Children ’ s Critical Care Centre

1. CRRT in Liver DisordersAkash DeepDirector - PICU King’s College HospitalLondonChairRenal/CRRT SectionEuropean Society of Pediatric and Neonatal Intensive Care (ESPNIC) 0

2. Children’s Critical Care Centre

3. Overview • Case Discussion • CRRT and AKI in ALF • CRRT in various Liver Disorders – Why AKI, When do you intervene, outcome • Single Pass Albumin Dialysis (SPAD)/ MARS • Anticoagulation in liver Patients

4. RRT in liver patients ALF Stable cirrhosis AoCLF Post Liver Transplant Metabolic disease- hyperammonaemia, primary hyperoxaluria CRRT – standard ICU indications in patients with liver disease

5. Survival in patients treated by RRT according to diagnoses: ppCRRT Registry Symons, Clin J Am SocNephrol, 2: 732, 2007 pCCRT Rome 2010

6. Case - 1 • 9 year old previously well child from Dublin • 4 day history of cough, fever • Recovered • 2 weeks later – lethargy, jaundice • Readmitted to hospital • Increasing Jaundice, raised INR, fully alert • Diagnosis???

7. KCH • Admission to King’s Hepatology Ward • INR > 9, Listed for super-urgent liver transplantation • Overnight – going in and out of sleep, decreased urine output, 3 fluid boluses • All alarm bells ringing • It was the weekend!!!!!!

8. Paediatric PICU • Patient wheeled to ICU • Distinctly looked encephalopathic • INR 7.8 Platelets 13 Hb 7.8 • Ammonia – 178 micromol/litre • Waiting for things to get ready – Transcranial Dopplers done- PI > 2.0

9. Raised ICP results in reduced diastolic flow, PI 2.4

10. PICU Care • Intubated ventilated • Inserted 12.0 F IJV vascath • Right Reversed Internal Jugular Vein • Right Femoral CVL and Left Femoral Arterial Line • NIRS started • Bilateral Pleural effusions – drains inserted

11. PICU ( 11:00 -13:00) • Within 60 minutes – HVHF started • Pump speed – 250 mls/min, Predilution- 2.5 litres, ACT- 200 Started on PGI2 – 4ng/kg/min • Ph 7.10 CO2-5.5 kpa Lactate 5.6 Base deficit- -14.1 Cl- 110 • Vasopressor support + 60 mls/kg Fluid • Steroids given • FFP+ Platelets+ Activated Factor –VII • Fentanyl + Midazolam started • Phenytoin loading given, hypertonic saline infusion

12. Neuro- monitoring • TCD – PI- 2.4 • RIJV – 42% • NIRS correlating with RIJV • Hb -10, CI 4.2 on vasopressor support • DECISION TO INSERT ICP BOLT

13. Neuroprotection ( 13:30) • Inserted a Camino epidural bolt- scalp bleeding for > 30 minutes • Opening pressure – 50 cm H2O • Immediately started hypothermia ( 32 degrees), full neuro-protection including thiopentone infusion with continuous EEG • ICP minimum – 45 cm H20 with good waveform

14. Case - continued • At 2 am- when every possible neuroprotection was thrown at her – Called the surgeon • Anhepatic – No sign of liver coming up, father had fatty liver • CRRT continued in OR for 16 hours • Increased turnover to 4 litres/hour

15. Temporary anhepatic state

16. Case ( 13:00) • Within 8 hours – cadaveric liver transplantation done ( liver not of great quality- but used as a bridge ) • Patient re-listed for another transplant • Complete normal neurology • Re-transplanted in 4 weeks • Progressive kidney involvement- Urea, creatinin``e, K rising and fluid overload • On CRRT from 28/7/12 till 24/01/2013 • Gradually weaned off CRRT

17. Progress • Progressive BM Suppression and CKD • Listed for BM transplant • Went on to IHD • Developed disseminated aspergillosis • Sadly WG RIP on 28/02/2013

18. Questions • Why did WG develop AKI in ALF? • Could we have acted more swiftly and started CRRT overnight – i.e, what is the exact time of initiation of CRRT? • What was our aim of starting CRRT? • The fact that she was neurologically completely intact – Did CRRT help or was it the aggressive neuro-protection?

19. CRRT in ALF

21. Ultimate Aim of RRT in ALF Conducive Environment for Either Liver Regeneration /Liver Transplant – Stable haemodynamics, removal of toxins, CPP • The potential for recovery of native organ function • Too little donor organ pool • To prolong the window of opportunity for LT : “Bridge to LT” • Risk of death awaiting liver transplant ( MODS) – Fluid manipulation, acid-base, ammonia, nutrition Liver Support Devices until recovery from ALF or bridging to transplant. Hepatology 1998:27:1050-5

22. King’s College Hospital PICU Admissions Jan 2003- Dec 2013 Liver n=1289 (18%) EXCLUDED: Post-transplant (18%) Primary HSV sepsis (5%) HDU (13%) EXCLUDED: Acute on chronic (5%) ALF n=165 (13%) Managed prior to transplant/recovery n=106 (64%) with CRRT n=45 (42%)

23. Distribution by Age and Aetiology Mean PIM2 score = 54

24. Use of CRRT in Paediatric ALF at KCH • Average time to start CRRT 29 hrs (1 in 3 <8hrs) • Commonest indication hepatic encephalopathy • 100% required mechanical ventilation • 93% required ionotropes • Mean duration of CRRT was 54 hours.

25. Mean Ammonia (umol/L) in Relation to CRRT in ALF PICU Patients by Outcome on Discharge n=45

26. Mean Lactate (umol/L) in Relation to CRRT in ALF PICU Patients by Outcome on Discharge n=45

27. Mean Fluid Overload (%) in Relation to CRRT in ALF PICU Patients by Outcome on Discharge

28. H24 H48 40 40 At 24 hours: Increase MAP (p=0.0002) Decrease serum creatinine (p=0.0002) At 48 hours: Increase MAP (p=0.0002) Decrease serum creatinine (p=0.0002) HE grade improvement (p=0.04) 20 20 0 0 Variation in serum creatinine, % -20 -20 -40 -40 -60 -60 -80 -80 p=0.0002 p=0.002 80 80 60 60 40 40 20 20 Variation in mean arterial pressure , % 0 0 -20 -20 -40 -40 p=0.0002 p=0.0005 Variation in hepatic encephalopathy grade p=0.04 p=0.90

29. 1 ,8 ,6 Cumulative Survival ,4 2002-2008 < 1 year > 1 year 2002-2008 ,2 HV- CVVH era HV- CVVH era 0 0 10 20 30 40 50 60 70 80 Days Effect on outcome of CVVH

30. 1 ,8 ,6 Cumulative Survival ,4 2002-2008 < 1 year > 1 year 2002-2008 ,2 HV- CVVH era HV- CVVH era 0 0 10 20 30 40 50 60 70 80 Days No effect on long term survival, but significant prolonged initial delay

31. Conclusion CVVH in Paediatric ALF • Improved hemodynamic, renal and neurological function • Allows a prolonged period of stability to ELT

32. Renal Support in Liver Failure • Why do patients with Liver failure develop AKI? • Why do patients with AKI in liver failure require RRT /detoxification modalities? • What is the best time to initiate RRT in patients with ALF? • Elective versus standard CRRT • What dose of RRT is the best dose – role of HVHF? • Anticoagulation in CRRT for ALF

33. Pathogenesis of AKI in ALF Arterial vasodilatation (‘’VASOPLEGIA’’) Decreased SVR High Cardiac Output Renal Auto-regulation becomes Pressure Dependent - Intra-renal Vasoconstriction

35. Aetiology of Kidney Involvement in ALF • Multifactorial • Pre-renal AKI • Acute tubular necrosis due to profound hypovolemia and hypotension • Direct drug nephrotoxicity (paracetamol, NSAIDs) • Hepatorenal syndrome • Intra-abdominal hypertension (IAH) and development of abdominal compartment syndrome - USCOM

37. Renal • Renal replacement therapy in ALF • Continuous filtration not intermittent dialysis • Improved metabolic stability • Improved cardiovascular stability Davenport et al Crit Care Med 1993;21:328-338 • Additional benefits from high filtration rates ? • 35 ml/kg/h as standard. • 90ml/kg/h severe lactic acidosis ++ vasopressors. • We use minimum of 60 mls/kg /hour and increase if lactate/ammonia not getting better

39. Patients who develop ICH tend to have persistently high ammonia levels. NH4 cut off 124 : pH, cerebral oedema + NH4 predict outcome Bhatia V Gut 2005 Bernal W Hepatology 2007

40. Evidence for Ammonia Comparison of arterial ammonia levels at admission between survivors and non‐ survivors among acute liver failure patients Gut. 2006 January; 55(1): 98–104

41. Mortality, advanced encephalopathy, and complications in acute liver failure patients as a function of plasma ammonia levels Higher percentages of cerebral oedema (71% vs 37%; P < .001) Gut. 2006 January; 55(1): 98–104 Clin Gastroenterol Hepatol. 2012 Aug;10(8):925-31

43. Timing of Initiation of RRT • Do NOT wait for frank signs of renal failure • Metabolic complications - metabolic acidosis, lactate, hyponatraemia and NH3 >150 µmol/litre • If child intubated for grade ¾ encephalopathy – insert vascath • Challenges – High INR, potential for bleeding and vascath complications

45. Authors – Akash Deep, Anil Dhawan

46. RRT – Indications in ALF • Hepatic encephalopathy grade 3-4 • NH3 >150 µmol/litre and not getting controlled or an absolute value >200 µmol/litre • Renal dysfunction (Oligo-anuria, Hyperkalemia, fluid overload) • Metabolic abnormalities ( hyponatremia Na <125 meq/litre, High lactate and increasing despite optimising fluid therapy, Metabolic acidosis) No one indication is an absolute one for initiation of RRT

47. If Early HVHF looks promising, what are the potential drawbacks? • Invasive procedure • Haemodynamic instability, decreased cerebral perfusion • Clearance of medications • Side effects

48. Acute kidney injury in patients admitted to a liver intensive therapy unit. O’Riordan A • 2000-2007 : 302 ALF managed without OLT • 21% did not develop AKI : all survived • 239 with AKI of whom 164 survived(68%) – LOS increased by 5 -7 days • 51% return of normal renal function • eGFR > 60 at time of discharge Nephrol Dial Transplant. 2011 Nov;26(11):3501-8.