Y-Site Compatibility of Intravenous Levetiracetam With Commonly Used Critical Care Medications

Abstract

Purpose: Levetiracetam is an antiepileptic medication commonly used in critical care areas for seizure treatment or prophylaxis. Compatibility data of levetiracetam with other critical care medications are limited, which can make administration challenging. This study aims to assess the physical Y-site compatibility of intravenous levetiracetam with some other commonly used critical care medications. Methods: Y-site administration was simulated by independently mixing levetiracetam with each of 11 selected medications in a 4-dram, colorless, screw-cap, glass vial, at a 1:1 ratio. Clinically used concentrations of each medication were compounded in 0.9% sodium chloride following United States Pharmacopeia chapter 797 standards. Physical compatibility was observed and assessed at 0, 15, and 30 minutes after mixing. Medication mixtures were considered physically incompatible if there was visual evidence of color change, gas evolution, haze, or particulate formation, pH change >10%, or if they had an absorbance value >0.010 A. Results: No evidence of physical incompatibility was observed during simulated Y-site testing with cisatracurium 1 mg/mL, dexmedetomidine 4 µg/mL, fosphenytoin 15 mg PE/mL, norepinephrine 16 mg/mL, norepinephrine 32 mg/mL, norepinephrine 64 mg/mL, piperacillin-tazobactam 33.75 mg/mL, propofol 10 mg/mL, vancomycin 5 mg/mL, or vasopressin 1 unit/mL when tested in 0.9% sodium chloride. Levetiracetam was incompatible with piperacillin-tazobactam 45 mg/mL. Conclusion: Levetiracetam 5 mg/mL in 0.9% sodium chloride was found to be physically compatible for 30 minutes with 10 of the 11 medications tested during simulated Y-site administration.

Introduction

Intravenous (IV) levetiraetam (LEV) use in critical care areas has recently increased due to positive outcomes and a low side effect profile.^1,2 LEV has been used for the treatment of several different seizures, including status epilepticus, stroke-related seizures, seizures following subarachnoid or intracerebral hemorrhage, and seizures in critically ill patients. ³ Treatment or prophylaxis against these events is common in intensive care settings due to the risk of significant complications.^4,5 Critically ill patients often require simultaneous administration of IV medications, including medications with long infusion times or that need to be administered continuously. When data regarding compatibility are sufficient, multiple medications are often concurrently administered via a Y-site. To date, published data regarding the compatibility of LEV with other IV medications are limited.^6,7 When medications cannot be concurrently administered, a separate line for independent infusion must be placed, or medications must be prioritized and administered independently. Either of these options increases the risk of errors and delays in therapy, which can negatively affect patient outcomes.

Consensus literature is lacking on which compatibility tests need to be performed to assess Y-site compatibility. Medication contact time during Y-site administration is variable based on the flow rate. For adults, the contact time of medications is typically 1 to 2 minutes, significantly shorter than medications mixed in the same syringe or IV bag. ⁸ Due to this short contact time, chemical incompatibility is less relevant for Y-site administration as this type of incompatibility occurs after hours, and could take up to days.^9-11 Physical compatibility testing is typically used for Y-site administration because changes can be immediate and are often seen by visual examination. A common method is to simulate Y-site administration by mixing two medications in a 1:1 ratio, and then assess for compatibility. Mixtures are often assessed for compatibility by visual inspection, pH evaluation, and turbidity assessment.^11-13

The purpose of this study was to use physical assessment to assess Y-site compatibility of IV LEV with some other commonly used critical care medications.

Methods

Calcium gluconate^a, cisatracurium^b 1 mg/mL, dexmedetomidine^c 4 µg/mL, fosphenytoin^d 15 mg/mL, levetiracetam^e 5 mg/mL, norepinephrine^f 16 µg/mL, 32 µg/mL and 64 µg/mL, piperacillin-tazobactam^g 33.75 mg/mL and 45 mg/mL, propofol^h 10 mg/mL, sodium phosphatesⁱ, vancomycin^j 5 mg/mL, vasopressin^k 1 unit/mL, fluids^l, and all supplies were obtained commercially. With the exception of propofol, which was premade, all medications were compounded in commercially available 0.9% sodium chloride poly vinyl chloride (PVC) bagsj according to United States Pharmacopeia chapter 797 standards. ¹⁴ Reconstitution of all medications was performed according to the manufacturers’ recommendations. Medications were stored at room temperature and received appropriate expiration dating. Owing to the 4-hour room temperature expiration dating listed in the monograph for LEV, testing occurred on 3 separate dates.

Y-site administration was simulated by mixing 5 mL of levetiracetam with 5 mL of another medication in a Thermo Scientific 4-dram, colorless, screw-cap, glass vial. To ensure reproducibility, testing was done in triplicate, and the order of mixing was alternated. A negative control solution was created for comparison by mixing 5 mL of levetiracetam with 5 mL of 0.9% sodium chloride. In addition, a positive control solution for visual analysis was created by mixing sodium phosphates 3 mM/mL with calcium gluconate 100 mg/mL in a 1:1 ratio. ⁷

Physical compatibility was observed and assessed at 0, 15, and 30 minutes after mixing. The timing of assessments was chosen to cover the duration of a 15-minute levetiracetam infusion and to allow for any residual medication to be cleared from the line during clinical applications. Medication mixtures were first assessed visually against black and white backgrounds for color change, gas evolution, haze, or particulate formation. Prior to analysis, vials were inverted to mobilize any precipitates and aid in inspection. Gas evolution was defined as bubble formation during any study point. Medication mixtures were also assessed at the same time points for pH and turbidity. These tests were used to confirm visual analysis and assess for a reaction or precipitant that was not visible in normal light. Due to availability of equipment, absorbance was used to measure turbidity instead of a turbidimeter or performing a particle count.^15-18 Absorbance was measured spectrophotometrically at 546 nm using a VersaMax tunable microplate reader with photometric accuracy of ±0.006 A. Absorbance readings <0.006 were reported as <0.006 A, owing to the spectrophotometer’s photometric accuracy. We selected 546 nm as the wavelength because that is the wavelength at which the ionized water blank had 100% transmittance. The pH of mixtures was tested with an Orion model 420A pH meter. The pH meter was calibrated using standard pH 4, 7, and 10 buffers before each use. Testing was performed by the authors and laboratory staff to reach a consensus. Study compatibility criteria was based on previously published literature, physical incompatibility was defined as visual evidence of color change, gas evolution, haze, or particulate formation, laboratory evidence of a change in absorbance value >0.010 A compared with the control solution, or a pH value change >10% over the course of the experiment.^15-18

Propofol physical compatibility was assessed using a different method due to its physical appearance as an opaque white emulsion. Propofol, 0.5 mL, was removed from the manufacturer’s vial and placed in a 2-mL Eppendorf with 0.5 mL of levetiracetam. The pH of the mixtures was assessed, and the samples were then centrifuged at 12 000 revolutions per minute for 15 minutes. ¹⁹ Analysis occurred 0, 15, and 30 minutes after mixing; the timer was stopped during centrifugation time. Propofol and levetiracetam were assessed for physical compatibility by visual inspection after centrifuging. Absorbance was not monitored due to the high baseline turbidity. Physical incompatibility was defined as the presence of an oil layer and possible precipitation formation at the bottom of the tube; physical compatibility was defined as an intact white layer on top of the sample, which signified an intact emulsion.^18,19

Results

LEV was clear, colorless, and without precipitation when initially compounded with 0.9% sodium chloride. The control solution was created as outlined in the methods, and its characteristics remained unchanged over the entire 30-minute observation period. None of the LEV-medication combination visual inspections yielded evidence of incompatibility. Absorbance and pH testing results are provided in Table 1. LEV was compatible with 10 of the 11 tested drugs. Piperacillin/tazobactam 45 mg/mL was the only medication to fail a compatibility test. The medication mixture passed visual inspection and pH testing; however, the 45 mg/mL concentration had two absorbance readings that differed from the control by >0.010 A. On visual examination, propofol had a visible white plug on top of the sample and no visible oil layer or precipitant.

Table 1.

Evaluation of Physical Compatibility of Levetiracetam With 11 Selected Medications Using Simulated Y-Site Administration.

Medication a	Time, minutes
	0		15		30
	Absorbance, A	pH	Absorbance, A	pH	Absorbance, A	pH
Cisatracurium 1 mg/mL
Sample 1	<0.006	4.95	<0.006	4.97	<0.006	5.03
Sample 2	<0.006	4.99	<0.006	4.98	<0.006	5.01
Sample 3	<0.006	5.00	<0.006	5.00	<0.006	5.02
Dexmedetomidine 4 µg/mL
Sample 1	<0.006	5.77	<0.006	5.81	<0.006	5.77
Sample 2	<0.006	5.77	<0.006	5.78	<0.006	5.77
Sample 3	<0.006	5.75	<0.006	5.75	<0.006	5.75
Fosphenytoin 15 mg/mL
Sample 1	<0.006	8.69	<0.006	8.70	<0.006	8.73
Sample 2	<0.006	8.70	<0.006	8.72	<0.006	8.72
Sample 3	<0.006	8.72	<0.006	8.71	<0.006	8.73
Norepinephrine 16 µg/mL
Sample 1	0.006	5.96	0.006	5.93	<0.006	5.97
Sample 2	<0.006	5.94	<0.006	5.97	<0.006	6.04
Sample 3	<0.006	6.03	<0.006	6.06	<0.006	6.09
Norepinephrine 32 µg/mL
Sample 1	<0.006	5.04	<0.006	5.03	<0.006	5.04
Sample 2	<0.006	4.92	<0.006	5.05	<0.006	5.08
Sample 3	<0.006	4.99	<0.006	4.99	<0.006	5.12
Norepinephrine 64 µg/mL
Sample 1	<0.006	4.68	0.007	4.67	<0.006	4.74
Sample 2	<0.006	4.71	<0.006	4.69	<0.006	4.71
Sample 3	<0.006	4.72	<0.006	4.71	<0.006	4.73
Piperacillin-Tazobactam 33.75 mg/mL
Sample 1	0.006	5.55	0.007	5.62	<0.006	5.63
Sample 2	<0.006	5.60	<0.006	5.60	<0.006	5.62
Sample 3	0.009	5.62	0.009	5.62	0.007	5.62
Piperacillin-Tazobactam 45 mg/mL
Sample 1	0.008	5.73	<0.006	5.72	0.007	5.72
Sample 2	<0.006	5.73	<0.006	5.73	0.007	5.74
Sample 3	0.011	5.74	0.015	5.75	0.009	5.73
Propofol 10 mg/mL b
Sample 1		7.00		6.98		6.97
Sample 2		7.01		7.02		7.03
Sample 3		6.98		7.03		7.03
Vancomycin 5 mg/mL
Sample 1	0.008	4.29	0.008	4.35	0.007	4.31
Sample 2	<0.006	4.27	<0.006	4.3	0.007	4.29
Sample 3	<0.006	4.26	0.006	4.29	0.006	4.26
Vasopressin 1 unit/mL
Sample 1	<0.006	4.94	<0.006	4.99	<0.006	4.96
Sample 2	<0.006	4.92	<0.006	4.92	<0.006	4.93
Sample 3	<0.006	4.93	<0.006	4.94	<0.006	4.94

^aAll medications were diluted to their final concentration in 0.9% sodium chloride.

^bThe absorbance of propofol was not monitored owing to its high baseline turbidity.

Discussion

Our study has several important limitations. First, Y-site administration was simulated by mixing 2 medications in a glass vial without the use of IV tubing. This is a common method of simulating Y-site administration as mixing medications in a glass vial simulates the static state of a paused infusion. This static state is a concerning time regarding compatibility and frequently occurs in clinical practice when infusions need to be stopped or paused. However, this method does not assess possible physiochemical interactions between the IV tubing and the medications. In addition, others have reported medications showing physical incompatibility only during the actual Y-site administration.^20-22 The methodology used in our study does not account for this possibility.

Second, the medications we tested were compounded in 0.9% sodium chloride and at commonly used concentrations within our health system. This base was selected for simplicity and because 0.9% sodium chloride is typically used unless a patient is hypernatremic. Often, a patient presenting to a critical care area may have contraindications to hypotonic solutions, such as cerebral edema or traumatic brain injuries. ²³ The findings of this study cannot be extrapolated to other concentrations or base solutions without further testing.

As outlined previously, there are several simulated Y-site physical compatibility studies that our study was based on. Visual analysis was performed in a similar manner, but turbidity and pH measurements differed as outlined below. Kufel et al ¹⁵ defined incompatibility as ≥1 pH unit change or any absorbance >0.01 A. Dotson et al ¹⁶ defined physical incompatibility as >10% pH unit change or any absorbance ≥0.015A. Housman et al ¹⁸ used a turbidimeter to assess turbidity and defined incompatibility as >1 pH unit change. We are not aware of validated methods that correlate absorbance values with size of particulate matter, particularly the 10 µm United States Pharmacopeia Reference Standard. ²⁴ Absorbance analysis was used to increase confidence in visual analysis. Without the presence of validated methods, we intentionally elected to use the stricter pH and absorption values to confer compatibility in this study. Previously studied medications were not included in this analysis for conformation due to time and budgetary concerns. We decided to focus resources on increasing the available literature, not confirming previously published results. The studied medications were selected after surveying pharmacists at our institution and choosing continuously infused or time-sensitive medications. As there are many medications that are used in the critical care setting, we elected to focus on medications that would aid in the treatment of seizures, be used to reverse the cause of the seizure, or to treat a consequence from the seizure. Notably, we intended to study fentanyl, but as fentanyl is a controlled substance, there were several obstacles that prevented us from performing this testing.

Conclusion

Levetiracetam 5 mg/mL in 0.9% sodium chloride was found to be physically compatible for 30 minutes with 10 of the 11 medications tested during simulated Y-site administration.

Piperacillin-tazobactam 45 mg/mL showed evidence of turbidity and was the only medication mixture that showed incompatibility.

Appendix

Appendix.

aFresenius Kabi, Lake Zurich, IL lot 6015986

bSandoz, Princeton, NJ lot WU816

cAccord Healthcare, Inc., Durham, NC lot W10633

dPfizer, New York, NJ lot W63471

eWest-Ward Pharmaceuticals, Eatontown, NJ lot 1705179.1

fHospira, Lake Forest, IL lot 800853A

gSandoz, Princeton, NJ 3.375 gram: lot HW7644 4.5 gram: lot HW8197

hFresenius Kabi, Lake Zurich, IL lot 10MF5472

iFresenius Kabi, Lake Zurich, IL lot 6018608

jHospira, Lake Forest, IL lot 781903A

kPar Pharmaceutical, Chestnut Ridge, NY lot 319237

lHospira, Lake Forest, IL 100-mL bags: Lot 92-073-JT 50-mL bags: Lot 90-065-JT 25-mL bags: Lot 86-097-JT