Topical anaesthesia in neonates, infants and children

S. Lillieborg1, I. Otterbom1, K. Ahlen1 and C. Long2

1 Södertälje, Sweden 2 Belfast, UK

Editor—While we share the interest of Long and colleagues1 in topical anaesthesia for procedural pain in neonates and applaud their initiative to evaluate a potential new agent, some of their statements are incorrect or outdated. When commenting on one case of methaemoglobinaemia reported in 1995 after injection of prilocaine for circumcision in a neonate,2 Long and colleagues write ‘this means that EMLA cream is contraindicated in infants of less than 3 months of age’. The authors of the case report also concluded that ‘in particular, prilocaine injections should be avoided in the newborn’,2 a statement with which we agree. However, EMLA cream and EMLA patches have been well studied for the treatment of acute pain in neonates.39 Although the use of large doses of prilocaine-containing formulations may cause an increase in the methaemoglobin (MetHb) concentration in infants and neonates, safe doses of EMLA in these age groups have been established. The application of a 1 g dose of EMLA cream to the prepuce for 1 h before circumcision in full-term neonates during their first week of life resulted in similar MetHb concentrations (mean 1.3%, monitored for 18 h) to placebo.4 In a similar study, using the same dosage of EMLA cream for circumcision, the upper 99% confidence interval for the post-treatment MetHb concentrations remained within the normal range.3 In their systematic review of 12 studies, Taddio and colleagues5 concluded that single doses of EMLA ranging from 0.5 to 2 g do not cause methaemoglobinaemia in neonates. Subsequently, Brisman and colleagues7 reported that a 1 g dose of EMLA applied to two skin sites (0.5 g each) for 1 h resulted in a mean MetHb concentration of 1.17% (range 0.50–2.53), which was slightly higher than placebo-treated neonates, 0.96% (range 0.50–1.53). In all patients, the MetHb values, which were monitored for 18 h, were well below potentially harmful concentrations. Normal physiological MetHb levels are <2%. In neonates, elevated MetHb concentrations up to 5–6% are considered to be of no clinical significance.3 5 10

Based on a wealth of available clinical data on the use of EMLA in neonates, infants and children, maximum dosage recommendations can be made (Table 1). These dosages are approved by regulatory agencies in a number of countries including most of the European Union member states and the USA (although not yet the UK).


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Table 1 Recommended maximum dosages of EMLA in full-term neonates, infants, and children
 
In infants aged 3–12 months, no clinically significant increase in MetHb was observed after a 2 g EMLA dose applied to the skin for 4 h.11 While the tabulated dosages have been shown to be safe, EMLA should not be given to children aged 0–12 months receiving other MetHb inducing agents such as sulphamethoxazole, because of possible additive effects. Caution is also advised in patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methaemoglobinaemia. The use of EMLA in premature infants with a gestational age <37 weeks needs further study.

For many medicines, data in children particularly in neonates are sparse, but in the case of EMLA clinical studies have enabled the identification of adequate doses for a number of painful procedures in these age groups.

S. Lillieborg

I. Otterbom

K. Ahlen

Södertälje, Sweden

Editor—I would like to thank the research team at AstraZeneca R&D for their interest in this study and to respond to the points they have raised about our article.1

The statement ‘this means that EMLA cream is contraindicated in infants of less than 3 months of age’ made by my colleagues and me is indeed now outdated, as the new British National Formulary states ‘Infant 1–12 months [unlicensed use] single application on intact skin under specialist supervision, under 1 month not recommended (risk of methaemoglobinaemia)’.12 Although the novel tetracaine anaesthetic patch has been specifically designed for application to neonatal infants including preterm babies, the risk of percutaneous systemic absorption must be considered as significantly increased.13 14 In their correspondence, Lillieborg and colleagues have presented a number of studies pertaining to the safe use of EMLA in infants <3 months old, but they also state ‘the use of EMLA in premature infants with a gestational age less than 37 weeks need further study’. One of the main issues that the introduction of our article1 stressed was that the use of tetracaine as an active ingredient would negate any possible risk of increased MetHb after application to neonatal skin.

C. Long

Belfast, UK

References

1 Long CP, McCafferty DF, Sittlington NM, Halliday HL, Woolfson AD, Jones DS. Randomized trial of novel tetracaine patch to provide local anaesthesia in neonates undergoing venepuncture. Br J Anaesth 2003; 91: 514–18[Abstract/Free Full Text]

2 Tse S, Barrington K, Byrne P. Methemoglobinemia associated with prilocaine use in neonatal circumcision. Am J Perinat 1995; 12: 331–2[ISI][Medline]

3 Law RMT, Halpern S, Martins RF, Reich H, Innanen V, Ohlsson A. Measurement of methemoglobin after EMLA® analgesia for newborn circumcision. Biol Neonate 1996; 70: 213–17[ISI][Medline]

4 Taddio A, Stevens B, Craig K, et al. Efficacy and safety of lidocaine-prilocaine cream for pain during circumcision. N Engl J Med 1997; 336: 1197–201[Abstract/Free Full Text]

5 Taddio A, Ohlsson A, Einarson TR, Stevens B, Koren G. A systematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neonates. Pediatrics 1998; 101: E1–E9[Medline]

6 Larsson BA, Tannfeldt G, Lagercrantz H, Olsson GL. Alleviation of the pain of venepuncture in neonates. Acta Paediatr 1998; 87: 774–9[CrossRef][ISI][Medline]

7 Brisman M, Ljung BML, Otterbom I, Larsson LE, Andreasson SE. Methaemoglobin formation after the use of EMLA cream in term neonates. Acta Paediatr 1998; 87: 1191–4[CrossRef][ISI][Medline]

8 Lindh V, Wiklund U, Håkansson S. Assessment of the effect of EMLA® during venipuncture in the newborn by analysis of heart rate variability. Pain 2000; 86: 247–54[CrossRef][ISI][Medline]

9 Halperin BA, Halperin SA, McGrath P, Smith B, Houston T. Use of lidocaine-prilocaine patch to decrease intramuscular injection pain does not adversely affect the antibody response to DTaP-inactivated poliovirus-Hib conjugate and hepatitis B vaccines in infants from birth to six months of age. Pediatr Infect Dis J 2002; 21: 399–405[CrossRef][ISI][Medline]

10 Hjelt K, Lund JT, Scherling B, et al. Methaemoglobinaemia among neonates in a neonatal intensive care unit. Acta Paediatr 1995; 84: 365–70[ISI][Medline]

11 Engberg G, Danielson K, Henneberg S, Nilsson A. Plasma concentrations of prilocaine and lidocaine and methaemoglobin formation in infants after epicutaneous application of a 5% lidocaine-prilocaine cream (EMLA). Acta Anaesthesiol Scand 1987; 31: 624–8[ISI][Medline]

12 British National Formulary. London: British Medical Association, 2003; 46

13 Cartlidge PHT. The epidermal barrier. Seminars in Neonatology 2000; 5: 273–80[CrossRef][Medline]

14 Rutter N. Clinical consequences of an immature barrier. Seminars in Neonatology 2000; 5: 281–7[CrossRef][Medline]





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