11

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.

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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

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

E Akriviadas Gastroenterology 2000; 119 : 1637; 119 : 1637

Pentoxifylline

Placebo

nonsurvivors

survivors

Survival : Age, creatinine level on randomization, and treatment with PTX

Pentoxifylline

Prevention • Avoid intravascular volume depletion & maintain an

effective circulating volumeo Gastrointestinal bleedingo Diureticso Diarrheao 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 pressureSugrue et al Arch Surg 1999 134:1082

Malbrain CCM 2005;33:315

263 patients 40.7% increased IAPRenal dysfunction:

32% with IAP elevated14% 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

Albumin

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Antioxidant effects and/or its high capacity to bind toxic substances

Stick to basics

Treatment - General

Treat associated conditions1.GI bleeding / hypovolaemia ( Surviving

Sepsis guidelines, measurement of haemodynamics, problems associated with IAP )

2.Infection3.Diuretics / nephrotoxic drugs4.Large volume ascites - TIPS / paracentesis5.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.

Vasoconstrictors to improve circulatory function:• Vasopressin analogueso Ornipressin- improvement of renal function but limited by

ischemic complicationso Terlipressin - lesser incidence of ischemia

• Midodrineo alpha-agonist, systemic vasoconstrictor

• Noradrenaline o alpha-agonist, systemic vasoconstrictor

• Octreotideo analogue of somatostatin, inhibitor of vasodilation.

Treatment

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

V2

V1a

V1b

Functional coupling

ATP

cAMPH

R s AC

PIP2

IP3, Ca2+

DAG, PKCH

R q/11 PLC

Asn5

NH2Arg8

Gly9

Pro7

Cys6

Cys1

Gln4

Phe3

Tyr2

SS

Vasopressin : Natural compound

Asn5

NH2Arg8

Gly9

Pro7

Cys6

Cys1

Gln4

Phe3

Tyr2

SS

Gly9

Gly9

Gly9

Asn5

NH2Lys8 Gly9

Pro7

Cys6

Cys1

Gln4

Phe3

Tyr2

SS

AVPAsn5

NH2Lys8 Gly9

Pro7

Cys6

Cys1

Gln4

Phe3

Tyr2

SS

LVP

Terlipressin

Vasopressin: Synthetic compounds

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).18

Vasopressin receptors

Action of Terlipressin

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Pathophysiology of CLD

Peripheral and splanchnic arterial dilatation

Reduced effective blood volume

Activation of renin-angiotensin-aldosterone systemSympathetic nervous system

ADH

Na retention &

Water retentionLow urinary Na

Dilutional hyponatraemia

AscitesSchrier et al Hepatol 1988

Plasma volume expansion

Renal vasoconstrictionReduced GFR

Ascites and OedemaHRS

Portal Hypertension

Vasopressin/

Terlipressin Increased blood volume

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 HRSSanyal A Gatroenterology 2008 :134:1360

1 mg 6 hrly vs placeboAlbumin in both groupsIf no response (30% decrease in creat) at day 4- dose doubled to 2mg 6 hrly14 days Rx : 56 in each grpSuccess defined as creatinine < 1.5 mg/dl for 48 hrs by Day 14Rx success : 34 vs 12.5 %

Best Predictor – Low baseline Serum creatinine

Similar survival between grps

HRS reversal improved180 day outcome

Sanyal A Gatroenterology 2008 :134:1360

• 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 albuminMartin-Llahi M Gastroenterology 2008:134

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 - 5.6 mg/dl.

No response – SCr > 7mg/dlWill there be a response in advanced disease ?????

terlipressin

placebo

Hepatology 2011

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

Survival outcome with Terlipressin

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Duvoux et al. Hepatology 2002

NA 0.5-3mg/hMAP >100mmHg increaase

or U.O >50ml/h

0

100

200

300

400

500

600

700

Day 0 Day 5 Day 10

Se

r. C

rea

t (u

mo

les

/l)

Norepinephrine for the treatment of HRS ?

HRS reversal -83% Almost all respond – Day 5

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

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Cost of noradrenaline 15 times << terlipressin82 % nor-ad responders – Transplant

80% terlipressin responders – Transplant80% Non-responders - DEATH

Noradrenalin is as effective and safe as terlipressin in patients with HRS.

Is there a single best vasoconstrictor ?

NO ADVANTAGE OF ONE VASOCONSTRICTOR OVER OTHER

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10 trials only type I and II376 patients

Drug ± alb vs no intervention

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 IRR 0.83 (0.65-1.05)

Terlipressin + Albumin vs Albumin

Comparative costs

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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)

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

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Conclusion• HRS often diagnosed - rarely present• Poor prognosis• Prevent infections, raised

IAP(paracentesis) and iatrogenic factors• Treat associated complications rapidly

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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

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