The Use of Albumin for the Prevention of Hepatorenal Syndrome in Patients with Spontaneous Bacterial Peritonitis and Cirrhosis http://www.funnyjunk.com/funny_pictures/1743659/enlarged/ Daniel Giddings, PharmD PGY-1 Pharmacy Practice Resident St. David's South Austin Medical Center October 4, 2013 Learning Objectives: 1. Describe the diagnostic criteria, pathogenesis and epidemiology of hepatorenal syndrome and spontaneous bacterial peritonitis (SBP). 2. Compare treatment guidelines for the use of albumin for the prevention of hepatorenal syndrome in SBP. 3. Examine the evidence base for use of albumin in these patients. 4. Determine albumin's role in the prevention of hepatorenal syndrome in SBP patients. 1
Hepatorenal Syndrome Introduction 1 Renal failure in patients with cirrhosis is relatively common, and can be attributed in some to dehydration or intrinsic renal parenchymal disease such as glomerulonephritis. In other cases, however, renal failure is not accompanied by any underlying renal pathology and cannot be attributed to other factors; this is known as hepatorenal syndrome. Diagnosis 1 Entirely a diagnosis of exclusion in patients with cirrhosis and ascites with associated renal impairment Treatment guidelines both reference diagnostic criteria put out by the International Ascites Club, updated last in 2007 The six criteria are: o Presence of cirrhosis with ascites o Renal impairment, as indicated by a serum creatinine of greater than 1.5mg/dL o No improvement in renal impairment (reduction in serum creatinine to < 1.5mg/dL) despite diuretic withdrawal and volume expansion with albumin (1g/kg actual body weight up to 100g) for 2 days o Absence of shock o No current or recent treatment with nephrotoxic drugs, such as aminoglycosides o Absence of parenchymal kidney disease as indicated by proteinuria of more than 500mg/day, microhematuria (> 50 RBC/hpf), and/or abnormal renal ultrasound Can be separated into two dynamic classes o Type 1 - A doubling in serum creatinine that reaches at least 2.5mg/dL over the course of at least two weeks o Type 2 - Cases that meet diagnostic criteria without meeting the criteria for Type 1 hepatorenal syndrome Pathogenesis 1,2 Centers around extreme renal vasoconstriction as a result of pathological splanchnic vasodilation The underlying cirrhotic process causes increased splanchnic vascular resistance and portal hypertension This leads to a decrease in systemic vascular resistance (SVR) through local release of vasodilators, including nitric oxide (NO), carbon monoxide, and endogenous cannabanoids o Bacterial translocation from the intestines may also play a role through the inflammatory response (could explain the relationship to SBP) Initially, cardiac output is increased to compensate for this decrease in vascular resistance (recall the formula: BP = SVR x CO) As portal hypertension and decrease in SVR progress, vasoconstrictor systems activate to keep blood pressure normal, including the RAAS system, the sympathetic nervous system, and the release of ADH These systems cause intense vasoconstriction in the renal arteries, leading to renal hypoperfusion, salt and water retention, and renal failure 2
Portal Hypertension Caused by underlying cirrhosis, leads to increased vascular resistance in splanchnic system Splanchnic Vasodilation Reponse to underlying cirrhosis and portal hypertension Compensatory Response Includes increased cardiac output and activation of vasoconstricting systems, including RAAS, ADH, and sympathetic nervous system activation Renal failure and Hepatorenal Syndrome Due to extreme vasoconstriction of the renal arteries mediated by the compensatory response Precipitating Factors 1 Bacterial infection, including spontaneous bacterial peritonitis (SBP) o SBP is the only infection with a clearly demonstrated relationship to hepatorenal syndrome Large-volume paracentesis without volume repletion Gastrointestinal bleeding Hypovolemic shock Over-diuresis (no study evidence for this) Epidemiology and Prognosis Overall incidence of hepatorenal syndrome was estimated to be 40% at 5 years in one study Renal failure in patients with cirrhosis and ascites is associated with a poor prognosis, but the development of hepatorenal syndrome indicates an even poorer one 3
Probability of survivial in cirrhotic patients with different renal impairments. SBP Diagnosis 3,4,5,6 Presentation is variable, and may include fever (mostly commonly), abdominal pain, altered mental status, diarrhea, or paralytic ileus Patients may be asymptomatic; thus diagnostic paracentesis should be performed in all patients who: o Have new-onset ascites o Develop symptoms such as unexplained encephalopathy or renal failure o Are stable, but suddenly deteriorate A PMN count > 250 cells/mm 3 is diagnostic of SBP Pathogenesis 3,4 Still unclear, but thought to be due to the translocation of bacteria from the intestinal lumen to the mesenteric lymph nodes, and thus to the peritoneum o Intestinal dysmotility and subsequent bacterial overgrowth may contribute o Oxidative stress and decreased bile acid synthesis may lead to increased permeability of the intestinal walls to bacteria and bacterial products (endotoxin, bacterial DNA) Could also be due to bacteremia from urinary or respiratory tract infections Cirrhotic patients are generally more susceptible to infections Risk Factors 3,4 GI bleeding Prior episode of SBP Ascitic fluid albumin concentrations of less than 1g/dL 4
Epidemiology and Mortality 3,4,5,6 Prevalence studies from the 1970's showed a prevalence of 5-10%, but newer studies using modern diagnostic criteria show a prevalence of roughly 10-30% of patients admitted to hospitals with cirrhosis In-hospital mortality rates have fallen from 90% to around 10-30% o Renal impairment is a strong predictor of mortality; progressive renal failure was associated with an in-hospital mortality of 100% in one study, with stable renal impairment being associated with a 31% mortality rate and no renal impairment only 7% o Other predictors of mortality include elevated BUN and serum bilirubin, positive ascitic fluid cultures, and age Treatment Guidelines 5,6 Two regularly updated guidelines that address the treatment and prevention of hepatorenal syndrome: o The American Association for the Study of Liver Diseases (AASLD) o The European Association for the Study of the Liver (EASL) AASLD Guidelines Class IIa, Level B Patients with ascitic fluid PMN counts greater than or equal to 250 cells/mm 3 (0.25 x 10 9 /L) and clinical suspicion of SBP, who also have a serum creatinine >1 mg/dl, blood urea nitrogen >30 mg/dl, or total bilirubin >4 mg/dl should receive 1.5 g albumin per kg body weight within 6 hours of detection and 1.0 g/kg on day 3. EASL Guidelines Class I, Level B Until more information is available, we recommend that all patients who develop SBP should be treated with broad spectrum antibiotics and intravenous albumin (1.5 g/kg at diagnosis and 1g/kg on day 3). Albumin 7,8 Overview Albumin is an endogenous protein 66,500 kda in molecular weight that exerts most (70-80%) of the colloid oncotic pressure in blood plasma Derived for pharmaceutical use from pooled human plasma Distributes widely in the vasculature and extravascular space Acts as a transport molecule for a variety of endogenous substances and drugs, including: o Nitric oxide o Fatty acids o Metals o Cholesterol o Phenytoin (recall corrected phenytoin level in hypoalbuminemia) o Digoxin Exerts a strong oncotic pressure and can serve as a vascular volume expander (this is its FDA labeled indication) Serves as a thiol sink and is the major contributor of extracellular thiols, which are scavengers of reactive oxygen and nitrogen species Available in the US as a 5% and 25% solution Mechanism of Action in the Prevention of Hepatorenal Syndrome 5
Albumin's function as a plasma volume expander may serve to compensate for the decrease in SVR caused by cirrhosis and portal hypertension (this is likely the primary mechanism of action in the prevention of hepatorenal syndrome) Antioxidant effects may play a role by decreasing the release of vasodilators from cirrhotic liver tissue Albumin may bind bacterial endotoxins and DNA fragments that contribute to hepatorenal syndrome via bacterial translocation As discussed in guidelines, albumin must be combined with a vasoconstrictor to maximize effectiveness in the treatment of SBP Costs and Adverse Effects Available as a generic: AWP for 25g of 25% albumin is $64.50 For reference, a guideline-recommended course of albumin in a 70kg SBP patient would cost roughly $450 at AWP Contraindications and Precautions o Contraindicated in cardiac failure: leads to circulatory overload o Use with caution in patients with renal or hepatic impairment, as protein load may precipitate azotemia or encephalopathy o Pulmonary or peripheral edema may result from overly rapid infusion o Hypersensitivity reactions have occurred o Blood product: though pasteurized, cannot rule out transmission of infective agents Literature Review Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis 9 Objective: To determine whether plasma volume expansion with albumin could prevent the impairment of renal function and reduce mortality in patients with SBP. Methods Multicenter, randomized, controlled trial Inclusion and exclusion criteria (notice parallels to hepatorenal syndrome and SBP diagnostic criteria) o Ascitic fluid PMN count > 250 cells/mm 3 o Absence of findings suggestive of secondary peritonitis o Absence of shock, GI bleed, grade 3 or 4 hepatic encephalopathy, HIV infection, cardiac failure, and other infections o Serum creatinine no more than 3 mg/dl o Severe dehydration within one week of diagnosis of peritonitis, as evaluated clinically or by CVP < 4 199 patients were evaluated, 126 were included Patients were randomized to either renally adjusted cefotaxime or renally adjusted cefotaxime plus 20% albumin 1.5g/kg on day 1 and 1g/kg on day 3 of enrollment Follow-up lasted 90 days from the enrollment period Renal impairment at the time of enrollment was defined as a BUN of > 40 mg/dl or a serum creatinine of > 1.5 mg/dl In patients without renal impairment at baseline, a 50% increase in BUN or serum creatinine to levels above 40 mg/dl and 1.5 mg/dl respectively was diagnostic for renal impairment during treatment 6
For patients with renal impairment at baseline, simply a 50% increase in BUN or serum creatinine was diagnostic for worsening renal failure 50 patients in each group were required for an 80% power to detect a 25% difference in the rate of renal failure Results Clinical outcome according to assigned treatment. Cefotaxime Outcome Variable Cefotaxime (n = 63) plus albumin (n = 63) p Value Resolution of infection - No. (%) 59 (94) 62 (98) 0.36 Duration of antibiotic therapy - days 6±1 5±1.48 Paracentesis for ascites after resolution of infection - 16 (25) 14 (22).83 no. (%) Hospital stay - days 13±1 14±1.48 Renal impairment - no. (%) 21 (33) 6 (10) 0.01 Death - no (%) In hospitals At three months 18 (29) 26 (41) In-hospital mortality according to variables with independent predictive value. Variable Bilirubin <4 mg/dl Prothrombin time 60% of control Prothrombin time < 60% of control Bilirubin 4 mg/dl Prothrombin time 60% of control Prothrombin time < 60% of control 6 (10) 14 (22) 0.01 0.03 Cefotaxime (n = 63) Cefotaxime plus albumin (n = 63) BUN <30 mg/dl BUN 30 mg/dl BUN <30 mg/dl BUN 30 mg/dl no. of patients who died/total no. (%) 0/13 0/7 3/6 (50) 2/8 (25) 0/10 0/14 1/10 (10) 2/5 (40) 1/3 (33) 1/5 (20) 0/0 0/1 4/12 (33) 7/9 (78) 0/16 3/7 (43) Total 5/35 (14) 13/28 (46) 0/40 6/23(26) Mortality and progression to renal failure were significantly reduced in the cefotaxime plus albumin group Importantly, BUN > 30 mg/dl, bilirubin > 4mg/dL, and prothrombin time > the control group were independent predictors of mortality All patients in the trial had a baseline serum creatinine of 1.1±0.1 (control group) or 1.2±0.1 (treatment group) 89% of patients who developed renal failure and 16% of patients who did not develop renal failure had died at 3-month followup Discussion and Conclusions 7
The authors conclude that albumin plus empiric antibiotic treatment is more effective at reducing mortality and progression to renal failure in patients with SBP than empiric antibiotics alone The trial helps confirm that progressive renal failure and hepatorenal syndrome are indicative of a poor prognosis Trial strengths o Randomized and adequately controlled o Endpoints and inclusion criteria consistent with the disease states being studied (PMN count in ascitic fluid, serum creatinine cutoffs, etc.) o Demonstrated a mortality benefit o Appropriate statistical analysis Trial weaknesses o Benefit was most apparent in patients with BUN > 30 mg/dl and bilirubin > 4mg/dL, and only patients with a serum creatinine above 1.0 were included in the trial o Does not shed light on whether albumin is unique or other plasma volume expanders would be effective for the same purpose (the authors address this in their discussion) o Control patients may have been sicker Restricted use of albumin for spontaneous bacterial peritonitis 10 Objective: To assess whether albumin treatment is needed in all cases of SBP or whether a risk stratification strategy is desirable. Methods A 28 patient prospective case series in two medical centers Patients with a bilirubin > 4 or a serum creatinine > 1.0 were treated with albumin 1.5g/kg on day 1 and 1g/kg on day 3 of treatment along with empiric antibiotics Low-risk patients (serum creatnine < 1.0 and bilirubin < 4) were treated only with empiric antibiotic therapy Results Selected clinical characteristics of patients at diagnosis of spontaneous bacterial peritonitis episodes who did receive (A) and who did not receive (B) albumin. A (n = 26) B (n = 18) p Value Total bilirubin(mmol/l) 115 (12-395) 39 (14-67) <0.001 BUN (mg/dl) 28.5 (7-74) 18(5-48) 0.003 Creatinine (mmol/l) 124 (35-327) 80 (53-106) 0.001 In the low-risk group, SBP resolved in all patients and no patients developed renal impairment. In the high-risk group, 12 patients developed renal impairment and five patients died. Discussion and Conclusions The authors conclude that albumin is not needed in all SBP patients Strengths o Used parameters based on the single randomized, controlled trial performed for this intervention o Used established guidelines for diagnosis and treatment of SBP and hepatorenal syndrome 8
o Calculated p values Weaknesses o No control group o Small case series Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials 11 Objective: To quantify the effect of albumin infusion on renal impairment and mortality in patients with SBP. Methods A meta-analysis limited to only randomized, controlled trials evaluation albumin in SBP patients o No language or time period restrictions All three investigators independently determined trial inclusion eligibility Endpoints of the analysis were renal impairment (as defined by the included trials) and mortality Heterogeneity was judged using the Cochran Q test and the I 2 test Results of the trials were combined under a fixed-effects model Results Renal impairment. Confidence interval (CI) is shown by error bars. Data points for individual trials scaled accordingly to meta-analytic weight. 9
Improvement in the incidence of renal impairment and mortality were shown o Removing either of the two most heavily weighted studies did not change the overall conclusion No differences shown between subgroups, however, a non-significant increase was seen in the incidence of renal impairment and mortality in patients with BUN > 30 mg/dl and/or bilirubin > 4 Discussion and Conclusions The authors conclude that albumin is effective for prevention of renal failure and mortality in SBP patients with cirrhosis. Strengths o Relied only on randomized, controlled trials o Appropriate statistical analysis o Robust results Weaknesses o Small sample size o 3 out of the 4 trials were not blinded Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study 12 Objective: To determine if albumin has beneficial effects outside of patients with cirrhosis that develop SBP. Methods Single center, randomized, controlled trial Inclusion criteria o Cirrhosis, diagnosed by liver biopsy or by clinical findings according to published guildelines o Presence of infection, diagnosed by cultures or clinical suspicion with at least one of the following: PMN count > 10,000 cells/mm 3 or 50% increase from baseline with a final value above 8,000 cells/mm 3 5% or greater bands Temperature > 37.5 C Exclusion criteria o GI bleed o Previous antibiotic treatment 10
o Malignancy o HIV infection o Presence of shock 51 patients were randomized to each group (control and treatment) Control group received only empiric antibiotic treatment with: o IV ceftriaxone for UTI, sepsis of unknown origin, or spontaneous bacteremia o IV ceftriaxone plus cloxacillin or Augmentin for SSTI o IV ceftriaxone and a macrolide or levofloxacin (with clindamycin for aspiration) for CAP o IV ceftazadime plus ciprofloxacin for HAP o IV vancomycin and ceftazadime for catheter-related infections Intervention group received empiric antibiotic therapy plus albumin 1.5g/kg on day 1 and 1g/kg on day 3 Primary endpoint was 3-month mortality Secondary endpoints were the effects on serum creatinine, percentage of patients who developed renal failure, and effects on circulatory and vasoactive variables Study sized for an 80% power to detect a 30% difference in survival rates Results Three-month probability of survival. Univariate analysis of the 3-month survival according to baseline variables, characteristics of infection, and occurrence of renal failure. 11
Variable Alive (n = 79) Death (n = 18) p Value Age (yr) 55 ± 11 60 ± 12 0.158 Ascites at inclusion 54 (68%) 17 (94%) 0.036 Hepatic encephalopathy at inclusion 24 (30%) 11 (61%) 0.027 Nosocomial infection 11 (14%) 10 (56%) <0.0001 Serum bilirubin (mg/dl) 3.5 ± 3.3 9.8 ± 8.6 0.007 Serum albumin (mg/dl) 29 ± 6 26 ± 4 0.024 Serum creatinine (mg/dl) 1.2 ± 0.6 1.3 ± 0.6 0.258 BUN (mg/dl) 24 ± 19 37 ± 21 0.010 Renal failure during infection 15 (19%) 10 (56%) 0.006 Overall, there were no significant differences in the unadjusted 3-month mortality rates between the control and intervention groups (80% survival in the control group vs. 82.6% survival in the intervention group) Significance was shown when the results were adjusted for variables shown in univariate analysis to have independent predictive value Differences in the incidence of renal failure and in serum creatnine concentrations between the control and intervention groups did not reach statistical significance o Compared to SBP patients, renal failure did not occur as often in the control group of this study o Mortality was also lower in the control group compared to SBP patients not treated with albumin Discussion and Conclusions The authors conclude that albumin treatment in patients with bacterial infections other than SBP is not associated with a significant decrease in either 3 month mortality or the incidence of renal failure The overall incidence of renal failure and mortality in the trial's control group reveals that the overall difference in prognosis between SBP and other bacterial infections may help explain the negative results of this trial Strengths o Randomized and controlled o Used mortality as an endpoint o Statistical analysis appropriate, including power calculation, and did not overstep with conclusions based on post-hoc adjustment of results Weaknesses o Power estimate greatly overstated the actual effect size o Needed to adjust results for statistical significance Conclusions Albumin is effective for the prevention of progression to hepatorenal syndrome and renal failure in SBP patients There is a small body of evidence that suggests that albumin is not needed in all SBP patients, but more study is needed No evidence to suggest that albumin is effective in other bacterial infections in cirrhotic patients More evidence is needed to inform about the optimal dose of albumin in SBP patients o Trials underway (ClinicalTrials.gov: NCT00761098) 12
References 1. Diagnosis, prevention, and treatment of hepatorenal syndrome in cirrhosis. Salerno F, Gerbes A, Gines P, et al. Gut. 2007;56:1310-1308. 2. Mechanisms promoting bacterial translocation from the gastrointestinal tract. Berg RD. Adv Exp Med Biol 1999;473:11-30 3. Spontaneous bacterial peritonitis: recent data on incidence and treatment. Mansour PA, Atreja A, Zein NN. Cleve Clin J Med. 2004;71(7):569-76. 4. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: Incidence, clinical course, predictive factors and prognosis. Follo A, Llovet JM, Navasa M, et al. Hepatology 1994;20:1495 1501. 5. Management of adult patients with ascites due to cirrhosis: update 2012. Runyon, BA for the AASLD. Hepatology 2013;57(4):1651-3. 6. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. EASL. Hepatology 2010;53:397-417. 7. Albumin. Lexi-Comp Online, Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.; Accessed September 22, 2013. 8. Albumin for end-stage liver disease. Lee JS. Korean J Intern Med 2012(27):13-19 9. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. Sort P, Navasa M, Arroyo V, et al. N Engl J Med 1999;341:403-409. 10. Restricted use of albumin for spontaneous bacterial peritonitis. Sigal SH, Stanca SM, Fernandez J, et al. Gut 2007;56(4):597-599 11. Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials. Salerno F, Navickis RJ, Wilkes MM. Clin Gastroenterol Hepatol 2013;11(2):123-130 12. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. Guevara M, Terra C, Nazar A, et al. Hepatology 2012;57:759-765 13
Appendix A: Included Trials in the Meta-analysis from Salerno et al. Table 1. Included Trials Trial N Age (SD) Sort et al, 1999 Xue et al, 2002 Fernandez et al, 2005 Chen et al, 2009 126 61.0 (7.9) Male, % Ethnicity Etiology Treatment regimen 64.3 Caucasian 29.4% alcohol, 70.6% other Cefotaxime intravenously dosed according to creatinine without vs with 1.5g/kg 20% albumin within first 6 h plus 1.0 g/kg on day 3 112 22-70 - Chinese - Ceftriaxone intravenously dosed according to creatinine without vs with 0.5-1.0 g/kg 20% albumin within first 6 h and every third day for 21 days 20 61.0 (9.5) 30 56.5 (11.5) 55 Caucasian 60.0% HCV, 40.0% other 60 Chinese 60.0% HBV<comma> 23.3% HCV<comma> 16.7% alcohol Ceftriaxone intravenously 2 g at diagnosis and then 1 g/d plus 1.5 g/kg at baseline and 1.0g/kg on day 3 of 20% albumin vs 6% HES 200/0.5 Cephalosporins without vs with 50 ml 20% albumin (0.14 g/kg∠1 for a 70-kg patient) on days 1â 3 14