Review Article

Systematic review of physical and chemical compatibility of

commonly used medications administered by continuous infusion
in 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
C
ritically ill patients cared for
in intensive care units (ICUs)
often require multiple intra-
venous medications adminis-
tered 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 num-
ber of available ports on central and pe-
ripheral venous access devices. In these
situations, potential solutions include ei-
ther obtaining additional venous access
or infusing two drugs through the same
port through a y-site connector in which
the separately prepared drugs mix to-
gether in the lumen of the catheter im-
mediately before entering the blood-
stream. 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 chromatogra-
phy to conrm at least 90% availability of
both drugs in combination over the du-
ration 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 administra-
tion, the contact time is often as little as
12 mins depending on the ow rates of
the infusions, whereas drugs that are
mixed together in the same bag or sy-
ringe can have a much longer time in
which chemical reactions can take place
(i.e., hours to days). Hence, chemical sta-
bility dictates the duration that drugs can
be 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 together
through 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, venous
access devices in critically ill patients
have been associated with a variety of
negative outcomes arising from mechan-
ical, infectious, and thrombotic compli-
cations (46). In practice, additional ve-
nous access may not always be practical
or feasible. We have recently conducted
an observational study of 434 patients in
13 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 Ottawa
Hospital, 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-
icts of interest.
For information regarding this article, E-mail:
skanji@ottawahospital.on.ca
Copyright 2010 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e3181e8adcc
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 Interna-
tional Pharmaceutical Abstracts as well as the references of
electronic drug compatibility textbooks for all English and French
language research publications evaluating the physical com-
patibility 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
conicting data in which both compatible and incompatible data
were identied.
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
nding of conicting data for specic 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. (Crit Care Med 2010; 38:18901898)
KEY WORDS: physical compatibility; chemical compatibility; drug
infusions; intensive care unit
1890 Crit Care Med 2010 Vol. 38, No. 9
appropriate combinations (dened 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 continu-
ously 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.
METHODOLOGY
Search Strategy. We conducted a system-
atic search of MEDLINE, EMBASE, and Inter-
national Pharmaceutical Abstracts from 1966
until 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 through
continuous infusion to critically ill ICU pa-
tients. This list of drugs was determined based
on Canadian use rates from a previously con-
ducted multicenter observational study (7).
Databases were searched using a combination
of the terms drug compat$, drug incom-
pat$, 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 Microme-
dex, Kings Guide, Trissels Tables, and Facts
and Comparisons, were manually screened for
additional studies. The search strategy was
reviewed by an information specialist and con-
ducted by a member of our team (JL). Two
experienced practitioners (SK and JL) inde-
pendently reviewed all citations retrieved from
the search to identify potentially relevant
studies.
Study Selection. To be eligible for inclu-
sion in this review, published peer-reviewed
papers in either French or English had to
describe the physical compatibility or chemi-
cal stability of at least one two-drug combina-
tion 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 re-
view articles were excluded, but their refer-
ences were manually searched for potentially
relevant studies.
Data Extraction and Risk of Bias. Using a
pilot-tested, standardized data extraction
form, data describing study methodology,
components of physical compatibility, analyt-
ical methods of chemical stability, and com-
patibility of all potential combinations of
drugs of interest were collected by two inde-
pendent 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
nal use. Discrepancies of data interpretation
were resolved by consensus using a third re-
viewer. Quality assessment tools were devel-
oped for physical compatibility studies and
chemical stability studies. Given that no pub-
lished, validated quality assessment instru-
ments were available, criteria for each were
developed from published opinion papers on
the conduct of stability and compatibility
studies (13, 8, 9), review and consensus
among investigators, and external expert re-
view (see Acknowledgments). The quality as-
sessment tool for physical compatibility stud-
ies consisted of eight questions, including the
following. 1) Was precipitate formation evalu-
ated? 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 manufac-
turers and lot numbers reported? 8) Was the
study methodology described? (including
number and frequency of observations, dura-
tion of study, testing containers, and study
conditions, including temperature). The qual-
ity assessment tool for chemical compatibility
studies consisted of six questions, including
the following. 1) Are the study materials de-
scribed, including drug concentrations, drug
diluents, testing containers and drug manu-
facturers, and lot numbers? 2) Are testing con-
ditions described, including temperature and
light? 3) Are the analytical methods described
or referenced? 4) Is the validation of the sta-
bility indicating analytical technique de-
scribed or referenced? 5) Is there a time zero
analysis? 6) Are assays performed in replicate?
Data Synthesis. Kappa coefcients were
calculated to assess the interrater agreement
between reviewers for study inclusion and
each quality assessment criterion. Drug com-
binations for which data were available were
categorized as compatible or incompatible as
concluded by the authors of each study. Com-
binations for which there were conicting re-
sults (i.e., one study states compatible,
whereas another states incompatible) were
identied and labeled as such. Compatibility
data for chemical stability studies alone and
also the combined data for chemical and phys-
ical 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 pos-
sible two-drug combinations. Each potential
combination was assigned C for compatible,
I for incompatible, I/C if two or more stud-
ies reported conicting results, or left blank if
no 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 of
electronic databases yielded 1945 cita-
tions. After the initial screen, 146 poten-
tial papers were retrieved and reviewed
for eligibility by two independent review-
ers. Fifty-three papers were excluded (no
drug combinations of interest [n 37];
not a research publication [n 16]) leav-
ing 93 studies that met inclusion criteria
and underwent data extraction (10102).
The calculated coefcient for study inclu-
sion was 0.978 (95% condence interval:
0.9561.0) after the independent screen
and 1.0 after consensus. Of these 93 stud-
ies, 86 (92%) evaluated physical compati-
bility (1014, 1633, 3564, 6673, 76
80, 8298, 100102) and 35 (38%)
evaluated chemical compatibility (10, 16,
1923, 26, 34, 39, 40, 43, 48, 49, 5153, 55,
56, 58, 59, 61, 62, 65, 74, 75, 7882, 88, 98,
99, 101) of at least one drug combination of
interest.
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 compat-
ibility data were available, 67 (15%) were
found to be incompatible combinations
(Table 1). Thirty-nine combinations (9%)
had conicting data in which both com-
patible and incompatible data were iden-
tied for the same drug combination. The
possible reasons for conicting studies
are summarized in Table 1. Of the 75
combinations for which chemical stabil-
ity data were available, 17 (23%) were
found 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 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 magnication in 23 (25%)
studies, ltration in ve (6%) studies,
electron microscopy in two (2%) studies,
and a Tyndall beam in seven (8%) stud-
ies. Absorbance was measured using a
spectrophotometer in ve (6%) studies,
whereas turbidity was measured using a
1891 Crit Care Med 2010 Vol. 38, No. 9
turbidimeter in ve (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 de-
ned a change in pH as being a measure
of incompatibility a priori (2 pH change
in one and 0.5 pH change in the oth-
er).(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 evalu-
ated chemical stability. Other techniques
used 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 presented
in Table 2. Quality assessment character-
istics 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%]; 24 hrs: n 26
[29%]; 524 hrs: 35 [39%]; 24 hrs: 21
[24%]). Glass test tubes or containers
were the most commonly described test-
ing 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 im-
plantable insulin pump (one of 93 [1%]).
Testing was done in replicate in 61 of 93
(66%) using more than one assessor in
ve of 93 (5%) studies. Study sample
blinding was never used.
DISCUSSION
For two drugs to be administered to-
gether 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., in-
travenous bag, syringe, etc). This system-
atic review not only identies 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 impli-
cation on patient safety in the ICU and
also safe medication practices. It is pos-
sible that the relative paucity in compat-
ibility data may result in the placement of
additional venous access devices in pa-
tients for the sole purpose of drug admin-
istration opening a possibility for infec-
tions, mechanical, and thrombotic
complications. We have previously de-
scribed that as a result of the absence of
supportive compatibility data, inappro-
priate 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 pre-
cipitation appears to be high in the ab-
sence of physical compatibility data, the
clinical consequences of such an incident
Figure 1. Physical compatibility and chemical stability summary. C, compatible; I (light gray), incompatible; I/C (dark gray), conicting data; TPN, total
parenteral nutrition.
1892 Crit Care Med 2010 Vol. 38, No. 9
are either not always clinically obvious or
underreported. We found two published
reports of fatal pulmonary embolism at-
tributed to incompatible combinations of
drug infusions.(103, 104) Mechanical fail-
ure of the venous access catheter is prob-
ably more common than embolic clinical
consequences.
The most common reason for a drug
combination to be deemed incompatible
in this review was precipitation on mix-
ing. Most often the precipitates were ob-
served 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 turbidimet-
ric analysis may not be as reliable as
visual assessment, especially when the
precipitate is slight (35). Several studies
attempted to evaluate physical compati-
bility of drugs in lipid emulsions (i.e.,
propofol, parenteral nutrition with lip-
ids). These studies considered disruption
of 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 separate
the oil phase from the aqueous phase and
combined secondary drugs with the aque-
ous 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, how-
ever, because separation of the aqueous
and lipid phases should reduce the solu-
bility 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 so-
lution.
We identied a considerable degree
of heterogeneity with respect to the
methodology of physical compatibility
studies regarding the components de-
termining 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 conicting
compatibility results were found for al-
most 10% of the combinations studied to
date. Wall charts and printed tables are
commonly used in ICUs and drug infor-
Figure 2. Chemical stability summary. C, compatible; I (light gray), incompatible; I/C (dark gray), conicting data; TPN, total parenteral nutrition.
Table 1. Incompatible and conicting 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 conicting
study outcomes (n 39)
Different drug concentrations
studied
24 (62)
Different drug diluents studied 4 (10)
Different drug manufacturers/
brands
6 (15)
Different study durations 5 (13)
1893 Crit Care Med 2010 Vol. 38, No. 9
mation centers to identify compatible
drug combinations, but these tools rarely
describe the study conditions (i.e., drug
diluents and concentrations, study dura-
tion, drug manufacturer and lot num-
bers, etc). All of these parameters are
important to consider when evaluating
the external validity of these compatibil-
ity studies (2). For example, heparin
mixed in dextrose solutions will precipi-
tate with dobutamine but not if mixed in
saline (35). Older formulations of dobut-
amine 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 tempera-
ture is 25C, whereas mannitol will
crystallize 15C (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 con-
sider these details of compatibility re-
ports, but it is even more important that
publications of these types of studies con-
sistently and uniformly report this vital
information (1, 2). Although the provi-
sion 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
ndings in a manner that the paucity of
available compatibility data be visually
obvious.
Our review identied that pH mea-
surement was inconsistently applied in
physical compatibility studies, possibly
because the clinical signicance of a pH
change over time is unclear. Only two
studies dened a threshold for change in
pH over time that would indicate physical
incompatibility (35, 100). Neither study
referenced their a priori-dened thresh-
old (one used a change of 0.5 pH units
and the other used a change of 2 pH
units) with clinical or biochemical justi-
cation. Most drug incompatibilities are
a manifestation of acid base changes and
most often pH measurement can be used
to explain or predict drug incompatibili-
ties (3). However, after two drugs are
mixed together, a change in pH over time
might indicate an ongoing chemical re-
action that may not be visually obvious
but perhaps clinically relevant. In this
event, it would be prudent to label these
combinations incompatible pending
chemical conrmation; however, sup-
portive evidence for a meaningful change
in pH over time is lacking. Irrespective of
whether a change in pH over time indi-
cates an ongoing chemical reaction, fu-
ture studies should measure pH at least
as a means to explain potential incompat-
ibilities.
We also observed signicant heteroge-
neity among physical compatibility stud-
ies 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 observa-
tion dictates the duration of stability that
can be afforded to a combination of
drugs, but clinical interpretation of phys-
ical compatibility studies 4 hrs be-
comes complicated. y-site administration
of drug combinations is based on the
principle that drugs would be physically
mixed in small volumes for short dura-
tions of time, but physical compatibility
studies that nd combinations incompat-
ible at 24 hrs are difcult to interpret.
From our own observations, the largest
volume 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 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 intra-
venous uid to low ow infusions to a
minimum of 10 mL/hr to maintain pa-
tency 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 method-
ologic rigor for physical compatibility
studies and may in fact have reduced clin-
ical applicability.
Almost all studies evaluated in this
review relied on subjective visual assess-
ment from a single assessor. The subjec-
tive 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 pre-
dictable physical signs of incompatibility
when mixed with other drugs. No study
reviewed incorporated any blinding strat-
egies 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 fac-
tor to the high frequency of conicting
reports identied by this review.
As expected, chemical stability studies
were encountered less frequently from
our 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) 1.0
Color change evaluated 75 (87) 1.0
pH change over time measured 39 (45) 0.95 (0.891.0)
Gas production evaluated 45 (53) 1.0
Testing was done in replicate 58 (67) 0.95 (0.871.0)
Methodology described (including number and
frequency of observations, duration of study, study
conditions AND testing containers)
68 (79) 0.88 (0.791.0)
Drug diluents reported for all drugs studied 35 (41) 0.95 (0.891.0)
Drug manufacturers and lot numbers reported 68 (79) 0.97 (0.901.0)
CI, condence 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 (0.551.0)
Testing conditions described (temperature and light) 29 (83) 1.0
Analytical methods described or referenced 32 (91) 0.85 (0.551.0)
Validation of stability indicating analytical
technique is described or referenced
28 (80) 0.91 (0.751.0)
Time zero analysis performed 30 (86) 1.0
Assays are performed in replicate 25 (71) 1.0
CI, condence interval.
1894 Crit Care Med 2010 Vol. 38, No. 9
cally important given the greater likeli-
hood 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 pre-
pared 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., intrave-
nous bag, syringe, etc). A variety of sta-
bility indicating analytical methods were
used, usually dictated by the properties of
the drug studied. High-performance liq-
uid chromatography was used most of-
ten, but one study assessed the stability of
sodium bicarbonate in parenteral nutri-
tion formulations by measuring total CO
2
concentrations as a measure of bicarbon-
ate loss over time (49). Another study
used microcalorimetry to identify exo-
thermic reactions as a marker of interac-
tion between heparin and dopamine at
low concentrations (74). The validity and
clinical applicability of these novel ana-
lytical techniques is unclear. Given the
relative paucity of chemical stability data
available for the drug combinations in-
vestigated in this review, clinicians
should be aware of the difference in clin-
ical applicability between physical com-
patibility studies and chemical stability
studies. Chemical stability cannot be in-
ferred or assumed from physically com-
patible drug combinations.
The methodologic heterogeneity de-
scribed in this study highlights the need
to improve the methodologic integrity
and external validity of future compatibil-
ity research. The most commonplace
bedside tools used in clinical decision-
making (i.e., wall charts, tables) do not
provide 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 the
quality of the data cannot be assumed.
We strongly suggest that future physical
and chemical compatibility studies incor-
porate all the items identied in our qual-
ity assessment tools in addition to incor-
porating multiple reviewers and blinding
strategies. Furthermore, a more compre-
hensive 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 min-
utes before being infused, there is no
justication for a physical compatibility
study that mixes drugs for days).
There are several limitations of this
review. There may be published compat-
ibility studies in other languages besides
English 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 this
review to continuously infused drugs be-
cause we felt that this was likely the
group of medications most susceptible to
y-site compatibility issues. Most ICU pa-
tients had a dedicated line for intermit-
tently administered medications and tim-
ing of medication administration can be
modied to accommodate coinfusion in-
compatibilities. 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 -lactam antimicrobials, which
may be administered as continuous infu-
sions at some centers. We also had to
develop our own quality assessment tools
because there were no published, vali-
dated tools appropriate for these types of
studies. Although we did not validate our
instrument, we report each item individ-
ually rather than calculating a score.
CONCLUSIONS
Physical compatibility studies that
provide the basis for y-site compatibility
are lacking for commonly used medica-
tions in ICU patients and may contribute
to unsafe medication practices, which
could impact patient safety. Further-
more, differences in the methodology of
these studies likely contribute to the
common nding of conicting data for
specic combinations of drugs. For safe
and effective care of our critically ill pa-
tients, the healthcare team must be able
to rely on the integrity and safety of med-
ication infusions. Availability of compre-
hensive physical compatibility data is an
important step toward achieving such a
practice. We therefore propose that fu-
ture studies apply standardized method-
ologic and reporting principles to be able
to contribute meaningful data that can be
readily applied to clinical use.
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
1897 Crit Care Med 2010 Vol. 38, No. 9
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
1898 Crit Care Med 2010 Vol. 38, No. 9