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BY 4.0 license Open Access Published by De Gruyter May 11, 2022

Y-site compatibility of intravenous medications commonly used in intensive care units: laboratory tests on 75 mixtures involving nine main drugs

Gillian Ayari, Elise d’Huart, Jean Vigneron and Béatrice Demoré

Abstract

Objectives

Patients hospitalized in intensive care units often require multiple drug infusions. Due to limited intravenous accesses, concomitant administration of drugs in the same infusion line is often necessary. Compatibility studies of Y-site administration are available in the literature, but data of several combinations are lacking. Previous work from d’Huart et al. have performed an observation of the administration of injectable drugs in three adults ICUs and identified a list of Y-site administration without compatibility data. The objective of this study was to test the physical compatibility of the main drugs of this list used in pairs in Y-site infusions in critical care units, in order to provide new compatibility data to the literature, and to secure the administration of intravenous drugs.

Methods

The physical compatibility in Y-site of nine drugs with other drugs commonly used in intensive care units has been tested. Examinations were performed on 75 mixtures after their preparation, after 1 and 4-h storage. This evaluation included a visual examination with a search for precipitation formation, color change, gas formation, and a subvisual evaluation: absorbance measurements by UV-visible spectrophotometry at 350, 410 and 550 nm, and Light Obscuration Particle Count Test. The pH evaluation was performed at each time of analysis.

Results

Laboratory tests led to an overall compatibility of 68.0% for all mixtures obtained in this study. Nefopam was found to be quite compatible with other drugs (95.0%). Amiodarone hydrochloride (84.6%), acetylsalicylic acid (80.0%), clonidine hydrochloride (75.0%) and insulin (71.4%) were compatible with other drugs too. Atenolol (42.9%), furosemide (25.0%), heparin sodium (25.0%) showed less compatible results. Pantoprazole sodium (0.0%) was not at all compatible with the other drugs analyzed.

Conclusions

By the results of these laboratory tests, missing compatibility data are now available, providing additional information to the literature.

Introduction

The intravenous (IV) route is the most common way of drug administration used in intensive care units (ICUs). Indeed, patients hospitalized in these units often require numerous infusions, due to their serious health conditions.

High concentrations of drugs are usually needed to limit the water intake and the infusion volume, using the minimum of IV accesses, as these are limited. For this reason, in most cases multiple IV drugs are administered simultaneously to patients in the same infusion line. For administrations in Y-site, compatibility tests must have been carried out and reliable data should be published in the literature, because incompatibility between drugs can lead to complications for the patient. A physical incompatibility between two drugs can be observed by the formation of a precipitate, a change in color, or the formation of gas [1, 2]. The formation of a precipitate may lead to catheter obstruction, venous irritation and pulmonary renal embolism [3]. In most cases, no physical compatibility data is available in the literature, while incompatibilities are one of the leading causes of IV medication errors in hospital with 25% of errors, including 2% of several clinical adverse effects [4]. Compatibility studies of Y-site administration are available in the literature, but many data are lacking. D’Huart et al. [5] performed an observational study in three different ICUs and have highlighted that in most cases (62.7%), physical compatibility data were missing from the literature.

The objective of this study was to test the physical compatibility of the main drugs of the list used in pairs in Y-site infusions in ICUs, in order to provide new compatibility data to the literature and to secure the administration of intravenous drugs.

Materials and methods

Compatibility tests were performed for drugs with the least data in the literature, according to three main databases: the 19th edition of the Handbook on Injectable Drugs® [6], Stabilis® [7] and the 36th edition of “Stability of injectable drugs in infusion” [8]. These tests were carried out on IV drugs the most frequently administered together in ICUs, reported in d’Huart’s observational thesis [9].

To simulate Y-site infusion, the physical compatibility of parenteral drugs was evaluated in pairs, even if more than two drugs were commonly administered simultaneously in the same IV line.

Each mixture was carried out according to data from d’Huart’s thesis [9]. Each drug was diluted in a solvent (water for injection (WFI), 0.9% sodium chloride (0.9% NaCl), 5% dextrose (D5W), 10% dextrose (D10W), Isofundine® (sodium chloride, potassium chloride, magnesium chloride, calcium chloride) or used pure, according to practices observed in ICUs in this previous work. When the solvent or the concentration of a drug was different between the three ICUs of the hospital, different variables were tested.

Each drug from each pair tested was prepared separately at the baseline. The drugs were reconstituted in their vials or used directly without prerequisite, according to their drug formulation and the corresponding summary of product characteristics. For the preparation of drugs, luer-lock polypropylene syringes identical to those used in ICUs were employed. Dilution with a specific solvent was obtained by using a Vygon® “female luer-lock to female luer-lock connector” between the drug syringe and the solvent syringe. For each pair of a main drug with another drug (drug A/drug B) tested, three ratios (9/1, 1/1 and 1/9) [1] were studied, allowing to simulate cases where the drug flow is different leading to higher or lower concentrations. Drugs were mixed in a 50 mL graduated flask and manually stirred during 30 s. They were kept at room temperature from 20 to 25 °C, upright and not protected from light, to simulate the storage conditions applied in ICUs.

Visual and subvisual evaluations

At each moment of the study, a visual evaluation was carried out on a white and a black background with a flashlight, with the unaided eye by two different technicians, before mixing, after mixing and after 1- and 4-h storage as recommended by the European Consensus Conference [1].

The subvisual aspect was analyzed by measuring the turbidity using a UV-visible spectrophotometer (SAFAS mc2, Monaco). This method allows to evaluate the formation of microparticles in solution. The absorbance light was scanned at three wavelengths (350, 410 and 550 nm), also recommended by the European Consensus Conference [1]. A change in the initial absorbance of more than 0.1 between the measurement after mixing and after the 4-h of storage was considered as a turbidity and so incompatibility of the two drugs involved.

A second subvisual test was performed applying the Light Obscuration Particle Count Test (PAMAS SVSS). The particle counter is based on the principle of light blocking which allows the automatic determination of the number of particles according to their size. Requirements exist for the number of particles larger than 10 µm and larger than 25 µm. According to European Pharmacopoeia Reference Standards [10], for containers of ≤100 mL, the values to be respected were ≤6,000 particles of ≥10 µm and ≤600 particles of ≥25 µm per container. For containers of >100 mL, the values were ≤25 particles of ≥10 µm per milliliter and ≤3 particles of ≥25 µm per milliliter. Measurements were carried out in 10 mL glass tubes. Before each measurement, the outer surfaces of the glass tube were cleaned with a water jet from E-POD® “Pure Water Remote Dispenser”. Before proceeding with particle counting, the contents of each sample were mixed by 20 successive slow inversions of the container, then the mixture was left to stand for 2 min to avoid the possible presence of bubbles which may be generated by agitation. A first portion of 1 mL of the mixture was removed and the number of particles was evaluated on the three next portions of 1 mL. The mean number of particles of these three portions (total volume of 3 mL) represented the number of particles in the mixture. Between each measurement, the particle counter tubing was flushed with two portions of 1 mL of water from the E-POD® “Pure Water Remote Dispenser”. Measurements for each pair were repeated three times and the mean number represented the particle count.

The last test performed at any time was the pH measurement (Bioblock Scientific pH meter) of each solitary drug before it was combined, and then after having mixed the drugs in pairs. For each pair, the pH had to show no change of more than 0.5 pH unit within 4 h to be stable.

These compatibility tests were assessed at different times: after mixing the two drugs (T 0H), 1 h after preparation (T 1H), and after a 4-h storage (T 4H), as 60% of the compatibility studies published in the literature are carried out over a 4-h period [11].

Results

Seventy-five mixtures involving nine main drugs and 34 other drugs commonly used in ICUs were evaluated. Table 1 gives the list of all the drugs tested in Y-site and the solvents used. The pairwise compatibility results are all presented in Table 2, which shows the details of combinations evaluated.

Table 1:

List of drugs and solvents used for laboratory tests.

Tradename Dosage Laboratory Batchs
Main drugs
Acetylsalicylic acid ASPEGIC INJECTABLE 500 mg/5 mL 500 mg Sanofi Aventis HY202/J710A
Amiodarone hydrochloride CORDARONE 150 mg/3 mL sol inj 150 mg/3 mL Sanofi Aventis H1963/J0860
Atenonol TENORMINE 5 mg/10 mL sol inj 5 mg/10 mL Astrazeneca F1016-1/F1021-1
Clonidine hydrochloride CATAPRESSAN 0.15 mg/mL sol inj 0.15 mg/1 mL Boehringer Ingelheim C13508/C13509
Furosemide FUROSEMIDE RENAUDIN 20 mg/2 mL sol inj 20 mg/2 mL Renaudin 207536/207685
Heparin sodium HEPARINE CHOAY 5000 UI/1 mL sol inj 5000 IU/1 mL Labo Choay AA003A
Heparin sodium HEPARINE CHOAY 25 000 UI/5 mL sol inj 25000 IU/5 mL Labo Choay 676
Insulin (human) UMULINE RAPIDE 100 UI/mL sol inj 100 IU/1 mL Lilly D257313/D262785
Nefopam ACUPAN 20 mg/2 mL sol inj 20 mg/2 mL Biocodex D8004
Pantoprazole sodium EUPANTOL 40 mg pdre p sol inj 40 mg Takeda 479857/488939
Other drugs
Bumetanide BURINEX 2 mg/4 mL sol inj 2 mg/4 mL Karo Pharma AD F1032FP1
Calcium chloride CHLORURE DE CALCIUM RENAUDIN 10% sol inj 1 g/10 mL Renaudin 207379
Cefazoline sodium CEFAZOLINE MYLAN 2 g pdre p sol inj IM IV 2 g Mylan 200520
Cefotaxime sodium CEFOTAXIME MYLAN 2 g pdre p sol inj 2 g Mylan 200656/200935/200936
Ciclosporine SANDIMMUN 50 mg/mL sol diluer p perf 50 mg/1 mL Novartis SAS SVP16/SCCU8
Furosemide FUROSEMIDE RENAUDIN 20 mg/2 mL sol inj 20 mg/2 mL Renaudin 207242
Hydrocortisone sodium succinate HYDROCORTISONE UPJOHN 100 mg prép inj 100 mg Serb 2708-W2T30/2685-W2T28/3012-W2S87/3012-W2T47
Insulin (human) UMULINE RAPIDE 100 UI/mL sol inj 100 IU Lilly D262785/D257313
Isofundine® ISOFUNDINE sol p perf 500 mL Renaudin 20045454/21084452
Isosorbide dinitrate ISOSORBIDE MEDISOL 10 mg/10 mL sol inj 10 mg/10 mL Medisol Labo H028/H025/H030
Levetiracetam LEVETIRACETAM MYLAN 100 mg/mL, solution à diluer pour perfusion 100 mg/1 mL Mylan 5002235/5002260
Levofloxacine hemihydrate LEVOFLOXACINE ARROW 5 mg/mL sol p perf en poche 250 mg/50 mL Arrow 156
Levofloxacine hemihydrate LEVOFLOXACINE ARROW 5 mg/mL sol p perf en poche 500 mg/100 mL Arrow 43
Magnesium sulfate SULFATE DE MAGNESIUM PROAMP 0.15 g/mL, solution injectable 1.5 g Chaix et du Marais 0P207/0P208/0P138/0P189/0P189/1 P100
Methylprednisolone hemisuccinate METHYLPREDNISOLONE MYLAN 20 mg, poudre pour solution injectable 20 mg Mylan B1156/206450/B1165
Metronidazole METRONIDAZOLE B BRAUN 0.5%, solution pour perfusion 500 mg Braun Medical 200738131
Midazolam hydrochloride MIDAZOLAM MYLAN 50 mg/10 mL sol inj 50 mg/10 mL Mylan F3573/F3585
Mycophenolate mofetil hydrochloride CELLCEPT 500 mg pdre p sol diluer p perf 500 mg Roche H3541/H3549/B8022
Nefopam ACUPAN 20 mg/2 mL sol inj 20 mg Biocodex D777/D783/D787/D798/H1047
Nicardipine NICARDIPINE ARROW 10 mg/10 mL sol inj 10 mg/10 mL Arrow 173
Nutryelt® NUTRYELT sol diluer p perf 10 mL Aguettant D0023A01/D0025A07
Pantoprazole sodium EUPANTOL 40 mg pdre p sol inj IV 40 mg Takeda 490195
Paracetamol PARACETAMOL B. BRAUN 10 mg/mL, solution pour perfusion 1 g/100 mL Braun Medical 20501450/20427451/20504452/20352453/21104453
Phloroglucinol PHLOROGLUCINOL/TRIMETHYLPHLOROGLUCINOL ARROW 40 mg/0.04 mg/4 mL sol inj 40 mg, 0.04 mg/4 mL Arrow 1163 / 1173 / 1177
Phytomenadione VITAMINE K1 CHEPLAPHARM 10 mg/1 mL sol buv/inj 10 mg/1 mL Cheplapharm F4029F01/F4046F03/F4061F02
Potassium canreonate SOLUDACTONE 200 mg, lyophilisat et solution pour usage parentéral 200 mg Pfizer 25A29D711
Potassium chloride CHLORURE DE POTASSIUM LAVOISIER 10% (0.10 g/mL) sol diluer p perf 2 g/20 mL Lavoisier 9P266/0P213
Pyridoxine hydrochloride PYRIDOXINE RENAUDIN 250 mg/5 mL sol inj 250 mg/5 mL Renaudin 207731
Remifentanil hydrochloride ULTIVA 2 mg pdre p sol inj ou perf 2 mg Aspen 9F7C/7H2N
Sodium selenite SELENIUM INJECTABLE 10 μg/mL sol diluer p perf 100 µg/10 mL Aguettant 4505451/G0136A01/105152
Spiramycine adipate ROVAMYCINE 1,5 MUI lyoph p us parentér 1.5 M IU Sanofi Aventis A5170
Thiamine hydrochloride BEVITINE 100 mg/2 mL sol inj 100 mg/2 mL DB Pharma F1441/F1138/F1142/F1143/F1145/F1146/F1154/F1155
Tramadol hydrochloride CONTRAMAL 100 mg/2 mL sol inj 100 mg/2 mL DB 00071S
Urapidil URAPIDIL STRAGEN 50 mg/10 mL sol inj 50 mg/10 mL Stragen F2112-01/F2101-01/F7130-02
Vancomycine hydrochloride VANCOMYCINE MYLAN 500 mg pdre p sol diluer p perf 500 mg Mylan B1601
Vancomycine hydrochloride VANCOMYCINE MYLAN 1000 mg pdre p sol diluer p perf 1 g Mylan B2398/B2434
Solvents
Water for injection EAU POUR PREPARATIONS INJECTABLES LAVOISIER sol ppi 250 mL Chaix et du Marais 8F447
Water for injection EAU POUR PREPARATIONS INJECTABLES LAVOISIER sol ppi 500 mL Chaix et du Marais 0F632
5% Dextrose GLUCOSE LAVOISIER 5% sol p perf 250 mL Chaix et du Marais 9F591
5% Dextrose GLUCOSE B BRAUN 5% sol p perf 250 mL Macopharma 19I27A/20H31B
0.9% Sodium chloride CHLORURE DE SODIUM 0.9% LAVOISIER sol p perf 500 mL Chaix et du Marais 0F648
0.9% Sodium chloride CHLORURE DE SODIUM 0.9% LAVOISIER sol p perf 250 mL Chaix et du Marais 0F654
0.9% Sodium chloride CHLORURE DE SODIUM B BRAUN 0.9% sol p perf 250 mL Macopharma 20C05C/20B11D
Isofundine® ISOFUNDINE sol p perf 500 mL B Braun 20442452/173338131/2000685/21084452
10% Dextrose GLUCOSE B BRAUN 10% sol p perf 500 mL B Braun 21063406

Table 2:

Mixtures of drugs performed in this study and results of compatibility.

Drugs Concentration Solvent Initial pH drugs value Initial pH mixtures value (9/1, 1/1, 1/9) Results Type of incompatibility
1 Acetylsalicylic acid 5 mg/mL 0.9% NaCl 5.27 7.28/7.98/8.62 Incompatible Precipitation at 9/1 and 1/1 ratios
Potassium canreonate 10 mg/mL 0.9% NaCl 8.92
2 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.29/5.33/5.35 Physically compatible
Isofundine® 5.35
3 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.24/5.22/5.23 Physically compatible
Potassium chloride 100 mg/mL None 5.61
4 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.24/5.24/5.23 Physically compatible
Insulin (human) 1 IU/mL 0.9% NaCl 5.44
5 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.16/5.15/5.07 Physically compatible
Magnesium sulfate 6 mg/mL 5% Dextrose 4.58
6 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.28/5.25/5.23 Physically compatible
Nefopam 80 μg/mL 0.9% NaCl 5.24
7 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.06/4.63/3.86 Incompatible Pink at 9/1 and 1/1 ratios
Nutryelt® 0.9% NaCl 3.22
8 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.01/5.45/6.83 Physically compatible
Hydrocortisone sodium succinate 2 mg/mL 0.9% NaCl 7.35
9 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.23/5.26/5.45 Physically compatible
Phytomenadione 0.2 mg/mL 0.9% NaCl 5.61
10 Acetylsalicylic acid 10 mg/mL 0.9% NaCl 5.27 5.07/4.77/4.23 Physically compatible
Thiamine hydrochloride 1 mg/mL 0.9% NaCl 3.65
11 Amiodarone hydrochloride 3 mg/mL 5% Dextrose 4.10 4.37/5.61/6.62 Physically compatible Particle count at the 9/1 ratio*
Bumetanide 0.2 mg/mL 0.9% NaCl 6.78
12 Amiodarone hydrochloride 3 mg/mL 5% Dextrose 4.10 4.40/4.89/4.98 Incompatible Whitish at the 1/1 ratio and opalescent at the 1/9 ratio. Turbidity at 1/1 and 1/9 ratios
Cefazolin sodium 40 mg/mL 5% Dextrose 5.01
13 Amiodarone hydrochloride 9 mg/mL 5% Dextrose 4.10 4.36/5.05/5.20 Physically compatible Particle count at all ratios*
Cefotaxime sodium 40 mg/mL 5% Dextrose 5.23
14 Amiodarone hydrochloride 3 mg/mL 5% Dextrose 4.10 4.18/4.47/5.11 Physically compatible Particle count at 9/1 and 1/1 ratios*
Potassium chloride 100 mg/mL None 6.44
15 Amiodarone hydrochloride 18 mg/mL 5% Dextrose 4.10 4.37/5.1/7.21 Incompatible Whitish at the 1/9 ratio at T 4H. Turbidity at the 1/9 ratio
Furosemide 5 mg/mL 0.9% NaCl 8.72
16 Amiodarone hydrochloride 9 mg/mL 5% Dextrose 4.10 4.24/5.44/6.52 Physically compatible Particle count at 9/1 and 1/1 ratios*
Hydrocortisone sodium succinate 2 mg/mL 0.9% NaCl 7.47
17 Amiodarone hydrochloride 6 mg/mL 5% Dextrose 4.10 3.90/4.21/4.71 Physically compatible Particle count at 9/1 and 1/1 ratios*
Insulin (human) 1 IU/mL 0.9% NaCl 5.83
18 Amiodarone hydrochloride 3 mg/mL 5% Dextrose 4.10 4.10/4.59/4.78 Physically compatible
Levofloxacine hemihydrate 5 mg/mL None 4.82
19 Amiodarone hydrochloride 9 mg/mL 5% Dextrose 4.10 4.84/5.26/5.31 Physically compatible Particle count at 9/1 and 1/1 ratios*
Magnesium sulfate 1.5 mg/mL Isofundine® 5.32
20 Amiodarone hydrochloride 9 mg/mL 5% Dextrose 4.10 4.78/5.23/5.29 Physically compatible Particle count at the 9/1 ratio*
Nefopam 160 μg/mL Isofundine® 5.29
21 Amiodarone hydrochloride 18 mg/mL 5% Dextrose 4.10 4.27/4.61/4.84 Physically compatible Particle count at the 9/1 ratio*
Paracetamol 10 mg/mL None 5.09
22 Amiodarone hydrochloride 3 mg/mL 5% Dextrose 4.10 3.91/3.77/3.71 Physically compatible Particle count at the 9/1 ratio*
Thiamine hydrochloride 2 mg/mL 0.9% NaCl 3.9
23 Amiodarone hydrochloride 9 mg/mL 5% Dextrose 4.10 3.64/3.37/3.27 Physically compatible Particle count at 9/1 and 1/1 ratios*
Vancomycine hydrochloride 31.3 mg/mL 5% Dextrose 3.24
24 Atenolol 100 μg/mL 0.9% NaCl 5.91 5.96/6.25/6.82 Incompatible Non- compliant particle count at all ratios except for 1/9 at T4H
Ciclosporine 10 mg/mL 5% Dextrose 6.98
25 Atenolol 100 μg/mL 0.9% NaCl 5.91 5.91/5.97/6.45 Physically compatible
Methylprednisolone hemisuccinate 200 μg/mL 0.9% NaCl 7.05
26 Atenolol 50 μg/mL 0.9% NaCl 5.91 5.63/5.24/4.92 Incompatible Non-compliant particle count at the 9/1 ratio at T 0H and T1H
Metronidazole 5 mg/mL None 4.85
27 Atenolol 100 μg/mL 0.9% NaCl 5.91 5.72/5.05/4.25 Incompatible Haze at the 1/1 ratio
Mycophenolate mofetil 10 mg/mL 5% Dextrose 3.75
28 Atenolol 100 μg/mL NaCl 0.9% 5.91 5.63/4.67/3.39 Incompatible Slightly yellow color*
Nutryelt® - 0.9% NaCl 3.18
29 Atenolol 100 μg/mL 0.9% NaCl 5.91 5.86/5.27/4.17 Physically compatible
Thiamine hydrochloride 1 mg/mL 0.9% NaCl 4.59
30 Atenolol 100 μg/mL 0.9% NaCl 5.91 5.96/5.99/6.02 Physically compatible
Urapidil 5 mg/mL None 6.03
31 Clonidine hydrochloride 12.5 μg/mL 0.9% NaCl 5.10 5.72/6.76/7.00 Incompatible Non-compliant particle count at the 1/9 ratio
Methylprednisolone hemisuccinate 0.2 mg/mL 0.9% NaCl 7.13
32 Clonidine hydrochloride 12.5 μg/mL 0.9% NaCl 5.10 4.26/3.97/3.86 Physically compatible Particle count at 1/1 and 1/9 ratios*
Mycophenolate mofetil hydrochloride 10 mg/mL 5% Dextrose 3.84
33 Clonidine hydrochloride 12.5 μg/mL 0.9% NaCl 5.10 4.23/3.89/3.77 Physically compatible
Thiamine hydrochloride 1 mg/mL 5% Dextrose 3.76
34 Clonidine hydrochloride 12.5 μg/mL 0.9% NaCl 5.10 5.85/5.99/6.09 Physically compatible
Urapidil 5 mg/mL None 6.13
35 Furosemide 10 mg/mL None 8.96 8.24/5.49/5.49 Incompatible Turbidity at the 1/1 ratio
Magnesium Sulfate 6 mg/mL Isofundine® 5.26
36 Furosemide 10 mg/mL None 8.96 6.71/6.01/5.50 Incompatible Turbidity at 1/1 and 1/9 ratios. Opalescence at 1/9
Nefopam 1.7 mg/mL 0.9% NaCl 5.40
37 Furosemide 10 mg/mL None 8.96 8.37/6.02/5.34 Physically compatible
Paracetamol 10 mg/mL None 5.21
38 Furosemide 10 mg/mL None 8.96 7.69/7.03/6.87 Incompatible Whiteness and turbidity at the 1/1 ratio. Opalescence at the 9/1 ratio.
Spiramycine adipate 60 mIU/mL 0.9% NaCl 6.86
39 Heparin sodium 208.3 IU/mL 0.9% NaCl 5.90 5.69/5.52/5.49 Incompatible Non-compliant particle count at the 1/9 ratio at T 0H and T1H
Levetiracetam 15 mg/mL 0.9% NaCl 5.51
40 Heparin sodium 208.3 IU/mL 0.9% NaCl 5.90 5.06/4.28/3.69 Incompatible Non-compliant particle count at 1/1 and 1/9 ratios at T 0H and T1H
Midazolam hydrochloride 1 mg/mL 0.9% NaCl 3.65
41 Heparin sodium 208.3 IU/mL 0.9% NaCl 5.90 5.50/5.45/5.43 Incompatible Non-compliant particle count at the 1/9 ratio at T 0H and T1H
Nefopam 1.7 mg/mL 0.9% NaCl 5.43
42 Heparin sodium 208.3 IU/mL 0.9% NaCl 5.90 5.19/5.01/5.04 Physically compatible
Paracetamol 10 mg/mL 0.9% NaCl 5.12
43 Insulin (human) 1 IU/mL 0.9% NaCl 5.60 5.69/5.56/5.58 Physically compatible
Isosorbide dinitrate 1 mg/mL None 5.53
44 Insulin (human) 1 IU/mL 0.9% NaCl 5.60 5.42/5.40/5.41 Physically compatible
Nefopam 160 μg/mL Isofundine® 5.36
45 Insulin (human) 1 IU/mL 0.9% NaCl 5.60 5.78/5.14/5.09 Physically compatible
Paracetamol 10 mg/mL None 5.16
46 Insulin (human) 1 IU/mL 0.9% NaCl 5.60 8.9/9.50/9.68 Incompatible Turbidity at the 1/9 ratio
Pantoprazole sodium 1 mg/mL None 9.70
47 Insulin (human) 2 IU/mL 0.9% NaCl 5.60 4.56/3.55/3.20 Physically compatible
Phloroglucinol 10 mg/mL None 3.11
48 Insulin (human) 3 IU/mL 0.9% NaCl 5.60 4.49/3.78/3.59 Incompatible Non-compliant particle count: T 0H at all ratios, T 1H at 1/1 and 1/9, T 4H at 1/9
Remifentanil hydrochloride 100 μg/mL 0.9% NaCl 3.58
49 Insulin (human) 3 IU/mL 0.9% NaCl 5.60 5.79/5.77/5.80 Physically compatible
Sodium Selenite 1 μg/mL 0.9% NaCl 6.22
50 Nefopam 160 μg/mL Isofundine® 5.32 5.28/5.02/4.41 Physically compatible
Nicardipine hydrochloride 1 mg/mL None 3.61
51 Nefopam 160 μg/mL 0.9% NaCl 5.32 4.21/3.60/3.57 Physically compatible
Nicardipine hydrochloride 1 mg/mL None 3.61
52 Nefopam 160 μg/mL Isofundine® 5.32 5.29/5.27/5.18 Physically compatible
Pyridoxine hydrochloride 0.5 mg/mL Isofundine® 5.15
53 Nefopam 160 μg/mL 0.9% NaCl 5.32 5.21/5.12/5.06 Physically compatible
Pyridoxine hydrochloride 0.5 mg/mL Isofundine® 5.15
54 Nefopam 160 μg/mL 0.9% NaCl 5.32 4.92/4.11/3.90 Physically compatible
Pyridoxine hydrochloride 0.5 mg/mL 0.9% NaCl 5.15
55 Nefopam 160 μg/mL Isofundine® 5.32 5.33/5.25/5.23 Physically compatible
Thiamine hydrochloride 0.5 mg/mL Isofundine® 3.89
56 Nefopam 160 μg/mL 0.9% NaCl 5.32 5.23/5.21/5.20 Physically compatible
Thiamine hydrochloride 0.5 mg/mL Isofundine® 3.89
57 Nefopam 160 μg/mL 0.9% NaCl 5.32 5.10/4.32/3.93 Physically compatible
Thiamine hydrochloride 0.5 mg/mL 0.9% NaCl 3.95
58 Nefopam 160 μg/mL 0.9% NaCl 5.32 5.55/5.64/5.85 Physically compatible
Tramadol hydrochloride 6.3 mg/mL 0.9% NaCl 6.79
59 Nefopam 160 μg/mL 0.9% NaCl 5.32 5.27/5.18/5.20 Incompatible Non-compliant particle count at the 1/9 ratio
Cefotaxime sodium 40 mg/mL 5% Dextrose 5.26
60 Nefopam 80 μg/mL Isofundine® 5.32 5.39/5.39/5.38 Physically compatible
Calcium chloride 2 mg/mL Isofundine® 5.44
61 Nefopam 80 μg/mL 0.9% NaCl 5.32 5.46/5.39/5.37 Physically compatible
Calcium chloride 2 mg/mL Isofundine® 5.46
62 Nefopam 80 μg/mL 0.9% NaCl 5.32 5.70/5.80/6.15 Physically compatible
Calcium chloride 2 mg/mL 0.9% NaCl 5.46
63 Nefopam 160 μg/mL Isofundine® 5.32 5.38/5.51/6.64 Physically compatible
Hydrocortisone sodium succinate 2 mg/mL 0.9% NaCl 7.55
64 Nefopam 160 μg/mL 0.9% NaCl 5.32 5.98/6.62/7.28 Physically compatible
Hydrocortisone sodium succinate 2 mg/mL 0.9% NaCl 7.55
65 Nefopam 2.5 mg/mL 0.9% NaCl 5.32 5.49/5.54/5.62 Physically compatible
Isosorbide dinitrate 1 mg/mL None 5.65
66 Nefopam 160 μg/mL Isofundine® 5.32 5.36/5.36/5.34 Physically compatible
Magnesium sulfate 3 mg/mL 10% Dextrose 4.89
67 Nefopam 160 μg/mL 0.9% NaCl 5.32 5.58/5.35/4.90 Physically compatible
Magnesium sulfate 3 mg/mL 10% Dextrose 4.89
68 Nefopam 160 μg/mL Isofundine® 5.32 5.36/5.35/5.32 Physically compatible
Magnesium sulfate 4.5 mg/mL 10% Dextrose 4.93
69 Nefopam 160 μg/mL Isofundine® 5.32 5.57/5.37/4.99 Physically compatible
Magnesium sulfate 4.5 mg/mL 0.9% NaCl 4.93
70 Pantoprazole sodium 80 μg/mL 0.9% NaCl 9.70 7.70/6.18/4.76 Incompatible Yellowish at 1/1 and 1/9 ratios at T 4H. Turbidity at the 1/9 ratio
Paracetamol 10 mg/mL None 4.74
71 Pantoprazole sodium 4 mg/mL 0.9% NaCl 9.70 5.56/4.02/3.17 Incompatible Orange at all ratios at T 1H. Precipitation at 9/1. Turbidity at 1/1 and 1/9 ratios
Pyridoxine hydrochloride 2.5 μg/mL 0.9% NaCl 2.84
72 Pantoprazole sodium 4 mg/mL 0.9% NaCl 9.70 9.72/9.59/9.17 Incompatible Turbidity at 9/1 and 1/1 ratios
Sodium Selenite 1 μg/mL 0.9% NaCl 5.32
73 Pantoprazole sodium 4 mg/mL 0.9% NaCl 9.70 9.36/8.56/4.82 Incompatible Orange at the 1/9 ratio at T 4H. Turbidity at the 1/9 ratio
Thiamine hydrochloride 1 mg/mL 0.9% NaCl 3.75
74 Pantoprazole sodium 4 mg/mL 0.9% NaCl 9.70 9.67/9.54/8.93 Incompatible Non-compliant particle count at all ratios
Phytomenadione 200 μg/mL 0.9% NaCl 5.80
75 Pantoprazole sodium 4 mg/mL 0.9% NaCl 9.70 9.50/8.80/8.10 Incompatible Precipitation and turbidity at all ratios at T 1H and T 4H
Phloroglucinol 400 μg/mL 0.9% NaCl 4.57

  1. *Method of Particle counter non applicable to amiodarone hydrochloride and mycophenolate mofetil because of the production of gas bubbles induced by polysorbate 80.

Acetylsalicylic acid

Acetylsalicylic acid is a drug compatible in pairs with 80.0% (8/10) of the drugs tested presented in Table 2. The acetylsalicylic acid/potassium canreonate mixture was incompatible because of visible precipitation at the 9/1 ratio after preparation and at the 1/1 ratio after a 1-h storage. Practices also revealed the frequent combination of acetylsalicylic acid with Nutryelt®, which is a nutritional intake of micro-nutrients: iron, copper, manganese, zinc, fluorine, iodine, selenium, chromium, molybdenum [12]. The acetylsalicylic acid/Nutryelt® combination in pair was pink at 9/1 and 1/1 ratios after the preparation within 4 h, while the ordinary Nutryelt® color is yellow. In the absence of chemical data and by applying the precautionary principle, this mixture was considered incompatible.

Amiodarone hydrochloride

Results for mixtures of amiodarone hydrochloride with other drugs tested were 84.6% compatible (11/13). The amiodarone hydrochloride/cefazolin mixture at 1/1 and 1/9 ratios demonstrated turbidity at all times of analysis. The absorbance variation between T 0H and T 4H was 0.48 at 350 nm, 1.29 at 410 nm and 1.10 at 550 nm at the 1/1 ratio and 0.37 at 350 nm, 0.23 at 410 nm and 0.12 at the 1/9 ratio. Figure 1 shows that the mixture was whitish at the 1/1 ratio and opalescent at the 1/9 ratio from T 0H and at each time of analysis. The amiodarone hydrochloride/furosemide mixture was whitish at the 1/9 ratio at all times studied and also exhibited turbidity. The absorbance variation between T 0H and T 4H was 1.42 at 410 nm and 1.71 at 550 nm to the 1/9 ratio. These mixtures were also considered incompatible and should be administered separately.

Figure 1: 
The amiodarone hydrochloride – cefazolin sodium pair was whitish at the 1/1 ratio (in the middle) and opalescent at the 1/9 ratio (right) at T 0H.

Figure 1:

The amiodarone hydrochloride – cefazolin sodium pair was whitish at the 1/1 ratio (in the middle) and opalescent at the 1/9 ratio (right) at T 0H.

Some mixtures with amiodarone hydrochloride were visually and at spectrophotometer compatible, while subvisual particles were counted. In this situation, it concerned mixtures with bumetanide, cefotaxime sodium, potassium chloride, hydrocortisone sodium succinate, insulin, magnesium sulfate, nefopam, paracetamol, thiamine and vancomycine hydrochloride, detailed in Table 2. These poor particle counter results could be correlated to the production of gas bubbles in solution induced by polysorbate 80 in amiodarone hydrochloride which should not be considered as a particulate contamination. These results by the particle counter were also not interpretable, because this method was unsuitable to mixtures containing amiodarone hydrochloride [10]. Eur Ph suggests the use of method 2 (microscopic evaluation) for these preparations. This technic was not available in our laboratory, however, according to the absence of turbidity nor visible particle, these 10 mixtures were considered as physically compatible.

Atenolol

Regarding drugs mixed with atenolol, only 3/7 pairs (42.9%) were compatible. The atenolol/mycophenolate mofetil mixture showed a haze at the 1/1 ratio from T 1H. The atenolol/Nutryelt® pair was incompatible because of the slightly yellow color of the mixture for the same reason as the acetylsalicylic acid Nutryelt® pair. More than 6,000 particles of ≥10 µm were counted by the particle counter in the container of the atenolol/ciclosporine pair at all ratios at all times studied, except for the 1/9 ratio at T 4H. According to European Pharmacopoeia Recommendations, it caused the incompatibility of these two drugs in the same IV line. For the atenolol/metronidazole mixture, more than 6,000 particles of ≥10 µm per container were also counted at the 9/1 ratio at T 0H and T 1H. These three mixtures containing atenolol were also not considered to be physically compatible and should not be administered in the same infusion line.

Clonidine hydrochloride

Clonidine hydrochloride results were compatible for 50.0% of the mixtures tested (3/4). The clonidine hydrochloride/methylprednisolone pair was incompatible due to particle count at the 1/9 ratio outside of European Pharmacopeia Recommendations at each time of the analysis. The clonidine hydrochloride/mycophenolate mofetil mixture showed more than 6,000 subvisible particles of ≥10 µm and more than 600 subvisible particles of ≥25 µm per container at 1/1 and 1/9 ratios at each time. As amiodarone hydrochloride, mycophenolate mofetil contains polysorbate 80 in its excipients producing gas bubbles, which could distort results by the light obscuration particle test. Excluding the particle counter results which were not operable, this mixture was physically compatible by spectrophotometry and by the visual evaluation.

Furosemide

Among the mixtures tested with furosemide, only the furosemide/paracetamol pair was compatible, representing 25.0% of the mixtures (1/4). Opalescence and white mixtures were observed for the three other pairs. The furosemide/magnesium sulfate pair showed turbidity at the 1/1 ratio with an absorbance variation of 0.43 from T 0H to T 4H at 550 nm. For the furosemide/nefopam pair, the absorbance variation from T 0H to T 4H was 0.19 at 410 nm and 0.45 at 550 nm at the 1/9 ratio and 1.93 at 550 nm at the 1/1 ratio. This mixture showed whiteness at the 1/1 ratio and opalescence at the 1/9 ratio after the preparation, visible on Figure 2. The mixture furosemide/spiramycine was white and produced haze at the 1/1 ratio with an absorbance variation of 0.78 at 410 nm and of 0.56 at 550 nm from T 0H to T 4H. This pair was opalescent at the 9/1 ratio. The subvisual evaluation made it possible to classify the pairs of furosemide/magnesium sulfate, furosemide/nefopam and furosemide/spiramycine as incompatible mixtures for the concentrations studied.

Figure 2: 
For the furosemide – nefopam mixture, the 1/9 ratio (right) was opalescent and the 1/1 ratio (in the middle) was whitish after its preparation (T 0H).

Figure 2:

For the furosemide – nefopam mixture, the 1/9 ratio (right) was opalescent and the 1/1 ratio (in the middle) was whitish after its preparation (T 0H).

Heparin sodium

The heparin sodium/paracetamol pair was the only pair with heparin sodium that was physically compatible (25.0%, 1/4). Other results for heparin sodium mixtures were wrong. The heparin sodium/levetiracetam mixture suggested the presence of subvisual incompatibility at the 1/9 ratio at T 0H and T 1H with more than 6,000 subvisible particles of ≥10 µm per container counted, same for the heparin sodium/midazolam pair at 1/1 and 1/9 ratios at T 0H and T 1H, and for the heparin sodium/nefopam pair at the 1/9 ratio at T 0H and T 1H. Based on European Pharmacopeia Recommendations, these three pairs could not be considered as compatible even if the results of the particle counter at T 4H were in conformity, because in practice, the mixture of drugs is supposed to be infused to the patient after its preparation.

Insulin

Regarding the mixtures made with insulin, 71.4% of them were compatible (5/7). The insulin/pantoprazole sodium pair was incompatible because of haze at the 1/9 ratio showing an absorbance variation of 0.46 at 350 nm from T 0H to T 4H. The insulin/remifentanil pair was also incompatible because of more than 6,000 subvisible particles of ≥10 µm per container counted at T 0H at all ratios, T 1H at 1/1 and 1/9 ratios, and at T 4H at the 1/9 ratio.

Nefopam

Of the 20 mixtures made with nefopam, 95.0% were physically compatible (19/20). Only the nefopam/cefotaxime sodium pair was incompatible due to a count of more than 6,000 subvisible particles of ≥10 µm per container at the 1/9 ratio at each time of the analysis.

Pantoprazole sodium

None of the mixtures obtained with pantoprazole sodium were compatible (0/6). The pantoprazole sodium/paracetamol pair became yellow at 1/1 and 1/9 ratios at T 4H and presented turbidity at the 1/9 ratio with an absorbance variation of 0.24 at 350 nm and of 0.13 at 410 nm from T 0H to T 4H. The pantoprazole sodium/pyridoxine mixture changed from white to orange after a 1-h storage at all ratios, and precipitated at the 9/1 ratio, visible on Figure 3. This pair also was incompatible at the 1/1 ratio with an absorbance variation of 0.87 at 350 nm, 1.94 at 410 nm and 0.83 at 550 nm, and at the 1/9 ratio with a variation of 0.98 unit at 350 nm, 0.92 at 410 nm and 0.27 at 550 nm. The pantoprazole sodium/sodium selenite pair also showed turbidity at 9/1 and 1/1 ratios with an absorbance variation at the 9/1 ratio of 0.15 at 350 nm and at the 1/1 ratio of 0.13 at 350 nm, while no change was visible to the naked eye. The pantoprazole sodium/thiamine mixture became orange at the 1/9 ratio at T 4H and the absorbance variation at this ratio was 1.85 at 350 nm, 0.68 at 410 nm and 0.37 at 550 nm. The pantoprazole sodium/phloroglucinol pair precipitated at all ratios after a 1-h storage. The pantoprazole sodium/phytomenadione mixture produced more than 6,000 particles of ≥10 µm per container at all ratios and at each time of the analysis leading to the incompatibility of this mixture according to European Pharmacopeia Recommendations.

Figure 3: 
Pantoprazole sodium – pyridoxine turned from white to orange after a 1-h storage and precipitated at the 9/1 ratio (left: T 0H, middle: T 1H, right: T 4H).

Figure 3:

Pantoprazole sodium – pyridoxine turned from white to orange after a 1-h storage and precipitated at the 9/1 ratio (left: T 0H, middle: T 1H, right: T 4H).

Table 3 summarizes the results of combinations with these nine main drugs presented above and allows the conclusion of an overall compatibility of 68.0% for all the mixtures included in this study (51/75).

Table 3:

Summary of the overall compatibility for each main drug.

Main drugs Number of mixtures with other drugs Compatibility, %
Acetylsalicylic acid 10 8 80.0%
Amiodarone hydrochloride 13 11 84.6%
Atenonol 7 3 42.9%
Clonidine hydrochloride 4 3 75.0%
Furosemide 4 1 25.0%
Heparin sodium 4 1 25.0%
Insulin 7 5 71.4%
Nefopam 20 19 95.0%
Pantoprazole sodium 6 0 0.0%
Total 75 51 68.0%

Discussion

Use of main drugs in ICUs

Systemic anticoagulation such as acetylsalicylic acid reduces mortality in patients on mechanical ventilation, decreasing cardiovascular events and preventing organ failure [13].

Amiodarone hydrochloride is widely used in ICUs for the treatment of arrhythmias, especially since its use in combination is usually effective and safe [14].

Atenolol is a commonly used β-blocker in the treatment of cardiovascular diseases and to reduce the risk of re-infarction and the related mortality after myocardial infarction. Its cardioselectivity reduces the risk of inducing a respiratory deficiency problem, making atenolol a drug of first choice in ICUs [15].

Clonidine hydrochloride is usually used in ICUs for its sedative, analgesic and anxiolytic effects, outside of its approved indications [16]. It also gets combined with other drugs in the same IV route.

Furosemide is used in ICUs to reduce short-term patient mortality. It helps limiting excessive fluid gain, while excessive fluid administration in post-operative and post-traumatic patients is a common occurrence [17].

Injectable anticoagulation such as heparin sodium is one of the most commonly prescribed therapies in ICUs. A low dose of heparin sodium is often needed to prevent a venous disease, which can contribute to the deterioration of organ functions. Higher doses treat a venous disease or an acute coronary syndrome [18].

Critically ill patients frequently develop high levels of sugar in the blood. An intensive insulin therapy with a tight blood sugar control reduces patient mortality in ICUs [19].

Nefopam is a centrally acting non-opioid analgesic agent commonly used for patients admitted in ICUs getting mechanical ventilation and receiving sedative and analgesic medications. They are integral parts of the complex management of these patients, to minimize their discomfort and to reduce the risk of agitation and accidental self-extubation [20]. Nefopam could be a safe and effective pain reliever in regards with the high risk of organ vulnerability of patients [21].

Critically ill patients in ICUs are at risk of developing gastrointestinal bleeding due to mechanical ventilation and coagulopathy. A low dose of heparin sodium is often required to prevent a venous disease, which can contribute to the deterioration of organ functions and liver or kidney failure. Proton-pump inhibitors, such as pantoprazole sodium are the most commonly used prophylactic acid suppressants in these circumstances [22].

Observational study

In this study, only mixtures which were visually and subvisually compatible by UV-visible spectrophotometer were tested using the particle counter, otherwise they were physically incompatible and the latter was not performed.

Sometimes, Isofundine® was employed as a drug in combination with another drug, e.g., acetylsalicylic acid/Isofundine®, sometimes it was used as a solvent, e.g., for the dilution of nefopam. Tests were not repeated on different batches of medications.

For combinations with amiodarone hydrochloride and mycophenolate mofetil, the presence of polysorbate 80, as an excipient contained in the formulation of these two drugs, led to the production of gas bubbles which could have been wrongly detected as particles by the particle counter. The production of bubbles was not due to a particulate contamination. For this type of mixture producing bubbles, a more suitable particle counting method would be a Microscopic Particle Count Test [10].

Large differences in pH between two drugs studied in Y-site were noticed, shown in Table 2. Pantoprazole sodium (4 mg/mL in 0.9% NaCl) pH was 9.70, while the pH of other drugs mixed with pantoprazole sodium was between 2.84 and 5.80. All seven mixtures containing pantoprazole sodium were incompatible. Furosemide had also an alkaline pH of 8.96 (in pure solution at 10 mg/mL resulting in large differences of pH with other mixed drugs. Four of five mixtures containing furosemide were incompatible. The combination of two drugs with opposite pH can also be a cause of drug incompatibility which should dissuade us from mixing two drugs with distant pH unless their Y-site compatibility is certain. This hypothesis is currently under study in our laboratory.

Data available in the literature

An incompatibility with the Light Obscuration Particle Test could equally represent an evolution of size, shape or count of particles, while the UV-visible spectrophotometer is useful for assessing subvisible aggregation and correlates to a visual incompatibility such as opalescence [1].

Care should be taken regarding intravenous administration of furosemide, as many drugs can interact with furosemide ranging from opalescence to precipitation, especially in combination with acid drugs, which can lead to vessel obstructions [23].

According to the summary of product characteristics, pantoprazole sodium powder should not be mixed with other drugs except for its dilution in 0.9% sodium chloride [24]. It was already known from other studies that pantoprazole sodium was often incompatible with other drugs [1]. No administration of mixture with pantoprazole sodium should be observed unless compatibility data can ensure this.

Many other combinations with heparin sodium and pantoprazole sodium are known to be incompatible in the literature. Heparin sodium is also a drug which must be administered alone when compatibility data are not available [25].

Limits

Only the physical compatibility has been tested. It cannot conclude on the chemical stability of these binary combinations, nor can it be extrapolated to associations of more than two drugs, nor to mixtures achieved in the same vial.

Physical compatibility studies should be performed for other drugs mixtures for which data are lacking. New requests must continue to be collected in ICUs and other units to achieve new Y-site compatibility assessments. In all cases, drug combination should always be administered with caution taking into account qualified data from the literature.

Conclusions

By the results of these laboratory tests, compatibility data which were lacking are now available, providing additional information to the literature and securing IV administrations in ICUs. An incompatibility could be due to a visible change, opalescence, precipitation, subvisual turbidity or particle count. Nefopam was found to be quite compatible with other drugs (95.0%). Amiodarone hydrochloride (84.6%), acetylsalicylic acid (80.0%), clonidine hydrochloride (75.0%) and insulin (71.4%) were compatible with other drugs too. Atenolol (42.9%), furosemide (25.0%), heparin sodium (25.0%) showed less compatible results. Pantoprazole sodium (0.0%) was not at all compatible with the other drugs analyzed.


Corresponding author: Gillian Ayari, Pharmacy Department, University Hospital, Allée du Morvan, 54511 Vandœuvre-lès-Nancy, Nancy, France, E-mail:

Acknowledgments

Thank you to Adèle Lombard and Alexandre Chevalier for their involvement in this study. Thank you to Elise d’Huart, Jean Vigneron and Jacques Kuhnlé for reading through all of it and making corrections.

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: The authors state no conflict of interest. The authors have read the journal’s publication ethics and publication malpractice statement available at the journal’s website and hereby confirm that they comply with all its parts applicable to the present scientific work.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The local Institutional Review Board deemed the study exempt from review.

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Received: 2022-02-16
Accepted: 2022-04-20
Published Online: 2022-05-11

© 2022 Gillian Ayari et al., published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.