DRUG DRUG INCOMPATIBILITIES IN INCOMPATIBILITIES IN

THE CICU: WHAT THE CICU: WHAT SHOULD YOU KNOW?SHOULD YOU KNOW?

Dr Caroline Fonzo-ChristePharmacie des HUG

1st EPNCIC ConferenceMontreux, May 21st 2009

MAIN POINTSMAIN POINTS

What are drug incompatibilities?How frequent in the ICU?How can we prevent them?How can we treat them?What should you know?

22

MAIN POINTSMAIN POINTS

What are drug incompatibilities?How frequent in the ICU?How can we prevent them?How can we treat them?What should you know?

33

WHICH PARTNERS?WHICH PARTNERS?Drug

incompatibility

44

Drug A

Drug B

Solvent + excipients

Solvent + excipients

Environment• Temperature• Light

Material• PVC (DEHP)• Silicone•…

Factors• Concentration• Time of contact

Drug incompatibility

WHERE?WHERE?

55

Drug incompatibility

INCIDENTS IN PATIENTS?INCIDENTS IN PATIENTS?

66McNearney T et al. Dig Dis Sci 2003;48:1352-4

Knowles JB et al. JPEN 1989;13:209-13

Hill SE et al. JPEN 1996;20:81-87

Drug incompatibility

CEFTRIAXONECEFTRIAXONE-- CALCIUMCALCIUM

Prescrire 1997;17:506

Bradley JS et al. Pediatrics 2009;123:609-13 77

Drug incompatibility

WHAT KIND OF REACTIONS?WHAT KIND OF REACTIONS?

Physico- chemical reactions:

• Acid-base reactions (pH)

• Solubility changes

• Emulsion cracking

Consequences• precipitates (visible)• coloration (visible)• gas formation (visible)• pH change (invisible)• drug concentration (invisible)

88

Drug incompatibility

Drug incompatibility

pH AND DRUGSpH AND DRUGS

Acidic drugs Basic drugs

low pH < 7 high pH > 7

Amiodarone (Cordarone®) pH = 4 Aciclovir (Zovirax®) pH = 11

Adrenaline pH = 3 Cotrimoxazole (Bactrim®) pH = 10

Dobutamine (Dobutrex®) pH = 3 Furosemide (Lasix®) pH = 9

Midazolam (Dormicum®) pH = 4 Ganciclovir (Cymevene®) pH = 9

Morphine HUG pH = 3.5 Omeprazole (Antra®) pH = 9

Vancomycine (Vancocin®) pH = 3 Phenytoin (Phenhydan®) pH = 12

99

Drug incompatibility

ACIDIC AND BASIC DRUGSACIDIC AND BASIC DRUGSTo be put in solution, salts of active substances are used• An acid is soluble in a basic solution drug solution is basic• A base is soluble in an acidic solution drug solution is acidic

1010

furosemide sodique (pH 9) + vancomycine HCl (pH 3)

From: KIK 2.1, BBraun, 2002

Don’t mix or infuse on Y-site acidic with basic drug solutions!

furosemide sodique (pH 9) + midazolam HCl (pH 4)

TheoryDrug incompatibility

SOLVENT (DILUENT)SOLVENT (DILUENT)

Glucose 5%-20% pH = 4.0 - 6.0 amiodarone, amphotericine BNaCl 0,9% pH = 7.0 - 7.5 aciclovir, phenytoin, furosemide

Solvent pH Appropriate for

From: KIK 2.1, BBraun, 2002

Be careful with solvent pH !1111

SOLUBILITYSOLUBILITY«« PastisPastis effecteffect »»

drug excipient

amiodarone Cordarone® polysorbate (tween)paracetamol Perfalgan® mannitol, phosphate, NaOHesomeprazole Nexium® NaOH, EDTAphenytoin Phenhydan® glycofurol-75, EDTAclonazepam Rivotril® propyleneglycol, acetic acid

Co-solvent and/or adjusting pH can increase the solubility of drugs in solution

Drug incompatibility

1212

Dilution of drugs dilution of co-solvents pH changeRisk of precipitation !

TheoryDrug incompatibility

LIPID EMULSION LIPID EMULSION

Increased risk of coalescence:

pH

conc. AA

electrolytes with high valence (Ca2+, Mg2+, PO4

3-)

reversible

irreversible

Lipid emulsion is not water !1313

MAIN POINTSMAIN POINTS

What are drug incompatibilities?How frequent in the ICU?How can we prevent them?How can we treat them?What should you know?

1414

Frequence

MEDICATION ERRORSMEDICATION ERRORSAdult ICU7.21 - 18.6%2 incompatible drug combinations, 26.3%2 potentially life-threateningPediatric ICU3.6%3 incompatible combinations

1515

1 Bertsche T et al. Am J Health Syst Pharm 2008;65:1834-402 Tissot E et al. Intensive Care Med 1999;25:353-9 3Gikic M et al. Pharm World Sci 2002;22:88-91

MAIN POINTSMAIN POINTS

What are drug incompatibilities?How frequent in the ICU?How can we prevent them?

in the wardHow can we treat them?What should you know?

1616

Prevention: ward

OCCLUSION ALARMSOCCLUSION ALARMS

• Y-site infusion of furosemide (F) and midazolam (M)• During 24h, at incompatible concentrations

• Four infusion rates tested: F 0.05 and 0.85 mg/kg/h, M 0.03 and 0.3 mg/kg/h

• With or without filters

Fonzo-Christe C. et al. ESCP 2009. http://pharmacie.hug-ge.ch/rd/posters/ACCP_ESCP09_pumps_cf.pdf

1717

Prevention: ward

OCCLUSION ALARMSOCCLUSION ALARMS

ConnectubSyringes

Stopcock

+/-in-line filter

CVC • Module DPS

Fresenius Kabi• Pressure offset :

300 mm Hg

Fonzo-Christe C. et al. ESCP 2009. http://pharmacie.hug-ge.ch/rd/posters/ACCP_ESCP09_pumps_cf.pdf

1818

Prevention: ward

OCCLUSION ALARMSOCCLUSION ALARMS5 kg 10 kg 20 kg

In-line filter Infusion rateF 0.5 mg/ml M 1 mg/ml

F 1 mg/ml M 2 mg/ml

F 2 mg/ml M 4 mg/ml

Drugs precipitate

in the stopcock

max-max no occlusion 1h18 (M) 1h15 (F)

max-min no occlusion no occlusion no occlusion

min-max no occlusion no occlusion no occlusion

min-min no occlusion no occlusion no occlusion

max-max no occlusion no occlusion 1h35 (F)

max-min no occlusion no occlusion no occlusion

min-max no occlusion no occlusion no occlusion

min-min no occlusion no occlusion no occlusion

max-max no occlusion 14' (M), 15' (F) 13' (M)

max-min no occlusion no occlusion no occlusion

min-max no occlusion 12h11 (F) no occlusion

min-min no occlusion no occlusion no occlusionNo filter

Present, less visible Present, visible

Present, highly visible

PALL

CODAN

Pressure offset at 300 mm Hg not efficient with very low infusion rates Pressure management (lower alarm levels) or in-line filters

Fonzo-Christe C. et al. ESCP 2009. http://pharmacie.hug-ge.ch/rd/posters/ACCP_ESCP09_pumps_cf.pdf1919

Prevention: ward

ININ--LINE FILTERSLINE FILTERS

Potential difficulties for implementation

• at least two types of filters (0.2 and 1.2 µm)• technical aspects (priming, flushing)• aseptic risks• no filtration for some products• blocked filters

Teaching, operating procedures and follow-up are essential

2020

Prevention: ward

USEFUL TOOLS USEFUL TOOLS

Assessment interpretation

adapted cross-tables (charts)pH- color code (Schaffhausen Model)

Main problems: - exhaustiveness- assessment of

drug pairs

De Giorgi et al. ESCP 2008. http://pharmacie.hug-ge.ch/rd/posters/escp08_idg_incompat.pdf

2121

Prevention: ward

CROSSCROSS--TABLESTABLES

http://files.chuv.ch/internet-docs/pha/medicaments/pha_phatab_compatibilitessip.pdfhttp://www.adhb.govt.nz/newborn/DrugProtocols/IVCompatibilities.htm

2222

Prevention: ward

pH COLOR CODEpH COLOR CODE

Adult ICU in Schaffhausen (Switzerland) since 10 years

Vogel Kahmann I. et al. Anaesthesist 2003;52:409-12

2323

Prevention: ward

pH COLOR CODEpH COLOR CODE

2424

Pharmacy ward

On IV-lines

Vogel Kahmann I. et al. Anaesthesist 2003;52:409-12

Prevention: ward

pH COLOR CODEpH COLOR CODEAbout 78 drug combinations (636 different drugs)

Y-site infusion of potentially incompatible drugsVogel Kahmann I. et al. Anaesthesist 2003;52:409-12

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MAIN POINTSMAIN POINTS

What are drug incompatibilities?How frequent in the ICU?How can we prevent them?

in the hospital pharmacyHow can we treat them?What should you know?

2626

Prevention: pharmacy

PN: reduced risk of particlesPN: reduced risk of particles

• GMP procedures in parenteral nutrition compounding

• Aseptic preparation

• Line flushing to reduce particles load*

* Stucki C et al. EAHP 2004. http://pharmacie.hug-ge.ch/rd/posters/eahp04_hi_particules_baxa_cs.pdf

2727

Prevention: pharmacy

PN: reduced risk of precipitationPN: reduced risk of precipitationPhosphate mmol/L (Na2HPO4)

Cal

cium

mm

ol/L

(CaC

l 2)

12

10

8

7

6

5

4.5

4

3.5

3

2

1

121087654.543.5321

StabilityZone

IntermediateZone

PrecipitateZone

Phosphate mmol/L (Na2HPO4)

Cal

cium

mm

ol/L

(CaC

l 2)

12

10

8

7

6

5

4.5

4

3.5

3

2

1

121087654.543.5321

12

10

8

7

6

5

4.5

4

3.5

3

2

1

121087654.543.5321

StabilityZone

IntermediateZone

PrecipitateZone

50

40

30

20

10

5040302010

Phosphate mmol/L (G1P)

Cal

cium

mm

ol/L

(CaC

l 2or

Ca-

Glu

)Stability Zone

50

40

30

20

10

5040302010

50

40

30

20

10

5040302010

Phosphate mmol/L (G1P)

Cal

cium

mm

ol/L

(CaC

l 2or

Ca-

Glu

)Stability Zone

Use of organic calcium and phosphates salts

Bouchoud Bertholet L. et al. GSASA 2008. http://pharmacie.hug-ge.ch/rd/posters/gsasa08_lb.pdf

2828

Prevention: pharmacy

READY READY --TO TO --USEUSE• High risk of preparation

(dilution) errors

• High risk of particles

• Ready-to use, 5mg/ml, 10 ml

• Particles per ml: - 10 µm: 3 - 25 µm: 1

• Standardised concentration: compatibility testing

2929

Prevention: pharmacy

READYREADY--TOTO--USEUSE : HUG: HUG

GMP procedures(dedicated environment, end-line filtration 0.2 µm)

3030

MAIN POINTSMAIN POINTS

What are drug incompatibilities?How frequent in the ICU?How can we prevent them?How can we treat them?What should you know?

3131

Treatment

CATHETER RESCUECATHETER RESCUE

Non–thrombotic catheter occlusions in pediatric patients:

Drug precipitates Lipid Residue

Acidic drugs Basic drugs

0.55 ml/kg 70% ethanol , max 3 ml

0.2 to 1 ml 0.1 N HCl

1 ml 0.1 N NaOH or Na -bicarbonate

Kerner J et al. JPEN 2006;30: S73-S81

3232

MAIN POINTSMAIN POINTS

What are drug incompatibilities?How frequent in the ICU?How can we prevent them?How can we treat them?What should you know?

3333

TO BE KNOWNTO BE KNOWN

3434

Drug A

Drug B

Solvent + excipients

Solvent + excipients

Acidic drugs

Basic drugs

TAKE HOME MESSAGETAKE HOME MESSAGE

Hospital pharmacists can help!

3535

WHICH DRUGS?WHICH DRUGS?Drug

incompatibility

Always ALONE:Blood and derivates : agglutination and hemolysis risks

Be careful WITH: Low and high pH: precipitation risks crystal deposit in kidney, lung, liverDrugs with co-solvent : precipitation risks crystal deposit in kidney, lung, liverLipid emulsions: cracking risks fat embolism

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DRUG DRUG INFORMATION CENTRE

Prevention: pharmacy

INFORMATION CENTRE

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Hospital pharmacists:

• Knowledge of formulations

• Access to information