Hypotensive states commonly require intravenous infusions of inopressors such as epinephrine, norepinephrine, and phenylephrine.  Traditionally, these high-alert medications were prepared in plastic bags at “standard” concentrations and administered using high-volume infusion pumps. Several studies have documented the stability of these medications in plastic bags for infusions, supporting compounded pharmacy and industry preparations.  The introduction of smart syringe infusion pumps has allowed for accurate lower infusion rates and decreased volume load but with a requirement of higher medication concentrations.

The U.S. Food and Drug Administration recommends against storing compounded medications in syringes after multiple reports of decreasing concentration (up to 70%) of multiple medications stored in Becton Dickinson syringes.  Other factors affecting the stability of compounded sympathomimetics include interactions with air, light, elevated temperature, heavy metals, and alkaline pH, which favor oxidative degradation. Previous sympathomimetics stability studies report a variety of experimental conditions, thus limiting comparisons.  For those reasons, our current institutional practice is to prepare syringe infusions at the point of care for immediate use. However, due to safety concerns about point-of-care intravenous medications prepared by health professionals, multiple organizations recommend abandoning this practice in favor of preparation by pharmacy or industry. 

To address some of these concerns, this study aimed to assess the stability of epinephrine, norepinephrine, and phenylephrine, when diluted in 0.9% isotonic sodium chloride solution, refrigerated (5 to 8°C), protected from light exposure, and stored in 50-ml syringes of three commercial brands—Becton Dickinson (USA), Covidien (USA), and Terumo (Philippines)—for 14 days using high-performance liquid chromatography–mass spectrometry (HPLC-MS/MS).

The Institutional Research Ethics Board waived approval for this study. A previous study optimized the methods of measurement of these medications using HPLC-MS/MS and determined a sample size of four syringes of each branch at each time interval.  Detailed methods can be found in Supplemental Digital Content 1 (https://links.lww.com/ALN/D464). United States Pharmacopeial grade (purity greater than 99.9%) epinephrine, norepinephrine, and phenylephrine and their corresponding labeled isotopologues were used as standards for the calibration curves. The area under the curve of each drug was obtained by HPLC-MS/MS using a custom-developed selected reaction monitoring method. For calibration purposes, four points were used for each medication: the expected concentration (which was 80 μg/ml for epinephrine and norepinephrine and 100 μg/ml for phenylephrine), 10 μg/ml above the expected concentration, and 10 and 20 μg/ml below the expected concentration. The calibration standards were measured in quadruplicate pre- and post-testing the syringe samples. The eight data points from the pre- and post-calibration standards were used for the linear regression analysis.

Pharmaceutical presentations diluted in 0.9% isotonic sodium chloride solution were used to prepare batches of 12 syringes, 4 of each syringe brand: Becton Dickinson, Covidien, and Terumo. The batches were prepared fresh (less than 4 h before testing) and 3, 7, and 14 days before testing. The syringes were prepared aseptically, protected from ultraviolet radiation with amber plastic bags, labeled with a computer generated random number blocked by date, and stored in a medical fridge (5 to 8°C). Laboratory personnel were blinded to both preparation time and syringe brand.

The experimental design is a fractional factorial design. The factors examined were syringe type (Becton Dickinson, Covidien, and Terumo), storage time (0, 3, 7, and 14 days), and medication concentration (epinephrine, 80 μg/ml; norepinephrine, 80 μg/ml; and phenylephrine, 100 μg/ml). Each factor combination was replicated four times; that is, four different syringes per brand (total of 12 syringes), per medication, per time period, measured once. Linear regression was used to estimate the effect of medication with 95% CI on the concentration standards. Comparison of pre- and posttesting calibration readings, the effect of syringe type and time interval on the medications’ concentration, and the effect of pH were performed using ANOVA. Tukey’s test was used for correcting for multiple comparisons. A P value less than 0.05 was considered significant. Statistical analyses were performed with the Rstudio 2021.09.0 + 351 software.

Medication calibration curves had a coefficient of determination of R2 = 0.88, 0.92, and 0.97, for epinephrine, norepinephrine, and phenylephrine, respectively (Supplemental Digital Content 2, https://links.lww.com/ALN/D465). Quadratic regressions on concentration were estimated, but ANOVA indicated that the quadratic terms were not significant (P = 0.289, 0.815, and 0.66 for epinephrine, norepinephrine, and phenylephrine, respectively). ANOVA indicated that pre- and postreading calibration concentration standards were not statistically different. Syringes’ mean medication concentrations were 82 SD ± 5.05 μg/ml, 77 SD ± 5.39 μg/ml, and 92 SD ± 3.56 μg/ml for epinephrine, norepinephrine, and phenylephrine respectively. There were no significant differences between syringe brands, storage time, or their interactions for epinephrine and norepinephrine. There was a significant effect of day (P = 0.03) for phenylephrine (fig. 1), as concentration on day 7 was significantly higher (93.34 μg/ml, SD ± 4.18 μg/ml) than on day 14 (89.9 μg/ml, SD ± 4.05 μg/ml). However, it was not considered clinically relevant as the concentrations were not less than 10% of the fresh preparations. There was a significant effect on pH in all medications with interaction between syringes and times (Supplemental Digital Content 3, https://links.lww.com/ALN/D466).

Fig. 1.
Concentration changes of epinephrine, norepinephrine, and phenylephrine stored in plastic syringes from Becton Dickinson (USA), Covidien (USA), and Terumo (Philippines). (A) Epinephrine. (B) Norepinephrine. (C) Phenylephrine. The dots are data points, and the red dash is the mean concentration. Concentration is presented in μg/ml. The interrupted red line represents 10% decrease concentration of the fresh medication preparation concentration.

Concentration changes of epinephrine, norepinephrine, and phenylephrine stored in plastic syringes from Becton Dickinson (USA), Covidien (USA), and Terumo (Philippines). (A) Epinephrine. (B) Norepinephrine. (C) Phenylephrine. The dots are data points, and the red dash is the mean concentration. Concentration is presented in μg/ml. The interrupted red line represents 10% decrease concentration of the fresh medication preparation concentration.

Our results demonstrated that medications’ concentrations were stable within ±10% of the fresh preparation concentration when stored refrigerated at 4 to 8°C and protected from ultraviolet light up to 14 days when prepared in isotonic sodium chloride solution. The concentrations used in our study are the ones currently used in our institution. These concentrations allow around 8 h of infusion at usual doses. Our medications were prepared aseptically as they were not intended for clinical use. The United States Pharmacopeial 797 standards for pharmacy compounding sterile medications10  recommends preparation in a clean room (particulate air quality ISO 5 or better), with a laminar flow hood and sterile technique.

  1. Our storage conditions included ultraviolet light protection with a pharmacy level amber bag, and refrigeration (4 to 8°C). Our storage time was limited to 14 days, which is the maximum storage for compounded sterile preparations not requiring microbiologic studies. Additional tests of the compounded samples with longer end of life use recommended by the guidelines include degradation and microbiologic studies.

In conclusion, our results demonstrated that epinephrine (80 μg/ml), norepinephrine (80 μg/ml), and phenylephrine (100 μg/ml) are stable for 14 days in commercially available syringes (Becton Dickinson, Covidien, and Terumo) when stored in a medical fridge and protected from light. The study findings support pharmacy and industry preparation of these medications.