ALF PPT for Liver patients ( ACUTE LIVER FAILURE)

ACUTE LIVER FAILURE

1. ACUTE LIVER FAILURE Presenter: Dr Rahul Kalshan

2. Acute liver failure (ALF) is a severe and complex condition that results from acute and massive hepatocellular destruction with very poor prognosis. ALF is an infrequent condition, with an incidence of 1–8 cases per million inhabitants, and it is responsible for 6% of deaths due to liver disease and up to 7–8% of liver transplants. It mainly affects young female adults, with a peak age between 35 and 45 years. The development of cerebral oedema , sepsis and multiple organ failure are the main causes of mortality here .

3. Definition and classification Acute liver failure was first described by Trey C and Davidson as “hepatocellular dysfunction of such severity that encephalopathy occurs within eight weeks of appearance of first symptoms in the absence of pre-existing liver disease. In 1993, O’Grady et al based on data from King’s College subdivided ALF into hyperacute, acute, and sub-acute presentation .

4. The most widely accepted definition is by American association of study of liver disease who in 2005 defined ALF as a clinical syndrome characterized by evidence of coagulopathy (international normalized ratio (INR >/= 1.5) and any degree of altered mental status in a patient without pre-existing liver disease and duration of illness <26 weeks. Hyperacute form has a better prognosis but a higher incidence of cerebral oedema . Acute and sub-acute presentations have a worse prognosis, but a lower incidence of cerebral oedema . The risk of developing intracranial hypertension (ICH) is higher in female and younger patients with severe liver failure (MELD >32), presenting in acute or hyperacute state with renal failure, ionotropic therapy, and ammonium concentrations above 200 mmol/L.

5. Five phenotypes of liver failure .

6. Etiology Viral Hepatitis : HEP A,B,E, HSV, VZV, CMV, EBV, HHV6, ADENOVIRUS,COXSACKIE B VIRUS. Drugs : Acetaminophen, Sulfonamides, Tetracycline, herbal supplements, Idiosyncratic RXN to INH, NSAIDs, Carbamazepine. Vascular Disease : RHF, Sinusoidal obstruction syndrome, Budd Chiari syndrome, Ischaemic hepatitis. Toxins : Amanita phalloides, Bacillus cereus, carbon tetrachloride. Metabolic Disease : Wilson disease, Reye syndrome, Acute fatty liver of pregnancy Autoimmune Hepatitis and Malignant Infiltration .

7. The pathophysiology depends on the etiology of the ALF. Most cases of ALF (except acute fatty liver of pregnancy and Reye syndrome) will have massive hepatocyte necrosis and/or apoptosis leading to liver failure. Hepatocyte necrosis occurs due to ATP depletion causing cellular swelling and cell membrane disruption. The pathophysiology of cerebral edema and hepatic encephalopathy is seen in ALF is multi-factorial and includes altered blood-brain barrier (BBB) secondary to inflammatory mediators leading to microglial activation, accumulation of glutamine secondary to ammonia crossing the BBB and subsequent oxidative stress leading to depletion of adenosine triphosphate (ATP) and guanosine triphosphate (GTP). This ultimately leads to astrocyte swelling and cerebral edema.

8. ICP Monitoring Direct & invasive : Intraparenchymal microtransducers and direct catheter ( intraventricular, subdural or epidural). Indirect & non invasive : MCA DOPPLER, Reverse jugular vein oxygen saturation [ values over 80% indicate hyperaemia and under 55% relative ischaemia ], ONSD [cut off of 5.7mm measured 3mm behind the globe], CT & MRI.

9. General supportive measures for ALF in ICU Head end elevation to 30 degree with neck in neutral position Intubation and mechanical ventilation in grade III and IV HE Use propofol and low-dose fentanyl, and if needed cisatracurium once intubated. Intermediate or long acting benzodiazepines should be avoided Deploy low-tidal volume lung protective strat egy to prevent ARDS. High-intrathoracic pressures result in cerebral venous outflow obstruction For non-invasive approach for BP monitoring in suspected ICH - target a higher mean arterial pressure goal (>80 mmHg).

10. In case of concern of seizure activity, EEG monitoring should be undertaken and antiepileptic drugs administered;– Phenytoin has traditionally been the medication of choice; however, agents without risk of hepatotoxicity and more easily achieved therapeutic levels such as levetiracetam or lacosamide are now more frequently utilized. Avoid acid-base and electrolyte disturbances. – Hypokalemia, and metabolic acidosis which increases renal proximal tubule ammoniagenesis – Metabolic alkalosis promotes formation of NH3+ from (NH4+) augmenting its pas sage across the blood–brain barrier – Hyponatremia, which is a risk factor for cerebral edema via reduced extracellular osmolarity Prevent hypoglycemia by initiating 10% or 20% dextrose infusion in central line.

11. Prophylactic strategies Hypertonic saline (3%NS) recommended to reduce ICT [MAINTAIN S.Na between 145-155meq/l] Prophylactic hyperventilation not recommended Prophylactic use of anti epileptics not warranted Prophylactic use of anti biotics recommended Prophylactic use of hypothermia not recommended

12. Specific strategies To reduce ammonia Lactulose (non absorbable disaccharide); gets metabolized in caecum by gut bacteria to lactate and acetate. It lowers the caecal pH leading to increased fecal nitrogen excretion and decrease in serum ammonia level. Avoid it via oral/ NG route. Rifaximin oral antibiotic with a broad spectrum activity against enteric bacteria. LOLA &LOPA (L Ornithine L aspartate & L Ornithine phenyl acetate) Glutamate + NH3------ glutamine with help of enzyme glutamine synthase Phenylacetate combine with glutamine & forms phenylacetyl glutamine(water soluble, excreted in urine) CRRT: Use hypertonic dialysate to prevent rebound cerebral oedema & brain hernitation .

13. Specific strategies B) To reduce ICT Maintain CPP above 50mmhg Use 3% NS either 30-100ml/ hr infusion or intermittent bolus of 200ml. Mannitol (0.5-1g/kg) Indomethacin, hypothermia in refractory cases Pentobarbitone and thiopentone Hepatectomy

14. Haemodynamics Management ALF is characterized by a hyperdynamic circulation with high cardiac output, low MAP, and low systemic vascular resistance. Elevation of troponin in the setting of ALF did correlate positively with requirements for vasopressors, renal failure, and organ failure scores. Management: restoration of effective circulating volume, Invasive monitoring devices are often used to optimize circulating volume and cardiac output. Echocardiography are superior to static hemodynamic measurements. volume overload should be avoided as much as volume depletion. choice of fluid should be normal saline or balanced salt solutions. albumin infusion can be considered which will enhance plasma oncotic pressure and maintain intravascular volume.

15. Haemodynamics Management Noradrenaline: raises mean arterial pressure and can increase hepatic blood flow in parallel with less tachycardia. Vasopressin may augment noradrenaline effect. Terlipressin increases CPP without changing ICP, decreased brain lactate, and unchanged lactate/pyruvate ratio. MAP of at least 80 mmHg is recommended to maintain optimal CPP. Treats PAH with pulmonary vasodilators (Prostaglandins and sildenafil) and ensuring adequate MAP. In profound and reversible acute cardiac dysfunction, venoarterial extracorporeal membrane oxygenation(VA ECMO) may be appropriate. Refractory hypotension should be treated by hydrocortisone at 200–300 mg daily in divided doses.

16. Nutrition Management Glucose transport across the blood–brain barrier is increased because of upregulation of glucose carriers in ALF and hyperglycemia contributes to raised ICP because this increased glucose influx leads to cerebral lactic acid accumulation. Maintain euglycaemia . Hyper lactataemia causes cerebral hyperemia and should be treated aggressively. ALF increases energy requirements are by 60%, and further by complicating infection. Body protein catabolism may be increased up to four times. Enteral feedings should be initiated as early as possible. Phosphorus, potassium, and magnesium are usully low and should be supplemented. Ventilated or with severe coagulopathic patients related to hepatic dysfunction, GI prophylaxis with H2 blockers or PPI is recommended.

17. Respiratory Management NIV should be avoided in ALF patients at risk of hepatic, metabolic or septic high risk of encephalopathy, aspiration, and poor compliance. Rapid sequence induction technique for intubation to minimize elevation in ICP by using nondepolarizing agents such as cisatracurium . Short acting opiate i.e. fentanyl for analgesia and propofol for sedation recommended. Low tidal volumes (6 ml/kg/ideal body weight) and appropriate levels of PEEP recommended. High PEEP (>12) can enhances ICP. Assessment of lung water, utilizing advanced hemodynamic monitoring such as volume view or PiCCO may optimize managing these patients. Hypoxaemia is common; HPS should be excluded from it by using bubble echo.

18. Renal Management Renal Dysfunction in ALF due to drug-induced nephrotoxicity, acute tubular necrosis, and abdominal compartment syndrome. Risk factors: increased age, hypotension, systemic inflammatory response Syndrome(SIRS) and infection. It resolves along with resolution of liver injury or with transplantation. Management : Avoid nephrotoxic agents, aggressively handling infection and sepsis, deploying various techniques to maintain adequate renal perfusion and instituting timely renal replacement therapy. Female gender, lower day three MELD scores, admission hypotension and lower grades of AKI are predictive factors for complete renal recovery following paracetamol induced ALF.

19. Renal Management CRRT Indications in ALF: Low-urine output in spite of adequate intravascular volume, fluid overload, and rise in serum creatinine of 0.3 mg/dl CRRT is recommended over intermittent hemodialysis, in most ALF patients, due to poor tolerance of HD owing to circulatory instability, sudden fluid shifts and ICT rise . ALF patients require standard heparinization for dialysis in spite of the coagulopathy, due to coexisting antithrombin III deficiency. Cirrhotic patients tolerate citrate anticoagulation, those with acute and hyperacute ALF may not, due to deranged metabolism of citrate. If citrate is used, close monitoring of total calcium compared with ionized calcium is warranted.

20. Haemostasis Management Derranged international normalized ratio (INR) and prothrombin time present while there is a significant increases in endogenous heparinoids, procoagulant microparticles, von Willebrand factor and factor VIII, reduced pro- and anticoagulant factors and release of “younger” more reactive platelets. Key rule: “rebalanced hemostasis” = prophylactic correction of derranged coagulation or platelets not required. Coagulation factors : fibrinogen and factors II, V, VII, IX, X, XI, and XII ( synthesised by the hepatocytes) markedly decreased ; factor VIII and vWF (derived from endothelium) increased. Anticoagulant factors: protein C, protein S, protein Z, protein Z-dependent protease inhibitor, antithrombin, heparin cofactor II, and α2- macroglobulin decreased . platelet derived microparticles as being potentially responsible for thrombocytopenia, which may create a hypercoagulable state in the micro circulation and lead to systemic complications and poor outcomes.

21. Haemostasis Management Prophylactic correction needed in ICP monitor insertion and Significant active hemorrhage. We need to target plasma fibrinogen levels 1.5–2 g/L by infusing fibrinogen concentrate at an initial dose of 25–50 mg/kg body weight, and a platelet count >60,000. Hemoglobin level of 7 g/dl acceptable. Vitamin K (5–10 mg) should be considered in all patients with ALF, because its deficiency can occur in >25% of patients.

22. Infection Management Bacterial infections are common in ALF: pneumonia (50%), followed by urinary tract infections (22%), intravenous catheter-induced bacteremia (12%), and spontaneous bacteremia (16%). Viral, fungal infections and reactivation of CMV is common in ALF patients. C reactive protein and procalcitonin measurements are unreliable. Admission HE and SIRS score >2 are significant predictors of bacteremia. Deterioration of mental status, unexplained fever, and leukocytosis may herald the onset of infection. Routine microbiologic surveillance may aid early detection and treatment of infec tions . Empirical broad spectrum antibiotics should be administered to ALF patients with SIRS, refractory hypotension or unexplained worsening of hepatic encephalopathy.

23. Prognosis and LTP 1) King’s college criteria for transplantation in acute liver failure. To improve the predictive value of the KCC, the measurement of lactate as an indicator of tissue dysfunction has been added to the criteria in the UK. An arterial lactate >3.0–3.5 mmol/L after fluid resuscitation is a marker of poor prognosis.

24. Prognosis and LTP 2) Clichy criteria. Factor V level of less than 20% may indicate a poor prognosis

25. Prognosis and LTP Cut-off MELD score of 30.5 should be used for prognosis and higher scores predict a need for LT. KCC has the most specificity (83%) but lowest sensitivity (47%) and MELD has the highest sensitivity (89%) but the lowest specificity (25%). Advanced grades 3/4 HE and severe coagulopathy defined as an INR >6.5= NEED FOR LTP IS MUST. Non liver specific scores such as Sequential Organ Failure Assessment (SOFA), and the Acute Physiology and Chronic Health Evaluation II (APACHE II) have also been evaluated. In paediatric population , criteria for LT are different from those in adults. An INR >4 and total bilirubin >17.6 mg/dl irrespective of Hepatic encephalopathy is the currently accepted criteria for LT in children.

26. Contra indications for LTP Irreversible brain injury Severe cardiopulmonary dysfunction Uncontrolled sepsis Haemorrhagic pancreatitis Few systemic diseases: Hypoxic hepatitis, Haemophagocytic lymphohistiocytosis , malaria, dengue, rickettsiosis, malignant infiltrations of liver or widespread mitochondrial failure following certain drug ingestions.

27. Liver Support Devices(LSD) IN ALF These devices help to either stabilize the patient while liver is recovering from insult or act as a bridge to liver transplantation. LSD functions: detoxification, synthesis of proteins, and regeneration. Artificial LSD: Molecular adsorbents recirculating system (MARS), fractionated plasma separation and adsorption (Prometheus), single pass albumin dialysis (SPAD), and selective plasma filtration therapy (SEPET) BAL LSD: HepatAssist , Extracorporeal Liver Assist Device (ELAD), Modular Extracorporeal Liver support (MELS), Bio-artificial Liver support system (BLSS), and Amsterdam Medical Centre Bio-artificial Liver (AMCBAL)

28. Peri operative Management Shifting to OT : proper communication with detailed handover between the intensivist and anaesthetist Use of portable ventilators should be preferred as opposed to manual ventilation to avoid any gross changes in pCO2 Maintain head end elevation Adequate sedation, analgesia, musle relaxants ET care, vascular access care, infusion pumps care BIS monitoring CRRT if required.

29. Peri operative Management OT management : Continue sedatives and muscle relaxants if already present Induction with RSI TECHNIQUE by using fentanyl, propofol, rocuronium. Try to avoid SCH as it causes transient rise in ICT Continue infusions of sedation, analgesia, muscle relaxants (cis-atracurium is preferred as its metabolism is independent of hepatic function and does not produce laudanosine as in case of atracurium) Propofol: has shorter duration of action, anticonvulsant properties as well as potential to decrease intracranial pressure, can be used as an adjunct to inhalational agent.

30. Peri operative Management Anaesthesia is maintained with air/oxygen/ isoflurane or sevoflurane Isoflurane has the ability to preserve Hepatic artery buffer response and splanchnic blood flow, made it as the preferred inhalational agent Maintain MAC <1 to prevent rise in ICP (try to avoid inhalational agents alone, use them with propofol instead) Maintain depth by using BIS monitoring Patients have increased level of endogeneous opioid peptides here along with altered neurotransmission caused by bilirubin---- decreased anaesthesia requirements here Patients with HE have shown good BIS with low MAC.

31. Peri operative Management Vascular access by standard 4 lumen cvc catheter 8.5 fr and dialysis catheter 11 fr Monitoring: Non-invasive cardiac output monitors using pulse power analysis through the pulse CO algorithm or arterial pressure-based cardiac output (APCO) method for continuous cardiac output monitoring are commonly used Pulmonary artery catheter (PAC) reserved for high risk patients with significant cardiac co-morbidities TEE- gives direct measurement of the cardiac filling, allowing real time assessment of fluid status during the surgery, detect any drastic events like pulmonary embolism, MI, strain on heart.

32. Peri operative Management Use of ppv & svv to assess fluid volume, give goal directed fluid therapy Avoid volume overload as it can increases cvp which leads to tissue oedema and impaired micro circulatory flow Vasopressors are recommended in event of severe hypotension (SBP< 90mmhg or MAP <65mmhg to maintain CPP >50mmhg Noradrenaline is the vasopressor of choice Target MAP: patients without pre-existing hypertension MAP>60 mmHg is considered to be adequate while in chronic hypertension who are at a risk of developing renal dysfunction, maintaining a MAP>75 mmHg should be consid ered . Avoid intraoperative hypertension as well to prevent rise in ICP.

33. Peri operative Management Dissection and reperfusion phase are associated with rise in ICP and consequently decreased cerebral perfusion pressure Anhepatic phase shows a decrease in intracranial pressure ICP shoud be maintained <25mmhg Maintain CPP between 50-80mmhg Target plasma fibrinogen levels 1.5–2 g/L by infusing fibrinogen concentrate at an initial dose of 25–50 mg/kg body weight Consider TEG based correction rather PT/INR Maintain intravascular volume, prevent acidosis.

34. Peri operative Management CRRT Indications in ALF: Low-urine output in spite of adequate intravascular volume, fluid overload, and rise in serum creatinine of 0.3 mg/dl It reduces cerebral oedema , maintain acid-base balance, fluid bal ance , and corrects metabolic derangements The extra corporeal circulation established with CCRT is prone to induce increased infection risk, hypothermia, thrombocytopenia, and coagulation abnormalities Consider to resume CRRT after carefully considering the benefit out weighs its deleterious side effects.

35. Peri operative Management Post operative care: Delayed recovery in the postoperative period is expected Cerebral oedema leading to encephalopathy takes time to recover postoperative ventilation needed for atleast 24–48  hrs Continue to check ONSD, Pupillometry, CT After LTP, cerebral oedema resolves slowly and restoration of cerebral autoregulation may take up to 48  hrs with good allograft function.

36. . Thank You