Clinical Pharmacokinetics and Disease Processes

Clin. Pharmacokinet. 17 (I): 10-26, 1989

031 2-5963/89/0007-00 I 0/$08. 50/0
© ADIS Press Limited
All rights reserved.
CPK003197a

Cardiopulmonary Bypass and the Pharmacokinetics

of Drugs
An Update

W.A. Buylaert, L.L. Herregods, E.P. Mortier

and M . G. Bogaert
Department of Emergency Medicine, Department of Anaesthesiology and Heymans
Institute of Pharmacology, University Hospital and State University of Ghent,
Belgium

Contents Summary .... ................... .................... .... ............. ................................................................. ......... 10

I. Technical and Physiological Aspects of Cardiopulmonary Bypass .............................. ....... 11
2. Theoretical Pharmacokinetic Considerations ............................................. ........................... 12
2.1 Absorption ..... ................................. ................................. ........................... ..... ....... ........... 12
2.2 Distribution .................................... ......... ............ .. ............ ................................................ 12
2.3 Elimination ..... ...... ....... ....................................................... ........... ......... .......... ................. 13
2.4 Limitations for Pharmacokinetic Analysis During and After Cardiopulmonary
Bypass ...................................................................... ...................................................... ..... 14
3. Pharmacokinetic Changes for Specific Drugs ..... .......... ................................... .... ................. 14
3.1 Benzodiazepines ........................................ ................. ........... .......... ........... ..... ............. ..... 14
3.2 Cephalosporins .............................................................................. ...................... .............. 15
3.3 Digitalis ........ ............................................ ....... ..... ............... ........... ..... .... ............. ............ .. 15
3.4 General Anaesthetics ...... ...... ................. ............................. .............. ..... ........................... 16
3.5 Glyceryl Trinitrate (Nitroglycerin) ............................................ ...................................... 17
3.6 Lignocaine (Lidocaine) ................ .......................................... ................. ..... .. .......... ......... 17
3.7 Muscle Relaxants ..... ...................................................................................................... ... 19
3.8 Nitroprusside ............. ........................ ..... ..................................... ........... .............. ... .......... 21
3.9 Opiates ........................ ................................... ........................................ ...................... ...... 22
3.10 Papaverine .................................................... ....... ...................... ...................................... 23
3.11 Propranolol .................................................................... ....................... ........................... 24
4. Conclusions .................................... ............................... ............................................ .. .............24

Summary Cardiopulmonary bypass is accompanied by profound changes in the organism that

may alter the pharmacokinetics of drugs. Drug distribution can be altered, for example,
by changes in blood flow and by haemodilution, with a decrease in protein binding; a
decrease in the elimination of some drugs can be caused by impairment of renal or hepatic
clearance, due, for example, to lowered perfusion and hypothermia.
The subject was reviewed in the Journal in 1982, and the emphasis ofthe present review
is on new data related to specific drugs. The following substances are dealt with: benzo-
diazepines, cephalosporins, digitalis glycosides, general anaesthetics, glyceryl trinitrate
(nitroglycerin), lignocaine (lidocaine), muscle relaxants, nitroprusside, opiates, papaverine
CP Bypass and Pharmacokinetics: An Update II

and propranolol. For many of these substances an abrupt decrease has been observed in
serum concentration upon initiation of bypass. which is explained by haemodilution and
an increase in distribution due to decreased protein binding. For nitrates and some opiates.
adsorption to the bypass apparatus was shown to be important. The gradual increase in
serum concentrations seen during cardiopulmonary bypass with some drugs after the in-
itial fall is usually explained by redistribution of the drug and/or decrease in its elimin-
ation. The same phenomena are thought to explain why in the post-bypass period a con-
centration increase occurs. or at least a slower decrease than expected. However. drug
elimination has been directly measured in only a few studies. The short duration of the
bypass procedure and the continuous changes during the process hamper a rigorous phar-
macokinetic evaluation. Studies allowing more precise understanding of the mechanisms
underlying the observed concentration changes are needed. but are difficult to design. Sim-
ilarly. more data are awaited on the pharmacodynamic and clinical consequences of the
concentration changes.

In procedures such as coronary bypass graft op-
eration and corrective surgery for heart valves, heart
and lung function is artificially maintained with a
pump-oxygenator device. This cardiopulmonary
bypass causes profound changes in the organism
that may lead to alterations in the pharmacokin-
etics and serum concentrations of drugs, in addi-
tion to those induced by anaesthesia (Nimmo &
Peacock 1988). The subject was reviewed in the
Journal by Holley et al. (1982), who concluded that
this was still 'a little-explored area'. Since then other
studies about the influence of cardiopulmonary by-
pass on the kinetics of different drugs have been
published, and this review focuses mainly on the
more recent information. The technical and phys-
iological aspects of cardiopulmonary bypass and
the theoretical pharmacokinetic considerations are
discussed only briefly, as they were extensively dealt
with in the previous review.
1. Technical and Physiological Aspects 0/
Cardiopulmonary Bypass
For a detailed account of the cardiopulmonary
bypass procedure (CPB), the reader is referred to
the review of Holley et al. (1982). After heparini-
sation, the blood of the patient is led, most often
from the caval veins, via tubing to the oxygenator
(membrane or bubbles), and is then pumped to the
ascending aorta by means of a roller pump; the flow
delivered by the pump is usually non-pulsatile.
Before bypass is initiated, the pump is primed
with approximately 1.5 to 2L of an electrolyte so-
lution (usually Ringer lactate) which leads to hae-
modi/ution. The haemodilution and the rather low
pump flow rate (approximately 1.2 to 2.4 L/m2/
min; Tinker 1987) lead to hypotension with a mean
arterial pressure around 40mm Hg, with altera-
tions in the regional flow distribution, and to a
marked decrease of perfusion of some organs. Data
on blood flow to the vital organs are, however,
scarce. There is indirect evidence for a decrease in
blood flow to non-vital organs such as skeletal
muscle (Stanley 1978), as can be expected during
a shock-like state (Benowitz et al. 1974). A de-
crease in hepatic blood flow, as measured by the
clearance of indocyanine green, has been reported
(Koska et al. 1981). Administration of vasoactive
substances during bypass surgery can also alter re-
gional blood flow: e.g. an increase in hepatic flow
occurs with isoproterenol or glucagon, and a de-
crease with p-adrenoceptor antagonists (Pentel &
Benowitz 1984).
During the bypass procedure, hypothermia is in-
duced in order to diminish metabolic require-
ments, and the patient is rewarmed towards the
end of the procedure.
Haemodilution, hypotension, altered regional
blood flow and hypothermia can be expected to
profoundly alter the pharmacokinetics of drugs, as
can additional factors such as the administration
of vasoconstrictors at the moment of restoration
12 Clin. Pharmacokinet. 17 (1) 1989

of normal circulation. It should be stressed that the Table I. Possible alterations to the disposition of drugs due to
different factors which can influence the phar- the physiological changes induced by cardiopulmonary bypass
macokinetics of a drug do not remain constant Pharmacokinetic Physiological Expected
throughout the bypass procedure, a feature which parameter change alterations
hampers detailed analysis of the pharmacokinetic
Absorption Hypotension and Reduced or delayed
changes seen.
blood flow changes absorption
Distribution Lung sequestration Decreased volume
2. Theoretical Pharmacokinetic of distribution;
Considerations redistribution upon
restoration of
spontaneous
The physiological changes induced by cardio-
circulation
pulmonary bypass which are expected to influence Hypotension and Decreased volume
the disposition of drugs are given in table I. blood flow changes of distribution
Haemodilution and Increased volume
2.1 Absorption decreased of distribution
concentration of
binding proteins
It is possible that absorption could be altered. Post-bypass <wacid Decreased volume
In the context of the bypass procedure, however, glycoprotein of distribution
the majority of drugs are administered intraven- increase
ously. The intramuscular route was used in only a Elimination
hepatic Decreased hepatic Decreased
few studies; as these studies do not allow an eval-
blood flow clearance of drugs
uation of absorption kinetics, this problem is not with flow-dependent
discussed further here. elimination
Decreased Increased clearance
2.2 Distribution concentration of of drugs with
binding proteins restrictive
elimination
Distribution can be altered by several mech- Hypothermia, Decreased intrinsic
anisms. During bypass surgery the circulation to severely decreased clearance
the lungs is restricted to the bronchial circulation; hepatic blood flow (metabolism)
it can be expected that, if drugs are given during renal Hypotension and Decreased active
reduced blood flow tubular secretion
the procedure, the isolation of the lung will de-
Decreased Increased
crease the distribution of substances which are concentration of glomerular filtration
known to accumulate in that organ [e.g. lignocaine binding proteins
(lidocaine), imipramine, propranolol; Roth & pH and filtration Tubular
Wiersma 1979]. On restoration of normal circu- volume changes reabsorption
changes
lation, wash-out from the lungs of drug which had
accumulated before initiation of the bypass could
lead to an increase in post-bypass serum drug con-
centration. the brain in analogy to what has been described for
The altered regional blood flow during cardio- lignocaine during shock (pentel & Benowitz 1984).
pulmonary bypass can also affect the distribution The haemodilution after addition of the prim-
of drugs to other organs. If drug distribution to tis- ing solution to the blood of the patient leads to an
sues is flow-limited, this factor will favour distri- immediate, proportional reduction in total serum
bution to parts of the organism for which the per- drug concentration. This reduction is, however,
fusion is best preserved. This could lead, for relatively soon counteracted by redistribution of
example, to an increased passage of some drugs into drug from tissues to the serum. The eventual result
CP Bypass and Pharmacokinetics: An Update
will depend upon the characteristics of the drug,
and for one with a high initial volume of distri-
bution, the drug serum concentrations after re-
equilibration will be only slightly lower than those
before haemodilution. The degree of serum protein
binding of the drug will also influence this phen-
omenon: for drugs which are highly bound, the de-
creased concentration of the binding proteins due
to haemodilution will lead to an increase in the
fraction of unbound drug. This will favour distri-
bution of drug from the serum to the tissues, and
contribute to the lowering of the serum concentra-
tion. In many of the studies discussed below, a good
correlation has been found between the decrease in
albumin concentration and the fall in drug serum
concentration.
To what extent the administration of heparin
decreases protein binding of some drugs, through
an increase in non-esterified fatty acids, is not clear,
as the results published on the subject are possibly
influenced by in vitro artefacts (Giacomini et al.
1980). Similarly, it is not known whether plasti-
cisers, which invade the bloodstream during car-
diopulmonary bypass, influence drug binding in
serum.
Changes in binding, of course, alter the rela-
tionship between free and total concentrations in
serum: measurement of total serum concentrations
only can therefore be misleading if the researcher
wants to speculate about alterations in the effect
of a drug as a consequence of the pharmacokinetic
changes.
In the days following bypass surgery, drug dis-
tribution can be altered as ai-acid glycoprotein
concentrations may increase, due to the inflam-
matory reaction to the intervention; this leads to
an increased binding of basic drugs such as lig-
nocaine, propranolol and disopyramide.
2.3 Elimination
Elimination of a drug from the body can be af-
fected by several of the changes occurring during
and after cardiopulmonary bypass. Some sub-
stances are cleared by the lungs, either by local me-
tabolism or by exhalation: changes during the by-
13
pass procedure, when the lung is isolated, can be
expected.
Many drugs are cleared by the kidney. Circu-
latory changes are expected to affect mainly the ac-
tive secretion of drugs, which is flow-dependent.
The glomerular filtration of a drug is, within cer-
tain limits, not flow-dependent, but depends on
serum protein binding. Tubular reabsorption is
likely to be affected by changes in pH and filtration
volume. The impairment of the metabolic state of
the kidney, due to the hypoperfusion and hypo-
thermia, can be expected to decrease its function.
However, in the few studies where renal clearance
of drugs has been measured, a decrease is not al-
ways found (Miller et al. 1980).
For many other drugs, the 'liver is the main or-
gan for clearance. The determinants of hepatic
clearance of drugs are blood flow, drug binding in
serum and the activity of the metabolic enzymes
(often expressed as 'intrinsic clearance'). Hepatic
flow decreases during cardiopulmonary bypass, al-
though redistribution of blood flow limits this de-
crease. Protein binding, as already discussed, can
decrease during the procedure but in the days fol-
lowing, an increase in binding of basic drugs bound
to ai-acid glycoprotein is possible. The intrinsic
drug-metabolising activity of the liver is difficult
to measure in clinical situations, but deterioration,
due for example to hypoperfusion and hypo-
thermia, can be expected.
The influence of these 3 factors (blood flow,
serum binding and intrinsic activity) upon hepatic
drug clearance differs according to the character-
istics of the drug. For high extraction drugs (e.g.
lignocaine, propranolol) clearance is mainly flow-
dependent, and protein-bound molecules are also
cleared (non-restrictive elimination). For low ex-
traction drugs, a category to which most drugs be-
long, the critical factors are the intrinsic drug me-
tabolising capacity and the degree of serum binding:
only free drug can be cleared (restrictive elimina-
tion). It should be stressed, however, that these
statements are only valid within certain limits and
that a pronounced fall in liver perfusion, for ex-
ample, will also affect clearance of a low extraction
drug, while a marked deterioration ofthe drug me-
14
tabolising enzymes will also lead to a change in the
clearance of a high extraction drug. As discussed
below, a decrease in hepatic clearance during by-
pass surgery has been assumed by many authors
to explain kinetic changes in the course of the pro-
cedure, but direct evidence is almost entirely lack-
ing.
2.4 Limitations for Pharmacokinetic Analysis
During and After Cardiopulmonary Bypass
The changes in drug distribution and elimina-
tion during cardiopulmonary bypass will, of course,
affect the serum concentrations of a drug, and the
changes in concentrations found in the studies are
discussed below. It is often difficult, however, to
find an explanation for the concentration changes
observed in these studies. Indeed, any attempt at
pharmacokinetic evaluation and modelling as-
sumes that the condition of the organism remains
steady over the period considered. However, there
are continuous changes both during and after by-
pass surgery, due to the release of vasoactive en-
dogenous substances, fluctuation of the metabolic
state, changes in temperature, etc. Moreover, phar-
macokinetic analysis is often best done under
steady-state conditions, but for most drugs a steady-
state cannot be reached during the bypass proce-
dure, which lasts at most a few hours. If a sub-
stance is given by intravenous bolus, or as an intra-
venous infusion that is discontinued either during
or after bypass surgery, observations over a period
several times longer than the half-life of the sub-
stance are needed to measure the distribution and
elimination parameters correctly.
These difficulties notwithstanding, for some
pharmacokinetic changes a satisfactory explana-
tion can be found. The abrupt fall in concentra-
tion, for example, which is seen for many sub-
stances upon initiation of cardiopulmonary bypass,
can be attributed to changes in distribution, as even
marked changes in elimination affect serum con-
centrations only much more slowly: e.g. if the
clearance of a drug changes during intravenous in-
fusion, a new steady-state will only be attained after
a period 4 to 5 times as long as the half-life, and
Clin. Pharmacokinet. 17 (1) 1989
it takes the equivalent of 1 half-life before 50% of
the expected change is achieved. Another general
remark: in many studies, conclusions about elim-
ination are made on the basis of half-life alone.
This can be misleading in situations such as car-
diopulmonary bypass, where the volume of distri-
bution changes. For the proper quantitative eval-
uation of changes in elimination, it is necessary for
clearances to be calculated.
Finally, the discussion of the pharmacodynamic
consequences of pharmacokinetic changes is often
based on total serum concentrations; however, the
change in serum binding occurring during the by-
pass procedure necessitates discussion of free con-
centrations, which are not measured in most stud-
ies.
For all these reasons, only limited conclusions
can be drawn from the studies discussed below
about the mechanisms underlying the changes seen
in concentration. The suggestions made by the
authors are in some instances based on rather shaky
grounds.
3. Pharmacokinetic Changes for
Specific Drugs
3.1 Benzodiazepines
Aaltonen et al. (1982) found that the total serum
concentrations oflorazepam (and of its conjugate)
decreased abruptly after initiation of the bypass
procedure. Boscoe et al. (1984) came to the same
conclusion on the basis of a limited number of
sampling points. In both studies the abrupt de-
crease of the serum concentrations was explained
by haemodilution and changes in protein binding,
but binding was not measured. An increase in the
serum concentrations of lorazepam following car-
diopulmonary bypass was found by both groups,
and this was explained by redistribution of the drug
from the tissues. The elimination half-life post-
bypass was not different from that in healthy
volunteers (Aaltonen et al. 1982).
For midazolam, as for lorazepam, a fall in con-
centration on initiation of bypass, and an increase
in concentration at the end, have been reported
(Kanto et al. 1985). The authors conclude from a
CP Bypass and Pharmacokinetics: An Update
comparison of the half-life with that found in stud-
ies in healthy volunteers that there is a slower elim-
ination of the drug in the post-bypass period. Lowry
et al. (1985) administered midazolam after discon-
tinuation of the procedure, and they suggest that
there is no marked alteration in the elimination of
the drug at that time.
3.2 Cephalosporins
The 2 studies with cephazolin have already been
reviewed by Holley et al. (1982). Miller et al. (1980)
found a decrease of the serum concentrations at
the initiation of cardiopulmonary bypass, followed
by either a plateau or a gradual increase in the
course of the procedure. The decrease can be ex-
plained by the haemodilution and the decreased
binding of this highly protein-bound drug (85% un-
der normal circumstances); the gradual secondary
increase in some patients is possibly due to redis-
tribution. The renal clearance of cephazolin (which
is entirely eliminated by the kidney and whose
elimination is already decreased at the start of the
surgery, presumably because of an anaesthesia-
induced decrease in glomerular filtration) did not
show deterioration during bypass surgery when
compared with the value present at the start of the
surgical procedure. A fall in cephazolin concentra-
tion upon initiation of the procedure was also found
by Akl and Richardson (1980) who concluded, on
the basis of indirect evidence, that the renal clear-
ance of the drug was decreased during cardiopul-
monary bypass.
The studies by Miller et al. (1979) and by Wil-
liams and Steele (1976) on cephalothin, which is
moderately protein-bound (65%) and cleared both
by the kidneys and the liver, were discussed by
Holley et al. (1982). The effects of the bypass pro-
cedure on serum concentrations and renal clear-
ance of cephalothin (Miller et al. 1979) are essen-
tially similar to those seen with cephazolin by the
same group (Miller et al. 1980). Williams and Steele
(1976) also observed a reduction in serum concen-
trations upon institution of the bypass, and found
that there was little further change, or only a very
slow decline in the levels of cephalothin, during the
15
procedure. The authors concluded that the rate of
metabolism and excretion of the drug was altered,
but their data do not allow a distinction between
changes of distribution and changes of elimination.
Goldmann et al. (1977) mention briefly, in a
paper on antibacterial eflicacy, that cardiopulmon-
ary bypass did not alter the serum concentration
profile of cephalothin. Finally, there is a recent
study by Sato et al. (1984) which showed that the
half-life of cephalothin is significantly prolonged
both during and after bypass surgery.
For cefamandol, Polk et al. (1978) reported that
the serum concentrations declined much more rap-
idly during cardiopulmonary bypass than before.
The drug was, however, given as a single short
intravenous infusion at the induction of anaes-
thesia, and the possibility cannot be excluded that
the more rapid decline of the concentrations before
bypass than during the procedure was due to on-
going distribution. The half-life during the bypass
was, however, much longer than that found in
healthy patients, and the decline of serum concen-
trations remained slow after restoration of the nor-
mal circulation. The authors suggest a decrease in
renal function as the cause of the decreased elim-
ination.
Mizuta et al. (1985) studied the serum concen-
trations of cefotiam during bypass surgery. They
observed a fall in serum concentration upon ini-
tiation; the authors mention also a brief initial rise,
although this is not apparent from the serum con-
centration-time profiles shown. The authors de-
veloped a pharmacokinetic model in which changes
in volume of distribution, elimination and inter-
compartmental transfer are taken into account, but
no conclusions can be drawn from these prelimi-
nary data.
3.3 Digitalis
Four papers (Carruthers et al. 1975; Coltart et
al. 1971; Krasula et al. 1974; Morrison & Killip
1973) on digoxin have already been discussed by
Holley et al. (1982). In 3 of the 4 studies, digoxin
concentrations fell significantly at initiation of car-
diopulmonary bypass, which can be explained by
16
dilution; digoxin binding in serum is too low to be
of importance in this process. The digoxin concen-
trations remained low during the procedure and for
several hours afterwards. As digoxin has a very high
volume of distribution and is mainly stored in
skeletal muscle, Holley et al. (1982) suggest that the
absence ofa secondary increase of the digoxin con-
centration during the bypass is due to the poor per-
fusion of skeletal muscle during the procedure. Re-
bound after termination of the bypass occurs late,
probably because the substance is stored in very
deep compartments. In some patients the post-
bypass digoxin concentrations rose to values higher
than those pre-bypass, which can only be explained
by changed distribution.
Digoxin clearance was found to be decreased
post-bypass in some studies, a fact which corre-
sponds with the decreased creatinine clearance
during that period. Since 1982 no new studies on
digoxin have become available, except for one by
Koren et a1. (1984a) mentioning that digoxin is not
adsorbed to the cardiopulmonary bypass appara-
tus.
A paper on digitoxin, which is more than 90%
protein-bound and has a much smaller volume of
distribution and a longer half-life than digoxin
(Storstein et a1. 1979), was discussed by Holley et
a1. (1982). Digitoxin concentrations fell on initia-
tion of the bypass but again increased somewhat
during the procedure, and the free fraction in-
creased from 4.2 to 6.5%, which was attributed to
heparin administration. Serum concentrations rose
again after the bypass. Essentially similar findings
were made in 4 patients by Morrison and Killip
(1973).
It is not possible to draw conclusions from these
papers on digitalis glycosides about the importance
of the effect of differences in serum binding or vol-
ume of distribution between digitoxin and digoxin,
on the pharmacokinetic consequences of cardio-
pulmonary bypass (such as the fall in concentra-
tions upon initiation of the procedure).
3.4 General Anaesthetics
3.4.1 Barbiturates
Nancherla et a1. (1986) gave thiopentone as an
intravenous bolus injection after initiation of car-
diopulmonary bypass and measured plasma drug
Clin. Pharmacokinet. 17 (1) 1989
concentrations over 90 minutes. The volume of
distribution and rate of distribution were similar
to those reported for healthy volunteers or in
patients undergoing minor surgical procedures, but
total clearance and metabolic clearance were
smaller.
Morgan et a1. (1986) administered thiopentone
as an exponential infusion calculated to give a
steady-state concentration of 15 mgJL in 7 patients
undergoing bypass surgery. After the start of the
bypass, total thiopentone concentrations declined
abruptly to a value of approximately 50% of pre-
bypass levels; during the procedure they rose grad-
ually to a new plateau of about 70% of pre-bypass
levels. Binding of the drug decreased markedly at
initiation, and had partially recovered at cessation;
calculated free concentrations also fell at initiation,
but to a lesser extent than total concentrations, and
they had normalised at the end of the bypass pro-
cedure. The decrease in free fraction is probably
due to the dilution; interference by heparin was
considered less likely by the authors. The un-
changed concentration of free thiopentone at the
end of cardiopulmonary bypass is consistent with
an unchanged intrinsic clearance for this low-
extraction drug, in contrast with the findings of
Nancherla et a1. (1986).
The same group of authors (Bjorksten et a1.
1988) compared the effect of cardiopulmonary by-
pass on the serum concentrations of thiopentone
and methohexital under infusion conditions simi-
lar to those in the previous study. The findings for
thiopentone in their first study were confirmed. For
methohexital, which is less protein bound (73%) in
serum than thiopentone (84%), the total serum
concentrations also showed a marked drop upon
initiation of the bypass, with a gradual recovery
during the process; the free concentrations of the
drug showed a small initial decrease, followed,
however, by an increase that was not statistically
significant. The authors found a strong correlation
between the albumin concentrations and the de-
gree of plasma protein binding for both thiopen-
tone and methohexital in the subset of patients in
whom this was studied during cardiopulmonary
bypass, confirming that the binding changes are in-
CP Bypass and Pharmacokinetics: An Update
deed due to dilution. The results with methohexital
are similar to those with thiopentone, although the
former is less bound in serum and thiopentone is
a low-extraction and methohexital a high-extrac-
tion drug.
3.4.2 Etomidate
Oduro et al. (1983) studied the influence of car-
diopulmonary bypass on the serum concentrations
of etomidate given as a bolus, followed by a con-
tinuous infusion. After initiation of bypass, a
marked drop in the serum drug concentrations was
observed, and was attributed to haemodilution.
During the procedure the etomidate concentra-
tions increased again, and the authors ascribe this
to the hypothermia resulting in a decreased meta-
bolic rate of this drug, although it is cleared in a
flow-dependent way by the liver (Arden et al. 1976).
However, it is possible that steady-state concentra-
tions had not yet been reached, as etomidate has
a half-life of approximately 5 hours. Near the end
of the procedure, when the patient was rewarmed,
and afterwards, the serum concentrations de-
creased. This observation is explained by an in-
crease in metabolism. Following the decrease in
serum concentration, an increase was again seen in
the post-bypass period and this is explained by the
authors as a release of etomidate from the bypass
apparatus.
3.4.3 Isoflurane
Isoflurane is frequently used during cardiopul-
monary bypass to provide anaesthesia and to con-
trol blood pressure (Price et al. 1988). Concentra-
tions of isoflurane during cardiopulmonary bypass
could be expected to decrease due to the haemo-
dilution with cristalloids (Lerman et al. 1984), and
to increase because of the higher solubility of the
gas during hypothermia.
Isoflurane concentrations during bypass surgery
were measured by Loomis et al. (1986) in patients
who were given the anaesthetic to control hyper-
tension. The doses of isoflurane were adapted to
the clinical needs and no conclusions can be drawn
about the influence of cardiopulmonary bypass on
pharmacokinetics. The authors, however, observed
17
marked effects on the central nervous system (as
measured with an electroencephalogram) at rela-
tively low isoflurane concentrations, and they
speculate that this might be due to enhanced dis-
tribution to the brain.
Price et al. (1988) measured the elimination of
isoflurane via the oxygenator during cardiopul-
monary bypass, i.e. immediately after the admin-
istration of isoflurane was discontinued following
the removal of the aortic cross clamp. The drug
was measured in the exhaust from the bubble oxy-
genator and the authors assumed that there was an
equilibration between the concentrations in the ox-
ygenator and those in the blood; they found that
isoflurane was washed out with a time constant of
± 2 minutes, i.e. a half-life of approximately 5
minutes; in most patients, the elimination could be
described with a I-compartment model. The study
was made without a control group, so it is difficult
to draw any conclusions with regard to the influ-
ence of cardiopulmonary bypass on the pharmaco-
kinetics of the drug.
3.5 Glyceryl Trinitrate (Nitroglycerin)
The influence of cardiopulmonary bypass on
glyceryl trinitrate clearance was studied by Dasta
et al. (1986) in patients receiving an intravenous
infusion of that agent. The authors report a 20%
increase in clearance of glyceryl trinitrate but in
view of the intraindividual variability in the phar-
macokinetics of the drug (Bogaert 1987), no con-
clusions can be drawn from these results. In an in
vitro study the same group found an important ad-
sorption of glyceryl trinitrate to the bypass appa-
ratus, mainly to the polyurethane defoaming sponge
in the oxygenator (Dasta et al. 1983); their results
were to be expected in the light of the well-known
problem of adsorption of this drug to several plas-
tics (Bogaert 1987).
3.6 Lignocaine (Lidocaine)
Morrell and Harrison (1983) gave a bolus in-
jection of lignocaine during cardiopulmonary by-
pass and measured the serum concentrations for
Table II. Muscle relaxants: pharmacokinetic changes related to cardiopulmonary bypass
I
00

Drug Dosage a Controls Serum concentration After CPS Reference

(no. of patients) (IV)
start of during C CLb tY2#b Vssb
CPS CPS

Alcuronium (10) 0.27 mg/kg + 'Normal' Increase New apparent Transient rise; Decrease Increase Unchanged Walker et al.
1 ltg/kg/min patients steady-state (50% biexponential (1983)
(younger, higher than decline atter
smaller body contrOl) infusion
weight) discontinued

Gallamine (22) 480mg (n = 11) or Surgical Increase in Increase in some Increase in some Decrease Increase Decrease Shanks et al.
240mg + 240mg patients without some patients patients (1983)
in priming fluid CPS patients
(n = 11)

Metocurine (10) 0.3 mg/kg + 0.04 Patients Transient New apparent Small Unchanged Unchanged Avram et al.
mg/kg/h undergoing hip decrease steady-staie, decrease (1987)
replacement higher than
control but not
higher than pre-
CPS

d- Tubocurarine 0.6 mg/kg +3 'Normal' Increase New apparent Siexponential Decrease Increase Comparable Walker et al.
(13) ltg/kg/min patients steady-state (4X decline after with (1984)
increase) infusion controls
discontinued

Q
;';.
~
'~"
l;s.
~
a For the purpose of clarity, details of the dosage (e.g. time of start and end of infusion) have been omitted. ......
b In most papers these pharmacokinetic parameters reflect the post-cardiopulmonary bypass situation rather than the changes during bypass. "
Abbreviations; CPS = cardiopulmonary bypass; C = serum concentration; CL = total plasma clearance; tY2# = terminal half-life; Vss = apparent volume of distribution at ---
-:::
......
steady-state; IV = intravenous. ~
'0
CP Bypass and Pharmacokinetics: An Update
30 minutes (i.e. during the period of hypothermia).
As stressed by the authors themselves, the data are
difficult to interpret because of the comparatively
short sampling period; nevertheless, from a com-
parison with literature data in patients who did not
undergo bypass surgery, the authors suggest an in-
crease in volume of distribution, without change
in clearance, leading to an increased elimination
half-life. The changes in distribution are explained
by haemodilution leading to an increase in the
drug's free fraction.
Holley et al. (1984) also administered lignocaine
in a bolus intravenous injection, before cardiopul-
monary bypass and at 15 minutes and I day after
termination of the procedure. The authors found,
to their surprise, no changes in either clearance,
volume of distribution or elimination half-life.
These findings suggest that the changes in the phar-
macokinetics of this drug, reported by Morrell and
Harrison (1983), are quickly reversible after bypass
surgery. Holley et al. (1984) also gave intravenous
bolus injections of lignocaine, before and at 3 and
7 days after cardiopulmonary bypass. Three days
after the bypass the free fraction of lignocaine,
which is bound to ai-acid glycoprotein, had de-
creased to 16% compared with 30% before the by-
pass. The authors explain this finding by a 200%
rise in ai-acid glycoprotein concentrations. One
would expect that, for this drug with a high, non-
restrictive elimination, the reduced volume of dis-
tribution, caused by the increased serum binding,
would lead to an increased clearance; in contrast,
Holley et al. (1984) found a marked decrease in
clearance on the third day after the bypass, and
speculate upon possible reasons. In the same way,
it is not clear why on the seventh day after the
bypass, when ai-acid glycoprotein levels and lig-
nocaine binding are quite similar to those on the
third day, the clearance had more or less normal-
ised. In the absence of measurement of hepatic
blood flow, these findings are difficult to interpret.
Schiavello et al. (1988) gave an intravenous
bolus injection of lignocaine before and during car-
diopulmonary bypass. Serum drug concentrations
during the first 10 minutes after the injection were
lower during bypass than before. The authors do
19
not mention similar experiments by Morrell and
Harrison (1983). An elaborate 3-compartment
model analysis is performed but can be questioned
in the absence of steady-state following aortic un-
clamping. The lower initial concentrations during
the bypass procedure can probably be explained by
haemodilution.
3.7 Muscle Relaxants
The influence of cardiopulmonary bypass has
been studied for different muscle relaxants, and the
results are summarised in table II. Walker et al.
(1983, 1984) studied alcuronium and d-tubocurar-
ine, given as a continuous infusion, and found,
during the procedure, an increase in serum con-
centrations for both substances to a new apparent
steady-state. The authors attribute this increase to
a reduction in distribution of the substances to
normally well-perfused tissues; the lung (which is
thought to accumulate these substances to a large
extent) is virtually excluded from the circulation
during bypass surgery. This factor gives rise to an
increased serum concentration, despite the hae-
modilution.
Protein binding of d-tubocurarine was meas-
ured and a marked increase in free fraction was
found during cardiopulmonary bypass, related to
the haemodilution. Therefore during the procedure
free concentrations were increased even more than
total concentrations. A decrease in renal clearance
(which was shown for d-tubocurarine), and in he-
patic clearance, could certainly contribute to the
increase in serum concentrations. There is no def-
inite explanation for the decreased renal clearance
of d-tubocurarine during bypass: indeed, it could
be expected that the increased free fraction would
favour its glomerular filtration.
After cardiopulmonary bypass, the steady-state
volume of distribution of both alcuronium and d-
tubocurarine was comparable with that in control
patients, but there was a decrease in plasma clear-
ance leading to a prolonged elimination half-life.
The same group also studied gallamine (Shanks
et al. 1983). In some patients concentrations did
not change either during or after cardiopulmonary
Table III. Opiates: pharmacokinetic changes related to cardiopulmonary bypass N
0

Drug Dosage a Controls Serum concentration After CPB Reference

(no. of patients) (IV)
start of CPB during CPB C CL t'hP V••

Fentanyl (5) 60l'g/kg Decrease (53%) Stable or increase Constant during Increase Bovill & Sebel
before CPB towards the end 211 (1980)
(18) 75 I'g/kg over Decrease (40%) Stable Constant Lunn et al.
± 10 min (1979)
(6) 0.5 mg/70 kg Surgical Decrease Relatively Increase followed Increase Koska et al.
patients constant by decrease (1981)
without CPB
(30) 30-50 I'g/kg + Decrease Sprigge et al.
0.3-0.5 I'g/kg/ (1982)
min
(6) 300 l'g/min Decrease Stable Hug et al.
until 75 I'g/kg (1982)
or 2.4 I'g/kg/
min for 20 min
followed by
0.15 I'g/kg/ Decrease Stable
min or
0.30 I'g/kg/ Decrease Stable
min for
duration of
anaesthesia
(10)b 50l'g/kg Decrease (74%) Stable Koren et al.
bolus + 0.15 (1984a)
I'g/kg/min
(n = 4) or
+ 0.3 I'g/kg/
min (n = 6)
(8) 30 I'g/kg/min +
0.3 I'g/kg/min
(n = 8)e
Q
Fentanyl (20
?i'
ng/ml) added
to priming
.,..,~
fluid (700- .,;:
1750ml) ::5i';"
Alfentanil (5) 1251'g/kg Same patients Unchanged Increase Increase Hug et al. ;;;.
before and 30 before CPB (1983) ~
min after CPB .....
"
......
C
.....
~
'0
CP Bypass and Pharmacokinetics: An Update 21

bypass, while in others increases during and/or after

"iii "iii
OJ the procedure were seen. It is not clear why there
"iii
Gi iii
Gi
Gi ~ ·2 was such a wide interindividual variability in the
~
",-
E~
~­
.cit) "'-
lU~
N .....
NCO bypass-induced changes for this agent.
,,0> .~ ~ Q)O>
Glen
~~ u..~ U:::::..
ai With metocurine the same group (Avram et al.
0..
<..>
U 1987) observed only minimal changes, with a fall
$;!
in the serum concentration immediately after ini-
.g tiation of cardiopulmonary bypass and a subse-
0..

o
CJ quent increase towards fairly stable values; no fur-
ther change was seen after the end of the procedure.
c::
The initial fall was explained by the haemodilu-
f!! tion, with gradual re-equilibration afterwards. No
:g
:E important changes in clearance seem to have oc-
<..>
.0 curred. The authors do not have a convincing ex-
planation for the marked contrast with the changes
described for d-tubocurarine and alcuronium; they
Q)
CI)
III
U> ~.~ speculate that differences in the methodology of in-
'o~"
lU

CJ
itiating the bypass and of cooling might be respon-
.5 c:
sible. Finally, the authors draw attention to the in-
~
.c
.t:
~ fluence of cooling on sensitivity to the effects of
t:
:::I
"
u..
U. !
.c metocurine, which makes it difficult to link the
5l Q)
5l
g- pharmacokinetic changes during bypass to the
U> ·iii
'" ~ pharmacodynamic effects of the drug.
Q)
~

.~
c:
0
~
Q).c
'" Ql
Cl CD
o~ ._
c: .c 0~
.-
o
.5
:s" D'Hollander et al. (1983) studied pancuronium
'0
0;-'1: (ij~i(/)(ij "0 infused at rates adapted to the clinical needs. The
::J.!Q) :1> .... (1):1 c:
"00 0 'OCDs:::::CG"C Q) •
"'_C: ~-caa.~ conclusion seems to be that the serum concentra-
c!i.58 (!J.s -5 ~<!) "0=
c: Q)
~:g tions decreased upon initiation of cardiopulmon-
~
-
'0 _';
c: +1 +1
'"
"t;; -
~
ary bypass, probably due to haemodilution. Futter
et al. (1983) came to the same conclusions without
o
- U>
U>
?fl. OJ Q) Q) c:
Q)
5l measuring serum concentrations, on the basis of a
~~
U> <:> c: U>
mlt)~<..>
t;+I0Q) '"~~ '~a;
"
Q)-
c». 'S;Q) study of pancuronium dose requirements for
CD-Om
cC,,)z~ ~~ OC\l
Q)
-.0
Q) .0
~
neuromuscular blockade.
Cl",
'"o ~ The effects of cardiopulmonary bypass on the
~ U> Q)
.c
.~
"0 (5 pharmacokinetics ofatracurium (Flynn et al. 1984)
~S Q) ~
and vecuronium (Buzello et al. 1985) remain a
~
Q)
c:
Q)
=.e
r.-.:: '0 U> matter for speculation, as no serum concentrations
51l U> U>
-]j 'E" were measured in these studies.
>-.c c: Q) >-
C) CD --.- I "0"0
~<:>O;:::i! Cl~E 0 It)~ • 0
c:('I'):s..al:S 0 ... -co i!'.o
'E o.,.......J rnLt)C\I-g rn~"O c: "''! 'i:: c: 3.8 Nitroprusside
'C; - + ~ C) + " Q) f/J
::t:2 0 c:.§ C):i5 i a. Q.!
.Q ~ 0
E 'in ~.-~.!
.!!!
o '"Q)
'0-;;-
~~ 5l·E-6~ §'tii~8 ::l:5.~ ~~ 5l :::i! Moore et al. (1985) infused nitroprusside in
om patients undergoing bypass surgery and measured
§:
Gl~
Q )-
C:1t)
0-
0"
~
"e-...J
0. ~
.. cyanide and thiocyanate, metabolites of nitroprus-
:;:;-
'i
"i0. >.
c: 5~ side, in red blood cells and serum. The authors
0 E ... 'S
c:
Q)
CI)
.c
.l!1 ~~ concluded that during cardiopulmonary bypass, the
.t:
0.. ":::I
CJ)
'" « non-enzymatic release of cyanide from nitroprus-
22
side was not changed, but that the enzymatic de-
toxification of cyanide to thiocyanate was delayed,
due to the hypothermia.
3.9 Opiates
The influence of cardiopulmonary bypass on the
pharmacokinetics of opiates has been studied ex-
tensively and a summary of the data is shown in
table III.
Several studies have been made of fentanyl, a
very liposoluble, high extraction drug with only
moderate (80%) binding to serum proteins. Three
of these studies (Bovill & Sebel 1980; Koska et al.
1981; Lunn et al. 1979) were discussed by Holley
et al. (1982), who concluded that there is a marked
fall in total serum concentrations upon initiation
of the bypass procedure. This fall can be ascribed
to haemodilution, but an important adsorption to
the bypass apparatus has since been shown, as dis-
cussed below. During bypass the concentration of
fentanyl, which was not further infused during the
procedure, did not change markedly; after the by-
pass either no change or an increase of the serum
concentrations was found. The latter is explained
by redistribution caused by disappearance of hae-
modilution and normalisation of protein binding;
also, the role of washout from the lung cannot be
excluded. After cardiopulmonary bypass, a pro-
longed elimination half-life was found and 1 study
(Koska et al. 1981) indicates that this was related
to a decrease in hepatic perfusion, as estimated with
indocyanine green. Holley et al. (1982) drew atten-
tion to the fact that, from the change in total serum
concentrations reported, it is difficult to predict the
changes in concentrations in the biophase (i.e. the
brain). Indeed, fentanyl has a very high volume of
distribution, and measurements of free concentra-
tions are not available.
Since Holley's review, several other studies of
fentanyl have been published. Sprigge et al. (1982)
compared different infusion rates of the drug in
patients undergoing coronary bypass surgery, and
tried to correlate serum fentanyl concentrations
with the haemodynamic responses to surgical
stimulation. There was a fall in serum fentanyl
Clin. Pharmacokinet. 17 (I) 1989
concentrations when the bypass was instituted; this
decrease was calculated by the authors to be about
30%, but that figure could be an overestimation
since the serum concentrations were still declining
when the procedure was initiated. Hug et al. (1982)
likewise compared different infusion schemes, and
also found a decrease of the serum concentrations
of fentanyl upon starting the bypass. The serum
concentrations remained stable during the proce-
dure; after restoration of normal circulation, they
seemed to remain lower than before the bypass
procedure. Elimination half-life in these patients
(probably measured after cardiopulmonary bypass)
was longer than in control patients who had not
undergone bypass surgery, due to both an in-
creased volume of distribution and a decreased
clearance.
Bentley et al. (1983) also found a fall in fentanyl
concentrations upon institution of bypass, and the
concentrations remained constant during the
procedure. The fall in fentanyl concentrations was
correlated with the decrease in haematocrit and al-
bumin. After restoration of ventilation and perfu-
sion to the lungs near the end of the procedure, the
radial artery concentrations of fentanyl rose ab-
ruptly while those in the pulmonary artery de-
creased to values lower than the former, although
they had initially been higher; these findings point
to a washout from the lungs at that point.
Koren et al. (1984a) pursued the finding that the
fall in fentanyl concentrations upon institution of
cardiopulmonary bypass was in several studies
larger than that expected from haemodilution alone.
In children, they found a mean fall of 74% in fen-
tanyl serum concentrations at initiation of bypass,
while the haemodilution was only 50%. In an in
vitro study they demonstrated that fentanyl was ad-
sorbed by the apparatus, mainly the membrane
oxygenator. These data confirm the findings ofRo-
sen et al. (1985) and Skacell et al. (1986), who also
showed in in vitro studies that fentanyl is adsorbed
by parts of the apparatus. The latter study fur-
thermore demonstrated that alfentanil was not ad-
sorbed, possibly because of its lower lipid solubil-
ity. Priming of the pump with fentanyl in the in
vivo part of the study of Koren et al. (1984a) did
CP Bypass and Pharmacokinetics: An Update
not prevent the fall in concentrations of that drug.
In other children, Koren et al. (1984a) measured
the albumin concentrations before and during
cardiopulmonary bypass; the concentrations de-
creased on average from 32 to 15 mmol/L. As the
decrease of albumin concentrations was propor-
tional to the dilution, the authors concluded that
' ... it is unlikely that there was any change in free
fentanyl concentration from that observed in the
pre-bypass period'. However, as fentanyl in normal
circumstances is about 80% bound to plasma pro-
teins, one would expect that haemodilution during
bypass would at least temporarily change the free
concentrations. In another paper from the same
group (Koren et al. 1984b) the same data on car-
diopulmonary bypass are reported, with additional
data on the influence of the underlying cardiac dis-
ease on the pharmacokinetics of fentanyl.
In an abstract, Hug et al. (1983) report a pro-
longed elimination half-life of alfentanil after by-
pass, due to an increase in volume of distribution;
the authors postulate that this is based on the di-
lution-induced decrease of the protein binding of
the drug. The clearance of alfentanil, which is a
low-extraction drug, was not affected, in contrast
to the decrease of clearance after bypass found by
the same group (Hug et al. 1982) for fentanyl, a
high-extraction drug.
In a recent paper, Kumar et al. (1988) found
that upon initiation of cardiopulmonary bypass the
total serum concentrations of alfentanil decreased
by about 50%, while those of unbound alfentanil
did not change, notably because of an increase in
the unbound fraction. The decrease in total alfen-
tanil concentrations was explained by a dilution of
ex I-acid glycoprotein. These data illustrate that it is
important to measure free concentrations of the
drug.
Sufentanyl was studied by Flezzani et al. (1987).
Upon initiation of cardiopulmonary bypass, the
serum concentrations decreased, gradually increas-
ing again during the bypass procedure. In the case
of sufentanyl, in contrast to fentanyl, the fall in
concentration was smaller than that expected
through haemodilution; the authors suggest that this
is due to rapid redistribution from the tissues to
23
the plasma, since the drug has a very high volume
of distribution. However, the steady-state volume
of distribution of sufentanyl is not markedly dif-
ferent from that of fentanyl (2 and 3 L/kg respec-
tively) and the comparison may be hampered by
the possibility that sufentanyl (in contrast with fen-
tanyl) is not adsorbed in the bypass apparatus; fur-
ther data are needed to confirm this hypothesis.
With continued infusion of sufentanyl during by-
pass, serum concentrations rose gradually, possibly
due to redistribution of the drug from the tissue to
the blood and to reduced hepatic metabolism. Al-
though the data suggest that a steady-state was
reached before initiation of the bypass, it should
be stressed that studies in control patients are not
available. The difference between fentanyl and su-
fentanyl cannot be explained by differences in he-
patic extraction, since both are high-extraction
drugs.
FishIer et al. (1985) studied phenoperidine, an-
other short-acting opiate. Serum concentrations
during continuous infusion decreased upon initi-
ation of the procedure: haemodilution is again given
as an explanation for the fall. There was no sug-
gestion of adsorption. Continuous infusion during
cardiopulmonary bypass led to an increase of the
concentrations to values higher than those before
bypass in 4 of 5 patients; the authors explain this
as a decrease in hepatic clearance linked to a fall
in hepatic blood flow or to the exclusion of the
lungs. A further increase was seen after the bypass.
3.10 Papaverine
Kramer and Romagnoli (1984) measured the
serum concentrations of papaverine in patients
undergoing bypass surgery after direct administra-
tion of the drug into the coronary arteries with the
cardioplegic solution. They found a considerably
longer half-life than in control patients under an-
aesthesia receiving intravenous papaverine. A pos-
sible explanation is the decreased liver perfusion
leading to a decreased clearance for this high-ex-
traction drug, but changes in distribution cannot
be excluded.
24
3.11 Propranolol
Holley et al. (1982) discussed the paper by
McAllister et al. (1979), who found a marked fall
of serum propranolol concentrations upon initia-
tion of cardiopulmonary bypass; in some patients
there was a gradual increase during the procedure,
sometimes rising above pre-bypass values as illus-
trated by the mean data and the data in a single
patient given in the paper. There is an important
interindividual variability, which is certainly due
in part to the fact that changes in serum concen-
trations are caused by more than one factor.
McAllister et al. tried to evaluate the relative con-
tributions of haemodilution and of hypothermia,
also on the basis of observations in dogs. The auth-
ors came to the conclusion that hypothermia, by
an influence on clearance and distribution, leads
to a marked increase in propranolol concentra-
tions, which is counteracted during bypass by the
haemodilution.
The paper by Wood et al. (1979) on serum bind-
ing of propranolol during cardiopulmonary bypass
was also discussed by Holley et al. (1982), who em-
phasised that the decreased binding attributed by
the authors to heparin administration could to a
large extent be explained by an artefact occurring
during the in vitro procedure for protein binding
measurement.
Plachetka et al. (1981) found upon initiation of
cardiopulmonary bypass that the serum concentra-
tions of propranolol decreased as expected. During
the bypass, the concentrations remained on aver-
age low. After the end of the procedure they rose
suddenly, but remained lower than the pre-bypass
values; this post-bypass rise is attributed by the
authors to washout of propranolol from the lungs
which were excluded from the circulation during
the procedure, and therefore protected from redis-
tribution. Plachetka et al. (1981) attributed the dif-
ferences between their results and those of Mc-
Allister et al. (1979) to methodological differences
(e.g. the degree of hypothermia). It should be
stressed that, in view of the marked interindividual
variability apparent, e.g. in the paper of McAllister
et al. (1979), and undoubtedly also present in
Clin. Pharmacokinet. 17 (1) 1989
Plachetka's patients, differences between the re-
sults of the 2 groups are perhaps more apparent
than real.
4. Conclusions
The data that have appeared since the review
by Holley et al. (1982) on the influence of cardio-
pulmonary bypass on the pharmacokinetics of drugs
have confirmed the marked changes in serum con-
centrations that can occur. Although changes in
distribution and elimination are invoked to ex-
plain these observations, direct measurements of
these parameters during bypass are scarce. Al-
though some authors have attempted to approach
these changes quantitatively by the use of phar-
macokinetic models, their results are questionable
because the lack of steady-state during bypass pre-
cludes the application of these models. There is
evidence now that adsorption to the bypass ap-
paratus can contribute to the decrease in serum
concentrations of glyceryl trinitrate and certain
opiates. Finally, more data are needed on the in-
fluence of cardiopulmonary bypass on the free con-
centrations of drugs, since total serum concentra-
tions may be misleading because of the changes in
protein binding induced by the bypass procedure.
Acknowledgement
The authors wish to thank R. Vanlangendonck for her
excellent secretarial work.
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Authors' address: Dr W. Buyiaert, Department of Emergency
Medicine, University Hospital, De Pintelaan 185,8-9000 Ghent,
Belgium.