Critical Care Journal Reading

1. Critical Care Journal Reading Medical management of hepatorenal syndrome Nephrol Dial Transplant (2012) 27: 34–41 doi: 10.1093/ndt/gfr736 Andrew Davenport1, Jawad Ahmad2, Ali Al-Khafaji3, John A. Kellum3, Yuri S. Genyk4 and Mitra K. Nadim5 2012/03/26 R2鄭雅婷/ Supervisor 張智翔醫師

2. Introduction • Hepatorenal syndrome (HRS) is defined as the occurrence of acute kidney injury (AKI) in patients with end-stage liver cirrhosis in the absence of another identifiable cause • Untreated, median survivalis 2 weeks for patients with Type 1 HRS and 4–6 months inpatients with Type 2 HRS

3. The International Ascites Club

4. Acute Dialysis QualityInitiative (ADQI) • A consensus conferenceunder the auspices of the Acute Dialysis QualityInitiative (ADQI) was held in 2010 • Appraise the existingevidence • Develop a set of consensus recommendations to standardize care and direct further research

5. Materials and methods • The ADQI methods comprise • Systemic search for evidence with review and evaluation of the available literature • The establishment of clinical and physiologic outcomes as well as measures to be used for comparison of different treatments • The description of the current practice and the rationale for the use of current techniques • Analysis of areas in which evidence is lacking and future research is required

6. Materials and methods

7. Systemic review of the literature • Using key terms relevant to the topic and electronic reference libraries • Focus on human studies • Limited to English language articles • Published between January 1960 and December 2009 • The majority of the work group resources were devoted to review of randomized trials, as these were deemed to be most likely to provide data to support Level 1 recommendations with very high- or high-quality (A or B) evidence

8. Evaluation of studies • A three-phase approach was used to construct the evidence-based recommendations • A systematic literature review of studies in HRS and AKI in patients with cirrhosis • A comprehensive appraisal of prior studies • Convening an expert panel to synthesize information and develop consensus-based recommendations • Recommendation statements were incorporated • if there was strong literature-based evidence • if the expert panel voted that the recommendation was appropriate

9. Grading evidence and recommendations

10. ADQI process

11. Result General management strategies

12. Prevention of HRS • Patients with hypotensive may have a reduced cortisol response (hepatoadrenal syndrome) and thus covert hypoadrenalism should be considered and treated appropriately to improve response not only to vasopressors but also survival • Drugs reported to precipitate HRS in patients with cirrhosis should be avoided • Radiocontrast media have not been established as causing AKI in cirrhotics

13. Drugs reported to precipitate HRS in patients with cirrhosis

14. Antibiotic prophylaxis to reduce SBP • Norfloxacin • Reduction in SBP (7 versus 61%) • Rreduction in the incidence of HRS (28 versus 41%) • Oxypentifyllin • A tumor necrosis factor-a antagonist • Reduced complications in patients with advanced cirrhosis, including renal dysfunction • Albumin infusions have been reported to decrease the incidence of HRS in patient with SBP

15. Recommendations for clinical practice • Type 1 HRS patients should be closely monitored and precipitating factors including bacterial infection should be actively sought and treated (not graded) • Drugs reducing renal perfusion or directly causing nephrotoxicity should be avoided (1C) • Exposure to contrast should be minimized to reduce contrastinduced kidney injury (1D)

16. Assesment of intravascular volumn in patient with cirrhosis • Intravascular volume expansion, which is often necessary to treat HRS, can potentially lead to worsening of ascites, pleural effusion or heart failure • Assessment of intravascular volume in HRS is difficult as the standard static hemodynamics measurements of CVP and PCWP are not reliable markers of circulatory • An infusion of 20% albumin significantly increasing central blood volume and cardiac index, without changes in CVP • The response to a fluid challenge in cirrhotics is likely to be abnormal, as any fluid bolus which initially expands the intravascular space, will subsequently expand the ‘third space’

17. Recommendations for clinical practice • Excessive administration of fluids should be avoided to prevent volume overload due to the presence of kidney injury and development or progression of dilutional hyponatremia (1D). • Traditional methods in predicting volum responsiveness and should not be relied on (1C).

18. Recommendation for future research • Prospective studies, specifically of volume assessment with hemodynamic monitoring tools in patients with HRS

19. Fluid resuscitation in HRS • In advanced liver disease, volume expansion does not always resolve hypotension, most likely due to the increased vascular compliance in cirrhotics • The choice of intravenous fluids used in cirrhotics remains controversial • Volume expansion with albumin has been shown to reduce plasma renin, suggesting an improvement in the effective circulating volume • In randomized controlled clinical trials, albumin infusions reduced both the incidence of HRS and mortality

20. Fluid resuscitation in HRS • Studies have shown that the use of vasopressors with albumin improves renal function and mortality compared to vasopressor alone • In one randomized study in patients with SBP, albumin significantly • Increased mean arterial pressure (MAP) and suppressed plasma renin activity, compared to hetastarch • Serum nitrates increased with hetastarch but not with albumin • Less neurohumeral activation compared to other colloids • Less volume expanders post-large-volume paracentesis • Plasma von Willebrand-related antigen fell significantly

21. Recommendations for clinical practice • Intravenous administration of albumin (initially 1 g of albumin/kg of body weight, up to a maximum of 100 g, followed by 20–40 g/day) in combination with vasopressor therapy (1A) • For up to 14 days (2D)

22. Paracentesis • AKI due to abdominal compartment syndrome is well recognized with intra-abdominal pressures (IAP) typically >18 mmHg • Uncontrolled studies have reported an improvement in renal function in patients with HRS following paracentesis for raised IAP

23. Recommendation for future research • Prospective studies are required to investigate the effect of reducing IAP on renal function in patients at risk of developing or with established HRS

24. Pharmacological treatment of HRS • Splanchnic vasodilatation plays a key role in the pathogenesis of HRS • The prospective trials focused on treatment if type 1 HRS with vasocontrictiors reported an improvement in renal function (but not a survival benefit)

25. Vasopressin • Activation V1 receptor leads to vascular smooth muscle contraction • High density of V1 receptors in the splanchnic bed make this vasculature especially responsive to vasopressin

26. Terlipressin • Distinctive vasopressin analog • Preferential effects on the V1 receptor • Lower rate of ischemic complications • The most widely studied agent for Type 1 HRS • Several small studies have demonstrated that terlipressin significantly decreases plasma renin and aldosterone, with an improvement in glomerular filtration rate (GFR) in patients with type 1 HRS • The importance of albumin infusion to terlipressin therapy was emphasized in a prospective study of predominantly Type 1 HRS

27. Three randomized prospective trials • Terlipressin dosages ranged from 2 to 12 mg/day in divided doses and 20–40 g/day of albumin. • The duration of therapy is usually ≤ 2 weeks • The aim is to improve renal function sufficiently to decrease the Scr <1.5 mg/dL (complete response) • Renal function was improved in Type 1 HRS • There are no studies on how best to discontinue terlipressin therapy, and whether this affects HRS recurrence • Studies have focused on changes in Scr rather than titrating terlipressin to achieve a target MAP • In most studies, there were no overall survival benefits

28. Trials for Terlipressin • More recent studies have focused on early predictors of response with a baseline serum bilirubin (<10 mg/dL) and an increase in MAP of 5 mmHg by Day 3 predicting response • Terlipressin may be beneficial in cirrhotics with ascites and renal impairment before they fulfill the diagnostic criteria for HRS, by decreasing plasma renin and norepinephrine and increasing GFR and natriuresis • Patients with additional comorbidities such as ischemic heart and peripheral vascular disease have typically been excluded from studies

29. Norepinephrine (noradrenaline) • A catecholamine but its alpha-adrenergic activity • Potent vasoconstrictor of both the venous and arterial vasculature • A pilot study Type 1 HRS used norepinephrine at a dose titrated to achieve an increase in MAP of 10 mmHg or an increase in 4-h urine output to >200 mL • Reversal of HRS occurred in 83%, with improvement in urine output, sodium excretion, serum sodium concentration, creatinine clearance, MAP, plasma renin activity and aldosterone

30. Octreotide and midodrine • Oral midodrine, an alpha-adrenergic receptor agonist • Vascular smooth muscle vasoconstriction • Subcutaneous octreotide : long-acting somatostatin analogue which is used reduce portal hypertension after variceal hemorrhage • Early studies in Type 2 HRS demonstrated no improvement in renal function with midodrine or octreotide • The combination of thrice daily midodrine 7.5–12.5 mg and octreotide 100–200 μg, and albumin, improved renal plasma flow, GFR and urinary sodium extraction in Type 1 HRS after 3 weeks of treatment

31. Other agents • Ornipressin, a vaspressin analogue • High rate of ischemic complications (including ischemic colitis and tongue ischemia) requiring ornipressin withdrawal • N-acetyl cysteine reported to help reverse HRS in case reports, but awaits confirmation • Oxypentifylline, used in alcoholic hepatitis, has been reported to reduce the incidence of HRS, but has not been shown to improve renal function in established HRS

32. Recommendations for clinical practice • In type 1 HRS, patients optimally resuscitated with albumin (initially 1 g of albumin/kg of body weight for 2 days, up to a maximum of 100 g/day, followed by 20–40 g/day) in combination with a vasoconstrictor (1A), preferentially terlipressin (2C) • Therapy should be discontinued after 14 days in non-responders and only continued thereafter in partial responders while awaiting the outcome of salvage techniques (2D).

33. Recommendation for future research • Prospective trials are required to determine the optimum mode of delivery of terlipressin (bolus versus infusion). • Comparative trials of vasoconstrictors are required to determine the merits of vasopressin analogs against norepinephrine

34. Conclusions • Although the introduction of terlipressin and albumin has improved the outlook for patients with HRS, only ~50% of patients respond to therapy • Questions remain • Whether earlier introduction of this therapy would help prevent the development of HRS • In patients with established HRS how best to administer terlipressin and if targeting vasoconstrictor dosage to an absolute or relative increase in MAP improves response • The effects of changes in IAP on renal function have not been explored