Parenteral drug solutions

Editor, – Many thanks for the excellent article about compatibilities of parenteral drug solutions (Aust Prescr 2008;31:98-101), written from a pharmacy point of view. It certainly contains much practical information for everyday clinical practice, but it might be helpful to add a few extra points from a clinical perspective.

Table 1 shows an incompatibility between lignocaine 2% and sodium bicarbonate solution. In practice, however, the two substances make an excellent marriage; the intense stinging of local anaesthetic injections is markedly reduced by mixing the two. The only problem (in practice) is that left to stand for a few minutes, crystals do form and can block fine needles. The practice is well known and has stood the test of decades.

It is also noted that diazepam precipitates in water. Is this really the case or could the cloudiness be an innocent emulsion? In any case, dilute diazepam (for example 10 mg in 10 mL saline) has been given intravenously for years and works very well. It is standard practice and certainly far easier to titrate than the 10 mg in 1 mL in the ampoule.

The article states that phenytoin must not be diluted as it will precipitate. With its extreme pH of 12, intravenous injection of phenytoin is made easier and less irritating by dilution in saline. Although not described in the product information, it is thankfully normal practice. 'Phenytoin - must be diluted in 0.9% saline (rather than dextrose) to avoid crystallization'.¹

Andrew Montanari
General practitioner
Merewether, NSW

Mr Peter Murney, author of the article, comments:

Lignocaine hydrochloride is an acidic solution (pH = 2.3) which causes pain upon injection. Adding sodium bicarbonate injection to raise the pH and reduce pain is widely practised and supported by a wealth of literature. Nonetheless, the solutions are incompatible and mixing them precipitates lignocaine from its hydrochloride salt. Intradermal injection of suspended lignocaine crystals is of no concern as lignocaine has no local toxicity and will absorb into tissue eventually.

However, intravenous injection of precipitated particulate matter concerns me as I suspect it would many other health practitioners. Diazepam injections are painful, probably because of venous irritation from the propylene glycol/ethanol/water solvent system. Appropriately slow administration of the small volume may also be difficult. There is no component of the mixture which would produce an emulsion and the haze is probably due to precipitated microcrystalline or colloidal diazepam. After 24 hours, the diluted solution clears with deposition of a thin oily film (presumably diazepam) on the syringe barrel. At a total mass of 10 mg, it is unlikely to cause harm upon injection and should rapidly redissolve in plasma. Larger amounts of precipitated drug may result in an embolism of precipitated drug sludge although I could find only one report of an associated fatality.

While some references support addition of phenytoin to normal saline infusion solution for short periods, the diversity of stability studies is disconcerting with some reporting presence of suspended crystals immediately after addition to the bag. Contrary to the current product information, a number of institutional protocols permit addition to a saline infusion bag but generally specify use of an in-line filter to remove crystals.

Slow administration of undiluted injection solutions can be facilitated with spring-loaded devices which, with a flow restrictor fitted to the syringe, allow administration of a specified volume over a specified time.