Durante mucho tiempo no había principios uniformes para la Atribución de nombres a los antibióticos https://antibioticos-wiki.es . Más a menudo se les llama por el nombre genérico o especie del producto, con menos frecuencia-de acuerdo con la estructura química. Algunos antibióticos se nombran de acuerdo con el lugar donde se asignó el producto.
Anae20p242
Acta Anaesthesiol Scand 2001; 45: 929–934 Copyright C Acta Anaesthesiol Scand 2001Printed in Denmark. All rights reservedACTA ANAESTHESIOLOGICA SCANDINAVICA Pharmacokinetics and drug dosing adjustments during continuous venovenous hemofiltration or hemodiafiltration in critically ill patients
J. F. BUGGEDepartment of Anesthesia, Rikshospitalet, Oslo, Norway
Continuous renal replacement therapy (CRRT) in critically ill
gested, but it has the same limitations in overestimating drug
patients with renal failure may significantly increase drug clear-
clearance when dialysis is combined with filtration. For non-
ance, requiring drug dosing adjustments. Drugs significantly
toxic drugs, doses can safely be increased 30% above actual esti-
eliminated by the kidney often undergo substantial removal
mates to ensure adequate dosing. For drugs with a narrow
during CRRT, and a supplemental dose corresponding to the
therapeutical margin, monitoring plasma concentrations are
amount of drug removed by CRRT should be administered.
mandatory. When appropriate, the use of a readily available ref-
Clearance by CRRT can either be measured or estimated. The
erence for drug dosing is recommended.
high-flux membranes used in CRRT make no filtration barrierto most drugs, and the filtrate concentration can be estimated
Key words: Acute renal failure; continuous renal replacement
by the unbound fraction of the drug in plasma. When adding
therapy; drug dosing; hemofiltration; hemodiafiltration; pharm-
dialysis to filtration, this approach overestimates drug clearance,
and a correcting factor should be used. A method for estimatingdrug clearance as a function of creatinine clearance is also sug-
c Acta Anaesthesiologica Scandinavica 44 (2001)
INTHEINTENSIVEcareunit(ICU)bothintermittentand CRRT, and to provide some practical guidance for
continuous renal replacement therapies (CRRTs) are
used for treatment of acute renal failure (ARF). Duringthe last two decades there has been an evolution of con-
Drug properties
tinuous therapies from the initial arteriovenous hemo-filtration (CAVH) driven by the patient’s arterioven-
Total body clearance of a drug is the sum of clearances
ous pressure difference, to the more sophisticated
from different sites in the body which may include he-
pumpdriven devices performing continuous venoven-
patic, renal, and other metabolic pathways. It is the con-
ous hemofiltration (CVVH), hemodialysis (CVVHD) or
tribution of renal clearance to total body clearance that
hemodiafiltration (CVVHDF). In critically ill patients,
is the major determinant of making drug dosing adjust-
CRRT is superior to intermittent hemodialysis (IHD) in
ments in renal failure. If the renal clearance of a drug is
maintaining hemodynamic stability (1). Together with
normally less than 25–30% of total body clearance, im-
better volume, electrolyte, and acid-base control, this is
paired renal function is unlikely to have clinically sig-
probably the main reason for it becoming the therapy
nificant influence on drug removal (3). Similarily, drug
removal by CRRT will have little influence on total
Critically ill patients with ARF often have multi-
body clearance and dosing adjustments do not have to
organ dysfunction, sepsis, or other conditions that re-
be considered. If patients develop hepatic failure, the
quire complex drug therapy, and which may influence
extent to which CRRT contributes to total body clear-
drug concentrations through changes in absorption,
ance may increase, and dose adjustments may become
distribution, metabolism, and elimination. The ad-
necessary. Drugs significantly eliminated by the kidney
dition of CRRT may further complicate drug therapy,
often undergo substantial removal during CRRT, and
and the purpose of this review is to outline the gen-
dosing adjustments are frequently required.
eral principles determing whether a dose adjustment
However, there are other drug properties affecting
is required to compensate for drug elimination during
clearance by CRRT, including protein binding, vol-
J. F. Bugge
ume of distribution (Vd), molecular weight, and drug
IHD and CRRT. A drug with a large Vd and high
charge. Only the unbound fraction of a drug is avail-
clearance during high-flux IHD will rapidly be re-
able for filtration, and drugs with a high protein bind-
moved from plasma, but only a small amount of the
ing are poorly cleared by CRRT. Many factors may
body’s drug content is removed during one dialysis
alter the fraction of unbound drug such as systemic
session, and plasma concentration will be restored be-
pH, heparin therapy, hyperbilirubinemia, concen-
tween therapies. CRRT by its continuous and slower
tration of free fatty acids, relative concentration of
action has much less influence on plasma concen-
drug and protein, as well as presence of uremic prod-
trations of drugs with large Vds, because there is time
ucts and other drugs that may act as competetive dis-
for continuous redistribution of the drug from the
placers (4–6). Most of our knowledge about alter-
tissues to the blood. Although drug elimination dur-
ations in protein binding and pharmacokinetics is de-
ing CRRT is much slower for drugs with large Vds
rived from studies on chronic renal insufficiency. The
than for drugs with small, the same is true for endoge-
influence of ARF on protein binding is not well de-
nous (hepatic) elimination which has to clear the same
scribed. Critically ill patients often have low albumin
Vd. As a consequence, drug dosing adjustments to be
values which may increase the unbound fraction of
made during CRRT are much more dependent on the
many drugs with possible deleterious effects, as docu-
relative contribution of CRRT to total body clearance
mented for phenytoin (7). These patients also often
of the drug than on the drug’s Vd (9).
have increased levels of acid a1-glycoprotein, which
Most drugs have a molecular weight Æ500 Da, and
may increase protein binding of some drugs. Thus,
very few are greater than 1500 Da (vancomycin at
the reported unbound fraction in healthy volunteers
1448 Da). Conventional dialysis membranes favor
and in patients with chronic renal insufficiency may
diffusive clearance of low molecular weight solutes
differ substantially from the unbound fraction of
below 500 Da, whereas the typical high-flux mem-
drugs in critically ill patients receiving CRRT.
branes used for CRRT have larger pores (20 000–
Drug charge affects clearance by the Gibbs-Donnan
30 000 Da), making no significant filtration barrier to
effect: Retained proteins on the blood side of the
membrane make the membrane negatively chargedand the filtered fraction of cationic drugs will be a
Methods of drug removal
little less than expected from the unbound fraction,whereas the opposite is true for anionic drugs.
Essential to rational drug prescribing in patients un-
A large Vd reflects a drug that is highly tissue
dergoing CRRT is an understanding of the different
bound, and consequently only a small proportion ac-
methods of solute removal that occur with the various
tually resides in the vascular compartment available
types of treatments. Diffusion, convection, and ad-
for clearance by endogenous or extracorporal routes.
sorption are the three mechanisms for solute removal
The Vd is a mathematical reflection of the volume in
during CRRT. The process of moving a solute through
which a drug would need to be dissolved to obtain
a membrane from an area of high concentration to an
the observed blood concentration, assuming homoge-
area of lower concentration is called diffusion, and it
neous mixing in the body. For intravenously adminis-
is the primary method of solute removal during dialy-
tered drugs, the Vd determines the dose (D) needed
sis. Diffusive clearances varies between filter mem-
to achieve the desired plasma concentration (C):
branes and are greater for polyacrylonitrile (PAN,AN-69) than for polyamide membranes (10). In a
study by Morabito et al. (10), diffusive equilibrium
In critically ill patients the actual Vd may differ
between dialysate and plasma for urea could only be
from values obtained from pharmacological tables,
obtained with the AN-69 filter at a dialysate flow rate
and it shows great inter- and intraindividual vari-
of 1.5 l ¡ hª1 during CAVHDF. Similarily, the diffusive
ations (8). This may increase the error when using Vd
clearances of drugs will vary depending on the filter
in estimating drug dosing. The Vd of aminoglycosides
increases approximately 25% in the critically ill,
Convection is the removal of solutes along with the
whereas vancomycin, metronidazole, and most b-lac-
solvent in which they are present, and the rate of ul-
tam antibiotics show near normal values, but with in-
trafiltration determines the convective clearance of a
dividual variations (8). A drug with a small Vd (Æ1
solute during CRRT. It is not influenced by the con-
l ¡ kgª1) is more likely to be cleared by extracorporal
centration gradients across the membrane and is only
therapies than a drug with a large Vd (Ø2 l ¡ kgª1).
However, there is a significant difference between
The diffusion of a solute is inversely proportional
Drug dosing during CRRT
to its molecular weight, and the relative importance
placement fluid is administered distal to the filter, and
of convection increases with increasing molecular
mass removal per unit volume of effluent fluid is rela-
weight. Diffusion favors clearance of small solutes
tively high. For small solutes the effluent concen-
whereas middle- and large-sized molecules mainly
tration may be the same as in plasma water. However,
are removed by convection. As an example: for the
the ultrafiltration rate is limited by the operating
1448 Da molecule, vancomycin, convection is quanti-
characteristics of the system, mainly the hematocrit
tatively more important than diffusion for its removal
and the blood flow rate. The upper limit of ultrafil-
tration rate is approximately 25–30% of plasma flow
Adsorption to filter membranes leads to increased
rate (17). In pre-dilution procedures, the replacement
removal from plasma (12) and the various filters have
fluid is administered proximal to the filter, diluting
different absorptive capacity. Some filter membranes,
the concentration of solutes in the blood, and thus re-
such as the commonly used polyacrylonitrile, may ad-
ducing solute clearances approximately 15–20% (16).
sorb a substantial amount of drug to its surface (13,
This modest decrease in efficiency can be overcome
14). However, adsorption is a saturant process, and
by increasing the ultrafiltration rate which in this set-
the influence on drug removal will depend on the fre-
ting is not restricted by hematocrit and blood flow
quency of filter changes. In general, with filters lasting
approximately 18–24 h, adsorption probably has mi-nor influence on drug removal, but at present, infor-mation about the various filters’ adsorptive capacity
Drug dosing adjustments
for most drugs is lacking. Filter adsorption is not ac-counted for in drug dosing guidelines (9, 15). CRRT
The critically ill patient with renal failure is at risk for
drug accumulation and overdose, but also for under-
In CVVH, solutes are removed only by convection,
dosing that may be life threatening, such as in the case
and drug removal is limited by the ultrafiltration
of insufficient antibiotic treatment. Drug dosing ad-
rate. By adding dialysis to filtration, as in CVVHDF,
justments can be performed by reducing the dose in
solutes are removed by both convection and dif-
proportion to the reduction in total body drug clear-
fusion, increasing the removal of small molecules
more than middle-sized and large molecules. It also
gives the possibility for the two processes to interact
in such a manner that solute removal is significantly
where DN is the normal dose, ClANUR is drug clear-
less than what is expected if the individual compo-
ance in anuric patients, and ClN is normal drug clear-
nents are simply added together. In a study by Bru-
ance. ClANUR and ClN are retrieved from pharmaco-
net et al. (16), the clearance during CVVHDF of
logical tables. If CRRT contributes significantly to the
small molecules, such as urea and creatinine, was
total body clearance of a drug (Ø25–30% of total body
approximately the sum of the two clearances ob-
clearance), a supplemental dose, corresponding to the
tained when CVVHD and CVVH were performed
amount of drug removed by CRRT, should be ad-
separately. Even with the highest flow rates of 2.5
and 2.0 l ¡ hª1 of dialysate and ultrafiltration, re-
spectively, the differences between actual and pre-
dicted clearances from addition of the two pro-
where ClCRRT is the CRRT drug clearance. Clearance
cedures differed by less than 10%, indicating mini-
mal interaction between diffusion and convection.
2-microglobulin, however, combining diffusion
and convection did not increase clearance compared
where, CE and CP are drug concentrations in effluent
to convection alone, indicating that this small pro-
fluid and plasma, respectively. QE is the effluent flow
tein was only removed by convection. This means
rate which is the sum of ultrafiltration flow rate (QUF)
that the diffusive clearance of a drug during
and dialysate flow rate (QD). Substitution into the
CVVHDF is difficult to predict and will depend on
its molecular weight, blood and dialysate flow rates,
In CVVH and CVVHDF, the method by which re-
For most drugs, measurements are not available, and
placement fluids are administered influences solute
CRRT clearances have to be estimated. The sieving co-
removal efficiency. In post-dilution procedures the re-
efficient (S) of a drug is the concentration in ultrafil-
J. F. Bugge
trate (CUF) devided by the concentration in plasma,
was underestimated in the range of 30%. This means
that the actual non-CRRT clearance was greater thanestimated from P
correlations between doses calculated from measured
The exact formula for the sieving coefficient is SΩ2
kinetic data and doses estimated by the above equa-
CUF/(CPinπCPout ), but the differences between CPin
tion during CVVH, but they did not tell how PX was
and CPout are negligible, making the above equation
estimated. For CVVHDF data are lacking, but when
almost correct. For readily filtrable molecules CUF ap-
using the Kdrel on CAVHDF clearances reported in the
proximates the concentration of unbound drug in
literature, Kroh et al. (22) found very good corre-
plasma, and S can be estimated by the unbound frac-
lations between observed and estimated clearances
For non-toxic drugs, doses can safely be increased
ClCRRTΩfu ¡ QUF or ClCRRTΩfu ¡ (QUFπQD)
beyond actual estimates and a 30% increase is recom-
during CVVH or CVVHDF, respectively. The value of
mended to ensure adequate dosing (8).
fu is retrieved from pharmacological tables, but as out-
Making these estimates is time consuming, requir-
lined above, the unbound fraction in the critically ill
ing a careful search for basic pharmacokinetic data,
may differ from these values. However, with some ex-
and they are based on totally non-functioning kid-
ceptions and individual variations, Golper and Marx
neys. Today there is a tendency to start CRRT earlier
found that for most of the 60 drugs measured, the
in the course of illness, and residual renal function
filtered fraction during CRRT correlated well with the
may contribute to drug clearance. According to
unbound fraction known from studies on healthy sub-
Dettli’s equation as quoted by Keller and Czock (24),
jects (19). If CRRT is performed in a predilution mode,
actual total body clearance (ClACTUAL) of a drug is a
fu has to be corrected by the dilution factorΩplama
linear function of creatinine clearance (ClCR):
flow rate/(plasma flow rateπreplacement fluid flow
rate). The dialysate flow rate during CVVHDF is low
(750–2500 ml ¡ hª1), allowing almost diffusive equilib-
where aΩ(ClNªClANUR)/ClCRn. ClCRn is normal crea-
rium to occur between dialysate and plasma concen-
tinine clearance. To simplify and individualize drug
trations for small molecules, making fu ¡ QD an ac-
dosing estimation, Keller et al. (25) suggested to apply
ceptable estimate of diffusive clearance. However, it
this equation during CRRT by introducing the total
will always be overestimated, and increasingly over-
ClCR concept (ClCRtot) as the sum of renal ClCR
estimated with increasing molecular weight and di-
(ClCRren) and extracorporal ClCR (ClCRfilt):
alysate flow rate. Vos and Vincent (20, 21) found a
close exponential correlation of a drug’s diffusive
mass transfer coefficient through membranes in
ClCRtot can easily be calculated from creatinine meas-
urements in urine, effluent fluid and blood. These cal-culations can then be substituted into dosing adjust-
ment equations. Using the same approach as above,
where Kd and Kdc are the diffusive mass transfer co-
and setting PXΩClANUR/ClN, the estimated dose will
efficients for the drug and creatinine, respectively, and
MW is the drug’s molecular weight (113 is the mol-
ecular weight of creatinine). The limiting factor of dif-
fusive clearance can be approximated by Kdrel (22),
This equation uses an individual’s actual creatinine
clearance to estimate drug clearance and drug dosing,and dose estimates will automatically be adjusted as
changes occur in the patient’s renal function. How-
ever, extracorporal creatinine clearance may overesti-mate extracorporal drug clearance, especially diffus-
DEΩDN ¡ [PXπfu ¡ (QUFπQD ¡ Kdrel)/ClN]
ive clearance of high molecular drugs during
where PX is the extrarenal clearance fraction of the
CVVHDF. PX is not measured, and patients with se-
drug (ΩClANUR/ClN). Using this approach for anti-
vere ARF have a residual clearance that is sometimes
microbiological agents during CVVH (QDΩ0), Joos et
remarkable (22), leading to underestimating of drug
al. (23) found that CCVH clearance deviated less than
dosing. The applicability of this approach to drug
15% from estimated, whereas total body clearance
dosing has not been clinically evaluated yet, and it
Drug dosing during CRRT
remains to be seen whether it represents any improve-
recommended to ensure adequate dosing. For drugs
ment in making drug dosing adjustments during
with a narrow therapeutical margin, drug monitoring
Another and strongly suggested approach to drug
dosing during CRRT is to utilize a readily available
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e-mail: jan.fredrik.bugge/rikshospitalet.no
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