Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Is life worth living? It depends on the liver by Dr Stephen Warrillow

352 views

Published on

Management of the patient with decompensated liver disease is clearly more straightforward in specialist centres with multi-disciplinary input, access to liver transplantation teams and advanced technology. Bioartificial extra-corporeal liver support systems are undergoing evaluation and include the extra-corporeal liver assist device (ELAD developed by Vital Technologies).

ELAD is an investigational, extra-corporeal, human cell-based system. The human liver-derived cells (VTL C3A) may mimic certain functions of in vivo human liver cells. The principles of operation of the ELAD system are as follows: plasma ultrafiltrate is passed through hollow fibre cartridges containing human liver-derived cells (VTL C3A cells) and allowing two-way transfer of toxins, metabolites and nutrients, mimicking liver function. Toxins, such as bilirubin, glucose and oxygen pass from the ultrafiltrate to the VTL C3A cells. Treated plasma ultrafiltrate is then reconstituted with blood cells and returned to the patient. Data evaluating this system shows trends indicating a potential for ELAD to increase survival rates in selected patients with decompensated liver failure.

Issues in the management of liver failure include cardiorespiratory support, and the management of cerebral oedema. The principles for haemodynamic support are as for most critically ill patients, with early restoration of organ perfusion and use of vasopressors if hypotension persists despite restoration of volume. For the patient with liver failure, lactate-containing solutions and fluid overload should be avoided. New monitoring techniques for encephalopathy have been developed, including brain tissue oxygen tension, continuous EEG, transcranial Doppler and cerebral microdialysis.

Key issues for regional centres are basic management principles, liaison with specialist centres and timing of transfer. Who and when to refer is a difficult problem for the regional Australasian unit, given the tyranny of distance and issues relating to retrieval and transfer of the critically ill patient. Early liaison with the regional liver unit is key.

Published in: Health & Medicine
  • Be the first to comment

Is life worth living? It depends on the liver by Dr Stephen Warrillow

  1. 1. Critical Care Hepatology Is life worth living? It all depends on the liver. - William James Stephen Warrillow FRACP FCICM Grad Cert Emerg Health (Aeromedicine & Retrieval) Director, Department of Intensive Care Austin Health, Melbourne, Australia Senior Lecturer and Research Fellow, The University of Melbourne
  2. 2. Austin Health • University Teaching Hospital founded as a ‘hospital for incurables’ in 1882 • Serves North-Eastern suburbs of Melbourne • Affiliated with The University of Melbourne • All major medical & surgical specialties • State Liver Transplant Centre
  3. 3. Scope The Liver in ICU: A sprint through critical care hepatology with tips and tricks • Acute Liver Failure • Decompensated Chronic Liver Disease • Weirdly abnormal LFTs in ICU • Liver injury in MOFS • Ischaemic hepatitis • Liver Transplantation • Hepatic Disorders of Pregnancy • Malignant hepatic infiltration A truly miraculous and transformative intervention that helps maintain one’s essential ‘incurable optimism’
  4. 4. ICU APPROACH TO ALF
  5. 5. Acute Liver Failure • Also known as Fulminant Hepatic Failure (FHF) • No pre-existing liver disease – first symptom to encephalopathy < 8 weeks • Presence of Hepatic Encephalopathy + Derangements of measured clotting parameters +/- Haemodynamic instability +/- Renal failure +/- Severe metabolic disturbance +/- Susceptibility to infection
  6. 6. Fulminant Hepatic Failure • Hyper-acute: Jaundice - Encephalopathy < 8 days • Acute: Jaundice - Encephalopathy 8-28 days • Sub-acute: Jaundice - Encephalopathy > 28 days Acute Liver Failure
  7. 7. Aetiology (in ANZ) • Paracetamol, paracetamol, paracetamol……. • Viral Hepatitis: HAV, HBV, CMV, HSV, VSV, HEV • Idiopathic (actually viral?) • Idiosyncratic drug reactions, herbal medicines • Miscellaneous: – Amanita mushrooms, Wilson's, Budd-Chiari, Autoimmune, Pregnancy-related • Ischaemic • Malignancy
  8. 8. • Cerebral oedema and elevated intra-cranial pressure (ICP) – Cerebral oedema occurs in the majority of patients with grade three or four encephalopathy and is a major cause of death – Oedema formation is secondary to marked hyperaemia and cytotoxic processes » Ammonia seems to be an important player – Can progress suddenly • Cerebral oedema and elevated intra-cranial pressure (ICP) – Cerebral oedema occurs in the majority of patients with grade three or four encephalopathy and was once major cause of death – Oedema formation is secondary to marked hyperaemia and cytotoxic processes » Ammonia seems to be an important player – Can progress suddenly • Sepsis (particularly G- and fungal). – Infection is a major cause of death in patients with FHF – High risk of overwhelming gram negative and fungal sepsis Key Management Problems
  9. 9. Key Management Problems • Complex coagulopathy/pro- thrombotic state • Renal failure • Vasodilatory shock • Fluid and electrolyte management
  10. 10. Haematological Issues in Liver Failure • ↑PT, ↑INR, ↓platelets, ↓fibrinogen (differentiating from DIC may be hard) • INR on its own is a poor guide to bleeding risk in liver failure • ↑APTT and ↓↓platelets probably does predict risk of bleeding • If not bleeding and no invasive procedures are planned, avoid clotting factor administration if INR <5(?) • Vitamin K is OK for all patients with liver failure • If giving clotting factors, use FFP, rather than prothrombin concentrates e.g. prothrombinX • Be alert to potential thrombotic complications – PV thrombosis, DVT, PE, stroke
  11. 11. 4H THERAPY Practical Strategies for Preventing Neurological Deaths in ALF
  12. 12. A Key Management Problem in Severe ALF • Cerebral oedema and elevated intra-cranial pressure (ICP) – Cerebral oedema occurs frequently with high grade encephalopathy and remains a major cause of death if not managed well – Can progress suddenly and occur even during or immediately after OLTx – No single effective therapy and management approaches are often institution specific1 – Many of the usual clinical guides are hard to assess in the critically ill CT on admissionCT day 4 1. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: Recommendations of the U.S. Acute Liver Failure Study Group. Critical Care Medicine 2007;35:2498-508
  13. 13. Pathophysiology of Cerebral Oedema in ALF A mix of two processes • Cytotoxic cerebral oedema1 – Metabolic/Toxic injury to astrocytes results in swelling • Vasogenic cerebral oedema2 – Loss of normal autoregulation of cerebral blood flow – Hyperaemia and disruption of the BBB such that plasma constituents seep into the brain parenchyma 1. Tofteng F, Hauerberg J, Hansen BA, Pedersen CB, Jorgensen L, Larsen FS. Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure. J Cereb Blood Flow Metab 2006;26:21-7 2. Durham S, Yonas H, Aggarwal S, Darby J, Kramer D. Regional cerebral blood flow and CO2 reactivity in fulminant hepatic failure. J Cereb Blood Flow Metab 1995;15:329-35
  14. 14. Development of Hyperammonaemia in ALF • Hepatic processing of ammonia extremely efficient (≈85%) • Minimal extra-hepatic metabolism (≈15%) – Skeletal muscle – Brain • Hyperammonaemia is a hallmark of severe liver failure • Renal failure further reduces ammonia excretion Warrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver failure; the case for quadruple-H therapy. Anaesth Intensive Care 2014:42:78-88
  15. 15. Ammonia & Glutamine Cytotoxic Hypotheses Ammonia is neuro-cytotoxic: – induces membrane depolarisation – increases calcium influx – interferes with neurotransmitter release – causes glutamate release (contributes to osmotic drag) – activates lipases & proteases – increases production of free radicals – induces neuronal protein nitration – causes mitochondrial damage Warrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver failure; the case for quadruple-H therapy. Anaesth Intensive Care 2014:42:78-88
  16. 16. Why no Cerebral Oedema in CLD? Why doesn’t cerebral oedema occur in cirrhotic patients with hyperammonaemia? – Astrocytes have sufficient time to adapt to higher levels of ammonia and the cytotoxicity is attenuated markedly – Systemic inflammation is less – Cerebral hyperaemia does not occur
  17. 17. Management of Cerebral Oedema in ALF • Accumulating evidence that cerebral oedema in severe ALF can be effectively managed • No evidence of benefit from ICP monitoring1,2 Now no reason to place ICP monitors? 1. Vaquero J, Fontana RJ, Larson AM, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2005;11:1581-9. 2. Keays RT, Alexander GJ, Williams R. The safety and value of extradural intracranial pressure monitors in fulminant hepatic failure. Journal of hepatology 1993;18:205-9.
  18. 18. 4H Components 1. Hyperventilation (Mild) 2. Hypernatraemia 3. Haemo(dia)filtration 4. Hypothermia (Mild)
  19. 19. (Mild) Hyperventilation • Ensure mechanical ventilation provides a minute volume sufficient to achieve a low normal PaCO2 (PaCO2 32-35 mmHg)1 or similar level to that achieved by the patient prior to intubation • Monitor with frequent ABG and EtCO2 monitoring • Reserve extreme hyperventilation for use as a recue therapy2 whilst awaiting imminent transplantation 1. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: Recommendations of the U.S. Acute Liver Failure Study Group. Critical Care Medicine 2007;35:2498-508 2. Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. Hepatology 2012;55:965-7.
  20. 20. Hypernatraemia • An ‘osmotherapy’, largely reliant on an intact BBB to be effective • Creates an osmotic gradient which favours egress of water from brain tissue to the circulation • Also expands circulating volume with minimal total volume of fluid administration • Better than other osmotherapies? – Therapeutic hypernatraemia seems safe1 – Theoretically safer than mannitol? (does not accumulate in brain tissue) – At least as effective as mannitol? 1. Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2004;39:464-70
  21. 21. Hypernatraemia • How? – Continuous infusion using syringe driver of 20% NaCl via dedicated CVC lumen – Target serum sodium of 150 mmol/L (148-155 mmol/L) – Monitor serum sodium on regular blood gas analysis »Preferably every hour – Beware fluctuations during initiation of RRT
  22. 22. Haemo(dia)filtration • Continuous Renal Replacement Therapy provides a range of potential benefits in setting of FHF – Effective reduction in ammonia concentrations – Intervention for Acute Renal Failure (almost universal in severe ALF) » Manages fluid balance » Manages electrolyte disturbance » Corrects Acid-Base derangement » (Uraemia)
  23. 23. RRT and Ammonia Clearance CRRT is remarkably effective at ammonia clearance1 • similar kinetics to urea clearance Ammonia level 0 200 400 600 800 1000 0 5 10 15 20 25 30 48 Time (hours) Plasmaammonia(mcg/l) dialysis started CVVH started dialysis started 1. Licari E, Calzavacca P, Warrillow SJ, Bellomo R. Life-threatening sodium valproate overdose: a comparison of two approaches to treatment. Critical care medicine 2009;37:3161-4.
  24. 24. Managing CRRT in Severe ALF • Start early and keep to an even daily fluid balance • Aim for near normal blood ammonia levels (<60 μmol/L) • Mode probably doesn’t matter a lot: – Haemofiltration vs Diafiltration → probably not a big deal – Diffusive clearance might provide better ammonia clearance • Anticoagulation often unnecessary if good flows and 50% of replacement fluid given as pre-dilution (for CVVH), or consider prostacyclin + low dose heparin • Turn heater off and use circuit for temperature management • Run fairly high blood flows (>250 ml/min) • Try to achieve exchanges of plasma water of 40-50 ml/kg/hr
  25. 25. Pitfalls of Managing CRRT in ALF • Starting too late – Do not wait for usual indications associated with ARF • Not lowering the ammonia sufficiently • Not providing truly continuous RRT • Not achieving satisfactory blood flow – Circuit clotting/failure • Not managing electrolyte status – Especially sodium, potassium, phosphate and magnesium • Anticoagulant management issues
  26. 26. (Mild) Hypothermia • Multiple animal and small clinical studies studies demonstrating benefit • Suggested mechanisms1 – Reduced CBF/hyperaemia – Reduced cerebral ammonia uptake – Neuro-inhibitory – Lowers glutamate production – Anti-inflammatory effects within the CNS • Target Temperature- 35°C – Most of benefit achieved with mild reductions in temperature?2 – Problems with lowering core temperature further ↓Vasogenic oedema ↓Cytotoxic oedema 1. Warrillow SJ, Bellomo R. Preventing cerebral oedema in acute liver failure; the case for quadruple-H therapy. Anaesth Intensive Care 2014:42:78-88 2. Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis 2003:23:271-82
  27. 27. DECOMPENSATED CLD
  28. 28. Decompensated CLD • Regardless of the cause, advanced chronic liver disease/cirrhosis results in fragile patients with complex multisystem problems • Decompensation is common and frequently results in critical illness that may necessitate ICU admission
  29. 29. Consequences of Advanced Cirrhosis • Encephalopathy • Coagulopathy • Cachexia – Sarcopenia – Nutritional deficits • Immunosuppression • Portal HT – Varices – PHT gastropathy – Hypersplenism – Ascites
  30. 30. Complications of Advanced Cirrhosis • Variceal Haemorrhage • Encephalopathy • Renal Failure – HRS I and HRS II – Other causes • Sepsis/Septic Shock – Especially from SBP • Hepatopulmonary syndrome • Portopulmonary hypertension
  31. 31. Variceal Haemorrhage • Often dramatic and often fatal • Amount of bleeding quite variable, but generally brisk • Prognosis closely associated with severity of liver disease and associated organ failure
  32. 32. Variceal Haemorrhage- Resuscitation • Wide-bore IV access • Blood and clotting factors – Prepare for massive transfusion • Give iv ABx e.g. ampicillin & ceftriaxone • Endoscopic banding is the optimal approach • Balloon tamponade can buy time until endoscopist arrives
  33. 33. Variceal Haemorrhage- Drug Therapy • Always in combination with other measures – Intention is to reduce portal pressures and blood flow • Vasopressin (0.2-0.4 Units/min) • Terlipressin a good alternative – Both may also improve systemic arterial pressure • Somatostatin or analogue e.g. octreotide
  34. 34. Balloon Tamponade • SSB (three lumen) or Minnesota Tube is a means of achieving temporary control when other measures have failed • Correct insertion technique important • Only gastric balloon usually needs to be inflated • Traction very important- usually 0.5 kg • High risk of complications – especially after 24 hours
  35. 35. TIPS • Transjugular intrahepatic portosystemic shunt – Requires and experienced interventional radiologist who can achieve >90% success rate • Portal pressures reliably reduced and effectively controls variceal bleeding • Does not prevent subsequent OLTx • Reserved for instances where other measures have failed
  36. 36. Traps in Variceal Bleeding • Sepsis a common complication • Encephalopathy almost always ensues • Many patients are beta-blocked • Risks of over-transfusion causing rebound in portal pressures • Delayed re-bleeding
  37. 37. Spontaneous Bacterial Peritonitis • Important to consider especially when site of infection not obvious • Need to have a high index of suspicion • Undertake diagnostic taps as part of septic work-up – Look at Gram stain and WCC >250 x 106 /l • Always start broad spectrum gram negative cover – Beta-lactams preferred • Usually gram negatives, especially E. coli and enterococcus spp. (n.b. CLD patients often harbour VRE)
  38. 38. Hepatic Encephalopathy • Pathophysiology complex and incompletely understood • Failure to achieve hepatic clearance of various substances – Ammonia – Mercaptans – False neurotransmitters
  39. 39. Hepatic Encephalopathy Grading system (West-Haven) 0 Normal 1 Confusion- flap often present 2 Drowsiness- foetor sometimes present 3 Somnolent 4 Coma • GCS might be a better system for ICU because we’re more familiar with it • Correlation between ammonia levels and degree of encephalopathy is not great, but still useful
  40. 40. Precipitants • Stopping medications • Sedatives • Protein loads in gut (especially blood) • Electrolyte and pH abnormalities (especially from loop diuretics) • Infection (e.g. UTI, SPB, pneumonia etc) • Constipation • Alcohol • New shunt (e.g. post-TIPS, but may be spontaneous)
  41. 41. Hepatic Encephalopathy • Correction of precipitants • Avoid sedation • Treat infection • Protect airway • Lactulose – fairly safe and probably effective – reduces ammonia production and absorption • Non-absorbable antibiotics (e.g. rifamixin) • BCAA?- probably no additional benefit if on other treatments • CRRT?- maybe, but usually only if also in significant renal failure
  42. 42. Renal Failure in Cirrhosis • When is it HRS? • When is it not HRS? • Does it really change the management? A key consideration is whether the patient is a transplant candidate….. What are the goals of care?
  43. 43. HRS I • Rapid onset – Doubling of Cr to greater than 221 µmol/l in two weeks • Absence of – Hypovolaemia – Infection – Nephrotoxins – Other explanations for renal failure (e.g. GN) • No improvement after stopping diuretic and giving fluid • Not nephrotic or nephritic • Very low urinary sodium <10mmol/l HRS II • Slowly progressive • Strongly associated with presence of significant ascites
  44. 44. HRS Management • Treat reversible precipitants • Albumin • Vasopressors – Terlipressin (used for suitably trained ward staff or home- based care) – Noradrenaline (restricted to the ICU) • Treat for likely sepsis (although definition excludes this) • Tap ascites – avoid massive fluid shifts that produce intravascular volume depletion
  45. 45. Thank you Mt Feathertop and the Razorback, Victorian Alps
  46. 46. HEPATIC DISEASE IN PREGNANCY
  47. 47. Liver Disease and Pregnancy • Acute Fatty Liver of Pregnancy • HELLP • Viral Hepatitis • Intrahepatic Cholestasis of Pregnancy • Liver Rupture • Cirrhosis
  48. 48. AFLP • 1 per 10 000 pregnancies • 2nd or, (more commonly) 3rd trimester • More common in older primips and assoc with pre- eclampsia • Assoc with 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency • A microvesicular steatohepatisis – Histology looks like valproate and Reye’s syndrome
  49. 49. AFLP • Symptoms of liver failure occur over days to weeks • ARF in 50% • Encephalopathy in 60% • Clinical syndrome c/w pre-eclampsia in 50% • Liver biopsy reveals microvesicular steatosis, fat droplets surrounding a centrally placed nucleus (rarely done!)
  50. 50. AFLP • Delivery is the definitive treatment – Usually caesarean (75% are pre-term with assoc issues) • All infants of mothers with AFLP are tested for defects in fatty acid oxidation because prompt recognition and treatment can decrease mortality and morbidity • Mortality previously reported as high as 70%, but now less than 15% • Full recovery is expected, but may occasionally take months
  51. 51. Haemolysis, elevated liver enzymes, and low platelets (HELLP) • Usually as a complication of pre-eclampsia • Affects 1-6 per 1,000 pregnancies and 4-12% of patients with severe preeclampsia • 70% present before delivery • 30% develop in the postpartum period
  52. 52. HELLP • Caused by several mechanisms combining to cause, – Haemolysis – Liver necrosis – Thrombocytopenia • Initial source of the insult is unknown • Evidence of endothelial injury with fibrin deposit that causes a microangiopathic hemolytic anemia and platelet activation and consumption • Fibrin deposits cause obstruction in the hepatic sinusoids, which leads to areas of haemorrhage
  53. 53. HELLP • Clinical presentation – Right upper quadrant or epigastric pain – Nausea and vomiting, malaise – Nonspecific viral-like symptoms – Headache (30-60%) – Visual disturbance – Hypertension and proteinuria are common, as most of the patients have preeclampsia • Ix show elevated ALT, elevated LDH, low haptaglobin thrombocytopenia and an abnormal blood film
  54. 54. HELLP • Definitive management if foetal delivery • Management as per pre-eclampsia care – Magnesium sulphate infusion • Maternal mortality around 1% • Complications: – pulmonary oedema – ARF – DIC – abruptio placenta – liver heamorrhage, failure or rupture – acute respiratory distress syndrome – stroke
  55. 55. Intrahepatic Cholestasis of Pregnancy • Approx 1 per 1000 pregnancies • Almost always in third trimester • Geographic/Racial variation • Risk factors include: – advanced maternal age – Multiparity – personal or family history of the disease – history of cholestasis while taking OCP
  56. 56. Intrahepatic Cholestasis of Pregnancy • ICP is due to abnormal biliary transport resulting in saturation of the hepatic transport system • Recurrent familial ICP likely to be a heritable defect in the multidrug resistance 3 (MDR3) gene, which encodes for a canalicular phospholipid translocator involved in bile duct secretion of phospholipids – 15% of cases?? • Female sex hormones important – Almost all cases are seen in the third trimester, when oestrogen levels are rising – oestrogens are known to be cholestatic, and administration to nonpregnant women with a history of ICP has been shown to induce signs of cholestasis
  57. 57. Intrahepatic Cholestasis of Pregnancy • Clinical presentation – generalized pruritus that begins in the periphery, often worse on the palms and soles, and moves centrally to the trunk and face – Pruritus persists and worsens as pregnancy continues and resolves within 48 hours of delivery – Often worse at night - may cause sleep disturbance, irritability, and psychiatric disturbances – 10-25% of patients develop jaundice, usually 1-4 weeks after the onset of pruritus – Rarely, constitutional symptoms » chills, abdominal pain, diarrhoea » steatorrhoea • Markedly cholestatic LFTs
  58. 58. Intrahepatic Cholestasis of Pregnancy • Treatment is ursodeoxycholic acid (UDCA) – doses of 1 gram per day – may allow progress through to term • LFTs may take weeks to normalise • Maternal prognosis extremely good • Infants usually premature and may have associated morbidity
  59. 59. Viral Hepatitis • Hepatitis A, B, C, D and E • CMV, EBV, HSV • Similar management issues to non-pregnant state

×