Compatibility of i.v. drugs in paediatric intensive care (ComPICU)

Neonatal and paediatric intensive care patients need numerous intravenous (i.v.) drugs, including parenteral nutrition (PN) and buffered electrolyte solutions, and the majority are administered via the central venous catheter. Often two or more drugs have to be co-administered in the same i.v. line, due to limited venous access ports. A major challenge associated with such co-administration is the risk of incompatibility meaning that combination may negatively impact one or more of the components that are co-administered. Incompatibilities can be of chemical nature (i.e. causing a chemical reaction, e.g. oxidation or hydrolysis) or of physical nature (e.g. precipitation of particles, formation of gas, change in colour, increase in fat droplets size of emulsions). In this project we mainly focus on the physical stability, and the consequences of physical incompatible co-administration range from transient catheter obstruction to lethal embolism.

The primary objective of ComPICU is to enable health personnel at paediatric intensive care to administer intravenous drugs and fluids in a safe manner. The specific objectives were to:

1. record the most frequently used drugs, fluids and combinations and their administration parameters and identify potential compatibility concerns
2. test intravenous drugs and fluids for physical compatibility simulating a typical infusion scenario using a dynamic model and comparing the results with those from a static set-up
3. develop new methods to establish the chemical identity of precipitated drug particles upon co-administration of intravenously administered drugs
4. create an electronic searchable compatibility database for health personnel working at paediatric intensive care

The project has contributed to identify frequently used drugs in paediatric intensive care and identify potentially risky combinations (a), conducted physical compatibility tests for a number of frequently used drugs, parenteral nutrition, and fluids in pairs of two components, three components, and multi-drug mixtures (five and six components) (b). Raman spectroscopy was explored for detection and identification of precipitated particles from a multi-drug mixture (c). Data has been collected for a compatibility database and the results has been included in the Guidelines for safe drug administration at the paediatric intensive care (d). At the PhD-project end, it was considered to early for establishing a searchable database, the focus forward will be to obtain more quality assured compatibility data through laboratory analyses. Further studies will be conducted as part of ComPEL.

The project has resulted in following Theses and degrees:

Niklas Nilsson, 2022, Intravenous drug co-administration in neonatal and paediatric intensive care patients – examining clinically relevant multi-drug compatibility, PhD-Thesis UiO

Camilla Tomine Østerberg, 2018, Forlikelighet mellom legemidler og total parenteral ernæring som parallellinfusjon til barn, Master Thesis, UiO

Anette Lima Hansen, 2018, Uforlikelighet ved parallellinfusjon av legemidler til pediatriske pasienter, Master Thesis, UiO

Liv Vidas, 2020, Forlikelighet av TPN og legemidler som parallellinfusjon til nyfødte, Master Thesis, UiO

Ingebjørg Storesund, 2020, Parallellinfusjon av legemidler og total parenteral ernæring ved intensivavdeling for nyfødte - En studie med kvalitative intervjuer av sykepleiere og test av forlikelighet mellom utvalgte kombinasjoner, Master Thesis, NTNU

Vanja Katana, 2021, En kvalitativ studie om kompatibilitet av legemidler og parenteral ernæring brukt ved Barne- og ungdomsklinikken ved Haukeland Universitetssjukehus: Fokusgruppeintervju med vaktfarmasøyter, Master Thesis, UiO

Slavisa Stojkovic, 2021, «Går dette sammen?» Hvordan løses kompatibilitetsproblemer mellom intravenøse legemidler og parenteral ernæring på Nyfødtintensiv ved Barne- og ungdomsklinikken, Haukeland universitetssjukehus? En kvalitativ studie basert på flere metoder, Master Thesis, UiO

Tone Huseby Holm, 2021, Forlikelighet av legemidler og TPN gitt som parallellinfusjon til premature og nyfødte - Hyppig brukte legemidler ved nyfødtintensivavdelinger og fysikalske forlikelighetstester av utvalgte kombinasjoner, Master Thesis, UiO

The project has resulted in following peer-reviewed publications:

N.Nilsson, K.Nezvalova-Henriksen, I.Tho, Emulsion stability of different propofol formulations when intravenously co-administered with remifentanil hydrochloride, Pharm. Technol. Hosp. Pharm., 4 (2019) 77-87 https://doi.org/10.1515/pthp-2019-0014 

K.Nezvalova-Henriksen, C.T.Østerberg, N.Nilsson, V.Staven Berge, I.Tho, Y-site physical compatibility of Numeta G13E with drugs frequently used at Neonatal Intensive Care, Pharmaceutics 12 (2020) 677 https://doi.org/10.3390/pharmaceutics12070677

V.Staven Berge, K. Nezvalova-Henriksen, N.Nilsson, Y.Andersson, J.Brustugun, I.Tho, Er legemidlene kompatible? - Farmatid artikkel 2668 (Norsk Farmaceutisk Tidsskrift, 2 (2021) 32-36)

N.Nilsson, I.Storesund, I.Tho, K.Nezvalova-Henriksen, Co-administration of drugs with parenteral nutrition in the neonatal intensive care unit – Physical compatibility between three components, European Journal of Pediatrics 181 (2022) 2685-2693 https://doi.org/10.1007/s00431-022-04466-z

K.Nezvalova-Henriksen, T.H.Holm, N.Nilsson, I.Kjønniksen, I.Tho, Frequently acquired drugs in neonatal intensive care and their physical compatibility, Acta Paediatrica (2022) https://doi.org/10.1111/apa.16526

N.Nilsson, V.Nguyen, K.Nezvalova-Henriksen, I.Tho, Exploring a case of incompatibility in a complex regimen containing Plasma-Lyte 148 in the pediatric intensive care, Pediatric Anesthesia 33 (2023) 211-218 https://doi.org/10.1111/pan.14598

N.Nilsson, K.Nezvalova-Henriksen, J.P.Boetker, N.Højmark Andersen, B.S.Larsen, J.Rantanen, I.Tho, J.Brustugun, Co-administration of intravenous drugs: Rapid troubleshooting solid form composition of precipitate in a multi-drug mixture using on situ Raman spectroscopy, Molecular Pharmaceutics  20 (2023) 2853-2863 https://doi.org/10.1021/acs.molpharmaceut.2c00983