Drug Incompatibility Risk Prevention in Inusion Therapy
Drug Incompatibility
Denition The diference between interactions and incompatibilities
Denition o incompatibilities
Incompatibility is an undesirable reaction that occurs between the drug and the solution, container or another drug. The two types o incompatibilities associated with intravenous administration are physical and chemical [Josephson 2006, RCN 2005, Douglas et al. 2001].
The preparation o intravenous drugs and solutions is accompanied with the risk o undesirable reactions o the drug interacting with other substances. In this context it is important to distinguish an incompatibility reaction rom an interaction. An interaction occurs inside the body and thereore cannot be seen. In contrast to the interaction, an incompatibility reaction occurs inside a uid container or inusion line and is usually visible. This text will ocus on drug incompatibilities associated with IV therapy. The two types o incompatibilities 1. Physical reactions
Denition o interactions
A drug interaction describes the alteration o a drug eect due to the inuence o another substance (i.e. drug, chemical substance, nutrition) resulting in a solution that is no longer optimal for the patient after the substances are mixed [Craven
Physical reactions o drugs usually reer to either phase separation or precipitation (e.g. ater the dilution o alcoholic solutions) due to a change o the relation between ionization and nonionization and solubility [Newton 2009].
The alteration may result in �
Synergism
Increased drug eectiveness, as the combined eect is greater than the sum o each drug acting independently
et al. 2007a, Josephson 2006, Douglas et al. 2001, Nemec et al. 2008]. �
Antagonism
Decreased drug eectiveness, as the combined eect o two or more agents is less than the sum o each drug acting alone �
New efect
An eect that neither drug shows on its own (e.g. toxicity)
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Fig. 1a: Chemical precipitation of Midazolam (turbidity) and Ketamin (particle formation) [Riemann et al. 2005].
Fig. 1b: Physical precipitation of Midazolam as a result of an unfavorable pH medium [Riemann et al. 2005].
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Drug Incompatibility
Denition 1. Physical reactions continued ... The pH-value and the bufer capacity (pKa value) o the IV
solutions and the drugs used are major actors responsible or physical interactions [Newton 2009]. The situation in an inusion regimen is specifc to the combination o drugs and solution used. Usually, the drug has the greatest inuence and thereore defnes the pH-value o the solution inused. Many drugs are weak bases, present as the water soluble salts o the corresponding acids. Changes in pH-value in the inusion tubing, e.g. rom simultaneous addition o another drug, may release the bases rom their salts. Because o the low aqueous solubility o such bases, particles may precipitate (Fig.1). The process o precipitation is inuenced by the relative quantity o the drugs added, as well as their buering capacity. These pHdependent precipitation reactions are usually very rapid and can be identifed within a ew centimeters in the inusion tubing system. They can visibly be observed as crystals, haziness or turbidity (Fig.1+2) [Newton 2009]. Precipitations based on drug incompatibilities are responsible or the most common particle ormation seen in complex ICU inusion lines [Schröder 1994]. Further invisible physical incompatibilities are reactions between drugs and plastic materials (adsorption eects). This leads to the drugs becoming immobilized at the inner surace o inusion containers or inusion lines and so lowers the concentration and drastically decreases the quantity o the drug administered to a patient [Trissel 1996].
2. Chemical reactions
A chemical incompatibility means that the drug is chemically degraded, due to oxidation, reduction, hydrolysis, or decomposition. Chemical reactions can maniest themselves through turbidity, precipitation and color changes. As a consequence, the amount o the active agent decreases and / or toxic by-products orm [RCN 2005, Douglas et al. 2001, Höpner et al. 2003].
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Fig. 2a: Physical incompatibilities of Diazepam. Picture by courtesy of F. Schröder, Pharmacist Bremen, Germany.
Fig. 2b: Precipitation of Midazolam (Turbidity). Picture by courtesy of F. Schröder, Pharmacist Bremen, Germany.
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Drug Incompatibility
Causes Causes
Incompatibilities o drugs can occur between drugs and inappropriate IV solutions as diluent two drugs (drug-drug incompatibility) when they are - mixed together, e.g. within the same inusion line (simultaneous inusion) and/or IV container - administered one ater the other, but within the same inusion line drugs and adjuvants (preservative, buer, stabilizer, solvent) drugs and materials o IV containers (e.g. PVC) or medical devices, which can concern the nature o the material used and/or reactions at the inner surace (e.g. adsorption) [Trissel 1996, Giki et al. 2000, Newton 2009] �
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Examples o drug-drug incompatibilities
[Josephson 2006, Höpner et al. 2003] Incompatible drugs in combination with any other drug
Drugs with limited compatibility
Aminoglycosides
Alprostadile
Chlordiazepoxide
Clonidine
Diazepam Digitalis glycosides
Dobutamine Dopamine Doxaprame
Pentobarbital Epinephrine Phenytoin Secobarbital
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Glycerol trinitrate Milrinon
Sodium bicarbonate
Norepinephrine
Theophylline derivatives
Sodium nitroprusside
Fig. 3: Main causes of incompatibilities in standard IV therapy.
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Drug Incompatibility
Consequences Consequences or the patient �
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damage rom toxic products particulate emboli rom crystallization and separation
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tissue irritation due to major pH changes
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therapeutic ailure
The unintended presence o precipitation and toxic products can cause various negative consequences or the patient. This can range rom thrombophlebitis up to multi-organ ailure. The reduction or elimination o the active drug can lead to a therapeutic ailure. The extent o the damage mainly depends on the patient’s condition (age, weight, nature, severity o the disease etc.) and on the type o drug administered. Consequences o physicochemical drug incompatibilities are particularly severe in neonate and pediatric patients [Höpner 2007].
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There is little published scientifc inormation about the requency o drug incompatibility reactions. In one study, incompatibility was investigated in a pediatric intensive care ward showing that 3.4 % o drug combinations were incompatible and thus potentially dangerous [Gikic et al. 2000]. A lie threatening nature was ound or 26 % o incompatibilities in an intensive care unit (ICU) by Tissot et al. [2004]. Another survey collected 78 dierent medication regimes and ound 15 % with incompatibility reactions [Vogel Kahmann et al. 2003]. Taxis and Barber [2004] reported that in the ICU clinical incompatibilities can contribute to 25 % o medication errors. Further publications showed that, depending on the ward type, up to 80 % o IV drug doses were prepared with the wrong diluent [Cousins et al. 2005, Hoppe-Tichy et al. 2002].
Fig. 4: Estimation of possible additional costs as a consequence of complications caused by drug incompatibilities. In order to facilitate the attribution of each complication to the cost calculation, severity levels were introduced. RICU: Respiratory Intermediate Care Unit
Financial impact
Adverse eects o drug incompatibilities extend periods o patients’ hospitalization and the total costs or hospitals. Severe respiratory complications caused by toxic drug-drug interactions may lead to an additional cost or the healthcare provider o up to 56,670 € per single case.
Risk related costs or the healthcare institution
A cost evaluation o the risk can be done by assigning costs to their related clinical treatment and resulting extended length o stay. The cost can be calculated using the average daily cost [Gianino 2007, Bertolini 2005] o the expected clinical treatment. Fig. 4 shows the results o such a calculation or selected examples o complications. Conclusion
The prevention o adverse drug events due to drug-drug interactions can result in budget savings or the healthcare provider. In the case o severe complications which require ull ICU treatment or diverse days o hospitalization, a hospital may save between 7,556 € and 56,670 € per single case.
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Drug Incompatibility
Preventive strategies Fig. 5: Assessment and planning of regimes to avoid mixing of drugs, which have to be administered separately.
Fig. 6: Compatibility checking using available literature, databases, services and information material.
Fig. 7: Color coding and drug separation to prevent drug incompatibilities through a clear indication of the drug.
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Preventive strategies
Dangerous incompatibilities can be prevented by �
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a plausibility check regarding the SPC and available sources on compatibility inormation, also considering the material used or therapy (e.g. diluent, IV container, IV lines) and the inusion regimen (Fig. 5)
Prevention �
plausibility check
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strict indications or each drug preparation
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separation o drug doses by time and place
individual labeling or each drug preparation (including drug, concentration, patient name) (Fig. 7)
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consistently checking alternative modes o administration and/or using multi-lumen catheters (Fig. 6)
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consistent check o alternative modes o administration usage o multi-lumen catheters
separating the drug doses by time and place. This can include the rinsing o the inusion system with a neutral IV solution prior to the application o another drug (Fig. 5) [Craven et al. 2007b, RCN 2005, Riemann et al. 2005, Höpner et al. 2003, Vogel Kahmann et al. 2003, Hoppe-Tichy et al. 2002] �
Furthermore, in-line flters can reduce inux o particles which result rom incompatibilities. Moreover, they can be used to monitor physical and chemical incompatibilities. In-line flters are able to retain solid particles o at least 0.2 µm [Schröder 1993, Schröder 1994]. As a consequence, the flter may block. This is not a malunction o the flter, but should initiate a check o the medication in order to eliminate any incompatibility.
Protection o particle inusion �
use appropriate in-line flters
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Drug Incompatibility
Riskprevention Ecoflac® plus
The state o the art IV solution container that oers sae and convenient application o all IV procedures rom drug admixture to drug delivery. Container based incompatibilities are prevented by a special polyethylene container material which is: Chemically inert. Toxicologically sae Free rom plasticizers, additives and other compounds. Free rom substances that may potentially migrate into the fnished preparation. �
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ConComp®
Free database on drugs compatible with Ecoac® plus. Oers inormation on interactions between certain drugs, carrier solutions and container materials. Oers overview o scientifc literature on drug compatibility with the container. �
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Intrax® SaeSet Neutrapur® (PVC ree)
Prevention o interactions between certain drugs and material: These inusion lines may be used with drugs which are not recommended to be applied with PVC material, e.g. Taxol. �
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Intrapur® and Sterifix® Infusion Filters
A whole range o flters or sae inusion therapy. Retains solid particles and precipitations o drug incompatibilities preventing their inux into the organism. Functions like an indicator when flter blocks as a result o chemical or physical reactions. �
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cross-section
Certox® Multilumen Catheters
Central venous catheters or high-level and versatile IV therapy. Multilumen catheters prevent drug incompatibilities by Separate lumens (distal, middle, proximal) averting the mixing o solutions and drugs. Separate vents achieving an immediate dilution o the individual solution/drug in the blood, high enough to prevent urther incompatibility reaction. �
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Omniflush®
Preflled ush syringe or sae and convenient ushings with saline solution.
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Drug Incompatibility
Literature Literature
Craven RF, Hirnle CJ. Chapter 29: Medication administration. In: Craven RF, Hirnle CJ. Fundamentals o nursing – human health and unction. 5. Edition, Philadelphia [u.a.]: Lippincott Williams & Wilkins 2007a; 558-559 Craven RF, Hirnle CJ. Chapter 30: Intravenous therapy. In: Craven RF, Hirnle CJ. Fundamentals o nursing – human health and unction. 5. Edition, Philadelphia [u.a.]: Lippincott Williams & Wilkins 2007b; 604-639 Cousins DH, Sabatier B, Begue E, Schmitt C and Hoppe-Tichy T. Medication errors in intravenous drug preparation and administration: a multicentre audit in UK, Germany and France. Qual Saf Health Care 2005; 14: 195-195 Douglas JB, Hedrick C. Pharmacology. In: Perucca R Inusion therapy equipment: types o inusion therapy equipment. In: Inusion therapy in clinical practise. Philadelphia: Saunders 2001; 176-208 Gianino MM, Vallino A, Minniti D, Abbona F, Mineccia C, Silvaplana P and Zotti CM. A method to determine hospital costs associated with nosocomial inections (transl), Ann Ig 2007; 19(4): 381-392 Gikic M, Di Paolo ER, Pannatier A and Cotti ng J. Evaluation o physicochemical incompatibilities during parenteral drug administration in a paediatric intensive care unit. Pharm World Sci 2000; 22(3): 88-91
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Höpner JH, Schulte A, Thiessen J, Knu M and Huth RG. Preparation o a compatibility chart or intravenous drug therapy in neonatal and pediatric intensive care units. Klin Padiatr 2007; 219(1): 37-43
Riemann T, Schröder F. More eective prevention o incompatibility reactions through the use o our lumen central venous catheters in critically ill patients. PflegenIntensiv 2005; 2(1): 57
Hoppe-Tichy T, Noe-Schwemm S, Wahlig A and Taxis K. Medikationsehler bei der Applikation Parenteraler Arzneimittel. [Medication errors in parenteral drug administration.] Krankenhauspharmazie 2002; 23:11-17 in German
Schröder F. Kompatibilitätsprobleme in der Intensivmedizin. Infusionsther Transfusionsmed 1994; 21: 52-58
Josephson DL. Risks, complications, and adverse reactions associated with intravenous inusion therapy. In: Josephson DL. Intravenous inusion therapy or medical assistants. The American association o Medical Assistants. Cliton Park: Thomson Delmar Learning 2006; 56-82 Krähenbühl-Melcher A, Schlienger R, Lampert M, Haschke M, Drewe J, Krähenbühl S. Drug-related problems in hospitals: a review o the recent literature. Drug Saf 2007; 30(5): 379-407
Schröder F. Ursachen und Prävention von Inkompatibilitäten i n der Intensivmedizin. In: Heeg P, Lenz G. Inusionstherapie. Melsungen: Bibliomed 1993; 27-41 Trissel LA. Handbook on Injectable Drugs. 9th ed. Bethesda: American Society o Pharmacists 1996 Tissot E, Cornette C, Demoly P, Jacquet M, Barale F and Capellier G. Medication errors at the administration stage in an intensive care unit. Intensive Care Med 1999; 25: 353-359
Nemec K, Kopelent-Frank H, Grei R. Standardization o inusion solutions to reduce the risk o incompatibility. Am J Health System Pharm 2008; 65(Sep): 1648-1654
Vogel Kahmann I, Bürki R, Denzler U, Högler A, Schmid B and Splisgardt H. Incompatibility reactions in the intensive care unit. Five years ater the implementation o a simple “colour code system”. Anaesthesist 2003; 52(5): 409-412
Newton, D. Drug incompatibility chemistry. Am J Health Syst Pharm 2009; 66(Feb): 348-357
Taxis K, Baber N. Incidence and severity o intravenous drug errors in a German hospital. Eur J Clin Pharmacol 2004; 59: 815-817
RCN. Royal College o Nursing. Standards or inusion therapy. 2005
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The summarized scientifc inormation in this document has been prepared or healthcare proessionals. It is based on an analysis o public literature and guidelines. The intention is to give an introduction to the risks commonly associated with inusion therapy and to increase the awareness o healthcare workers to these kinds o problems. Due to its summary nature, this text is limited to an overview and does not take into account all types o local conditions. B. Braun does not assume responsibility or any consequences that may result rom therapeutical interventions based on this overview.
B. Braun Melsungen AG | Hospital Care | 34209 Melsungen | Germany Tel. +49 5661 71-0 | www.bbraun.com | www.saeinusiontherapy.com
Nr. 6069092 Edition: 03/2011
