SYSTEM~1

Review Article

Systematic review of physical and chemical compatibility ofcommonly used medications administered by continuous infusionin intensive care units

Salmaan Kanji, PharmD; Jason Lam, BSc, Pharm; Christel Johanson, BSc, Pharm;Avinder Singh, BSc, Pharm; Rob Goddard, BSc, Pharm; Jennifer Fairbairn, BSc, Pharm;Tammy Lloyd, BSc, Pharm; Danny Monsour, BSc; Juzer Kakal, MSc

Critically ill patients cared forin intensive care units (ICUs)often require multiple intra-venous medications adminis-

tered by continuous infusion. Separatevenous access sites for each drug infusionwould be ideal, but in reality, the numberof drug infusions often exceeds the num-ber of available ports on central and pe-ripheral venous access devices. In thesesituations, potential solutions include ei-ther obtaining additional venous accessor infusing two drugs through the same

port through a y-site connector in whichthe separately prepared drugs mix to-gether in the lumen of the catheter im-mediately before entering the blood-stream. For two drugs to be infusedtogether through a y-site, they need to beat least physically compatible. Physicalcompatibility refers to the absence of anyobviously visible signs of incompatibilitywhen two drugs are mixed in a 1:1 ratio(i.e., gross precipitation, color change,gas production). (1, 2) In contrast, drugsthat are mixed together in the same bagor syringe must also be chemically stablein combination. Chemical compatibilityrequires analytical techniques such ashigh-performance liquid chromatogra-phy to confirm at least 90% availability ofboth drugs in combination over the du-ration of mixing (3). The primary reasonfor differentiating between these twocompatibilities is based on the time thatboth drugs are in contact with eachother. In the case of y-site administra-tion, the contact time is often as little as1–2 mins depending on the flow rates of

the infusions, whereas drugs that aremixed together in the same bag or sy-ringe can have a much longer time inwhich chemical reactions can take place(i.e., hours to days). Hence, chemical sta-bility dictates the duration that drugs canbe mixed together in bags or syringes (3).

A lack of supporting data is often en-countered for common drug combina-tions intended to be infused togetherthrough a y-site connector. In this event,nurses are often instructed to obtain ad-ditional venous access for the sole pur-pose of drug infusion. However, venousaccess devices in critically ill patientshave been associated with a variety ofnegative outcomes arising from mechan-ical, infectious, and thrombotic compli-cations (4–6). In practice, additional ve-nous access may not always be practicalor feasible. We have recently conductedan observational study of 434 patients in13 Canadian ICUs suggesting that inap-propriate y-site combinations of continu-ously infused drugs are common (7).Among all patients, the prevalence of in-

From the Departments of Pharmacy (SK, JL, CJ,AS, RG, JF, TL) and Critical Care (SK), The OttawaHospital, and the Clinical Epidemiology Program (SK,DM, JK), The Ottawa Hospital Research Institute, Ot-tawa, Ontario, Canada.

The authors have not disclosed any potential con-flicts of interest.

For information regarding this article, E-mail:[email protected]

Copyright © 2010 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e3181e8adcc

Objective: To quantify the physical and chemical stability datapublished for commonly used continuously infused medications inthe intensive care unit and to evaluate the quality of the studiesproviding these data.

Data Sources and Study Selection: We conducted a systematicelectronic literature search of MEDLINE, EMBASE, and Interna-tional Pharmaceutical Abstracts as well as the references ofelectronic drug compatibility textbooks for all English and Frenchlanguage research publications evaluating the physical com-patibility or chemical stability of the 820 possible two-drugcombinations of 41 commonly used drugs in an adult intensivecare unit.

Data Extraction and Synthesis: A total of 93 studies comprisedof 86 (92%) studies evaluating physical compatibility and 35(38%) studies evaluating chemical compatibility of at least onedrug combination of interest were included. Physical and/orchemical compatibility data exist for only 441 of the possible 820

two-drug combinations (54%), whereas chemical compatibilitydata exist for only 75 (9%) of the possible combinations. Of the441 combinations for which compatibility data are available, 67(15%) represent incompatible combinations and 39 (9%) hadconflicting data in which both compatible and incompatible datawere identified.

Conclusions: Physical compatibility studies that provide thebasis for y-site compatibility are lacking for commonly usedmedications in intensive care unit patients and may contribute tounsafe medication practices. Furthermore, the heterogeneity inthe methodology of these studies likely contributes to the commonfinding of conflicting data for specific combinations of drugs. Futurestudies should apply similar methodologic and reporting principles tobe able to reproduce and compare outcomes both clinically and inthe laboratory. (Crit Care Med 2010; 38:1890–1898)

KEY WORDS: physical compatibility; chemical compatibility; druginfusions; intensive care unit

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appropriate combinations (defined asdata supporting an incompatibility or alack of supportive data) was 8.5%. Theprevalence increased to 18.7% in thosepatients receiving at least two continu-ously infused drugs. We hypothesize thatthis high prevalence of inappropriatepractice is, in part, the result of a relativelack of compatibility data (chemical orphysical) for commonly administereddrugs through continuous infusion inICU patients. This systematic review wasconducted to quantify the physical andchemical stability data published forcommonly used continuously infusedmedications in the ICU and to evaluatethe quality of the studies providing thesedata.

METHODOLOGY

Search Strategy. We conducted a system-atic search of MEDLINE, EMBASE, and Inter-national Pharmaceutical Abstracts from 1966until September 2009 to identify research re-ports of chemical stability or physical compat-ibility involving two or more of 41 predeter-mined drugs commonly administered throughcontinuous infusion to critically ill ICU pa-tients. This list of drugs was determined basedon Canadian use rates from a previously con-ducted multicenter observational study (7).Databases were searched using a combinationof the terms “drug compat$,” “drug incom-pat$,” “drug stability,” “y-site,” and “y-injection” in addition to text words for thedrugs of interest (Appendix 1). Reference listsof published articles as well as electronic drugcompatibility databases, including Microme-dex, King’s Guide, Trissel’s Tables, and Factsand Comparisons, were manually screened foradditional studies. The search strategy wasreviewed by an information specialist and con-ducted by a member of our team (JL). Twoexperienced practitioners (SK and JL) inde-pendently reviewed all citations retrieved fromthe search to identify potentially relevantstudies.

Study Selection. To be eligible for inclu-sion in this review, published peer-reviewedpapers in either French or English had todescribe the physical compatibility or chemi-cal stability of at least one two-drug combina-tion involving two or more of the drugs listedin the search strategy. The paper also had tohave some description of study methodologyregardless of publication type (i.e., researchpublication, letter, short report). Case reportsstrictly describing clinical experiences and re-view articles were excluded, but their refer-ences were manually searched for potentiallyrelevant studies.

Data Extraction and Risk of Bias. Using apilot-tested, standardized data extractionform, data describing study methodology,components of physical compatibility, analyt-

ical methods of chemical stability, and com-patibility of all potential combinations ofdrugs of interest were collected by two inde-pendent reviewers. Pilot testing of the casereport form involved iterations over time byall investigators using ten papers (which weresubsequently included in this review) beforefinal use. Discrepancies of data interpretationwere resolved by consensus using a third re-viewer. Quality assessment tools were devel-oped for physical compatibility studies andchemical stability studies. Given that no pub-lished, validated quality assessment instru-ments were available, criteria for each weredeveloped from published opinion papers onthe conduct of stability and compatibilitystudies (1–3, 8, 9), review and consensusamong investigators, and external expert re-view (see Acknowledgments). The quality as-sessment tool for physical compatibility stud-ies consisted of eight questions, including thefollowing. 1) Was precipitate formation evalu-ated? 2) Was color change evaluated? 3) WaspH evaluated at time zero and over time? 4)Was gas production evaluated? 5) Was testingdone in replicate? 6) Were the drug diluentsdescribed for all drugs? 7) Are drug manufac-turers and lot numbers reported? 8) Was thestudy methodology described? (includingnumber and frequency of observations, dura-tion of study, testing containers, and studyconditions, including temperature). The qual-ity assessment tool for chemical compatibilitystudies consisted of six questions, includingthe following. 1) Are the study materials de-scribed, including drug concentrations, drugdiluents, testing containers and drug manu-facturers, and lot numbers? 2) Are testing con-ditions described, including temperature andlight? 3) Are the analytical methods describedor referenced? 4) Is the validation of the sta-bility indicating analytical technique de-scribed or referenced? 5) Is there a time zeroanalysis? 6) Are assays performed in replicate?

Data Synthesis. Kappa coefficients werecalculated to assess the interrater agreementbetween reviewers for study inclusion andeach quality assessment criterion. Drug com-binations for which data were available werecategorized as compatible or incompatible asconcluded by the authors of each study. Com-binations for which there were conflicting re-sults (i.e., one study states compatible,whereas another states incompatible) wereidentified and labeled as such. Compatibilitydata for chemical stability studies alone andalso the combined data for chemical and phys-ical stability studies were summarized in tableform. Tables were created with all 41 drugs ofinterest listed on both the y- and x-axes withcorresponding boxes for each of the 820 pos-sible two-drug combinations. Each potentialcombination was assigned “C” for compatible,“I” for incompatible, “I/C” if two or more stud-ies reported conflicting results, or left blank ifno data were available. Data extracted describ-ing study methodology and each component

of the quality assessment tools were summa-rized using proportions.

RESULTS

Study Selection. The initial search ofelectronic databases yielded 1945 cita-tions. After the initial screen, 146 poten-tial papers were retrieved and reviewedfor eligibility by two independent review-ers. Fifty-three papers were excluded (nodrug combinations of interest [n � 37];not a research publication [n � 16]) leav-ing 93 studies that met inclusion criteriaand underwent data extraction (10–102).The calculated � coefficient for study inclu-sion was 0.978 (95% confidence interval:0.956–1.0) after the independent screenand 1.0 after consensus. Of these 93 stud-ies, 86 (92%) evaluated physical compati-bility (10–14, 16–33, 35–64, 66–73, 76–80, 82–98, 100 –102) and 35 (38%)evaluated chemical compatibility (10, 16,19–23, 26, 34, 39, 40, 43, 48, 49, 51–53, 55,56, 58, 59, 61, 62, 65, 74, 75, 78–82, 88, 98,99, 101) of at least one drug combination ofinterest.

Compatibility Data. Physical andchemical compatibility of the drugs ofinterest are summarized in Figures 1 and2. Physical and/or chemical compatibilitydata exist for only 441 of the possible 820two-drug combinations (54%), whereaschemical compatibility data exist for only75 (9%) of the possible combinations. Ofthe 441 combinations for which compat-ibility data were available, 67 (15%) werefound to be incompatible combinations(Table 1). Thirty-nine combinations (9%)had conflicting data in which both com-patible and incompatible data were iden-tified for the same drug combination. Thepossible reasons for conflicting studiesare summarized in Table 1. Of the 75combinations for which chemical stabil-ity data were available, 17 (23%) werefound to be incompatible based on a re-duction in drug availability.

Study Methodologies. Multiple meth-ods of assessing physical compatibility(n � 86) were often used in all of thepapers examined. Visual inspections forcolor change and precipitate againstblack and white backgrounds were usedin 46 studies (53%). Visual inspectionswere aided by magnification in 23 (25%)studies, filtration in five (6%) studies,electron microscopy in two (2%) studies,and a Tyndall beam in seven (8%) stud-ies. Absorbance was measured using aspectrophotometer in five (6%) studies,whereas turbidity was measured using a

1891Crit Care Med 2010 Vol. 38, No. 9

turbidimeter in five (6%) studies. Onestudy used a HIAC-Royce particle sizerand counter (25). Change in pH over timewas measured in 39 of 86 (45%) studies ofphysical compatibility and two studies de-fined a change in pH as being a measureof incompatibility a priori (�2 pH changein one and �0.5 pH change in the oth-er).(35, 100) Color and gas productionwere always assessed visually. High-performance liquid chromatography wasthe most common analytical technique(28 [80%]) in the 35 studies that evalu-ated chemical stability. Other techniquesused included thin layer chromatography(n � 3) and binding assays such as radio-immunoassays (n � 1) and enzyme-linked immunosorbent assays (n � 1).

Risk of Bias. Quality assessment char-acteristics for the 86 papers that evalu-ated physical compatibility are presentedin Table 2. Quality assessment character-istics of the 35 papers that evaluatedchemical compatibility are summarizedin Table 3. Drug diluents were reportedfor all drugs studied in 39 of 93 studies(42%). Drug diluents were reported for at

least one drug in 87 of 93 studies (94%)and multiple diluents were tested for atleast one drug in 30 of 93 studies (32%).Dwell times (duration of mixing) weredescribed in 89 of 93 studies (96%) andranged from 5 mins to 90 days (dwelltime �1 hr: n � 7 [8%]; 2–4 hrs: n � 26[29%]; 5–24 hrs: 35 [39%]; �24 hrs: 21[24%]). Glass test tubes or containerswere the most commonly described test-ing vessel (69 of 93 [74%]). Other vesselsincluded y-site tubing (six of 93 [6%]),polyvinyl chloride bags (ten of 93 [11%]),syringes (seven of 93 [8%]), and one im-plantable insulin pump (one of 93 [1%]).Testing was done in replicate in 61 of 93(66%) using more than one assessor infive of 93 (5%) studies. Study sampleblinding was never used.

DISCUSSION

For two drugs to be administered to-gether through a y-site connector, theymust be at least physically compatible,whereas studies of chemical stability are

required before two drugs can be mixedtogether in the same container (i.e., in-travenous bag, syringe, etc). This system-atic review not only identifies that thevast majority of compatibility studies areof physical compatibility, but that almosthalf of the potential combinations of the41 most commonly used ICU drugs havenever been studied. This has direct impli-cation on patient safety in the ICU andalso safe medication practices. It is pos-sible that the relative paucity in compat-ibility data may result in the placement ofadditional venous access devices in pa-tients for the sole purpose of drug admin-istration opening a possibility for infec-tions, mechanical, and thromboticcomplications. We have previously de-scribed that as a result of the absence ofsupportive compatibility data, inappro-priate combinations of drug infusions arebeing infused together through a y-site in8.5% of all patients admitted to CanadianICUs (7). Although the potential for pre-cipitation appears to be high in the ab-sence of physical compatibility data, theclinical consequences of such an incident

Figure 1. Physical compatibility and chemical stability summary. C, compatible; I (light gray), incompatible; I/C (dark gray), conflicting data; TPN, totalparenteral nutrition.


are either not always clinically obvious orunderreported. We found two publishedreports of fatal pulmonary embolism at-tributed to incompatible combinations ofdrug infusions.(103, 104) Mechanical fail-ure of the venous access catheter is prob-ably more common than embolic clinicalconsequences.

The most common reason for a drugcombination to be deemed incompatiblein this review was precipitation on mix-ing. Most often the precipitates were ob-served by the unaided eye against a blackbackground, but other techniques suchas turbidimetric analysis and absorbancemeasurement using a spectrophotometerhave also been used. The need for thesesophisticated assessment techniques isunclear and the clinical value of thesetechniques has never been studied. Onepaper reviewed suggests that turbidimet-ric analysis may not be as reliable asvisual assessment, especially when theprecipitate is slight (35). Several studiesattempted to evaluate physical compati-bility of drugs in lipid emulsions (i.e.,propofol, parenteral nutrition with lip-ids). These studies considered disruptionof the emulsion as a sign of incompati-bility and this was described as “cream-ing,” “phase separation,” “cracking,” or“oiling out.” One study of propofol com-patibility used a centrifuge to separatethe oil phase from the aqueous phase andcombined secondary drugs with the aque-

ous phase (67). The same study alsoadded methylene blue dye to the intactpropofol before mixing with other drugs.The authors claim that the addition ofdye improves the visualization of globulesand phase separation. The validity of thismethodology should be questioned, how-ever, because separation of the aqueousand lipid phases should reduce the solu-bility of propofol in itself. Furthermore, itis unclear if the addition of dye to theintact emulsion would affect the integrityof the emulsion itself or the drug in so-lution.

We identified a considerable degreeof heterogeneity with respect to themethodology of physical compatibilitystudies regarding the components de-termining incompatible combinationsof drugs, the conditions under whichthe study was conducted, and also theduration of study. We hypothesize thatthis is a major reason why conflictingcompatibility results were found for al-most 10% of the combinations studied todate. Wall charts and printed tables arecommonly used in ICUs and drug infor-

Figure 2. Chemical stability summary. C, compatible; I (light gray), incompatible; I/C (dark gray), conflicting data; TPN, total parenteral nutrition.

Table 1. Incompatible and conflicting drug com-binations

No. (%)

Incompatible drug combinations(n � 67)

Precipitation 48 (72)Reduced potency 12 (18)Change in color 3 (4)Disruption of emulsion (propofol

and/or TPN with lipids)4 (6)

Possible reasons for conflictingstudy outcomes (n � 39)

Different drug concentrationsstudied

24 (62)

Different drug diluents studied 4 (10)Different drug manufacturers/

brands6 (15)

Different study durations 5 (13)


mation centers to identify compatibledrug combinations, but these tools rarelydescribe the study conditions (i.e., drugdiluents and concentrations, study dura-tion, drug manufacturer and lot num-bers, etc). All of these parameters areimportant to consider when evaluatingthe external validity of these compatibil-ity studies (2). For example, heparinmixed in dextrose solutions will precipi-tate with dobutamine but not if mixed insaline (35). Older formulations of dobut-amine would oxidize and turn pink overtime, whereas current formulations ofdobutamine include an antioxidant thatprevents this color change (34, 35).Lorazepam becomes unstable in dextroseand may precipitate when the tempera-ture is �25°C, whereas mannitol willcrystallize �15°C (71, 105). Dobutamineand calcium chloride are compatible at 3hrs but a precipitate may form after 20hrs, only at high concentrations (33, 35,47, 55). Not only is it important to con-sider these details of compatibility re-ports, but it is even more important thatpublications of these types of studies con-sistently and uniformly report this vitalinformation (1, 2). Although the provi-sion of a compatibility table in this articlemay seem contradictory, it is not ourintent that this be used clinically withoutsupporting information as previouslystated. Our intent was to present our

findings in a manner that the paucity ofavailable compatibility data be visuallyobvious.

Our review identified that pH mea-surement was inconsistently applied inphysical compatibility studies, possiblybecause the clinical significance of a pHchange over time is unclear. Only twostudies defined a threshold for change inpH over time that would indicate physicalincompatibility (35, 100). Neither studyreferenced their a priori-defined thresh-old (one used a change of �0.5 pH unitsand the other used a change of 2 pHunits) with clinical or biochemical justi-fication. Most drug incompatibilities area manifestation of acid base changes andmost often pH measurement can be usedto explain or predict drug incompatibili-ties (3). However, after two drugs aremixed together, a change in pH over timemight indicate an ongoing chemical re-action that may not be visually obviousbut perhaps clinically relevant. In thisevent, it would be prudent to label thesecombinations incompatible pendingchemical confirmation; however, sup-portive evidence for a meaningful changein pH over time is lacking. Irrespective ofwhether a change in pH over time indi-cates an ongoing chemical reaction, fu-ture studies should measure pH at leastas a means to explain potential incompat-ibilities.

We also observed significant heteroge-neity among physical compatibility stud-ies with respect to the duration of study.More than 60% of studies observed drugcombinations for �4 hrs. In chemicalstability studies, the duration of observa-tion dictates the duration of stability thatcan be afforded to a combination ofdrugs, but clinical interpretation of phys-ical compatibility studies �4 hrs be-comes complicated. y-site administrationof drug combinations is based on theprinciple that drugs would be physicallymixed in small volumes for short dura-tions of time, but physical compatibilitystudies that find combinations incompat-ible at 24 hrs are difficult to interpret.From our own observations, the largestvolume distal to the y-connector is ap-proximately 1.1 and 1.2 mL within a sin-gle- and triple-lumen central venous ac-cess catheter, respectfully. Even at a lowinfusion rate of 1 mL/hr for both drugsadministered through the y-site, themaximum time during which drugs mixwithin the lumen of the catheter is a little�1 hr. Having said this, it is commonpractice to piggyback some form of intra-venous fluid to low flow infusions to aminimum of 10 mL/hr to maintain pa-tency of the catheter. This would suggestthat the contact time for even the slowestinfusions should rarely be longer than 10mins. Therefore, unlike chemical stabilitystudies, longer durations of study (i.e.,�2 hrs) do not infer increased method-ologic rigor for physical compatibilitystudies and may in fact have reduced clin-ical applicability.

Almost all studies evaluated in thisreview relied on subjective visual assess-ment from a single assessor. The subjec-tive nature of these assessments lendsitself to bias that is easily addressed byusing multiple assessors. Because drugincompatibility is most often a functionof pH, drugs known to have extremes ofpH (i.e., midazolam, furosemide, sodiumbicarbonate) are more likely to have pre-dictable physical signs of incompatibilitywhen mixed with other drugs. No studyreviewed incorporated any blinding strat-egies to further minimize bias. There isno logistic reason why these types ofstudies could not be blinded and the lackof blinding may be one contributing fac-tor to the high frequency of conflictingreports identified by this review.

As expected, chemical stability studieswere encountered less frequently fromour search strategy. This disproportion-ate availability of data may not be clini-

Table 2. Quality assessment for physical compatibility studies (n � 86)

Quality Indicator No. of Studies (%) Kappa (95% CI)

Precipitate formation evaluated 86 (100) 1.0Color change evaluated 75 (87) 1.0pH change over time measured 39 (45) 0.95 (0.89–1.0)Gas production evaluated 45 (53) 1.0Testing was done in replicate 58 (67) 0.95 (0.87–1.0)Methodology described (including number and

frequency of observations, duration of study, studyconditions AND testing containers)

68 (79) 0.88 (0.79–1.0)

Drug diluents reported for all drugs studied 35 (41) 0.95 (0.89–1.0)Drug manufacturers and lot numbers reported 68 (79) 0.97 (0.90–1.0)

CI, confidence interval.

Table 3. Quality assessment for chemical stability studies (n � 35)

Quality Indicator No. of Studies (%) Kappa (95% CI)

Study materials described 32 (91) 0.85 (0.55–1.0)Testing conditions described (temperature and light) 29 (83) 1.0Analytical methods described or referenced 32 (91) 0.85 (0.55–1.0)Validation of stability indicating analytical

technique is described or referenced28 (80) 0.91 (0.75–1.0)

Time zero analysis performed 30 (86) 1.0Assays are performed in replicate 25 (71) 1.0

CI, confidence interval.


cally important given the greater likeli-hood of a clinical scenario in which twodrugs are infused together through a y-site than the scenario in which the samecombination of drugs needs to be pre-pared in the same container. The mostcommon purpose of these studies was todetermine the duration of stability fortwo drugs intended to be mixed togetherin the same delivery vehicle (i.e., intrave-nous bag, syringe, etc). A variety of sta-bility indicating analytical methods wereused, usually dictated by the properties ofthe drug studied. High-performance liq-uid chromatography was used most of-ten, but one study assessed the stability ofsodium bicarbonate in parenteral nutri-tion formulations by measuring total CO2

concentrations as a measure of bicarbon-ate loss over time (49). Another studyused microcalorimetry to identify exo-thermic reactions as a marker of interac-tion between heparin and dopamine atlow concentrations (74). The validity andclinical applicability of these novel ana-lytical techniques is unclear. Given therelative paucity of chemical stability dataavailable for the drug combinations in-vestigated in this review, cliniciansshould be aware of the difference in clin-ical applicability between physical com-patibility studies and chemical stabilitystudies. Chemical stability cannot be in-ferred or assumed from physically com-patible drug combinations.

The methodologic heterogeneity de-scribed in this study highlights the needto improve the methodologic integrityand external validity of future compatibil-ity research. The most commonplacebedside tools used in clinical decision-making (i.e., wall charts, tables) do notprovide an easy way to evaluate the qual-ity of the data presented. This study ex-poses critical weaknesses in medication“best practices” and the fact that thequality of the data cannot be assumed.We strongly suggest that future physicaland chemical compatibility studies incor-porate all the items identified in our qual-ity assessment tools in addition to incor-porating multiple reviewers and blindingstrategies. Furthermore, a more compre-hensive approach to identifying whichdrugs to study is warranted as opposed tothe traditional approach in which oneprimary drug is studied in a handful ofarbitrarily chosen combinations. Finally,duration of study should be chosen basedon clinical applicability (i.e., if drugs areclinically mixed through a y-site for min-utes before being infused, there is no

justification for a physical compatibilitystudy that mixes drugs for days).

There are several limitations of thisreview. There may be published compat-ibility studies in other languages besidesEnglish and French, in non-peer-re-viewed journals and of other drugs com-monly used in the ICU in other countries.We intentionally limited the scope of thisreview to continuously infused drugs be-cause we felt that this was likely thegroup of medications most susceptible toy-site compatibility issues. Most ICU pa-tients had a dedicated line for intermit-tently administered medications and tim-ing of medication administration can bemodified to accommodate coinfusion in-compatibilities. However, there are stillsome medications that are administeredin the ICU through continuous infusionthat we did not include in our searchbecause our criteria for inclusion werebased on use rates (7). Potentially, thislist of drugs could also be expanded toinclude �-lactam antimicrobials, whichmay be administered as continuous infu-sions at some centers. We also had todevelop our own quality assessment toolsbecause there were no published, vali-dated tools appropriate for these types ofstudies. Although we did not validate ourinstrument, we report each item individ-ually rather than calculating a score.

CONCLUSIONS

Physical compatibility studies thatprovide the basis for y-site compatibilityare lacking for commonly used medica-tions in ICU patients and may contributeto unsafe medication practices, whichcould impact patient safety. Further-more, differences in the methodology ofthese studies likely contribute to thecommon finding of conflicting data forspecific combinations of drugs. For safeand effective care of our critically ill pa-tients, the healthcare team must be ableto rely on the integrity and safety of med-ication infusions. Availability of compre-hensive physical compatibility data is animportant step toward achieving such apractice. We therefore propose that fu-ture studies apply standardized method-ologic and reporting principles to be ableto contribute meaningful data that can bereadily applied to clinical use.

ACKNOWLEDGMENTS

We acknowledge the methodologiccontributions of Dr. Dean Fergusson, Mr.Lawrence Trissel, and Mr. Scott Walker.

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APPENDIX 1

Continuously Infused Drugs ofInterest Included in theSystematic Search

AcetylcysteineAmiodaroneArgatrobanCalcium chlorideCalcium gluconate


CisatracuriumDanaparoidDiltiazemDobutamineDopamineDrotrecogin alfaEpinephrine and adrenalineEsmololFentanylFurosemideHeparinHydromorphone

InsulinPotassium chlorideKetamineLabetalolLorazepamMannitolMagnesiumMetoprololMidazolamMilrinoneMorphineSodium bicarbonate

NitroglycerinNitroprussideNorepinephrine and noradrenalineOctreotidePantoprazoleThiopental and pentothalPhenylephrinePropofolTotal parenteral nutrition (with and

without lipids)VasopressinVerapamil


SYSTEM~1

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