1. 2021;24;E829-E837Microbiological and Physicochemical Stability of Fentanyl, Oxycodone, Hydromorphone, Ketorolac, Ramosetron, and Ondansetron for Intravenous Patient-controlled Analgesia: An In Vitro Study
   Laboratory Study
   Young Sung Kim, MD, PhD, Chung Hun Lee, MD, PhD, Ah Rahn Kim, PhD, Sang Sik Choi, MD, PhD, Mi Kyoung Lee, MD, PhD, Heezoo Kim, MD, PhD, and Seok Kyeong Oh, MD, PhD.

BACKGROUND: Postoperative patient-controlled analgesia provides pain relief, encourages early mobilization, and results in a shortened hospital stay. Patient-controlled analgesia involves the mixing of different types of drugs. When using patient-controlled analgesia, it is important to confirm the microbiological and physicochemical stability of each drug in a mixture to guarantee that the drug is delivered to the patient in an unaltered form.

OBJECTIVES: To confirm the microbiological and physicochemical stability of various drug mixtures for intravenous patient-controlled analgesia.

STUDY DESIGN: An in vitro protocol to examine the microbiological and physicochemical stability of the most commonly used postoperative intravenous patient-controlled analgesia mixtures at our institution.

SETTING: In vitro laboratory study.

METHODS: Each mixture contained a total of 4 drugs: fentanyl 400 µg, ketorolac 30 mg, either hydromorphone 4 mg or oxycodone 10 mg, and either ramosetron 0.3 mg or ondansetron 10 mg. Each mixture was placed in a portable patient-controlled analgesia system containing 0.9% saline and stored at a constant temperature of 24°C for 96 hours. Physical properties (color, transparency, and sedimentation) were observed with the naked eye and optical microscopy. Sterility testing was performed to assess microbiological contamination in the drug mixture during the 96-hour study period. The pH of each mixture was evaluated for up to 96 hours after mixing. The concentration of each drug was evaluated by high-performance liquid chromatography every 24 hours until 96 hours after mixing.

RESULTS: All mixtures appeared visibly transparent, and no sediments were visible under the microscope. Bacterial or fungal growth was not observed in any of the samples after 14 days of incubation. The pH variations in all mixtures were maintained within 0.25 over the 96-hour study period. The concentration of drugs, except ketorolac, ranged from 90–110% of the initial concentration up to 96 hours after mixing. In the mixtures with a pH of 4.21–4.39, the concentration of ketorolac significantly decreased at 24 hours and 48 hours.

LIMITATIONS: Confirmation of the stability of drugs in vitro does not automatically ensure that the pharmacokinetics and pharmacodynamics of the drugs are not altered in vivo.

CONCLUSION: With the exception of ketorolac, the drugs used in the intravenous patient-controlled analgesia drug mixtures in this study were physicochemically stable up to 96 hours after mixing. The concentration of ketorolac decreased in more acidic mixtures.

KEY WORDS: Patient-controlled analgesia, multimodal analgesia, stability, fentanyl, oxycodone, hydromorphone, ketorolac, ondansetron, ramosetron