Chemical and Physical Compatibility of Continuous Intravenous Drug Infusion Combinations used in Paediatric Intensive Care Andy Fox and Marisa van der Merwe

What’s the Problem? Multiple Infusions Lack of data Line Insertion Two or more drugs Diluents Concentration – Non standard Environment Line Insertion

Aims and Objectives Provide evidence for the safety of current practice Clinical Relevance by replicating PICU conditions Identify combinations not suitable for single lumen administration Satisfy legislation in relation of mixing of meds to enable informed decisions to be made.

Study Design 5 IV administered drugs: 3 Environmental conditions: Morphine, clonidine, ketamine, midazolam, furosemide 3 Environmental conditions: Diluent, temperature, blue light phototherapy Drug mixtures: Maximum mass interaction within clinical dosage range and rate range Clonidine was used at maximum available concentration of 150mcg/ml

Study Design SCHOTT Type I glass vials plus® Incubation time was either 4 or 8 hrs depending on drug combination. Based on flow rate and distal volume after y-connector Physical and chemical compatibility assessed 4608 individual analyses

Physical Compatibility pH measurement: Upon mixing After incubation Precipitation: Sympatec Helos particle sizer (cuvette module) Colour change: UV/Vis absorbance Above 400nm

Chemical Compatibility Assessed with HPLC using a DAD Absorption at 200 nm Time (min) Mo Cl Ke Mi Fu

Chemical Compatibility (No Precipitation) Room temp High temp No phototherapy Phototherapy a) 90

Chemical Compatibility (Precipitation) Room temp High temp No phototherapy Phototherapy a) 90

Summary of Initial Results No noticable effect on stability from the environmental conditions tested All combinations of morphine, clonidine, ketamine and midazolam are fully compatible. Some treatment combinations containing furosemide are compatible and some not. Mo + Fu(9), Cl + Fu(12) and Mo, Cl and Fu(18) Further investigation into effect of change of pH after mixing of drugs Depends on initial formulation pH

IV Formulation pH Range of Drugs Min allowed pH Max allowed pH Morphine 2.5a 6.5a Clonidine 4b 7b Ketamine 3.5b 5.5b Midazolam 2.9b 3.7b Furosemide 8b 9.2b Value for Astramorph from Astrazeneca BP specified limit

pH Threshold Compatibility Study pH of each supplied formulation was adjusted to the extreme formulation pH allowed. Drugs were mixed in various combinations covering entire study range 10 µL of another drug at extreme pH added to “sensitive” drug Solutions were observed for precipitation.

pH Threshold Compatibility Study Results All combinations are compatible apart from: Combination 9: Morphine and furosemide INCOMPATIBLE at extreme formulation pH Combination 12: Clonidine and furosemide INCOMPATIBLE at extreme formulation pH Combination 18: Mixture of morphine, clonidine and furosemide compatible, however clinically this is very risky therefore INCOMPATIBLE.

The Ketamine “Mystery” Ketamine in short supply Initial experiments: 10 mg/mL Ketalar®  precipitation Later experiments: 100mg/mL Ketalar® diluted to 10 mg/mL  no precipitation Benzethonium chloride

No noticable influence from the environmental factors Summary No noticable influence from the environmental factors All drug combinations which do not contain furosemide are compatible Furosemide should not be mixed with any of these drugs pH effect Presence of preservative Visible precipitation Reduction of intial concentration of one or more drugs in combination below 90 %

Conclusions Avoidance of unnecessary additional line insertion Balance of Risk vs Benefit is better informed Caution with furosemide is justified Beware extrapolation between products and effect of excipients

Analysis of survey to select next drug combinations of interest Future Work Analysis of survey to select next drug combinations of interest Numerous potential combinations Inotropes next Funding applications to support further work University of Portsmouth invested in more HPLC equipment to support work

Respondents to online survey Thank You NPPG Respondents to online survey Karen Ball, Luke Dickson, Marissa van der Merwe, Caroline Cole, John Pappachan, Adam Hocking, Andy Fox, Amanda Bevan