Intravenous Paracetamol Safety in Paediatrics

Dr Kirsten Joyce

Medication errors pose a significant burden on our healthcare systems, and yet are also the most preventable. In the United States alone, between 7,000 and 9,000 annual deaths occur secondary to these errors and the annual cost incurred amounts to an excess of 40 billion dollars[1]. In Ireland, the Institute of Medicine published a report estimating one medication error was made per patient per hospital day, equating to up to three million medication errors per year[2]. In paediatrics, medication dosages are calculated and administered based on patient weight, which adds an additional safety risk. Thus, it is unsurprising that incorrect dosage represents the most common reason for medication error in children[3]. Paracetamol has been present in the anaesthesiologist’s armamentarium for over 50 years, with both potent anti-inflammatory and anti-pyretic properties. Since its intravenous formulation was introduced to the Irish market in the mid-2000s, it has become one of the most frequently administered analgesics during anaesthesia due to its opioid-sparing nature. Despite its widespread use and perceived safety profile, paracetamol is a drug associated with significant morbidity and mortality when ingested or administered in overdose. Medication errors relating to incorrect paracetamol prescription and administration are relatively common, including ten-fold overdose in infants and neonates[4]. In a recent study performed in Australia and New Zealand, paracetamol overdose was the single most commonly identified cause of acute liver failure in paediatric patients, responsible for 14 out of 54 cases[5]. Three of these children required transplantation, one of which subsequently died. While the oral bioavailability of paracetamol is almost 100%, there are significant inter-person differences in the rate of absorption and peak plasma levels. This was illustrated nicely in a study conducted in Sweden in 2004, where plasma levels were compared between the enteral and intravenous route in adult patients presenting for elective day-case surgery[6]. The intravenous preparation resulted in a more rapid and predictable peak plasma concentration, with some patients in the enteral arm without recordable plasma levels at 80 minutes. This difference becomes especially relevant when we consider that the universal Rumack-Matthew normogram for serum paracetamol levels and the threshold for N-acetylcysteine (NAC) administration is based on paracetamol ingestion. In 2011, a case series published in the UK illustrated two cases of inadvertent paracetamol overdose in infants under ten kilograms[7]. In both cases, the patients were administered a ten-fold dosing error of 75mg/kg when the drug was calculated in millilitres instead of milligrams. When the error was noted in the first child, a serum paracetamol level taken was below the threshold for NAC on the concentration-time normogram. Despite this, the following day her liver function tests were deranged with a prolongation of her international normalised ratio to 2.9. NAC was subsequently administered, and she made a good recovery over the coming days. She had no significant risk factors for liver impairment. The second infant received NAC immediately after recognition of the error and also made a good recovery. It is possible that the rapid peak plasma concentration and presumed rapid hepatocyte uptake seen in intravenous paracetamol resulted in its particularly potent effect on the first infant. As a result of these two cases, the UK national guidance (Toxbase) on the threshold for the administration of NAC has reduced and it is now deemed appropriate to consider its use in cases of single administration errors of 60mg/kg or more in the paediatric population[7].

“While electronic prescribing may be regarded as an expensive solution, its potential benefits to patient safety are clear, and data such as this may be useful for future hospital and administration planning”

As anaesthesiologists it is easy to understand where inadvertent paracetamol administration errors can arise. We often work alone or in pairs, and rarely check medication doses with other healthcare staff prior to administration. We rely on the quality of handover and documentation of our colleagues, and busy theatre lists with high turnover can easily lead to omission of crucial information. In Ireland, trainees rotate through specialist paediatric centres every six months, many of whom may have never been exposed to anaesthetising children prior to starting. Familiarity with intravenous paracetamol administration in the adult population can easily result in complacency with drug calculations. In tackling this preventable patient safety risk, several potential strategies have been explored in centres across the UK and Australia. Relatively low-cost options currently employed include:

  • The use of single concentration/single volume formulations
  • Online site-specific formularies
  • Visual aids
  • “Smart pumps” or programmed syringe drivers
  • Removal of intravenous paracetamol from the anaesthetic trolley and placement in the locked controlled drugs press[8]

It has been suggested at Children’s Health Ireland Crumlin to consider the near-complete elimination of intravenous paracetamol in paediatric anaesthesia, and to opt instead for an enteral dose administered in either the day of surgery unit, theatre reception, or theatre recovery. While this may seem an easy solution, the practicalities of this delegation and added responsibility of prescription and administration to an already over-burdened nurse-led unit may not always be feasible and would require meticulous planning for successful implementation. Finally, in 2009, a study performed in a large US family practice observed the rate of paracetamol and ibuprofen prescription errors over a six month period both before and after the introduction of electronic weight-based prescribing[9]. Drug errors were defined as being overdosage or underdosage of strength or regimen, and “incomprehensible dosing directions”. They noted a significant reduction in the absolute number of prescribing errors postintervention (103 vs 46, p = 002) including a reduction in overdosing errors (8.9% vs 4.0%, p=0.028). While electronic prescribing may be regarded as an expensive solution, its potential benefits to patient safety are clear, and data such as this may be useful for future hospital and administration planning. This study was limited to two medications, but if we extrapolate to include an entire formulary electronic prescribing could avoid significant morbidity. Excepting the above, there is limited data available that any of the other solutions are effective in the prevention of paracetamol medication errors; however, it is reasonable to assume that any intervention designed to slow us down during our drug calculations and administration could be beneficial. While paracetamol may seem a relatively benign analgesic, it is important to be aware of its potential harm, especially in our smallest and most vulnerable patients.

References:

  1. Tariq RA, Vashisht R, Sinha A, et al. Medication Dispensing Errors And Prevention. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519065/
  2. Institute of Medicine. Preventing Medication Errors. Washington, DC: The National Academies Press. 2007. [Online] Available from: https://doi.org/10.17226/11623
  3. Ghaleb MA, Barber N, Franklin BD et al. Systematic review of medication errors in pediatric patients. Ann Pharmacother. 2006; 40:1766-76.
  4. Rishoej, R. M., Almarsdóttir, A. B., Christesen, H. T., Hallas, J. & Kjeldsen, L. J. Medication errors in pediatric inpatients: a study based on a national mandatory reporting system. Eur. J. Pediatr. 2017; 176, 1697-1705.
  5. Rajanayagam, J., Bishop, J. R., Lewindon, P. J. & Evans, H. M. Paracetamol-associated acute liver failure in Australian and New Zealand children: high rate of medication errors. Arch. Dis. Child. 2015; 100, 77–80
  6. Holmer Pettersson P, Owall A, Jakobsson J. Early bioavailability of paracetamol after oral or intravenous administration. Acta Anaesthesiol Scand. 2004; 48: 867—870
  7. Beringer RM, Thompson JP, Parry S, Stoddart PA. Intravenous paracetamol overdose: two case reports and a change to national treatment guidelines. Arch Dis Child. 2011; 96:307–308
  8. Tan JYX, Robert SA. Avoiding aberrant paracetamol prescriptions in paediatric patients. British Journal of Anaesthesia. 2021; 127(2) e48-50. doi: 10.1016/j.bja.2021.05.019
  9. Ginzburg R, Barr WB, Harris M, Munshi S. Effect of a weight-based prescribing method within an electronic health record on prescribing errors. American Journal of Health-System Pharmacy. 2009;66(22):2037-2041. doi:10.2146/AJHP080331