Effect of low dose albumin administration in spontaneous bacterial peritonitis on renal function and survival

Arab Journal of Gastroenterology xxx (xxxx) xxx

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Original article

Effect of low dose albumin administration in spontaneous bacterial peritonitis on renal function and survival Elloumi Hela, Sabbah Mériam ⇑, Bibani Norsaf, Trad Dorra, Elleuch Nour, Gargouri Dalila, Ouakaa Asma, Kharrat Jamel Department of Gastroenterology, Habib Thameur Hospital, 3, rue Ali Ben Ayed, Montfleury 1002, Tunis, Tunisia

a r t i c l e

i n f o

Article history: Received 14 November 2016 Accepted 3 November 2019 Available online xxxx Keywords: Spontaneous bacterial peritonitis Cirrhosis Low dose albumin

a b s t r a c t Background and Study Aims: Current guidelines favour albumin administration during spontaneous bacterial peritonitis (SBP). However, its use is limited in clinical practice and low doses are preferred. The aim of our study was to determine the effect of low dose albumin perfusion during SBP on mortality and prevention of hepatorenal syndrome (HRS) in cirrhotic patients. Patients and methods: A retrospective study including consecutive patients with SBP hospitalized from 2002 to 2015 was performed. All patients were treated by intravenous empiric antibiotics associated with albumin infusion (30 g/day the first and third day) irrespective of patient’s weight. The diagnosis of HRS was assessed according to the International Ascites Club criteria. The survival, the frequency of HRS and any disturbance in renal function were recorded. Results: Fourty nine patients (sex ratio = 0.81, mean age 60.6 years [23–89]) were included. Main cause of cirrhosis was hepatitis B and C in 42.9% of cases. 63.3% were of Child Pugh C score%. The first line intravenous antibiotic treatment was based on cefotaxime in 87.8% of cases, followed by ofloxacin in 6.1% of cases. The outcome was favourable in 85.7% of cases. HRS was observed in 9 patients (18.3%) within 18 months [1–55]. Otherwise, 10 patients (20.4%) experienced an increase in creatinine level despite of albumin perfusion. The immediate mortality was 4%, and the six months survival was of 81.8%. Conclusion: Despite even a low dose administration of albumin during SBP, renal dysfunction and HRS occurred less than described in literature. These results associated with cost considerations could suggest to use such an intervention during SBP or to select high risk patients who must receive albumin perfusion during SBP. Ó 2019 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Introduction Spontaneous bacterial peritonitis (SBP) may precipitate deterioration of circulatory dysfunction with severe hepatic insufficiency, hepatic encephalopathy, and type-1 hepatorenal syndrome (HRS) and has a 30% hospital mortality even with resolution of infection [1]. Therefore, current international guidelines [2,3] support albumin administration during SBP. However, recent studies showed that only high risk patients (with high level of bilirubin and creatinine during SBP) should be treated by albumin perfusion [4]. The dose usually used is 1;5g/kg at diagnosis and 1 g/kg in the third day. This regimen has been shown to decrease the frequency of HRS and to reduce mortality. However, due to the high costs of albumin, and according our experience, a maximal dose of 30 g per ⇑ Corresponding author at: Department of Gastroenterology, Habib Thameur Hospital, Faculty of Medecine of Tunis, University of Tunis El Manar, Tunisia. E-mail address: [email protected] (S. Mériam).

day of albumin is allowed by our internal pharmacy which limits its use in clinical practice. The aim of our study was to determine the impact of low dose of albumin perfusion during SBP on mortality and prevention of HRS in cirrhotic patients. Patients and methods A retrospective study including consecutive patients with SBP hospitalized in the department of gastroenterology of Habib Thameur Hospital from January 2002 to December 2015 was performed. Diagnosis of SBP was based on a level of neutrophils greater than 250 in the ascitic fluid as recommended by EASL guidelines [2]. All patients were treated by intravenous empiric antibiotics based on a third generation cephalosporin:cefotaxime 4 g/day or fluoroquinolone: ofloxacin 500 mg twice a day for five days in combinqtion with albumin infusion (30 g/day in the first and the third day) irrespective of patient’s weight.

https://doi.org/10.1016/j.ajg.2019.11.002 1687-1979/Ó 2019 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.

Please cite this article as: E. Hela, S. Mériam, B. Norsaf et al., Effect of low dose albumin administration in spontaneous bacterial peritonitis on renal function and survival, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.11.002

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E. Hela et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx

Ascitic cellular examination was done after 48 h of treatment. A favourable outcome was defined by the decrease of neutrophils level by more than 50%. If no favourable outcome occurs, antibiotic therapy was changed to fluoroquinolone (ofloxacin 500 mg twice a day) if cefotaxime was received as first line treatment or association of amoxicillin and clavulanic acid 1 g three times a day otherwise. If culture and sensitivity results were available, antibiotherapy was then adapted to the results of culture and sensitivity.. The diagnosis of HRS was assessed according to the International Ascites Club criteria [5]. Patients were categorized as being at low or high risk for mortality, with high risk defined as creatinine level greater than 100 lmol/L or bilirubin  60 lmol/L before SBP. Also, a statistical analysis (Chi square of Pearson test) was performed in order to compare the prevalence of HRS in high versus low risk patients (defined by the bilirubin and the creatinine levels before SBP). A p°value lower than 0.05 was considered statistically significant. The survival using Kaplan Meier method (SPSS 18.0) and the frequency of HRS as evident by any disturbance of renal function (based on creatinine level) were recorded. All patients with preexisting HRS were excluded from the study as well as lost in view patients within less than 3 months. Approval for the study was obtained from the ethical committee of Habib Thameur Hospital. Results During the study period, 55 SBP occurred. Five patients (9%) were excluded because of preexisting HRS. Fourty nine patients (mean age 60.6 years+/- 13.8 years [23–89]) were then included. Cirrhosis was mainly due to hepatitis B or C in 42.9% of cases. Child Pugh score was C in 63.3%. 4.1% of patientshqd received primary antibiotic prophylaxis of SBP and beta Blockers had been given (propranolol) in 57.1% of cases. Patients were often asymptomatic (55%), and symptoms if present were mainly diarrhoea in 40.8% of cases. Clinical data of our cohort is summarized in Table 1.

Table 2 Complications occurring after SBP. Complications

n (%)

Time to onset in moths (mean, [extremes])

Variceal hemorrhage Recurrence of SBP HRS Refractory ascites Hepatic encephalopathy Hepatocellular carcinoma Death

8 (16.3%) 8 (16.3%) 8 (16.3%) 8 (16.3%) 14 (28.5%) 4 (8.2%) 8 (16.3%)

4.29 [1–13] 15.63 [3–42] 7.04 [0–55] 8.78 [0–55] 8.07 [1–24] 1.75 [1–3] 8.06 [0–46]

Ascitic fluid examination revealed turbid ascites in 48.9% of patients with a mean protein level of 12 g/L [1.1 – 52] and exudative ascites was detected in five cases. The first line intravenous antibiotic treatment was based on cefotaxime in 87.8% of cases, followed by ofloxacin in 6.1% of cases. The outcome was favourable in 85.7% of cases and treatment failure was observed in 8 patients, necessitating change of antibiotic. SBP recurred in 16.3% of cases within an average period of 16 months [3–42]. HRS occurred in 9 patients (18.3%) within 18 months [1–55]. Otherwise, an increase of creatinine level was detected in 10 patients (20.4%). Other complications observed after SBP included hepatic encephalopathy in 28.5% of cases within 8 months [1– 24], variceal haemorrhage in 22.4%, refractory ascites in 20.4% and hepatocellular carcinoma in 4 cases. All complications observed during the study are summarized in Table 2. On comparing high risk group of HRS (creatinine level higher than 100 lmol/L or bilirubin level  60 lmol/L) with low risk group no difference in the occurrence of HRS between the two groups could be detected (group 1 : n = 30 patients with 6 HRS, group 2 : n = 19 patients with 3 HRS, p greater than 0.05) The immediate mortality was 4%, and the six months survival was of 81.8%. The overall survival after SBP as well as the survival of patients having developed a HRS are illustrated in Figs. 1 and 2.

Discussion Table 1 Clinical characteristics of our cohort. Characteristics

n

%

Sex Male Female

n = 22 n = 27

Etiology of cirrhosis Viral Autoimmune Alcoholic Biliary Undetermined

n = 21 n=8 n=2 n=2 n = 16

42.8% 16.3% 4.1% 4.1% 32.7%

Child Pugh score A B C

n=1 n = 17 n = 31

2% 34.7% 63.3%

Symptoms Diarrhea Hepatic encephalopathy Nausea and/or vomiting Fever Abdominal pain Sepsis

n = 20 n = 10 n=7 n=5 n=5 n=1

40.8% 20.4% 14.3% 10.2% 10.2% 2%

Esophageal varices No Grade I Grade II Grade III Red signs

n = 11 n = 24 n=7 n=4 n=3

22.4% 48.9% 14.3% 8.2% 6.1%

Our study, showed that despite a low dose administration of albumin during SBP, renal dysfunction and HRS occurred in 20.4% and 18.3% respectively. Intravascular albumin administration has become the standard of care to prevent deterioration of renal function and subsequent death in cirrhotic patients. Its benefits have been documented for example in patients with SBP [6,7], HRS [8] and more recently, a randomized trial proved its efficiency during bacterial infections other than SBP [9]. However, other trials showed that only patients with risk factors such as increased serum bilirubin, blood urea nitrogen or serum creatinine appeared to benefit from albumin [10]. Elevated levels of bilirubin and creatinine prior to infection would according to this study indicate that patients with pre-existing advanced cirrhosis and impaired renal function are predisposed to the development of HRS. In contrast to patients at high risk for mortality, albumin administration is not recommended for patients with low mortality risk [3]. In general, mortality due to renal failure is uncommon following SBP, regardless of albumin administration. However, failure to follow risk-based albumin administration guidelines presents an important issue related to quality and cost of care. Evidence from clinical practice suggests the best costbenefit ratio for albumin therapy is achieved when it is used only in circumstances in which there is clinical evidence of efficacy and avoided in instances when clinical evidence suggests that

Please cite this article as: E. Hela, S. Mériam, B. Norsaf et al., Effect of low dose albumin administration in spontaneous bacterial peritonitis on renal function and survival, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.11.002

E. Hela et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx

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Fig. 1. Overall survival of the patients with SBP.

Fig. 2. Survival of patients with and without HRS.

administration is futile [11]. Therefore, some studies, investigated a substitutive molecule to albumin either efficiency of low dose perfusion of albumin.

Concerning substitutive molecule, some studies have suggested that with artificial plasma expanders, which are less expensive, may have similar beneficial effects on renal function and survival

Please cite this article as: E. Hela, S. Mériam, B. Norsaf et al., Effect of low dose albumin administration in spontaneous bacterial peritonitis on renal function and survival, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.11.002

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E. Hela et al. / Arab Journal of Gastroenterology xxx (xxxx) xxx

and may be comparable with standard dose albumin for lowering renal impairment and mortality[12,13].Regarding the dose of albumin, a recent study confirmed that albumin has a dose-dependent effect on survival in patients with acute renal failure and SBP, with the persistence of the dose effect even for patients with renal failure for reasons other than HRS. Furthermore, albumin also has a dose-dependent effect on complications such as fluid overload and pulmonary oedema [14]. These results have been extrapolated in other indications of albumin such as large volume paracentesis [15]. Another way to reduce hospitalization costs due to albumin perfusion was to differentiate high risk groups of HRS during SBP, as has been shown in the study of Sigal et al. [10,16]. Finally, for clinicians interested in improving the quality of care provided to patients with ascites, many questions remain unanswered regarding the use of albumin. The benefits of albumin in low-risk SBP patients continue to be debated [17]. Also, the minimum effective albumin dose needed to prevent renal failure in SBP has not been established given the cost of albumin [18] as well as the potential for complications. Our results associated with cost considerations could advocate for the use of low dose albumin perfusion during SBP. In conclusion, in our study, despite a low dose administration of albumin during SBP, renal dysfunction and HRS occurred less than described in literature. These results associated with cost considerations could suggest the use of low dose albumin perfusion during SBP or to select high risk patients who must receive albumin perfusions during SBP.

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Please cite this article as: E. Hela, S. Mériam, B. Norsaf et al., Effect of low dose albumin administration in spontaneous bacterial peritonitis on renal function and survival, Arab Journal of Gastroenterology, https://doi.org/10.1016/j.ajg.2019.11.002