Drug incompatibility is a condition in which an undesirable interaction occurs during the preparation or administration process1. Patients admitted to the Intensive Care Unit (ICU) will require several intravenous medications due to the patient's condition2. This condition will be more complicated when the patient is in Neonatal Intensive Care Unit (NICU) because the condition of patients who have fluid restriction, low infusion rate, and poor venous access3,4. This condition may increase the likelihood that the patient will receive concurrent intravenous medications4. In Indonesia, studies related to intravenous drug compatibility have only been carried out in the Pediatric Intensive Care Unit (PICU)5 but never in the NICU. Based on above problems, this study aims to determine the most common incompatible and unknown compatibility drug combinations based on reference books and journals.

We performed prospective cross-sectional study to see the drug combination given in one line (y-site) in the NICU of a tertiary hospital in Central Java (Indonesia). All babies who were admitted to the NICU from May 1 to July 31 2021 were sample. Patients who did not receive at least two drug coadministrated concurrently and who stayed less than 24 hours were excluded. The ethic statement from faculty of medicine, Muhammadiyah University of Surakarta was obtained for this study No. 3860/C.2/KEPK-FKUMS/XI/2021.

A drug combination is defined as a combination of two or more drugs administered concurrently. While pairs of drugs are defined as involving drugs obtained from drug combinations. It includes administration of drug by bolus, infusion, or syring. Only drug-drug combinations were considered and the other non-drug administrations (electrolyte solutions, parenteral nutritions, and blood products) were excluded. Compatibility data were obtained from literature and online search engines. The main source used is Micromedex NeoFax Essentials 2020, other supporting data such as UCL Hospitals Injectable Medicines Administration Guide: Pharmacy Department, 3rd Edition, Trissel Handbook on injectable drugs 15th edition, and published journal were used during this study. Drug compatibility was classified in three categories: compatible (C), incompatible (I), and No Information Available (NI).

A total of 112 neonates was included to the study with 6,173 drug administrations and 1,558 drug combinations administered concurrently. The drug combinations consisted of 2 drugs co-administered as many as 1130 (72.53%), combination of 3 drugs in one line (314, 20.15%), 4 drug combinations (104, 6.68%), and 5 drug combinations (10, 0.64%). Clinical characteristics and demographics are displayed on Table 1.

A total of 1,558 drug combinations consisted of 244 drug combinations (15.66%) were compatible, 702 drug combinations (45.06%) were incompatible, and 612 drug combinations (39.28%) were classified as no information available. The most common drug classified incompatible, compatible, and unknown compatibility was shown on Table 1. While the drugs which often administered were ampicillin sulbactam (22.10%), ampicillin (12.98%), gentamicin (10.22%), aminophylline (9.20%), amikacin (8.44%), paracetamol (7.31%), meropenem (6.95%), cefotaxime (6.11%), metronidazole (4.60%) and ciprofloxacin (2.28%).

There were 702 incompatibles drug combination in which more than 50% is contributed by ampicillin–gentamicin. This incompatibility is due to the inactivation of aminoglycosides by beta-lactam antibiotics. Gentamicin should be given 1 hour before the administration of ampicillin6. Ampicillin, furosemide, phenobarbital, phenytoin, and meropenem are drugs that have a high pH (> 7) and in theory will precipitate if they are in a solution with a low pH such as 5% glucose (pH 4-4.5)5. The solubility of the drug can be increased by the ionization process of a molecule. If the drug molecule acts as a proton acceptor (lowry-bronsted base), ionization may occur if the molecule is in a low pH solution usually as a hydrochloride or hydrogen sulfate salt. Conversely, if a molecule can lose a proton or hydrogen ion (a lowry-bronsted weak acid), ionization occurs if the molecule is present at a high pH7. Changes in concentration will affect the drug incompatibility. Drugs that are compatible at low concentrations will increase incompatibility at higher concentrations1.

No international guidelines exist for handling incompatibility issues. Decision-supporting tools such as handbooks, two-dimensional incompatibility charts, online databases, and published research are available to assist in minimizing the incidence8. To reduce the occurrence of incompatibility, it can be done by making a list of frequently used drugs with theirs compatibility, so that health workers will quickly and easily check before administration2. Expertise in identifying incompatibility especially in the NICU is very important. Taking into account things such as optimal concentration, solvent’s pH, container and also the characteristics of the drugs before administration is the main step to minimize drug incompatibility.

The limitation of this study is that the study was conducted in single hospital only. So that the incidence of intravenous incompatibility is only described in that one place. In addition, the period of the study was only carried out within three months. Therefore, further research can be carried out in multi center studies so it can describe the incidence rate and compatibility profile in NICU in Indonesia.

Based on the explanation above, there are 1,558 drug combinations consisting of 244 compatible drug combinations, 702 incompatible drug combinations, and 612 drug combinations classified as unknown. The most incompatible and no information available are combination of ampicillin-gentamicin (31.71%) and amikacin- ampicillin sulbactam (9.05%), respectively. The first step in reducing and minimizing the incidence was by seeing at a glance the compatibility between drugs using a two-dimensional chart (Table 2).

• 1.

  The study concept and design, or the data collection, or the data analysis and interpretation: ADM, SH, CPS

• 2.

  Writing the article or critical review with significant intellectual contributions: ADM, SH, CPS

• 3.

  Approval of the final version for publication: ADM, SH, CPS

This work was funded by Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Islamic University of Indonesia.

The research has been conducted in accordance to the ethical standards of the Declaration of Helsinki. The ethical statement was obtained from faculty of medicine, Muhammadiyah University of Surakarta No. 3860/C.2/KEPK-FKUMS/XI/2021.

This is the first study to describe potential incompatibility of intravenous medication in a Neonatal Intensive Care Unit in Indonesia. Several studies in Indonesia describe potential incompatibility in Intensive Care Unit or Pediatric Intensive Care Unit but not in Neonatal Intensive Care Unit. Therefore, this study can serve as a reference in future Neonatal Intensive Care Unit studies with updated intravenous medication compatibility based on the latest references.