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Terlipressin /Medical Management in Hepatorenal Syndrome Akash Deep, Director PICU King’s College Hospital London 0 HRS in children • No literature on HRS in children exists • All evidence extracted from adult literature. 2 Prevention - Potential targets • Portal Hypertension • Bacterial translocation • Splanchnic vasodilators and mediators – TNF- alpha • Raised IAP • Iatrogenic factors Prevention • Norfloxacin: Ascitic protein < 15g/L, Bilirubin > 50 + Crea > 106 µmol/L or Na < 130 mmol/L, CPC >10 • Daily norfloxacin was associated with lower 1year SBP probability (7% compared with 61%)and lower 1-year HRS probability. Prevention with Pentoxifylline –anti TNF-alpha E Akriviadas Gastroenterology 2000; 119 : 1637 nonsurvivor s survivors Pentoxifylline Pentoxifylline 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 Placebo Survival : Age, creatinine level on randomization, and treatment with PTX 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. 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 Significant increase in urine flow rate and of vascular volume and intraperitoneal creatinine clearance following reduction in IAP pressure on renal and hepatic function. from 22 to 10mm Hg following paracentesis Albumin Antioxidant effects and/or its high capacity to bind toxic substances 8 Stick to basics 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. 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 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. Treatment 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. Vasopressin 8-Arginine Vasopressin- Synthesised as a prohormone 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 Tyr2 Cys1 S S Vasopressin : Natural compound Phe3 Gln4 Functional coupling Asn5 Cys6 H Pro7 Arg8 Gly9 NH2 V2 R cAMP as AC ATP V1a V1b IP3, Ca2+ H R aq/11 PLC DAG, PKC PIP2 Tyr2 Cys1 S S Vasopressin: Synthetic compounds Phe3 Gln4 Asn5 LVP Cys6 Pro7 Arg8 Gly9 NH2 Tyr2 Cys1 AVP S S Phe3 Gln4 Asn5 Terlipressin Cys6 Pro7 Lys8 Gly9 NH 2 Tyr2 Gly9 Gly9 Gly9 Cys1 S S Phe3 Gln4 Asn5 Cys6 Pro7 Lys8 Gly9 NH 2 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 Vasopressin receptors Action of Terlipressin 19 Portal Hypertension Pathophysiology of CLD Peripheral and splanchnic arterial dilatation Vasopressin/ Terlipressin Reduced effective blood volume Increased blood volume Activation of renin-angiotensin-aldosterone system Sympathetic nervous system ADH Renal vasoconstriction Reduced GFR HRS Na retention & Water retention Ascites and Oedema Low urinary Na Dilutional hyponatraemia Plasma volume expansion Ascites Schrier et al Hepatol 1988 Blue fingers and toes Myocardial events Diarrhoea – gut ischaemia Vasopressin : Gut ischaemia Terlipresin +Albumin vs Albumin 24 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 Sanyal A Gatroenterology 2008 :134:1360 Terlipressin and albumin vs albumin • • • • • • • Martin-Llahi M Gastroenterology 2008:134 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 Previous studies CP score 11 Martin-Llahi M Gastroenterology 2008:134 • 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 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 • 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 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 ????? terlipressin Hepatology 2011 placebo Predictors of response to Terlipressin 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 Reversal of HRS with Terlipressin 36 Survival outcome with Terlipressin 37 Norepinephrine for the treatment of HRS ? Ser. Creat (umoles/l) Duvoux et al. Hepatology 2002 700 HRS reversal -83% Almost all respond – Day 5 600 500 400 300 200 100 0 Day 0 Day 5 Day 10 NA 0.5-3mg/h MAP >100mmHg increaase or U.O >50ml/h 22 patients : Terlipressin -12, Noradrenaline -10 HRS Reversal : Terlipressin -83%, Noradrenaline-70% 39 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. 40 Is there a single best vasoconstrictor ? NO ADVANTAGE OF ONE VASOCONSTRICTOR OVER OTHER 42 10 trials only type I and II 376 patients Drug ± alb vs no intervention Terlipressin + Albumin vs Albumin 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) Comparative costs Drug Strength Presentation Cost Cost/unit Terlipressin 1mg 1 x 5 vial £69.95 £13.99/ 1mg vial Vasopressin 20units/ml (2ml) 1 x 10 (2ml amps) £320.50 £32.50/ vial (40units/2ml) Vasopressin 20units/ml (1ml) 1 x 25 (1ml amps) £133 £5.32/ vial (20units/ml) Noradrenaline 1:1000 (2ml) 1 x 5 (2ml amp) £9.50 £1.90/vial (2ml) Noradrenaline 1:1000 (4ml) 1 x 10( 4ml amp) £19 £1.90/vial (4ml) Noradrenaline 1:1000 (8ml) 1 x 10 (8ml amp) £45 £4.50/vial (8ml) 45 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 Comparison of various treatments 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 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 Conclusion • HRS often diagnosed - rarely present • Poor prognosis • Prevent infections, raised IAP(paracentesis) and iatrogenic factors • Treat associated complications rapidly 50 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? Acknowledgements • Jules Wendon and George Auzinger • Tim and Stuart • CRRT Working Group at King’s 52