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Article

Non-Selective Beta-Blockers Decrease Infection, Acute Kidney Injury Episodes, and Ameliorate Sarcopenic Changes in Patients with Cirrhosis: A Propensity-Score Matching Tertiary-Center Cohort Study

by
Tzu-Hao Li
1,2,3,4,
Chih-Wei Liu
2,3,5,
Chia-Chang Huang
2,3,6,
Yu-Lien Tsai
3,7,
Shiang-Fen Huang
2,3,
Ying-Ying Yang
2,3,6,8,*,
Chang-Youh Tsai
2,3,5,
Ming-Chih Hou
3,8 and
Han-Chieh Lin
3,8
1
Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital, No.95, Wen Chang Rd., Shihlin District, Taipei 111, Taiwan
2
Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No.155, Sec. 2, Linong St., Beitou District, Taipei City 112, Taiwan
3
School of Medicine, National Yang Ming Chiao Tung University, No.155, Sec. 2, Linong St., Beitou District, Taipei City 112, Taiwan
4
School of Medicine, Fu Jen Catholic University, No.510, Zhongzheng Rd., Xinzhuang Dist., New Taipei City 242, Taiwan
5
Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei City 112, Taiwan
6
Division of Clinical Skills Training, Department of Medical Education, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei City 112, Taiwan
7
Department of Medicine, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei City 112, Taiwan
8
Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei City 112, Taiwan
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2021, 10(11), 2244; https://doi.org/10.3390/jcm10112244
Submission received: 19 April 2021 / Revised: 17 May 2021 / Accepted: 18 May 2021 / Published: 21 May 2021
(This article belongs to the Collection Clinical Research in Hepatology)
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Abstract

:
Background: Cirrhotic complications resulting from portal hypertension can be considerably reduced by non-selective beta-blockers (NSBBs); however, scarce studies have investigated therapeutic agents for other complications. We aimed to investigate the effects of NSBBs on common cirrhotic complications of infection, acute kidney injury (AKI), chronic renal function declination, and sarcopenic changes. Methods: Medical records of hospitalization for cirrhosis with at least a 4-year follow-up were analyzed and selected using propensity-score matching (PSM). Generalized estimating equation (GEE) was applied to assess the association of NSBBs with infection requiring hospitalization and AKI. Chronic renal function declination was evaluated by slope of regression lines derived from reciprocal of the serum creatinine level. The covariates of CT-measured skeletal muscle index (SMI) alterations were analyzed by generalized linear mixed model. Results: Among the 4946 reviewed individuals, 166 (83 NSBB group, 83 non-NSBB group) were eligible. Using GEE, Charlson comorbidity index, Child-Pugh score and non-NSBB were risk factors for infection; non-NSBB group revealed a robust trend toward AKI, showed no significant difference with chronic renal function declination of NSBB group, and was negatively associated with SMI alteration. Conclusion: Chronic NSBB use lowered the episodes of infection requiring hospitalization and AKIs, whereas non-NSBB was associated with sarcopenic changes.

1. Introduction

Cirrhosis is a deleterious multisystem condition, comprising the complications associated with portal hypertension (PH), such as ascites, variceal bleeding, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE) and hepatorenal syndrome (HRS) [1]. Moreover, in cirrhosis, intestinal bacterial translocation aggravates proinflammatory and profibrogenic reaction, and the resultant endotoxemia leads to immune dysfunction as well as antimicrobial resistance [2,3]; association between bacterial translocation and HE or renal dysfunction has been reported [3,4]. Owing to multiorgan disruption, cirrhosis usually heralds poor life quality in addition to less life expectancy, but the medical treatment remains an enormous unmet need [5].
Non-selective beta-blockers (NSBBs), including propranolol, carvedilol, nadolol, and timolol, improve hemodynamic parameters and impede the cirrhotic process [6]. Robust data support the clinical benefit of NSBBs in PH-related complications such as variceal formation or growth, bleeding or re-bleeding, and ascites; likewise, NSBBs prevent the development of liver decompensation [7]. NSBB-responders have fewer events of SBP and HE [8]. Furthermore, NSBBs reduce the incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis because of various etiologies, and improve survival in cirrhotic patients with ascites or referral for liver transplantation [9,10,11,12].
Therapeutic options for treating other complications are relatively insufficient. For kidney injury, medical treatment has exclusively consisted of terlipressin in combination with albumin, specifically for patients with HRS, and volume replacement with albumin for patients with acute kidney injury (AKI) [13]. Less attention has been paid to the prevention or treatment of chronic kidney disease (CKD) in cirrhotic patients, even though CKD is accompanied by more acute-on-chronic liver failure (ACLF) events and higher mortality [14]. Recent literature indicates that CKD in patients with cirrhosis can be attributed to cardiorenal syndrome resulting from the activation of sympathetic nerve that can theoretically be blocked by NSBBs [15]. Similarly, few medication options other than antimicrobial agents are available with protective effects on infection in cirrhotic patients, which is currently the most common cause of mortality in cirrhosis, while NSBBs ameliorate systemic and splenic immune dysfunction in cirrhotic patients [16]. Therefore, whether NSBBs have clinical benefits in CKD or infection events is worth pursuing.
A growing corpus of research on sarcopenia has displayed an interrelation to manifold chronic diseases, and the higher prevalence of sarcopenia in patients with cirrhosis than that in the general population [17]. A recent meta-analysis revealed an association between sarcopenia and adverse clinical outcomes in cirrhotic patients, such as poorer survival rates and an increased risk of infection [18]. However, few studies have investigated the association between medication and sarcopenia in cirrhosis; besides, propranolol improves muscle synthesis at the hypermetabolic phase, which is compatible with cirrhotic status [19,20]. Hence, we aimed to investigate the effects of NSBBs on sarcopenic changes, renal dysfunction and infection events.

2. Methods

2.1. Study Subjects

In this retrospective longitudinal tertiary-center cohort study, the medical records of patients older than 18 years who were hospitalized for cirrhosis between 2006 and 2016 were reviewed. Patients who were regularly treated with NSBBs (including propranolol, carvedilol, nadolol, and timolol) and were followed up for at least 4 years were assigned to the NSBB-group, and those not using NSBBs were assigned to the control (non-NSBB) group. Patients treated with hepatobiliary surgery or liver transplantation, and those with a history of malignancy before enrolment, severe immunodeficiency/acquired immune deficiency syndrome, end-stage renal disease with renal replacement therapy, improper or undetermined diagnosis, inadequate NSBB administration (which was defined as occasional treatment without regular use, or discontinuation of NSBBs because of various reasons such as intolerance and non-responders) and the initiation of NSBB prescription before 2005 were excluded. The follow-up duration of each patient was four years retrieving from the available medical records.
Basic demographic data on age, sex, etiologies of cirrhosis, date of cirrhosis diagnosis, type and initiation date of NSBB administration, and Child-Pugh scores were obtained. Comorbidities were recorded and the Charlson comorbidity index (CCI) was calculated. As to data abstraction, a preset stepwise protocol had been previously developed and reviewed by authors; three physicians and two nurses, who were familiar with the health records and trained in the data systems, retrieved the data according to the protocol step-by-step. All the processes abided by the methodological steps for retrospective chart review research as previously mentioned [21]. Furthermore, the recorded data were checked and confirmed by three physician authors. The protocol was approved by the Institutional Review Board of Taipei Veterans General Hospital.

2.2. Outcome Measurements

Serious infection episodes requiring hospitalization during the follow-up period were determined, and SBP was analyzed separately for its predisposition in patients with cirrhosis. A serious infection episode was objectively confirmed, defined as positive results of either microbiologic cultures or radiologic imaging, or both, in addition to corresponding antibiotics administration [22]. Plural infections at multiple sites at the same admission were counted as separate episodes if the previous one was treated completely.
Renal dysfunction was assessed through the number of AKI episodes during the follow-up period. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline as the presence of any of the following: (1) increase in serum creatinine (SCr) by ≥0.3 mg/dL within 48 h; (2) increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; and (3) urine volume less than 0.5 mL/kg/h for 6 h. Furthermore, we calculated the decline of renal function by plotting the reciprocal of the serum creatinine level versus time, as previously reported [23]; a negative slope was considered as the progression of renal dysfunction.
For skeletal muscle measurement, we evaluated the area of the total skeletal muscle (cm2) at the third lumbar (L3) level in computed tomography (CT) images through picture archiving and communication system, in which the skeletal muscles were identified by the Hounsfield unit threshold range of −29 to 150 at the corresponding site. The skeletal muscle index (SMI) was determined using the following formula: SMI = Area of total skeletal muscle (cm2) at the L3 level/ height squared (m2) [24].

2.3. Statistical Analyses

Concerning the potential baseline discrepancies between NSBBs and those in the non-NSBBs group, we conducted a 1:1 pair-matched case-control cohort by means of nearest-neighbor propensity-score matching (PSM), which was adjusted for age, sex, Child-Pugh score, CCI, and etiologies of cirrhosis after estimating the probability by logistic regression. Because liver diseases were included in the CCI, we deducted the points of relevant items while performing PSM, as previously described [25]. The pair-t and McNemar’s tests were used for continuous and categorical variables, respectively, when comparing the NSBB group versus the non-NSBB group. For estimating the episodes of infection and AKI, we performed the generalized estimating equation (GEE) to assess the relationship between NSBBs use and the occurrence of episodes after adjustment of the covariates such as age, sex, Child-Pugh score, and CCI. Differences in CKD between groups were examined from the slope of regression lines deriving from the reciprocal of the SCr level. A generalized linear mixed model (GLMM) with a mixed-effect model was used to investigate the covariates associated with SMI alteration after PSM. All p-values were subjected to two-sided tests; values <0.05 were considered significant. Data analyses were performed using Statistical Product and Service Solutions V.26 (SPSS, IBM, Armonk, NY, USA).

3. Results

As shown in Figure 1, the medical records of 4946 individuals had been elaborately reviewed, and 248 patients with well-documented 4-year data fulfilled our criteria; of these, 166 patients (83 NSBB users and 83 NSBB non-users) were eligible for analysis after PSM. Baseline demographics data are presented in Table 1, with mean age of 57.9 in the NSBB group and 56.5 in the non-NSBB group. In the NSBB group, 64, 16, and 3 patients were regularly treated with propranolol (average of 41.22 mg/day), carvedilol (average of 18.25 mg/day) and nadolol (average of 40 mg/day), respectively. No significant differences were observed between the groups in the baseline variables of age, sex, CCI, Child-Pugh score, MELD-Na score, serum creatinine and sodium level, presence of ascites and etiologies of cirrhosis (Table 1).
During the 4-year observation period, there were 34 independent infection episodes requiring hospitalization of 24 subjects in the NSBB group, and 50 episodes in 40 subjects in the non-NSBB group; three and four episodes of SBP occurred in the NSBB and non-NSBB groups, respectively (p = 0.719). According to the GEE model built on repeated measurement of infection episodes, CCI (odds ratio (OR): 1.467, p = 0.04), Child-Pugh score (OR: 1.175, p = 0.005) and those not using NSBBs (OR: 1.666, p = 0.035) posed significant risks to the infection requiring hospitalization; alternatively, age and sex did not influence infection (Table 2).
Regarding AKI, 13 episodes of AKI were recorded in 10 NSBB users, and 25 episodes of AKI occurred among 20 subjects in the non-NSBB group within four years. The GEE analysis demonstrated that no use of NSBB led to a robust trend toward the occurrence of AKI (OR 2.070, p = 0.05, Table 3); otherwise, age, sex, CCI and Child-Pugh score were not associated with the AKI occurrence (Table 3). As for chronic renal function declination, the slope of the reciprocal of SCr concentration versus time in NSBB group was −0.0136 ± 0.0664 dL/mg/year, marginally lower than the counterpart, −0.0309 ± 0.0601 dL/mg/year in the non-NSBB group (p = 0.09, Figure 2).
Overall, 20 PSM pairs (40 patients) had abdominal CT profiles at the time of enrollment and the fourth year. The mean SMI alteration was 1.195 ± 5.633 cm2/m2 in the NSBB group, and −1.782 ± 4.624 cm2/m2 in the non-NSBB group. Using GLMM analysis with random effects of baseline SMI data, NSBB non-use was significantly associated with reduced SMI, compared to that in NSBB users (coefficient: −4.108, p = 0.049, Table 4); instead, age, sex, CCI, Child-Pugh score, episodes of infection/AKI, 4-year renal function declination, MELD-Na score, serum sodium and creatinine level, and presence of ascites were not correlated with SMI alteration (Table 4).

4. Discussion

In the present 4-year observational study, we investigated the relevant factors of infection requiring hospitalization, AKI and chronic renal function declination in patients with cirrhosis. Notably, the findings indicated that NSBB significantly decreased the infection, attained fewer AKI episodes, and marginally alleviated chronic renal function declination. Furthermore, sarcopenic changes in patients with cirrhosis were determined, and a negative correlation between SMI alteration and non-use of NSBBs was observed.
Owing to the widespread expression of the corresponding receptors on various immune cells, β-adrenergic signaling is considered as an essential immunomodulator [26]. In bacterial infection, β-adrenergic signaling suppressed inflammatory cytokines secretion, and immune response was centered by immune cells with additional apoptotic effects [27,28,29]; in experimental animal models, β-adrenergic blockade provided survival benefit and enhanced both cellular and humoral immunity against miscellaneous bacteria [30]. Similarly, propranolol corrected lymphopenia in cirrhotic mice [16]. Clinical studies have substantiated the beneficial results of the β-adrenergic blockade in patients with sepsis [31]; however, in other scenarios like stroke, the effects of β-blockers on protection from infection such as nosocomial pneumonia and urinary tract infection have been controversial [32,33].
In the context of cirrhosis, immune dysfunction including T-cell depletion and subset dysregulation is attributed to augmented sympathetic tone, mainly resulting from chronic endotoxemia following exaggerated intestinal permeability and bacterial translocation [34,35]. In previous studies, propranolol treatment decreased intestinal permeability and bacterial translocation, normalized the homeostasis and function of T cell subsets, ameliorated systemic immune dysfunction in cirrhosis, and increased phagocytic activity in the presence of bacteria [16,36,37]. Accordingly, NSBBs theoretically not only attenuate SBP, the major infectious complication stemming from bacterial translocation, but also mitigate the severity of systemic infection.
This study showed that, in line with the aforementioned deduction, in addition to age, Child-Pugh score and comorbidities, the absence of NSBBs (non-NSBB group) independently posed the risks of infection. Several studies have also reported lower rates of infection and alleviation of infection-related morbidity and mortality, as well as the reduction of likelihood of hospitalization for infection in cirrhotic patients, which was compatible with our findings [38,39]. In SBP, the infection directly related to intestinal bacterial translocation, albeit the data were debatable; previous studies and meta-analyses have indicated that NSBBs can prevent its occurrence and improve short-term survival in cirrhotic patients [12,40]. In the present work, an insignificant difference in SBP occurrence was observed between two groups, possibly due to relatively low incidence in the enrolled participants, although the proportions of SBP were approximate to those in previous study [39].
Hemodynamic aberrance in cirrhosis triggers activation of sympathetic tone and the renin-angiotensin-aldosterone system, leading to ischemia on kidney function [41]; β-adrenergic signaling blockade relieves the sympathetic tone and reduces serum renin level, consequently tempering resistance of renal blood flow and protecting against renal injury in cirrhotic patients [42,43]. However, insufficient blood volume resulting from the suppressed cardiac output and compromised arterial pressure may further deteriorate renal function, especially in decompensated cirrhosis or SBP [44]. Partially in line with the controversial roles of the β-adrenergic blockade in cirrhotic kidneys, foregoing studies have shown neutral results [45,46]. Our work yields a clear protective tendency of AKI occurrence by NSBB; one possible reason is comparatively less severity of the enrolled subjects, and NSBBs per se may prevent decompensation, thus manifesting the protective effects on AKI [7]. Evidence for the effect of long-term NSBB use in cirrhotic patients on chronic renal insufficiency is still limited; this 4-year study reveals marginal effects of deferring deterioration.
Sympathetic overactivation in association with pro-inflammatory responses contributes to muscle wasting in cirrhosis; NSBB use can counteract sympathetic hyperactivity and ameliorate overwhelmed inflammation in patients with cirrhosis [16,47]. Additionally, sympathetic hyperactivity in hypermetabolic states, including burn injury and cirrhosis, can lead to muscle wasting [20,48]; NSBB use has been shown to attenuate catabolic muscle wasting in patients with burn injury, and furthermore promote anabolism in addition to enabling greater protein net balance [19,49]. In our study, the average SMI of patients with NSBB treatment increased, and non-NSBB was significantly negatively correlated with SMI, independent of other comorbidities and complications, all of which may be substantiated by the aforementioned literature.
Previous literature has also investigated the risk factors of skeletal muscle wasting in patients with cirrhosis, reporting that Child-Pugh scores were not significantly associated with muscle wasting; this is analogous to our findings [50]. Unlike the previous literature that analyzed Child-Pugh scores by grade, we evaluated the association between the levels of scoring and muscle wasting to derive more explicit results. Although previous studies have purported greater infection rates but insignificant higher infection-related mortality, little research has been conducted on the impact of infection on SMI; in our retrospective cohort, infection episodes were likely but not significantly associated with sarcopenic change [50,51].
Despite its designing as meticulously as possible, our retrospective observational study had some limitations. First, to explore the long-term effects and improve the comparability, we carefully reviewed the records and selected the cases using PSM, thus generating a relatively low case number; accordingly, we applied the statistical analyses proper for small sample sizes to reconcile the relevant bias. Second, the SMIs measured through CT imaging were recorded at a four-year interval rather than with a time-dependent evaluation, thus precluding the dynamic changes during NSBB use. Third, we defined the NSBB users as those whom were regularly treated with NSBB regardless of the dosage, which might have differed between individuals depending on their tolerance. Hence, well-designed prospective studies are warranted to elucidate more clear effects of NSBBs.

5. Conclusions

In conclusion, this study demonstrated the reduction of episodes of AKI and infection demanding hospitalization in cirrhosis by NSBBs; in addition, we also surfaced the mitigation of sarcopenic change in cirrhotic patients with NSBB treatment. We anticipate that this study may provide a basis of future comprehensive investigations on the effects of NSBBs in patients with cirrhosis.

Author Contributions

Conceptualization, T.-H.L. and Y.-Y.Y.; methodology, T.-H.L. and Y.-Y.Y.; software, T.-H.L.; validation, C.-W.L. and C.-C.H.; formal analysis, T.-H.L.; investigation, C.-W.L. and Y.-L.T.; resources, S.-F.H.; data curation, C.-C.H. and Y.-L.T.; writing—original draft preparation, T.-H.L.; writing—review and editing, Y.-Y.Y.; supervision, C.-Y.T., M.-C.H. and H.-C.L.; project administration, C.-W.L., C.-C.H.; funding acquisition, Y.-Y.Y. and H.-C.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Ministry of Science and Technology (grant No.: MOST Funding: 109-2314-B-010-032-MY3, to Y.-Y.Y.), grant No. PED1090388 from the Ministry of Education (to Y.-Y.Y.), grant No. V110C-033 (Taipei Veterans General Hospital) and grant No. 107F-M01-0603 from National Yang-Ming Chiao Tung University (to Y.-Y.Y.); this work was not supported by any industrial funding.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Taipei Veteran General Hospital (protocol code 2017-11-005CC and approval on 31 December 2017).

Informed Consent Statement

According to the regulation, patient consent was exempted because the present study was based on retrospective chart review.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

The authors are grateful to Chien-Fu Hsu, Cen-Hua Lin and Yuan-Chi Chen for the efforts of data collection.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

AKI, acute kidney injury; ALD, alcoholic liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; CCI, Charlson comorbidities index; CIL confidence interval; CKD, chronic kidney disease; GEE, generalized estimating equation; GLMM, generalized linear mixed model; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; NSBB, non-selective beta-blocker; OR, odds ratio; PH, portal hypertension; PSM, propensity-score matching; SBP, spontaneous bacterial peritonitis; SMI, skeletal muscle index.

References

  1. Poordad, F.F. Presentation and complications associated with cirrhosis of the liver. Curr. Med. Res. Opin. 2015, 31, 925–937. [Google Scholar] [CrossRef] [PubMed]
  2. Patel, V.C.; Williams, R. Antimicrobial resistance in chronic liver disease. Hepatol. Int. 2019, 14, 24–34. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Noor, M.T.; Manoria, P. Immune Dysfunction in Cirrhosis. J. Clin. Transl. Hepatol. 2017, 5, 50–58. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Wiest, R.; Lawson, M.; Geuking, M. Pathological bacterial translocation in liver cirrhosis. J. Hepatol. 2014, 60, 197–209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Woodland, H.; Hudson, B.; Forbes, K.; McCune, A.; Wright, M.; British Association for the Study of the Liver (BASL) End of Life Special Interest Group. Palliative care in liver disease: What does good look like? Frontline Gastroenterol. 2019, 11, 218–227. [Google Scholar] [CrossRef] [PubMed]
  6. Iredale, J.P.; Campana, L. Regression of Liver Fibrosis. Semin. Liver Dis. 2017, 37, 1–10. [Google Scholar] [CrossRef]
  7. Villanueva, C.; Albillos, A.; Genescà, J.; Garcia-Pagan, J.C.; Calleja, J.L.; Aracil, C.; Bañares, R.; Morillas, R.M.; Poca, M.; Peñas, B.; et al. β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2019, 393, 1597–1608. [Google Scholar] [CrossRef]
  8. Turco, L.; Villanueva, C.; La Mura, V.; García-Pagán, J.C.; Reiberger, T.; Genescà, J.; Groszmann, R.J.; Sharma, B.C.; Merkel, C.; Bureau, C.; et al. Lowering Portal Pressure Improves Outcomes of Patients with Cirrhosis, with or without Ascites: A Meta-Analysis. Clin. Gastroenterol. Hepatol. 2020, 18, 313–327. [Google Scholar] [CrossRef] [Green Version]
  9. Thiele, M.; Albillos, A.; Abazi, R.; Wiest, R.; Gluud, L.L.; Krag, A. Non-selective beta-blockers may reduce risk of hepatocellular carcinoma: A meta-analysis of randomized trials. Liver Int. 2015, 35, 2009–2016. [Google Scholar] [CrossRef]
  10. Li, T.H.; Tsai, Y.L.; Hsu, C.F.; Liu, C.W.; Huang, C.C.; Yang, Y.Y.; Tsai, H.C.; Huang, S.F.; Hsieh, Y.C.; Liu, H.M.; et al. Propranolol Is Associated with Lower Risk of Incidence of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis: A Tertiary-Center Study and Indirect Comparison with Meta-Analysis. Gastroenterol. Res. Pract. 2020, 2020, 1892584. [Google Scholar] [CrossRef]
  11. Sinha, R.; Lockman, K.A.; Mallawaarachchi, N.; Robertson, M.; Plevris, J.N.; Hayes, P.C. Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites. J. Hepatol. 2017, 67, 40–46. [Google Scholar] [CrossRef] [Green Version]
  12. Ngwa, T.; Orman, E.; Gomez, E.V.; Bluff, D.; Hoskin, B.; Bargo, D.; Ghabril, M. Non-selective beta blocker use is associated with improved short-term survival in patients with cirrhosis referred for liver transplantation. BMC Gastroenterol. 2020, 20, 4. [Google Scholar] [CrossRef]
  13. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J. Hepatol. 2018, 69, 406–460. [Google Scholar] [CrossRef] [Green Version]
  14. Wong, F.; Reddy, K.R.; O’Leary, J.G.; Tandon, P.; Biggins, S.W.; Garcia-Tsao, G.; Maliakkal, B.J.; Lai, J.C.; Fallon, M.B.; Vargas, H.E.; et al. Impact of Chronic Kidney Disease on Outcomes in Cirrhosis. Liver Transplant. 2019, 25, 870–880. [Google Scholar] [CrossRef]
  15. Møller, S.; Bendtsen, F. The pathophysiology of arterial vasodilatation and hyperdynamic circulation in cirrhosis. Liver Int. 2018, 38, 570–580. [Google Scholar] [CrossRef] [Green Version]
  16. Tsai, H.-C.; Hsu, C.-F.; Huang, C.-C.; Huang, S.-F.; Li, T.-H.; Yang, Y.-Y.; Lin, M.-W.; Lee, T.-Y.; Liu, C.-W.; Huang, Y.-H.; et al. Propranolol Suppresses the T-Helper Cell Depletion-Related Immune Dysfunction in Cirrhotic Mice. Cells 2020, 9, 604. [Google Scholar] [CrossRef] [Green Version]
  17. Peterson, S.J.; Braunschweig, C.A. Prevalence of Sarcopenia and Associated Outcomes in the Clinical Setting. Nutr. Clin. Pract. 2016, 31, 40–48. [Google Scholar] [CrossRef] [Green Version]
  18. Kim, G.; Kang, S.H.; Kim, M.Y.; Baik, S.K. Prognostic value of sarcopenia in patients with liver cirrhosis: A systematic review and meta-analysis. PLoS ONE 2017, 12, e0186990. [Google Scholar] [CrossRef] [Green Version]
  19. Diaz, E.C.; Herndon, D.N.; Porter, C.; Sidossis, L.S.; Suman, O.E.; Børsheim, E. Effects of pharmacological interventions on muscle protein synthesis and breakdown in recovery from burns. Burns 2015, 41, 649–657. [Google Scholar] [CrossRef] [Green Version]
  20. Müller, M.J.; Böttcher, J.; Selberg, O.; Weselmann, S.; Böker, K.H.; Schwarze, M.; Mühlen, A.V.Z.; Manns, M.P. Hypermetabolism in clinically stable patients with liver cirrhosis. Am. J. Clin. Nutr. 1999, 69, 1194–1201. [Google Scholar] [CrossRef] [Green Version]
  21. Gearing, R.E.; Mian, I.A.; Barber, J.; Ickowicz, A. A methodology for conducting retrospective chart review research in child and adolescent psychiatry. J. Can. Acad. Child. Adolesc. Psychiatry 2006, 15, 126–134. [Google Scholar] [PubMed]
  22. Valdez-Ortiz, R.; Sifuentes-Osornio, J.; Morales-Buenrostro, L.E.; Ayala-Palma, H.; Dehesa-López, E.; Alberú, J.; Correa-Rotter, R. Risk factors for infections requiring hospitalization in renal transplant recipients: A cohort study. Int. J. Infect. Dis. 2011, 15, e188–e196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Mitch, W.E.; Walser, M.; Buffington, G.A.; Lemann, J., Jr. A simple method of estimating progression of chronic renal failure. Lancet 1976, 2, 1326–1328. [Google Scholar] [CrossRef]
  24. Sergi, G.; Trevisan, C.; Veronese, N.; Lucato, P.; Manzato, E. Imaging of sarcopenia. Eur. J. Radiol. 2016, 85, 1519–1524. [Google Scholar] [CrossRef] [PubMed]
  25. Jepsen, P.; Vilstrup, H.; Andersen, P.K.; Lash, T.L.; Sørensen, H.T. Comorbidity and survival of Danish cirrhosis patients: A nationwide population-based cohort study. Hepatology 2008, 48, 214–220. [Google Scholar] [CrossRef] [PubMed]
  26. Xu, B. The importance of beta-adrenergic receptors in immune regulation: A link between neuroendocrine and immune system. Med. Hypotheses 2001, 56, 273–276. [Google Scholar] [CrossRef]
  27. Emeny, R.T.; Gao, D.; Lawrence, D.A. Beta1-adrenergic receptors on immune cells impair innate defenses against Listeria. J. Immunol. 2007, 178, 4876–4884. [Google Scholar] [CrossRef] [Green Version]
  28. Grailer, J.J.; Haggadone, M.D.; Sarma, J.V.; Zetoune, F.S.; Ward, P.A. Induction of M2 regulatory macrophages through the β2-adrenergic receptor with protection during endotoxemia and acute lung injury. J. Innate Immun. 2014, 6, 607–618. [Google Scholar] [CrossRef]
  29. Gu, C.; Ma, Y.C.; Benjamin, J.; Littman, D.; Chao, M.V.; Huang, X.Y. Apoptotic signaling through the beta -adrenergic receptor. A new Gs effector pathway. J. Biol. Chem. 2000, 275, 20726–20733. [Google Scholar] [CrossRef] [Green Version]
  30. Mazloomi, E.; Jazani, N.H.; Shahabi, S. A novel adjuvant, mixture of alum and the beta-adrenergic receptor antagonist propranolol, elicits both humoral and cellular immune responses for heat-killed Salmonella typhimurium vaccine. Vaccine 2012, 30, 2640–2646. [Google Scholar] [CrossRef]
  31. Lee, Y.R.; Seth, M.S.; Soney, D.; Dai, H. Benefits of Beta-Blockade in Sepsis and Septic Shock: A Systematic Review. Clin. Drug Investig. 2019, 39, 429–440. [Google Scholar] [CrossRef]
  32. Sykora, M.; Siarnik, P.; Diedler, J.; VISTA Acute Collaborators. β-Blockers, Pneumonia, and Outcome After Ischemic Stroke: Evidence from Virtual International Stroke Trials Archive. Stroke 2015, 46, 1269–1274. [Google Scholar] [CrossRef] [Green Version]
  33. Maier, I.L.; Karch, A.; Mikolajczyk, R.; Bähr, M.; Liman, J. Effect of beta-blocker therapy on the risk of infections and death after acute stroke—A historical cohort study. PLoS ONE 2015, 10, e0116836. [Google Scholar] [CrossRef]
  34. Fukui, H. Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia. World J. Hepatol. 2015, 7, 425–442. [Google Scholar] [CrossRef]
  35. MacNeil, B.J.; Jansen, A.H.; Greenberg, A.H.; Nance, D.M. Activation and selectivity of splenic sympathetic nerve electrical activity response to bacterial endotoxin. Am. J. Physiol. 1996, 270, R264–R270. [Google Scholar] [CrossRef]
  36. Senzolo, M.; Fries, W.; Buda, A.; Pizzuti, D.; Nadal, E.; Sturniolo, G.C.; Burroughs, A.K.; D’incà, R. Oral propranolol decreases intestinal permeability in patients with cirrhosis: Another protective mechanism against bleeding? Am. J. Gastroenterol. 2009, 104, 3115–3116. [Google Scholar] [CrossRef]
  37. Gimenez, P.; Garcia-Martinez, I.; Francés, R.; Gonzalez-Navajas, J.M.; Mauri, M.; Alfayate, R.; Almenara, S.; Miralles, C.; Palazon, J.M.; Carnicer, F.; et al. Treatment with non-selective beta-blockers affects the systemic inflammatory response to bacterial DNA in patients with cirrhosis. Liver Int. 2018, 38, 2219–2227. [Google Scholar] [CrossRef] [Green Version]
  38. Merli, M.; Lucidi, C.; Di Gregorio, V.; Giannelli, V.; Giusto, M.; Ceccarelli, G.; Riggio, O.; Venditti, M. The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis. Liver Int. 2014, 35, 362–369. [Google Scholar] [CrossRef]
  39. Sasso, R.; Rockey, D.C. Non-selective beta-blocker use in cirrhotic patients is associated with a reduced likelihood of hospitalisation for infection. Aliment. Pharmacol. Ther. 2020, 53, 418–425. [Google Scholar]
  40. Senzolo, M.; Cholongitas, E.; Burra, P.; Leandro, G.; Thalheimer, U.; Patch, D.; Burroughs, A.K. Beta-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: A meta-analysis. Liver Int. 2009, 29, 1189–1193. [Google Scholar] [CrossRef]
  41. John, S.; Thuluvath, P.J. Hyponatremia in cirrhosis: Pathophysiology and management. World J. Gastroenterol. 2015, 21, 3197–3205. [Google Scholar] [CrossRef]
  42. Zhang, Y.; Wu, J.; Zhang, Z.; Wang, B.; Chen, P.; Jing, X. Effect of low sodium intake and β-blockade on renin synthesis and secretion in mice with unilateral ureteral ligation. Hypertens. Res. 2010, 33, 1258–1263. [Google Scholar] [CrossRef] [Green Version]
  43. Ozcan, H.; Aytaç, S.K.; Yağmurlu, B.; Erten, A. Effect of propranolol on renal hemodynamics in patients with cirrhosis: Assessment with Doppler US. Tani Girisim. Radyol. 2004, 10, 230–233. [Google Scholar]
  44. Mandorfer, M.; Bota, S.; Schwabl, P.; Bucsics, T.; Pfisterer, N.; Kruzik, M.; Hagmann, M.; Blacky, A.; Ferlitsch, A.; Sieghart, W.; et al. Nonselective β Blockers Increase Risk for Hepatorenal Syndrome and Death in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis. Gastroenterology 2014, 146, 1680–1690.e1. [Google Scholar] [CrossRef] [Green Version]
  45. Bataille, C.; Bercoff, E.; Pariente, E.A.; Valla, D.; Lebrec, D. Effects of propranolol on renal blood flow and renal function in patients with cirrhosis. Gastroenterology 1984, 86, 129–133. [Google Scholar] [CrossRef]
  46. Scheiner, B.; Parada-Rodriguez, D.; Bucsics, T.; Schwabl, P.; Mandorfer, M.; Pfisterer, N.; Riedl, F.; Sieghart, W.; Ferlitsch, A.; Trauner, M.; et al. Non-selective beta-blocker treatment does not impact on kidney function in cirrhotic patients with varices. Scand. J. Gastroenterol. 2017, 52, 1–8. [Google Scholar] [CrossRef]
  47. Lin, S.Y.; Wang, Y.Y.; Chuang, Y.H.; Chen, C.J. Skeletal muscle proteolysis is associated with sympathetic activation and TNF-α-ubiquitin-proteasome pathway in liver cirrhotic rats. J. Gastroenterol. Hepatol. 2016, 31, 890–896. [Google Scholar] [CrossRef]
  48. Rivas, E.; Herndon, D.N.; Porter, C.; Meyer, W.; Suman, O.E. Short-term metformin and exercise training effects on strength, aerobic capacity, glycemic control, and mitochondrial function in children with burn injury. Am. J. Physiol. Endocrinol. Metab. 2018, 314, E232–E240. [Google Scholar] [CrossRef]
  49. Cheema, S.A.; Ahmed, U.T.; Nasir, H.; Dogar, S.R.; Mustafa, Z. Effects of Propranolol in Accelerating Wound Healing and Attenuation of Hypermetabolism in Adult Burn Patients. J. Coll. Physicians Surg. Pak. 2020, 30, 46–50. [Google Scholar] [CrossRef]
  50. Chang, K.V.; Chen, J.D.; Wu, W.T.; Huang, K.C.; Han, D.S. Association of loss of muscle mass with mortality in liver cirrhosis without or before liver transplantation: A systematic review and meta-analysis. Medicine 2019, 98, e14373. [Google Scholar] [CrossRef]
  51. Krell, R.; Kaul, D.R.; Martin, A.R.; Englesbe, M.; Sonnenday, C.J.; Cai, S.; Malani, P.N. Association between sarcopenia and the risk of serious infection among adults undergoing liver transplantation. Liver Transplant. 2013, 19, 1396–1402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Jcm 10 02244 g001 550
Figure 1. Algorithm of subject selection and enrollment. Abbreviation: AIDS, acquired immune deficiency syndrome; ESRD, end-stage renal disease.
Figure 1. Algorithm of subject selection and enrollment. Abbreviation: AIDS, acquired immune deficiency syndrome; ESRD, end-stage renal disease.
Jcm 10 02244 g001
Jcm 10 02244 g002 550
Figure 2. Comparison of the slope of the reciprocal of serum-creatinine concentration.
Figure 2. Comparison of the slope of the reciprocal of serum-creatinine concentration.
Jcm 10 02244 g002
Table
Table 1. Demographics of subjects in the NSBB and non-NSBB groups.
Table 1. Demographics of subjects in the NSBB and non-NSBB groups.
NSBB (n = 83)Non-NSBB (n = 83)p-Value
Age (years)57.9 ± 12.456.5 ± 12.10.468
Male (n)49 (59.0%)54 (65.0%)0.511
CCI2.71 ± 0.972.62 ± 0.790.683
CCI with deduction of points from liver disease0.51 ± 0.6320.47 ± 0.5490.693
Child-Pugh score6.90 ± 1.626.77 ± 1.560.598
Etiologies
HBV29 (34.9%)30 (36.1%)0.946
HCV26 (31.3%)25 (30.1%)0.950
ALD23 (27.7%)28 (33.7%)0.424
Autoimmune5 (6.0%)3 (3.6%)0.625
Others6 (7.2%)6 (7.2%)0.966
Presence of ascites40 (48.2%)46 (55.4%)0.351
MELD-Na score12.96 ± 3.8613.22 ± 3.490.644
Serum sodium level (mmol/L) 119.39 ± 15.2122.05 ± 13.250.162
Systolic blood pressure (mmHg)138.01 ± 3.84137.12 ± 4.330.233
Serum creatinine level (mg/dL)1.01 ± 0.990.99 ± 0.560.883
Note: The data are expressed as the mean ± standard deviation or number (%). Abbreviations: ALD, alcoholic liver disease; CCI, Charlson comorbidity index; HBV, hepatitis B virus; HCV, hepatitis C virus.
Table
Table 2. Factors associated with infection episode in patients with cirrhosis by generalized estimating equation.
Table 2. Factors associated with infection episode in patients with cirrhosis by generalized estimating equation.
Odds Ratio95% Confidence Intervalp-Value
Age1.0060.978–1.0340.698
Female0.9840.556–1.7420.955
CCI1.4671.019–2.1140.04 *
Child-Pugh score1.1751.051–1.3130.005 *
Non-NSBB1.6661.036–2.6790.035 *
NSBBReference--
* p value < 0.05 indicates statistical significance. Abbreviation: CCI, Charlson comorbidity index.
Table
Table 3. Factors associated with acute kidney injury episode in patients with cirrhosis by generalized estimating equation.
Table 3. Factors associated with acute kidney injury episode in patients with cirrhosis by generalized estimating equation.
Odds Ratio95% Confidence Intervalp-Value
Age1.0040.971–1.0380.825
Female1.5900.868–2.9130.133
CCI0.8650.493–1.5200.814
Child-Pugh score1.0430.868–1.2550.651
Non-NSBB2.0701.000–4.2870.05
NSBBReference--
Abbreviation: CCI, Charlson comorbidity index.
Table
Table 4. Factors associated with skeletal muscle index alteration in patients with cirrhosis by generalized linear mixed model.
Table 4. Factors associated with skeletal muscle index alteration in patients with cirrhosis by generalized linear mixed model.
Coefficient95% Confidence Intervalp-Value
Age−0.043−0.233–1.4170.507
Female0.259−4.374–4.8910.909
CCI−1.194−4.663–2.2750.486
Child-Pugh score0.508−4.663–2.2750.446
Non-NSBB−4.108−8.204–−0.0120.049 *
NSBBReference--
Infection episode1.839−0.716–4.3940.150
AKI episode−0.407−7.202–6.3870.902
Slope of creatinine reciprocal−8.107−36.284–20.0710.554
MELD-Na score−0.235−1.049–0.580.559
Serum creatinine level−3.399−12.03–5.2310.427
Serum sodium level−0.191−0.871–0.4880.568
Presence of ascites−1.645−22.62–19.3320.873
* p value < 0.05 indicates statistical significance. Abbreviation: AKI, acute kidney injury; CCI, Charlson comorbidity index.
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Li, T.-H.; Liu, C.-W.; Huang, C.-C.; Tsai, Y.-L.; Huang, S.-F.; Yang, Y.-Y.; Tsai, C.-Y.; Hou, M.-C.; Lin, H.-C. Non-Selective Beta-Blockers Decrease Infection, Acute Kidney Injury Episodes, and Ameliorate Sarcopenic Changes in Patients with Cirrhosis: A Propensity-Score Matching Tertiary-Center Cohort Study. J. Clin. Med. 2021, 10, 2244. https://doi.org/10.3390/jcm10112244

AMA Style

Li T-H, Liu C-W, Huang C-C, Tsai Y-L, Huang S-F, Yang Y-Y, Tsai C-Y, Hou M-C, Lin H-C. Non-Selective Beta-Blockers Decrease Infection, Acute Kidney Injury Episodes, and Ameliorate Sarcopenic Changes in Patients with Cirrhosis: A Propensity-Score Matching Tertiary-Center Cohort Study. Journal of Clinical Medicine. 2021; 10(11):2244. https://doi.org/10.3390/jcm10112244

Chicago/Turabian Style

Li, Tzu-Hao, Chih-Wei Liu, Chia-Chang Huang, Yu-Lien Tsai, Shiang-Fen Huang, Ying-Ying Yang, Chang-Youh Tsai, Ming-Chih Hou, and Han-Chieh Lin. 2021. "Non-Selective Beta-Blockers Decrease Infection, Acute Kidney Injury Episodes, and Ameliorate Sarcopenic Changes in Patients with Cirrhosis: A Propensity-Score Matching Tertiary-Center Cohort Study" Journal of Clinical Medicine 10, no. 11: 2244. https://doi.org/10.3390/jcm10112244

APA Style

Li, T.-H., Liu, C.-W., Huang, C.-C., Tsai, Y.-L., Huang, S.-F., Yang, Y.-Y., Tsai, C.-Y., Hou, M.-C., & Lin, H.-C. (2021). Non-Selective Beta-Blockers Decrease Infection, Acute Kidney Injury Episodes, and Ameliorate Sarcopenic Changes in Patients with Cirrhosis: A Propensity-Score Matching Tertiary-Center Cohort Study. Journal of Clinical Medicine, 10(11), 2244. https://doi.org/10.3390/jcm10112244

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