Beta Blockers in Spontaneous Bacterial Peritonitis
Beta Blockers in Spontaneous Bacterial Peritonitis
A total of 607 consecutive patients with cirrhosis who underwent their first paracentesis at the Medical University of Vienna between 2006 and 2011, had bacterial cultures from ascites, and did not display any exclusion criteria, were included in this retrospective study. Patients with other causes of ascites, such as severe cardiovascular disease, renal insufficiency, extrahepatic malignancies, and noncirrhotic portal hypertension, were excluded from the study.
Epidemiological characteristics, etiology of cirrhosis, presence of varices, and information on previous variceal bleeding, as well as follow-up variceal bleeding and liver transplantation, were assessed from patient medical history. In addition, information on NSBB and rifaximin treatment, as well as systemic hemodynamics, was obtained from patient medical history. The following laboratory parameters were assessed at the time of the first paracenteses and the first diagnosis of SBP: platelet count, albumin, bilirubin, international normalized ratio, creatinine, and ascitic fluid neutrophil count. Hepatic venous portal pressure gradient measurements were performed as described previously. The model for end-stage liver disease and Child-Pugh score (CPS) were calculated based on laboratory parameters and patients' medical history.
Paracenteses were performed either in a diagnostic or therapeutic setting. In accordance with national guidelines, albumin was administered in all large-volume paracenteses. SBP was diagnosed if the ascitic fluid neutrophil count was >250 mL without an evident intra-abdominal source of infection or another explanation for an elevated ascitic fluid neutrophil count. Patients with SBP were receiving albumin in addition to antibiotic treatment, as recommended by national guidelines during the full study period.
The diagnosis of HRS was established if creatinine levels increased to >1.5 mg/dL or doubled to a level of >2.5 mg/dL in the absence of evidence for shock or hypovolemia within 90 days after the first SBP diagnosis. Patients with a history of chronic kidney disease other than HRS or evidence for parenchymal kidney disease, such as proteinuria, microhematuria, or abnormal renal ultrasonography were excluded from this analysis.
AKI was diagnosed if a patient fulfilled the criteria of group C of the modified AKI classification proposed by Fagundes et al, comprising both stages 2 and 3 of the Acute Kidney Injury Network criteria. AKI was defined as an increase of serum creatinine >2-fold from baseline or a serum creatinine ≥4.0 mg/dL with an acute increase >0.5 mg/dL. In addition, urine output <0.5 mL/kg per hour for >12 hours was considered as AKI.
Statistical analyses were conducted using IBM SPSS Statistics 21 (SPSS Inc., Armonk, NY) and R.3.0.1 (R Development Core Team 2008, The R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were reported as mean ± standard deviation (SD) or median (interquartile range [IQR]), and categorical variables were reported as number (n) of patients with the certain characteristic (proportion of patients with the certain characteristic [%]). Student t test was used for group comparisons of continuous variables when applicable. Otherwise, Mann-Whitney U test was applied. Group comparisons of categorical variables were performed using either Pearson's χ or Fisher's exact test. The impact of NSBB treatment on SBP incidence and transplant-free survival was analyzed using semi-parametric proportional hazard Cox models. The proportional hazard assumption was verified by inspecting the cumulative hazard plot for parallel curves.
Patients entered the SBP incidence model (Model 1) with their first paracentesis and were followed until their last paracentesis. In liver transplant recipients and in case of death, the last paracentesis before the liver transplantation or death was the end of follow-up. Patients who had only one paracentesis, as well as patients with SBP at their first paracentesis, were excluded from this analysis. NSBB treatment and CPS stage were considered as covariates. In addition, SBP incidence rates among patients with NSBB treatment, and without, as well as the SBP incidence rate ratio were calculated.
The rates of follow-up paracentesis and variceal bleeding after the first paracentesis were calculated for NSBB and no-NSBB patients. Similarly, follow-up paracentesis and bleeding rates after the first development of SBP were calculated.
Patients entered the first transplant-free survival model (Model 2) with their first paracentesis and were followed until 2013. Transplant-free survival time was defined as the time to liver transplantation, death, or end of follow-up. Patients who received a liver transplantation were censored at the day of surgery. Besides NSBB treatment, the model included presence of varices, CPS stage, and SBP status as covariates. The latter variable was treated as a time-dependent covariate in the following fashion: The first development of SBP in patients without SBP at the first paracentesis separated the follow-up into 2 adjoining time intervals. In the first (right censored) interval the SBP status is negative, and it is positive in the second (left or interval censored) time period. To assess the modulating effect of SBP development on the impact of NSBB treatment on transplant-free survival, the interaction term NSBB × SBP was incorporated into the model.
A second transplant-free survival model (Model 3) restricted to SBP patients was calculated with patients entering the model with the first development of SBP and NSBB treatment, presence of varices and CPS stage at the time of SBP diagnosis as covariates. Kaplan-Meier curves are shown for all models.
P values <.05 were considered as statistically significant. No adjustment for multiplicity was performed.
This study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee of the Medical University of Vienna (EK Nr. 1008/2011).
Patients and Methods
Study Design
A total of 607 consecutive patients with cirrhosis who underwent their first paracentesis at the Medical University of Vienna between 2006 and 2011, had bacterial cultures from ascites, and did not display any exclusion criteria, were included in this retrospective study. Patients with other causes of ascites, such as severe cardiovascular disease, renal insufficiency, extrahepatic malignancies, and noncirrhotic portal hypertension, were excluded from the study.
Assessed Parameters
Epidemiological characteristics, etiology of cirrhosis, presence of varices, and information on previous variceal bleeding, as well as follow-up variceal bleeding and liver transplantation, were assessed from patient medical history. In addition, information on NSBB and rifaximin treatment, as well as systemic hemodynamics, was obtained from patient medical history. The following laboratory parameters were assessed at the time of the first paracenteses and the first diagnosis of SBP: platelet count, albumin, bilirubin, international normalized ratio, creatinine, and ascitic fluid neutrophil count. Hepatic venous portal pressure gradient measurements were performed as described previously. The model for end-stage liver disease and Child-Pugh score (CPS) were calculated based on laboratory parameters and patients' medical history.
Paracenteses and Diagnosis of Spontaneous Bacterial Peritonitis
Paracenteses were performed either in a diagnostic or therapeutic setting. In accordance with national guidelines, albumin was administered in all large-volume paracenteses. SBP was diagnosed if the ascitic fluid neutrophil count was >250 mL without an evident intra-abdominal source of infection or another explanation for an elevated ascitic fluid neutrophil count. Patients with SBP were receiving albumin in addition to antibiotic treatment, as recommended by national guidelines during the full study period.
Diagnosis of Hepatorenal Syndrome and Acute Kidney Injury
The diagnosis of HRS was established if creatinine levels increased to >1.5 mg/dL or doubled to a level of >2.5 mg/dL in the absence of evidence for shock or hypovolemia within 90 days after the first SBP diagnosis. Patients with a history of chronic kidney disease other than HRS or evidence for parenchymal kidney disease, such as proteinuria, microhematuria, or abnormal renal ultrasonography were excluded from this analysis.
AKI was diagnosed if a patient fulfilled the criteria of group C of the modified AKI classification proposed by Fagundes et al, comprising both stages 2 and 3 of the Acute Kidney Injury Network criteria. AKI was defined as an increase of serum creatinine >2-fold from baseline or a serum creatinine ≥4.0 mg/dL with an acute increase >0.5 mg/dL. In addition, urine output <0.5 mL/kg per hour for >12 hours was considered as AKI.
Statistics
Statistical analyses were conducted using IBM SPSS Statistics 21 (SPSS Inc., Armonk, NY) and R.3.0.1 (R Development Core Team 2008, The R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were reported as mean ± standard deviation (SD) or median (interquartile range [IQR]), and categorical variables were reported as number (n) of patients with the certain characteristic (proportion of patients with the certain characteristic [%]). Student t test was used for group comparisons of continuous variables when applicable. Otherwise, Mann-Whitney U test was applied. Group comparisons of categorical variables were performed using either Pearson's χ or Fisher's exact test. The impact of NSBB treatment on SBP incidence and transplant-free survival was analyzed using semi-parametric proportional hazard Cox models. The proportional hazard assumption was verified by inspecting the cumulative hazard plot for parallel curves.
Patients entered the SBP incidence model (Model 1) with their first paracentesis and were followed until their last paracentesis. In liver transplant recipients and in case of death, the last paracentesis before the liver transplantation or death was the end of follow-up. Patients who had only one paracentesis, as well as patients with SBP at their first paracentesis, were excluded from this analysis. NSBB treatment and CPS stage were considered as covariates. In addition, SBP incidence rates among patients with NSBB treatment, and without, as well as the SBP incidence rate ratio were calculated.
The rates of follow-up paracentesis and variceal bleeding after the first paracentesis were calculated for NSBB and no-NSBB patients. Similarly, follow-up paracentesis and bleeding rates after the first development of SBP were calculated.
Patients entered the first transplant-free survival model (Model 2) with their first paracentesis and were followed until 2013. Transplant-free survival time was defined as the time to liver transplantation, death, or end of follow-up. Patients who received a liver transplantation were censored at the day of surgery. Besides NSBB treatment, the model included presence of varices, CPS stage, and SBP status as covariates. The latter variable was treated as a time-dependent covariate in the following fashion: The first development of SBP in patients without SBP at the first paracentesis separated the follow-up into 2 adjoining time intervals. In the first (right censored) interval the SBP status is negative, and it is positive in the second (left or interval censored) time period. To assess the modulating effect of SBP development on the impact of NSBB treatment on transplant-free survival, the interaction term NSBB × SBP was incorporated into the model.
A second transplant-free survival model (Model 3) restricted to SBP patients was calculated with patients entering the model with the first development of SBP and NSBB treatment, presence of varices and CPS stage at the time of SBP diagnosis as covariates. Kaplan-Meier curves are shown for all models.
P values <.05 were considered as statistically significant. No adjustment for multiplicity was performed.
Ethics
This study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee of the Medical University of Vienna (EK Nr. 1008/2011).
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