farmacocinetica y farmacodinamia

1. Clin Pharmacokinet 2008; 47 (7): 449-462
REVIEW ARTICLE 0312-5963/08/0007-0449/$48.00/0
© 2008 Adis Data Information BV. All rights reserved.
Clinical Relevance of Pharmacokinetics
and Pharmacodynamics in
Cardiac Critical Care Patients
Federico Pea, Federica Pavan and Mario Furlanut
Institute of Clinical Pharmacology & Toxicology, Department of Experimental and Clinical Pathology and Medicine, Medical
School, University of Udine, Udine, Italy
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
1. Pathophysiological Situations Affecting the Pharmacokinetics of Drugs in Cardiac Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
1.1 Cardiac Surgery and Gastrointestinal Drug Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
1.2 Cardiac Surgery and Drug Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
1.3 Cardiac Surgery and Drug Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
1.4 Cardiac Surgery and Drug Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
2. Pharmacokinetics and Pharmacodynamics of Drugs During Cardiopulmonary Bypass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug
Abstract
in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care
patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs.
Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so
patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs
whenever feasible. Variations in the extracellular fluid content as a response to the trauma of surgery and the
fluid load or significant drug loss through thoracic drainages may significantly lower plasma concentrations of
extracellularly distributed hydrophilic antimicrobials (β-lactams, aminoglycosides and glycopeptides). Drug
metabolism may be altered by the systemic inflammatory response and/or multiple organ failure and/or drug-
drug pharmacokinetic interactions that can potentially occur during polytherapy, especially in immunosup-
pressed cardiac transplant patients. Instability of renal function may promote significant changes in body fluid
concentrations of renally eliminated drugs, even in a brief period of hours. Finally, the application of
extracorporeal circulation by means of cardiopulmonary bypass may significantly alter the disposition of several
drugs during the operation because of acute haemodilution, hypoalbuminaemia, hypothermia and/or adsorption
to the bypass equipment. Accordingly, to avoid either overexposure and the consequent increased risk of toxicity
or underexposure and the consequent risk of therapeutic failure in critically ill cardiac patients, the dosing
regimens of several drugs are expected to be significantly different from those suggested for clinically stable
patients. Additionally, therapeutic drug monitoring may be helpful in the management of drug therapy and
should be routinely used to guide individualized dose adjustments for (i) immunosuppressants whenever
cytochrome P450 3A4 isoenzyme inhibitors (e.g. macrolide antibacterials, azole antifungals) or inducers
(e.g. rifampicin [rifampin]) are added to or withdrawn from the regimen; and (ii) glycopeptide and aminoglyco-
side antibacterials whenever haemodynamically active agents (such as dopamine, dobutamine and furosemide
[frusemide]) are added to or withdrawn from the regimen, and also whenever significant changes of haemodyna-
mics and/or of renal function occur.

2. 450 Pea et al.
Pharmacokinetics is the discipline that studies the time-course 1.1 Cardiac Surgery and Gastrointestinal Drug Absorption
of drug concentrations in body fluids. It describes how drug
concentrations may vary over time due to the different phases that Drug absorption in the gastrointestinal tract after oral adminis-
follow drug administration: namely, absorption, distribution, met- tration is a kinetic process, and its rapidity and extent may be
abolism and elimination. Generally speaking, the aim of pharma- altered in the early postoperative period.
cokinetic studies in humans is to predict what may be the best A significant decrease of gastrointestinal motility, namely,
dosage and dosing regimen in order to obtain optimal pharmaco- postoperative ileus, may occur for some days immediately after
dynamics for each single drug; that is, to ensure and maintain over surgery, mainly as a consequence of different factors stimulating
time therapeutically effective concentrations at the action sites. sympathetic activity and reducing parasympathetic nerve activity
(e.g. local tissue trauma, inflammation and pain, administration of
Indeed, the studies for regulatory purposes are usually carried out
drugs).[2]
Recovery of bowel motility usually occurs in a stepwise
in healthy volunteers who, by definition, are not patients. This
and predictable fashion, with complete recovery of the entire
aspect is of particular relevance in the case of critical illness,
intestinal tract taking 3–5 days.[2]
considering that various pathophysiological conditions may sig-
Although postoperative ileus is expected to be especially rele-
nificantly alter the pharmacokinetic behaviour of drugs.[1]
Accord-
vant after major abdominal surgery, it has also been documented
ingly, in critically ill patients, the dosing regimens for several
after operations involving other parts of the body.[2]
drugs are expected to be significantly different from those suggest-
It should not be overlooked that the extensive use of analgesic
ed for clinically stable patients, with the intent of avoiding either
opioids after cardiac surgery may significantly contribute to slow-
overexposure and the consequent increased risk of toxicity or
ing of gastrointestinal motility,[3,4]
even though this issue has been
underexposure and the consequent risk of therapeutic failure.[1]
specifically addressed in this context by only a few authors.
In the peculiar setting of cardiac surgery, it should not be
In a pilot study involving eight cardiac transplant patients
overlooked that additional significant alterations in the pharmaco-
receiving ciclosporin by the oral route via a nasogastric tube
kinetics of several drugs may be expected during the perioperative
immediately after transplantation,[5]
total body drug exposure (in
period as a consequence of different factors, e.g. the trauma of
terms of the area under the plasma concentration-time curve
surgery, coadministration of various drugs and the application of
[AUC]) was found to be very low on day 1 post-transplantation.
cardiopulmonary bypass (CPB) during extracorporeal circulation.
However, significant improvement was observed over the first
The intent of this review is to summarize the major findings on 5 days after surgery, with a 41% increase in the AUC from days 1
this topic in order to provide some principles for the correct to 3 and a further 40% increase from days 3 to 5. This delay in
management of drug therapy during the perioperative period in optimal drug absorption observed in the early postoperative period
patients undergoing major cardiac surgery. The relevant literature led the investigators to conclude that oral administration of
ciclosporin immediately after cardiac transplantation may result in
from 1980 to 2007 was identified and reviewed using the MED-
inadequate immunosuppression, potentially contributing to acute
LINE database of the US National Library of Medicine, but only
rejection.[5]
Accordingly, the use of the intravenous route was
studies specifically carried out in cardiac surgical patients were
advocated in the very early days after cardiac transplantation to
analysed in depth. For this purpose, the search was performed
prevent drug underexposure. Interestingly, in a population phar-
using the keywords ‘cardiac surgery’ and/or ‘heart transplant’
macokinetic study aimed at determining factors that affect oral
combined with ‘drug pharmacokinetics’ or ‘drug disposition’ or
ciclosporin disposition in cardiac allograft recipients during the
‘drug absorption’ or ‘drug distribution’ or ‘drug metabolism’ or
first 3 weeks after surgery, adjustment of apparent bioavailability
‘drug elimination’ or ‘drug-drug interactions’ or ‘cardiopulmon-
as a function of the postoperative day resulted in improved fits.[6]
ary bypass’. Additionally, the original articles that were found
In an attempt to define the pathogenesis of altered drug absorp-
were explored in the ‘related articles’ function in order to identify
tion after cardiac surgery in patients presenting with differing
and check any other relevant article.
haemodynamic status, taking into account that paracetamol (aceta-
minophen) is normally absorbed only in the small intestine and not
1. Pathophysiological Situations Affecting the in the stomach, Berger et al.[7] assessed its intestinal absorption
Pharmacokinetics of Drugs in Cardiac Surgery rate after administration either through a gastric tube or through a
postpyloric tube. On days 1 and 3 after surgery, the pharmacokine-
In order to better understand the correct principles of drug tic profile of paracetamol was separately assessed in patients
dosing in cardiac surgical patients, it becomes necessary to identi- with adequate or altered postoperative haemodynamics and then
fy the pathophysiological changes that may affect the different compared with that observed in a control group of healthy volun-
phases of drug pharmacokinetics in the perioperative period. teers. In all patients, irrespective of whether the haemodynamic
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)

3. Clinical Relevance of PK/PD in Cardiac Critical Care 451
status was adequate or altered, paracetamol absorption on day 1 ing to the gradient of concentration may occur. On the other hand,
was normal after postpyloric delivery (maximum plasma concen- this cannot happen for the hydrophilic compounds whose distribu-
tration [Cmax] 26.9 ± 10.3 and 22.8 ± 9.0 mg/L, respectively; AUC tion is limited to the extracellular compartment because of their
2350 ± 983 and 2513 ± 870 mg • h/L, respectively), but signifi- inability to passively diffuse through the plasmatic membrane of
cantly lower than in healthy volunteers after gastric administration the eukaryotic cells.[1]
From a clinical point of view, this aspect
(Cmax 3.9 ± 2.3 and 5.0 ± 2.8 mg/L, respectively, vs 16.5 ± 3.7 mg/ may be especially relevant for the hydrophilic antimicrobial agents
L; AUC 892 ± 926 and 826 ± 384 mg • h/L, respectively, vs (namely, β-lactams, aminoglycosides and glycopeptides) whose
2075 ± 509 mg • h/L), subsequently becoming close to normal on efficacy in the treatment of deep-seated infections when using
day 3. On the basis of these results, it was concluded that haemo- standard dosages may be significantly impaired by dilution and
dynamic instability did not preclude intestinal absorption of para- lowering of concentrations in the tissue interstitium.[1]
cetamol and that the decreased intestinal absorption observed on This aspect was specifically addressed in cardiac surgical pa-
day 1 after surgery was related mainly to delayed gastric emptying tients by Brunner et al.,[11] who assessed the changes in target site
and decreased intestinal transit due to pylorus closure promoted by distribution of piperacillin occurring in the immediate post-
the opioid derivatives administered during the perioperative operative period in the interstitium of muscle and the subcutis in
period.[7]
patients compared with healthy volunteers. After administering a
In summary, from these data, it appears that in cardiac surgical single 4.0-g intravenous dose of piperacillin after the end of
patients, gastrointestinal drug absorption may be erratic and unpre- surgery (271 ± 22 minutes), drug exposure in peripheral tissues,
dictable in the early postoperative period, especially when opioid assessed by means of microdialysis and expressed as the AUCinter-
analgesics are used extensively.[2]
This means that during this stitium/AUCserum ratios, was found to be significantly lower in
period, attention should be paid whenever patients are unrespon- patients than in healthy volunteers (mean ± standard error
sive to oral therapy and that in order to always ensure therapeutic 0.27 ± 0.04 vs 1.22 ± 0.31 in muscle, p = 0.00006; 0.25 ± 0.03 vs
effective concentrations of life-saving drugs, such as immunosup- 0.43 ± 0.11 in the subcutis, p = 0.007). These results were
pressive agents, the intravenous route should be preferred whenev- attributed to the increased capillary permeability induced by the
er feasible. release of various endogenous mediators in response to the trauma
of surgery, coupled with the subsequent fluid sequestration occur-
1.2 Cardiac Surgery and Drug Distribution ring in the interstitial space when large amount of fluids are
administered during surgery (the so-called ‘third spacing’).[8,11,12]
In surgical patients, drug distribution may be altered as a
Consistently higher than standard dosages were advocated for
consequence of blood loss, fluid accumulation in traumatized
appropriate treatment of postoperative soft tissue infections with
tissues and changes in plasma protein levels.[8]
piperacillin, and it was suggested that this may also be true for
Interestingly, in a recent article reviewing trials that measured
other hydrophilic antimicrobials. However, to the best of our
extracellular fluid changes occurring specifically in patients un-
knowledge, no other study has addressed this issue specifically in
dergoing cardiothoracic operations, in almost all of the 12 identi-
cardiac surgical patients.
fied studies, the postoperative extracellular volume was shown to
The effect of surgery in increasing the Vd of the aminoglyco-
be significantly increased.[9] Of note, in surgical patients, the
sides was documented in 52 consecutive, critically ill surgical
expansion of the extracellular space may become especially rele-
patients admitted to an intensive care unit and treated with
vant when the administration of copious quantities of intravenous
gentamycin or tobramycin because of suspected or documented
fluids in the perioperative period may significantly exceed the
Gram-negative infections.[13]
Interestingly, due to a 1.34-fold in-
measured losses in volume.[9,10]
crease in the Vd (median value 0.29 L/kg, range 0.20–0.54 L/kg)
Indeed, during cardiac surgery, the administration of large
the initial loading dose of 3 mg/kg enabled the achievement of an
volumes of fluids is a relatively common practice,[11] and so the
adequate target Cmax (defined as ≥8.3 mg/L) in only about half of
consequent expansion of the extracellular space occurring in the
the patients, and the Cmax was lower than 4 mg/L in 11.5% of
perioperative period may affect the volume of distribution (Vd) of
cases. This study confirmed previous results suggesting a signif-
drugs. However, the relevance of this is expected to be significant-
icant increase in the Vd of aminoglycosides in surgical pa-
ly different depending on the physicochemical properties of the
tients.[14-16] Given the concentration-dependent bactericidal ac-
drugs.[1]
As a general rule, for most lipophilic compounds, the
tivity exhibited by these antimicrobial agents, it was concluded
decrease in the concentration in the interstitium occurring under
that larger doses per kg should be administered for appropriate
these circumstances may be considered transient and therefore not
treatment with aminoglycosides.
clinically significant. In fact, in this case, by acting as a reservoir,
cells may enable passive redistribution between the intra- and Indeed, it should not be overlooked that in postsurgical cardiac
extracellular compartments, and so a rapid re-equilibrium accord- patients, further expansion of the extracellular compartment may
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)

4. 452 Pea et al.
occur in the presence of sepsis in relation to the capillary leakage drugs during the systemic inflammatory response was related to
promoted by the systemic inflammatory response.[17,18] Addition- the extensive production of cytokines, which may be responsible
ally, in patients with thoracic drainages, a so-called ‘false in- for downregulation of individual CYP forms at the level of
crease’ in the Vd of hydrophilic antimicrobials may be document- transcription, resulting in a decrease of the corresponding messen-
ed as a result of significant drug loss, lowering target site concen- ger RNA (mRNA), protein and enzyme activity.[25]
trations.[1]
The magnitude of the impairment of CYP-related drug meta-
In summary, from these data, it appears that in cardiac surgi- bolism may become even more relevant in patients developing
cal patients, the expansion of the extracellular compartment severe liver impairment during multiple organ failure (MOF),
may especially alter the distribution of hydrophilic compounds, which, among other factors, may be the result of an exaggerated
and this means that when starting antimicrobial therapy with β- and overwhelming systemic inflammatory response.[24]
lactams, aminoglycosides or glycopeptides, the initial loading This aspect was emphasized by Carcillo et al.,[26] who compara-
dose should frequently be higher than normally to avoid underex- tively assessed phenazone (antipyrine) metabolism as a measure of
posure related to drug dilution and/or drug loss. mixed CYP-mediated drug metabolism in critically ill children
with sepsis (n = 51) or without sepsis (n = 6). Interestingly,
1.3 Cardiac Surgery and Drug Metabolism phenazone clearance was significantly lower in patients with
sepsis than in those without sepsis (0.38 ± 0.28 vs 0.74 ± 0.31 mL/
Changes in liver function may affect drug metabolism, espe-
min/kg, p < 0.05) but to a significantly greater extent in pa-
cially when phase I mechanisms are involved.
tients who also had MOF (0.22 ± 0.15 mL/min/kg in patients
There is little published work on factors that may influence
with persistent MOF, p < 0.05). The much higher decrease in
drug metabolism in surgical patients,[8]
but one of the most rele-
phenazone clearance observed in children with persistent MOF led
vant factors is the expected reduction in blood flow to the liv-
the investigators to conclude that studies of rational drug dosing
er.[8,19,20] Additionally, some experimental studies have shown that
should be developed in order to avoid drug toxicity due to overex-
hepatic enzymes involved in oxidation may be markedly de-
posure under these circumstances.[26]
creased in the presence of low oxygen tension.[21,22]
Although, generally speaking, sepsis related to bacterial infec-
Braun et al.[23]
first assessed the influence that CPB may have in
tions is one of the most frequent and challenging causes of MOF in
changing hepatic blood flow, oxygen transport-consumption and
the critically ill population,[24]
it should be noted that in the
cytochrome P450 (CYP) metabolism in 31 patients undergoing
specific context of cardiac surgery, even the application of CPB
cardiac valve replacement surgery. Hepatic blood flow was mea-
may be an additional leading cause of MOF.[27]
sured by means of constant infusion of indocyanine green through
Drug-drug pharmacokinetic interactions, which can potentially
a hepatic venous catheter, whereas liver oxidative metabolism was
occur during polytherapy, are another relevant mechanism that
assessed by means of a monoethylglycinexylidide (MEGX) test as
may alter drug metabolism in critically ill patients.[28]
a marker of the CYP system activity. Comparative evaluations
This aspect may be of particular interest in cardiac transplant
were carried out at baseline, during CPB, 2 hours and 7 hours
patients who receive immunosuppressive drug therapy. In fact,
after admission to the intensive care unit. Interestingly, whereas
most immunosuppressive agents – namely, ciclosporin, ever-
hepatic blood flow and oxygen delivery did not decrease during
olimus, sirolimus and tacrolimus – are metabolized by the
and after surgery (median hepatic blood flow 0.58 L/min/
CYP3A4 isoenzyme, whose activity may be significantly reduced
m2 [25th–75th percentile 0.46–0.66 L/min/m2] at baseline; 0.78 L/
or increased by simultaneous administration of other drugs acting
min/m2 [0.65–1.1 L/min/m2] during CPB; 0.67 L/min/
as inhibitors or inducers of its activity.[29,30] A synopsis reporting
m2 [0.52–0.93 L/min/m2] after 2 hours; 0.67 L/min/
several examples of drug-drug interactions potentially occurring
m2 [0.61–0.87 L/min/m2] after 7 hours), on the other hand,
during cotreatment of critically ill patients is depicted in figure 1.
splanchnic oxygen consumption increased and MEGX test results
Additionally, it should not be overlooked that another potentially
decreased only slightly.[23]
The increased oxygen consumption
relevant mechanism of drug interaction may be represented by
observed during CPB was possibly attributed to an inflammatory
inhibition of the activity of P-glycoprotein (P-gp), an efflux pump
reaction due to the pump starting in the splanchnic area, but no
extensively represented in the emunctory organs, which promotes
significant or prolonged reduction of liver metabolic function was
the elimination of several xenobiotics, including ciclosporin,
specifically attributed to CPB.[23]
sirolimus and tacrolimus, and whose activity may be inhibited by
Indeed, the development of a systemic inflammatory response
several drugs.[31]
to either infectious conditions (e.g. sepsis) or noninfectious condi-
tions (e.g. trauma or pancreatitis)[24] was found to significantly Indeed, an extensive analysis of this topic is beyond the aims of
reduce CYP-related drug metabolizing activity in critically ill this article. For a complete overview, readers are referred to a
patients.[25]
The compromise of the capacity of the liver to handle recent review by Page et al.[32]
What we would like to emphasize
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)

5. Clinical Relevance of PK/PD in Cardiac Critical Care 453
Fluconazole
Ketoconazole
Voriconazole
CYP2C19
• Antiepileptics
(phenytoin)
• Others (diazepam,
imipramine)
• Proton pump
inhibitors
(lansoprazole,
omeprazole)
CYP inhibitors
Rifampicin
CYP inducers
Amiodarone
Fluoroquinolones
CYP1A2
• Theophylline
• Verapamil
• R-warfarin
• Haloperidol
• Naproxen
• Ondansetron
• Propranolol
Rifampicin
?
Amiodarone
CYP2D6
• β-adrenoreceptor
antagonists (metoprolol,
propranolol, timolol)
• Antidepressants
(amitriptyline, clomipramine,
desipramine, imipramine)
• Antipsychotics
(thioridazine)
Amiodarone
Macrolides
Fluoroquinolones
Ketoconazole
Itraconazole
Fluconazole
Posaconazole
Voriconazole
CYP3A4-5
• Macrolides
• Benzodiazepines (midazolam,
triazolam, alprazolam)
• Immunosuppressants (ciclosporin,
everolimus, sirolimus, tacrolimus)
• Opioid analgesics (alfentanil,
fentanyl, sufentanil)
• Antiepileptics (carbamazepine)
• Anti-arrhythmics (disopiramide, quinidine)
• Calcium-channel antagonists
(verapamil, nifedipine, felodipine)
• R-warfarin
• Corticosteroids (methylprednisolone)
• HMG-CoA reductase inhibitors
(lovastatin, simvastatin)
Rifampicin
Amiodarone
Fluconazole
Ketoconazole
Voriconazole
CYP2C9
• Antiepileptics
(phenytoin)
• S-warfarin
• NSAIDs (diclofenac,
flurbiprofen,
ibuprofen, naproxen,
piroxicam)
Rifampicin
Inhibition of CYP activity
Induction of CYP activity
Conflicting data
?
Fig. 1. Antiarrhythmic and antimicrobial agents acting as inhibitors or inducers of the major cytochrome P450 (CYP) isoenzymes involved in the
metabolism of the drugs most frequently used in critically ill patients.[28]
here is the particular relevance that some antiarrhythmic agents verapamil is added to the therapy, and carefully monitoring blood
and/or antimicrobial agents could have in altering the disposition concentrations in order to avoid toxicity.
of immunosuppressants when used in the perioperative period. As far as antimicrobial agents are concerned, some macrolides
As far as antiarrhythmics are concerned, amiodarone is one of – especially erythromycin and clarithromycin (but not azithro-
the most challenging in terms of potential drug-drug pharmacokin- mycin) – have been shown to consistently inhibit CYP3A4-related
etic interactions, considering that, other than being a substrate metabolism of ciclosporin in transplant patients.[28] In six trans-
of CYP3A4, it is a potent inhibitor of several CYP isoforms plant recipients (four liver transplant patients and two cardiac
(CYP1A2, 2C9, 2D6 and 3A4) and P-gp.[33]
transplant patients) treated with ciclosporin, simultaneous admin-
istration of clarithromycin led to a 2- to 3-fold increase in plasma
Significant interactions between amiodarone and ciclosporin in
trough concentrations of ciclosporin, and so a significant dosage
cardiac transplant patients, leading to a marked decrease in
reduction guided by therapeutic drug monitoring (TDM) was
ciclosporin clearance with potential drug overexposure, has pre-
necessary to avoid ciclosporin-related nephrotoxicity.[39]
A similar
viously been reported by various authors.[34-36]
In addition, a case
increase in drug exposure was found when clarithromycin was
report has recently been published, suggesting that a relevant drug-
coadministered with tacrolimus to renal transplant patients[40] or
drug pharmacokinetic interaction occurred during cotreatment
when erythromycin was coadministered with ciclosporin,[41] tacro-
with amiodarone and sirolimus/tacrolimus in a paediatric cardiac
limus[42]
or sirolimus[43]
to renal transplant patients. Clinicians
transplant patient.[37]
Interestingly, a similar effect may also be
should therefore be aware of the necessity to immediately lower
expected when verapamil is added to immunosuppressant therapy,
immunosuppressant dosages whenever erythromycin or clarithro-
considering its potent inhibitory effect on either CYP3A4 or P-
mycin is added to therapy and to strictly monitor blood concentra-
gp.[31,38]
Therefore clinicians should consider prospectively de-
tions in order to manage therapy appropriately.
creasing doses of immunosuppressants whenever amiodarone or
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)

6. 454 Pea et al.
Likewise, azole antifungal agents are known to be inhibitors of optimal immunosuppressant activity during rifampicin cotreat-
ment could be very difficult to achieve.
several different CYP isoenzymes[28] but, interestingly, their inhib-
In summary, whenever CYP3A inhibitors or inducers are added
itory potency against CYP3A4 has been shown to differ among the
to or withdrawn from the regimen in cardiac transplant patients,
various compounds, being significantly greater for itraconazole,
routine TDM should be used to guide individualized dosage ad-
posaconazole and voriconazole in comparison with flucona-
justments of immunosuppressive agents, with the intent of avoid-
zole.[30]
ing either overexposure or underexposure, respectively.
In eight renal transplant patients treated with ciclosporin, con-
comitant administration of fluconazole led to a 1.8-fold increase in
1.4 Cardiac Surgery and Drug Elimination
drug exposure in terms of the AUC, and so TDM-guided dosage
adjustment of ciclosporin was needed.[44]
Even larger increases in Variations occurring in renal function may be considered the
most relevant and frequent pathophysiological mechanism that
ciclosporin exposure were observed when ketoconazole,[45]
itra-
could possibly affect drug disposition in critically ill patients.[1]
conazole,[46]
posaconazole[47]
or voriconazole[48]
was added to the
Indeed, fluctuation in renal function is a relatively frequent occur-
immunosuppressant therapy. Likewise, pharmacokinetic interac-
rence in cardiac surgical patients[55]
and may be related to changes
tions of a similar extent may be expected when azole antifungals
in haemodynamics as a direct consequence of surgery. Although
are added to therapy with other immunosuppressants such as
much work has been completed towards better understanding of
tacrolimus, sirolimus and everolimus.[30,49]
this phenomenon, the specific mechanisms of renal injury during
Therefore, when adding azole antifungals to the therapy of
surgery are incompletely understood.[55]
cardiac transplant patients, an immediate dose reduction of im-
Instability of renal function may promote significant changes in
munosuppressants must be applied to avoid overexposure and
body fluid concentrations of renally eliminated drugs, even in the
consequent potential drug-related neurotoxicity and nephrotoxici-
brief period of hours. Additionally, various iatrogenic conditions
ty. An interesting table summarizing how to manage dosage
may modify renal blood flow and hence glomerular filtration and
reduction of the different immunosuppressants according to the
tubular secretion rates.
various interacting azole antifungals was recently reported by
Of note, haemodynamically active drugs such as furosemide
Saad et al.[30]
(table I).
(frusemide), dopamine and dobutamine, which are frequently used
Conversely, in contrast to CYP inhibitors, cotreatment with the in cardiac critical care with the intent of improving haemodynami-
potent CYP3A4 inducer rifampicin (rifampin) is expected to cause cs and renal blood flow, may consistently enhance the clearance of
a significant increase in total body clearance of ciclosporin,[50]
drugs eliminated by the renal route. This has been documented, for
tacrolimus,[51]
sirolimus[52]
or everolimus,[49]
thus potentially lead- example, with vancomycin. Its renal elimination was found to be
ing to insufficient immunosuppression. Importantly, considering significantly improved among 18 cardiac surgical patients, espe-
that in in vitro studies, rifampicin was shown to induce about 50- cially during cotreatment with at least two of these drugs (dobuta-
fold CYP3A4 mRNA expression,[53,54]
it may be hypothesized that mine plus furosemide in four patients and dopamine plus dobuta-
mine plus furosemide in another four patients).[56]
As a conse-
quence, in order to maintain therapeutic concentrations, the
administered dosages of vancomycin during cotreatment had to be
1.25- to 1.90-fold higher than is suggested normally on the basis of
standard nomograms.[56]
Generally speaking, the risk of underdosing during cotreatment
with haemodynamically active drugs may be particularly relevant
not only for vancomycin but for most hydrophilic antimicrobials
(namely, β-lactams, aminoglycosides and glycopeptides), consid-
ering that most of these agents are almost completely excreted by
the kidney as the unchanged moiety.[1]
In summary, in critically ill cardiac surgical patients with
fluctuating renal function, frequent dosing adjustment of renally
eliminated drugs should be performed according to the estimated
or, preferably, the measured creatinine clearance, considering that
creatinine clearance may be considered the best surrogate of the
glomerular filtration rate. Additionally, TDM is strongly recom-
mended, at least for glycopeptides and aminoglycosides, whenever
Table I. Recommended percentage dose reductions of immuno-
suppressants during concomitant azole therapy (reproduced from Saad et
al.,[30] with permission)
Azole Ciclosporin Tacrolimus Sirolimus
Ketoconazole 70–80 50–60 80–90
Fluconazole (≥200 mg/day) 21–50a 40b 50–70c
Itrazonazole 50–60 50–60 No data
Voriconazole 50 66d 90e
Posaconazole 0–30c 75–80c,f No dataf
a The extent of the interaction depends on the route of administration
of ciclosporin.
b Based on studies of low-dose fluconazole 100 mg/day.
c Based on limited data.
d Variable.
e Used in clinical practice. Coadministration is contraindicated,
according to the manufacturer.
f At the time of writing.
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)

7. Clinical Relevance of PK/PD in Cardiac Critical Care 455
haemodynamically active agents are added to or withdrawn from ing its high plasma protein binding, an increase in both the Vd and
the regimen, and also whenever significant changes of haemody- renal clearance may be expected during CPB as a consequence of
namics and/or renal function occur. an increase in the free moiety. Fellinger et al.[65]
assessed the
adequacy of intraoperative free serum concentrations of prophy-
lactic cefazolin during CPB in ten patients who received 1 g
2. Pharmacokinetics and Pharmacodynamics of
intravenously at the induction of anaesthesia and another 1 g
Drugs During Cardiopulmonary Bypass
intravenously immediately after the onset of CPB. Interestingly,
throughout the operation, free serum cefazolin concentrations
In the specific context of cardiac surgery, the application of
remained above the minimum inhibitory concentration against
extracorporeal circulation by means of CPB may significantly
90% (MIC90) of susceptible Staphylococcus aureus and S. epider-
alter the disposition of drugs during the operation.
midis. However, the lowest concentration (6.34 mg/L) observed
Indeed, several factors may concur in modifying the pharmaco-
immediately before administering the second dose was found to
kinetic behaviour of drugs during CPB.
be subinhibitory against some Gram-negative pathogens, namely,
First of all, acute haemodilution leads to a significant decrease
Escherichia coli and Proteus mirabilis. Although these pathogens
in plasma concentrations of almost any drug.[57]
However, whereas
are less frequently involved in cardiac surgical site infections, in
this effect may be rapidly corrected in the case of drugs that are
order to avoid potential underexposure at the onset of CPB,
highly accumulated intracellularly (namely, those with a high Vd
the investigators suggested that a higher preoperative dose of
of >1 L/kg) due to redistribution from the intracellular compart-
cefazolin 2 g may be needed at the induction of anaesthesia.[65]
Of
ment to the extracellular compartment, this will result in perma-
note, in a subsequent study assessing cefazolin exposure after
nent dilution in the case of hydrophilic compounds, considering
intravenous administration of a 2-g dose 60 minutes before the
that their distribution is limited to the extracellular space.
induction of anaesthesia, an average drop of 46.6% in plasma
Additionally, by causing hypoalbuminaemia, haemodilution
concentrations starting 5 minutes after CPB and remaining steady
may increase the free moiety of normally highly protein-bound
until 5 minutes after CPB suspension was observed in 6 patients
drugs.[58] Considering that only the free moiety is biologically
undergoing cardiac surgery.[88]
active, this means that an increased pharmacodynamic effect is
Caffarelli et al.[66]
compared the influence of CPB and profound
expected under these circumstances.
hypothermic circulatory arrest on plasma cefazolin concentrations
The free fraction of normally highly protein-bound drugs may
in four groups of patients (n = 10 per group) receiving 1 g
be further increased as a consequence of the effect of heparin
intravenously at the induction of anaesthesia plus 1 g intra-
administration on plasma protein binding. In fact, by promoting
venously at the time of wound closure. Group A underwent
the hydrolysis of plasma triglycerides, heparin contributes to com-
vascular surgery without CPB; group B underwent cardiac surgery
petitive binding of free fatty acids to plasma proteins, which may
with a CPB time of <120 minutes; group C underwent cardiac
result in displacement of bound drugs.[59]
surgery with a CPB time of >120 minutes; and group D underwent
Hypothermia induced at bypass may reduce metabolic activity
cardiac surgery with CPB and profound hypothermic circulatory
in the liver, and so the hepatic clearance of drugs may be de-
arrest. According to plasma concentrations observed at the end of
creased.[60,61]
surgery, cefazolin inhibitory activity against S. aureus was defined
Finally, significant amounts of drugs may sometimes be se-
as optimal, intermediate or ineffective when plasma concentra-
questered into the bypass equipment due to adsorption.[62-64]
tions were ≥32 mg/L, 16 mg/L or ≤8 mg/L, respectively. Whereas
While readers are referred to the work of Mets[57]
for supple-
in group A, plasma concentrations remained at >16 mg/L during
mental information on this topic, here we report the most recent
the entire surgical procedure, they diminished to <16 mg/L in 30%
studies assessing the pharmacokinetics mainly of some antimicro-
of patients in group B, in 60% of patients in group C and in 66% of
bials and anaesthetics in patients undergoing major cardiac sur-
patients in group D. Additionally, they fell to <8 mg/L in 50% of
gery with CPB, and the relative pharmacodynamic consequences
patients in group C and in 10% of patients in group D. On the basis
(table II).
of these results, it was concluded that this protocol of prophylaxis
First- and/or second-generation cephalosporins (namely, cefa-
did not provide optimal pharmacodynamic exposure against S. au-
zolin, cefuroxime and cefamandole) may be considered the gold
reus in patients undergoing long, complicated cardiac surgical
standard for antimicrobial prophylaxis during elective cardiac
operations, especially when the CPB time was >120 minutes, even
surgery, mainly because they provide appropriate coverage against
if better protection was observed in those patients undergoing
methicillin-susceptible staphylococci, which are the most relevant
hypothermic circulatory arrest.[66]
pathogens in cardiac surgical site infections.[87]
Cefazolin has been one of the most intensively investigated In summary, from these studies, it appears that the optimal
antimicrobial agents during the application of CPB and, consider- prophylaxis dosage of cefazolin during cardiac surgery with CPB
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)

8. 456 Pea et al.
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)
Table
II.
Pharmacokinetics
and
pharmacodynamics
of
drugs
during
cardiopulmonary
bypass
(CPB)
Study
Drug
Dosage
Pharmacokinetic
effect
Comment/clinical
significance
Antimicrobials
Fellinger
et
al.,
2002
[65]
Cefazolin
1
g
IV
at
induction
of
anaesthesia
+
Lowest
free
cefazolin
C
min
at
the
Therapeutically
effective
cefazolin
1
g
IV
after
the
onset
of
CPB
onset
of
CPB
(6.34
mg/L)
free
serum
concentrations
(>MIC
90
)
against
Staphylococcus
aureus
and
S.
epidermidis
for
the
entire
operation
time
Caffarelli
et
al.,
2006
[66]
Cefazolin
1
g
IV
at
induction
of
anaesthesia
+
Cefazolin
concentration
at
the
end
of
No
optimal
drug
exposure
against
1
g
IV
at
the
time
of
wound
closure
in
surgery
–
group
A:
always
>16
mg/L;
S.
aureus
for
the
entire
operation
time
four
groups
of
patients:
group
A,
no
group
B:
<16
mg/L
in
30%
of
cases
when
CPB
time
was
>120
min;
better
CPB;
group
B,
CPB
<120
min;
group
but
always
>8
mg/L;
group
C:
exposure
in
patients
undergoing
C,
CPB
>120
min;
group
D,
CPB
+
<16
mg/L
in
60%
of
cases
and
hypothermic
circulatory
arrest
hypothermic
circulatory
arrest
<8
mg/L
in
50%
of
cases;
group
D:
<16
mg/L
in
34%
of
cases
and
<8
mg/L
in
10%
of
cases
Menges
et
al.,
1997
[67]
Cefamandole
Three
groups:
group
1,
2
g
IV
at
Plasma
concentrations
at
the
end
2
g
IV
at
induction
of
anaesthesia
+
induction
of
anaesthesia;
group
2,
of
CPB
were
significantly
higher
in
2
g
intraoperatively
after
the
onset
of
2
g
IV
at
induction
of
anaesthesia
+
group
2
(170.3
±
105.8
mg/L)
than
CPB
would
ensure
optimal
activity
for
2
g
IV
10
min
after
cannulation
of
the
in
groups
1
and
3
(111.8
±
42.2
and
the
entire
procedure
in
terms
of
aorta;
group
3,
4
g
IV
at
the
time
of
101.2
±
57.2
mg/L,
respectively).
plasma
concentrations
>MIC
90
against
skin
incision
Concentrations
in
mammary
artery
common
pathogens
and
sternum
samples
at
the
end
of
CPB
were
significantly
higher
in
group
2
(15.6
±
4.7
and
9.5
±
4.7
mg/L,
respectively)
than
in
group
1
(5.7
±
1.9
and
3.8
±
2.9
mg/L,
respectively)
and
group
3
(6.3
±
3.5
and
3.6
±
1.8
mg/L,
respectively)
Nascimento
et
al.,
2005
[68]
Cefuroxime
1.5
g
IV
in
four
bolus
doses
over
24
h
Concentration
<16
mg/L
just
A
change
in
the
dose
scheme
should
in
patients
undergoing
coronary
artery
after
6
h,
but
higher
in
group
2
be
recommended
for
maintenance
of
bypass
grafting
with
(group
2)
or
(95%
CI
12,
20)
than
in
adequate
concentrations
(>16
mg/L)
without
(group
1)
hypothermic
CPB
group
1
(95%
CI
6,
12)
Mand’
ák
et
al.,
2007
[69]
Cefuroxime
3
g
IV
at
induction
of
anaesthesia
+
Free
concentrations
↓
significantly
Free
concentrations
in
plasma
and
1.5
g
IV
after
CPB
+
1.5
g
IV
8
h
at
the
onset
of
CPB
both
in
in
interstitium
of
skeletal
respiratory
after
surgery
plasma
(from
119.5
±
35.2
to
muscles
were
>MIC
for
common
67.7
±
15.5
mg/L)
and
in
the
pathogens
(2
mg/L
for
Gram-positive;
dialysate
from
muscle
interstitium
4
mg/L
for
Gram-negative)
for
the
from
44.4
±
15.8
to
36.1
±
11.7
mg/L)
entire
course
of
cardiac
surgery
Miglioli
et
al.,
1998
[70]
Vancomycin
15
mg/kg
IV
at
induction
of
AUC
↓
31.7%
during
CPB
During
CPB,
vancomycin
serum
anaesthesia
concentrations
↓
but,
at
the
dosage
of
15
mg/kg,
remained
in
a
potentially
effective
range
Continued
next
page

9. Clinical Relevance of PK/PD in Cardiac Critical Care 457
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)
Table
II.
Contd
Study
Drug
Dosage
Pharmacokinetic
effect
Comment/clinical
significance
Kitzes-Cohen
et
al.,
2000
[71]
Vancomycin
15
mg/kg
IV
1
h
before
skin
incision
Mean
plasma
concentrations
during
Therapeutically
effective
vancomycin
CPB
(200
min
after
dosing)
were
concentrations
(>MIC
90
of
5
mg/L)
18.1
±
4.5
mg/L
and
dropped
to
against
S.
aureus
and
S.
epidermidis
16.2
±
4.5
after
CPB
(210
min
after
for
the
entire
operation
time
dosing)
and
to
7.6
±
2.3
mg/L
12
h
after
dosing
Krivoy
et
al.,
2002
[64]
Vancomycin
1
g
IV
at
induction
of
anaesthesia
↑
V
d
;
vancomycin
serum
331.7
mg
of
vancomycin
were
concentrations
<10
mg/L
after
4
h
sequestered
by
the
CPB
apparatus;
dosage
of
12
mg/kg
was
recommended
at
induction
of
anaesthesia
Ortega
et
al.,
2003
[72]
Vancomycin
1
g
IV
1–2
h
before
surgery
↑
V
d
;
↑
CL
Significant
drop
in
serum
concentration
due
to
haemodilution
Miglioli
et
al.,
1997
[73]
Teicoplanin
12
mg/kg
at
induction
of
anaesthesia
Average
drop
of
35%
in
plasma
Therapeutically
effective
concentrations
starting
5
min
after
concentrations
(>MIC
90
)
against
CPB
and
persisting
until
CPB
S.
aureus
and
S.
epidermidis
for
suspension
the
entire
operation
time
Martin
et
al.,
1997
[74]
Teicoplanin
Group
1,
6
mg/kg
at
induction
of
↑
V
d
;
plasma
concentration
12
mg/kg
dosing
regimen
useful
anaesthesia;
group
2,
12
mg/kg
at
significantly
dropped
after
the
onset
in
achieving
and
maintaining
induction
of
anaesthesia
of
CPB:
from
13.5
±
6.1
mg/L
to
therapeutically
effective
9.1
±
2.8
mg/L
in
group
1;
from
concentrations
>MIC
90
against
29.7
±
11.0
to
16.9
±
6.4
mg/L
in
S.
aureus
and
S.
epidermidis
for
the
group
2
entire
operation
time
both
in
plasma
and
in
tissues
Lewis
et
al.,
1999
[75]
Gentamycin
4
mg/kg
IV
at
induction
of
↑
t
1
/
2
;
↓
CL
during
and
after
CPB;
Length
of
CPB
probably
adversely
anaesthesia
mean
plasma
concentration
5.3
mg/L
affected
renal
perfusion.
Higher
doses
(range
3.4–7.1
mg/L)
6
h
after
dosing
not
recommended
Lonski
et
al.,
2000
[76]
Ceftazidime,
1
g
IV
(ceftazidime),
400
mg
IV
Sharp
↓
in
serum
concentrations
Higher
doses
recommended
ciprofloxacin,
(ciprofloxacin),
900
mg
(clindamycin)
at
the
onset
of
CPB
(55%
for
clindamycin
at
induction
of
anaesthesia
ceftazidime,
42%
for
ciprofloxacin,
78%
for
clindamycin)
Anaesthetics/opioid
analgesics
Hudson
et
al.,
2003
[77]
Fentanyl
Initial
target
concentration
4–8
ng/mL
Pre-CPB
concentrations
(5.7
ng/mL)
Effect
of
CPB
is
clinically
insignificant
higher
than
during
CPB
after
5
min
(4.3
ng/mL)
and
30
min
(4.5
ng/mL)
Hudson
et
al.,
2004
[77]
Sufentanil
Loading
dose
0.5
μg/kg;
initial
target
Pre-CPB
concentrations
(0.47
ng/mL)
Effect
of
CPB
is
clinically
insignificant
concentration
0.7
ng/mL
lower
than
during
CPB
after
5
min
(0.35
ng/mL)
and
30
min
(0.40
ng/mL)
Continued
next
page

10. 458 Pea et al.
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)
Table
II.
Contd
Study
Drug
Dosage
Pharmacokinetic
effect
Comment/clinical
significance
Russell
et
al.,
1997
[78]
Remifentanil
2
or
5
μg/kg
IV
over
1
min
before
20%
↓
CL
during
hypothermic
CPB
Hypothermic
CPB
reduces
esterase-
CPB,
during
hypothermic
CPB
and
related
blood
and
tissue
metabolism
during
CPB
after
rewarming
of
remifentanil
Michelsen
et
al.,
2001
[79]
Remifentanil
1.0,
2.0
or
3.0
μg/kg
IV
continuous
86%
↑
V
d
and
6.37%
↓
CL
for
each
Infusion
rate
of
remifentanil
can
be
infusion
degree
Celsius
<37°C
during
CPB
↓
almost
immediately
after
starting
moderately
hypothermic
CPB
(infusion
rate
↓
by
30%
for
each
5°C
decrease)
Hammaren
et
al.,
1996
[80]
Propofol
LD
10
mg/kg/h
continuous
IV
infusion
↑
plasma
unbound
fraction
during
Potential
enhancement
of
propofol
for
20
min
then
MD
3
mg/kg/h
CPB
(2.3–3.5%,
p
<
0.05)
efficacy
during
hypothermic
CPB
continuous
IV
infusion
Dawson
et
al.,
1997
[81]
Propofol
1
mg/kg
LD
then
3
mg/kg/h
↓
total
concentration
and
↑
unbound
Infusion
algorithm
must
not
be
concentrations
during
CPB
adjusted
to
compensate
for
the
fall
in
total
drug
concentrations
to
avoid
unwanted
effects
Yoshitani
et
al.,
2003
[82]
Propofol
4
mg/kg/h
(group
A),
5
mg/kg/h
After
the
start
of
CPB,
plasma
Enhancement
of
propofol
efficacy
(group
B),
6
mg/kg/h
(group
C)
by
concentrations
↓
41%,
35%
and
30%
during
normothermic
CPB
continuous
IV
infusion
vs
control
values
in
groups
A,
B
and
(probably
due
to
higher
unbound
C,
respectively.
Then
unchanged
in
concentrations)
group
A,
but
gradually
rising
to
pre-
CPB
concentrations
in
groups
B
and
C
Hiroaka
et
al.,
2004
[83]
Propofol
4
mg/kg/h
by
continuous
IV
infusion
↑
free
drug,
≈
total
drug
↑
efficacy
expected
concentrations
Takizawa
et
al.,
2006
[84]
Propofol
4–6
mg/kg/h
by
continuous
IV
infusion
↑
free
drug,
≈
total
drug
Significantly
↑
anaesthetic
effect
concentrations
Gouche
et
al.,
2007
[85]
Enflurane
Enflurane
concentration:
group
1,
Groups
1
and
2:
no
significant
Enflurane
input
concentration
at
or
0.5%
v/v;
group
2,
0.8%
v/v;
changes
in
enflurane
concentrations
below
0.8%
v/v
group
3,
1%
v/v
during
CPB;
group
3:
significant
increase
Other
drugs
Dawson
et
al.,
1997
[81]
Midazolam
0.2
mg/kg
LD
then
0.07
mg/kg/h
↓
total
concentration
and
↑
unbound
Infusion
algorithm
must
not
be
concentrations
during
CPB
adjusted
to
compensate
for
the
fall
in
total
drug
concentrations
to
avoid
unwanted
effects
Carmona
et
al.,
2005
[86]
Propranolol
80–240
mg
↑
t
1
/
2
,
↑
V
d
,
≈
CL
↑
myocardial
depression
expected
AUC
=
area
under
the
plasma
concentration-time
curve;
CL
=
total
body
clearance;
C
min
=
trough
plasma
concentration;
IV
=
intravenously;
LD
=
loading
dose;
MD
=
maintenance
dose;
MIC
90
=
minimum
inhibitory
concentration
against
90%
of
susceptible
pathogens;
t
1
/
2
=
elimination
half-life;
V
d
=
volume
of
distribution;
↓
indicates
decreased;
↑
indicates
increased;
≈
indicates
similar.

11. Clinical Relevance of PK/PD in Cardiac Critical Care 459
is still to be defined. However, it could be reasonably suggested (from 119.5 ± 35.2 to 67.7 ± 15.5 mg/L) and in the dialysate from
that a preoperative dose of at least 2 g followed by an intraopera- muscle interstitium (from 44.4 ± 15.8 to 36.1 ± 11.7 mg/L).
tive dose of 1–2 g readministered whenever the procedure lasts Despite this, free concentrations remained higher than the MIC for
>3.5 hours[87]
– and not at the predefined time of wound closure – common pathogens (2 mg/L for Gram-positive pathogens; 4 mg/L
could be a suitable approach, even if further studies are obviously for Gram-negative pathogens) for the entire course of cardiac
warranted. surgery, both in plasma (102.6 ± 26.0 mg/L) and in dialysate from
the interstitium of skeletal respiratory muscles (56.7 ± 17.6 mg/L),
The pharmacokinetic behaviour of cefamandole was assessed
suggesting that readministration of a 1.5-g dose after CPB might
in 69 men undergoing coronary artery bypass grafting (CABG)
ensure optimal protection.[69]
after random administration of 2 g intravenously at the induction
In summary, on the basis of these studies, it may be suggested
of anaesthesia (group 1, n = 24) or 2 g intravenously at the
that, given the short elimination half-life (t1
/2) of most first- and
induction of anaesthesia plus 2 g intravenously 10 minutes after
second-generation cephalosporins, the most important aspect in
cannulation of the aorta (group 2, n = 22) or 4 g intravenously at
order to ensure optimal pharmacodynamic antibacterial activity
the time of skin incision (group 3, n = 23).[67] Plasma concentra-
during prophylaxis in patients undergoing CPB is represented by
tions at the end of CPB were significantly higher in group 2
the necessity of redosing no more than 3 or 4 hours after starting
(170.3 ± 105.8 mg/L) than in group 1 (111.8 ± 42.2 mg/L) and
the procedure.
group 3 (101.2 ± 57.2 mg/L) [p < 0.05]. Likewise, cefamandole
concentrations in mammary artery and sternum samples collected The use of glycopeptide antimicrobials during cardiosurgical
at the end of CPB were significantly higher in group 2 (15.6 ± 4.7 prophylaxis may be preferable in patients who are allergic to β-
and 9.5 ± 4.7 mg/L, respectively) than in group 1 (5.7 ± 1.9 and lactams or in environments where there is a very high incidence of
3.8 ± 2.9 mg/L, respectively) and group 3 (6.3 ± 3.5 and methicillin-resistant staphylococci.[87]
3.6 ± 1.8 mg/L, respectively) [p < 0.05]. On the basis of these Four different studies have assessed plasma exposure to vanco-
findings, the investigators suggested that the most suitable proto- mycin during the application of CPB. Vancomycin serum concen-
col to ensure optimal antibacterial activity with cefamandole for trations were always shown to drop immediately after starting
the entire cardiosurgical procedure, in terms of plasma concentra- CPB, but to a different extent, according to the different investiga-
tions higher than the MIC90 against common pathogens, could be tors. Whereas the decrease in serum concentrations was about 40%
administration of 2 g intravenously at the induction of anaesthesia in two of the studies,[70,72]
it was much lower (10–11%) in the other
plus 2 g intraoperatively after the onset of CPB.[67]
two studies,[64,71]
probably as a consequence of a shorter CPB
duration and/or lower patient bodyweight. All of the investigators
Two different group of investigators investigated the disposi-
agreed that a single preoperative dose of 12–15 mg/kg may pro-
tion of cefuroxime in patients undergoing CPB. Nascimento et
vide effective antimicrobial prophylaxis with vancomycin during
al.[68]
comparatively assessed cefuroxime plasma concentrations in
CPB.
patients undergoing CABG with (group 2, n = 10) or without
(group 1, n = 7) hypothermic CPB during administration of 1.5 g In two studies assessing teicoplanin exposure in patients under-
intravenously in four bolus doses over 24 hours. Plasma concen- going cardiac surgery, a significant drop in plasma concentrations,
trations dropped below the targeted optimal concentrations of averaging 35–50%, was observed during the application of
16 mg/L just after 6 hours in both groups but, at that time, higher CPB,[73,74] probably due to haemodilution and a decrease in protein
drug exposure was observed in group 2 (95% CI 12, 20) than in binding. Interestingly, both groups of investigators concluded that
group 1 (95% CI 6, 12). This different exposure was thought to be a single preoperative dose of teicoplanin 12 mg/kg may be suitable
related to a harmful effect of CPB on drug clearance in patients to achieve and maintain therapeutically effective concentrations
undergoing hypothermic CPB, but the suboptimal concentrations higher than the MIC90 of S. aureus and S. epidermidis for the
observed in both groups led the investigators to recommend a complete surgical procedure, both in plasma and in the periopera-
change in the dose scheme of cefamandole, with a more frequent tive environment.
dosing schedule for the maintenance of therapeutically adequate The pharmacokinetic profile of gentamycin after administration
concentrations (>16 mg/L).[68]
of a single 4-mg/kg intravenous bolus dose was assessed in nine
In another recently published study, plasma and skeletal muscle patients undergoing cardiac valve replacement surgery.[75]
Of note,
tissue concentrations of cefuroxime were assessed (by means of highly effective concentrations were observed up to 6 hours after
microdialysis) during a prophylaxis protocol (3 g intravenously at dosing (mean plasma concentration 5.3 mg/L, range 3.4–7.1 mg/
the induction of anaesthesia plus 1.5 g intravenously after CPB L), probably due to significant prolongation of the t1
/2 during CPB
plus 1.5 g intravenously 8 hours after surgery) in nine patients (median 5.1 hours, range 2.0–15.1 hours) and post-CPB (median
undergoing open-heart surgery.[69] At the onset of CPB, a signif- 7.1 hours, range 3.0–13.9 hours) compared with pre-CPB (median
icant drop in free concentrations was observed, both in plasma 1.6 hours, range 1.2–2.2 hours). It was concluded that the length of
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)

12. 460 Pea et al.
CPB probably adversely affected renal perfusion, and so higher Likewise, it has been suggested that the increase in the free
doses were not recommended.[75] moiety of midazolam occurring during the application of CPB
may potentially lead to an unwanted excessive effect whenever the
In 75 consecutive coronary patients receiving ceftazidime 1 g,
total intravenous anaesthesia algorithm is adjusted to compensate
ciprofloxacin 400 mg and clindamycin 900 mg as antimicrobial
for the observed fall in total drug concentrations.[81]
prophylaxis during cardiac surgery, Lonsky et al.[76] observed a
Goucke et al.[85] recently evaluated blood enflurane concentra-
sharp decrease in serum concentrations immediately after the
tions before, during and after CPB in three different groups of
onset of CPB (55% for ceftazidime, 42% for ciprofloxacin and
patients undergoing cardiac surgery requiring hypothermic CPB
78% for clindamycin). These results led the investigators to
and receiving mean delivered enflurane concentrations of 0.5%,
recommend higher doses when using these antimicrobials for
0.8% or 1% (v/v). Whereas in patients receiving enflurane 0.5%
prophylaxis in patients undergoing cardiac surgery and CPB.[76]
and 0.8%, no significant changes were observed when comparing
In summary, all of these studies documented that CPB may
concentrations pre-CPB and during CPB (from 48 to 44 mg/L for
potentially hamper the efficacy of antimicrobial prophylaxis, espe-
enflurane 0.5%; from 52 to 56 mg/L for enflurane 0.8%), in
cially when using hydrophilic antimicrobials at fixed standard
patients receiving enflurane 1%, cooling caused a significant
dosages, and so higher dosages were advocated.
increase in enflurane blood concentrations (from 115 to 145 mg/L,
Conversely, conflicting results were observed when assessing p = 0.006). Although the exact mechanism underlying this phar-
the pharmacokinetic behaviour of some anaesthetics and opioid macokinetic effect was unclear, it was hypothesized that by de-
analgesics during the application of extracorporeal circulation, creasing the tissue perfusion rate, cooling might have reduced the
since they were clinically relevant only in some cases. partition coefficient of enflurane in fat. Consistently, it was con-
cluded that to avoid potential unwanted effects, it may be prudent
In two different studies assessing the pharmacokinetic beha-
to keep input enflurane concentrations at or below 0.8% (v/v).[85]
viour of two powerful synthetic opioid agonists – namely, fentanyl
Finally, the effect of CPB under moderate hypothermia on the
and sufentanil – during the application of CPB for cardiac sur-
pharmacokinetics of propranolol was comparatively investigated
gery,[77,89]
the same group of investigators observed only a moder-
pre- and postoperatively in 11 patients undergoing CABG.[86]
ate drop in drug serum concentrations after starting extracorporeal
After CPB, the t1
/2 of propranolol was found to be increased (from
circulation (approximately 25% and 26% for fentanyl and sufent-
4.5 to 10.6 hours, p < 0.01), mainly as a consequence of a larger Vd
anil, respectively). Indeed, this is no surprise, considering that
(from 4.9 to 8.3 L/kg, p < 0.05) and unchanged total body
because of their high lipophilicity, both of these compounds may
clearance (9.2 vs 10.7 mL/min/kg; not significant). This was
greatly accumulate intracellularly. Consistently, the extensive tis-
attributed mainly to haemodilution occurring during CPB, even if
sue reservoir tends to buffer any acute decrease in the blood
the moderate hypothermia could have also at least partially re-
concentration of fentanyl and sufentanil, such as occurred with
duced the hepatic metabolism of propranolol. Since greater myo-
initiation of CPB, and so the effect of CPB was considered
cardial depression would be expected in response to these pharma-
clinically insignificant.
cokinetic changes, the investigators suggested the use of a less
In two studies assessing the pharmacokinetics of remifentanil,
lipophilic β-adrenoceptor antagonist for pre- and postoperative
other than an increase in the Vd, a significant decrease in drug
treatment of patients undergoing CABG with CPB in order to
clearance was observed during the application of hypothermic
avoid possible unwanted adverse effects.[86]
CPB.[78,79]
Of note, this effect was attributed to significant impair-
ment of the metabolism of remifentanil by means of ubiquitous
3. Conclusions
blood and tissue esterase occurring when lowering the body tem-
perature to <37°C. It was therefore concluded that the infusion rate In critically ill cardiac patients, several drugs may need dosing
of remifentanil should be decreased almost immediately after regimens significantly different from those suggested in clinically
starting moderately hypothermic CPB, by about 30% for each 5°C stable patients, with the intent of avoiding either overexposure and
decrease in temperature.[79]
the consequent increased risk of toxicity, or underexposure and the
consequent risk of therapeutic failure.
In five other studies,[80-84] the efficacy of the highly protein-
bound lipophilic nonbarbiturate anaesthetic propofol was found to This may be due to several different causes: erratic gastrointes-
be significantly enhanced during the application of CPB, even if tinal absorption in the early postoperative period due to post-
no changes in the total drug concentrations were observed. This operative ileus; variations in the extracellular fluid content as a
increased anaesthetic effect was probably due to an increase in the response to the trauma of surgery and the fluid load and/or
free drug moiety as a consequence of haemodilution and hypoal- significant drug loss through thoracic drainages; altered drug
buminaemia occurring during CPB, and suggests that care should metabolism due to the systemic inflammatory response or MOF or
be taken when using propofol under these circumstances. drug-drug pharmacokinetic interactions during polytherapy; or
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)

13. Clinical Relevance of PK/PD in Cardiac Critical Care 461
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Acknowledgements
26. Carcillo JA, Doughty L, Kofos D, et al. Cytochrome P450 mediated-drug metabol-
ism is reduced in children with sepsis-induced multiple organ failure. Intensive
No sources of funding were used to assist in the preparation of this review.
Care Med 2003; 29: 980-4
Federico Pea has been a consultant for Pfizer and Sanofi-Aventis, and
27. Asimakopoulos G. Systemic inflammation and cardiac surgery: an update. Perfu-
has been on the speakers’ bureau for Pfizer, Sanofi-Aventis, Abbott, sion 2001; 16: 353-60
Bayer, Gilead, GlaxoSmithKline and Merck Sharp & Dohme. Mario Furlanut 28. Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the intensive
has received grant support from GlaxoSmithKline and Sanofi-Aventis. Federi- care unit: focus on drug interactions. Clin Pharmacokinet 2001; 40: 833-68
29. Pea F, Brollo L, Lugano M, et al. Therapeutic drug monitoring-guided high
ca Pavan has no potential conflicts of interest.
teicoplanin dosage regimen required to treat a hypoalbuminemic renal trans-
plant patient undergoing continuous venovenous hemofiltration. Ther Drug
Monit 2001; 23: 587-8
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Correspondence: Dr Federico Pea, Institute of Clinical Pharmacology &
cardiopulmonary bypass. J Hosp Infect 2005; 59: 299-303
Toxicology, University of Udine, P. le S. Maria della Misericordia 3,
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DPMSC, 33100 Udine, Italy.
cephuroxime during cardiac surgery in cardiopulmonary bypass: a microdial-
E-mail: pea.federico@aoud.sanita.fvg.it
ysis study. Perfusion 2007; 22: 129-36
© 2008 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2008; 47 (7)