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

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

3. 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.

4. 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

5. 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

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

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

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

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

10. 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

11. 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

12. 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.

13. 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.

14. 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

15. 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 %

16. 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

17. 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

18. 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