchiche B, Debon R, Goudable J, et al. Oxidative stress status during exposure to propofol, sevoflurane and desflurane. Anesth Analg
24. Marik PE. Propofol: an immunomodulating agent. Pharmacotherapy
25. Kang MY, Tsuchiya M, Packer L, Manabe M. In vitro study on antioxidant potential of various drugs used in the perioperative period. Acta Anaesthesiol Scand
26. Wong I, St John-Green C, Walker SM. Opioid-sparing effects of perioperative paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) in children. Paediatr Anaesth
27. Michelet D, Andreu-Gallien J, Bensalah T, et al. A meta-analysis of the use of nonsteroidal antiinflammatory drugs for pediatric postoperative pain. Anesth Analg
28. Hamunen K, Kalso E. A systematic review of trial methodology, using the placebo groups of randomized controlled trials in paediatric postoperative pain. Pain
29. Ashley PF, Parekh S, Moles DR, et al. Preoperative analgesics for additional pain relief in children and adolescents having dental treatment. Cochrane Database Syst Rev
30. McNicol ED, Tzortzopoulou A, Cepeda MS, et al. Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis. Br J Anaesth
31. Korpela R, Silvola J, Laakso E, Meretoja OA. Oral naproxen but not oral paracetamol reduces the need for rescue analgesic after adenoidectomy in children. Acta Anaesthesiol Scand
32. Veyckemans F, Anderson BJ, Wolf AR, Allegaert K. Intravenous paracetamol dosage in the neonate and small infant. Br J Anaesth
33. Anderson BJ. Comparing the efficacy of NSAIDs and paracetamol in children. Paediatr Anaesth
34. Morton NS, Arana A. Paracetamol-induced fulminant hepatic failure in a child after 5 days of therapeutic doses. Paediatr Anaesth
35. Savino F, Lupica MM, Tarasco V, et al. Fulminant hepatitis after 10 days of acetaminophen treatment at recommended dosage in an infant. Pediatrics