1. 00 Terlipressin /Medical Management in Hepatorenal Syndrome Akash Deep, Director - PICU King’s College Hospital London

3. HRS in children No literature on HRS in children exists All evidence extracted from adult literature. 2

4. Prevention - Potential targets Portal Hypertension Bacterial translocation Splanchnic vasodilators and mediators –TNF- alpha Raised IAP Iatrogenic factors

5. Prevention Norfloxacin: Ascitic protein 50 + Crea > 106 µmol/L or Na 10 Daily norfloxacin was associated with lower 1-year SBP probability (7% compared with 61%)and lower 1-year HRS probability.

6. Prevention with Pentoxifylline –anti TNF-alpha Mortality –12/49 (24.5%) PTX –24/52 (46.1%) –p=0.036 HRS as cause of death –6/12 (50%) PTX vs –22/24 (91.7%) –p=0.009 ; 119 : 1637 E Akriviadas Gastroenterology 2000 ; 119 : 1637 Pentoxifylline Placebo nonsurvivor s survivors Survival : Age, creatinine level on randomization, and treatment with PTX Pentoxifylline

7. Prevention Avoid intravascular volume depletion & maintain an effective circulating volume o Gastrointestinal bleeding o Diuretics o Diarrhea o Large-volume paracentesis without adequate volume repletion Prompt diagnosis and treatment of infections (peritonitis, sepsis) Bleeding and associated management Temporary omission of nephrotoxic drugs together with appropriate adjustment of drug doses for the eGFR.

8. Intra-abdominal pressure Sugrue et al Arch Surg 1999 134:1082 Malbrain CCM 2005;33:315 263 patients 40.7% increased IAP Renal dysfunction: 32% with IAP elevated 14% with normal IAP Albumin 20% albumin : 6-8g per 1 litre better than saline if > 6 l drained Sola-Vera et al Hepatology 2003 ;37:1147 ;50:90 Hepatorenal syndrome. Studies of the effect of vascular volume and intraperitoneal pressure on renal and hepatic function. Significant increase in urine flow rate and creatinine clearance following reduction in IAP from 22 to 10mm Hg following paracentesis

9. Albumin 8 Antioxidant effects and/or its high capacity to bind toxic substances

10. Stick to basics

11. Treatment - General Treat associated conditions 1.GI bleeding / hypovolaemia ( Surviving Sepsis guidelines, measurement of haemodynamics, problems associated with IAP ) 2.Infection 3.Diuretics / nephrotoxic drugs 4.Large volume ascites - TIPS / paracentesis 5.Adrenal insufficiency.

12. Goals of treatment Assessment for OLT should start early – HRS -1 realistic expectations, HRS-2 case by case Prolong survival until a liver transplant becomes available and to optimize conditions for successful liver transplantation. 11

13. Treatment Vasoconstrictor therapy + “Albumin” survival versus live longer RRT in non responders especially if OLT considered – no head to head comparison Target portal hypertension - TIPS MARS no evidence of benefit OLT.

14. Vasoconstrictors to improve circulatory function: Vasopressin analogues o Ornipressin- improvement of renal function but limited by ischemic complications o Terlipressin - lesser incidence of ischemia Midodrine o alpha-agonist, systemic vasoconstrictor Noradrenaline o alpha-agonist, systemic vasoconstrictor Octreotide o analogue of somatostatin, inhibitor of vasodilation. Treatment

15. Vasopressin  8-Arginine Vasopressin- Synthesised as a pro-hormone in the paraventricular and supra-optic nuclei of the hypothalamus  Migrates and stored in pars nervosa of the posterior pituitary  Vasopressin is a direct systemic vasoconstrictor (mediated by V1 receptors)  Osmoregulation and maintenance of normovolaemia (mediated by renal V2 receptors)  It also maintains haemostasis, plays a role in temperature regulation  Plasma half life of vasopressin is 24 min

16. V2V2 V 1a V 1b Functional coupling ATP cAMP H R ss AC PIP 2 IP 3, Ca 2+ DAG, PKC H R  q/11 PLC Asn 5 NH 2 Arg 8 Gly 9 Pro 7 Cys 6 Cys 1 Gln 4 Phe 3 Tyr 2 S S Vasopressin : Natural compound

17. Asn 5 NH 2 Arg 8 Gly 9 Pro 7 Cys 6 Cys 1 Gln 4 Phe 3 Tyr 2 S S Gly 9 Asn 5 NH 2 Lys 8 Gly 9 Pro 7 Cys 6 Cys 1 Gln 4 Phe 3 Tyr 2 S S AVP Asn 5 NH 2 Lys 8 Gly 9 Pro 7 Cys 6 Cys 1 Gln 4 Phe 3 Tyr 2 S S LVP Terlipressin Vasopressin: Synthetic compounds

18. Pharmacology of Terlipressin Prodrug - converted to its active form lysine vasopressin - ‘slow release’ of the vasoactive lysine vasopressin Half–life - 6 hrs Bolus dosage 1-2 mg 4-6 hourly ( some centres use infusion – no real benefit over boluses) Elimination half-life - 50 min Maximum serum concentration occurs after 120 min Degradation by endo and exopeptidases (1% through kidneys). 17

19. Vasopressin receptors

20. Action of Terlipressin 19

21. Pathophysiology of CLD Peripheral and splanchnic arterial dilatation Reduced effective blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system ADH Na retention & Water retention Low urinary Na Dilutional hyponatraemia Ascites Schrier et al Hepatol 1988 Plasma volume expansion Renal vasoconstriction Reduced GFR Ascites and Oedema HRS Portal Hypertension Vasopressin/ Terlipressin Increased blood volume

22. Blue fingers and toes Myocardial events Diarrhoea – gut ischaemia

24. Vasopressin : Gut ischaemia

25. Terlipresin +Albumin vs Albumin 24

26. RCT Terlipressin in Type I HRS Sanyal A Gatroenterology 2008 :134:1360 1 mg 6 hrly vs placebo Albumin in both groups If no response (30% decrease in creat) at day 4- dose doubled to 2mg 6 hrly 14 days Rx : 56 in each grp Success defined as creatinine < 1.5 mg/dl for 48 hrs by Day 14 Rx success : 34 vs 12.5 % Best Predictor – Low baseline Serum creatinine Similar survival between grps HRS reversal improved 180 day outcome

27. Sanyal A Gatroenterology 2008 :134:1360

28. 1-2 mg 4hrly Albumin daily 1g/kg N=23 each group Primary outcome-Renal function & survival Improved renal function 43 vs 8% No difference in 2 month survival Predictors of response – Baseline creat, treatment with terlipressin +albumin Terlipressin and albumin vs albumin Martin-Llahi M Gastroenterology 2008:134

29. Previous studies CP score 11 Martin-Llahi M Gastroenterology 2008:134

30. Six randomised trials were eligible for inclusion 3 trials (total 51 patients) assessed terlipressin 1 mg bd for 2 to 15 days Co-interventions included albumin, fresh frozen plasma, and cimetidine Terlipressin reduced mortality rates by 34% The control group mortality rate was 65% Terlipressin improved renal function assessed by creatinine clearance, serum creatinine and urine output. 2009

31. Conclusion Terlipressin appears to have an independent beneficial effect on HRS reversal. Best response in those with low baseline serum creatinine HRS at transplantation – high morbidity and mortality Though no survival benefit, improved renal function improved post transplant outcomes. 30

32. Do all patients treated with terlipressin respond ? 52% HRS respond to terlipressin ( Meta-analysis: terlipressin therapy for the hepatorenal syndrome F. Fabrizi, V. Dixit & P. Martin APT 2006 24:935-44 ) If not, can we identify those who will not respond ? Side effect profile, implications for transplantation and development of new therapies. 31

33. Best response - SCr <3.0 mg/dl Highest baseline serum creatinine in a terlipressin responder - 5.6 mg/dl. No response – SCr > 7mg/dl Will there be a response in advanced disease ?????

34. terlipressin placebo Hepatology 2011

35. Predictors of response to Terlipressin

36. Conclusions Best response - SCr < 3 mg/dl or 3-5 mg/dl Poor response - SCr > 7 Mg/dl If no response by Day 4 - NO response thereafter Sustained rise in MAP rather than only initial rise required for response Therefore start treatment early!!! 35

37. 36 Reversal of HRS with Terlipressin

38. Survival outcome with Terlipressin 37

39. Duvoux et al. Hepatology 2002 NA 0.5-3mg/h MAP >100mmHg increaase or U.O >50ml/h Norepinephrine for the treatment of HRS ? HRS reversal -83% Almost all respond – Day 5

40. 39 22 patients : Terlipressin -12, Noradrenaline -10 HRS Reversal : Terlipressin -83%, Noradrenaline-70%

41. 40 Cost of noradrenaline 15 times << terlipressin 82 % nor-ad responders – Transplant 80% terlipressin responders – Transplant 80% Non-responders - DEATH Noradrenalin is as effective and safe as terlipressin in patients with HRS.

43. Is there a single best vasoconstrictor ? NO ADVANTAGE OF ONE VASOCONSTRICTOR OVER OTHER 42

44. 10 trials only type I and II 376 patients Drug ± alb vs no intervention

45. Vasoconstrictors + Alb : Effect on mortality at 15 days but not at 30, 90 or 180 days RR 0.6 (0.37-0.97) Terlipressin + Albumin vs Albumin : decreased mortality in type I RR 0.83 (0.65-1.05) Terlipressin + Albumin vs Albumin

46. Comparative costs 45 DrugStrengthPresentationCostCost/unit Terlipressin1mg1 x 5 vial£69.95£13.99/ 1mg vial Vasopressin20units/ml (2ml) 1 x 10 (2ml amps) £320.50£32.50/ vial (40units/2ml) Vasopressin20units/ml (1ml) 1 x 25 (1ml amps) £133£5.32/ vial (20units/ml) Noradrenaline1:1000 (2ml)1 x 5 (2ml amp) £9.50£1.90/vial (2ml) Noradrenaline1:1000 (4ml)1 x 10( 4ml amp) £19£1.90/vial (4ml) Noradrenaline1:1000 (8ml)1 x 10 (8ml amp) £45£4.50/vial (8ml)

47. Other treatments TIPS – Transjugular Intrahepatic porto-systemic shunts Renal Replacement therapy – Volume overload, intractable metabolic acidosis, and hyperkalemia - CRRT/MARS Liver Transplantation ( Not all recover kidney function) Combined Liver-kidney Transplantation. 46

48. Comparison of various treatments

49. What is my management strategy for HRS? Differentiate between natural progression of liver disease with its complications versus acute deterioration of kidney function – HRS-1 or AKI Fluid resuscitation Treat raised IAP(Drain and replace with albumin) Aggressive antibiotics (cephalosporins) Recognise and treat precipitating factors Once in ICU – Cardiac output monitoring, fluids, full organ support, prioritise transplant listing Early vasoconstrictors

50. HRS at KCH Start with noradrenaline, if no response at 0.5 mcg/kg/min, add terlipressin 1mg 6 hourly Monitor ischaemic side effects Steroids for adrenal suppression If no response by day 3, double terlipressin 2mg No response Day -5 stop terlipressin RRT – fluid oveload, high lactate, acidosis Temporary delisting if progressive MOF 49

51. Conclusion HRS often diagnosed - rarely present Poor prognosis Prevent infections, raised IAP(paracentesis) and iatrogenic factors Treat associated complications rapidly 50

52. Unanswered questions Does HRS relapse after stopping terlipressin ? When do you prioritise and at what point should one be denied transplant ? Can prolonged vasoconstrictors be used as bridge to transplant?

53. Acknowledgements Jules Wendon and George Auzinger Tim and Stuart CRRT Working Group at King’s 52