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National Guideline Centre (UK). Cirrhosis in Over 16s: Assessment and Management. London: National Institute for Health and Care Excellence (NICE); 2016 Jul. (NICE Guideline, No. 50.)
14.1. Introduction
Hepatorenal syndrome is a common complication in hospitalised people with decompensated cirrhosis, with an annual incidence in those with ascites of approximately 8%. It is characterised by impaired renal function.184 The diagnostic criteria of hepatorenal syndrome include: i) cirrhosis with ascites; ii) serum creatinine >133 μmol/L; iii) no improvement of serum creatinine after volume expansion with albumin; iv) absence of shock; v) no current or recent treatment with nephrotoxic drugs; and vi) absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells per high power field), or abnormal renal ultrasonography. Two types of hepatorenal syndrome have been described: type 1 is characterised by rapidly progressive reduction in renal function as defined by a doubling of the initial serum creatinine to a level greater than 220 μmol/litre or a 50% reduction of the initial 24-hour creatinine clearance to a level lower that 20 ml per minute in less than 2 weeks; type 2 has a slower time course.184 People with type 2 hepatorenal syndrome are especially predisposed to develop type 1 hepatorenal syndrome after infections, such as SBP. The prognosis of people with type 1 hepatorenal syndrome is bleak, with a mortality rate exceeding 50% after 1 month.11 Although people with type 2 hepatorenal syndrome have a median survival of 6 months, their prognosis is markedly worse than those with cirrhosis and ascites without renal impairment.11
Terlipressin, a vasoconstrictor most active in the splanchnic circulation, has been used to treat hepatorenal syndrome. It is given with a plasma volume expander, which serves to maintain the blood volume and increase the blood oncotic pressure, reducing the movement of free fluid into the peritoneum.
Liver transplantation is the definitive treatment for hepatorenal syndrome but vasopressor agents are used to treat hepatorenal syndrome in conjunction with a plasma volume expander as a bridge to transplantation in those participants considered suitable for this procedure. Human albumin solution is widely used as the plasma volume expander in people with hepatorenal syndrome due to cirrhosis but it is expensive. Therefore, the GDG decided to investigate which is the most clinical and cost-effective volume replacer for people with hepatorenal syndrome who are also receiving vasoactive drugs.
14.2. Review question: Which is the most clinical and cost-effective volume replacer for patients with hepatorenal syndrome due to cirrhosis who are also receiving vasoactive drugs?
For full details see review protocol in Appendix C.
Table 92
PICO characteristics of review question.
14.3. Clinical evidence
No relevant clinical studies comparing volume replacers in people with cirrhosis and hepatorenal syndrome and receiving vasoactive drugs were identified.
No studies were included in the review. See the excluded studies list in Appendix L.
14.4. Economic evidence
14.4.1. Published literature
No relevant economic evaluations were identified.
See also the economic article selection flow chart in Appendix F.
14.4.2. Unit costs
See Table 98 in Appendix O.
14.5. Evidence statements
14.5.1. Clinical
- No relevant clinical studies were identified.
14.5.2. Economic
- No relevant economic evaluations were identified.
14.6. Recommendations and link to evidence
| Recommendations | No recommendation was made. |
|---|---|
| Research recommendation |
|
| Relative values of different outcomes | The GDG compared albumin with other volume replacers for the management of hepatorenal syndrome in people with cirrhosis. The population considered was people receiving vasoactive drugs, as the GDG agreed that people with hepatorenal syndrome would always be given a vasopressor. The GDG also agreed that vasopressors would never be given in isolation without volume expansion, and they highlighted that there is evidence in the literature that vasopressors used without volume expansion are not efficacious.152 Current European and American guidelines support the use of intravenous albumin in combination with vasopressors for patients with hepatorenal syndrome. The GDG looked specifically for any evidence that other volume replacers may be more clinically and cost-effective than albumin. The GDG prioritised the critical outcomes of survival, health-related quality of life and reversal of hepatorenal syndrome when considering its recommendation for this question. The GDG also considered the important outcomes of hospital length of stay, hospital readmission rates and any reported adverse events related to the use of volume expanders. |
| Trade-off between clinical benefits and harms | No relevant clinical studies were identified. In the absence of clinical evidence, the GDG discussed the clinical benefits and harms associated with albumin and other volume replacers. The GDG agreed that a volume expander should be given due to the low intravascular volume state of patients with cirrhosis and hepatorenal syndrome. The GDG was in agreement that there would be potential harm in not offering volume expansion in combination with vasopressors in this situation. It also noted that whilst these patients are intravascularly deplete, the pathophysiology of decompensated cirrhosis is such that they are also fluid overloaded, but that the majority of fluid is outside the vascular compartment. People with decompensated cirrhosis are therefore more prone to complications of fluid overload, such as pulmonary oedema, if given intravenous fluids. The GDG felt that the ideal volume expander in this situation should be able to provide its effect with a minimum of infused fluid (that is, have a high oncotic pressure). The GDG favoured albumin as the volume expander in treating patients with hepatorenal syndrome as it provides volume expansion with a minimum of infused fluid (especially if the 20% solution is used); is not associated with any increased risk of renal injury; and is currently the most-studied fluid in patients with decompensated cirrhosis and infections, as discussed below. Potential harms of albumin were discussed, such as evidence that giving albumin can decrease the production of endogenous albumin. The GDG noted that there were some excluded studies, which provided data on the efficacy of intravenous fluids in patients with cirrhosis outside the specific situation of hepatorenal syndrome (for example, in people with SBP or people undergoing large-volume paracentesis). The GDG agreed that studies in these populations should be excluded, as there are different underlying physiological mechanisms which result in the need to give volume replacement and differences in effectiveness of volume replacers would be expected. Therefore, it was concluded that evidence from these populations could not be used as an indirect evidence base. These studies were not systematically reviewed, but some of these studies are referred to in ‘Other considerations’ below regarding the use of albumin and other volume replacers in people with cirrhosis. During large-volume paracentesis, intravenous volume replacement is recommended and current evidence supports the use of intravenous albumin in this situation.20 In SBP, intravenous albumin is recommended in combination with antibiotics when the serum creatinine is >1 mg/dl, blood urea nitrogen >30 mg/dl, or total bilirubin >4 mg/dl but is not necessary in patients who do not meet these criteria.201 Albumin has been shown to be superior to hydroxyethyl starch in spontaneous bacterial peritonitis (SBP).68 A separate consideration was the data (predominantly from critical care literature) which suggest that synthetic colloids (starch and gelatine) are associated with an increased risk of renal injury or the need for renal replacement therapy in patients with sepsis. The GDG considered that patients with decompensated cirrhosis are already at an increased risk of renal injury and so these synthetic colloids may not be appropriate.137,163,171 Although the GDG favoured the use of albumin over other volume expanders, given the lack of clinical evidence the GDG did not feel it could make a recommendation based on these potential benefits and harms without proof that patient outcomes would be improved. Instead the GDG chose to make a recommendation for future research. |
| Trade-off between net clinical effects and costs | No relevant published economic evidence was identified. The GDG noted the relative expense of albumin in comparison to crystalloids, however it also noted the points raised above regarding the greater safety of albumin and the greater quantity of evidence for the use of albumin in other situations. On balance, given the lack of evidence regarding comparative clinical effectiveness or cost-effectiveness, the GDG was not able to recommend any specific volume replacer. |
| Quality of evidence | No relevant clinical studies were identified. |
| Other considerations | The GDG noted the original question of the most clinically and cost-effective volume expander in the management of hepatorenal syndrome. There was no clinical evidence identified that specifically answered this question, however the GDG did feel that this was a clinically important question to have asked, as it is an issue that is often debated in the management of such patients. The GDG discussed the current dichotomy between intensive therapy unit (ITU) and hepatology wards in the volume replacers used for this population. For this reason, the GDG felt it was important to make a recommendation for future research to investigate the most clinically and cost-effective volume expander to be used in patients with hepatorenal syndrome receiving vasoactive drugs. Research recommendation Hepatorenal syndrome develops in people with cirrhosis with ascites and is characterised by impaired renal function.184 Terlipressin, a vasoconstrictor most active in the splanchnic circulation, is used to treat hepatorenal syndrome but it is given with a plasma volume expander, which serves to maintain the blood volume and increase the blood oncotic pressure, reducing the movement of free fluid into the peritoneum. Human albumin solution is the recommended intravenous volume replacement during large-volume paracentesis20 and in patients with SBP, in combination with antibiotics, when the serum creatinine is greater than 1 mg/dl, blood urea nitrogen greater than 0 mg/dl, or total bilirubin greater than 4 mg/dl.201 However, in hepatorenal syndrome there are no clinical studies examining the benefits and harms associated with albumin compared with other volume replacers. People with hepatorenal syndrome have a low intravascular volume state and there is general agreement that they require volume expansion in combination with vasopressors. Whilst these people have intravascular depletion, the pathophysiology of decompensated cirrhosis is such that they are also fluid overloaded, but that the majority of fluid is outside the vascular compartment. People with decompensated cirrhosis are therefore more prone to complications of fluid overload, such as pulmonary oedema, if given intravenous fluids. The ideal volume expander to be used in hepatorenal syndrome should be able to provide its effect with a minimum of infused fluid (that is, have a high oncotic pressure). |
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