British Journal of Anaesthesia 111 (S1): i50–i61 (2013)
doi:10.1093/bja/aet378
Monitoring and managing hepatic disease in anaesthesia
D. Kiamanesh, J. Rumley and V. K. Moitra*
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
* Corresponding author. E-mail: vm2161@columbia.edu
Editor’s key points
† Hepatic disease can lead to multisystem organ
dysfunction with multiple significant anaesthetic
implications.
† Pathophysiological alterations can occur in
pharmacological responses, the systemic and pulmonary
circulations, coagulation, and neurological function.
† Perioperative risk is determined by both patient-specific
and procedural factors.
The liver metabolizes drugs, food, and toxins; synthesizes pro-
coagulants and anticoagulants; and regulates temperature,
glucose, and metabolism. When patients with liver disease
need surgery, anaesthesiologists face several perioperative
challenges. Patients with liver disease have physiological per-
turbations that range from mild hyperbilirubinemia of no clin-
ical consequence to severe coagulopathy and metabolic
disarray (Fig. 1). This article reviews the current body of knowl-
edge of perioperative assessment, monitoring, and manage-
ment of hepatic disease in patients who will undergo surgery.
Perioperative risk assessment
Patients with liver disease who undergo non-hepatic surgery
have greater transfusion requirements, high infection risk,
cardiac compromise, longer hospital stays, and increased opera-
tive mortality.1 – 6 Patient-specific risk factors, various scoring
systems, and surgical procedures stratify risk for these
patients.6 – 9 Independent risk factors for complications and
mortality are outlined in Table 1.
The Child– Turcotte– Pugh (CTP) classification system, ori-
ginally devised in 1964 to predict outcomes in cirrhotic patients
undergoing portosystemic surgery, assesses perioperative risk
for patients with liver disease who undergo hepatic or non-
hepatic surgery.8 10 Scores are calculated from five variables:
serum albumin, serum bilirubin, ascites, prothrombin time
(PT), or INR (modified CTP score), and grade of encephalopathy
to stratify patients into three groups (Class A¼score 5–6; Class
B¼score 7–9; Class C¼score 10–15).11 This scoring system
relies on a subjective assessment of ascites and encephalop-
athy and does not consider preoperative infection, aetiology
of cirrhosis, or surgery type.6 Original studies suggested high
mortality rates in Class A patients (10%), Class B patients
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Summary. Patients with liver disease have multisystem organ
dysfunction that leads to physiological perturbations ranging
from hyperbilirubinaemia of no clinical consequence to severe
coagulopathy and metabolic disarray. Patient-specific risk
factors, clinical scoring systems, and surgical procedures
stratify perioperative risk for these patients. The anaesthetic
management of patients with hepatic dysfunction involves
consideration of impaired drug metabolism, hyperdynamic
circulation, perioperative hypoxaemia, bleeding, thrombosis,
and hepatic encephalopathy.
Keywords: liver; liver, cirrhosis; liver, disease; liver, function; liver,
metabolism
(82%), and Class C patients (82%) who undergo abdominal sur-
geries.12 13 A newer study reports lower mortality rates after
abdominal operations: Class A¼2%; Class B¼12%; Class
C¼12%.14 Improvements in surgical technique, anaesthetic
management, and perioperative care might explain the differ-
ence in these findings.
The model for end-stage liver disease (MELD) score is a vali-
dated and prognostic tool that estimates disease severity and
survival in patients with liver disease. The MELD score is object-
ive, ranges from 6 to 40 points, and is calculated from the
serum bilirubin, serum creatinine, INR, and aetiology of liver
disease.15 The MELD score has been validated across a
number of liver diseases (alcoholic hepatitis and variceal
bleeding)16 and surgeries (abdominal, orthopaedic, and car-
diovascular).5 8 17 – 19 In patients who have undergone abdom-
inal surgery, an elevated MELD score was a better predictor of
poor perioperative outcome than CTP classification.17 Patients
with MELD scores .15 should avoid elective surgery.20 In
2002, the United Network for Organ Sharing adopted the
MELD score as a method of allocation of organs to estimate sur-
vival. The incorporation of hyponatraemia, an important prog-
nostic factor in patients with cirrhosis, into the MELD score
might improve risk stratification among patients awaiting
liver transplantation.21
The type of surgical procedure influences perioperative out-
comes in patients with hepatic disease. During abdominal
surgery, reflexive systemic hypotension from visceral traction
and blood loss can reduce hepatic arterial blood flow.22 23
Patients with extensive liver disease who undergo abdominal
surgery have a mortality rate of 30%.12 24 Mortality rates in
cirrhotic patients who undergo open cholecystectomy are
23–50%; cardiac surgery, 16 –31%; laparotomy for trauma,
45%; and oesophageal surgery, 17– 26%.25 – 33 Patients with
Monitoring and managing hepatic disease in anaesthesia BJA

Renal/electrolytes/glucose
Acute kidney injury
Hepatorenal syndrome
Hyponatraemia
Hypoglycaemia
Insulin resistance

Hepatic disease
Cardiovascular Decreased metabolic function
Vasodilated state Decreased gluconeogenesis Neurologic
Hyperdynamic cardiac function Decreased lactate clearance Hepatic encephalopathy
Cirrhotic cardiomyopathy Hyperbilirubinemia Cerebral oedema
Drug-induced hypertension Varices Intracranial hypertension
Portopulmonary hypertension Portal hypertension
Ascites

Haematologic
Bleeding and thrombosis
Unreliable INR
Pulmonary Decreased factor synthesis
Aspiration risk Thrombocytopenia and platelet dysfunction
Hepatopulmonary syndrome Dysfibrinogenaemia
Compression atelectasis
Pleural effusions/hepatic hydrothorax
Acute respiratory distress syndrome

Fig 1 Organ response to hepatic dysfunction.

Table 1 Perioperative risk factors associated with complications coagulopathy or CTP Class C cirrhosis are at even higher risk
and mortality1 – 33 during open cholecystectomies, abdominal surgeries, and
cardiovascular procedures.25 27 29 30 32 Contraindications to
Scoring system
elective surgery include fulminant hepatic failure, acute viral
† Modified Child –Turcotte –Pugh (CTP)
† Model for end-stage liver disease (MELD)
or alcoholic hepatitis, chronic active symptomatic hepatitis,
† ASA-PS IV or V CTP Class C cirrhosis, severe coagulopathy (platelet
Patient-specific risk factors count,50 000 ml21, uncorrectable PT .3 s above control),
† Male gender hypoxaemia, heart failure, and acute kidney injury.3 34
† Age .70 yr
† Preoperative infection
† Cirrhosis other than primary biliary cirrhosis Management of anaesthetic medications
† Elevated creatinine and metabolism
† Chronic obstructive pulmonary disease
† Intraoperative hypotension The metabolic activity and clearance of anaesthetic medica-
† Upper gastrointestinal bleeding tions is impaired in patients with liver disease. Without
† Ascites adjusted doses of medications, duration of drug action is
High-risk surgeries extended and toxic levels can result.35 36 Emergence from an-
† Abdominal surgery aesthesia can be delayed.
† Open cholecystectomy
Hepatic metabolism takes place via two pathways: phase 1,
† Cardiothoracic surgery
† Trauma laparotomy biotransformation via the cytochrome P450 system (which
† Oesophageal surgery requires delivery of oxygen via hepatic perfusion); and phase 2,
† Emergency surgery glucuronide conjugation. The first is decreased in liver disease;
the second is relatively spared when dysfunction begins.37

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BJA
Many anaesthetic drugs (i.e. opioids, barbiturates) bind to
albumin in the circulation. Low albumin levels increase the
free fraction of drug and can theoretically exaggerate pharma-
cological effect.38 End-stage liver disease alters hepatic extrac-
tion, renal excretion, and levels of serum proteins in addition to
albumin. The net effect of these changes is unpredictable,
making general recommendations for drug administration diffi-
cult. For safety, drugs are titrated to desired effect.
Patients with hepatic dysfunction can be sensitive to seda-
tives such as midazolam and diazepam.39 40 In contrast, the
pharmacokinetics of lorazepam, which undergoes glucuronida-
tion, is less likely to be affected by liver disease.41 Benzodiaze-
pines can precipitate hepatic encephalopathy, and flumazenil
can reverse this condition.42 Conversely, patients who have a
history of alcohol abuse can require large doses of benzodiaze-
pines. Rapid redistribution of bolused propofol determines its
duration of action, which is not affected by impaired liver metab-
olism. In a small study of cirrhotic patients, propofol infusions
did not increase termination half-life or clearance to a clinically
significant degree.43
The adverse effects of morphine can be more pronounced
in patients with severe liver disease.44 45 Morphine is metabo-
lized by glucuronidation in the liver, and its intermediate
metabolites are eliminated renally. Although the pharmaco-
kinetics of morphine can be unaltered in patients with mild
hepatic disease, a prolonged half-life is associated with a pro-
longed PT, hypoalbuminaemia, encephalopathy, ascites, and
jaundice.37 46 47 The elimination of morphine metabolites can
be prolonged in patients with hepatorenal syndrome (HRS).
Metabolism of fentanyl, sufentanil, and morphine, which
have a high hepatic extraction ratio, is slowed by impaired
hepatic blood flow.38 44 48
In patients with liver disease and oedema, neuromuscular
blocking agent doses must be augmented because fluid reten-
tion increases the volume of distribution. Neuromuscular
blocking agents that are metabolized by the liver, such as
vecuronium and rocuronium, have a slower onset and longer
duration of action.49 – 54 Liver disease reduces plasma cholin-
esterase activity, and prolonged neuromuscular block after
succinylcholine has been reported.55 Acute kidney injury with
elevated potassium levels or immobilization for long periods
might preclude the use of succinylcholine.
Vasodilating anaesthetic agents such as propofol and vola-
tile anaesthetics cause hypotension if intravascular volume is
depleted (i.e. by overdiuresis or gastrointestinal losses), and
reduce liver perfusion. In addition to perioperative haemor-
rhage and hypotension, volatile anaesthetic agents can
reduce hepatic blood flow and hepatic oxygen uptake. Com-
pared with the vasoconstrictive effects of halothane, isoflur-
ane and desflurane can improve hepatic blood flow and
splanchnic perfusion via hepatic vasodilation.56 57
Patients with end-stage liver disease often exhibit coagula-
tion disorders. The presence of a coagulopathy is a contraindica-
tion to regional anaesthesia, particularly epidural anaesthesia.
In patients without a preoperative disorder of coagulation,
intraoperative or postoperative coagulopathy from hepatic is-
chaemia, insufficient residual hepatic parenchyma, and dilution
i52
Kiamanesh et al.
can develop.58 – 60 Delayed epidural catheter removal has been
suggested in patients who undergo hepatectomy.61
Organ response, assessment, and
management
Hepatic response
Laboratory tests, such as albumin and bilirubin, are non-specific
and can be affected by other diseases and medications. Even
with hepatic disease, patients can have normal liver function
and laboratory values because the liver, the largest organ and
gland in the body, has a large reserve capacity.
Albumin, produced exclusively in the liver, has been used to
assess hepatic synthetic function.62 Low levels of this non-
specific marker are also found in patients with malnutrition,
renal disease, and capillary leak syndrome. This prognostic
marker in hospitalized patients is a negative acute phase react-
ant because the production of albumin decreases during states
of inflammation with cytokine release and surgical tissue
trauma.62 63 Albumin, with a long half-life of 20 days, can be
normal even in acute liver failure.64
The breakdown of red blood cells within the reticuloendo-
thelial system forms unconjugated (‘indirect’) bilirubin. Uncon-
jugated bilirubin is transported to the liver to be conjugated
and secreted into bile.64 65 Increased production, decreased
hepatic uptake, and decreased conjugation of bilirubin
cause unconjugated hyperbilirubinaemia. The most common
causes of unconjugated hyperbilirubinaemia are haemolysis,
resolution of haematomas, inborn errors of bilirubin conjuga-
tion (Gilbert’s syndrome and Crigler –Najjar syndrome), or
portal hypertension.64 Under normal circumstances, levels of
conjugated bilirubin in serum are negligible after rapid excre-
tion into the biliary system. Conjugated hyperbilirubinaemia
can indicate intrinsic liver disease, especially in conjunction
with elevated aminotransferase levels, a sign of hepatocellular
injury. Conjugated hyperbilirubinaemia with elevated alkaline
phosphatase and minimal increase in aminotransferase
levels is consistent with a purely cholestatic process and can
result from numerous causes, including cholestatic drug reac-
tions or obstructive jaundice.64 – 67
The normal portosystemic arterial pressure gradientbetween
the portal vein and hepatic vein is ,5 mm Hg. Intrahepatic vas-
cular resistance and portal venous blood flow increase the gra-
dient, characteristic of portal hypertension. Vascular resistance
in the liver can result from several factors: liver fibrosis, re-
generative nodules, collagen deposits in the space of Disse,
endothelial dysfunction, imbalance between endogenous
vasoconstrictors (i.e. norepinephrine, thromboxane A, endothe-
lin I, angiotensin II, and leukotrienes) and vasodilators (nitric
oxide), and contraction of portal and septal myofibroblasts
and smooth muscle cells.68 – 70 As the pressure gradient
between the portal vein and the hepatic vein increases, gastro-
oesophageal and haemorrhoidal varices develop to decompress
the portal system. Portal hypertension produces endogenous
vasodilators that cause splanchnic vasodilation.68 69 71 Splanch-
nic vasodilation in turn increases portal blood flow and exacer-
bates portal hypertension.
Monitoring and managing hepatic disease in anaesthesia
Complications of portal hypertension include gastrointestinal
bleeding from expansion and rupture of varices, intraoperative
bleeding from intra-abdominal collaterals, and formation of
ascites and pleural effusions.68 72 Almost half of patients with cir-
rhosis have oesophageal varices at the time of diagnosis, with
the 1 yr risk of variceal haemorrhage at 12% and a 1 yr rate of re-
current haemorrhage at 60%. The 6 week mortality with each
episode of variceal haemorrhage is between 15% and 20%.73
In patients with acute upper gastrointestinal bleeding, a restrict-
ive transfusion strategy (transfusion when the haemoglobin is
,7 g dl21) can decrease subsequent bleeding and prevent an in-
crease in the portal-pressure gradient.74 Patients who have
received multiple previous transfusions, such as patients with a
history of gastrointestinal bleeding, should be evaluated in
advance for cross-matching large quantities of blood products
possibly required for a procedure.
Before operation, ascites is initially managed with a low
sodium diet and diuretic therapy. Patients with ascites refrac-
tory to treatment with diuretics require large-volume paracen-
tesis and albumin replacement to prevent hypotension and
HRS.75 Large-volume abdominal ascites can lead to a lower
venous return and, in conjunction with pleural effusions, can
decrease pulmonary reserve and prevent patients from lying
flat. If there is evidence of tense ascites, recent food ingestion,
or a propensity for delayed gastric emptying, a rapid-sequence
induction of general anaesthesia with tracheal intubation
should be considered.
A transjugular intrahepatic portosystemic shunt (TIPS) pre-
vents recurrent variceal bleeding and manages refractory
ascites.76 During the procedure, an expandable stent is placed
into the liver parenchyma for portosystemic exchange to de-
crease portal hypertension. The procedure is performed under
local or general anaesthesia as a ‘bridge’ to liver transplantation
in patients with severe liver disease.77 General anaesthesia
might be preferred because of the duration of the procedure
and the potential for a life-threatening event such as bleeding,
infection, haemobilia, arrhythmias, liver ischaemia, and stent
migration.78 Preoperative evaluation of cardiac function (par-
ticularly right ventricular function) is essential because stent
placement can rapidly increase venous return and cardiac
output to unmask underlying cardiomyopathy.79 80 Encephal-
opathy can worsen from enhanced systemic delivery of biogenic
amines normally cleared by the liver.
Cardiovascular response
The cardiovascular system of patients with end-stage liver
disease mimics the hyperdynamic circulatory changes in
patients with sepsis. Tachycardia, elevated cardiac output, low
arterial pressure, and low systemic vascular resistance are char-
acteristic.81 Enhanced endogenous production or diminished
hepatic clearance of vasodilating substances (nitric oxide,
carbon monoxide, and endogenous cannabinoids, tumour ne-
crosis factor-a, adrenomedullin, and hydrogen sulfide) and the
inflammatory response to bacterial translocation cause
splanchnic arterial vasodilation (Fig. 2).81 82 These changes
have been reversed with liver transplantation.81 83 In response
BJA
to splanchnic vasodilation and decreased systemic vascular re-
sistance, the body retains sodium and water, which increases
plasma volume. An increase in cardiac output and heart rate
follow.81 84 Venous capacitance increases from formation of por-
tosystemic shunts with portal hypertension to contribute to a
hyperdynamic circulation.
Management of vasodilatory hypotension focuses on
expanding the intravascular volume, administering a vasocon-
stricting agent such as norepinephrine or vasopressin, and de-
termining the underlying cause of vasodilation to target.
Aggressive fluid resuscitation without assessment of fluid re-
sponsiveness should be avoided because excessive i.v. fluid ad-
ministration to a non-fluid-responsive patient can increase
cardiac filling pressures, which can cause hepatic congestion,
pulmonary oedema, and resulting respiratory failure.
Systemic conditions such as haemochromatosis (ventricular
hypertrophy with increased end-diastolic and end-systolic
volumes), amyloidosis (restrictive cardiomyopathy), Wilson’s
disease (supraventricular extrasytolic beats), and alcoholism
(systolic and diastolic dysfunction) can affect liver and cardiac
function.85 During the perioperative period, the circulatory
system can be challenged with shunt insertion or greater after-
load from surgical stress, unmasking underlying cirrhotic cardio-
myopathy. Echocardiography shows impaired myocardial
function similar to that found in sepsis.86 This condition is also
characterized by QT prolongation and systolic and diastolic dys-
function.87 Reduced b-adrenoceptor function might explain
these findings.85 Cirrhotic cardiomyopathy is often reversible
and requires inotropic and diuretic support to prevent elevation
of central venous pressure and hepatic congestion.
Patients with portal hypertension can develop portopulmon-
ary hypertension (PPHTN) and right ventricular dysfunction.
While the exact pathogenesis of PPHTN remains unclear, histo-
pathological findings are indistinguishable from those observed
in idiopathic pulmonary artery hypertension (medial hyper-
trophy, concentric intimal proliferation, plexiform lesions, in
situ thrombosis, and fibrotic changes).88 89 A hyperdynamic cir-
culation might increase shear stress on the pulmonary vascula-
ture to cause remodelling and pulmonary hypertension.88 90 The
mean pulmonary artery pressure .25 mm Hg at rest and pul-
monary vascular resistance .240 dyn s cm25 define PPHTN.
PPHTN has been reported in 6–9% of patients with advanced
liver disease.91 92 In a retrospective study of patients who
underwent orthotopic liver transplantation (OLT), mortality
was 50% in patients with the mean pulmonary artery pressures
between 35 and 50 mm Hg and 100% in patients with pressures
.50 mm Hg.93 Calcium channel blockers, which can be used in
patients with pulmonary arterial hypertension, are not recom-
mended in PPHTN because they produce mesenteric vasodilata-
tion and worsen portal hypertension. b-Blocker therapy, which
is often used in patients with portal hypertension to reduce
the risk of variceal bleeding, is contraindicated in patients
with PPHTN because its negative inotropic effect decreases
exercise tolerance.88 90 Finally, while liver transplantation is a
tempting option to reduce PPHTN, moderate or severe uncon-
trolled PPHTN is associated with significant mortality risk and
is a contraindication to OLT.93 – 95 Intraoperative management
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BJA Kiamanesh et al.

Increased levels of vasodilating substances

Nitric oxide
Carbon monoxide
Prostacyclin
Endocannabinoids
Endothelium-derived hyperpolarizing factor
Tumour necrosis factor-a
Adrenomedullin
Hydrogen sulfide

Liver dysfunction Splanchnic vasodilation

Portal hypertension Systemic vasodilation
Bacterial translocation and inflammation

Increased plasma volume

Increased cardiac output

Fig 2 Vasodilation from hepatic dysfunction.

is targeted to prevent increases in pulmonary vascular resist-
ance by controlling hypoxia, hypercarbia, acidosis, pain, and
hypothermia.
Because of these cardiovascular changes, invasive monitors
usually are used during the perioperative period. Beat-to-beat
arterial pressure is monitored and blood is sampled frequently
via a radial artery catheter. Pulse pressure variation, calculated
from the invasive arterial tracing, assesses fluid responsive-
ness. Peripheral arterial pressure measurements can be unre-
liable in patients with severe vasoconstriction or vasodilation.
Central venous access is established to measure right atrial
pressure and to administer drugs. Monitoring central venous
pressure does not reliably measure blood volume or change
in blood volume.96 Echocardiography assesses ventricular
filling, contractility, and function. Myocardial ischaemia, pul-
monary embolism, pleural effusion, and inadequate inferior
vena cava reconstruction can be observed with transoesopha-
geal echocardiography (TOE). The risk of rupture of oesopha-
geal varices with TOE is rare.97 98 Bladder pressures should
be measured if intra-abdominal hypertension from ascites is
suspected.
Pulmonary response
Up to 70% of patients with end-stage liver disease complain of
dyspnoea.99 100 Potential causes of preoperative hypoxaemia
and respiratory failure in patients with cirrhosis include atel-
ectasis from the compressive effects of ascites, hepatic
hydrothorax, hepatopulmonary syndrome (HPS), underlying
chronic pulmonary disease and occasionally acute respiratory
distress syndrome.99 Chest radiography rules out pulmonary
oedema, pleural effusions, or cardiomegaly in patients with
symptoms of dyspnoea. Muscle wasting and intra-abdominal
hypertension from ascites increase the work of breathing.
Ascites fluid can enter the pleural space through small chan-
nels in the diaphragm to cause a hepatic hydrothorax (usually
on the right side). Compressive atelectasis from ascites and
pleural effusions reduce functional residual capacity and de-
crease the time to oxygen desaturation. Lung recruitment
and pleural fluid drainage can improve pulmonary mechanics.
Respiratory alkalosis can be observed in patients with a high
respiratory drive from liver dysfunction. The use of positive-
pressure mechanical ventilation and PEEP can lead to an
increased average intrathoracic pressure, which decreases
venous return from the inferior vena cava and hepatic veins
and can lead to congestion of the liver. This concern remains
controversial, as studies with PEEP of up to 10 cm H2O have
shown no adverse effects on hepatic arterial, portal venous, or
hepatic venous flow.101
A diagnosis of HPS is considered in patients without cardiopul-
monary disease who have a PaO2 ,8.0 kPa. The triad of liver
disease and/or portal hypertension, widened age-corrected al-
veolar–arterial oxygen gradient (.2–2.7 kPa) while breathing
room air, and documented intrapulmonary vascular dilation
(IPVD) define HPS.99 102 103 Enhanced production or impaired
hepatic clearance of endogenous vasodilators (i.e. nitric oxide,
vasodilator prostaglandins, substance P), or inhibition of vascon-
strictive substances (i.e. tyrosine, serotonin, and endothelin) by a

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Monitoring and managing hepatic disease in anaesthesia
damaged livercan cause IPVD. IPVD causes hypoxaemiaviaven-
tilation and perfusion mismatching, intrapulmonary shunt
physiology, and diffusion limitation.99 103 Patients with HPS
often complain of dyspnoea and fatigue; they can have clubbing
and spider angiomata. They may experience platypnoea (dys-
pnoea in the upright position relieved by recumbency) or have
orthodeoxia (arterial oxyhaemoglobin desaturation in the
upright position). Preferential perfusion of IPVDs with the
patient upright might cause these clinical manifestations.
Contrast-enhanced echocardiography or perfusion lung scan-
ning with technetium-99m-labelled macroaggregate albumin
detects intrapulmonary shunting suggestive of IPVD.102 103
Resolution of this syndrome after transplant has been reported.
Medical therapy for HPS has, to date, been relatively ineffective.
Currently, the only known treatment option for patients with HPS
is liver transplantation.104 – 106
Renal, electrolyte, and glucose response
Acute kidney injury commonly occurs in patients with chronic
liver disease and is present in up to 20% of patients hospitalized
with decompensated liver cirrhosis.107 Patients with acute
kidney injury and cirrhosis have more complications and
greater risk for mortality after liver transplantation than those
without renal failure. Gastrointestinal bleeding, diarrhoea from
infection or lactulose administration, and diuretic medications
change circulatory function via hypovolaemia and can cause pre-
renal injury. This injury rapidly reverses with correction of the
underlying pathophysiology and volume resuscitation.108 109
As cirrhosis progresses, reduction in systemic vascular resis-
tance activates the renin–angiotensin and sympathetic nervous
systems, which leads to ascites, oedema, and vasoconstric-
tion of the intrarenal circulation and renal hypoperfusion.
Ischaemic events and medications such as non-steroidal anti-
inflammatory drugs or aminoglycosides cause intrinsic renal
damage.108 109 Managing kidney injury, low urine output, and
electrolyte abnormalities in patients with hepatic disease is
challenging. Pre- or post-renal kidney injuries reverse with
enhanced renal perfusion or removal of the obstruction, re-
spectively. Optimizing renal perfusion and avoidance of
nephrotoxic drugs are also important in these patients.110 Con-
tinuous renal replacement therapy can be used perioperatively
to manage volume shifts, acid– base balance, and electrolyte
disturbances. Placement of a TIPS can improve serum creatin-
ine, with more profound effects on those patients with higher
baseline levels.111
HRS is caused by functional renal vasoconstriction (via activa-
tion of the renin–angiotensin system, the sympathetic nervous
system, and arginine vasopressin) in response to splanchnic ar-
terial vasodilation.109 112 Although histological findings and
diagnostic tests for HRS are lacking, diagnostic criteria are
used to categorize two types of HRS. Criteria for HRS include (i)
cirrhosis with ascites, (ii) serum creatinine .1.5 mg dl21, (iii)
no improvement of creatinine after 2 days of diuretic withdrawal
and volume expansion with albumin, (iv) absence of shock, (v)
no current or recent treatment with nephrotoxic drugs, and
(vi) absence of parenchymal kidney disease.113 In type I HRS,
BJA
renal function is impaired rapidly and progressively with a doub-
ling of the initial serum creatinine to .2.5 mg dl21 or a 50% re-
duction in the 24 h creatinine clearance to ,20 ml min21 in ,2
weeks. Patients with type II HRS have impaired renal function
and a serum creatinine .1.5 mg dl21 and do not meet the cri-
teria for type I HRS.107 Compared with patients diagnosed with
prerenal failure, patients with HRS lack a renal response to a
1.5 litre volume challenge. Distinguishing between HRS and
acute tubular necrosis is difficult. Fractional excretion of
sodium ,1% suggests tubular function and favours a diagnosis
of HRS. The presence of renal tubular epithelial cells in urinary
sediment favours a diagnosis of acute tubular necrosis.109 112
Administration of terlipressin, a vasopressin analogue, along
with i.v. albumin has been shown to have some benefit in
patients with type 1 HRS.114 115 Medical management of HRS
is marginally effective, but liver transplantation usually reverses
HRS.116 117
Hypervolaemic hyponatraemia from accumulated secretion
of anti-diuretic hormone acts on vasopressin-2 receptors of
the renal tubular collecting duct to impair excretion of solute-
free water.118 When extracellular volume expands, ascites and
oedema can result. In patients with hypovolaemic hyponatrae-
mia via loss of extracellular fluid from the kidneys (overdiuresis)
or gastrointestinal tract, ascites or oedema is rare. These
patients can have prerenal failure from low circulating volume
or hepatic encephalopathy from rapid reduction in serum
osmolality.109 118 Distinguishing between hypervolaemic and
hypovolaemic hyponatremia guides treatment. Hypervolaemic
hyponatraemia is managed with fluid restriction (1–1.5 litre
day21) and withholding of diuretics. Vaptans, medications
that block the V2 receptor, increase solute-free water excretion
dose-dependently and might preclude water restriction so that
diuretics can be continued.119 Patients with hypovolaemic hypo-
natraemia are not given diuretics; instead, saline is administered
to increase plasma volume.118
Patients with preoperative hyponatraemia are at risk for
central pontine myelinolysis (CPM) perioperatively. CPM is a
neurological condition characterized by symmetric non-
inflammatory demyelinating lesions in the basis pontis. The aeti-
ology of CPM is uncertain, but osmotic stress on central nervous
system cells has been suggested, and CPM correlates with rapid
correction of hyponatraemia.118 Rapid changes in concentration
of serum sodium cannot be predicted and a ‘safe’ rate of cor-
rection of hyponatraemia has not been definitively established;
some experts recommend sodium correction at a rate ,12 mEq
litre21 day21.120 – 122 Preoperative correction of hyponatraemia
can prevent a rapid increase in serum sodium levels intraopera-
tively and after operation. Sodium bicarbonate should be admi-
nistered cautiously because it has a high concentration of
sodium.
Calcineurin inhibitors, loop diuretics, and significant blood
loss can worsen hypomagnesaemia. Total serum calcium is
often low because patients commonly have low serum
albumin with reduced calcium binding. Failure to clear citrate
(metabolized by the liver) after the administration of a signifi-
cant volume of packed red blood cells, malnutrition, and
vitamin D deficiency can lead to perioperative hypocalcaemia.
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BJA
Disorders of glucose metabolism are observed in patients
with chronic liver disease and cirrhosis.123 124 Multiple factors
affect glucose levels, including the inflammatory response to
surgery, steroid administration, hepatic dysfunction, altered
glycogen stores, and insulin resistance in liver failure. Episodes
of hypoglycaemia are observed in patients with end-stage liver
disease.
Haematological response
In patients with hepatic disease, haemostatic changes
promote both bleeding and thrombosis. Inadequate synthesis
of all coagulation factors (except for von Willebrand’s factor
and factor VIII), thrombocytopenia, platelet function defects,
dysfibrinogenaemia, and elevated tissue plasminogen activa-
tor (tPA) levels cause bleeding. Elevation of von Willebrand’s
factor and Factor VIII and decreased levels of ADAMTS-13 (a
disintegrin and metalloproteinase with a thrombospondin
type 1 motif, member 13), protein C, protein S, antithrombin,
a 2-macroglobulin, plasminogen, and heparin cofactor II
favour thrombosis.
Factors VII, X, V, II (prothrombin), and I (fibrinogen) have a
short half-life (hours to days) and are synthesized solely by hepa-
tocytes, making possible a ‘semi real-time’ evaluation of hepatic
synthetic function.125 Although patients with liver disease can
have abnormal PT from decreased production of pro-coagulant
factors, the rebalanced state of pro- and anti-coagulants in
patients with liver disease makes the PT an unreliable tool for
evaluating tendency to bleed or clot.126 – 133
Levels of fibrinogen, an acute phase reactant, are normal or
increased in mild-to-moderate liver disease. In patients with
severe hepatic dysfunction, however, fibrinogen is poorly
synthesized and dysfunctional, which increases the risk of
bleeding.134 135 Although hyperfibrinolysis (from increased
levels of tPA and reduced levels of thrombin-activatable fibrin-
olysis inhibitor and plasmin inhibitor) has been observed in cir-
rhotic patients, its association with bleeding is unclear.126 136
Hypofibrinolysis (from increased levels of plasminogen activa-
tor inhibitor and reduced levels of plasminogen) can restore the
balance of fibrinolysis.126 137 138
Thrombocytopenia and platelet dysfunction are character-
istic of end-stage liver disease. Thrombocytopenia results
from several factors: portal hypertension with hypersplenism,
which sequesters platelets; consumption of platelets during
systemic intravascular coagulation; and impaired hepatic syn-
thesis of thrombopoietin, which stimulates platelet production
in the bone marrow.72 139 Defective signal transduction;
uraemia from acute kidney injury; and intrinsic defects of
ADP, arachidonic acid, collagen, and thrombin prevent platelet
aggregation.139
Patients with active sites of bleeding should be transfused
with fresh-frozen plasma, packed red blood cells, cryoprecipi-
tate, or platelets as dictated by clinical assessment and labora-
tory tests. In addition, desmopressin can be considered for
patients with concomitant renal dysfunction and uraemic
bleeding. Coagulation status should always be monitored by
inspection of the surgical field. Measurements from
i56
Kiamanesh et al.
thromboelastography or rotational thromboelastometry
assess the viscoelastic properties of a whole blood sample as a
function of time to reflect the function and interaction of
plasma, blood cells, and platelets. These measurements
detect a hypercoagulable state and distinguish hyperfibrinolysis
from other causes of coagulopathy, such as factor depletion or
thrombocytopenia to offer a composite picture of the clotting
cascade.129 130 140 141 Although both have been used to guide
haemostatic management during liver transplantation, there
are no studies evaluating these tests as predictors of intraopera-
tive bleeding in patients with hepatic disease.129 130 140
Uncontrolled haemorrhage and massive transfusion in the
operating theatre or the intensive care unit can cause the
lethal triad of acidosis, coagulopathy, and hypothermia. Left
uncorrected, each of these abnormalities can exacerbate the
others, creating a ‘bloody vicious cycle’. Additional early com-
plications of massive transfusion include (i) acute haemolytic
transfusion reactions, (ii) febrile non-haemolytic transfusion
reactions, (iii) transfusion-related acute lung injury (TRALI),
(iv) transfusion-associated circulatory overload, (v) allergic
reactions, (vi) bacterial sepsis, (vii) hypocalcaemia, and (viii)
hyperkalaemia (see Pham and Shaz,142 this issue).143
Warming the room, applying forced warming systems,
administering blood products and fluids through a fluid
warmer, and heating and humidifying inspired gases reduce
the risk of hypothermia. Dilutional coagulopathy and thrombo-
cytopenia may be prevented by transfusing packed red blood
cells, fresh-frozen plasma, and platelets in a 1:1:1 ratio.143 Occa-
sionally, recombinant Factor VIIa is administered.144 – 148 Factor
VIIa has not been shown to decrease red blood cell transfusion
requirements during hepatectomies.149 Potassium, magne-
sium, and calcium levels are frequently monitored to correct ab-
normal levels. Improving haemodynamic parameters, adjusting
minute ventilation, or administering sodium bicarbonate or tro-
methamine manage metabolic acidosis. The riskof TRALI can be
reduced by minimizing transfusions and transfusing packed red
blood cells with a short storage time (see Cohen and Matot,150
this issue) and fresh-frozen plasma from men or nulliparous
women.
Neurological response
Patients with liver disease can have encephalopathy before op-
eration or after operation. Brain dysfunction manifests in acute
or chronic liver failure or after a spontaneous or surgical porto-
systemic shunt.151 152 Hepatic encephalopathy is a neuro-
psychiatric complication of acute and chronic liver disease
with features that range from mild confusion to cerebral
oedema with intracranial hypertension.101 152 Patients have
disturbances in consciousness, cognitive abilities, behaviour,
fine motor skills, concentration, reaction time, memory,
and/or electroencephalogram.152 – 154 The pathogenesis of
hepatic encephalopathy is not understood, but most theories
implicate elevated levels of ammonia, a gut-derived neuro-
toxin, which is shunted to the systemic circulation from the
portal system. Bacteria in the intestinal tract produce
ammonia, which crosses the blood– brain barrier into
Monitoring and managing hepatic disease in anaesthesia
astrocytes that detoxify it to glutamine. An increased concen-
tration of intracellular glutamine leads to swollen astrocytes
with reduced ability to regulate neurotransmission.80 101 152
155
High serum ammonia levels are present in patients with
hepatic encephalopathy, even though the degree of elevation
of ammonia does not correlate with neurological dysfunction.
Other factors, such as hyponatraemia, gastrointestinal bleed-
ing, and infection, may contribute to the development of
hepatic encephalopathy.101 151 156 Left untreated, cerebral
oedema can progress to intracranial hypertension and brain
herniation. Multiple grading scales assess the severity of
hepatic encephalopathy. The most common scales are the
West Haven Criteria (Conn Score) which has grades 0 through
4 and the Glasgow coma score.157 158
Initial therapy for hepatic encephalopathy identifies
and treats reversible triggers (i.e. gastrointestinal bleeding,
hypokalaemia, alkalaemia, hypoglycaemia, hypovolaemia,
and infection) of this neuropsychiatric syndrome and considers
minimizing benzodiazepine medications.14 82 While there is no
evidence of a direct correlation between the degree of elevation
of ammonia and severity of hepatic encephalopathy, it is well
accepted that ammonia is a factor.159 Non-absorbable disac-
charides such as lactulose acidify the gut environment to de-
crease absorption of ammonia from the gut via catharsis.152
Excessive dosing of lactulose causes dehydration however.
Oral antibiotics (rifaximin, neomycin, vancomycin, paramomy-
cin, or metronidazole) reduce ammonia-producing enteric bac-
teria.156 Rifaximin, in combination with lactulose, might reduce
episodes of hepatic encephalopathy.151 156
Patients who develop fulminant hepatic failure are at risk for
hepatic encephalopathy, cerebral oedema with increased
intracranial pressure (ICP), and herniation. In cases of altered
mental status, a head CT scan is often indicated to evaluate
intracranial bleeding, herniation, the extent of cerebral
oedema, or both. ICP monitoring should be seriously consid-
ered for patients with fulminant hepatic failure and encephal-
opathy, even given the bleeding risks associated with invasive
monitors. Bleeding risk seems to be the greatest deterrent to
ICP monitoring.
ICP elevations to .25 mm Hg should be treated with manni-
tol to achieve hyperosmolarity. Preoperative hyperventilation
has not been shown to improve outcome and corticosteroids
are not indicated. Pentobarbital coma can be used for patients
unresponsive to mannitol, but can worsen cerebral hypo-
perfusion by causing systemic hypotension. Many centres con-
sider sustained cerebral hypoperfusion (cerebral perfusion
pressure ,40 mm Hg) a contraindication to transplant because
of the high risk for brain death. In the future, transcranial
Doppler ultrasonography, near-infrared spectrophotometry,
and measurements of extracellular lactate via cerebral micro-
dialysis could offer means of monitoring for elevated ICP in
these patients.160 161 For anaesthesia, drugs or conditions that
exacerbate elevations in ICP should be avoided. Recent evidence
shows that moderate hypothermia (32–338C) can reduce cere-
bral oedema and intracerebral hypertension; however, the side-
effects of these manoeuvres are greater risk of infection, cardiac
dysrhythmias, and coagulopathy.162 – 166
BJA
Conclusions
Patients with hepatic disease are at high risk for poor periopera-
tive outcomes. Assessment of the severity of liver dysfunction
and consideration of type of surgery stratifies risk and delays
elective surgery in patients with significant hepatic disease
(CTP Class C cirrhosis). Managing surgical patients with hepatic
disease considers anaesthetic dose adjustment and monitoring
the multisystem organ responses to liver dysfunction.
Authors’ contributions
All authors participated in literature search, writing of first
draft, editing, and final approval.
Acknowledgement
The authors would like to thank Sally Kozlik for her invaluable
editorial assistance.
Declaration of interest
None declared.
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