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Impact of admixture time and diluent order on metaraminol concentration.

Metaraminol is a commonly used vasopressor that is usually diluted prior to use due to its high-concentration presentation. Unexpected or precipitous hypotension may necessitate a short lag time between preparation of diluted metaraminol and administration. We conducted a study to determine whether the order of drawing up the drug and diluent, or the lag time before administration, affected the delivered concentration.

Materials used were a 10 mg/1 ml preparation of metaraminol tartrate (Metaraminol Sandoz Injection[R], Sandoz Pty. Ltd., Sydney, New South Wales), 10 ml 0.9% sodium chloride ampoules for dilution (Pfizer Pty. Ltd., Perth, Western Australia), 20 ml syringes (Terumo Corporation, Philippines) and 18 G x 1.5 inch drawing-up needles (Terumo Corporation, Tokyo, Japan). Six investigative sets were studied, varying both order of dilution (drug or diluent first) and lag time between mixing and analysis. Metaraminol 1.0 ml was drawn up with the syringe pointed vertically downward (Figure 1A) and then inverted 180[degrees] to the upward pointing position before dilution with 19 ml of saline (Figure 1B). The syringe was immediately turned 90[degrees] to the horizontal position, the needle removed and the first ml of solution (of intended concentration 0.5 mg/ml) dispensed into an analysis pipette after admixture times of 0, 10 or 30 seconds. The order of dilution was then reversed. Each set was repeated six times and to maximise consistency, dilution and titration was performed by a single operator. Metaraminol concentrations were measured using high-performance liquid chromatography.


Drawing up metaraminol first and then diluting with saline resulted in greater consistency of concentration (grand median = 0.53 mg/ml [total range: 0.50 to 0.57 mg/ml]), with median concentration the same at each time point (0.53 mg/ml). Metaraminol drawn up last resulted in a much greater spread of concentrations (grand median = 0.72 mg/ ml [total range 0.42 to 1.23 mg/ml]), with significantly increased median concentrations of 0.60 (range 0.42 to 0.81) mg/ml at 0 seconds, 0.76 (0.63 to 1.23) mg/ ml at 10 seconds and 0.73 (0.54 to 0.89) mg/ml at 30 seconds. When metaraminol was drawn up last, 16 of 18 measured metaraminol concentrations were greater than the metaraminol-first median. There was a statistically significant difference between the metaraminol-first and metaraminol-last groups (P=0.0001) but increasing admixture time between preparation and administration did not significantly alter measured concentration in either group (P=0.1411).

The uniformity of active drug distribution within a preparation has been addressed by the pharmaceutical industry, although such inquiries have been confined to non-injectable drug formulations such as ointments (1) and tablets (2). Adequate mixing of active drug and excipients in solid preparations has been quantified by parameters such as 'blend time' (time for mixing of ingredients), with a positive correlation demonstrated between increasing blend time and homogeneity of an admixture (3). However, no previous studies have addressed the issue of drug mixing in liquid diluent 'at the bedside'. Our study demonstrated that admixture times out to 30 seconds did not significantly normalise the initial raised concentration.

Drawing up metaraminol followed by saline produces turbulence within the syringe, and this dissipates the drug. Reduction in this turbulence when drawing up metaraminol last may result in more of the drug available close to the end of the syringe. The higher measured concentrations could also be due to undiluted drug residue remaining in the hub of the syringe, flushed out with the first ml. The magnitude of these concentrations was considerable, up to 1.23 mg/ml (or 2.5 times the desired concentration).

Our study was limited by restricting the analysis to only the first ml from the syringe. In addition, we did not examine the impact of agitation of the syringe on drug mixing nor the effect of longer admixture times. Nonetheless, this study demonstrates the importance of adequate drug mixing, ensuring no undiluted drug remains in the hub of the syringe, and supports drawing up the drug prior to the diluent, which we believe should be routine anaesthetic practice.


(1.) Orr NA, Hill EA, Smith JF. Dosage uniformity in hydrocortisone ointment B.P. J Pharm Pharmacol 1980; 32:766-772.

(2.) Orr NA, Sallam EA. Content uniformity of potent drugs in tablets. J Pharm Pharmacol 1978; 30:741-747.

(3.) Bai G, Armenante PM, Plank RV. Experimental and computational determination of blend time in USP Dissolution Testing Apparatus II. J Pharm Sci 2007; 96:3072-3086.

J. N. Darvall

A. R. Bjorksten

K. Leslie

Melbourne, Victoria
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Title Annotation:Correspondence
Author:Darvall, J.N.; Bjorksten, A.R.; Leslie, K.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:8AUST
Date:Sep 1, 2009
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