Altered Renal Function
the Effects of Anesthetic Agents
Most drugs commonly employed during anesthesia (other than
volatile anesthetics) are at leat partly dependent on renal excretion for
elimination. In the presence of renal impairment, dosage modifi-cations may be
required to prevent accumulation of the drug or its active metabolites.
Moreover, the systemic effects of AKI can potentiate the phar-macological
actions of many of these agents. This latter observation may be the result of
decreased protein binding of the drug, greater brain penetra-tion due to some
breach of the blood–brain barrier, or a synergistic effect with the toxins
retained in kidney failure.
The pharmacokinetics of both propofol and etomi-date are
minimally affected by impaired renal func-tion. Decreased protein binding of
etomidate in patients with hypoalbuminemia may enhance its pharmacological
effects.
Patients with kidney disease often exhibit increased sensitivity
to barbiturates during induction, even though pharmacokinetic profiles appear
to be unchanged. The mechanism appears to be an increase in free circulating
barbiturate as a result of decreased protein binding. Acidosis may also favor a
more rapid entry of these agents into the brain by increasing the nonionized
fraction of the drug.
Ketamine pharmacokinetics are minimally altered by kidney
disease. Some active hepatic metabolites are dependent on renal excretion and
can potentially accumulate in kidney failure.
Benzodiazepines undergo hepatic metabolism and conjugation prior
to elimination in urine. Because most are highly protein bound, increased
sensitiv-ity may be seen in patients with hypoalbuminemia. Diazepam and
midazolam should be administered cautiously in the presence of renal impairment
because of a potential for the accumulation of active metabolites.
Most opioids currently in use in
anesthetic man-agement (morphine, meperidine, fentanyl, sufent-anil, and
alfentanil) are inactivated by the liver; some of these metabolites are then
excreted in urine. Remifentanil pharmacokinetics are unaf-fected by renal
function due to rapid ester hydro-lysis in blood. With the exception of
morphine and meperidine, significant accumulation of active metabolites
generally does not occur with these agents. The accumulation of morphine
(morphine-6-glucuronide) and meperidine(normeperidine)
metabolites has been reported to prolong respiratory depression in patients
with kidney failure, and increased levels of normeperi-dine has been associated
with seizures. The phar-macokinetics of the most commonly used opioid
agonist–antagonists (butorphanol, nalbuphine, and buprenorphine) are unaffected
by kidney failure.
In doses used for premedication,
atropine and glyco-pyrrolate can generally be used safely in patients with
renal impairment. Because up to 50% of these drugs and their active metabolites
are normally excreted in urine, however, the potential for accumulation exists
following repeated doses. Scopolamine is less dependent on renal excretion, but
its central ner-vous system effects can be enhanced by the physi-ological
alterations of renal insufficiency.
Most phenothiazines, such as promethazine, are metabolized to
inactive compounds by the liver. Droperidol may be partly dependent on the
kidneys for excretion. Although their pharmacokinetic pro-files are not appreciably
altered by renal impairment, potentiation of the central depressant effects of
phe-nothiazines by the physiological milieu of renal insufficiency can occur.
All H2-receptor blockers are dependent on renal excretion, and their
dose must be reduced for patients with renal insufficiency. Proton pump
inhibitor dosage does not need to be reduced for patients with renal
insufficiency. Metoclopramide is partly excreted unchanged in urine and will
accu-mulate in kidney failure. Although up to 50% of dol-asetron is excreted in
urine, no dosage adjustments are recommended for any of the 5-HT3 blockers in patients
with renal insufficiency.
Volatile anesthetic agents are ideal for
patients with kidney disease because of lack of dependence on the kidneys for
elimination, ability to control blood pressure, and minimal direct effects on
renal blood flow. Although patients with mild to moderate renal impairment do
not exhibit altered uptake or distri-bution, accelerated induction and emergence
may be seen in severely anemic patients (hemoglobin <5 g/dL) with chronic kidney failure; this
observa-tion may be explained by a decrease in the blood:gas partition
coefficient or by a decrease in minimum alveolar concentration. Some clinicians
avoid sevo-flurane (with <2 L/min gas
flows) for patients with kidney disease who undergo lengthy procedures.
Some clinicians omit entirely or limit the use of nitrous oxide
to 50% concentration in severely anemic patients with end-stage renal disease
in an attempt to increase arterial oxygen content. This may be justified in
patients with hemoglobin below
7 g/dL, in whom even a small increase in the dissolved oxygen content may
represent a significant percentage of the arterial to venous oxygen difference
.
Succinylcholine can be safely used in
patients with kidney failure, in the absence of hyper-kalemia at the time of
induction. When the serum potassium is known to be increased or is in doubt, a
nondepolarizing muscle relaxant should be sub-stituted. Although decreased
plasma cholinesterase levels have been reported in uremic patients follow-ing
dialysis, significant prolongation of neuromus-cular blockade is rarely seen.
Cisatracurium and atracurium are degraded by plasma ester
hydrolysis and nonenzymatic Hofmann elimination. These agents are often the
drugs of choice for muscle relaxation in patients with kid-ney failure,
especially in clinical situations where neuromuscular function monitoring is
difficult or impossible.
The elimination of vecuronium is
primarily hepatic, but up to 20% of the drug is eliminated in urine. The
effects of large doses of vecuronium (>0.1
mg/kg) are only modestly prolonged in patients with renal insufficiency.
Rocuronium primarily undergoes hepatic elimination, but prolongation in
patients with severe kidney disease has been reported. In general, with
appropriate neuromuscular monitor-ing, these two agents can be used with few
problems in patients with severe kidney disease.
Elimination of d-tubocurarine is dependent on both renal and
biliary excretion; 40–60% of a dose of curare is normally excreted in urine.
Increasingly prolonged effects are observed following repeated doses in
patients with renal insufficiency. Smallerdoses and longer dosing intervals are
therefore required for maintenance of optimal muscle relax-ation. In the days
before intermediate acting neuro-muscular blockers, curare was the nondepolarizing
paralytic of choice for patients with kidney disease.
Pancuronium is primarily dependent on
renal excre-tion (60–90%). Although pancuronium is metabo-lized by the liver
into less active intermediates, its elimination half-life is still primarily
dependent on renal excretion (60–80%). Neuromuscular function should be closely
monitored if these agents are used in patients with abnormal renal function.
Renal excretion is the principal route
of elimina-tion for edrophonium, neostigmine, and pyridostig-mine. The
half-lives of these agents in patients with renal impairment are therefore
prolonged at least as much as any of the above relaxants, and problems with
inadequate reversal of neuromuscular blockade are usually related to other
factors . In other words, “recurarization” due to inadequate duration of
reversal agents is unlikely.
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