Download Deep-HepRenSyn-Terlipressin - Pediatric Continuous Renal

Terlipressin
/Medical
Management in
Hepatorenal
Syndrome
Akash Deep, Director PICU
King’s College Hospital
London
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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 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
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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.
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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
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
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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
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
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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 - 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!!!
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Reversal of HRS with Terlipressin
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Survival outcome with Terlipressin
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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%
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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
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)
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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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