In our prospective observational study, we analysed the efficacy and safety of intracameral combination of mydriatic/anesthetic for paediatric use, still considered an off-label use for children.
Our efficacy endpoint - an adequate mydriasis in order to perform capsulorhexis without additional mydriatic - was achieved in 52 out of 53 surgical procedures.
Capsulorhexis is a fundamental step in phacoemulsification surgery and is inevitably associated to the quality and stability of mydriasis. In our study, intracameral combination provided a significant pupil size change before and after intracameral administration, also showing a rapid reversal of mydriasis after the use of acetylcholine. In a similar study by Kaur et al., the combination of mydriatic/anesthetic injected intracamerally has been shown to be an effective and safe way to obtain stable mydriasis in pediatric cataract surgery .
Regarding safety, every pharmacological agent of the combination drug has its potential side effects. Even if absorption of phenylephrine could be unpredictable and occasional pressure spikes are possible collateral effect reported by many pediatric ophthalmologists -included the Authors-, a recent meta-analysis by Stavert et al. showed how systemic adverse events of topical phenylephrine in adults might have been overestimated for many years. This work demonstrated that the use of 2.5% phenylephrine is not correlated with clinically significant BP or HR changes, while changes in BP or HR seen with 10% phenylephrine may be transient and of uncertain clinical relevance. The commonest reported side effects with intravenous use of Tropicamide are confusion, vision changes, vomiting, low blood pressure, sleepiness, numbness, irregular heart rate[10,11]. Indeed, Tropicamide has a very low affinity for muscarinic receptors and therefore infrequently provokes systemic effects . Even lidocaine, when used as a local anesthetic, has rare adverse systemic reactions .
In adults the combination of Tropicamide/Phenylephrine/Lidocaine is associated with minor discomfort, sense of pressure and pain than the topical one . In the phase III trial conducted by Labetoulle et al., systemic exposure to the single components of the combination was very low, with almost undetectable plasma concentrations at all timepoints after a 0.2ml intracameral administration, in contrast with higher concentrations in patients receiving the tropicamide plus phenylephrine eye drops. The intracameral combination was also at least as effective as topical administration of tropicamide plus phenylephrine in achieving successful capsulorhexis without additional mydriatic.. In a post-hoc analysis by Guell et al., intracameral regimen of combination drug in adults was correlated with less clinically meaningful cardiovascular events (i.e.: a heart rate value > 120 bpm, a systolic BP value > 200 mmHg, a diastolic BP value > 100 mmHg) than topical regimen.
In our study, given the differences in vital parameters between a 6 weeks old child (median age of the study population) and older children, the values can differ and have to be interpreted carefully. Overall, the systolic blood pressure, diastolic blood pressure and heart rate were stable before and after the administration of the combination of mydriatic/anesthetic (respectively − 0.3 ± 1.51 mmHg, P = 0.20, 0.0 ± 1.14 mmHg P = 0.99 and 0.0 ± 2.72 bpm P = 0.99). The respiratory rate and temperature again shows no clinical difference between pre and post intracameral administration.
When talking about children, there is always a major concern of different biological reactions compared to adults, but these results are in line with previous clinical studies on intracameral mydriatic in adults, where no systemic adverse effects were reported [17,18].
For what may concern ocular adverse events, our findings are consistent with that reported in previous studies of intracameral mydriatic agents[19,20].
All the AEs are common findings after paediatric cataract surgery, not resulting neither in intraoperative concerns impeding the conclusion of the entire procedure nor in post-operative therapies or permanent vision loss.
In the previously cited study by Labetoulle et al. in adult cataract surgery, both intracameral combination of mydriatic/anesthetic and topical regimen resulted in a lack of any serious AEs requiring hospitalisation, resulting in permanent visual loss or post-operative issues concerning pachymetry, IOP, funduscopy and retinal thickness compared with baseline.
A drawback of our study was the absence of a comparison drug. Indeed, intracameral tropicamide/phenylephrine/lidocaine has been used off-label all these years by pediatric surgeon in phacoemulsification, thus creating a randomized placebo controlled study with another reference molecule is necessarily difficult. Moreover, given the small sample size and the heterogeneity of the study population -mainly in demographic terms-, an international, multi-centric study enrolling more patients could be needed in the future. Even if legislative efforts have increased emphasis of studying therapeutic agents in children, the need for consent from parents and the level of risk to which children may be exposed may limit participation in clinical trials when compared with adult trials.
Since the limited amount of resources available for conducting trials in children, efforts on safety and efficacy should be prioritized for agents that are used in children with high prevalence. In our study the combination of Tropicamide 0.02%/phenylephrine 0.31%/lidocaine 1% administered intracamerally with irrigation solution during cataract surgery in children from 4 weeks to nearly 4 years old has been proven to be effective for rapidly achieving mydriasis and maintaining a stable pupil size during the whole procedure. Our results show minimal (and most of all clinically insignificant) variations of the safety parameters combined with a statistically significant pupil diameter change before and after administration of the combination drug.