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Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units

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

doi: 10.1097/CCM.0b013e3181e8adcc
Review Article

Objective: To quantify the physical and chemical stability data published for commonly used continuously infused medications in the intensive care unit and to evaluate the quality of the studies providing these data.

Data Sources and Study Selection: We conducted a systematic electronic literature search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts as well as the references of electronic drug compatibility textbooks for all English and French language research publications evaluating the physical compatibility or chemical stability of the 820 possible two-drug combinations of 41 commonly used drugs in an adult intensive care unit.

Data Extraction and Synthesis: A total of 93 studies comprised of 86 (92%) studies evaluating physical compatibility and 35 (38%) studies evaluating chemical compatibility of at least one drug combination of interest were included. Physical and/or chemical compatibility data exist for only 441 of the possible 820 two-drug combinations (54%), whereas chemical compatibility data exist for only 75 (9%) of the possible combinations. Of the 441 combinations for which compatibility data are available, 67 (15%) represent incompatible combinations and 39 (9%) had conflicting data in which both compatible and incompatible data were identified.

Conclusions: Physical compatibility studies that provide the basis for y-site compatibility are lacking for commonly used medications in intensive care unit patients and may contribute to unsafe medication practices. Furthermore, the heterogeneity in the methodology of these studies likely contributes to the common finding of conflicting data for specific combinations of drugs. Future studies should apply similar methodologic and reporting principles to be able to reproduce and compare outcomes both clinically and in the laboratory.

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

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: skanji@ottawahospital.on.ca

Critically ill patients cared for in intensive care units (ICUs) often require multiple intravenous medications administered by continuous infusion. Separate venous access sites for each drug infusion would be ideal, but in reality, the number of drug infusions often exceeds the number of available ports on central and peripheral venous access devices. In these situations, potential solutions include either obtaining additional venous access or infusing two drugs through the same port through a y-site connector in which the separately prepared drugs mix together in the lumen of the catheter immediately before entering the bloodstream. For two drugs to be infused together through a y-site, they need to be at least physically compatible. Physical compatibility refers to the absence of any obviously visible signs of incompatibility when two drugs are mixed in a 1:1 ratio (i.e., gross precipitation, color change, gas production). (1, 2) In contrast, drugs that are mixed together in the same bag or syringe must also be chemically stable in combination. Chemical compatibility requires analytical techniques such as high-performance liquid chromatography to confirm at least 90% availability of both drugs in combination over the duration of mixing (3). The primary reason for differentiating between these two compatibilities is based on the time that both drugs are in contact with each other. In the case of y-site administration, the contact time is often as little as 1–2 mins depending on the flow rates of the infusions, whereas drugs that are mixed together in the same bag or syringe can have a much longer time in which chemical reactions can take place (i.e., hours to days). Hence, chemical stability dictates the duration that drugs can be mixed together in bags or syringes (3).

A lack of supporting data is often encountered for common drug combinations intended to be infused together through a y-site connector. In this event, nurses are often instructed to obtain additional venous access for the sole purpose of drug infusion. However, venous access devices in critically ill patients have been associated with a variety of negative outcomes arising from mechanical, infectious, and thrombotic complications (4–6). In practice, additional venous access may not always be practical or feasible. We have recently conducted an observational study of 434 patients in 13 Canadian ICUs suggesting that inappropriate y-site combinations of continuously infused drugs are common (7). Among all patients, the prevalence of inappropriate combinations (defined as data supporting an incompatibility or a lack of supportive data) was 8.5%. The prevalence increased to 18.7% in those patients receiving at least two continuously infused drugs. We hypothesize that this high prevalence of inappropriate practice is, in part, the result of a relative lack of compatibility data (chemical or physical) for commonly administered drugs through continuous infusion in ICU patients. This systematic review was conducted to quantify the physical and chemical stability data published for commonly used continuously infused medications in the ICU and to evaluate the quality of the studies providing these data.

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METHODOLOGY

Search Strategy.

We conducted a systematic search of MEDLINE, EMBASE, and International Pharmaceutical Abstracts from 1966 until September 2009 to identify research reports of chemical stability or physical compatibility involving two or more of 41 predetermined drugs commonly administered through continuous infusion to critically ill ICU patients. This list of drugs was determined based on Canadian use rates from a previously conducted multicenter observational study (7). Databases were searched using a combination of the terms “drug compat$,” “drug incompat$,” “drug stability,” “y-site,” and “y-injection” in addition to text words for the drugs of interest (Appendix 1). Reference lists of published articles as well as electronic drug compatibility databases, including Micromedex, King's Guide, Trissel's Tables, and Facts and Comparisons, were manually screened for additional studies. The search strategy was reviewed by an information specialist and conducted by a member of our team (JL). Two experienced practitioners (SK and JL) independently reviewed all citations retrieved from the search to identify potentially relevant studies.

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Study Selection.

To be eligible for inclusion in this review, published peer-reviewed papers in either French or English had to describe the physical compatibility or chemical stability of at least one two-drug combination involving two or more of the drugs listed in the search strategy. The paper also had to have some description of study methodology regardless of publication type (i.e., research publication, letter, short report). Case reports strictly describing clinical experiences and review articles were excluded, but their references were manually searched for potentially relevant studies.

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Data Extraction and Risk of Bias.

Using a pilot-tested, standardized data extraction form, data describing study methodology, components of physical compatibility, analytical methods of chemical stability, and compatibility of all potential combinations of drugs of interest were collected by two independent reviewers. Pilot testing of the case report form involved iterations over time by all investigators using ten papers (which were subsequently included in this review) before final use. Discrepancies of data interpretation were resolved by consensus using a third reviewer. Quality assessment tools were developed for physical compatibility studies and chemical stability studies. Given that no published, validated quality assessment instruments were available, criteria for each were developed from published opinion papers on the conduct of stability and compatibility studies (1–3, 8, 9), review and consensus among investigators, and external expert review (see Acknowledgments). The quality assessment tool for physical compatibility studies consisted of eight questions, including the following. 1) Was precipitate formation evaluated? 2) Was color change evaluated? 3) Was pH evaluated at time zero and over time? 4) Was gas production evaluated? 5) Was testing done in replicate? 6) Were the drug diluents described for all drugs? 7) Are drug manufacturers and lot numbers reported? 8) Was the study methodology described? (including number and frequency of observations, duration of study, testing containers, and study conditions, including temperature). The quality assessment tool for chemical compatibility studies consisted of six questions, including the following. 1) Are the study materials described, including drug concentrations, drug diluents, testing containers and drug manufacturers, and lot numbers? 2) Are testing conditions described, including temperature and light? 3) Are the analytical methods described or referenced? 4) Is the validation of the stability indicating analytical technique described or referenced? 5) Is there a time zero analysis? 6) Are assays performed in replicate?

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Data Synthesis.

Kappa coefficients were calculated to assess the interrater agreement between reviewers for study inclusion and each quality assessment criterion. Drug combinations for which data were available were categorized as compatible or incompatible as concluded by the authors of each study. Combinations for which there were conflicting results (i.e., one study states compatible, whereas another states incompatible) were identified and labeled as such. Compatibility data for chemical stability studies alone and also the combined data for chemical and physical stability studies were summarized in table form. Tables were created with all 41 drugs of interest listed on both the y- and x-axes with corresponding boxes for each of the 820 possible two-drug combinations. Each potential combination was assigned “C” for compatible, “I” for incompatible, “I/C” if two or more studies reported conflicting results, or left blank if no data were available. Data extracted describing study methodology and each component of the quality assessment tools were summarized using proportions.

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RESULTS

Study Selection.

The initial search of electronic databases yielded 1945 citations. After the initial screen, 146 potential papers were retrieved and reviewed for eligibility by two independent reviewers. Fifty-three papers were excluded (no drug combinations of interest [n = 37]; not a research publication [n = 16]) leaving 93 studies that met inclusion criteria and underwent data extraction (10–102). The calculated κ coefficient for study inclusion was 0.978 (95% confidence interval: 0.956–1.0) after the independent screen and 1.0 after consensus. Of these 93 studies, 86 (92%) evaluated physical compatibility (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 of interest.

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Compatibility Data.

Physical and chemical compatibility of the drugs of interest are summarized in Figures 1 and 2. Physical and/or chemical compatibility data exist for only 441 of the possible 820 two-drug combinations (54%), whereas chemical compatibility data exist for only 75 (9%) of the possible combinations. Of the 441 combinations for which compatibility data were available, 67 (15%) were found to be incompatible combinations (Table 1). Thirty-nine combinations (9%) had conflicting data in which both compatible and incompatible data were identified for the same drug combination. The possible reasons for conflicting studies are summarized in Table 1. Of the 75 combinations for which chemical stability data were available, 17 (23%) were found to be incompatible based on a reduction in drug availability.

Figure 1

Figure 1

Figure 2

Figure 2

Table 1

Table 1

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Study Methodologies.

Multiple methods of assessing physical compatibility (n = 86) were often used in all of the papers examined. Visual inspections for color change and precipitate against black and white backgrounds were used in 46 studies (53%). Visual inspections were 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%) studies. Absorbance was measured using a spectrophotometer in five (6%) studies, whereas turbidity was measured using a turbidimeter in five (6%) studies. One study used a HIAC-Royce particle sizer and counter (25). Change in pH over time was measured in 39 of 86 (45%) studies of physical compatibility and two studies defined a change in pH as being a measure of incompatibility a priori (>2 pH change in one and >0.5 pH change in the other).(35, 100) Color and gas production were always assessed visually. High-performance liquid chromatography was the most common analytical technique (28 [80%]) in the 35 studies that evaluated chemical stability. Other techniques used included thin layer chromatography (n = 3) and binding assays such as radioimmunoassays (n = 1) and enzyme-linked immunosorbent assays (n = 1).

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Risk of Bias.

Quality assessment characteristics for the 86 papers that evaluated physical compatibility are presented in Table 2. Quality assessment characteristics of the 35 papers that evaluated chemical compatibility are summarized in Table 3. Drug diluents were reported for 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 at least one drug in 30 of 93 studies (32%). Dwell times (duration of mixing) were described in 89 of 93 studies (96%) and ranged from 5 mins to 90 days (dwell time ≤1 hr: n = 7 [8%]; 2–4 hrs: n = 26 [29%]; 5–24 hrs: 35 [39%]; >24 hrs: 21 [24%]). Glass test tubes or containers were the most commonly described testing vessel (69 of 93 [74%]). Other vessels included y-site tubing (six of 93 [6%]), polyvinyl chloride bags (ten of 93 [11%]), syringes (seven of 93 [8%]), and one implantable insulin pump (one of 93 [1%]). Testing was done in replicate in 61 of 93 (66%) using more than one assessor in five of 93 (5%) studies. Study sample blinding was never used.

Table 2

Table 2

Table 3

Table 3

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DISCUSSION

For two drugs to be administered together through a y-site connector, they must be at least physically compatible, whereas studies of chemical stability are required before two drugs can be mixed together in the same container (i.e., intravenous bag, syringe, etc). This systematic review not only identifies that the vast majority of compatibility studies are of physical compatibility, but that almost half of the potential combinations of the 41 most commonly used ICU drugs have never been studied. This has direct implication on patient safety in the ICU and also safe medication practices. It is possible that the relative paucity in compatibility data may result in the placement of additional venous access devices in patients for the sole purpose of drug administration opening a possibility for infections, mechanical, and thrombotic complications. We have previously described that as a result of the absence of supportive compatibility data, inappropriate combinations of drug infusions are being infused together through a y-site in 8.5% of all patients admitted to Canadian ICUs (7). Although the potential for precipitation appears to be high in the absence of physical compatibility data, the clinical consequences of such an incident are either not always clinically obvious or underreported. We found two published reports of fatal pulmonary embolism attributed to incompatible combinations of drug infusions.(103, 104) Mechanical failure of the venous access catheter is probably more common than embolic clinical consequences.

The most common reason for a drug combination to be deemed incompatible in this review was precipitation on mixing. Most often the precipitates were observed by the unaided eye against a black background, but other techniques such as turbidimetric analysis and absorbance measurement using a spectrophotometer have also been used. The need for these sophisticated assessment techniques is unclear and the clinical value of these techniques has never been studied. One paper reviewed suggests that turbidimetric analysis may not be as reliable as visual assessment, especially when the precipitate is slight (35). Several studies attempted to evaluate physical compatibility of drugs in lipid emulsions (i.e., propofol, parenteral nutrition with lipids). These studies considered disruption of the emulsion as a sign of incompatibility and this was described as “creaming,” “phase separation,” “cracking,” or “oiling out.” One study of propofol compatibility used a centrifuge to separate the oil phase from the aqueous phase and combined secondary drugs with the aqueous phase (67). The same study also added methylene blue dye to the intact propofol before mixing with other drugs. The authors claim that the addition of dye improves the visualization of globules and phase separation. The validity of this methodology should be questioned, however, because separation of the aqueous and lipid phases should reduce the solubility of propofol in itself. Furthermore, it is unclear if the addition of dye to the intact emulsion would affect the integrity of the emulsion itself or the drug in solution.

We identified a considerable degree of heterogeneity with respect to the methodology of physical compatibility studies regarding the components determining incompatible combinations of drugs, the conditions under which the study was conducted, and also the duration of study. We hypothesize that this is a major reason why conflicting compatibility results were found for almost 10% of the combinations studied to date. Wall charts and printed tables are commonly used in ICUs and drug information centers to identify compatible drug combinations, but these tools rarely describe the study conditions (i.e., drug diluents and concentrations, study duration, drug manufacturer and lot numbers, etc). All of these parameters are important to consider when evaluating the external validity of these compatibility studies (2). For example, heparin mixed in dextrose solutions will precipitate with dobutamine but not if mixed in saline (35). Older formulations of dobutamine would oxidize and turn pink over time, whereas current formulations of dobutamine include an antioxidant that prevents this color change (34, 35). Lorazepam becomes unstable in dextrose and may precipitate when the temperature is >25°C, whereas mannitol will crystallize <15°C (71, 105). Dobutamine and calcium chloride are compatible at 3 hrs but a precipitate may form after 20 hrs, only at high concentrations (33, 35, 47, 55). Not only is it important to consider these details of compatibility reports, but it is even more important that publications of these types of studies consistently and uniformly report this vital information (1, 2). Although the provision of a compatibility table in this article may seem contradictory, it is not our intent that this be used clinically without supporting information as previously stated. Our intent was to present our findings in a manner that the paucity of available compatibility data be visually obvious.

Our review identified that pH measurement was inconsistently applied in physical compatibility studies, possibly because the clinical significance of a pH change over time is unclear. Only two studies defined a threshold for change in pH over time that would indicate physical incompatibility (35, 100). Neither study referenced their a priori-defined threshold (one used a change of >0.5 pH units and the other used a change of 2 pH units) with clinical or biochemical justification. Most drug incompatibilities are a manifestation of acid base changes and most often pH measurement can be used to explain or predict drug incompatibilities (3). However, after two drugs are mixed together, a change in pH over time might indicate an ongoing chemical reaction that may not be visually obvious but perhaps clinically relevant. In this event, it would be prudent to label these combinations incompatible pending chemical confirmation; however, supportive evidence for a meaningful change in pH over time is lacking. Irrespective of whether a change in pH over time indicates an ongoing chemical reaction, future studies should measure pH at least as a means to explain potential incompatibilities.

We also observed significant heterogeneity among physical compatibility studies with respect to the duration of study. More than 60% of studies observed drug combinations for >4 hrs. In chemical stability studies, the duration of observation dictates the duration of stability that can be afforded to a combination of drugs, but clinical interpretation of physical compatibility studies >4 hrs becomes complicated. y-site administration of drug combinations is based on the principle that drugs would be physically mixed in small volumes for short durations of time, but physical compatibility studies that find combinations incompatible at 24 hrs are difficult to interpret. From our own observations, the largest volume distal to the y-connector is approximately 1.1 and 1.2 mL within a single- and triple-lumen central venous access catheter, respectfully. Even at a low infusion rate of 1 mL/hr for both drugs administered through the y-site, the maximum time during which drugs mix within the lumen of the catheter is a little >1 hr. Having said this, it is common practice to piggyback some form of intravenous fluid to low flow infusions to a minimum of 10 mL/hr to maintain patency of the catheter. This would suggest that the contact time for even the slowest infusions should rarely be longer than 10 mins. Therefore, unlike chemical stability studies, longer durations of study (i.e., >2 hrs) do not infer increased methodologic rigor for physical compatibility studies and may in fact have reduced clinical applicability.

Almost all studies evaluated in this review relied on subjective visual assessment from a single assessor. The subjective nature of these assessments lends itself to bias that is easily addressed by using multiple assessors. Because drug incompatibility is most often a function of pH, drugs known to have extremes of pH (i.e., midazolam, furosemide, sodium bicarbonate) are more likely to have predictable physical signs of incompatibility when mixed with other drugs. No study reviewed incorporated any blinding strategies to further minimize bias. There is no logistic reason why these types of studies could not be blinded and the lack of blinding may be one contributing factor to the high frequency of conflicting reports identified by this review.

As expected, chemical stability studies were encountered less frequently from our search strategy. This disproportionate availability of data may not be clinically important given the greater likelihood of a clinical scenario in which two drugs are infused together through a y-site than the scenario in which the same combination of drugs needs to be prepared in the same container. The most common purpose of these studies was to determine the duration of stability for two drugs intended to be mixed together in the same delivery vehicle (i.e., intravenous bag, syringe, etc). A variety of stability indicating analytical methods were used, usually dictated by the properties of the drug studied. High-performance liquid chromatography was used most often, but one study assessed the stability of sodium bicarbonate in parenteral nutrition formulations by measuring total co2 concentrations as a measure of bicarbonate loss over time (49). Another study used microcalorimetry to identify exothermic reactions as a marker of interaction between heparin and dopamine at low concentrations (74). The validity and clinical applicability of these novel analytical techniques is unclear. Given the relative paucity of chemical stability data available for the drug combinations investigated in this review, clinicians should be aware of the difference in clinical applicability between physical compatibility studies and chemical stability studies. Chemical stability cannot be inferred or assumed from physically compatible drug combinations.

The methodologic heterogeneity described in this study highlights the need to improve the methodologic integrity and external validity of future compatibility research. The most commonplace bedside tools used in clinical decisionmaking (i.e., wall charts, tables) do not provide an easy way to evaluate the quality of the data presented. This study exposes critical weaknesses in medication “best practices” and the fact that the quality of the data cannot be assumed. We strongly suggest that future physical and chemical compatibility studies incorporate all the items identified in our quality assessment tools in addition to incorporating multiple reviewers and blinding strategies. Furthermore, a more comprehensive approach to identifying which drugs to study is warranted as opposed to the traditional approach in which one primary drug is studied in a handful of arbitrarily chosen combinations. Finally, duration of study should be chosen based on clinical applicability (i.e., if drugs are clinically mixed through a y-site for minutes before being infused, there is no justification for a physical compatibility study that mixes drugs for days).

There are several limitations of this review. There may be published compatibility studies in other languages besides English and French, in non-peer-reviewed journals and of other drugs commonly used in the ICU in other countries. We intentionally limited the scope of this review to continuously infused drugs because we felt that this was likely the group of medications most susceptible to y-site compatibility issues. Most ICU patients had a dedicated line for intermittently administered medications and timing of medication administration can be modified to accommodate coinfusion incompatibilities. However, there are still some medications that are administered in the ICU through continuous infusion that we did not include in our search because our criteria for inclusion were based on use rates (7). Potentially, this list of drugs could also be expanded to include β-lactam antimicrobials, which may be administered as continuous infusions at some centers. We also had to develop our own quality assessment tools because there were no published, validated tools appropriate for these types of studies. Although we did not validate our instrument, we report each item individually rather than calculating a score.

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CONCLUSIONS

Physical compatibility studies that provide the basis for y-site compatibility are lacking for commonly used medications in ICU patients and may contribute to unsafe medication practices, which could impact patient safety. Furthermore, differences in the methodology of these studies likely contribute to the common finding of conflicting data for specific combinations of drugs. For safe and effective care of our critically ill patients, the healthcare team must be able to rely on the integrity and safety of medication infusions. Availability of comprehensive physical compatibility data is an important step toward achieving such a practice. We therefore propose that future studies apply standardized methodologic and reporting principles to be able to contribute meaningful data that can be readily applied to clinical use.

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ACKNOWLEDGMENTS

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

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APPENDIX 1

Continuously Infused Drugs of Interest Included in the Systematic Search

Acetylcysteine

Amiodarone

Argatroban

Calcium chloride

Calcium gluconate

Cisatracurium

Danaparoid

Diltiazem

Dobutamine

Dopamine

Drotrecogin alfa

Epinephrine and adrenaline

Esmolol

Fentanyl

Furosemide

Heparin

Hydromorphone

Insulin

Potassium chloride

Ketamine

Labetalol

Lorazepam

Mannitol

Magnesium

Metoprolol

Midazolam

Milrinone

Morphine

Sodium bicarbonate

Nitroglycerin

Nitroprusside

Norepinephrine and noradrenaline

Octreotide

Pantoprazole

Thiopental and pentothal

Phenylephrine

Propofol

Total parenteral nutrition (with and without lipids)

Vasopressin

Verapamil

Keywords:

physical compatibility; chemical compatibility; drug infusions; intensive care unit

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