Fig. 1. Minims™ of (from top left, clockwise) Fluorescein, Phenylephrine, Proxymetacaine and Tropicamide
Fig. 2. Unit doses of Minims™ ready for mixing
Previously, G. proxymetacaine and G. fluorescein have been available in a combination drops, but since the withdrawal of these in 2013 due to ‘significant manufacturing challenges’, it has become common practice for ophthalmologists in the UK to pre-mix these drops for application to the patient’s fornixi. We wondered whether this could be extended to include mydriatics.
Purpose. We wished to establish whether it was possible to extend the common practice of mixing G. proxymetacaine and G. fluorescein drops in the Minims™ vial may be extended effectively to include G. tropicamide 1% and G. phenylephrine 2.5% drops. We aimed to establish whether reducing the drop load to only 1 drop per eye would permit adequate anaesthesia Goldmann applanation tonometry and adequate dilated fundoscopy.
Materials and Methods. Minims™ Tropicamide 1% and Minims™ Phenylephrine 2.5% Fluorescein 1% and Proxymetacaine 0.5% unit doses were prepared (Fig. 1) and then removed from their over-wrap retaining the rigid plastic sleeve of one unti dose (Fig. 2). A single unit dose of Minims™ Proxymetacaine 0,5% is emptied into the receptacle in its entirety, followed by the contents of a Minims™ of Fluorescein 2%. This is done in an aseptic fashion, and the resulting fluid is gently mixed. The contents of a Minims™ of Tropicamide 1% and a Minims™ of Phenylephrine 2.5% are then added and gently mixed (Fig. 3). The empty vials of proxymetacaine, tropicamide and phenylephrine are then refilled with the resulting mixture (Fig. 4), which we call “Charlie’s Cocktail”.
Ten consecutive patients were asked if they felt any pain after GAT, and pupil diameters were measured using the slit lamp beam at 20 minutes after administration.
Results. We assessed 10 patients with their consent. We were able to produce a cocktail of 29 drops using the technique above, or enough for 14 patients which approximates to a single doctor’s sessional clinic workload. No patient felt any discomfort during GAT and it was possible to visualise the mires perfectly adequately. The pupil diameters varied from 5,5 to 8,0 mm at 20 minutes with an average of 6,6 mm and a modal value of 6,5mm. It was easily possible to perform a standard fundoscopy in all patients.
Fig. 3. Mixed solution of “Charlie’s Cocktail” prior to refillin G
Fig. 4. 3 Vials of Charlie’s Cocktail ready for use
Discussion. We noted that the solution was initially milky, although this seemed to clear after about 5 minutes. This appears to have no effect on the efficacy. We think it is important not to refill the vial of the fluorescein Minims™, as such a move could lead to the cocktail being mistaken for pure fluorescein. In contrast, because of the fluorescein, there was no possibility of confusing the containers of proxymetacaine, tropicamide or phenylephrine for the original solutions.
Charlie’s Cocktail was ergonomic and easy to use. It effectively achieved comfortable GAT and sufficient dilation for fundal examination on all patients at 20 minutes post application.
Criticisms of our method are likely to lie in two camps. Firstly this method advocates “kitchen pharmacy” with off-label mixing of medications that could potentially lead to unknown concentrations or variable efficacy. The reasons we consider this necessary are as follows. Minimising patient discomfort is among our chief concerns. Clearly this must be offset against any potential risk to the patient. We feel that mixing the medications immediately before administration to the fornix varies very little from mixing them within the patient’s fornix following separate application of drops. NHS clinics unfortunately do not allow us time to follow the advice we issue to patients about leaving several minutes between drop applications. All the effects of the medications (or failure thereof) would be identifiable either immediately (GAT) or 20 minutes later (dilated fundoscopy).
Secondly, our method reuses one Minim™ vial repeatedly for multiple patients. Herein lies the potential for significant economies in both money and time spent mixing drops. However, reuse of Minims™ is also off-label and does raise the question of a potential risk of cross contamination between patients. In previous work assessing the risks of this, Rautenbach was unable to conclude whether the small risk of contamination of the Minim™ outweighed the very significant 3 fold increase in cost implicated if Minims™ are not used repeatedly (1 Minim per 5 patients).ii 17% of vials used on multiple patients in this study grew normal conjunctival flora after culture. Their method of drop application was not specifically noted in their work. Logically, any direct contact with lash, lid or conjunctiva would increase the risk of this. We strongly advocate a “no-touch” technique in which each drop is allowed to free fall through the air to the fornix, which should negate the risk of cross-contamination. Also, any suspected contamination should prevent the reuse of any given vial.
However, there do remain occult infections which may theoretically be spread by droplet or inadvertent contact which remain a theoretical concern. In previous experimental work, Claoue has demonstrated that after immersion in high titre Sp.Pseudomonas Minim™ contamination could lead to drop contamination. This was, however, in conditions unlikely to be replicated in clinical practice.iii The debate remains open about the potential risk posed by the reuseiv of Minims™.
An audit of ophthalmologists’ practice by Qureshi has demonstrated that 79% of ophthalmologists, spanning all grades, reuse Minims™ on more than one patient.v We must consider the practical implications of not reusing Minims™ – a not insignificant amount of time would be required if Charlie’s Cocktail were prepared repeatedly for each patient. Our anecdotal experience is that patients rarely present to clinic or eye casualty with iatrogenic infections related to eye drops and perhaps similar experience may be deduced elsewhere from the results of Qureshi’s audit.
This experiment is an example of necessity arising from the pharmaceutical industry thus far failing to meet the needs of practitioners patients in busy NHS clinics which would be met by pre-prepared fixed combinations of commonly used drops. We feel this particularly now, having experienced the convenience of industrially prepared proxymetacaine/fluorescein combination drops and their subsequent withdrawal from the market. Had we a licensed alternative to reduce the need for multiple drop application then perhaps opening a new packet for each patient would be less of a problem.
In the absence of more clinical evidence about the risk of contamination by the reuse of Minims™ and considering the significant practical advantages of the Charlie’s Cocktail method, we think that Charlie’s Cocktail is ergonomic, economic and easy to use. There appear to be no disadvantages to mixing the 4 drugs into a single drop, and we believe that patients would prefer a single drop to multiple separate applications.
