Terlipressin /Medical Management in Hepatorenal Syndrome

Akash Deep, Director PICU King’s College Hospital London

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 1 year 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

Mortality

– 12/49 (24.5%) PTX – 24/52 (46.1%) – p=0.036

Pentoxifylline Pentoxifylline

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 o o Diuretics Diarrhea 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 of vascular volume and intraperitoneal

Significant increase in urine flow rate and 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

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Stick to basics

Treatment - General

2.

3.

4.

5.

Treat associated conditions 1.

GI bleeding / hypovolaemia ( Surviving Sepsis guidelines, measurement of haemodynamics, problems associated with IAP ) Infection Diuretics / nephrotoxic drugs Large volume ascites - TIPS / paracentesis 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.

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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

• o • o o • 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

alpha-agonist, systemic vasoconstrictor

Noradrenaline

alpha-agonist, systemic vasoconstrictor

Octreotide

analogue of somatostatin, inhibitor of vasodilation.

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

Phe 3 Tyr 2 Gln 4 Cys 1 S S Cys 6 Asn 5 Pro 7 Arg 8 Gly 9 NH 2 Vasopressin : Natural compound V 2 H

Functional coupling

cAMP R

a

s AC ATP V 1a V 1b H R

a

q/11 PLC IP 3 , Ca 2+ DAG, PKC PIP 2

Phe 3 Tyr 2 Gln 4 Cys 1 S S Cys 6 Asn 5 Pro 7 Arg 8 Gly 9 NH 2 Vasopressin: Synthetic compounds

LVP AVP

Phe 3 Tyr 2 Gln 4 Cys 1 S S Cys 6 Asn 5 Pro 7

Terlipressin

Lys 8 Gly 9 NH 2 Gly 9 Gly 9 Gly 9 Phe 3 Tyr 2 Gln 4 Cys 1 S S Cys 6 Asn 5 Pro 7 Lys 8 Gly 9 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).

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Vasopressin receptors

Action of Terlipressin

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Portal Hypertension

Pathophysiology of CLD

Peripheral and splanchnic arterial dilatation Reduced effective blood volume Vasopressin/ Increased blood volume Terlipressin Activation of renin-angiotensin-aldosterone system Sympathetic nervous system Na retention & Water retention ADH Plasma volume expansion Ascites Ascites and Oedema Low urinary Na Dilutional hyponatraemia Renal vasoconstriction Reduced GFR HRS

Schrier et al Hepatol 1988

Blue fingers and toes Myocardial events Diarrhoea – gut ischaemia

Vasopressin : Gut ischaemia

Terlipresin +Albumin

vs

Albumin

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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.

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• 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.

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Best response

-

SCr <3.0 mg/dl Highest baseline serum creatinine in a terlipressin responder

-

No response

–

SCr > 7mg/dl Will there be a response in advanced disease ?????

5.6 mg/dl.

Hepatology 2011 terlipressin 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!!!

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Reversal of HRS with Terlipressin 36

Survival outcome with Terlipressin

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Norepinephrine for the treatment of HRS ?

Duvoux et al. Hepatology 2002

700 600 500 400 300 200 100 0 Day 0 Day 5

NA 0.5-3mg/h MAP >100mmHg increaase or U.O >50ml/h

Day 10

HRS reversal -83% Almost all respond – Day 5

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.

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Is there a single best vasoconstrictor ?

NO ADVANTAGE OF ONE VASOCONSTRICTOR OVER OTHER

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10 trials only type I and II Drug ± 376 patients 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)

Drug

Terlipressin Vasopressin Vasopressin Noradrenaline Noradrenaline Noradrenaline

Comparative costs

Strength Presentation Cost

£69.95

1mg 1 x 5 vial

Cost/unit £13.99/ 1mg vial

20units/ml (2ml) 20units/ml (1ml) 1:1000 (2ml) 1 x 10 (2ml amps) £320.50

1 x 25 (1ml amps) £133 1 x 5 (2ml amp) £9.50

£32.50/ vial (40units/2ml)

£5.32/ vial (20units/ml)

£1.90/vial (2ml)

1:1000 (4ml) 1 x 10( 4ml amp) £19 1 x 10 (8ml amp) £45 £1.90/vial (4ml) £4.50/vial (8ml) 1:1000 (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.

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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