British Journal of Anaesthesia 111 (S1): i50i61 (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

Editors 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.

The liver metabolizes drugs, food, and toxins; synthesizes procoagulants 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 perturbations that range from mild hyperbilirubinemia of no clinical consequence to severe coagulopathy and metabolic
disarray (Fig. 1). This article reviews the current body of knowledge of perioperative assessment, monitoring, and management 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 operative 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, originally devised in 1964 to predict outcomes in cirrhotic patients
undergoing portosystemic surgery, assesses perioperative risk
for patients with liver disease who undergo hepatic or nonhepatic 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 Ascore 56; Class
Bscore 79; Class Cscore 1015).11 This scoring system
relies on a subjective assessment of ascites and encephalopathy 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

Keywords: liver; liver, cirrhosis; liver, disease; liver, function; liver,

metabolism

(82%), and Class C patients (82%) who undergo abdominal surgeries.12 13 A newer study reports lower mortality rates after
abdominal operations: Class A2%; Class B12%; Class
C12%.14 Improvements in surgical technique, anaesthetic
management, and perioperative care might explain the difference in these findings.
The model for end-stage liver disease (MELD) score is a validated and prognostic tool that estimates disease severity and
survival in patients with liver disease. The MELD score is objective, 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 cardiovascular).5 8 17 19 In patients who have undergone abdominal 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 survival. The incorporation of hyponatraemia, an important prognostic 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 outcomes 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
2350%; cardiac surgery, 16 31%; laparotomy for trauma,
45%; and oesophageal surgery, 17 26%.25 33 Patients with

& The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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Perioperative risk is determined by both patient-specific

and procedural factors.

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.

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Monitoring and managing hepatic disease in anaesthesia

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

Hepatic disease
Cardiovascular
Vasodilated state
Hyperdynamic cardiac function
Cirrhotic cardiomyopathy
Drug-induced hypertension
Portopulmonary hypertension

Decreased metabolic function

Decreased gluconeogenesis
Decreased lactate clearance
Hyperbilirubinemia
Varices
Portal hypertension
Ascites

Neurologic
Hepatic encephalopathy
Cerebral oedema
Intracranial hypertension

Pulmonary
Aspiration risk
Hepatopulmonary syndrome
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

and mortality1 33
Scoring system
Modified Child Turcotte Pugh (CTP)
Model for end-stage liver disease (MELD)
ASA-PS IV or V
Patient-specific risk factors

Male gender
Age .70 yr
Preoperative infection
Cirrhosis other than primary biliary cirrhosis
Elevated creatinine
Chronic obstructive pulmonary disease
Intraoperative hypotension
Upper gastrointestinal bleeding
Ascites

High-risk surgeries

Abdominal surgery
Open cholecystectomy
Cardiothoracic surgery
Trauma laparotomy
Oesophageal surgery
Emergency surgery

coagulopathy or CTP Class C cirrhosis are at even higher risk

during open cholecystectomies, abdominal surgeries, and
cardiovascular procedures.25 27 29 30 32 Contraindications to
elective surgery include fulminant hepatic failure, acute viral
or alcoholic hepatitis, chronic active symptomatic hepatitis,
CTP Class C cirrhosis, severe coagulopathy (platelet
count,50 000 ml21, uncorrectable PT .3 s above control),
hypoxaemia, heart failure, and acute kidney injury.3 34

Management of anaesthetic medications

and metabolism
The metabolic activity and clearance of anaesthetic medications is impaired in patients with liver disease. Without
adjusted doses of medications, duration of drug action is
extended and toxic levels can result.35 36 Emergence from anaesthesia can be delayed.
Hepatic metabolism takes place via two pathways: phase 1,
biotransformation via the cytochrome P450 system (which
requires delivery of oxygen via hepatic perfusion); and phase 2,
glucuronide conjugation. The first is decreased in liver disease;
the second is relatively spared when dysfunction begins.37

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Haematologic
Bleeding and thrombosis
Unreliable INR
Decreased factor synthesis
Thrombocytopenia and platelet dysfunction
Dysfibrinogenaemia

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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 nonspecific 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 reactant 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 reticuloendothelial system forms unconjugated (indirect) bilirubin. Unconjugated 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 conjugation (Gilberts syndrome and Crigler Najjar syndrome), or
portal hypertension.64 Under normal circumstances, levels of
conjugated bilirubin in serum are negligible after rapid excretion 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 reactions or obstructive jaundice.64 67
The normal portosystemic arterial pressure gradientbetween
the portal vein and hepatic vein is ,5 mm Hg. Intrahepatic vascular resistance and portal venous blood flow increase the gradient, characteristic of portal hypertension. Vascular resistance
in the liver can result from several factors: liver fibrosis, regenerative nodules, collagen deposits in the space of Disse,
endothelial dysfunction, imbalance between endogenous
vasoconstrictors (i.e. norepinephrine, thromboxane A, endothelin 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, gastrooesophageal and haemorrhoidal varices develop to decompress
the portal system. Portal hypertension produces endogenous
vasodilators that cause splanchnic vasodilation.68 69 71 Splanchnic vasodilation in turn increases portal blood flow and exacerbates portal hypertension.

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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 pharmacological effect.38 End-stage liver disease alters hepatic extraction, 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 difficult. For safety, drugs are titrated to desired effect.
Patients with hepatic dysfunction can be sensitive to sedatives such as midazolam and diazepam.39 40 In contrast, the
pharmacokinetics of lorazepam, which undergoes glucuronidation, is less likely to be affected by liver disease.41 Benzodiazepines 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 benzodiazepines. Rapid redistribution of bolused propofol determines its
duration of action, which is not affected by impaired liver metabolism. 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 metabolized by glucuronidation in the liver, and its intermediate
metabolites are eliminated renally. Although the pharmacokinetics of morphine can be unaltered in patients with mild
hepatic disease, a prolonged half-life is associated with a prolonged 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 retention 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 cholinesterase 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 volatile anaesthetics cause hypotension if intravascular volume is
depleted (i.e. by overdiuresis or gastrointestinal losses), and
reduce liver perfusion. In addition to perioperative haemorrhage and hypotension, volatile anaesthetic agents can
reduce hepatic blood flow and hepatic oxygen uptake. Compared with the vasoconstrictive effects of halothane, isoflurane and desflurane can improve hepatic blood flow and
splanchnic perfusion via hepatic vasodilation.56 57
Patients with end-stage liver disease often exhibit coagulation disorders. The presence of a coagulopathy is a contraindication to regional anaesthesia, particularly epidural anaesthesia.
In patients without a preoperative disorder of coagulation,
intraoperative or postoperative coagulopathy from hepatic ischaemia, insufficient residual hepatic parenchyma, and dilution

Kiamanesh et al.

Monitoring and managing hepatic disease in anaesthesia

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 characteristic.81 Enhanced endogenous production or diminished
hepatic clearance of vasodilating substances (nitric oxide,
carbon monoxide, and endogenous cannabinoids, tumour necrosis 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

to splanchnic vasodilation and decreased systemic vascular resistance, 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 portosystemic shunts with portal hypertension to contribute to a
hyperdynamic circulation.
Management of vasodilatory hypotension focuses on
expanding the intravascular volume, administering a vasoconstricting agent such as norepinephrine or vasopressin, and determining the underlying cause of vasodilation to target.
Aggressive fluid resuscitation without assessment of fluid responsiveness should be avoided because excessive i.v. fluid administration 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), Wilsons
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 afterload from surgical stress, unmasking underlying cirrhotic cardiomyopathy. Echocardiography shows impaired myocardial
function similar to that found in sepsis.86 This condition is also
characterized by QT prolongation and systolic and diastolic dysfunction.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 portopulmonary hypertension (PPHTN) and right ventricular dysfunction.
While the exact pathogenesis of PPHTN remains unclear, histopathological findings are indistinguishable from those observed
in idiopathic pulmonary artery hypertension (medial hypertrophy, concentric intimal proliferation, plexiform lesions, in
situ thrombosis, and fibrotic changes).88 89 A hyperdynamic circulation might increase shear stress on the pulmonary vasculature to cause remodelling and pulmonary hypertension.88 90 The
mean pulmonary artery pressure .25 mm Hg at rest and pulmonary vascular resistance .240 dyn s cm25 define PPHTN.
PPHTN has been reported in 69% 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 recommended in PPHTN because they produce mesenteric vasodilatation 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 uncontrolled PPHTN is associated with significant mortality risk and
is a contraindication to OLT.93 95 Intraoperative management

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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 cirrhosis have oesophageal varices at the time of diagnosis, with
the 1 yr risk of variceal haemorrhage at 12% and a 1 yr rate of recurrent 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 restrictive transfusion strategy (transfusion when the haemoglobin is
,7 g dl21) can decrease subsequent bleeding and prevent an increase 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 refractory to treatment with diuretics require large-volume paracentesis 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) prevents recurrent variceal bleeding and manages refractory
ascites.76 During the procedure, an expandable stent is placed
into the liver parenchyma for portosystemic exchange to decrease 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 (particularly right ventricular function) is essential because stent
placement can rapidly increase venous return and cardiac
output to unmask underlying cardiomyopathy.79 80 Encephalopathy can worsen from enhanced systemic delivery of biogenic
amines normally cleared by the liver.

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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
Splanchnic vasodilation
Systemic vasodilation

Liver dysfunction
Portal hypertension
Bacterial translocation and inflammation

Fig 2 Vasodilation from hepatic dysfunction.

is targeted to prevent increases in pulmonary vascular resistance 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 responsiveness. Peripheral arterial pressure measurements can be unreliable 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, pulmonary embolism, pleural effusion, and inadequate inferior
vena cava reconstruction can be observed with transoesophageal echocardiography (TOE). The risk of rupture of oesophageal 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 atelectasis from the compressive effects of ascites, hepatic
hydrothorax, hepatopulmonary syndrome (HPS), underlying

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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 channels 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 decrease 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 positivepressure 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 cardiopulmonary disease who have a PaO2 ,8.0 kPa. The triad of liver
disease and/or portal hypertension, widened age-corrected alveolararterial oxygen gradient (.22.7 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 vasconstrictive substances (i.e. tyrosine, serotonin, and endothelin) by a

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Increased plasma volume

Increased cardiac output

Monitoring and managing hepatic disease in anaesthesia

damaged livercan cause IPVD. IPVD causes hypoxaemiaviaventilation 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 (dyspnoea 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 scanning 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

renal function is impaired rapidly and progressively with a doubling of the initial serum creatinine to .2.5 mg dl21 or a 50% reduction 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 criteria 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 solutefree water.118 When extracellular volume expands, ascites and
oedema can result. In patients with hypovolaemic hyponatraemia 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 (11.5 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 hyponatraemia 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 noninflammatory demyelinating lesions in the basis pontis. The aetiology 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 correction 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 intraoperatively and after operation. Sodium bicarbonate should be administered 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 significant volume of packed red blood cells, malnutrition, and
vitamin D deficiency can lead to perioperative hypocalcaemia.

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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 prerenal injury. This injury rapidly reverses with correction of the
underlying pathophysiology and volume resuscitation.108 109
As cirrhosis progresses, reduction in systemic vascular resistance activates the reninangiotensin and sympathetic nervous
systems, which leads to ascites, oedema, and vasoconstriction of the intrarenal circulation and renal hypoperfusion.
Ischaemic events and medications such as non-steroidal antiinflammatory 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, respectively. Optimizing renal perfusion and avoidance of
nephrotoxic drugs are also important in these patients.110 Continuous renal replacement therapy can be used perioperatively
to manage volume shifts, acid base balance, and electrolyte
disturbances. Placement of a TIPS can improve serum creatinine, with more profound effects on those patients with higher
baseline levels.111
HRS is caused by functional renal vasoconstriction (via activation of the reninangiotensin system, the sympathetic nervous
system, and arginine vasopressin) in response to splanchnic arterial 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,

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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

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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 intraoperative 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 complications 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 thrombocytopenia may be prevented by transfusing packed red blood
cells, fresh-frozen plasma, and platelets in a 1:1:1 ratio.143 Occasionally, recombinant Factor VIIa is administered.144 148 Factor
VIIa has not been shown to decrease red blood cell transfusion
requirements during hepatectomies.149 Potassium, magnesium, and calcium levels are frequently monitored to correct abnormal levels. Improving haemodynamic parameters, adjusting
minute ventilation, or administering sodium bicarbonate or tromethamine 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 operation or after operation. Brain dysfunction manifests in acute
or chronic liver failure or after a spontaneous or surgical portosystemic shunt.151 152 Hepatic encephalopathy is a neuropsychiatric 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 neurotoxin, 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

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In patients with hepatic disease, haemostatic changes

promote both bleeding and thrombosis. Inadequate synthesis
of all coagulation factors (except for von Willebrands factor
and factor VIII), thrombocytopenia, platelet function defects,
dysfibrinogenaemia, and elevated tissue plasminogen activator (tPA) levels cause bleeding. Elevation of von Willebrands
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 hepatocytes, 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 fibrinolysis inhibitor and plasmin inhibitor) has been observed in cirrhotic patients, its association with bleeding is unclear.126 136
Hypofibrinolysis (from increased levels of plasminogen activator inhibitor and reduced levels of plasminogen) can restore the
balance of fibrinolysis.126 137 138
Thrombocytopenia and platelet dysfunction are characteristic 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 synthesis 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, cryoprecipitate, or platelets as dictated by clinical assessment and laboratory 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

Kiamanesh et al.

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Monitoring and managing hepatic disease in anaesthesia

Conclusions
Patients with hepatic disease are at high risk for poor perioperative 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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