European Journal of Clinical Pharmacology (2019) 75:179–187

https://doi.org/10.1007/s00228-018-2602-6

PHARMACODYNAMICS

Drug incompatibilities in intravenous therapy: evaluation

and proposition of preventive tools in intensive care
and hematology units
Ophélie Maison 1 & Cléa Tardy 1 & Delphine Cabelguenne 1 & Stéphanie Parat 1 & Sophie Ducastelle 2 & Vincent Piriou 3 &
Alain Lepape 3 & Laure Lalande 1

Received: 1 August 2018 / Accepted: 21 November 2018 / Published online: 12 December 2018
# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Purpose Physicochemical incompatibility (PCI) between drugs infused together is frequent, but under-recognized. PCI
can lead to drug inactivity, catheter occlusion, embolism or inflammatory reactions. The aims of this work were to
identify most frequent and relevant drug incompatibilities and to review and develop strategies for their prevention.
Method This was an observational prospective survey conducted between January and March 2015 in an intensive care unit
(ICU) and in September 2014 in a hematology sterile unit (HSU). Drugs administered to patients were recorded and their
compatibility assessed based on published compatibility data.
Results Drug incompatibilities accounted for 12% (23/189) and 17% (116/686) of drug pairs infused in the ICU and
the HSU, respectively. Pantoprazole was the most frequent drug implied in PCI. Regarding drug classes, anti-
infective agents and gastrointestinal drugs were the most frequently implied. Among the incompatible pairs, 78%
and 61% implicated a drug with extreme pH in the ICU and HSU, respectively. The tools proposed to reduce the
frequency of PCI included: compatibility cross-tables, labeling of drugs with extreme pH and optimized administra-
tion schedules.
Conclusions Given the frequency and the potential for severe consequences of PCI, pharmacists have a role to play in raising
awareness of nurses and practitioners, and proposing adequate tools and solutions to reduce their incidence.

Keywords Drug incompatibilities . Intravenous therapy . Adverse drug events prevention . Pharmacist . Intensive care unit

Introduction

Drug incompatibilities are undesirable physical and/or chem-

Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00228-018-2602-6) contains supplementary
material, which is available to authorized users.
* Ophélie Maison
ophelie.maison@chu-lyon.fr
1
Department of Pharmacy, Groupement Hospitalier Sud, Hospices
Civils de Lyon, 165 Chemin du Grand Revoyet, 69495 Pierre
Bénite, France
2
Department of Hematology Oncology, Groupement Hospitalier Sud,
Hospices Civils de Lyon, 165 Chemin du Grand Revoyet,
69495 Pierre Bénite, France
3
Department of Critical Care, Groupement Hospitalier Sud, Hospices
Civils de Lyon, 165 Chemin du Grand Revoyet, 69495 Pierre
Bénite, France
ical reactions that occur between two or more drugs when
solutions are combined in the same syringe, tubing or bottle.
Incompatibility can also occur between drug and diluent, or
between drug and materials of an intravenous (IV) container
or medical devices [1–3]. They occur before entering the body
as opposed to drug interactions (pharmacologic or pharmaco-
kinetic) that occur inside the body.
Chemical causes of visibly observable precipitations
are numerous, but most drug-drug and drug-diluent in-
compatibilities result from acid-base reactions [1].
Physical reactions cause visible changes such as precipi-
tations, changes in color, consistency or opalescence,
emulsion cracking (phase separation) or gas production.
Chemical reactions are caused by molecular changes, and
are considered significant when more than 10%
180
degradation of one or more of the solution’s components
occur [1]. Whether physical or chemical, incompatibilities
between IV drugs represent preventable adverse drug
events.
Potential complications of co-administration of incompati-
ble drugs include precipitation, central venous catheter (CVC)
occlusion or malfunction, reduced potency of medication, em-
bolism, and local or systemic inflammatory reactions [4–6].
Unfortunately, the real clinical consequences of drug precipi-
tation have only been documented for a few drugs and paren-
teral nutrition [6–8]. Consequences also depend on the type of
drugs administered and the patient condition (age, weight,
nature and severity of disease). CVC occlusion is the most
common complication, occurring in up to 25% of all CVCs
used, and can interrupt the infusion of vital medications or
total parenteral nutrition [9]. In addition to the inherent risks
associated with replacing a nonfunctioning catheter, the con-
sequences of under-recognition of catheter occlusion include
venous thrombosis, sepsis, chronic venous insufficiency, and
pulmonary embolism. Lipid residue from parenteral nutrition
or propofol infusions is an excellent medium for bacterial
growth and has been implicated in up to 10% of CVC-
related bloodstream infections [9]. Some fatal cases secondary
to drug incompatibilities have already been reported and re-
sulted in safety alerts from the FDA [10, 11].
This study was conducted in two settings. In hematology,
the study was prompted by nurses’ unexpected and unex-
plained reports of IV drug precipitation (violet precipitates)
observed in 6-m long tubings of four patients from the hema-
tology sterile unit (HSU) between December 2013 and April
2014. These 6-m long tubings allow patients to stroll across
the room in which they stay for several weeks (average of
6 weeks) following bone marrow transplant. The analysis of
the tubing excluded an incompatibility with the device mate-
rial, so the standing hypothesis was physicochemical incom-
patibility (PCI) between IV drugs. In the ICU, the evaluation
of drug incompatibilities was requested by practitioners and
nurses.
Patients hospitalized in ICUs or hematology units are
considered as being a high-risk group for the occurrence
of incompatibilities because they commonly require the
use of multiple drugs, most of which are administered in-
travenously and by continuous infusion. These patients
usually have a limited number of venous accesses, which
complicates the safe administration of drugs. Clinical con-
sequences are all the more severe as these patients are in a
critical health status and combine several risk factors of
adverse events severity: immunodepression, endotracheal
intubation, septicemia, and multi-organ failure. Finally,
consequences of drug incompatibilities such as drug inac-
tivation are a large concern given that some drugs admin-
istered to the patients, such as catecholamines, anti-
infective drugs or immunosuppressants, are vital drugs.
Eur J Clin Pharmacol (2019) 75:179–187
The aims of this work were to identify most frequent and
relevant drug incompatibilities and to review and develop
strategies for their prevention.
Material and method
This was an observational prospective survey conducted in
two different units from a French teaching hospital: hematol-
ogy sterile unit (HSU, three wards) and intensive care unit
(ICU, two wards).
An audit was conducted in the ICU and HSU. All pa-
tients from the different wards of both units were included
in the audit if they had at least two IV drugs prescribed
and a minimal hospital stay of 24 h. Patients were exclud-
ed if they did not meet both criteria. In the ICU, the audit
was carried out between January and March 2015 (inclu-
sion of all new patients). For the HSU, given the con-
straints of a sterile environment, the audit was performed
on a given day in September 2014 (inclusion of all pa-
tients present that day). All the IV drugs administered
over a 24-h period were included. For each drug, the
following elements were recorded: name, dosage, nature
and volume of the diluent, infusion duration and infusion
method (gravity, pump or syringe pump). The pH of each
drug was also recorded, drugs with pH below 4 being
considered as acidic, and above 8 as basic. In the ICU,
as patients usually present a triple-lumen CVC, the lumen
used for each IV drug administration was also recorded.
For the HSU, even if patients presented a multi-lumen
CVC or peripheral inserted central catheter, most of the
time, all IV drugs are infused through the same lumen
connected to the 6-m single-lumen tubing. A second 6-
m tubing would increase the risk of falls and impair pa-
tients’ comfort. All data were recorded in Excel® files for
subsequent analysis.
For the analysis of PCIs, drugs concurrently infused via the
same lumen were considered as drug pairs and their Y-site
compatibility assessed. Six tools were considered for the com-
patibility analysis: Internet website Stabilis [12], Internet
website Theriaque [13], the handbook for injectable drugs
[14], the compatibility of commonly used IV drugs chart
[15], the Hôpitaux Universitaires de Genève (HUG) cross-
table [16] and the Grenoble hospital onco-hematology cross-
table [17]. Drug pairs were classified as compatible, incom-
patible or unknown. When conflicting data existed between
tools, the pair was considered incompatible if at least one
source reported an incompatibility. For each drug, pH values
were also recorded [14].
Following this audit, the pharmaceutical team performed a
literature search in order to list the different tools that have
already been proposed to healthcare providers for prevention
of drug incompatibilities. Nurses were also interviewed in
Eur J Clin Pharmacol (2019) 75:179–187
order to know their expectations regarding these tools. Several
tools were thus developed and will be presented further in this
article.
Results
Evaluation of incompatibilities risk
Fifty patients in the ICU and 29 patients in the HSU
were included in the study (Table 1). For the ICU pa-
tients, among 189 drug pairs, 47 (25%) were considered
compatible, 23 (12%) were considered incompatible and
the compatibility was unknown for 119 (63%) pairs. For
HSU patients, among 686 drug pairs, 193 (28%) were
considered compatible, 116 (17%) were considered in-
compatible and the compatibility remained unknown for
377 (55%). Among the 50 patients included in the ICU,
12 patients had at least one IV drug incompatibility.
Also, the maximum number of incompatible pairs in-
fused to one patient over 24 h was 6. In the HSU, among
the 29 patients included, 22 had at least one IV drug
incompatibility. And the maximum number of incompat-
ible pairs infused to one patient over 24 h was 20.
Pantoprazole was identified as the most frequent drug
involved in PCIs both in the ICU and HSU (Table 2).
Other drugs implicated were specific to each unit: mid-
azolam and hydrocortisone for the ICU, and total paren-
teral nutrition and aciclovir for the HSU. For ICU pa-
tients, 70% of the incompatibilities reported occurred for
drugs infused through the distal lumen. For the ICU,
drugs most frequently implicated in an IV drug incom-
patibility belonged to the anti-infectious drug class; they
accounted for 50% of incompatibilities. For the HSU,
drugs most frequently implicated in an IV drug incom-
patibility belonged to the anti-infectious (64 drugs) and
to the gastrointestinal drug (64 drugs) classes. Among
the 23 incompatible pairs administered in the ICU, 18
(78%) implicated a drug with an extreme pH. Among
the 116 incompatible pairs administered in the HSU, 71
(61%) implicated a drug with an extreme pH.
Table 1 Patients’ characteristics
Number of patients
Average age + range [years]
Sex ratio (M/F)
Number of IV medications
Number of different drugs
Number of pairs administered via a common lumen
181
Implementation of preventive tools for drugs
incompatibilities
The assessment of the frequency and nature of PCIs in two
critical hospital units was a necessary step in order to develop
appropriate tools to prevent these incompatibilities. Different
documents were elaborated for feedback to both units. They
included a short list of the drugs most frequently involved in
PCIs, the most frequent incompatible pairs reported in the
study, common drugs with extreme pH and drugs with specif-
ic solvents (furosemide dissolved in sodium chloride, and my-
cophenolate mofetil dissolved in dextrose, for example).
Along with the presentation of these documents, a short train-
ing was provided to practitioners and nurses that explained the
potential consequences of such incompatibilities and major
risk factors for PCIs.
Three main information tools were presented, ex-
plained and proposed to improve healthcare providers’
knowledge and ability to prevent PCIs. The first tool
consisted of two in-house cross-tables, one for each unit
(Figs. 1 and 2). Drug pair selection was based on the
frequency of use of these substances in the ICU and
HSU. The cross-tables present Y-site administration com-
patibility for drug pairs (compatible, incompatible or un-
known compatibility), but also with common solvents (so-
dium chloride, dextrose, ringer and parenteral nutrition).
The pH of the different drugs was also indicated in these
cross-tables and drugs with an extreme pH were outlined
(acidic drugs in red and basic drugs in blue).
The second tool relied on the labeling of drugs with ex-
treme pH. We drew on a published work to develop our label-
ing of drugs with extreme pH [18]. In the ICU, the drawers in
which drugs are stored were labeled with color stickers: red
for strong acids, blue for strong bases and black for the drugs
most frequently implied in PCI and that should not be in
contact with others. This way, when nurses take a medication
from the medication storage, they have a rapid identification
of drugs potentially incompatible between each other or with a
high risk of incompatibility.
The third tool proposed was an optimized administra-
tion schedule especially for drugs with continuous ad-
ministration (Fig. 3). These schedules were based on
Intensive care unit Hematology sterile unit
50 29
48 [25; 86] 49 [23; 68]
32/18 20/9
415 305
84 56
189 686
182 Eur J Clin Pharmacol (2019) 75:179–187

Table 2 The most frequent

incompatible drug pairs and drugs
most frequently involved in PCI
Most frequent incompatible pairs
Most frequent drugs involved in
PCI
Intensive care unit
Midazolam + hydrocortisone
succinate
Vancomycin + piperacillin
tazobactam
Pantoprazole + vancomycin
Pantoprazole
Midazolam
Hydrocortisone succinate
Vancomycin
Piperacillin tazobactam
Onco-hematology sterile unit
Ciclosporin + magnesium sulfate
Ondansetron + sodium
bicarbonate
Pantoprazole + sodium
bicarbonate
Pantoprazole
Parenteral nutrition with lipids
Aciclovir
Ciclosporin
Piperacillin tazobactam

the most frequent medication protocols prescribed in Finally, as pharmacists and pharmacy residents are regular-
each unit and combined compatibility data available for ly asked about incompatibility issues, we elaborated a deci-
several drugs. sion tree which recalls the different sources of compatibility

Fig. 1 PCI cross-table onco-hematology

Eur J Clin Pharmacol (2019) 75:179–187 183

Fig. 2 PCI cross table ICU

Fig. 3 Administration schedule

184
data, and proposes several corrective actions in case of incom-
patibility (Fig. 4).
Discussion
The first aim of this work was to characterize PCIs in two
critical units of our hospital. The frequencies of IV drug in-
compatibilities reported in other ICUs are quite variable but
consistent with our observations: 18.7% incompatible combi-
nations via Y-site administration were reported in patients of a
Canadian ICU receiving two or more medication infusions
[19], 15% of drugs added to IV fluids were reported incom-
patible either with each other or with the infusion fluid in ICU
patients [20], 14.6% of 1854 drug combinations were reported
incompatible in a Brazilian adult ICU [21], and 7.2% of drug
pairs were reported incompatible in a German ICU, but pro-
cedures recommending separate administration through inde-
pendent lines were already in place at that time [22].
Fig. 4 PCI decision tree
Eur J Clin Pharmacol (2019) 75:179–187
In our audit, the higher frequency of drug incompatibilities
observed for the patients from the HSU can be explained by
the impossibility to separate drug administration through in-
dependent lines as the majority of patients had a 6-m-long
single-lumen tubing through which all IV drugs were infused.
Still, this higher frequency is not as high as could be expected
in these infusion conditions, first because the proportion of
medications administered by continuous infusion is lower in
the HSU compared to ICU, and second because, except in the
case of severe graft versus host disease, most patients in the
HSU receive part of their medications orally.
In the present study, the most frequent drug implicated in
PCIs was pantoprazole. Omeprazole, another proton pump
inhibitor, was also reported as one of the most frequent drugs
implicated in physico-chemical incompatibilities in the ICU
[21]. Indeed, this pharmaceutical class belongs to alkaline
drugs and they are incompatible with various drugs [14].
What is more, proton pump inhibitors are widely prescribed
drugs, often with the indication of prophylaxis of stress ulcer-
ation in critically ill patients. Also, for curative indications,
Eur J Clin Pharmacol (2019) 75:179–187
they are regularly administered as continuous infusion, thus
increasing the risk of drug incompatibilities. In this work,
other drugs mostly implicated in incompatibilities were anti-
infective agents as they accounted for 50% of drugs implicat-
ed in the ICU and 48% in the HSU. Similar results were
reported in a German ICU [22]. This can be explained by
the high frequency of antibiotics and antiviral prescriptions
due to comorbidities of patients from these units (immunode-
ficiency, septic shock). Besides, some widely used antibiotics
such as vancomycin, ceftazidime or piperacillin tazobactam
can be administered through prolonged or continuous infusion
[23]. Detecting incompatibilities with anti-infective agents is
particularly important because of the risk of treatment failure
secondary to drug inactivation. For other drug families, de-
crease in activity can sometimes be clinically or biologically
measured (Richmond Agitation Sedation Scale score, or acti-
vated partial thromboplastin time) and be compensated by an
increase in dosage or in rate of continuous infusion. In terms
of drugs implicated in PCIs, differences were observed be-
tween the ICU and the HSU. These can be explained by dif-
ferences in medical conditions and medical management of
patients from both units. Midazolam with hydrocortisone was
the most frequent incompatible pair reported in the ICU unit
and it was also the case in a Brazilian adult ICU [21].
Conversely, parenteral nutrition, but also sodium bicarbonate,
appeared among the most frequent drugs implicated in PCIs in
the HSU, but not in the ICU. The absence of total parenteral
nutrition in the ICU was explained by data collection occur-
ring within the 24 h after admission, and thus before parenteral
nutrition initiation. Also in the ICU, parenteral nutrition is
usually administered through a specific line of the CVC.
Drug pH was reported as a key element for physico-
chemical compatibility in this study. Indeed, 78% and 61%
of PCIs in the ICU and HSU, respectively, implicated drugs
with extreme pH. The association of drugs with different pH
values may lead to a change in one of the components in the
solution mixture, generating drug instability and increasing
the risk of incompatibility [24]. One of our preventive actions
thus focused on drugs with extreme pH and implementation of
a simple Bcolor system^ in order for nurses to identify these
drugs at risk and alert them of the risk of PCI.
The evaluation and analysis of drug compatibilities relies
on compatibility data available in the literature. 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 (IV bag, syringe, etc.) as con-
tact time will be longer. A systematic review of 93 studies
evaluating physical and/or chemical compatibility of at least
one drug combination was conducted and highlighted the fact
that compatibility data was lacking [25]. Another problem is
that compatibility studies usually only address the risk of the
incompatibility of drug pairs and ignores the possibility that
185
incompatibilities may emerge with more than two drugs com-
bined. Indeed, there is limited information available on trip-
lets, quadruplets or higher combinations. Finally, compatibil-
ity studies present methodological heterogeneity, impairing
their external validity. This could explain the conflicting re-
sults regularly observed [26]. In order to improve future re-
search work, physical and chemical compatibility studies
should incorporate study materials, testing conditions (tem-
perature and light), analytical methods, validation of stability
techniques, drug diluents and concentrations, and drug manu-
facturers. Also, the duration of compatibility studies should be
based on clinical applicability (physical or chemical compat-
ibility) [25].
When incompatibilities between drugs are identified, or in
the absence of compatibility data, several solutions can be pro-
posed. The second aim of our work was to review these solu-
tions. The use of a multi-lumen CVC, with one lumen fully
reserved for parenteral nutrition, is recommended [27]. But
their use could be limited by an increased number of catheter-
related bloodstream infections compared with single-lumen de-
vices [28]. Another solution is to use a separate catheter for IV
administration of drugs. In practice, additional venous access
may not always be practical or feasible, and the number of
venous accesses increases the risk of mechanical, infectious
and thrombotic complications, especially in critically ill patients
[29, 30]. A promising solution could be the use of multi-lumen
infusion devices, but their clinical evaluation with their possible
complications is still lacking [31].
In some cases, especially in critical care units, the number
of concurrently administered drugs usually exceeds the num-
ber of available infusion lines or lumens of the catheter. In this
work, this was confirmed by the higher frequency of PCIs
occurring on the distal lumen of the catheter. Indeed, most
drugs were infused through this lumen given that the proximal
lumen was dedicated to catecholamines and the median lumen
to drugs with a narrow therapeutic range (insulin, heparin,
opioids). Changing the dose scheme to avoid co-
administration of drugs, reducing the number of medications
or temporarily suspending drugs that are not urgently needed
are some of the measures to be undertaken. Changing the
route of administration (like switching IV drug by oral formu-
lation as soon as possible) or using a different drug having the
same therapeutic activity should be considered. Two incom-
patible drugs can also be administered consecutively, which
makes it important to flush the infusion line with a compatible
fluid between each administration. An observational study
carried out in Canadian ICUs revealed that the use of existing
catheters could be improved by appropriately combining med-
ications. Indeed, 25 out of the 37 patients with inappropriate
combinations of concurrent medication infusions could have
their drugs reorganized into acceptable combinations, based
on existing compatibility data [19]. Similarly, in a German
ICU, procedures were established to prevent frequent and
186
well-documented incompatibilities. This enabled reduction of
the frequency of incompatible pairs from 5.8 to 2.4% [22]. A
French study recorded a 6% decrease in hematology and a
10% decrease in the ICU of incompatible drugs administered
thanks to cross-tables and guidelines presented and given to
the nursing staff [32]. The optimized administration schedules
we developed were particularly appreciated by nurses as they
are easily understandable, especially when the number of IV
medications to infuse is important. Equivalent tools and
guidelines cited above proved their efficacy in reducing the
number of incompatible drugs infused simultaneously. But
they require compatibility analysis, usually performed by
pharmacists, which is time-consuming and thus hardly appli-
cable in real time and to all the patients in need.
Informative tools on drug compatibility should be devel-
oped concurrently with nurses as they are daily in charge of
drug administrations. Indeed, these tools should be readily
understandable, adapted to their practices, and regularly eval-
uated. In a Swiss hospital, teamwork between nurses, doctors
and pharmacists resulted in a color code system that reduced
the frequency of incompatible drugs from 15 to 2%, even
5 years after implementation of the system [18]. Also, several
cross-tables were developed for adult and pediatric drug in-
compatibilities [15, 16, 25, 33]. They are considered by nurses
as useful and easily understandable. Their main drawback is
the limited number of drugs that can be integrated to the table.
Ideally, such tables should be generated for a specific unit
(example: ICU, pediatry, orthopedic surgery, etc.) or ideally
for each patient, as was previously done by Huddelston et al.
[33]. Herein, two different cross-tables were developed for the
HSU and the ICU. The other drawback of cross-tables is that
they rarely describe study conditions (drug diluents, concen-
trations, study duration, drug manufacturer, etc.). All these
parameters are important to consider when evaluating the ex-
ternal validity of these compatibility studies [26].
Electronic decision support tools are probably the most
promising strategies in preventing medication errors such as
PCIs. To be meaningful, they would require input on the num-
ber of available IV lines and the drugs currently being deliv-
ered into a given lumen, which is more information than is
routinely available in patient records. Also, another way to
minimize the risk of incompatibilities includes the use of elec-
tronic prescriptions with alerts regarding the possible incom-
patibilities between the drugs prescribed.
Pharmacists have a key role in drug incompatibility pre-
vention. Indeed, pharmacy prerequisites and professional cur-
ricula provide more courses on drug chemistry than do those
of other health care professionals. Health care professionals
expect hospital pharmacists, in particular, to articulate exper-
tise on drug compatibility: elucidate, explain and predict com-
patible and incompatible results of drug-drug and drug-diluent
mixtures [34]. Pharmacists develop the skill of combining
drug information with patient clinical and biological variables
Eur J Clin Pharmacol (2019) 75:179–187
to formulate an intervention that can minimize compatibility
errors, thereby contributing to drug therapy efficacy and pa-
tient safety. Among the interventions to reduce the occurrence
of PCIs, pharmacists can propose switching IV drugs to oral
formulations, reorganize an administration scheme through
different routes or at different times, propose a pharmacolog-
ically equivalent drug causing less incompatibilities, etc. Such
interventions performed by pharmacists present in a Canadian
ICU enabled reduction of 68% of the number of drug incom-
patibilities [19]. To be relevant, hospital pharmacists first need
to gain expertise in medical devices for drug administration
and treatment protocols specific to each medical unit. That
way, pharmacists contribute to improve public health through
prevention of adverse events and promotion of effective and
appropriate use of medications.
The work conducted here presents several limitations. The
number of potential drug incompatibilities was determined a
posteriori by analysis of drug pair compatibility using litera-
ture data, and not from visual examination of tubings. Also,
only drug-drug incompatibilities were considered, while in-
compatibilities may also occur with excipients or tubing
[1–3]. For the corrective actions proposed and implemented
in our hospital, their impact on the frequency of drug incom-
patibilities has not yet been evaluated with a new audit.
Conclusion
Administration of incompatible IV drugs in critically ill pa-
tients is frequent. In the absence of established guidelines for
the clinical management of drug incompatibilities, clinicians
and nurses must be aware of this problem. This work proposed
different tools to evaluate and prevent drug incompatibilities.
Pharmacists can play an important role in preventing drug
incompatibilities thanks to their chemistry knowledge and
their collaborative work with nurses and practitioners.
Acknowledgments Marion Nouvel, Anne-Gaëlle Caffin, Géraldine Iroir,
Bérengère Clerc, Carole Dugrenier, Corinne Béal, Gilles Salles,
Catherine Rioufol.
Publisher’s Note Springer Nature remains neutral with regard to juris-
dictional claims in published maps and institutional affiliations.
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