# Inhomogeneity of noradrenaline levels in syringe pump systems and how to prevent it: an in vitro study

## TL;DR

This study shows that mixing noradrenaline solutions with a Bubble-Flip method prevents dangerous concentration variations in syringe pumps, improving patient safety.

## Contribution

The Bubble-Flip method is introduced as a safe and effective manual mixing technique to ensure homogeneity in noradrenaline solutions.

## Key findings

- The Bubble-Flip method achieved ≤2% variability in noradrenaline concentration, comparable to pre-mixed commercial products.
- Manual preparation without proper mixing resulted in up to 39.9% variability, posing risks to patient safety.
- Three-dimensional reconstructions revealed significant local concentration spikes and drops in poorly mixed solutions.

## Abstract

Accurate drug delivery in intensive care depends on precise and reliable preparation of intravenous solutions. Manual preparation is prone to error, and fluctuations in the delivery of vasoactive agents such as noradrenaline can cause haemodynamic volatility, leading to direct patient harm or being misinterpreted as instability and prompting unnecessary interventions. This study evaluated how different mixing techniques affect the homogeneity of noradrenaline solutions in 50 mL syringes to identify a safe preparation method for clinical use.

Six preparation methods, combining two target concentrations and three mixing techniques - no mixing; a single end-over-end syringe inversion; and inversion after aspiration of 5 mL air (the “Bubble-Flip”) - were tested in a simulated syringe pump infusion experiment, with a pre-manufactured noradrenaline solution as reference. Each method was tested in five replicates. To illustrate three-dimensional concentration heterogeneity, additional syringes were flash-frozen in liquid nitrogen (four replicates each for two methods). In total, 38 experiments were performed. Noradrenaline concentrations were quantified by high-performance liquid chromatography.

Mixing technique had a marked impact on solution homogeneity. The highest method-level variability (as coefficients of variation) were 30.7 % with no mixing and 12.2 % with a syringe inversion without air. Within-syringe variability ranged overall from 0.61 % to 39.9 %, with the highest values recorded for no mixing (39.0 %, 20.1 %) and inversion without air (14.8 %). By contrast, the Bubble-Flip method and the pre-mixed solution both achieved overall variability ≤2 %, within-syringe variability consistently < 5 %, and no samples deviated more than ±15 % from target. Three-dimensional reconstructions confirmed complex inhomogeneities with pronounced local spikes and drops, highlighting the risks of inadequate mixing.

Commercial pre-mixed products guarantee homogeneity but are costly. Comparable safety and consistency can be achieved with the Bubble-Flip method - a simple syringe inversion in the presence of 5 mL air. In contrast, manual preparation without proper mixing produced unsafe variability. These findings support the adoption of standardised mixing techniques to ensure reliable drug delivery and patient safety, with principles likely generalisable to other intravenously administered drugs requiring dilution.