Acta Anaesthesiologica Taiwanica xxx (2014) 1e8

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Review Article

Obstructive jaundice and perioperative managements

Long Wang, Wei-Feng Yu*
Department of Anesthesia and Intensive Care, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China

a r t i c l e i n f o a b s t r a c t

Article history: The causes of obstructive jaundice are varied, but it is most commonly due to choledocholithiasis; benign
Received 5 December 2013 strictures of the biliary tract; pancreaticobiliary malignancies; and metastatic disease. Surgery in patients
Received in revised form with obstructive jaundice is generally considered to be associated with a higher incidence of compli-
24 December 2013
cations and mortality. Therefore, it poses a considerable challenge to the anesthesiologist, surgeons, and
Accepted 27 December 2013
the intensive care team. However, appropriate preoperative evaluation and optimization can greatly
contribute to a favorable outcome for perioperative jaundiced patients. This article outlines the associ-
Key words:
ation between obstructive jaundice and perioperative management, and reviews the clinical and
adverse reaction;
anesthesia;
experimental studies that have contributed to our knowledge of the underlying pathophysiologic
cardiovascular effect; mechanisms. Pathophysiology caused by obstructive jaundice involving coagulopathies, infection, renal
obstructive jaundice; dysfunction, and other adverse events should be fully assessed and reversed preoperatively. The
perioperative management depressed cardiovascular effects of obstructive jaundice are worth noticing because it has complicated
mechanisms and needs to be further explored. Alterations of anesthesia-related drugs induced by
obstructive jaundice are varied and clinicians should be aware of the possible need for a decrease in the
anesthetic dose. Recommendations concerning the perioperative management of the patients with
obstructive jaundice including preoperative biliary drainage, anti-infection, nutrition support, coagula-
tion reversal, cardiovascular evaluation, perioperative uid therapy, and hemodynamic optimization
should be taken.
Copyright 2014, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights
reserved.

1. Introduction Choledocholithiasis undoubtedly is the leading cause of biliary

Patency of the biliary tree and free drainage of bile into the in-
testine are important for normal hepatic function. Substances
normally excreted into the bile will accumulate in the vascular
system owing to obstruction of the biliary tree and the inability to
excrete bile into the intestine. These substances, including bile salts,
have systemic toxic effects.1 Patients with obstructive jaundice are
inclined to develop nutritional decits, infectious complications,
acute renal failure, and impairment of cardiovascular function.
Adverse events such as coagulopathy, hypovolemia, and endotox-
emia can be insidious and signicantly increase mortality and
morbidity. Postoperative morbidity of patients with obstructive
jaundice is up to about 20e30%.2 The anesthesiologist and critical
care team play a crucial role in the perioperative management of
such patients.
Conicts of interest: All contributing authors declare no conicts of interest.
* Corresponding author. Department of Anesthesiology and Intensive Care,
Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University,
225 Changhai Road, Shanghai 200438, China.
E-mail address: ywf808@yeah.net (W.-F. Yu).
obstruction, although malignancies such as cholangiocarcinoma,
periampullary and pancreatic cancers, and benign stricture
including chronic pancreatitis have become increasingly preva-
lent.3e5 It is not surprising that iatrogenic injury of biliary tract and
cholangitis are becoming more important with the increase of
invasive procedures performed on the biliary tract. In China, but
much less frequently in the USA, parasites absorb nutrition by
attaching themselves to the walls of the bile duct, causing bile duct
obstruction and brosis.6,7
2. Pathophysiology of obstructive jaundice
2.1. Changes in gastrointestinal tract
2.1.1. Malnutrition
Long-term obstruction of bile can induce pathophysiological
changes involving malnutrition, acute renal failure, and infections
that may be fatal. Prolonged obstruction of bile can lead to:
malabsorption of fats and steatorrhea; poorly absorbed fat-soluble
vitamins because of impaired enterohepatic circulation;

http://dx.doi.org/10.1016/j.aat.2014.03.002
1875-4597/Copyright 2014, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.

Please cite this article in press as: Wang L, Yu W-F, Obstructive jaundice and perioperative managements, Acta Anaesthesiologica Taiwanica
(2014), http://dx.doi.org/10.1016/j.aat.2014.03.002
2 L. Wang, W.-F. Yu
susceptibility to night blindness because of vitamin A deciency;
vitamin D deciency and chronic cholestasis contributing to hep-
aticosteopathy; and neuromuscular weakness in children attrib-
utable to vitamin E deciency.8 Deciency of vitamin K requires
vigilance especially when invasive procedures are implemented,
because vitamin K plays an important role in blood coagulation.
Prolonged prothrombin time is attributed to lack of vitamin K-
dependent clotting factors resulting from vitamin K deciency. If
vitamin K deciency is not treated, patients will bleed easily,
resulting in unnecessary blood loss during the perioperative
period.9 Sepsis may also deteriorate disseminated intravascular
coagulation. In these conditions, necessary precautions should be
implemented.
The presence of liver disease or a prolonged partial throm-
boplastin time or active hemorrhage usually indicates a serious
prognosis, but appropriate replacement therapy is indicated in
this situation.10 Reversal of coagulopathy is the premise not only
in case of intraoperative bleeding but also for the insertion of an
epidural catheter preoperatively. Hepatocellular dysfunction re-
sults in insufcient protein synthesis, gluconeogenesis, and
ketogenesis disorders. Therefore, malnutrition is stubborn to
correct if obstructive jaundice is not relieved promptly.11 When
coagulopathy is present, it can be corrected with intramuscular
vitamin K (1e10 mg). When liver failure is present, synthetic
function should be the main priority for improvement. Fresh
frozen plasma should be administered intravenously in emer-
gency situations.12 Patients with obstructive jaundice need to
replenish nutrients preferably through the enteral pathway. If
enteral nutrition is not allowed because of gastric dilatation, cli-
nicians should consider a nasojejunal tube feeding. If enteral
nutrition is not available and meanwhile severe malnutrition
exists, dened as recent weight loss of >10e15% or actual body
weight <90% of ideal body weight, parenteral nutrition can be
adopted 5e7 days prior to the operation and continued after the
operation.
2.1.2. Bacterial translocation
The tendency of bacteria accumulated in bile to develop into
infectious complications is also an important consequence of
obstructive jaundice. The sphincter of Oddi presents a barrier to
retrograde bacteria of the intestine under normal physiological
conditions. It is believed that bacteria routinely regress into the
biliary tract from the intestine.13 However, bile salts can limit their
proliferation,14 and they are efciently eliminated from bile by the
reticuloendothelial system. Furthermore, bile excretion from the
bile tract into the intestine can also clear bacteria.3,13e17 Flemma
et al13 reported that bacteria were more easily cultured from bile of
patients with partial biliary obstruction than with complete biliary
obstruction. This indicates that retrograde contamination of bile
may be an essential factor. Alternatively, bacteria may contaminate
bile possibly through the hepatic artery, the portal venous systems,
or even biliary lymphatics.14,16 Furthermore, with the absence of
biliary intervention, sepsis may occur because of a combination of
gut failure with increased bacterial translocation through the portal
system or signicant biliary colonization.18,19 The incidence of
bacterial contamination increases in patients with sphincterotomy
or cholangioenterostomy and in those treated with internal biliary
drains and biliary stents. About two-thirds of patients with ma-
lignant obstructive jaundice have positive bacterial cultures of bile
after initial endoscopic retrograde cholangiopancreatography. Pa-
tients with a biliary intervention have a colonized rate of almost
100%, and these infections tend to be polymicrobial. Repeated
reux of bacteria and endotoxin into the vascular system eventually
leads to systemic inammatory response syndrome and even
sepsis.
Please cite this article in press as: Wang L, Yu W-F, Obstructive jaundice and perioperative managements, Acta Anaesthesiologica Taiwanica
(2014), http://dx.doi.org/10.1016/j.aat.2014.03.002
Bacteria isolated from bile of patients with cholangitis mainly
include Gram-negative organisms: usually Escherichia coli and
Klebsiella, Proteus, Pseudomonas species; and Gram-positive organ-
isms: mainly Streptococcus and Enterobacter species.15,20e25 A b-lac-
tam inhibitor combined with aminoglycoside can be used
empirically. Quinolones and carbapenams excreted into the bile are
generally effective monotherapy in the treatment of cholangitis.26e28
Enterococci and anaerobes targeted antibiotics can also be used in
those who have antibiotic resistance, and in those with previous
biliary intervention and elderly patients.29,30 However, antibiotics
alone are unlikely to be effective until effective biliary drainage has
been done.
2.2. Renal pathophysiology
Patients with obstructive jaundice are considered at a particu-
larly high risk for acute renal failure, which may be a life-
threatening complication.31e38 Previous study has reported that
renal failure was nonoliguric in 80% and was related to severe
jaundice, Gram-negative infection (42%), hypotension (31%),
hypoproteinemia (30%), hyponatremia (56%), and hypokalemia
(63%).39
Mechanisms of the renal failure have not been fully claried and
need to be further explored. The possible explanations may be as
follows. (1) Renal failure in the patient with jaundice is associated
with the presence of enteric endotoxin in the peripheral blood, and
the absence of bile lead to both increased growth of the intestinal
ora and absorption of endotoxin. Furthermore, cirrhosis causes
increased spillover into the systemic circulation.31,40 Endotoxin
absorbed from the intestine and entering the systemic circulation
may then cause renal vasoconstriction. (2) Blood loss, shifts in uid,
especially when sepsis is present, may cause severe disturbances of
body-uid compartments, which may be the basic mechanism
underlying kidney dysfunction in obstructive jaundice. The risk of
renal failure is increased in obstructive jaundice patients with
decreased intravascular volume, especially when they undergo
various invasive procedures.41,42 Correction of volume decits in
patients with bile duct obstruction can increase renal blood ow
and urine output for the excretion of hepatic metabolites, and
decrease circulating concentrations of toxic substances.43e46 This
indicates that renal impairment is attributed primarily to a lack of
renal blood ow. The most effective precaution to reduce the risk of
postoperative renal dysfunction is preoperative intravenous uid
therapy to maintain an adequate intravascular volume.47 (3) Car-
diovascular function in patients with obstructive jaundice is
depressed,1,48e53 and responsiveness to the vasoactive substances
is blunted.49,50 Data in animals have demonstrated that serum
jaundice decreases the heart rate, causing an early cessation of
beating,53 and is associated with blunted contractile response to
vasoconstrictor drugs such as b-adrenoreceptor and angiotensin II
stimulation.49,52 Depressed Cardiovascular function can give rise to
low pressure of systemic circulation, then may lead to pre-renal
failure. This will be described in detail below. In brief, these factors
lead to reduced blood ow and renal function damage. In addition,
renal impairment is partially attributed to direct toxic effects of
hepatic metabolites on the kidneys.37
2.3. Cardiovascular effects
2.3.1. Vascular hyporesponsiveness
Vasodilatory properties of jaundice have been explored by both
in vivo and in vitro studies in animal experimental models and in
humans. Patients with both acute and chronic biliary obstruction
are at particular risk for hypotension after surgery to relieve the
obstruction.12 Complications are highly morbid and contribute to
Obstructive jaundice and perioperative managements
the high mortality.54 Zollinger and Williams55 found that patients
with obstructive jaundice undergoing biliary surgery were more
liable to a hypotensive crisis after hemorrhage. The same result has
been found in dogs with obstructive jaundice.56 It has also been
established that dogs with chronic bile duct ligation (BDL) man-
ifested hypotension and peripheral vascular hyporesponsive-
ness,48,57 could be attributed to blunted response to vasoactive
agents.49,50,58 Although Bomzon et al59 reported that systemic
blood pressure was normal at rest, there was always hypores-
ponsiveness for the skeletal muscle vasculature to norepinephrine
in baboons. Likewise, the contractile response of arterial strips or
rings isolated from rats with obstructive jaundice is markedly
blunted.60 The effects of bile acids components including taurine-
conjugated ursodeoxycholic acid (UDCT), taurine-conjugated che-
nodeoxycholic acid (CDCT), and taurine-conjugated deoxycholic
acid (DCT) on vascular responsiveness have also been evaluated.61
Lautt and Daniels62 reported that intravenously administrated
taurine-conjugated bile acid induced vasodilation of mesenteric
and hepatic arteries in cats. Similarly, intravenous infusion of doses
of CDCT and DCT, not UDCT, correlated with the increased mesen-
teric arterial blood ow and reduced arterial pressure.61 Vascular
blunted responsiveness in jaundiced patients and experimental
animals has also been suggested.56,63,64
The opposite conclusion, that is BDL animal models may have
normal basal systemic blood pressure, has also been reported. There
may be a transient hypotension during the rst 1e2 days after the
BDL procedure. Blood pressure in BDL rats for periods longer than
1 week returned to normal levels.65,66 Regardless of the basal state of
systemic hemodynamics, the subtle deleterious consequences of
BDL on the circulation may be masked by various experimental
procedures. Thus, the preliminary conclusion is that the effects of
obstructive jaundice on the peripheral vasculature are the decreased
vascular resistance, perhaps without decreased blood pressure. This
vascular hyporesponsiveness may in some cases be manifested as
vulnerability to hypotension after hemorrhage, and a higher inci-
dence rate of postoperative complications in patients or animals
with obstructive jaundice. The mechanisms may be as follows.
2.3.1.1. Role of nitric oxide. There is evidence that nitric oxide
(NO), the production of endothelium-derived L-arginine, plays a
role in the diminished systemic vascular resistance in cirrhotic
patients. NO synthesis has been found to mediate the vasodilation
and decreased vascular responsiveness that occur in response to
endotoxin or cytokines.67,68 Deoxycholyltaurine (DCT) partici-
pates in concentration-dependent vasodilation, which could be
attenuated by incubation with L-NAME, an inhibitor of endothe-
lial NO synthase (eNOS), or endothelium denudation, in rat and
mouse aorta.69 Taurolithocholate (TLC), taurocholate (TC) and
taurochenodeoxycholate (TCDC) have been reported to increase
eNOS mRNA expression induced by cAMP and NO production.70
Moreover, there is indirect evidence concerning the enormous
contribution of bile acids in the pathogenesis of endotoxemia, and
the causality between endotoxin and NO production has been
studied.71e73 Peripheral vasodilation occurs after endotoxin
infusion in humans74 or in patients with septic shock,75 and this
phenomenon can be explained by the induction of NO synthase
with the increased production of NO. Considering that obstructive
jaundice is always associated with endotoxemia, it is reasonable
to propose that high levels of endotoxin induce a high level
expression of vascular NO synthesis, thereby leading to peripheral
vasodilation.76 This calls for more studies to evaluate the role of
NO in the hemodynamic disturbances associated with obstructive
jaundice. Furthermore, the effects of inducible NO synthase in-
hibitors to systemic and renal hemodynamic indices should be
also evaluated.
Please cite this article in press as: Wang L, Yu W-F, Obstructive jaundice and perioperative managements, Acta Anaesthesiologica Taiwanica
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3
2.3.1.2. Role of potassium channels. Dopico et al,77 using patch-
clamp techniques, found that bile acids reversibly activate BKCa
channels in rabbit mesenteric artery smooth muscle cells, and that
endothelium-independent vasodilation can be eliminated after
administration of the BKCa channel blocker. Previous studies
revealed left carotid artery (LCA)-induced vascular hypores-
ponsiveness are mediated by the second transmembrane domain of
the BK b-1 subunit.78,79 Furthermore, LCA-induced vasodilation of
arteries disappeared in BK b-1 subunit knockout mice implicating
BK b-1 played an important role in LCA-induced vascular
hyporesponsiveness.80
2.3.1.3. Role of receptors. Fluorescence microscopy has been used
to explore the effect of bile acids on endothelial cells.81 Khurana
et al69 found that the vasodilation of mouse aortic rings mediated
by DCT was abolished by M3 receptor gene ablation. Likewise, a
synthetic acetylcholine, which acts as an M3 receptor antagonist,
can block DCT-induced vasodilation.82 These data indicate that
DCT-induced vasodilation is mediated by the M3 receptor.
Farnesoid X receptor (FXR), a nuclear receptor that can regulate
bile acid synthesis, is encoded by the NR1H4 gene in humans.83 The
studies about the effects of FXR on vascular function became a hot
spot once the identication of its expression in the vasculature was
revealed.84 Because FXR belongs to transcription factor, it is ex-
pected that FXR can regulate vascular function by regulating the
expression of vasoactive factors (NO). eNOS expression was
signicantly increased by chenodeoxycholic acid (CDCA) and
GW4064 (a chemical FXR agonist) in cultured endothelial cells,85
which indicates that NO can act as a bridge between FXR and
vascular vasodilation. On the contrary, when smooth muscle cells
were chronically stimulated by FXR, NO-dependent vasodilation
was impaired because of blunted increase of cGMP.86 Thus, acute
and chronic stimulation of FXR exhibit different effects on NO-
dependent vasodilation and FXR knockout model may be needed
to delineate the role of vascular FXR in BA-mediated vasodilation in
vascular tone.
A functionally defective expression of a-1 adrenoreceptors was
found both in vivo and in vitro in a 3-day BDL rat model,87 but the
response to a-2 agonists in BDL rats was unchanged. Investigators
provided a hypothesis that bile acids in conjunction with accu-
mulated endotoxin during obstructive jaundice could lead to the
modication of the vascular a-1 receptor.88,89 However, it has not
been determined whether the defect of a-1 receptor was due to
decreased ligand-receptor binding or not.
2.3.1.4. Others. Evidence of neural regulation of vascular tone
induced by bile acids is limited. Baroreex sensitivity is impaired in
patients with obstructive jaundice, which may contribute to their
enhanced susceptibility to the well-known perioperative compli-
cations. The underlying mechanisms for such a change may be
associated with an increased level of plasma atrial natriuretic
peptide.90,91 However, these results are preliminary and require
further study.
2.3.2. Volume depletion
The effects of obstructive jaundice on the vascular tone also
include those of an exaggerated hypotensive response to volume
depletion, because investigators have found that the increased risk
of cardiovascular complications can be ameliorated by volume
expansion prior to surgery.92 However, studies regarding intra-
vascular volume in patients and animals with obstructive jaundice
have not reached a consensus.32,55,56,66,93,94 The conicting results
are mainly due to variations in experimental time after the BDL
procedure, which is the obvious confounding factor to extracellular
uid volume. Other factors including different uid intake, the use
4 L. Wang, W.-F. Yu
of diuretics, and liver disease can also inuence the extracellular
uid volume.
Topuzlu and Stahl95 reported a decrease in Na absorption of
proximal tubules in dogs with infusing bile intravenously. Similarly,
increased Na excretion in 6-day BDL resulted from bile acid accu-
mulation.96 Fluid absorption in proximal tubules was reduced by
about 30% after the microperfusion of sodium taurocholate, which
could be explained by the inhibition of sodium reabsorption.97
Intrarenal infusion of bile was reported to be associated with an
increase in Na excretion, urine ow, and K excretion in dogs.98,99
The mechanisms have not been well claried. The dysfunction of
sodium re-absorption referring to cyclooxygenase has been sug-
gested.100 It can also be associated with a direct membrane toxicity
of bile acids. Indomethacin, a nonsteroidal anti-inammatory drug,
abolished the increased PGE2 synthesis induced by the intrarenal
infusion of bile acids, thereby evanishing the natriuresis, indicating
increased PGE2 is also involved in impaired renal conservation. On
the contrary, the effects of chronically accumulated bile acids were
described to increase Na and water absorption in BDL ani-
mals.66,101e103 Likewise, natriuretic response to extracellular vol-
ume expansion was impaired in chronic BDL dogs.101 Electroneutral
Na/H antiporter may play a fundamental role in changes of secre-
tion and reabsorption of Na in the proximal tubule, and it can be
regulated by sulfated bile acids at low concentrations (30 mM).104
Patients with obstructive jaundice were generally accompanied
with elevated sulfated bile acid in the plasma and urine,105 which
lends further credence to the pathophysiological mechanism. Pa-
tients with chronic obstructive jaundice manifest consistent results
with the experimental studies.106 Thus, acute and chronic stimu-
lation of bile acids exhibit different effects on electroneutral Na/H
antiporter. Its overexpression and a knockout model may be
needed to determine the role of electroneutral Na/H antiporter in
Na excretion.
2.3.3. Cardiac depression (jaundice heart)
Bile acids have direct effects on myocytes, and can inuence
myocardial conduction and contraction. Actually, the effects of bile
acids on the heart were reported long ago. Binah et al1 found that
bile acid induces a negative inotropic effect manifested as
maximum rate of tension relaxation, maximum rate of tension
activation, and a reduction inactive tension. King and Steward107
indicated that an atropine sensitive bradycardia and hypotension
were induced by biliverdin in dogs mediated by cholinergic
mechanisms. Serum containing jaundice from common BDL rats
can exert inhibition to cultured heart cells, which manifests as
decreased beating rate, an early cardiac arrest, and production of
higher levels of lactate in the media.53 Dose-dependent bradycardia
was found in 7-day BDL rats and in the infusion of cholic acid,
which can be inhibited by vagotomy and atropine.108,109 These early
studies provide initial evidence that bile acids can exert a direct
effect on cardiac function. The mechanism may be as follows.
2.3.3.1. Changes of membrane current. The effects of bile acids on
the contractile force and the electrophysiological properties of rat
ventricular muscle have been studied extensively. Alternations of
membrane currents are probably responsible for the negative
inotropic effect of bile acids. Voltage clamp experiments in rat
ventricular myocytes showed that sodium taurocholate decreases
the slow inward current and slightly increased the outward po-
tassium current.1 Kotake et al110 demonstrated that sodium taur-
ocholate slows the spontaneous discharge of the sinoatrial node
through decreases in both inward and outward current systems.
Taurocholate can alter calcium dynamics characterized as cellular
calcium overload or a biphasic change in calcium wave fre-
quency.111,112 Sodium taurocholate reduces the duration of the
Please cite this article in press as: Wang L, Yu W-F, Obstructive jaundice and perioperative managements, Acta Anaesthesiologica Taiwanica
(2014), http://dx.doi.org/10.1016/j.aat.2014.03.002
action potential due to the suppression of the slow inward current
of calcium.1 From the foregoing discussion, the pacemaker func-
tion of cardiac myocytes was altered by bile acids.
2.3.3.2. Membrane receptors. Guanosine-binding protein coupled
receptor may be a potential target of bile acids. Muscarinic receptor
activation by bile acids as well as those needed for acetylcholine
production may play key roles.113 Bile acid taurocholate binding to
the muscarinic M2 receptor in cultured neonatal rat car-
diomyocytes exerted an inhibitory effect on intracellular cAMP and
negative chronotropic response.114 Likewise, taurochenodeox-
ycholic acid and lithocholic acid inhibited glycogen synthase ki-
nase-3b, and led to multiple adaptations including metabolism,
electrophysiology, and cardiac hypertrophy in the mouse heart.115
The relationship between TGR5 (a novel G-protein-coupled re-
ceptor mediating several nongenomic functional responses
induced by binding of bile acids) and modulation of cardiac func-
tion has not yet been established, and calls for more denitive
experiments. In summary, considering the interactions of bile acids
with multiple receptors, receptor-specic effects of bile acids on
cardiac function can be elucidated by the availability of knock-out
mice.
2.3.3.3. Vagal stimulation. The negative effects of bile acids on
cardiac function are induced by vagal stimulation and can be
eliminated by atropine.108,109,116 Bradycardia caused by vagal
stimulation can be antagonized by sodium tauroglycocholate.
2.3.3.4. Energy depletion of cardiomyocytes. Bradycardia, increase
in PR and QT intervals, and arrhythmia can be attributed to a
depletion of intracellular glycogen and defective energy meta-
bolism within the cardiac myocyte.117
2.3.3.5. Bile interference. Joubert108 found that cholic acid has a
dose-dependent negative chronotropic effect on isolated atria of
Wistar rats, and bile acids exert a negative chronotropic effect by
forming a monolayer on the surface of the cell membrane, thereby
mechanically interfering with membrane function.
2.3.3.6. Others. Indirect evidence suggests that there are additional
mechanisms that mediate bile acid-induced suppression in cardiac
function. Serum levels of atrial natriuretic peptide can be increased
by the bile constituents.118 The relationship between elevated atrial
natriuretic peptide (ANP) levels and myocardial dysfunction has
been established by the same group.159 Obstructive jaundice
relieved by biliary drainage can both reduce ANP levels and
improve cardiac function.119 It is reasonable to infer that bile acids
can induce ANP release from cardiomyocytes, which may be the
possible mechanism. Traditionally, this hemodynamic instability is
attributed to the presence of large anatomical arteriovenous
shunts. There is, however, no clear evidence that any of these
agents are involved in the pathogenesis of hypotension in liver
disease.120
3. Obstructive jaundice and anesthesia
Hepatic blood ow may be affected (reduced) by obstructive
jaundice through various mechanisms.121,122 Furthermore,
obstructive jaundice may cause hepatic cell damage via various
mechanisms.123,124 Patients with obstructive jaundice have
different levels of hepatic dysfunction, and impaired hepatic
elimination (i.e., metabolism, biliary excretion, or both) of drugs in
general is to be expected. Therefore, the use of anesthetics in pa-
tients with obstructive jaundice poses a considerable challenge to
the anesthesiologist and the intensive care team. Interaction of
Obstructive jaundice and perioperative managements
unconjugated bilirubin with synaptosomal membrane vesicles
leads to oxidative injury, loss of membrane asymmetry and func-
tionality, and calcium intrusion, thus potentially contributing to the
pathogenesis of encephalopathy by hyperbilirubinemia.125e127
Furthermore, acute hyperbilirubinemia induces presynaptic neu-
rodegeneration at central glutamatergic synapses.128 Unconjugated
bilirubin may also disorder the release and uptake of the neuro-
transmitter glutamate,129,130 indicating possible excitotoxic dam-
age. Therefore, the pharmacokinetics prole of anesthesia-related
drugs, especially those that target the central nervous system,
changes owing to the pathological mechanism described above. We
have done a series of studies about alteration of anesthesia-related
drugs in patients with obstructive jaundice.
The MACawake of desurane is statistically reduced in obstructive
jaundice patients compared with nonjaundice controls; moreover,
the concentration of serum total bilirubin is inversely correlated
with the MACawake of desurane in jaundiced patients.131 Likewise,
compared with controls, patients with obstructive jaundice have an
increased sensitivity to isourane, and are vulnerable to hypoten-
sion and bradycardia during anesthesia induction and mainte-
nance.132 As both isourane and desurane possess relatively low
blood solubility and undergo minimal metabolism in vivo, the
pharmacokinetic characteristics are unlikely to be signicantly
different in obstructive jaundiced patients, even though liver
function is impaired. As it is known that the targets of anesthetics
inducing hypnosis and amnesia locate in the brain,133 alteration in
the functional status of the brain secondary to obstructive jaundice
seem to be a more likely reason for the increased hypnotic potency
of isourane. Recently, it has been suggested that defective sero-
toninergic neurotransmission, which is considered to be sensitive
to inhaled anesthetics,134,135 and neurotoxicity of jaundice in the
brain may partly contribute to the reduction of anesthetic
requirement.136 Cardiovascular function should be monitored
closely in these patients and clinicians should be aware of the
possible need for a decrease in the anesthetic dose.
Obstructive jaundice does not affect the pharmacokinetics of
propofol administered by a single intravenous bolus.137 By contrast,
etomidate requirements to reach a predened level of anesthesia
were reduced in patients with obstructive jaundice.138 The differ-
ence between etomidate and propofol sensitivity in patients with
obstructive jaundice can be partly attributed to the different targets
of two drugs. Propofol not only inhibits the function of g-amino-
butyric acid (GABA) via GABAA receptors, but also acts at other
receptors (e.g., glycine, M1 muscarinic, and nicotinic re-
ceptors).139,140 By contrast, etomidate is a pure hypnotic GABA
agonist.141e143 Also, GABA/glycinergic synaptic transmission can be
enhanced by bilirubin in lateral superior olivary nucleus neurons,
which theoretically could lead to increased etomidate sensitivity.144
Accordingly, extra-hepatic metabolism of propofol may be present.
However, this is a very preliminary hypothesis, and it calls on more
studies to determine the specic mechanisms. It is well known that
propofol has the effects of cardiovascular depression, and patients
with obstructive jaundice are prone to hypotension and vascular
hyporesponsiveness, so it is debatable whether propofol can be
used in jaundiced patients. Propofol depresses cardiac parameters
at low and intermediate doses to a similar degree in BDL-treated
and sham-operated rats; however, at a high dose, propofol may
cause exaggerated cardiac depression in jaundiced rats.145 Inter-
estingly, propofol itself might have eliminated the risk factors and
protected the cardiovascular function.146 The possible cardiovas-
cular protective effect of propofol under clinical conditions is not
yet clear. Vascular endothelial cells play a pivotal role in main-
taining cardiovascular homeostasis. Propofol can reduce H2O2-
induced damage and apoptosis in endothelial cells and increase
protein kinase C activity in rat ventricular myocytes.147,148 It has
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(2014), http://dx.doi.org/10.1016/j.aat.2014.03.002
5
been reported that administration of a large dose of propofol during
cardiopulmonary bypass attenuates postoperative myocardial
cellular damage as compared with small-dose propofol anes-
thesia.149 Therefore, propofol is a safe alternative anesthetic agent
in patients with obstructive jaundice and normal cardiac function
at low and intermediate doses.
Rocuronium, a quaternary aminosteroidal neuromuscular
blocking agent, is eliminated unchanged, principally in bile,
whereas urinary elimination is a minor pathway.150,151 However, no
signicant reduction in rocuronium infusion requirements was
observed during the anhepatic phase compared with the paleo-
hepatic phase, which was documented by studies in patients with
liver transplantation.152,153 In addition, two previous studies re-
ported that the plasma clearance of rocuronium was not signi-
cantly inuenced by dysfunction of the liver or kidney.154,155 Hence,
it seems that other pathways, maybe kidney, instead of liver
excretion may contribute to the continued clearance of rocuronium
as concentrations continued to decrease,153,156 and organic anion
transporting polypeptides seem to take responsibility for the extra-
hepatic excretion of rocuronium because of its wide expression in
various organs and involvement in the absorption and elimination
of rocuronium. However, obstructive jaundiced patients without
renal or hepatic dysfunction had a prolonged neuromuscular effect
of rocuronium caused by some other mechanisms.157,158 The
metabolism prole of rocuronium is not well understood. Further
studies focusing on the hepatic function and serum jaundice
respectively are needed.
4. Summary
Issues including preoperative biliary drainage, nutritional sup-
port, cardiovascular assessment, perioperative uid therapy, and
hemodynamic optimization are the main considerations for anes-
thesiologist and clinicians, and the corresponding treatment and
monitoring concerning the perioperative management of patients
with obstructive jaundice should be taken. There are still many
complex pathophysiological mechanisms that require further study
in obstructive jaundice. Based on current knowledge, clinicians and
anesthesiologists should optimize perioperative management of
the patient with obstructive jaundice.
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