Drug incompatibilities: a problem in clinical practice

Incompatibilities between drug solutions can jeopardise the safety and effectiveness of intravenous drug therapies, especially when managing patients in intensive care units. Patients receive many drugs simultaneously, but through limited venous access sites. A number of intravenous therapies have to be administered through the same catheter, thereby increasing the risk of physicochemical incompatibilities. Although the stability of drug mixtures and their compatibilities is a vast subject, published data are scarce and sometimes contradictory.(1)

Drug incompatibility can provoke physical and/or chemical reactions. Physical incompatibilities result in visible (precipitate, colour change, gas production) and invisible (sub-visible particles, variations in pH) reactions, and even in the absence of precipitate could result in a significant reduction in the amount of drug delivered to the patient. Chemical incompatibilities can lead to drug degradation, a decrease in drug amount and/or the formation of toxic substances.

Although physicochemical incompatibilities have been reported in several observational studies in intensive care units,(2-4) health workers’ knowledge is limited in this field. Physicochemical incompatibility can have serious clinical consequences and cause many complications, such as catheter obstruction, loss of drug efficacy, formation of toxic derivatives or the occurrence of embolism. Fatalities resulting from drug incompatibilities have been reported.(5,6)

If injectable drugs are to be administered safely, incompatibility must be prevented. Although a number of publications and databases deal with the subject,(7) discrepancies exist among available references, data are often non-existent or incomplete,(8,9) and usually describe only one mixture. The use of separate catheter lumens can prevent contact between incompatible drugs, and yet there are some limitations to this solution: a slight increase in the risk of infection with multi-lumen central venous catheters versus single-lumen catheters and an increase in resistance to flow.(10-12) However, as the number of catheter lumens is typically lower than the number of drugs infused, it is preferable to use multi-port manifolds. Filters can be placed on the infusion line to prevent drug particles from being administered to the patient but these will not be able to prevent a drop in drug mass flow rates resulting from incompatibility.

Some hospitals have implemented strategies to facilitate the work of caregivers and avoid mixing incompatible drugs. For example, drugs might be labelled with a specific colour code according to their pH to reduce incompatibility risks between acid and alkaline drugs infused simultaneously.(13) Double-entry tables, listing the drugs commonly used in a ward and whether they are compatible with each other at given concentrations can be made on request.(14) Specific databases can be created and made available to the wards to control physicochemical compatibility of the drugs used.(15,16)

The recent marketing of a new multi-lumen infusion access device (Edelvaiss-Multiline®, Doran International, Toussieu-Lyon, France) may pave the way to a new approach to preventing incompatibility.

This device (Figure 1) comprises an extension set with eight accesses connected to nine separate lumens in a single tube (outside diameter = 4mm, length = 150cm). Seven accesses are for drug infusion and each is connected to a peripheral lumen (dead volume = 0.9ml). The eighth access with high flow rate capacity (HF access) is for the carrier fluid. It is connected to two lumens (peripheral and central) for a total dead space volume of 2.9ml. The fluids administered through the eight ports mix only at the tube outlet.

We performed a controlled in vitro study to assess the impact of the Edelvaiss-Multiline® on the occurrence of known drug incompatibility (furosemide/midazolam) versus a standard set with two-port manifold and one-metre extension set.(17) Drug incompatibility in the latter case results from an acid-base reaction. Mixing a furosemide solution (alkaline) with a midazolam solution (acidic) decreases the pH in the mixture sufficiently to result in immediate furosemide precipitation and the formation of a visible milky-white precipitate. As precipitate formation may differ according to the distribution of accesses, three different access combinations were used in relation to the distance between midazolam and furosemide, with one port solely dedicated to saline.

The combinations were: (i) closest to the saline port: furosemide on access 7 and midazolam on access 1 (F7/M1); (ii) at an intermediate distance: furosemide on access 6 and midazolam on access 2 (F6/M2); and (iii), furthest away from the saline port and closest together: furosemide on access 4 and midazolam on access 3 (F4/M3) (Figure 1).

Three furosemide concentrations were tested (10, 5 and 2.5mg/ml). Midazolam concentration was kept constant at 1mg/ml. The infusion flow rate of saline (carrier) was initially set at 100ml/hour and decreased in a stepwise fashion by 10ml/hour until precipitate formation. Physical incompatibility was assessed by two tests: visual inspection and the sub-visible particle count test, according to the European Pharmacopeia.(18) The lowest saline infusion flow rate to prevent visible precipitate and attain an acceptable particle count (that is, to pass ‘the two tests’) was reported for each infusion set (Figure 2).

Visible precipitates were revealed with the standard set even at the highest saline flow rate (100ml/hour). The Edelvaiss‑Multiline® device prevented drug precipitation whatever the furosemide concentration for two access combinations using saline infusion rates of between 20 and 60ml/hour but not for a third access combination, despite saline infusion rates equal to 100ml/hour.

Our main hypothesis is that fluid dynamics differ according to infusion devices and accesses, which modify the contact time between drugs and saline. In the case of the two-port manifold and one-metre extension set, furosemide and midazolam are immediately in contact and therefore precipitate because they have insufficient time to be diluted with the saline. In the case of the Edelvaiss‑Multiline® device, the lumen arrangement – that is, two carrier-fluid lumens, one central and one peripheral, situated between the lumens of drugs to be infused – prevents contact between concentrated solutions until their dilution at the outlet.

The Edelvaiss-Multiline® device offers a new way of preventing drug incompatibility but, in our study, results depended on the access combination and saline flow rate associated. To confirm our fluid dynamics hypothesis, another experiment is underway to determine the limits of the device by testing more access combinations, infusion vehicles and drug incompatibilities commonly encountered in clinical practice. The aim is to validate the use of the Edelvaiss-Multiline® device in preventing physical incompatibilities for up to six drugs infused simultaneously.

Infusion device characteristics appear to have an impact on the physical compatibility of the two drugs. Under specified conditions, the 9-lumen infusion access device prevents physical furosemide-midazolam incompatibility.

• Physicochemical incompatibilities between injectable drugs frequently occur in hospitals, and especially in intensive care units, because patients receive treatments that can include numerous drugs infused simultaneously.
• There are many ways to prevent drug incompatibilities, but often they are not well known by clinicians or have their own limits.
• The recent marketing of a new multi-lumen infusion access device (Edelvaiss-Multiline®) complements other preventive means of drug incompatibility.
• The first in vitro results obtained showed that characteristics of the Edelvaiss-Multiline® have an impact on the occurrence of the physical incompatibility between two drugs under specified conditions.
• These results must be confirmed by further studies replicating common situations in clinical practice (changeover of drug infusion pump, interruption and resumption of drug flow, changes in drug flow rate) and by assessing other drug incompatibilities to validate the ability of the Edelvaiss-Multiline® to prevent physical drug incompatibilities.

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