- Email: [email protected]
Anaesthesia for children with liver disease
Anaesthesia for children with liver disease Peter Bromley MBBS FRCA James Bennett MBBS FRCA
Key points
Acute liver failure (which includes fulminant failure) is typified by coagulopathy, encephalopathy, hypoglycaemia, and metabolic acidosis. Children with liver disease are physiologically fragile during anaesthesia. Key objectives of anaesthesia are to maintain haemodynamic stability, targeted support of coagulation, and careful maintenance of electrolyte and glucose levels. Liver transplantation is often a very successful treatment for end-stage liver disease.
Serious liver disease in children is uncommon and patients with all but the most trivial and selflimiting illness are looked after by or in partnership with a specialist centre. Liver disease may be chronic, which implies there is a process which will lead or has led to cirrhosis (irreversible fibrosis with nodular regeneration), or it may be acute, where there is liver dysfunction in an architecturally normal liver. End-stage liver disease is a result of chronic conditions in about 85% of cases. The frequency of the various aetiologies differs between age groups, and this is reflected in the frequency of the causes of end-stage liver disease in patients undergoing liver transplantation (Fig. 1).
General principles of anaesthesia for children with liver disease Many of the potential problems associated with anaesthesia for children with liver disease can be predicted from the features of the condition. Chronic liver disease is quite different from acute liver failure; since chronic liver disease is much commoner, it will be discussed first.
Chronic liver disease Mechanical effects
Peter Bromley MBBS FRCA Consultant Anaesthetist Department of Anaesthesia Birmingham Children’s Hospital Steelhouse Lane Birmingham B4 6NH UK E-mail: [email protected] (for correspondence) James Bennett MBBS FRCA Consultant Anaesthetist Department of Anaesthesia Birmingham Children’s Hospital Steelhouse Lane Birmingham B4 6NH UK Tel: þ44 121 333 9623
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In cirrhosis, the fibrotic process will tend to distort hepatic blood vessels and obstruct the flow of blood through the liver, causing portal hypertension. The most obvious consequences of portal hypertension are described below.
Ascites The abdomen may become very distended resulting in diaphragmatic splinting. This can lead to a loss of functional residual capacity, closure of small airways, and an increase in the work of breathing, so that during the perioperative period, patients readily become hypoxaemic. The situation may be aggravated by pleural
effusions and hepatosplenomegaly. Ascites is also a risk factor for spontaneous bacterial peritonitis, which can result in serious and possibly overwhelming sepsis, and subsequent formation of peritoneal adhesions.
Splenomegaly In addition to an intra-abdominal mass effect, splenomegaly can cause pancytopaenia; thrombocytopaenia generally appears first and can be severe.
Varices The high portal venous pressures will tend to open capillary connections between the portal and systemic venous systems, and varices are very common if the portal venous pressure is significantly raised. Varices most commonly develop around the stomach and lower oesophagus, the rectum, or visibly on the anterior abdominal wall. Varices may bleed spontaneously, with the potential for torrential, catastrophic haemorrhage. For this reason, regular endoscopic surveillance for varices is carried out at intervals on patients known to have portal hypertension, and significant varices may be occluded by endoscopic banding.1 Variceal vessels may cause severe difficulties with uncontrollable bleeding during abdominal surgery, particularly around the liver. Chronic minor bleeding into the gastrointestinal tract or from a stoma can be troublesome, causing anaemia and iron deficiency. Portal hypertension can be treated by the placement of a percutaneously inserted transjugular intrahepatic porto-systemic shunt (TIPS).2 These radiologically inserted devices can effectively lower portal venous pressures. Their application can be limited by hepatic decompensation; blood passing through the shunt by definition bypasses the liver, and if hepatic function is marginal, this can result in encephalopathy. TIPS procedures are therefore usually only considered if liver synthetic function is well maintained.
doi:10.1093/bjaceaccp/mkt057 Advance Access publication 3 January, 2014 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 14 Number 5 2014 & The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://ceaccp.oxfordjournals.org/ at Tufts University on September 26, 2014
The key characteristics of chronic liver disease are cirrhosis, portal hypertension, and its associated features.
Matrix reference 2D02,3A04
Anaesthesia for children with liver disease
more minor interventions, it is possible to accept coagulation parameters well outside the normal range without having bleeding complications.
Drug metabolism
Extra-hepatic manifestations of chronic liver disease Haemodynamic effects
Fig 1 Birmingham Children’s Hospital and University Hospitals Birmingham, Primary indications for liver transplantation in paediatric patients, 1983–2013. Data kindly provided by Carla Lloyd, Liver Unit, Birmingham Children’s Hospital.
Coagulopathy Significant coagulopathy is not usual in chronic liver disease until the very end stage. All the clotting factors, except factor VIII vWF, are synthesized in the liver. The synthesis of factors II, VII, IX, and X is vitamin K-dependent and since vitamin K is fat soluble, its absorption depends on bile salt excretion into the gut, so biliary obstruction will tend to cause coagulopathy due to failure of synthesis of these factors, even if hepatocellular synthetic function is normal. Coagulopathy from biliary obstruction is readily corrected with parenteral vitamin K or with relief of the biliary obstruction, whereas coagulopathy secondary to hepatocellular failure is not improved. To what extent, if any, the coagulation should be supported perioperatively depends on the degree of the derangement and the nature of the planned procedure. It is rarely necessary or indeed possible to completely normalize abnormal clotting (except in vitamin K deficiency), and even if it were feasible, it risks causing more problems than it solves. Infusing large volumes of clotting factors and platelets can cause circulatory overload in a patient whose ability to excrete excess fluid may be poor, and who probably already has a volumeloaded circulation. Of course, clotting factors need to be available if major surgery is planned, and a careful infusion of coagulation factors, avoiding fluid overload, may be prudent if time allows. For
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Liver disease is normally associated with a high-output lowresistance systemic circulation. In children, a flow murmur is often heard, and echocardiography will often show volume loading and atrial enlargement. Haemodynamic instability is not usually a major problem during anaesthesia, although hypovolaemia may not be well tolerated. Co-existent cardiovascular pathology may present problems, especially those which cause pulmonary hypertension, outflow tract obstruction (right or left), or conditions where there is potential for significant right-to-left shunts (large patent foramen ovale or atrial septal defects). Children with liver disease should be screened for these conditions because of the implications of their presence (there is no particular association with liver disease).
Respiratory system Ascites can be severe enough to produce diaphragmatic splinting and pleural effusions may further reduce respiratory reserve (see paragraph on ascites, under features of chronic liver disease). This may be further complicated by the hepatopulmonary syndrome.
Hepatopulmonary syndrome This condition, which is seen in only a small proportion (5–10%) of patients with chronic liver disease, produces hypoxaemia by a combination of the redistribution of pulmonary blood flow which tends to cause a V/Q mismatch, and the formation of new blood vessels which cause a true right-to-left shunt.3,4 The changes are most marked in the lung bases, and so the hypoxaemia is unusual in that it is sometimes improved by lying the patient flat, because this posture diverts pulmonary blood flow towards less affected areas. The degree of hypoxaemia is not linearly related to the severity of the liver disease, so severe hypoxaemia can occur in the presence of fairly mild liver impairment. The hypoxaemia can progress and be
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 5 2014
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The effect of chronic liver disease on drug metabolism is difficult to define. Shifts in the volumes of fluid compartments and alterations in the levels of albumin and other plasma proteins can affect volumes of distribution and unbound fractions unpredictably. Phase 1 reactions are also variably altered depending on the degree of impairment of hepatocellular function. Conjugation reactions will probably be impaired, but again the degree is variable. Adapting drug doses in a scientific way is therefore difficult. But some general principles apply, and it can be expected that drugs with sedative effects will show enhanced and prolonged action.
Anaesthesia for children with liver disease
severely limiting with occasional patients requiring home oxygen therapy. The only effective treatment is liver transplantation, which usually produces complete resolution, although this may take several months.
Renal impairment
Encephalopathy A decreased level of consciousness can be seen in the setting of a combination of hyperammonaemia, raised intracranial pressure, and neuronal inflammation. It is most often seen where there has been a sudden insufficiency of hepatocellular function, usually in acute liver failure, but also sometimes in chronic conditions where decompensation has been precipitated, for example, by sepsis or a nitrogen load from a bleed into the gastrointestinal tract. Early signs may be subtle, especially in very young children, in whom it is difficult to apply tests used to grade encephalopathy in adults and older children, but early signs might include inversion of day/night sleep pattern, and later, irritability or lethargy.
Other systems Electrolyte disturbance, particularly hyponatraemia, is commonly seen, and is in part a result of enhanced water retention by the kidneys. The disturbance may be worsened by the use of diuretics to control oedema and ascites. Poor nutritional status retards growth, contributes to poor wound healing, and may further impair immune function. Supplementary enteral feeding is often required. Failure of vitamin D absorption may cause rickets and the resulting osteopaenia may cause pathological fractures. The child may suffer from intractable itching secondary to bile acid retention.
Acute liver failure Fulminant liver failure is defined by a short interval (,8 weeks) between the appearance of symptoms and the onset of encephalopathy. These patients are at high risk in any case, and require careful management.6,7 Encephalopathic patients may show enhanced
Administering anaesthesia Children with advanced liver disease should be transferred to a specialist centre. With regard to the choice of drugs commonly used for anaesthesia, there are a few key points to remember. Isoflurane, sevoflurane, and desflurane are all acceptable. Desflurane is often used as the very low proportion metabolized implies a low risk from toxic metabolites, and it preserves hepatic blood flow, possibly slightly better than the alternatives, although it is doubtful whether this is clinically significant. Atracurium and remifentanil have obvious advantages where the integrity of drug metabolism is in doubt. Cisatracurium may offer an advantage over atracurium in that the lower levels of the metabolite laudanosine produced reduces any risk of neurotoxicity from its cumulation, although likelihood of this adverse effect is small in any case. Opioids should not be withheld or under-dosed because of fears about their adverse effects; humanitarian considerations dictate that analgesia should be adequate, and if opioid use results in prolonged recovery requiring high dependency care then that has to be accepted. For minor procedures, for example, endoscopy or central venous line insertion, the preoperative assessment should particularly focus on whether there is any significant respiratory impairment from ascites, organomegaly, or pleural effusion. Even for minor procedures, patients who have to be starved should have preoperative i.v. fluids to prevent dehydration or hypoglycaemia. If an inhalation induction is used, basic monitoring should be instituted as soon as practicable. It may be better to keep the child in a moderate head-up position to minimize diaphragmatic splinting, and to reduce the risk of aspiration, which may be increased in these patients. The airway is best secured with a tracheal tube for all but the very shortest procedures. If the patient is very fragile then merely the anaesthesia alone may be enough to jeopardize return to a safe conscious level and adequate respiratory function. Beware of endoscopic procedures introducing more gas into the gut and worsening diaphragmatic splinting. For intermediate procedures, which might include extraperitoneal body surface procedures which take a little more time (e.g. hernia repairs), tracheal intubation and measures to preserve normothermia and normovolaemia are advisable. A higher level of postoperative care may be required. Even relatively minor procedures
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Confusion often exists around the topic of renal impairment in liver disease. The hepato-renal syndrome is a circulatory disturbance seen in end-stage chronic liver disease, rare in children, where intense renal vasoconstriction produces pre-renal failure.5 Treatment is largely ineffective, apart from liver transplantation. More frequently seen is acute renal impairment produced by dehydration, both intravascular depletion and reduction in total body water, to which patients with chronic liver disease seem particularly susceptible, which generally reflects their delicate physiological state. The anaesthetic management does not need to be any more sophisticated than ensuring adequate preoperative hydration, optimal volume loading, a good cardiac output, and adequate perfusion pressure, which may be lower than normal, provided there is satisfactory oxygen delivery.
sensitivity to anaesthetic and sedative agents and may have a very prolonged recovery. They often require continuous i.v. glucose support because of the failure of hepatocellular glucose regulation (glycogenesis, glycogenolysis, and gluconeogenesis)—this glucose support must not be interrupted and the blood glucose level must be monitored throughout the perioperative period. The circulation is typically hyperdynamic and volume loaded with a low systemic vascular resistance. Anaesthesia may result in the need for inotropic support, if it is not already required. Death in acute liver failure is usually the result of one or more of cerebral oedema and tentorial herniation, circulatory and multi-organ failure, or sepsis (bacterial or fungal).
Anaesthesia for children with liver disease
Approximately, one-third of portoenterostomy procedures are at least partially successful (for some years—the long-term outcomes remain uncertain); another third do initially result in a reduction in jaundice but have persistent problems, such as recurrent cholangitis and develop cirrhosis later; and the final third never achieve a significant decrease in serum bilirubin and will require early transplantation.9,10
Choledochal cysts Cystic dilatations originating from the biliary tree are rare abnormalities which may cause pain, obstructive jaundice, and an abdominal mass. The cysts may occur anywhere along the biliary tree and there are various classification systems. They may present at any age but are increasingly identified by antenatal ultrasound scanning. Treatment is usually with complete excision of the cyst, due to a potential for later malignant change, with biliary drainage via a portoenterostomy. Anaesthesia is essentially similar to that for cases of biliary atresia.
Cholelithiasis Anaesthesia for specific hepatobiliary procedures In order to illustrate the anaesthetic principles of paediatric hepatobiliary surgery, some of the commoner or more major conditions and procedures are reviewed in greater detail.
Biliary atresia and Kasai portoenterostomy Biliary atresia is a rare congenital anomaly involving absence of intra- and extra-hepatic bile ducts leading to cholestasis, hepatic fibrosis, and cirrhosis. It has an incidence of around 1:14 000 live births in the UK and is the most common indication for paediatric liver transplantation. Around 25% of cases have associated anomalies including polysplenia, abdominal situs inversus, and atrial septal defect. Affected babies appear normal, but the signs of cholestasis ( pale stools, failure to thrive, malabsorption, and conjugated hyperbilirubinaemia) appear soon after birth. The Kasai portoenterostomy is a surgical procedure which may establish bile drainage and halt the progression to hepatic fibrosis and cirrhosis, but success is unlikely if it is performed after 8 weeks of age. Timely assessment and investigation is thus important to distinguish biliary atresia from other (much commoner) causes of neonatal jaundice. The main anaesthetic challenges are fluid loss, intermittent interruption of venous drainage via the inferior vena cava by surgical retraction, and provision of adequate postoperative analgesia. Coagulopathy is unlikely once the babies have been given vitamin K. Central venous catheters are often used and may be retained after operation for fluid and drug administration and blood sampling. In the absence of associated cardiac anomaly or other compelling indication, arterial cannulae are not required. Epidural analgesia can usually be offered with safety.
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Gallstone disease is relatively rare in younger children, and often associated with haemoglobinopathies, where a high rate of haemolysis may cause pigment stones. Teenagers are increasingly suffering from cholesterol gallstones, which are related to the increasing prevalence of obesity. A familiarity with laparoscopic and open cholecystectomy is assumed—the management of the paediatric case is broadly the same as in the adult.
Liver tumours Primary liver tumours are rare in children. Hepatoblastoma is the most common paediatric liver tumour with an increasing incidence, of around 1 per million, and usually presents in the first 3 yr of life, with an obvious abdominal mass, lethargy, and pallor. Liver function is usually normal. Treatment is with chemotherapy (doxorubicin or cisplatin) followed by surgical resection if possible; if not, liver transplantation can be curative if there is no extrahepatic disease. Doxorubicin can cause cardiomyopathy, which requires echocardiographic assessment.11 There are essentially three important perioperative challenges for the anaesthetist: haemorrhage, air embolus, and post-resection liver insufficiency. Major haemorrhage is an ever-present risk in liver tumour resection. Venous access should include a large-bore central venous cannula (such as an introducer sheath) dedicated to transfusion, in addition to a standard triple-lumen central venous catheter for drugs and pressure monitoring; the veins used for access should be those in the upper body which drain into the superior vena cava, as the inferior vena cava may be occluded during surgery. Existing Hickman catheters are not ideal for intraoperative use and should generally not be used, to minimize the risk of sepsis. Rapid transfusion and fluid warming devices appropriate to the size of the child are necessary, as is timely access to large quantities of blood
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 5 2014
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may warrant securing central venous access—this can be done with a very low level of risk by experienced practitioners, even allowing for the somewhat increased potential for adverse events in coagulopathic patients, and it allows volume status to be accurately optimized, regular venous blood gas analysis is possible, and also sampling for coagulation monitoring. For major procedures, which in this patient group would probably include any intraperitoneal procedure, full invasive monitoring is usual. Haemodynamic optimization reduces the risk of worsening hepatic or renal function because of poor organ perfusion. Coagulation is monitored with bedside prothrombin/INR measurement and thromboelastography (TEG or ROTEM).8 Coagulation may need to be supported with clotting factors, although normal values are not necessary—surgical problems are relatively unlikely if the INR is ,2 and platelet count over 80109 litre21. Postoperative intensive care may be required, particularly if opioid analgesia is used. Peripheral nerve blocks may be helpful, but neuraxial block is often contraindicated because of coagulopathy, thrombocytopaenia, or the presence of epidural varices, which are likely in the presence of portal hypertension.
Anaesthesia for children with liver disease
Liver transplantation Liver transplantation remains the only effective treatment for endstage liver disease, and results are generally excellent with 5 yr survival around 90% for chronic indications (Fig. 2); most deaths occur within the first 3 months after operation, but intraoperative mortality is uncommon (,1%). The procedure is much the same as in an adult, the main differences being that for smaller children, the great majority of grafts are now split adult organs, the smaller left lobe
usually being used for the child, and because of the size of the vena cava, it is often not possible to avoid total caval cross-clamping. Livers need only be matched for blood group. The aim is to have the liver reperfused within 12 –16 h of harvest. The procedure itself is conventionally described in three phases: dissection, anhepatic, and reperfusion. The dissection phase involves the skeletonization of the explant and preparation of the liver vessels. The main problems at this stage usually relate to bleeding. The anhepatic stage starts when the portal vein and hepatic artery are clamped and divided, after which there is no liver function. Usually, it is not possible to isolate the rather short and awkwardly placed hepatic veins, so a segment of cava is removed with the native liver, and a short length of donor cava attached to the liver graft restores vessel continuity. During the anhepatic phase, there is an inexorable increase in base deficit and lactate and a decrease in ionized calcium and glucose. At reperfusion, almost always via the portal vein, there is often considerable haemodynamic instability from the effects of reperfusing an ischaemic organ—including a decrease in systemic vascular resistance (sometimes precipitous)13 together with myocardial stunning, and changes in circulating volume from filling the new liver, and blood losses from the cut surface and vascular anastomoses. After reperfusion, the arterial supply is restored and a biliary drainage system fashioned, most often draining the bile duct into a short length of small bowel (Roux-en-Y). If the new liver functions well, then there will usually be a gradual reduction in base deficit (within an hour or two) followed by a decrease in serum lactate and a restoration of haemodynamic stability. Anaesthetic management of liver transplantation is highly complex, involving preparation for massive blood loss, management of severe electrolyte and acid/base disturbance, and careful circulatory support. Success requires an experienced team of surgeons, anaesthetists, and theatre staff.
Declaration of interest None declared.
1.0 Chronic n = 443
Cum survival
0.8
References 1. McKiernan PJ, Beath SV, Davison SM. A prospective study of endoscopic esophageal variceal ligation using a multiband ligator. J Paediatr Gastroenterol Nutr 2002; 35: 609– 15
Acute n = 96
0.6
2. Rosenthal P. When should we perform TIPS in children? J Paediatr Gastroenterol Nutr 2012; 54: 577
0.4
3. Palma DT, Fallon MB. The hepatopulmonary syndrome. J Hepatol 2006; 45: 617–25
0.2
4. Noli K, Solomon M, Golding F, et al. Prevalence of hepatopulmonary syndrome in children. Pediatrics 2008; 121: 522– 7
0.0
5. Salerno F, Gerbes A, Gines P et al. Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis. Gut 2007; 56: 1310–8
0.00 5.00 10.00 15.00 Patient survival post-trasplant years
6. Cochran JB, Losek JD. Acute liver failure in children. Pediatr Emerg Care 2007; 23: 129–35
Fig 2 Liver transplantation, patient survival 1993–2013, Birmingham Children’s Hospital. Data kindly provided by Carla Lloyd, Liver Unit, Birmingham Children’s Hospital.
7. Squires RH, Schneider BL, Buchuvalas J et al. Acute liver failure in children: the first 348 patients in the Acute Liver Failure Study Group. J Pediatr 2006; 148: 652– 8
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products. The use of intraoperative red cell salvage for cases of malignant tumour resection is controversial; the benefits of avoiding allogenic blood transfusion and potential immunomodulation must be balanced against the systemic infusion of malignant cells and possible metastasis. Leucocyte depletion filters appear effective at removal of tumour cells from salvaged blood.12 Surgery usually involves hemi-hepatectomy; this can expose large hepatic veins which are held open with the risk of air entrainment and embolus. Relative fluid restriction is often used to decrease liver congestion and bleeding. Intermittent clamping of the portal vein and hepatic artery may be used to reduce bleeding and expedite surgery, but these manoeuvres may lead to cardiovascular instability and dysfunction in the remaining liver. Hepatic dysfunction may also result from large-volume parenchymal resection, which is suggested by increasing metabolic acidosis, hypoglycaemia, and coagulopathy. Management is supportive while the liver recovers, comprising correction of hypovolaemia and hypotension, maintaining blood glucose, administration of clotting factors, and N-acetylcysteine (which is protective against liver ischaemia by replenishment of hepatic glutathione stores and possibly other effects). Epidural analgesia may be inadvisable in cases involving large parenchymal resections. The majority of cases can return to a high dependency unit after surgery.
Anaesthesia for children with liver disease
8. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008; 106: 1366– 75 9. Kelly DA, Davenport M. Current management of biliary atresia. Arch Dis Child 2007; 92: 1132– 5 10. Fouquet V, Alves A, Branchereau S, et al. Long-term outcome of paediatric liver transplantation for biliary atresia: a 10-year follow-up in a single centre. Liver Transpl 2005; 11: 152 –60
11. Stringer M. The role of liver transplantation in the management of paediatric liver tumours. Ann R Coll Surg Engl 2007; 89: 12– 21 12. Esper SA, Waters JH. Intra-operative cell salvage: a fresh look at the indications and contraindications. Blood Transfus 2011; 9: 139–47 13. Aggarwal S, Kang Y, Freeman JA, et al. Postreperfusion syndrome: hypotension after reperfusion of the transplanted liver. J Crit Care 1993; 8: 154–60
Please see multiple choice questions 9–12.
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Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 5 2014
Key points
Acute liver failure (which includes fulminant failure) is typified by coagulopathy, encephalopathy, hypoglycaemia, and metabolic acidosis. Children with liver disease are physiologically fragile during anaesthesia. Key objectives of anaesthesia are to maintain haemodynamic stability, targeted support of coagulation, and careful maintenance of electrolyte and glucose levels. Liver transplantation is often a very successful treatment for end-stage liver disease.
Serious liver disease in children is uncommon and patients with all but the most trivial and selflimiting illness are looked after by or in partnership with a specialist centre. Liver disease may be chronic, which implies there is a process which will lead or has led to cirrhosis (irreversible fibrosis with nodular regeneration), or it may be acute, where there is liver dysfunction in an architecturally normal liver. End-stage liver disease is a result of chronic conditions in about 85% of cases. The frequency of the various aetiologies differs between age groups, and this is reflected in the frequency of the causes of end-stage liver disease in patients undergoing liver transplantation (Fig. 1).
General principles of anaesthesia for children with liver disease Many of the potential problems associated with anaesthesia for children with liver disease can be predicted from the features of the condition. Chronic liver disease is quite different from acute liver failure; since chronic liver disease is much commoner, it will be discussed first.
Chronic liver disease Mechanical effects
Peter Bromley MBBS FRCA Consultant Anaesthetist Department of Anaesthesia Birmingham Children’s Hospital Steelhouse Lane Birmingham B4 6NH UK E-mail: [email protected] (for correspondence) James Bennett MBBS FRCA Consultant Anaesthetist Department of Anaesthesia Birmingham Children’s Hospital Steelhouse Lane Birmingham B4 6NH UK Tel: þ44 121 333 9623
207
In cirrhosis, the fibrotic process will tend to distort hepatic blood vessels and obstruct the flow of blood through the liver, causing portal hypertension. The most obvious consequences of portal hypertension are described below.
Ascites The abdomen may become very distended resulting in diaphragmatic splinting. This can lead to a loss of functional residual capacity, closure of small airways, and an increase in the work of breathing, so that during the perioperative period, patients readily become hypoxaemic. The situation may be aggravated by pleural
effusions and hepatosplenomegaly. Ascites is also a risk factor for spontaneous bacterial peritonitis, which can result in serious and possibly overwhelming sepsis, and subsequent formation of peritoneal adhesions.
Splenomegaly In addition to an intra-abdominal mass effect, splenomegaly can cause pancytopaenia; thrombocytopaenia generally appears first and can be severe.
Varices The high portal venous pressures will tend to open capillary connections between the portal and systemic venous systems, and varices are very common if the portal venous pressure is significantly raised. Varices most commonly develop around the stomach and lower oesophagus, the rectum, or visibly on the anterior abdominal wall. Varices may bleed spontaneously, with the potential for torrential, catastrophic haemorrhage. For this reason, regular endoscopic surveillance for varices is carried out at intervals on patients known to have portal hypertension, and significant varices may be occluded by endoscopic banding.1 Variceal vessels may cause severe difficulties with uncontrollable bleeding during abdominal surgery, particularly around the liver. Chronic minor bleeding into the gastrointestinal tract or from a stoma can be troublesome, causing anaemia and iron deficiency. Portal hypertension can be treated by the placement of a percutaneously inserted transjugular intrahepatic porto-systemic shunt (TIPS).2 These radiologically inserted devices can effectively lower portal venous pressures. Their application can be limited by hepatic decompensation; blood passing through the shunt by definition bypasses the liver, and if hepatic function is marginal, this can result in encephalopathy. TIPS procedures are therefore usually only considered if liver synthetic function is well maintained.
doi:10.1093/bjaceaccp/mkt057 Advance Access publication 3 January, 2014 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 14 Number 5 2014 & The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://ceaccp.oxfordjournals.org/ at Tufts University on September 26, 2014
The key characteristics of chronic liver disease are cirrhosis, portal hypertension, and its associated features.
Matrix reference 2D02,3A04
Anaesthesia for children with liver disease
more minor interventions, it is possible to accept coagulation parameters well outside the normal range without having bleeding complications.
Drug metabolism
Extra-hepatic manifestations of chronic liver disease Haemodynamic effects
Fig 1 Birmingham Children’s Hospital and University Hospitals Birmingham, Primary indications for liver transplantation in paediatric patients, 1983–2013. Data kindly provided by Carla Lloyd, Liver Unit, Birmingham Children’s Hospital.
Coagulopathy Significant coagulopathy is not usual in chronic liver disease until the very end stage. All the clotting factors, except factor VIII vWF, are synthesized in the liver. The synthesis of factors II, VII, IX, and X is vitamin K-dependent and since vitamin K is fat soluble, its absorption depends on bile salt excretion into the gut, so biliary obstruction will tend to cause coagulopathy due to failure of synthesis of these factors, even if hepatocellular synthetic function is normal. Coagulopathy from biliary obstruction is readily corrected with parenteral vitamin K or with relief of the biliary obstruction, whereas coagulopathy secondary to hepatocellular failure is not improved. To what extent, if any, the coagulation should be supported perioperatively depends on the degree of the derangement and the nature of the planned procedure. It is rarely necessary or indeed possible to completely normalize abnormal clotting (except in vitamin K deficiency), and even if it were feasible, it risks causing more problems than it solves. Infusing large volumes of clotting factors and platelets can cause circulatory overload in a patient whose ability to excrete excess fluid may be poor, and who probably already has a volumeloaded circulation. Of course, clotting factors need to be available if major surgery is planned, and a careful infusion of coagulation factors, avoiding fluid overload, may be prudent if time allows. For
208
Liver disease is normally associated with a high-output lowresistance systemic circulation. In children, a flow murmur is often heard, and echocardiography will often show volume loading and atrial enlargement. Haemodynamic instability is not usually a major problem during anaesthesia, although hypovolaemia may not be well tolerated. Co-existent cardiovascular pathology may present problems, especially those which cause pulmonary hypertension, outflow tract obstruction (right or left), or conditions where there is potential for significant right-to-left shunts (large patent foramen ovale or atrial septal defects). Children with liver disease should be screened for these conditions because of the implications of their presence (there is no particular association with liver disease).
Respiratory system Ascites can be severe enough to produce diaphragmatic splinting and pleural effusions may further reduce respiratory reserve (see paragraph on ascites, under features of chronic liver disease). This may be further complicated by the hepatopulmonary syndrome.
Hepatopulmonary syndrome This condition, which is seen in only a small proportion (5–10%) of patients with chronic liver disease, produces hypoxaemia by a combination of the redistribution of pulmonary blood flow which tends to cause a V/Q mismatch, and the formation of new blood vessels which cause a true right-to-left shunt.3,4 The changes are most marked in the lung bases, and so the hypoxaemia is unusual in that it is sometimes improved by lying the patient flat, because this posture diverts pulmonary blood flow towards less affected areas. The degree of hypoxaemia is not linearly related to the severity of the liver disease, so severe hypoxaemia can occur in the presence of fairly mild liver impairment. The hypoxaemia can progress and be
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 14 Number 5 2014
Downloaded from http://ceaccp.oxfordjournals.org/ at Tufts University on September 26, 2014
The effect of chronic liver disease on drug metabolism is difficult to define. Shifts in the volumes of fluid compartments and alterations in the levels of albumin and other plasma proteins can affect volumes of distribution and unbound fractions unpredictably. Phase 1 reactions are also variably altered depending on the degree of impairment of hepatocellular function. Conjugation reactions will probably be impaired, but again the degree is variable. Adapting drug doses in a scientific way is therefore difficult. But some general principles apply, and it can be expected that drugs with sedative effects will show enhanced and prolonged action.
Anaesthesia for children with liver disease
severely limiting with occasional patients requiring home oxygen therapy. The only effective treatment is liver transplantation, which usually produces complete resolution, although this may take several months.
Renal impairment
Encephalopathy A decreased level of consciousness can be seen in the setting of a combination of hyperammonaemia, raised intracranial pressure, and neuronal inflammation. It is most often seen where there has been a sudden insufficiency of hepatocellular function, usually in acute liver failure, but also sometimes in chronic conditions where decompensation has been precipitated, for example, by sepsis or a nitrogen load from a bleed into the gastrointestinal tract. Early signs may be subtle, especially in very young children, in whom it is difficult to apply tests used to grade encephalopathy in adults and older children, but early signs might include inversion of day/night sleep pattern, and later, irritability or lethargy.
Other systems Electrolyte disturbance, particularly hyponatraemia, is commonly seen, and is in part a result of enhanced water retention by the kidneys. The disturbance may be worsened by the use of diuretics to control oedema and ascites. Poor nutritional status retards growth, contributes to poor wound healing, and may further impair immune function. Supplementary enteral feeding is often required. Failure of vitamin D absorption may cause rickets and the resulting osteopaenia may cause pathological fractures. The child may suffer from intractable itching secondary to bile acid retention.
Acute liver failure Fulminant liver failure is defined by a short interval (,8 weeks) between the appearance of symptoms and the onset of encephalopathy. These patients are at high risk in any case, and require careful management.6,7 Encephalopathic patients may show enhanced
Administering anaesthesia Children with advanced liver disease should be transferred to a specialist centre. With regard to the choice of drugs commonly used for anaesthesia, there are a few key points to remember. Isoflurane, sevoflurane, and desflurane are all acceptable. Desflurane is often used as the very low proportion metabolized implies a low risk from toxic metabolites, and it preserves hepatic blood flow, possibly slightly better than the alternatives, although it is doubtful whether this is clinically significant. Atracurium and remifentanil have obvious advantages where the integrity of drug metabolism is in doubt. Cisatracurium may offer an advantage over atracurium in that the lower levels of the metabolite laudanosine produced reduces any risk of neurotoxicity from its cumulation, although likelihood of this adverse effect is small in any case. Opioids should not be withheld or under-dosed because of fears about their adverse effects; humanitarian considerations dictate that analgesia should be adequate, and if opioid use results in prolonged recovery requiring high dependency care then that has to be accepted. For minor procedures, for example, endoscopy or central venous line insertion, the preoperative assessment should particularly focus on whether there is any significant respiratory impairment from ascites, organomegaly, or pleural effusion. Even for minor procedures, patients who have to be starved should have preoperative i.v. fluids to prevent dehydration or hypoglycaemia. If an inhalation induction is used, basic monitoring should be instituted as soon as practicable. It may be better to keep the child in a moderate head-up position to minimize diaphragmatic splinting, and to reduce the risk of aspiration, which may be increased in these patients. The airway is best secured with a tracheal tube for all but the very shortest procedures. If the patient is very fragile then merely the anaesthesia alone may be enough to jeopardize return to a safe conscious level and adequate respiratory function. Beware of endoscopic procedures introducing more gas into the gut and worsening diaphragmatic splinting. For intermediate procedures, which might include extraperitoneal body surface procedures which take a little more time (e.g. hernia repairs), tracheal intubation and measures to preserve normothermia and normovolaemia are advisable. A higher level of postoperative care may be required. Even relatively minor procedures
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Confusion often exists around the topic of renal impairment in liver disease. The hepato-renal syndrome is a circulatory disturbance seen in end-stage chronic liver disease, rare in children, where intense renal vasoconstriction produces pre-renal failure.5 Treatment is largely ineffective, apart from liver transplantation. More frequently seen is acute renal impairment produced by dehydration, both intravascular depletion and reduction in total body water, to which patients with chronic liver disease seem particularly susceptible, which generally reflects their delicate physiological state. The anaesthetic management does not need to be any more sophisticated than ensuring adequate preoperative hydration, optimal volume loading, a good cardiac output, and adequate perfusion pressure, which may be lower than normal, provided there is satisfactory oxygen delivery.
sensitivity to anaesthetic and sedative agents and may have a very prolonged recovery. They often require continuous i.v. glucose support because of the failure of hepatocellular glucose regulation (glycogenesis, glycogenolysis, and gluconeogenesis)—this glucose support must not be interrupted and the blood glucose level must be monitored throughout the perioperative period. The circulation is typically hyperdynamic and volume loaded with a low systemic vascular resistance. Anaesthesia may result in the need for inotropic support, if it is not already required. Death in acute liver failure is usually the result of one or more of cerebral oedema and tentorial herniation, circulatory and multi-organ failure, or sepsis (bacterial or fungal).
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Approximately, one-third of portoenterostomy procedures are at least partially successful (for some years—the long-term outcomes remain uncertain); another third do initially result in a reduction in jaundice but have persistent problems, such as recurrent cholangitis and develop cirrhosis later; and the final third never achieve a significant decrease in serum bilirubin and will require early transplantation.9,10
Choledochal cysts Cystic dilatations originating from the biliary tree are rare abnormalities which may cause pain, obstructive jaundice, and an abdominal mass. The cysts may occur anywhere along the biliary tree and there are various classification systems. They may present at any age but are increasingly identified by antenatal ultrasound scanning. Treatment is usually with complete excision of the cyst, due to a potential for later malignant change, with biliary drainage via a portoenterostomy. Anaesthesia is essentially similar to that for cases of biliary atresia.
Cholelithiasis Anaesthesia for specific hepatobiliary procedures In order to illustrate the anaesthetic principles of paediatric hepatobiliary surgery, some of the commoner or more major conditions and procedures are reviewed in greater detail.
Biliary atresia and Kasai portoenterostomy Biliary atresia is a rare congenital anomaly involving absence of intra- and extra-hepatic bile ducts leading to cholestasis, hepatic fibrosis, and cirrhosis. It has an incidence of around 1:14 000 live births in the UK and is the most common indication for paediatric liver transplantation. Around 25% of cases have associated anomalies including polysplenia, abdominal situs inversus, and atrial septal defect. Affected babies appear normal, but the signs of cholestasis ( pale stools, failure to thrive, malabsorption, and conjugated hyperbilirubinaemia) appear soon after birth. The Kasai portoenterostomy is a surgical procedure which may establish bile drainage and halt the progression to hepatic fibrosis and cirrhosis, but success is unlikely if it is performed after 8 weeks of age. Timely assessment and investigation is thus important to distinguish biliary atresia from other (much commoner) causes of neonatal jaundice. The main anaesthetic challenges are fluid loss, intermittent interruption of venous drainage via the inferior vena cava by surgical retraction, and provision of adequate postoperative analgesia. Coagulopathy is unlikely once the babies have been given vitamin K. Central venous catheters are often used and may be retained after operation for fluid and drug administration and blood sampling. In the absence of associated cardiac anomaly or other compelling indication, arterial cannulae are not required. Epidural analgesia can usually be offered with safety.
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Gallstone disease is relatively rare in younger children, and often associated with haemoglobinopathies, where a high rate of haemolysis may cause pigment stones. Teenagers are increasingly suffering from cholesterol gallstones, which are related to the increasing prevalence of obesity. A familiarity with laparoscopic and open cholecystectomy is assumed—the management of the paediatric case is broadly the same as in the adult.
Liver tumours Primary liver tumours are rare in children. Hepatoblastoma is the most common paediatric liver tumour with an increasing incidence, of around 1 per million, and usually presents in the first 3 yr of life, with an obvious abdominal mass, lethargy, and pallor. Liver function is usually normal. Treatment is with chemotherapy (doxorubicin or cisplatin) followed by surgical resection if possible; if not, liver transplantation can be curative if there is no extrahepatic disease. Doxorubicin can cause cardiomyopathy, which requires echocardiographic assessment.11 There are essentially three important perioperative challenges for the anaesthetist: haemorrhage, air embolus, and post-resection liver insufficiency. Major haemorrhage is an ever-present risk in liver tumour resection. Venous access should include a large-bore central venous cannula (such as an introducer sheath) dedicated to transfusion, in addition to a standard triple-lumen central venous catheter for drugs and pressure monitoring; the veins used for access should be those in the upper body which drain into the superior vena cava, as the inferior vena cava may be occluded during surgery. Existing Hickman catheters are not ideal for intraoperative use and should generally not be used, to minimize the risk of sepsis. Rapid transfusion and fluid warming devices appropriate to the size of the child are necessary, as is timely access to large quantities of blood
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may warrant securing central venous access—this can be done with a very low level of risk by experienced practitioners, even allowing for the somewhat increased potential for adverse events in coagulopathic patients, and it allows volume status to be accurately optimized, regular venous blood gas analysis is possible, and also sampling for coagulation monitoring. For major procedures, which in this patient group would probably include any intraperitoneal procedure, full invasive monitoring is usual. Haemodynamic optimization reduces the risk of worsening hepatic or renal function because of poor organ perfusion. Coagulation is monitored with bedside prothrombin/INR measurement and thromboelastography (TEG or ROTEM).8 Coagulation may need to be supported with clotting factors, although normal values are not necessary—surgical problems are relatively unlikely if the INR is ,2 and platelet count over 80109 litre21. Postoperative intensive care may be required, particularly if opioid analgesia is used. Peripheral nerve blocks may be helpful, but neuraxial block is often contraindicated because of coagulopathy, thrombocytopaenia, or the presence of epidural varices, which are likely in the presence of portal hypertension.
Anaesthesia for children with liver disease
Liver transplantation Liver transplantation remains the only effective treatment for endstage liver disease, and results are generally excellent with 5 yr survival around 90% for chronic indications (Fig. 2); most deaths occur within the first 3 months after operation, but intraoperative mortality is uncommon (,1%). The procedure is much the same as in an adult, the main differences being that for smaller children, the great majority of grafts are now split adult organs, the smaller left lobe
usually being used for the child, and because of the size of the vena cava, it is often not possible to avoid total caval cross-clamping. Livers need only be matched for blood group. The aim is to have the liver reperfused within 12 –16 h of harvest. The procedure itself is conventionally described in three phases: dissection, anhepatic, and reperfusion. The dissection phase involves the skeletonization of the explant and preparation of the liver vessels. The main problems at this stage usually relate to bleeding. The anhepatic stage starts when the portal vein and hepatic artery are clamped and divided, after which there is no liver function. Usually, it is not possible to isolate the rather short and awkwardly placed hepatic veins, so a segment of cava is removed with the native liver, and a short length of donor cava attached to the liver graft restores vessel continuity. During the anhepatic phase, there is an inexorable increase in base deficit and lactate and a decrease in ionized calcium and glucose. At reperfusion, almost always via the portal vein, there is often considerable haemodynamic instability from the effects of reperfusing an ischaemic organ—including a decrease in systemic vascular resistance (sometimes precipitous)13 together with myocardial stunning, and changes in circulating volume from filling the new liver, and blood losses from the cut surface and vascular anastomoses. After reperfusion, the arterial supply is restored and a biliary drainage system fashioned, most often draining the bile duct into a short length of small bowel (Roux-en-Y). If the new liver functions well, then there will usually be a gradual reduction in base deficit (within an hour or two) followed by a decrease in serum lactate and a restoration of haemodynamic stability. Anaesthetic management of liver transplantation is highly complex, involving preparation for massive blood loss, management of severe electrolyte and acid/base disturbance, and careful circulatory support. Success requires an experienced team of surgeons, anaesthetists, and theatre staff.
Declaration of interest None declared.
1.0 Chronic n = 443
Cum survival
0.8
References 1. McKiernan PJ, Beath SV, Davison SM. A prospective study of endoscopic esophageal variceal ligation using a multiband ligator. J Paediatr Gastroenterol Nutr 2002; 35: 609– 15
Acute n = 96
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2. Rosenthal P. When should we perform TIPS in children? J Paediatr Gastroenterol Nutr 2012; 54: 577
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3. Palma DT, Fallon MB. The hepatopulmonary syndrome. J Hepatol 2006; 45: 617–25
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4. Noli K, Solomon M, Golding F, et al. Prevalence of hepatopulmonary syndrome in children. Pediatrics 2008; 121: 522– 7
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5. Salerno F, Gerbes A, Gines P et al. Diagnosis, prevention and treatment of the hepatorenal syndrome in cirrhosis. Gut 2007; 56: 1310–8
0.00 5.00 10.00 15.00 Patient survival post-trasplant years
6. Cochran JB, Losek JD. Acute liver failure in children. Pediatr Emerg Care 2007; 23: 129–35
Fig 2 Liver transplantation, patient survival 1993–2013, Birmingham Children’s Hospital. Data kindly provided by Carla Lloyd, Liver Unit, Birmingham Children’s Hospital.
7. Squires RH, Schneider BL, Buchuvalas J et al. Acute liver failure in children: the first 348 patients in the Acute Liver Failure Study Group. J Pediatr 2006; 148: 652– 8
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products. The use of intraoperative red cell salvage for cases of malignant tumour resection is controversial; the benefits of avoiding allogenic blood transfusion and potential immunomodulation must be balanced against the systemic infusion of malignant cells and possible metastasis. Leucocyte depletion filters appear effective at removal of tumour cells from salvaged blood.12 Surgery usually involves hemi-hepatectomy; this can expose large hepatic veins which are held open with the risk of air entrainment and embolus. Relative fluid restriction is often used to decrease liver congestion and bleeding. Intermittent clamping of the portal vein and hepatic artery may be used to reduce bleeding and expedite surgery, but these manoeuvres may lead to cardiovascular instability and dysfunction in the remaining liver. Hepatic dysfunction may also result from large-volume parenchymal resection, which is suggested by increasing metabolic acidosis, hypoglycaemia, and coagulopathy. Management is supportive while the liver recovers, comprising correction of hypovolaemia and hypotension, maintaining blood glucose, administration of clotting factors, and N-acetylcysteine (which is protective against liver ischaemia by replenishment of hepatic glutathione stores and possibly other effects). Epidural analgesia may be inadvisable in cases involving large parenchymal resections. The majority of cases can return to a high dependency unit after surgery.
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8. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008; 106: 1366– 75 9. Kelly DA, Davenport M. Current management of biliary atresia. Arch Dis Child 2007; 92: 1132– 5 10. Fouquet V, Alves A, Branchereau S, et al. Long-term outcome of paediatric liver transplantation for biliary atresia: a 10-year follow-up in a single centre. Liver Transpl 2005; 11: 152 –60
11. Stringer M. The role of liver transplantation in the management of paediatric liver tumours. Ann R Coll Surg Engl 2007; 89: 12– 21 12. Esper SA, Waters JH. Intra-operative cell salvage: a fresh look at the indications and contraindications. Blood Transfus 2011; 9: 139–47 13. Aggarwal S, Kang Y, Freeman JA, et al. Postreperfusion syndrome: hypotension after reperfusion of the transplanted liver. J Crit Care 1993; 8: 154–60
Please see multiple choice questions 9–12.
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