Drug Incompatibility

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Risk Prevention in Infusion Therapy Drug Incompatibility

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Drug Incompatibility

Transcript of Drug Incompatibility

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Risk Prevention in Infusion Therapy

Drug Incompatibility

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DefinitionDefinition of incompatibilities Incompatibility is an undesirable reaction that occurs between the drug and the solution, container or another drug. The two types of incompatibilities associated with intravenous administration are physical and chemical [Josephson 2006, RCN 2005, Douglas et al. 2001].

The difference between interactions and incompatibilities

The preparation of intravenous drugs and solutions is accompanied with the risk of undesirable reactions of the drug interacting with other substances. In this context it is important to distinguish an incompatibility reaction from an interaction.

An interaction occurs inside the body and therefore cannot be seen.

In contrast to the interaction, an incompatibility reaction occurs inside a fluid container or infusion line and is usually visible. This text will focus on drug incompatibilities associated with IV therapy.

The two types of incompatibilities1. Physical reactions

Physical reactions of drugs usually refer to either phase separation or precipitation (e.g. after the dilution of alcoholic solutions) due to a change of the relation between ionization and nonionization and solubility [Newton 2009].

The alteration may result in �Synergism Increased drug effectiveness, as the combined effect is greater than the sum of each drug acting independently

�Antagonism Decreased drug effectiveness, as the combined effect of two or more agents is less than the sum of each drug acting alone

�New effect An effect that neither drug shows on its own (e.g. toxicity)

Definition of interactions A drug interaction describes the alteration of a drug effect due to the influence of another sub-stance (i.e. drug, chemical substance, nutrition) resulting in a solution that is no longer optimal for the patient after the substances are mixed [Craven et al. 2007a, Josephson 2006, Douglas et al. 2001, Nemec et al. 2008].

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Defi nition

Fig. 1b: Physical precipitation of Midazolam as a result of an unfavorable pH medium [Riemann et al. 2005].

Fig. 1a: Chemical precipitation of Midazolam (turbidity) and Ketamin (particle formation) [Riemann et al. 2005].

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1. Physical reactions continued ...The pH-value and the buffer capacity (pKa value) of the IV solutions and the drugs used are major factors responsible for physical interactions [Newton 2009].

The situation in an infusion regimen is specific to the combination of drugs and solution used. Usually, the drug has the greatest influence and therefore defines the pH-value of the solution in-fused. Many drugs are weak bases, present as the water soluble salts of the corresponding acids. Changes in pH-value in the infu-sion tubing, e.g. from simultaneous addition of another drug, may release the bases from their salts. Because of the low aqueous solubility of such bases, particles may precipitate (Fig.1). The process of precipitation is influenced by the relative quantity of the drugs added, as well as their buffering capacity. These pH-dependent precipitation reactions are usually very rapid and can be identified within a few centimeters in the infusion tubing system. They can visibly be observed as crystals, haziness or turbidity (Fig.1+2) [Newton 2009]. Precipitations based on drug incompatibilities are responsible for the most common particle formation seen in complex ICU infusion lines [Schröder 1994].

Further invisible physical incompatibilities are reactions between drugs and plastic materials (adsorption effects). This leads to the drugs becoming immobilized at the inner surface of infusion containers or infusion lines and so lowers the concentration and drastically decreases the quantity of the drug administered to a patient [Trissel 1996].

2. Chemical reactionsA chemical incompatibility means that the drug is chemically de-graded, due to oxidation, reduction, hydrolysis, or decomposition. Chemical reactions can manifest themselves through turbidity, precipitation and color changes.

As a consequence, the amount of the active agent decreases and / or toxic by-products form [RCN 2005, Douglas et al. 2001, Höpner et al. 2003].

Definition

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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.

Defi nition

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CausesIncompatibilities of 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 infusion line (simultaneous infusion) and/or IV container - administered one after the other, but within the same infusion line � drugs and adjuvants (preservative, buffer, stabilizer, solvent)� drugs and materials of IV containers (e.g. PVC) or medical devices, which can concern the nature of the material used and/or reactions at the inner surface (e.g. adsorption)[Trissel 1996, Giki et al. 2000, Newton 2009]

Incompatible drugs in combi-nation with any other drug

Aminoglycosides

Chlordiazepoxide

Diazepam

Digitalis glycosides

Pentobarbital

Phenytoin

Secobarbital

Sodium bicarbonate

Theophylline derivatives

Drugs with limited compatibility

Alprostadile

Clonidine

Dobutamine

Dopamine

Doxaprame

Epinephrine

Glycerol trinitrate

Milrinon

Norepinephrine

Sodium nitroprusside

Examples of drug-drug incompatibilities [Josephson 2006, Höpner et al. 2003]

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Causes

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CausesIncompatibilities of 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 infusion line (simultaneous infusion) and/or IV container - administered one after the other, but within the same infusion line � drugs and adjuvants (preservative, buff er, stabilizer, solvent)� drugs and materials of IV containers (e.g. PVC) or medical devices, which can concern the nature of the material used and/or reactions at the inner surface (e.g. adsorption)[Trissel 1996, Giki et al. 2000, Newton 2009]

Drugs with limited compatibility

Alprostadile

Clonidine

Dobutamine

Dopamine

Doxaprame

Epinephrine

Glycerol trinitrate

Milrinon

Norepinephrine

Sodium nitroprusside

Fig. 3: Main causes of incompatibilities in standard IV therapy.

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Causes

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The unintended presence of precipitation and toxic products can cause various negative consequences for the patient. This can range from thrombophlebitis up to multi-organ failure. The reduc-tion or elimination of the active drug can lead to a therapeutic failure. The extent of the damage mainly depends on the patient’s condition (age, weight, nature, severity of the disease etc.) and on the type of drug administered. Consequences of physicochemical drug incompatibilities are particularly severe in neonate and pediatric patients [Höpner 2007].

Consequences for the patient

�damage from toxic products

�particulate emboli from crystallization and separation

�tissue irritation due to major pH changes

�therapeutic failure

Consequences

There is little published scientific information about the frequencyof drug incompatibility reactions. In one study, incompatibility was investigated in a pediatric intensive care ward showing that 3.4 % of drug combinations were incompatible and thus potentially dan-gerous [Gikic et al. 2000]. A life threatening nature was found for 26 % of incompatibilities in an intensive care unit (ICU) by Tissot et al. [2004]. Another survey collected 78 different medication regimes and found 15 % with incompatibility reactions [Vogel Kahmann et al. 2003]. Taxis and Barber [2004] reported that in the ICU clinical incompatibilities can contribute to 25 % of medication errors. Further publications showed that, depending on the ward type, up to 80 % of IV drug doses were prepared with the wrong diluent [Cousins et al. 2005, Hoppe-Tichy et al. 2002].

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Financial impact

Adverse eff ects of drug incompatibilities extend periods of patients’ hospitalization and the total costs for hospitals.

Severe respiratory complications caused by toxic drug-drug interactions may lead to an additional cost for the healthcare provider of up to 56,670 € per single case.

Consequences

Risk related costs for the healthcare institutionA cost evaluation of the risk can be done by assigning costs to their related clinical treatment and resulting extended length of stay. The cost can be calculated using the average daily cost [Gianino 2007, Bertolini 2005] of the expected clinical treatment. Fig. 4 shows the results of such a calculation for selected examples of complications.

ConclusionThe prevention of adverse drug events due to drug-drug inter-actions can result in budget savings for the healthcare provider. In the case of severe complications which require full ICU treatment for diverse days of hospitalization, a hospital may save between 7,556 € and 56,670 € per single case.

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

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Fig. 7: Color coding and drugseparation to prevent drug incompatibilities through a clear indica-tion of the drug.

Fig. 5: Assessment and planning of regimes to avoid mixing of drugs, which have to be administered separately.

Fig. 6: Compatibility checking using available litera-ture, databases, services and information material.

Preventivestrategies

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Prevention

�plausibility check

�strict indications for each drug preparation

�separation of drug doses by time and place

�consistent check of alternative modes of administration

�usage of multi-lumen catheters

Protection of particle infusion

�use appropriate in-line fi lters

Preventive strategiesDangerous incompatibilities can be prevented by

� a plausibility check regarding the SPC and available sources on compatibility information, also considering the material used for therapy (e.g. diluent, IV container, IV lines) and the infusion regimen (Fig. 5)

� individual labeling for each drug preparation (including drug, concentration, patient name) (Fig. 7)

� consistently checking alternative modes of administration and/or using multi-lumen catheters (Fig. 6)

� separating the drug doses by time and place. This can include the rinsing of the infusion system with a neutral IV solution prior to the application of 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 fi lters can reduce infl ux of particles which re-sult from incompatibilities. Moreover, they can be used to monitor physical and chemical incompatibilities. In-line fi lters are able to retain solid particles of at least 0.2 µm [Schröder 1993, Schröder 1994]. As a consequence, the fi lter may block. This is not a mal-function of the fi lter, but should initiate a check of the medication in order to eliminate any incompatibility.

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Intrafi x® SafeSet Neutrapur® (PVC free)Prevention of interactions between certain drugs and material:�These infusion lines may be used with drugs which are not recommended to be applied with PVC material, e.g. Taxol.

ConComp®Free database on drugs compatible with Ecofl ac® plus. � Off ers information on interactions between certain drugs, carrier solutions and container materials. � Off ers overview of scientifi c literature on drug compatibility with the container.

Ecofl ac® plusThe state of the art IV solution container that off ers safe and convenient application of all IV procedures from drug admixture to drug delivery. Container based incompatibilities are prevented by a special polyethylene container material which is:� Chemically inert.� Toxicologically safe� Free from plasticizers, additives and other compounds. � Free from substances that may potentially migrate into the fi nished preparation.

Riskprevention

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Omnifl ush®Prefi lled fl ush syringe for safe and convenient fl ushings with saline solution.

Certofi x® Multilumen CathetersCentral venous catheters for high-level and versatile IV therapy.Multilumen catheters prevent drug incompatibilities by� Separate lumens (distal, middle, proximal) averting the mixing of solutions and drugs.� Separate vents achieving an immediate dilution of the individual solution/drug in the blood, high enough to prevent further incompatibility reaction.

Intrapur® and Sterifix® Infusion FiltersA whole range of fi lters for safe infusion therapy.�Retains solid particles and precipitations of drug incompatibilities preventing their infl ux into the organism. �Functions like an indicator when fi lter blocks as a result of chemical or physical reactions.

cross-section

Risk

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LiteratureCraven RF, Hirnle CJ. Chapter 29: Medication administration. In: Craven RF, Hirnle CJ. Fundamentals of nursing – human health and function. 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 of nursing – human health and func-tion. 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 administra-tion: a multicentre audit in UK, Germany and France. Qual Saf Health Care 2005; 14: 195-195

Douglas JB, Hedrick C. Pharmacology. In: Perucca R Infusion therapy equipment: types of infusion therapy equipment. In: Infusion thera-py in clinical practise. Philadelphia: Saunders 2001; 176-208

Gianino MM, Vallino A, Minniti D, Abbona F, Mineccia C, Silva- plana P and Zotti CM. A method to determine hospital costs associated with nosocomial infections (transl), Ann Ig 2007; 19(4): 381-392

Gikic M, Di Paolo ER, Pannatier A and Cotting J. Evaluation of phys-icochemical incompatibilities during parenteral drug administration in a paediatric intensive care unit. Pharm World Sci 2000; 22(3): 88-91

Literature

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Höpner JH, Schulte A, Thiessen J, Knuf M and Huth RG. Preparation of a compatibility chart for intravenous drug therapy in neonatal and pediatric intensive care units. Klin Padiatr 2007; 219(1): 37-43

Hoppe-Tichy T, Noe-Schwemm S, Wahlig A and Taxis K. Medika-tionsfehler bei der Applikation Parenteraler Arzneimittel. [Medica-tion errors in parenteral drug administration.] Krankenhaus-pharmazie 2002; 23:11-17 in German

Josephson DL. Risks, complications, and adverse reactions associated with intravenous infusion therapy. In: Josephson DL. Intravenous infusion therapy for medical assistants. The American association of Medical Assistants. Clifton 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 of the recent literature. Drug Saf 2007; 30(5): 379-407

Nemec K, Kopelent-Frank H, Greif R. Standardization of infusion so-lutions to reduce the risk of incompatibility. Am J Health System Pharm 2008; 65(Sep): 1648-1654

Newton, D. Drug incompatibility chemistry. Am J Health Syst Pharm 2009; 66(Feb): 348-357

RCN. Royal College of Nursing. Standards for infusion therapy. 2005

Riemann T, Schröder F. More eff ective prevention of incompatibility reactions through the use of four lumen central venous catheters in critically ill patients. Pfl egenIntensiv 2005; 2(1): 57

Schröder F. Kompatibilitätsprobleme in der Intensivmedizin. Infusionsther Transfusionsmed 1994; 21: 52-58

Schröder F. Ursachen und Prävention von Inkompatibilitäten in der Intensivmedizin. In: Heeg P, Lenz G. Infusionstherapie. Melsungen: Bibliomed 1993; 27-41

Trissel LA. Handbook on Injectable Drugs. 9th ed. Bethesda: American Society of 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

Vogel Kahmann I, Bürki R, Denzler U, Högler A, Schmid B and Splis-gardt H. Incompatibility reactions in the intensive care unit. Five years after the implementation of a simple “colour code system”. Anaesthesist 2003; 52(5): 409-412

Taxis K, Baber N. Incidence and severity of intravenous drug errors in a German hospital. Eur J Clin Pharmacol 2004; 59: 815-817

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Nr. 6069092 Edition: 03/2011

B. Braun Melsungen AG | Hospital Care | 34209 Melsungen | GermanyTel. +49 5661 71-0 | www.bbraun.com | www.safeinfusiontherapy.com

The summarized scientifi c information in this document has been prepared for healthcare professionals. It is based on an analysis of public literature and guidelines. The intention is to give an introduction to the risks commonly associated with infusion therapy and to increase the awareness of healthcare workers to these kinds of problems. Due to its summary nature, this text is limited to an overview and does not take into account all types of local conditions. B. Braun does not assume responsibility for any consequences that may result from therapeutical interventions based on this overview.