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Anaesthetic management of the pregnant patient with liver disease
Trends in Anaesthesia and Critical Care 1 (2011) 162e167
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REVIEW
Anaesthetic management of the pregnant patient with liver disease T.C. Collyer, S.P. Holbrook*, G. Lyons Department of Anaesthesia, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
s u m m a r y Keywords: Pregnancy Liver disease Anaesthesia Obstetric Anaesthetic techniques Regional Liver transplantation
The incidence of pregnant women with liver failure presenting for delivery is fortunately rare but presents a number of complex anaesthetic problems. Liver dysfunction in pregnancy may be the result of obstetric diseases or may simply be the result of liver disease occurring in a pregnant patient. Little is currently written to advise the anaesthetist about the management of these cases. Successful anaesthetic management not only requires an understanding of the causes but also the challenges that may be encountered perioperatively. Thorough pre-operative assessment, judicious use of regional anaesthesia, and multidisciplinary care in an appropriate environment is essential for an optimal maternal outcome. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction The overall incidence of acute liver failure during pregnancy is unknown but it is an important cause of mortality. The last three Confidential Enquiries into Maternal and Child Health (CEMACH) in the United Kingdom recorded 8 direct deaths as a result of acute fatty liver of pregnancy: thus giving a mortality rate of 1.3 per million maternities.1e3 CEMACH also recorded a further 17 direct deaths due to hepatic complications of pre-eclampsia during this period: including 2 as a result of hepatic rupture and 2 as a result of hepatic failure or necrosis. The most frequent causes of acute liver failure during pregnancy are viral hepatitis, paracetamol overdose, acute fatty liver of pregnancy and HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelet count).4 In addition, an exacerbation of a chronic liver disease may also present with a clinical picture indistinguishable from acute liver failure.5 An accurate diagnosis is crucial, as management is dependent on aetiology. Delivery of the foetus often helps reverse the liver diseases of late pregnancy, including acute fatty liver of pregnancy and HELLP syndrome. Conversely, delivery does not necessarily improve maternal outcome when acute liver failure is secondary to incidental causes such as viral hepatitis and drug overdose. The presentation of women with acute liver failure requiring caesarean section is rare but creates a number of complex problems for the anaesthetist. To aid management there are a number of reviews and case series on the medical management of acute fatty liver of pregnancy and a smaller number of articles on the medical
* Corresponding author. Tel.: þ44 1423 553559; fax: þ44 1423 553501. E-mail address: [email protected] (S.P. Holbrook). 2210-8440/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tacc.2011.02.003
management of chronic liver failure in pregnancy, but there is little guidance to inform anaesthetic practice.4,6e14 To remedy this we reviewed the issues important to the anaesthetic management of these complex and rare cases. 2. Liver dysfunction unique to pregnancy Liver dysfunction as a result of hyperemesis gravidarum and intrahepatic cholestasis generally follows a benign course. Whilst pre-eclampsia, HELLP syndrome and acute fatty liver of pregnancy have the potential for severe and possibly fatal complications. These disorders might represent a spectrum of disease, as there is considerable overlap in their clinical presentation. What is more important, with respect to their management, is the fact that they are potentially reversible. Early diagnosis and delivery of the foetus are central to successful management. Their potential for grave complications means that these patients require multidisciplinary input and may require intensive care. 2.1. Pre-eclampsia Pre-eclampsia is the occurrence of hypertension, proteinuria and oedema typically complicating the late second or third trimester. Endothelial dysfunction is thought to be the underlying pathophysiological process but a variety of mechanisms have been proposed. It occurs in 5e10% of pregnancies but severe cases may infrequently exhibit hepatic involvement.15,16 Hepatic aminotransferases are variably raised, but less so than in HELLP syndrome, and jaundice is unusual. Hepatic haemorrhage and subcapsular haematoma formation may arise. The latter is often associated with disseminated intravascular coagulation (DIC), but
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severe right upper quadrant pain, nausea and vomiting with grossly elevated aminotransferases should raise suspicions.4 Investigation with ultra-sound or MRI scan should be undertaken if the patient’s condition permits but the presence of concomitant shock may indicate hepatic rupture. This can occur at any time and is associated with a high maternal mortality.17 Emergency laparotomy under general anaesthesia may be the only option. As a rule, even haemodynamically stable patients should be managed in a critical care environment. Hepatic infarction does occur rarely but communication between the portal vein and the hepatic artery generally prevent this.4 2.2. HELLP syndrome HELLP syndrome complicates up to 0.6% of all pregnancies and occurs in up to 15% of patients with pre-eclampsia, but may occur in the absence of hypertension.18e20 Aetiologically it is thought to be the result of vascular endothelial damage and subsequent fibrin deposition in organ micro-vasculature. This process results in microangiopathic haemolytic anaemia, platelet consumption and end organ injury. Periportal hepatic fibrin deposition leads to areas of haemorrhage and necrosis. It typically presents in the third trimester but it may present mid-second trimester and in 25% it becomes evident postpartum.15 Patients may present with non-specific symptoms such as upper abdominal pain, nausea, vomiting, headache and malaise, with or without clinical features of pre-eclampsia. Again jaundice is infrequent. Laboratory evidence of haemolysis, raised aminotransferases, and thrombocytopaenia (platelet count < 100 109/L) points to the diagnosis of HELLP but haemolysis is not invariable (ELLP syndrome). Anaemia in the presence of blood stained or black urine (free haemoglobin in the urine) indicates severe haemolysis.21 Differential diagnoses to be considered include acute fatty liver of pregnancy, haemolytic uraemic syndrome, thrombotic thrombocytopaenic purpura, and systemic lupus erythematosus. There is significant risk to both the patient and the foetus as complications are common. Spontaneous and postpartum haemorrhage rank highly but others include placental abruption, acute respiratory distress syndrome, and acute renal failure.22 Hepatic problems again include hepatic haemorrhage and infarction, and rarely hepatic rupture. Immediate delivery is recommended if gestation is greater than 34 weeks or if there is evidence of foetal distress. In the stable patient at less than 34 weeks gestation, corticosteroid administration for 24e48 h may aid foetal lung maturity and may increase the platelet count.15 Blood products should be used to correct coagulopathy and anaemia, and ultrasound or MRI scanning may be required to verify pathology. Delay in the diagnosis of HELLP syndrome is considered to be a significant contributory factor in all-cause fatalities and because of the potential for severe complications it is advised that patients should be transferred to a tertiary referral centre at an early stage.19 On a final note it must be remembered that the patient may deteriorate postpartum: liver enzymes may continue to rise and the platelet count may continue to fall and may not demonstrate signs of recovery for 72 h or more after delivery.23,24 Critical care support should be sustained to ensure a favourable outcome. 2.3. Acute fatty liver of pregnancy Acute fatty liver of pregnancy is rare. Its reported incidence, based on case series or retrospective cohort studies, varies between 1 in 900 and 16000 deliveries.25e27 The most recent report from the United Kingdom Obstetric Surveillance System quoted an incidence of 1 in 20,000 maternities.28 It is reported to be associated with nullipara, twin pregnancies, and male foetus in a 3:1 ratio; in
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addition, up to 60% of cases may have co-existent pre-eclampsia.4e6 The aetiology is uncertain and it is thought to be due to defects in hepatic fatty acid oxidation pathways.29e31 However, the hepatic histopathological changes are non-specific and are found in a multitude of conditions (including pre-eclampsia).32 It typically presents during the third trimester with a 1e2 week prodrome of malaise, abdominal pain, nausea, vomiting, headache and jaundice. There are reports of cases presenting in the second trimester and postpartum. Pruritis and fever may also be present, as may symptoms and signs of pre-eclampsia. The diagnosis should be considered in any patient presenting with any of these symptoms. Hepatic aminotransferase levels are typically raised to a greater level than in pre-eclampsia and HELLP syndrome (mean aspartate aminotransferase level 278 iu/L, compared to 53 iu/L in preeclampsia, and 66 iu/L in HELLP syndrome).25 Other laboratory features include a neutrophil leucocytosis, DIC and anaemia. Laboratory features that may help distinguish it from HELLP include severe hypoglycaemia, hypocholesterolaemia, hypotriglyceridaemia and low antithrombin III levels.33 In addition, DIC, renal insufficiency, ascites and encephalopathy are more common. Ultrasound scan and MRI may be useful to confirm the diagnosis and will identify hepatic haemorrhage or infarction due to pre-eclampsia or HELLP syndrome. However, a negative scan does not exclude acute fatty liver of pregnancy and a definitive diagnosis may only be obtained through liver biopsy, contraindicated in the presence of coagulopathy. Early diagnosis and delivery of the foetus is crucial for a favourable maternal and foetal outcome. High dependency or intensive care should be given in a unit with access to specialist liver services. 2.4. Intrahepatic cholestasis Intrahepatic cholestasis occurs in up to 2% of pregnancies and it is the second commonest cause of jaundice in the pregnant patient (after viral hepatitis).4,34 It seems to be the result of both genetic and environmental factors that increase sensitivity to the normal sex hormone changes occurring during pregnancy. Familial cases have been reported in addition to a seasonal variation in some countries.4,15,34 Patients classically present with pruritis in the third trimester but it may occur earlier.15,34 Jaundice is variable and may only be evident in severe cases.15 Symptoms include anorexia, malaise, dark urine, abdominal pain and steatorrhoea. Mild elevations in serum aminotransferases, alkaline phosphatase and conjugated bilirubin occur, but measurement of bile acid levels is the only specific laboratory test that will aid the diagnosis.4 Imaging of the liver is normal and the diagnosis is usually made on clinical grounds and through laboratory exclusion of other causes, such as screening for viral hepatitis. Management should be aimed at relieving pruritis and minimising risk to the foetus: there is an increased risk of premature labour, foetal distress, and sudden intrauterine death.35,36 The severity of pruritis and the foetal risks increase as gestation progresses. There is no way of identifying the at-risk foetus therefore delivery should be expedited as soon as foetal lung maturity has been attained. Pruritis typically resolves immediately after delivery but ursodeoxycholic acid or dexamethasone may be used to alleviate pruritis without risk to the foetus.37e39 The prognosis for the mother is generally good but intrahepatic cholestasis recurs in subsequent pregnancies in up to 70% of cases.36 2.5. Hyperemesis gravidarum Hyperemesis gravidarum is defined as severe nausea and vomiting with resultant dehydration and the need for intravenous
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fluid resuscitation. It occurs in 0.2e30 women per 1000 pregnancies.40,41 The aetiology is unclear but is probably multifactorial with genetic, hormonal, and environmental factors purporting to play a role.4,41 Those at risk include multiparous patients, and those with multiple pregnancy or gestational trophoblastic disease.41 It presents during the first trimester and is accompanied by elevations in serum aminotransferases in 15e25% of hospitalised patients, though the severity of the biochemical disturbance is highly variable.4,41 Management requires hospitalisation and treatment with antiemetics plus fluid and electrolyte replacement. Promethazine, prochlorperazine, chlorpromazine and metoclopramide are most frequently used, with steroids and ondansetron reserved for refractory cases. These measures usually lead to normalisation of hepatic enzymes, although enteral feeding with vitamin supplementation may be required and even parenteral nutrition may even be required in the most severe cases. 3. Non obstetric causes of liver disease These can broadly be divided into pregnant patients with coincidental causes of liver dysfunction, such as viral hepatitis, and those with chronic liver disease who subsequently become pregnant. Any cause of acute liver failure can present in pregnancy and likewise any disorder leading to chronic liver disease may occur in the pregnant patient. Patients with compensated cirrhosis and mild portal hypertension may still achieve a successful pregnancy. Management of complications is similar to the non-pregnant patient but requires intensive multidisciplinary care. We shall explore viral hepatitis and gallstone disease here and highlight specific management issues relating to chronic liver disease in the subsequent section. 3.1. Viral hepatitis The most frequent cause of jaundice in pregnancy is viral hepatitis.4,42 Acute liver failure is a rare consequence of all the Hepatitis viruses with only 0.2e4% developing severe disease overall: Hepatitis E and B are most frequently the cause.43 Hepatitis as a result of infection with herpes viruses (cytomegalovirus (CMV), EpsteineBarr virus (EBV), and Herpes Simplex Virus (HSV)) is extremely rare, however HSV has a propensity for causing severe disease in the pregnant patient. They may present in any trimester and the presenting symptoms are non-specific. Diagnosis frequently relies on a thorough assessment of the patient’s history and viral serology. Management varies little from that of the non-pregnant patient. In the presence of acute liver failure the potential for complications (such as postpartum haemorrhage) is high. In women with HSV early diagnosis and commencement of aciclovir is crucial for a favourable outcome, however mortality is in excess of 90% even with therapy.44 EBV infection is generally benign and CMV infection is only problematic in the immunosuppressed patient, with reports of biliary strictures and acalculous cholecystitis.44 3.2. Cholelithiasis Gallstone disease is second only to acute appendicitis in terms of non-obstetric conditions requiring surgery. The presentation is typical and the differential diagnosis includes any cause of cholestasis. Management is generally conservative with surgery being reserved for severe unresponsive cases. Cholecystectomy has been reported for acute cholecystitis in approximately 1 per 1000 deliveries.4 In terms of risk to the foetus, surgery should be preferably being undertaken during the second trimester: there is an increased risk of spontaneous abortion in the first trimester and
premature labour in the third.45,46 Laparoscopic cholecystectomy can be undertaken safely in the second trimester, but is obviously technically difficult in the last trimester. However, symptoms are frequently recurrent and laparoscopic cholecystectomy has been performed with caesarean section.47 4. Anaesthetic management 4.1. Pre-operative assessment 4.1.1. Liver dysfunction and coagulopathy The degree of liver dysfunction is most accurately monitored by the prothrombin time (PT), which should be performed at least once daily. If the PT is high, without overt signs of bleeding, fresh frozen plasma should not be given routinely as outcome is not improved and interpretation of the prothrombin time is then difficult. The pre-operative assessment of the coagulation profile should be conducted as close as possible to the time of surgery given the progressive nature of acute liver failure. In addition to the PT and international normalized ratio (INR) measurements should include an activated partial thromboplastin time (APTT) plus a fibrinogen and platelet level. Where significant coagulopathy or thrombocytopaenia exists, assessment of the whole blood coagulation profile by thromboelastography (TEGÒ) can provide useful additional information. TEGÒ enables a global assessment of haemostatic function from a single blood sample and documents the interaction of platelets, clotting factors and fibrin. The stages of coagulation from the initial platelet fibrin interaction and platelet aggregation, through to clot strengthening and fibrin cross linkage, with eventual clot lysis, are both graphically and numerically represented.48 This may help to guide blood product requirements but in addition, in our experience, has helped guide the use of regional anaesthetic techniques in obstetric patients. However, this is controversial. Further assessment of liver dysfunction includes daily measurement of liver enzymes and 1e4 hourly assessment of serum glucose: this is dependent on the patient’s clinical condition. Hypoglycaemia remains a common cause of maternal morbidity, especially in acute fatty liver of pregnancy.7 A centrally placed venous catheter is desirable for the provision of hypertonic glucose infusions in cases of severe and persistent hypoglycaemia to avoid thrombophlebitis. 4.1.2. Renal dysfunction Renal insufficiency may complicate acute liver failure and a careful assessment of renal function and fluid balance is required. Hyponatraemia may aggravate cerebral oedema but should be rectified slowly: the optimal rate is controversial. Urea levels may be misleadingly low because of impaired hepatic synthesis. Serum creatinine levels and creatinine clearance are the best monitors of renal function. The presence of renal impairment may indicate renal hypoperfusion secondary to circulatory failure or hepatorenal syndrome. Fluid balance can be difficult to assess, especially in the presence of hypoalbuminaemia, ascites and peripheral oedema. Pleural effusions due to fluid retention and diaphragmatic splinting, secondary to ascites and a gravid uterus, may lead to hypoxaemia and respiratory failure. Maintaining strict daily fluid balance charts and monitoring weight daily aid fluid balance. Central venous pressure trends should be monitored, as specific values are unreliable, unless coagulopathy precludes central venous catheterisation. A fluid volume load may help identify the cause of renal impairment, but patients may require renal replacement therapy to control fluid balance and malignant electrolyte disturbances, such as hyperkalaemia.49 Consideration must also be given to the influence of renal impairment and fluid status
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when selecting intravenous anaesthetic agents and neuromuscular blockers, and when calculating analgesic doses.
and therefore the timing of delivery is dictated by the progress of the mother and foetus.
4.1.3. Encephalopathy The presence of encephalopathy is important both prognostically and for planning of anaesthetic technique. Encephalopathy may be the result of hypoglycaemia, gastrointestinal bleeding, concurrent infection, constipation or cerebral oedema and all causes should be actively sought. Grade 3 and 4 encephalopathy are associated with up to 80% mortality and will usually require preoperative intubation and ventilation to protect the airway and maximize oxygenation.49 Any disruption in cognitive ability may prohibit the use of a regional anaesthetic technique. Cerebral oedema is a significant factor in the pathogenesis of hepatic encephalopathy and intracranial pressure (ICP) monitoring may improve outcome, although a raised ICP does not necessarily equate with the degree of encephalopathy.49 Mannitol may be utilised as first line therapy in the management of intracranial hypertension but a standard dose cannot be recommended: lower doses (0.25e0.5 g/kg boluses) may avoid dehydration and severe electrolyte and osmotic disturbances.50
4.3. Premedication
4.1.4. Infection Risk from infection is increased in liver failure and strict asepsis must be maintained at all times.7 When sepsis occurs it can be complicated by similarities in the clinical picture of sepsis and acute liver failure and a low index of suspicion is necessary. Low-grade fever and leukocytosis are unreliable markers of infection and microbiological cultures and analysis should be performed on sputum, blood, urine and peritoneal aspirate.6 4.1.5. Additional investigations Pre-operative investigations should also include an electrocardiogram and arterial blood gas analysis. Metabolic alkalosis and acidosis may occur in acute liver failure but an arterial pH less than 7.3 predicts a poor prognosis in paracetamol-induced acute liver failure and increases the likelihood of liver transplantation.43 An abdominal ultra-sound scan (see above) and transthoracic echocardiography may provide additional useful information. The latter is increasingly being utilised by intensivists as a non-invasive bedside tool to assess a patient’s left ventricular function and volaemic status. 4.1.6. Consideration of patients with known chronic liver disease Patients with acutely decompensated liver function on a background of known advanced liver cirrhosis with portal hypertension, require special consideration when planning surgery and anaesthesia. Abdominal surgery can be technically difficult due to the large collateral circulation and preparation for potentially significant blood loss is necessary.51 The risk of spinal haematoma, in the setting of raised portal venous pressure, collateral circulation, and coagulopathy, must be considered carefully when using regional anaesthetic techniques, though they are not an absolute contraindication.51,52
4.2. Timing of surgery The timing of surgery should be a multidisciplinary decision and should occur at the best time, in the best place and with the best team. When acute liver failure is secondary to acute fatty liver of pregnancy or severe HELLP syndrome, a rapid improvement in liver function is seen following delivery and argues strongly for induction of labour, or delivery by caesarean section.7 Acute liver failure secondary to other causes is unlikely to be influenced by delivery
4.3.1. N-Acetylcysteine The use of N-acetylcysteine (NAC) to prevent hepatotoxicity secondary to paracetamol overdose is widespread and well documented.53 It’s use is safe and effective during pregnancy for the management of paracetamol toxicity.54,55 Case series have established that there is placental transfer of NAC with no harmful effects suffered by the infant, and that delays in the treatment with NAC can result in an increased incidence of spontaneous abortion or foetal death.56,57 The evidence for the use of NAC in acute liver failure secondary to other causes is less convincing but should always be considered after discussion with a hepatologist. 4.3.2. Blood products In the presence of coagulopathy pre-operative transfusion of fresh frozen plasma (15 ml/kg) is advisable as well as the administration of parenteral vitamin K. Additional blood products available should include platelets and cryoprecipitate. Complete correction is probably unachievable but an INR 1.5, platelet count of 50,000/mm and a fibrinogen level 100 mg/dL are realistic goals.50 Recombinant factor VIIa should only be considered in the context of an invasive procedure with a high risk of bleeding and when these other constituents are replete.50 The procedure should be performed within 60 min of administration.50 Obviously transfusion requirements will vary between patients and a consultant haematologist should be actively involved throughout, especially where complex coagulopathies exist. 4.4. Anaesthetic technique The risks associated with general anaesthesia for caesarean section were emphasised in the last two CEMACH reports.2,3 A prolonged PT and thrombocytopaenia will necessitate caution when considering a regional technique but performance of TEGÒ may prove a useful adjunct in making this decision. Reviewing the literature we found a single case report using an epidural catheter to provide anaesthesia for caesarean section in a patient with acute fatty liver of pregnancy, and four case reports employing general anaesthesia, one of which highlighted the potential risk of suxamethonium apnoea.14,58e61 Post-operative analgesia must be considered and the risks of intravenous opioid use emphasised. There is an increased risk of opioid toxicity and precipitation of hepatic encephalopathy, especially in the context of renal failure. Patient controlled analgesic (PCA) systems employing remifentanil or fentanyl should be used: the clearance of morphine and alfentanil is reduced in liver failure. There is increasing support for the use of Remifentanil PCA for labour analgesia and it has been used successfully after major abdominal surgery in patients with normal liver function.62 However, an animal study demonstrated that both fentanyl and remifentanil clearance is reduced in acute hepatic failure, if administered by continuous intravenous infusion.63 Remifentanil’s metabolism may not be completely independent of hepatic metabolism. Ultimately regional techniques will provide superior post-operative analgesia. 4.5. Post-operative complications A multitude of complications have been reported in the postoperative period including hepatic failure, acute renal failure, acute respiratory distress syndrome, pancreatitis, severe uterine and gastrointestinal bleeding and sepsis.26,27,58,64e66 Post-operative
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care of the mother and baby should accordingly be in an environment affording a higher level of care, such as a high dependency or intensive care unit. 5. Liver transplantation In all cases of postpartum liver transplantation, maternal morbidity and mortality remains high. However, successful outcomes have been reported in a variety of conditions.4 Postpartum orthoptic liver transplantation for acute fatty liver of pregnancy has met with variable success rates.67e71 Castro et al. advise the use of caution when considering liver transplantation because of the reversible nature of the disease. They argue that whilst these patients frequently exhibit clinical and laboratory deterioration, initially requiring specialist intensive support, they ultimately recover their liver function.7 Transplantation should only be considered for emergency cases of severe hepatic failure and requires close coordination between the obstetric, transplant, neonatal, anaesthetic and intensive care teams to ensure optimal maternal and foetal outcomes.4 6. Summary The presentation of women with liver failure requiring caesarean section remains thankfully rare. Early diagnosis and treatment in a tertiary referral centre under the care of a multidisciplinary team can improve maternal outcome.4 Careful pre-operative anaesthetic assessment and planning allows many of the potential complications to be anticipated and managed early. The choice of anaesthetic technique is determined by the clinical state of the patient but where possible a regional anaesthetic technique is desirable. The role of the anaesthetist extends throughout the patients stay and includes active involvement in the management of many of the potential post-operative complications. Conflict of interest statement None. References 1. Department of Health. Scottish Executive Health Department, and Department of Health, Social services and Public safety, Northern Ireland. Why mothers Die. The Fifth report on Confidential Enquiries into maternal deaths in the United Kingdom, 1997e1999. London: RCOG Press; 2001. 2. Lewis G, editor. Confidential Enquiries into maternal and Child Health. Why mothers Die. The Sixth report of the United Kingdom Confidential Enquiries into maternal deaths in the United Kingdom. London: RCOG Press; 2004. 3. Lewis G, editor. The Confidential Enquiry into maternal and Child Health (CEMACH). Saving mothers’ Lives: reviewing maternal deaths to make motherhood safer e 2003-2005. The Seventh report on Confidential Enquiries into maternal deaths in the United Kingdom. London: CEMACH; 2007. 4. Fagan EA. Disorders of the liver, biliary system and pancreas. In: De Swiet M, editor. Medical disorders in obstetric practice. 4th ed. Blackwell Science; 2002. p. 282e345. 5. Pereira SP, O’Donohue J, Wendon J, Williams R. Maternal and perinatal outcome in severe pregnancy-related liver disease. Hepatology 1997;26: 1258e62. 6. Pockros PJ, Peters RL, Reynolds TB. Idiopathic fatty liver of pregnancy: findings in ten cases. Medicine (Baltimore) 1984;63:1e11. 7. Castro MA, Fassett MJ, Reynolds TB, Shaw KJ, Goodwin TM. Reversible peripartum liver failure: a new perspective on the diagnosis, treatment and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J Obstet Gynecol 1999;181:389e95. 8. Knox TA, Olans LB. Current concepts: liver disease in pregnancy. N Engl J Med 1996;335:569e76. 9. Lee WM. Pregnancy in patients with chronic liver disease. Gastroenterol Clin North Am 1992;21:889e903. 10. Sternlieb I. Wilson’s disease and pregnancy. Hepatology 2000;31:531e2 [comment]. 11. Swanson J, Scioscia E. Hepatic disease. In: Datta S, editor. Anesthetic and obstetric management of the high-risk pregnancy. Mosby; 1996. p. 558e73.
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Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology 2005;42:1399e405. 40. Abell TL, Riely CA. Hyperemesis gravidarum. Gastroenterol Clin North Am 1992;21:835e49. 41. Kuscu NK, Koyuncu F. Hyperemesis gravidarum: current concepts and management. Postgrad Med J 2002;78:76e9. 42. Hay JE. Viral hepatitis in pregnancy. Viral Hepat Rev 2000;6:205e15. 43. O’Grady. Acute liver failure. Postgrad Med J 2005;81:148e54. 44. Fagan EA, Harrison TJ. Viral hepatitis: a handbook for clinicians and scientists. New York: Bios Publications, Oxford Springer-Verlag; 2000. pp. 233e67. 45. Lu EJ, Curet MJ, El-Sayed YY, Kirkwood KS. Medical versus surgical management of biliary tract disease in pregnancy. Am J Surg 2004;188:755e9. 46. Rollins MD, Chan KJ, Price RR. Laparoscopy for appendicitis and cholelithiasis during pregnancy. Surg Endosc 2004;18:237e41. 47. Glasgow RE, Visser BC, Harris HW, Patti MG, Kilpatrick SJ, Mulvihill SJ. Changing management of gallstone disease during pregnancy. Surg Endosc 1998;12:241e6. 48. Mallett SV, Cox DJA. Thromboelastography. Br J Anaesth 1992;69:307e13. 49. Low J. Liver dysfunction. In: Craft TM, Nolan JP, Parr MJA, editors. Key topic in critical care. Oxford: BIOS; 2002p.147e50. 50. Stravitz RT, Kramer AH, Davern T, Shaikh OS, Caldwell SH, Mehta RL, et al. Intensive care of patients with acute liver failure: recommendations of the US acute liver failure study Group. Crit Care Med 2007;35:2498e508.
T.C. Collyer et al. / Trends in Anaesthesia and Critical Care 1 (2011) 162e167 51. Russell MA, Craigo SD. Cirrhosis and portal hypertension in pregnancy. Semin Perinatol 1998;22:156e65. 52. Soto-Albors CE, Rayburn WF, Taylor L, Musselman M. Portal tension and hypersplenism in pregnancy secondary to chronic schistosomiasis. A case report. J Reprod Med 1984;29:345e8. 53. Sklar GE, Subramaniam M. Acetylcysteine treatment for non-AcetaminophenInduced acute liver failure. Ann Pharmacother 2004;38:498e501. 54. Ludmir J, Main DM, Landon MB, Gabbe DG. Maternal acetaminophen overdose at 15 weeks of gestation. Obstet Gynecol 1986;67:750e1. 55. Kozer E, Koren G. Management of paracetamol overdose: current controversies. Drug Saf 2001;24:503e12. 56. Horowitz RS, Dart RC, Jarvie DR, Bearer CF, Gupta U. Placental transfer of N-acetylcysteine following human maternal acetaminophen toxicity. J Toxicol Clin Toxicol 1997;35:447e51. 57. Riggs BS, Bronstein AC, Kulig K, Archer PG, Rumack BH. Acute acetaminophen overdose during pregnancy. Obstet Gynecol 1989;74:247e53. 58. Brooks RR, Feller CM, Maye JP. Acute fatty liver of pregnancy: a case report. AANA J 2002;70:215e7. 59. Corke PJ. Anaesthesia for caesarean section in a patient with acute fatty liver of pregnancy. Anaesth Intens Care 1995;23:215e8. 60. Holzman RS, Riley LE, Aron E, Fetherston J. Perioperative care of a patient with acute fatty liver of pregnancy. Anaesth Analg 2001;92:1268e70. 61. Thomas SD, Boyd AH. Prolonged neuromuscular block associated with acute fatty liver of pregnancy and reduced plasma cholinesterase. Eur J Anaesthesiol 1994;11:245e9. 62. Kucukemre F, Kunt N, Kaygusuz K, Kiliccioglu F, Gurelik B, Cetin A. Remifentanil compared with morphine for postoperative patient-controlled analgesia after
63.
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major abdominal surgery: a randomized controlled trial. Eur J Anaesthesiol 2005;22:378e85. Kostopanagiotou G, Markantonis SL, Arkadopoulos N, Andreadou I, Charalambidis G, Chondroudaki C, et al. The effect of acutely induced hepatic failure on remifentanil and fentanyl blood levels in a pig model. Eur J Anaesthesiol 2006;23:598e604. Moldenhauer JS, O’Brien JM, Barton JR, Sibai BM. Acute fatty liver of pregnancy associated with pancreatitis; a life-threatening complication. Am J Obstet Gynecol 2004;190:502e5. Koroshi A, Babameto A. Acute renal failure during acute fatty liver of pregnancy. Nephrol Dial Transplant 2002;17:1110e2. Ortiz JCT, Dapena MJC, Pampalona IP, Lopez LT, Roura LC. Acute fatty liver of pregnancy. J Matern Fetal Neonatal Med 2002;12:277e8. Amon E, Allen SR, Petire RH, Belew JE. Acute fatty liver of pregnancy associated with preeclampsia: management of hepatic failure with postpartum liver transplantation. Am J Perinatol 1991;8:278e9. Gill EJ, Contos MJ, Peng TC. Acute fatty liver of pregnancy and acetaminophen toxicity leading to liver failure and postpartum liver transplantation. A case report. J Reprod Med 2002;47:584e6. Rahman TM, Phillips M, Wendon J. Rare fatal complications of acute fatty liver of pregnancy. Crit Care 1999;3(Suppl. 1):186. Remiszewski P, Pawlak J, Skwarek A, Grzelak I, Patkowski W, Grodzicki M, et al. Orthoptic liver transplantation for acute liver failure resulting from acute fatty liver of pregnancy. Ann Transplant 2003;8:8e11. Ockner SA, Brunt EM, Cohn SM, Krul ES, Hanto DW, Peters MG. Fulminant hepatic failure caused by acute fatty liver of pregnancy treated by orthoptic liver transplantation. Hepatology 1990;11:59e64.
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REVIEW
Anaesthetic management of the pregnant patient with liver disease T.C. Collyer, S.P. Holbrook*, G. Lyons Department of Anaesthesia, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
s u m m a r y Keywords: Pregnancy Liver disease Anaesthesia Obstetric Anaesthetic techniques Regional Liver transplantation
The incidence of pregnant women with liver failure presenting for delivery is fortunately rare but presents a number of complex anaesthetic problems. Liver dysfunction in pregnancy may be the result of obstetric diseases or may simply be the result of liver disease occurring in a pregnant patient. Little is currently written to advise the anaesthetist about the management of these cases. Successful anaesthetic management not only requires an understanding of the causes but also the challenges that may be encountered perioperatively. Thorough pre-operative assessment, judicious use of regional anaesthesia, and multidisciplinary care in an appropriate environment is essential for an optimal maternal outcome. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction The overall incidence of acute liver failure during pregnancy is unknown but it is an important cause of mortality. The last three Confidential Enquiries into Maternal and Child Health (CEMACH) in the United Kingdom recorded 8 direct deaths as a result of acute fatty liver of pregnancy: thus giving a mortality rate of 1.3 per million maternities.1e3 CEMACH also recorded a further 17 direct deaths due to hepatic complications of pre-eclampsia during this period: including 2 as a result of hepatic rupture and 2 as a result of hepatic failure or necrosis. The most frequent causes of acute liver failure during pregnancy are viral hepatitis, paracetamol overdose, acute fatty liver of pregnancy and HELLP syndrome (Haemolysis, Elevated Liver enzymes and Low Platelet count).4 In addition, an exacerbation of a chronic liver disease may also present with a clinical picture indistinguishable from acute liver failure.5 An accurate diagnosis is crucial, as management is dependent on aetiology. Delivery of the foetus often helps reverse the liver diseases of late pregnancy, including acute fatty liver of pregnancy and HELLP syndrome. Conversely, delivery does not necessarily improve maternal outcome when acute liver failure is secondary to incidental causes such as viral hepatitis and drug overdose. The presentation of women with acute liver failure requiring caesarean section is rare but creates a number of complex problems for the anaesthetist. To aid management there are a number of reviews and case series on the medical management of acute fatty liver of pregnancy and a smaller number of articles on the medical
* Corresponding author. Tel.: þ44 1423 553559; fax: þ44 1423 553501. E-mail address: [email protected] (S.P. Holbrook). 2210-8440/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tacc.2011.02.003
management of chronic liver failure in pregnancy, but there is little guidance to inform anaesthetic practice.4,6e14 To remedy this we reviewed the issues important to the anaesthetic management of these complex and rare cases. 2. Liver dysfunction unique to pregnancy Liver dysfunction as a result of hyperemesis gravidarum and intrahepatic cholestasis generally follows a benign course. Whilst pre-eclampsia, HELLP syndrome and acute fatty liver of pregnancy have the potential for severe and possibly fatal complications. These disorders might represent a spectrum of disease, as there is considerable overlap in their clinical presentation. What is more important, with respect to their management, is the fact that they are potentially reversible. Early diagnosis and delivery of the foetus are central to successful management. Their potential for grave complications means that these patients require multidisciplinary input and may require intensive care. 2.1. Pre-eclampsia Pre-eclampsia is the occurrence of hypertension, proteinuria and oedema typically complicating the late second or third trimester. Endothelial dysfunction is thought to be the underlying pathophysiological process but a variety of mechanisms have been proposed. It occurs in 5e10% of pregnancies but severe cases may infrequently exhibit hepatic involvement.15,16 Hepatic aminotransferases are variably raised, but less so than in HELLP syndrome, and jaundice is unusual. Hepatic haemorrhage and subcapsular haematoma formation may arise. The latter is often associated with disseminated intravascular coagulation (DIC), but
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severe right upper quadrant pain, nausea and vomiting with grossly elevated aminotransferases should raise suspicions.4 Investigation with ultra-sound or MRI scan should be undertaken if the patient’s condition permits but the presence of concomitant shock may indicate hepatic rupture. This can occur at any time and is associated with a high maternal mortality.17 Emergency laparotomy under general anaesthesia may be the only option. As a rule, even haemodynamically stable patients should be managed in a critical care environment. Hepatic infarction does occur rarely but communication between the portal vein and the hepatic artery generally prevent this.4 2.2. HELLP syndrome HELLP syndrome complicates up to 0.6% of all pregnancies and occurs in up to 15% of patients with pre-eclampsia, but may occur in the absence of hypertension.18e20 Aetiologically it is thought to be the result of vascular endothelial damage and subsequent fibrin deposition in organ micro-vasculature. This process results in microangiopathic haemolytic anaemia, platelet consumption and end organ injury. Periportal hepatic fibrin deposition leads to areas of haemorrhage and necrosis. It typically presents in the third trimester but it may present mid-second trimester and in 25% it becomes evident postpartum.15 Patients may present with non-specific symptoms such as upper abdominal pain, nausea, vomiting, headache and malaise, with or without clinical features of pre-eclampsia. Again jaundice is infrequent. Laboratory evidence of haemolysis, raised aminotransferases, and thrombocytopaenia (platelet count < 100 109/L) points to the diagnosis of HELLP but haemolysis is not invariable (ELLP syndrome). Anaemia in the presence of blood stained or black urine (free haemoglobin in the urine) indicates severe haemolysis.21 Differential diagnoses to be considered include acute fatty liver of pregnancy, haemolytic uraemic syndrome, thrombotic thrombocytopaenic purpura, and systemic lupus erythematosus. There is significant risk to both the patient and the foetus as complications are common. Spontaneous and postpartum haemorrhage rank highly but others include placental abruption, acute respiratory distress syndrome, and acute renal failure.22 Hepatic problems again include hepatic haemorrhage and infarction, and rarely hepatic rupture. Immediate delivery is recommended if gestation is greater than 34 weeks or if there is evidence of foetal distress. In the stable patient at less than 34 weeks gestation, corticosteroid administration for 24e48 h may aid foetal lung maturity and may increase the platelet count.15 Blood products should be used to correct coagulopathy and anaemia, and ultrasound or MRI scanning may be required to verify pathology. Delay in the diagnosis of HELLP syndrome is considered to be a significant contributory factor in all-cause fatalities and because of the potential for severe complications it is advised that patients should be transferred to a tertiary referral centre at an early stage.19 On a final note it must be remembered that the patient may deteriorate postpartum: liver enzymes may continue to rise and the platelet count may continue to fall and may not demonstrate signs of recovery for 72 h or more after delivery.23,24 Critical care support should be sustained to ensure a favourable outcome. 2.3. Acute fatty liver of pregnancy Acute fatty liver of pregnancy is rare. Its reported incidence, based on case series or retrospective cohort studies, varies between 1 in 900 and 16000 deliveries.25e27 The most recent report from the United Kingdom Obstetric Surveillance System quoted an incidence of 1 in 20,000 maternities.28 It is reported to be associated with nullipara, twin pregnancies, and male foetus in a 3:1 ratio; in
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addition, up to 60% of cases may have co-existent pre-eclampsia.4e6 The aetiology is uncertain and it is thought to be due to defects in hepatic fatty acid oxidation pathways.29e31 However, the hepatic histopathological changes are non-specific and are found in a multitude of conditions (including pre-eclampsia).32 It typically presents during the third trimester with a 1e2 week prodrome of malaise, abdominal pain, nausea, vomiting, headache and jaundice. There are reports of cases presenting in the second trimester and postpartum. Pruritis and fever may also be present, as may symptoms and signs of pre-eclampsia. The diagnosis should be considered in any patient presenting with any of these symptoms. Hepatic aminotransferase levels are typically raised to a greater level than in pre-eclampsia and HELLP syndrome (mean aspartate aminotransferase level 278 iu/L, compared to 53 iu/L in preeclampsia, and 66 iu/L in HELLP syndrome).25 Other laboratory features include a neutrophil leucocytosis, DIC and anaemia. Laboratory features that may help distinguish it from HELLP include severe hypoglycaemia, hypocholesterolaemia, hypotriglyceridaemia and low antithrombin III levels.33 In addition, DIC, renal insufficiency, ascites and encephalopathy are more common. Ultrasound scan and MRI may be useful to confirm the diagnosis and will identify hepatic haemorrhage or infarction due to pre-eclampsia or HELLP syndrome. However, a negative scan does not exclude acute fatty liver of pregnancy and a definitive diagnosis may only be obtained through liver biopsy, contraindicated in the presence of coagulopathy. Early diagnosis and delivery of the foetus is crucial for a favourable maternal and foetal outcome. High dependency or intensive care should be given in a unit with access to specialist liver services. 2.4. Intrahepatic cholestasis Intrahepatic cholestasis occurs in up to 2% of pregnancies and it is the second commonest cause of jaundice in the pregnant patient (after viral hepatitis).4,34 It seems to be the result of both genetic and environmental factors that increase sensitivity to the normal sex hormone changes occurring during pregnancy. Familial cases have been reported in addition to a seasonal variation in some countries.4,15,34 Patients classically present with pruritis in the third trimester but it may occur earlier.15,34 Jaundice is variable and may only be evident in severe cases.15 Symptoms include anorexia, malaise, dark urine, abdominal pain and steatorrhoea. Mild elevations in serum aminotransferases, alkaline phosphatase and conjugated bilirubin occur, but measurement of bile acid levels is the only specific laboratory test that will aid the diagnosis.4 Imaging of the liver is normal and the diagnosis is usually made on clinical grounds and through laboratory exclusion of other causes, such as screening for viral hepatitis. Management should be aimed at relieving pruritis and minimising risk to the foetus: there is an increased risk of premature labour, foetal distress, and sudden intrauterine death.35,36 The severity of pruritis and the foetal risks increase as gestation progresses. There is no way of identifying the at-risk foetus therefore delivery should be expedited as soon as foetal lung maturity has been attained. Pruritis typically resolves immediately after delivery but ursodeoxycholic acid or dexamethasone may be used to alleviate pruritis without risk to the foetus.37e39 The prognosis for the mother is generally good but intrahepatic cholestasis recurs in subsequent pregnancies in up to 70% of cases.36 2.5. Hyperemesis gravidarum Hyperemesis gravidarum is defined as severe nausea and vomiting with resultant dehydration and the need for intravenous
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fluid resuscitation. It occurs in 0.2e30 women per 1000 pregnancies.40,41 The aetiology is unclear but is probably multifactorial with genetic, hormonal, and environmental factors purporting to play a role.4,41 Those at risk include multiparous patients, and those with multiple pregnancy or gestational trophoblastic disease.41 It presents during the first trimester and is accompanied by elevations in serum aminotransferases in 15e25% of hospitalised patients, though the severity of the biochemical disturbance is highly variable.4,41 Management requires hospitalisation and treatment with antiemetics plus fluid and electrolyte replacement. Promethazine, prochlorperazine, chlorpromazine and metoclopramide are most frequently used, with steroids and ondansetron reserved for refractory cases. These measures usually lead to normalisation of hepatic enzymes, although enteral feeding with vitamin supplementation may be required and even parenteral nutrition may even be required in the most severe cases. 3. Non obstetric causes of liver disease These can broadly be divided into pregnant patients with coincidental causes of liver dysfunction, such as viral hepatitis, and those with chronic liver disease who subsequently become pregnant. Any cause of acute liver failure can present in pregnancy and likewise any disorder leading to chronic liver disease may occur in the pregnant patient. Patients with compensated cirrhosis and mild portal hypertension may still achieve a successful pregnancy. Management of complications is similar to the non-pregnant patient but requires intensive multidisciplinary care. We shall explore viral hepatitis and gallstone disease here and highlight specific management issues relating to chronic liver disease in the subsequent section. 3.1. Viral hepatitis The most frequent cause of jaundice in pregnancy is viral hepatitis.4,42 Acute liver failure is a rare consequence of all the Hepatitis viruses with only 0.2e4% developing severe disease overall: Hepatitis E and B are most frequently the cause.43 Hepatitis as a result of infection with herpes viruses (cytomegalovirus (CMV), EpsteineBarr virus (EBV), and Herpes Simplex Virus (HSV)) is extremely rare, however HSV has a propensity for causing severe disease in the pregnant patient. They may present in any trimester and the presenting symptoms are non-specific. Diagnosis frequently relies on a thorough assessment of the patient’s history and viral serology. Management varies little from that of the non-pregnant patient. In the presence of acute liver failure the potential for complications (such as postpartum haemorrhage) is high. In women with HSV early diagnosis and commencement of aciclovir is crucial for a favourable outcome, however mortality is in excess of 90% even with therapy.44 EBV infection is generally benign and CMV infection is only problematic in the immunosuppressed patient, with reports of biliary strictures and acalculous cholecystitis.44 3.2. Cholelithiasis Gallstone disease is second only to acute appendicitis in terms of non-obstetric conditions requiring surgery. The presentation is typical and the differential diagnosis includes any cause of cholestasis. Management is generally conservative with surgery being reserved for severe unresponsive cases. Cholecystectomy has been reported for acute cholecystitis in approximately 1 per 1000 deliveries.4 In terms of risk to the foetus, surgery should be preferably being undertaken during the second trimester: there is an increased risk of spontaneous abortion in the first trimester and
premature labour in the third.45,46 Laparoscopic cholecystectomy can be undertaken safely in the second trimester, but is obviously technically difficult in the last trimester. However, symptoms are frequently recurrent and laparoscopic cholecystectomy has been performed with caesarean section.47 4. Anaesthetic management 4.1. Pre-operative assessment 4.1.1. Liver dysfunction and coagulopathy The degree of liver dysfunction is most accurately monitored by the prothrombin time (PT), which should be performed at least once daily. If the PT is high, without overt signs of bleeding, fresh frozen plasma should not be given routinely as outcome is not improved and interpretation of the prothrombin time is then difficult. The pre-operative assessment of the coagulation profile should be conducted as close as possible to the time of surgery given the progressive nature of acute liver failure. In addition to the PT and international normalized ratio (INR) measurements should include an activated partial thromboplastin time (APTT) plus a fibrinogen and platelet level. Where significant coagulopathy or thrombocytopaenia exists, assessment of the whole blood coagulation profile by thromboelastography (TEGÒ) can provide useful additional information. TEGÒ enables a global assessment of haemostatic function from a single blood sample and documents the interaction of platelets, clotting factors and fibrin. The stages of coagulation from the initial platelet fibrin interaction and platelet aggregation, through to clot strengthening and fibrin cross linkage, with eventual clot lysis, are both graphically and numerically represented.48 This may help to guide blood product requirements but in addition, in our experience, has helped guide the use of regional anaesthetic techniques in obstetric patients. However, this is controversial. Further assessment of liver dysfunction includes daily measurement of liver enzymes and 1e4 hourly assessment of serum glucose: this is dependent on the patient’s clinical condition. Hypoglycaemia remains a common cause of maternal morbidity, especially in acute fatty liver of pregnancy.7 A centrally placed venous catheter is desirable for the provision of hypertonic glucose infusions in cases of severe and persistent hypoglycaemia to avoid thrombophlebitis. 4.1.2. Renal dysfunction Renal insufficiency may complicate acute liver failure and a careful assessment of renal function and fluid balance is required. Hyponatraemia may aggravate cerebral oedema but should be rectified slowly: the optimal rate is controversial. Urea levels may be misleadingly low because of impaired hepatic synthesis. Serum creatinine levels and creatinine clearance are the best monitors of renal function. The presence of renal impairment may indicate renal hypoperfusion secondary to circulatory failure or hepatorenal syndrome. Fluid balance can be difficult to assess, especially in the presence of hypoalbuminaemia, ascites and peripheral oedema. Pleural effusions due to fluid retention and diaphragmatic splinting, secondary to ascites and a gravid uterus, may lead to hypoxaemia and respiratory failure. Maintaining strict daily fluid balance charts and monitoring weight daily aid fluid balance. Central venous pressure trends should be monitored, as specific values are unreliable, unless coagulopathy precludes central venous catheterisation. A fluid volume load may help identify the cause of renal impairment, but patients may require renal replacement therapy to control fluid balance and malignant electrolyte disturbances, such as hyperkalaemia.49 Consideration must also be given to the influence of renal impairment and fluid status
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when selecting intravenous anaesthetic agents and neuromuscular blockers, and when calculating analgesic doses.
and therefore the timing of delivery is dictated by the progress of the mother and foetus.
4.1.3. Encephalopathy The presence of encephalopathy is important both prognostically and for planning of anaesthetic technique. Encephalopathy may be the result of hypoglycaemia, gastrointestinal bleeding, concurrent infection, constipation or cerebral oedema and all causes should be actively sought. Grade 3 and 4 encephalopathy are associated with up to 80% mortality and will usually require preoperative intubation and ventilation to protect the airway and maximize oxygenation.49 Any disruption in cognitive ability may prohibit the use of a regional anaesthetic technique. Cerebral oedema is a significant factor in the pathogenesis of hepatic encephalopathy and intracranial pressure (ICP) monitoring may improve outcome, although a raised ICP does not necessarily equate with the degree of encephalopathy.49 Mannitol may be utilised as first line therapy in the management of intracranial hypertension but a standard dose cannot be recommended: lower doses (0.25e0.5 g/kg boluses) may avoid dehydration and severe electrolyte and osmotic disturbances.50
4.3. Premedication
4.1.4. Infection Risk from infection is increased in liver failure and strict asepsis must be maintained at all times.7 When sepsis occurs it can be complicated by similarities in the clinical picture of sepsis and acute liver failure and a low index of suspicion is necessary. Low-grade fever and leukocytosis are unreliable markers of infection and microbiological cultures and analysis should be performed on sputum, blood, urine and peritoneal aspirate.6 4.1.5. Additional investigations Pre-operative investigations should also include an electrocardiogram and arterial blood gas analysis. Metabolic alkalosis and acidosis may occur in acute liver failure but an arterial pH less than 7.3 predicts a poor prognosis in paracetamol-induced acute liver failure and increases the likelihood of liver transplantation.43 An abdominal ultra-sound scan (see above) and transthoracic echocardiography may provide additional useful information. The latter is increasingly being utilised by intensivists as a non-invasive bedside tool to assess a patient’s left ventricular function and volaemic status. 4.1.6. Consideration of patients with known chronic liver disease Patients with acutely decompensated liver function on a background of known advanced liver cirrhosis with portal hypertension, require special consideration when planning surgery and anaesthesia. Abdominal surgery can be technically difficult due to the large collateral circulation and preparation for potentially significant blood loss is necessary.51 The risk of spinal haematoma, in the setting of raised portal venous pressure, collateral circulation, and coagulopathy, must be considered carefully when using regional anaesthetic techniques, though they are not an absolute contraindication.51,52
4.2. Timing of surgery The timing of surgery should be a multidisciplinary decision and should occur at the best time, in the best place and with the best team. When acute liver failure is secondary to acute fatty liver of pregnancy or severe HELLP syndrome, a rapid improvement in liver function is seen following delivery and argues strongly for induction of labour, or delivery by caesarean section.7 Acute liver failure secondary to other causes is unlikely to be influenced by delivery
4.3.1. N-Acetylcysteine The use of N-acetylcysteine (NAC) to prevent hepatotoxicity secondary to paracetamol overdose is widespread and well documented.53 It’s use is safe and effective during pregnancy for the management of paracetamol toxicity.54,55 Case series have established that there is placental transfer of NAC with no harmful effects suffered by the infant, and that delays in the treatment with NAC can result in an increased incidence of spontaneous abortion or foetal death.56,57 The evidence for the use of NAC in acute liver failure secondary to other causes is less convincing but should always be considered after discussion with a hepatologist. 4.3.2. Blood products In the presence of coagulopathy pre-operative transfusion of fresh frozen plasma (15 ml/kg) is advisable as well as the administration of parenteral vitamin K. Additional blood products available should include platelets and cryoprecipitate. Complete correction is probably unachievable but an INR 1.5, platelet count of 50,000/mm and a fibrinogen level 100 mg/dL are realistic goals.50 Recombinant factor VIIa should only be considered in the context of an invasive procedure with a high risk of bleeding and when these other constituents are replete.50 The procedure should be performed within 60 min of administration.50 Obviously transfusion requirements will vary between patients and a consultant haematologist should be actively involved throughout, especially where complex coagulopathies exist. 4.4. Anaesthetic technique The risks associated with general anaesthesia for caesarean section were emphasised in the last two CEMACH reports.2,3 A prolonged PT and thrombocytopaenia will necessitate caution when considering a regional technique but performance of TEGÒ may prove a useful adjunct in making this decision. Reviewing the literature we found a single case report using an epidural catheter to provide anaesthesia for caesarean section in a patient with acute fatty liver of pregnancy, and four case reports employing general anaesthesia, one of which highlighted the potential risk of suxamethonium apnoea.14,58e61 Post-operative analgesia must be considered and the risks of intravenous opioid use emphasised. There is an increased risk of opioid toxicity and precipitation of hepatic encephalopathy, especially in the context of renal failure. Patient controlled analgesic (PCA) systems employing remifentanil or fentanyl should be used: the clearance of morphine and alfentanil is reduced in liver failure. There is increasing support for the use of Remifentanil PCA for labour analgesia and it has been used successfully after major abdominal surgery in patients with normal liver function.62 However, an animal study demonstrated that both fentanyl and remifentanil clearance is reduced in acute hepatic failure, if administered by continuous intravenous infusion.63 Remifentanil’s metabolism may not be completely independent of hepatic metabolism. Ultimately regional techniques will provide superior post-operative analgesia. 4.5. Post-operative complications A multitude of complications have been reported in the postoperative period including hepatic failure, acute renal failure, acute respiratory distress syndrome, pancreatitis, severe uterine and gastrointestinal bleeding and sepsis.26,27,58,64e66 Post-operative
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care of the mother and baby should accordingly be in an environment affording a higher level of care, such as a high dependency or intensive care unit. 5. Liver transplantation In all cases of postpartum liver transplantation, maternal morbidity and mortality remains high. However, successful outcomes have been reported in a variety of conditions.4 Postpartum orthoptic liver transplantation for acute fatty liver of pregnancy has met with variable success rates.67e71 Castro et al. advise the use of caution when considering liver transplantation because of the reversible nature of the disease. They argue that whilst these patients frequently exhibit clinical and laboratory deterioration, initially requiring specialist intensive support, they ultimately recover their liver function.7 Transplantation should only be considered for emergency cases of severe hepatic failure and requires close coordination between the obstetric, transplant, neonatal, anaesthetic and intensive care teams to ensure optimal maternal and foetal outcomes.4 6. Summary The presentation of women with liver failure requiring caesarean section remains thankfully rare. Early diagnosis and treatment in a tertiary referral centre under the care of a multidisciplinary team can improve maternal outcome.4 Careful pre-operative anaesthetic assessment and planning allows many of the potential complications to be anticipated and managed early. The choice of anaesthetic technique is determined by the clinical state of the patient but where possible a regional anaesthetic technique is desirable. The role of the anaesthetist extends throughout the patients stay and includes active involvement in the management of many of the potential post-operative complications. Conflict of interest statement None. References 1. Department of Health. Scottish Executive Health Department, and Department of Health, Social services and Public safety, Northern Ireland. Why mothers Die. The Fifth report on Confidential Enquiries into maternal deaths in the United Kingdom, 1997e1999. London: RCOG Press; 2001. 2. Lewis G, editor. Confidential Enquiries into maternal and Child Health. Why mothers Die. The Sixth report of the United Kingdom Confidential Enquiries into maternal deaths in the United Kingdom. London: RCOG Press; 2004. 3. Lewis G, editor. The Confidential Enquiry into maternal and Child Health (CEMACH). Saving mothers’ Lives: reviewing maternal deaths to make motherhood safer e 2003-2005. The Seventh report on Confidential Enquiries into maternal deaths in the United Kingdom. London: CEMACH; 2007. 4. Fagan EA. Disorders of the liver, biliary system and pancreas. In: De Swiet M, editor. Medical disorders in obstetric practice. 4th ed. Blackwell Science; 2002. p. 282e345. 5. Pereira SP, O’Donohue J, Wendon J, Williams R. Maternal and perinatal outcome in severe pregnancy-related liver disease. Hepatology 1997;26: 1258e62. 6. Pockros PJ, Peters RL, Reynolds TB. Idiopathic fatty liver of pregnancy: findings in ten cases. Medicine (Baltimore) 1984;63:1e11. 7. Castro MA, Fassett MJ, Reynolds TB, Shaw KJ, Goodwin TM. Reversible peripartum liver failure: a new perspective on the diagnosis, treatment and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J Obstet Gynecol 1999;181:389e95. 8. Knox TA, Olans LB. Current concepts: liver disease in pregnancy. N Engl J Med 1996;335:569e76. 9. Lee WM. Pregnancy in patients with chronic liver disease. Gastroenterol Clin North Am 1992;21:889e903. 10. Sternlieb I. Wilson’s disease and pregnancy. Hepatology 2000;31:531e2 [comment]. 11. Swanson J, Scioscia E. Hepatic disease. In: Datta S, editor. Anesthetic and obstetric management of the high-risk pregnancy. Mosby; 1996. p. 558e73.
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