Discussion/Analysis
Our study has demonstrated that 5mg/kg dosing of lidocaine for airway topicalisation in paediatric airway endoscopy is safe. We had no incidences of clinical adverse events, symptoms of local anaesthetic toxicity and maintained good surgical conditions for the required procedure. This qualitative data supports the safety profile of this pilot study.
Our study primary outcome achieved significant results. We successfully demonstrated a quadratic correlation between higher peak lidocaine plasma levels and ages <18 months (p=0.00973) as shown in Figure 2. Previous studies have demonstrated similar findings with younger patients achieving higher peak lidocaine plasma levels. In 1978 Eyres et al found higher peak lignocaine plasma levels following topical application to mucous membranes in children under 3 years old, with those under 1 year occurring earliest at 2 minutes5. The median time to peak lidocaine plasma level in our study was found to be 10 minutes as demonstrated in Table 1. This is significantly longer than the 2 minutes demonstrated in 19785. Whilst we did not record the average length of the surgical procedures, our lidocaine plasma levels would most likely peak during the surgical procedure or following completion of the endoscopy in the recovery room. In 1983 Eyres et al repeated their 1978 study and again showed a variation in the time to peak level in different age groups2,5. In children less than 1 year of age the time to peak lignocaine plasma level was 5.8 minutes, increasing to 6.5 minutes between 1-3 years, and over 10 minutes in the 5 plus group. We did not demonstrate a significant relationship between age and time to peak lidocaine plasma level as our secondary outcome measure.
Whilst our covariates for patients’ with smaller weights achieving higher peak lidocaine plasma levels did not reach significance level (p=0.0516), it suggests an area for further review whilst supporting the safety profile of this pilot study. Figure 3 illustrates a trend for higher peak plasma lidocaine levels in patients weighing between 10 and 12kg. This correlates well with ages up to 18 months as shown in Figure 1. Extremes of weight are a known risk factor for local anaesthetic toxicity. Many previous studies2,5 have focused on age of patients rather than weight. Sitbon1 et al altered the dose administered dependent on weight as well as age. The dosing used was much smaller (0.9 and 2.6 mg/kg) with corresponding lower maximum peak levels of 1.05 mcg/ml. They concluded that younger children less than 6 months old did not present with peak levels earlier, although they did not analyse the relationship of weight versus lidocaine levels in more detail.
Our study cohort did not have extreme outliers regarding weight for age as indicated by Figure 1. As an urban tertiary paediatric hospital, our results can therefore reliably be extrapolated to a wider paediatric population ensuring the external validity of the study.
In 2016 Roberts and Gildersleve aimed to review practice amongst paediatric anaesthetists regarding their use of topical lignocaine4. As demonstrated in our study, variation in the dose of lidocaine was recognised with a range of 1-10 mg/kg (median dose 4 mg/kg). Amongst the respondents the most commonly documented dose was 3mg/kg as per the British National Formulary for Children10. In our study anaesthetic participants did not alter their usual practice. The median dose at [removed for blind peer review] was 5mg/kg. Despite this no significant adverse effects were recorded. Roberts and Gildersleve did note some respondents using significantly higher doses in line with adult bronchoscopy practice. Previous rationale for this was that some of the lidocaine would be suctioned by the surgeons or swallowed. We found no change in plasma lidocaine levels with the use of surgical suction, topical vasoconstrictors or by surgical procedure group.
An interesting and significant result from this study is shown in Figure 4. We demonstrated higher peak plasma lidocaine levels when utilising total dose volumes between 2 and 3mls of 2% lidocaine local anaesthetic (p=0.0352) when compared with volumes less than 2mls. The relationship between volume and time to peak lidocaine plasma levels however was not significant (p=0.68). This would suggest higher concentrations of local anaesthetic solution at lower total dose volumes could achieve a better safety profile. However whether this would affect surgical conditions or lead to clinical adverse effects would be an area for investigation in a larger future study.
A non-significant, but noteworthy result from this pilot study was the reduced IQR variation of peak plasma lidocaine levels when lidocaine dosing was <5mg/kg. With dosing <5mg/kg we again demonstrated no occurrences of clinical adverse events, signs of local anaesthetic (LA) toxicity or compromise of surgical conditions.
Most importantly, despite four patients exceeding recommended toxic levels of >5000ng/ml, no symptoms of LA toxicity or clinical adverse effects occurred. It is therefore possible differing toxic levels exist for mucosal application versus intravenous application of LA agents. Studies have previously failed to show clinical signs of toxicity in anaesthetised adults with serum lidocaine levels over 5000ng/ml2,7. One theory is some protection is offered by general anaesthesia8. Further research is needed to extrapolate this to the paediatric population. Pharmacological research has shown extremes of age including neonates and infants are at greatest risk of LA toxicity9. This age group have reduced plasma concentration of the proteins that bind the anaesthetic agents (alpha1- acid glycoprotein). The unbound portion undergoes metabolism and determines toxicity.
A limitation of our study was not standardising the dose and volume of lidocaine used. As this was a pilot study with an aim to avoid changes in usual practice variations were expected. The small sample size is acknowledged but felt to be adequate to allow relationships between outcomes and variables to be analysed. Further studies with larger samples sizes are planned.