If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, ItalyDepartment of Primary Health Care, Internal Medicine Unit Addressed to Frailty and Aging, “Santa Maria Delle Croci” Ravenna Hospital, AUSL Romagna, Ravenna, Italy
Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, ItalyDepartment of Primary Health Care, Internal Medicine Unit Addressed to Frailty and Aging, “Santa Maria Delle Croci” Ravenna Hospital, AUSL Romagna, Ravenna, Italy
Corresponding author. , Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Department of Primary Health Care, S. Maria delle Croci Hospital, AUSL Romagna, Ravenna, Italy.
Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, ItalyDepartment of Primary Health Care, Internal Medicine Unit Addressed to Frailty and Aging, “Santa Maria Delle Croci” Ravenna Hospital, AUSL Romagna, Ravenna, Italy
Corresponding author. , Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Unit of Semeiotics, Liver and Alcohol-related diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy. ,. Tel: +39 051 214 2919, Fax: +39 051 214 2930
Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, ItalyUnit of Semeiotics, Liver and Alcohol-related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
A considerable number of patients discharged after acute decompensation (AD) of cirrhosis have multiple readmissions over the following year
•
A low hemoglobin (Hb) level emerged as a new predictor for 30-day readmission in patients discharged after AD
•
Simple and inexpensive laboratory parameters (Hb and MELD-Na) at discharge predict early readmissions, thus contributing to identify high-risk patients to be included in programs of transitional care
Abstract
Background & Aims
Patients with decompensated cirrhosis present frequent hospitalizations with a relevant clinical and socio-economic impact. This study aims to characterize unscheduled re-admissions up to 1-year follow-up and identify predictors of 30-day readmission after an index hospitalization for acute decompensation (AD).
Methods
We performed a secondary analysis of a prospectively collected cohort of patients admitted for AD. Laboratory and clinical data at admission and at discharge were collected. Timing and causes of unscheduled readmissions and mortality were recorded up to 1 year.
Results
329 patients with AD were included in the analysis. Acute-on-chronic liver failure (ACLF) was diagnosed in 19% of patients at admission or developed in an additional 9% during index hospitalization. During the 1-year follow-up, 182 patients (55%) were re-hospitalized and 98 (30%) more than once. Most frequent causes of readmission were hepatic encephalopathy (36%), ascites (22%), and infection (21%). Cumulative incidence of readmission was 20% at 30 days, 39% at 90 days and 63% at 1 year. Fifty-four patients were readmitted for emergent liver-related causes within 30 days. Early readmission was associated to a higher 1-year mortality (47 vs 32%, p=0.037). Multivariable Cox regression analysis showed that Hb≤8.7 mg/dL (HR 2.63 [95%CI 1.38- 5.02], p=0.003) and MELD-Na>16 at discharge (HR 2.23 [95%CI 1.27- 3.93], p=0.005), were independent predictors of early readmission. In patients with MELD-Na> 16 at discharge, the presence of Hb ≤8.7 g/dl doubles the risk of early re-hospitalization (44% vs 22%, p=0.02).
Conclusion
Besides MELD-Na, a low hemoglobin level (Hb≤8.7 g/dl) at discharge emerged as a new risk factor for early readmission, contributing to identify those patients who deserve a closer surveillance after discharge.
Lay Summary
Patients with decompensated cirrhosis face frequent hospitalizations. In the present study, type and causes of readmissions were analyzed during one-year follow-up in patients discharged after the index hospitalization for an acute decompensation of the disease. Early (30-day) liver-related readmission was associated to higher one-year mortality. MELD-Na and low hemoglobin at discharge were identified as independent risk factors for early readmissions. Hemoglobin emerged as a new easy-to-use parameter associated with early readmission warranting further investigation.
The study was supported by a grant from Italian Ministry of Health (rf-2010-2310623), a grant from the Emilia-Romagna Region (PRUa1GR-2012-002) and by Fondazione del Monte di Bologna e Ravenna. The funders did not have any involvement in study design, in the collection, analysis and interpretation of data, in the drafting of the manuscript, and in the decision to submit the article for publication.
Conflicts of interest
All authors declare no conflicts of interest that are relevant to the content of this article.
Ethics approval statement
The study protocol was approved by the local institutional review boards.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Authors’ contributions
EP, MB, GZ, MD and PC: study concept and design, interpretation of data, drafting of the manuscript; EP, GZ, MB, MT, GI, DP, FP, LV and CF: collection of data; EP and MB: analysis of data; EP, MB, GZ, LV, CF, GB, MD and PC: critical revision for important intellectual content.
Introduction
Decompensated cirrhosis is associated with high morbidity and mortality and is characterized by a wide variety of acute complications resulting in frequent emergent hospitalizations.
The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.
For patients surviving their hospitalization, there is a high risk of readmission in the period after discharge due to the development of a new complication or a suboptimal management during the index hospitalization. Indeed, readmission rates after an unscheduled hospitalization are reported from 20% to 37% at 30 days and up to 53% at 90 days,
In Europe, a recent large French retrospective study showed that the annual cost of hospitalizations in patients with decompensated liver cirrhosis is around 25,000 euros.
Finally, hospitalization because of cirrhosis was 30% more expensive in Italy than that caused by heart failure or chronic obstructive pulmonary disease.
Therefore, discharging patients with decompensated cirrhosis can be a complex decision-making process and effective strategies to decrease readmission are needed. In this perspective, the identification of risk factors for early readmission can contribute to a better timing of discharge and to the inclusion of patients in programs of closer surveillance after discharge that have been shown able to improve outcomes.
Several independent risk factors for hospital readmission have been so far identified, being mostly related to the severity of the disease, such as prognostic scores (i.e., Child-Pugh, Model for End-Stage Liver Disease [MELD]) and to the presence of complications, such as ascites or hepatic encephalopathy (HE).
Other proposed risk factors not related to cirrhosis are represented by demographic factors (i.e., male gender and young age) or co-morbidities (i.e., diabetes and high Charlson comorbidity index).
Thus, the aim of this study was to characterize, in a cohort of decompensated cirrhotic patients with prospectively collected data, the re-hospitalizations up to 1 year and the risk factors for early (30-day) liver-related re-admissions after an index hospitalization due to acute decompensation (AD), some of whom complicated by acute-on-chronic liver failure (ACLF).
We performed a secondary analysis of prospectively collected data in consecutive patients with cirrhosis admitted to the regular wards of the IRCCS Azienda Ospedaliera-Universitaria di Bologna, Bologna, Italy
Prognostic Role of Bacterial and Fungal Infections in Patients With Liver Cirrhosis With and Without Acute-on-Chronic Liver Failure: A Prospective 2-Center Study.
from January 2014 to March 2016. The aim of the core study was to investigate the prognostic role of bacterial and fungal infections in patients with cirrhosis.
Prognostic Role of Bacterial and Fungal Infections in Patients With Liver Cirrhosis With and Without Acute-on-Chronic Liver Failure: A Prospective 2-Center Study.
The study protocol was approved by the local institutional review boards. Written informed consent was obtained from patients or from legal surrogates before enrolment, according to the 1975 Declaration of Helsinki.
Detailed information on inclusion and exclusion criteria were reported elsewhere.
Prognostic Role of Bacterial and Fungal Infections in Patients With Liver Cirrhosis With and Without Acute-on-Chronic Liver Failure: A Prospective 2-Center Study.
Briefly, all consecutive patients with cirrhosis were screened for enrolment at admission. Inclusion criteria were as follows: a) cirrhosis diagnosed by a composite of clinical signs, laboratory tests, endoscopy, and imaging; b) unscheduled hospital admission because of an episode of AD;
c) age >18. Additional inclusion criteria for this analysis were the availability of clinical and biochemical data at hospital discharge. Exclusion criteria were i) admission for a scheduled procedure; ii) hepatocellular carcinoma (HCC) beyond the Milan criteria;
iii) extrahepatic malignancy; iv) previous liver transplantation (LT). The follow-up period for patients included in the analysis starts from admission to index hospitalization up to 1 year or death or LT. For the purpose of the study, only unscheduled readmissions occurring during follow-up after discharge from the index hospitalization were considered. Scheduled liver or non-liver related readmissions were not included in the analysis. Early readmissions were defined as those occurring within 30 days from discharge.
Data collection
The following data were collected at the time of hospital admission: demographic characteristics, etiology of cirrhosis, laboratory and clinical data including the presence of HCC and/or other co-morbidities assessed by the Charlson score.
During index hospitalization, patients were assessed daily for the occurrence of bacterial infections and nosocomial ACLF. Finally, timing of re-hospitalization with the leading cause, LT and death were collected up to 1-year.
Definitions
AD and ACLF were diagnosed according to the criteria of the EASL-CLIF.
With AD we refer to patients with cirrhosis admitted to the hospital due to acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infection, or any combination of these. With ACLF, we refer to a distinct syndrome which is observed among patients admitted to the hospital for AD characterized by single or multiple organ failures and high 28-day mortality (>15% at 28 days).
Bacterial infections were diagnosed according to international
and local guidelines. Nosocomial infections were considered if infection signs and/or symptoms started more than 48 h after hospital admission. Nosocomial ACLF (nACLF) was defined as any occurrence of ACLF after 48 hours from hospital admission. Readmission were defined as “liver-related” when it occurred for ascites decompensation, HE, GI bleeding, bacterial infections, jaundice or renal failure complicated or not by ACLF.
Statistical analysis
For all continuous parameters the normality of distribution and homogeneity of variance were evaluated by the Kolmogorov-Smirnov and Levene tests, then variables were reported as mean and standard deviation or median and interquartile range (IQR) as appropriate. Accordingly, comparisons between groups were performed by means of Student’s t Test or Mann-Whitney U test when appropriate. Categorical parameters were reported as frequency and percentage and compared by the χ2 square or Fisher exact test. The cumulative incidence of early and total readmissions during follow-up was estimated according to the Kaplan Meier Method and compared by the Log Rank test. The cumulative incidence of death was estimated considering LT as competing event, cumulative incidence curves were compared using Gray’s test. Survival time to readmission, death, or LT was calculated from discharge from index hospitalization.
A multivariable Cox regression analysis with stepwise backward selection method was performed to identify predictors of early readmission. For each predictor the hazard ratio (HR) and the 95% confidence interval (CI) were reported. The internal validity of this model was evaluated by using bootstrap resampling in which 1000 replications were generated by sampling with replacement from the original dataset. A multivariable competing risk regression analysis with stepwise backward elimination according to the Fine and Gray method was also performed as sensitivity analysis. In this model, death, non-liver related readmission and LT not preceded by admission for AD were considered as competing events.
To the purpose of the analysis continuous parameters were categorized according to the Youden index computed by the Receiver Operating Characteristics (ROC) curve analysis. All tests were two sided and values of p less than 0.05 were considered statistically significant. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS version 27, IBM corp), STATA (StataCorp LLC) version 17 and the cmprsk package on R statistical software (http://www.R-project.org/).
Results
Study population
Five-hundred sixteen patients with cirrhosis admitted for AD were included. Fifty-seven patients died or were transplanted during the index hospitalization. Of the remaining 459 patients, 130 (28%) patients were excluded because clinical and biochemical data at discharge and information on their hospitalizations during follow-up were not available. Thus, 329 (72%) patients were included in the final analysis (Figure 1). Baseline anthropometric data, etiology of cirrhosis and clinical complications were comparable between patients included and those excluded from the final analysis (Supplementary Table 1). Moreover, also the 1-year cumulative incidence of death (considering LT as competing event) was similar between two groups (34% [95%CI 29-40%] vs 38 [95%CI 30-47%]; p=0.422).
Baseline characteristics of patients and index hospitalization
Baseline demographic, biochemical and clinical data of patients are reported in Supplementary Table 2. Overall, the median age of the patients was 63 years with a predominance of males. The more frequent complications of cirrhosis at admission were ascites (57%), renal dysfunction (18%), and grade III/IV HE (17%). Twenty-two percent of patients had bacterial infection at admission, while an additional 11% developed nosocomial infection during index hospitalization. Moreover, 19% of subjects had ACLF at admission and a further 9% developed nosocomial ACLF during hospital stay. Finally, 29 (9%) of patients had refractory ascites.
About 50% of patients were in class B Child-Pugh, while the median MELD score was 15. Patients with hepatocellular carcinoma (HCC) were 69 (21%). Finally, the median length of the index hospitalization was 11 days (range 7-19) (Supplementary Table 2).
Readmissions
During the follow-up period, 369 hospitalizations were recorded in 182 patients. Eighty-four patients (25%) were re-admitted once, while 98 patients (30%) were readmitted more than once. Namely, 48 patients were readmitted twice, 33 patients 3 times, and 17 patients 4 or more times (Figure 2A). The more frequent causes of readmissions were HE (26%), ascites (16%), and bacterial infections (15%). In 101 cases (27%), readmission was not related to liver disease. Main causes for non-liver related readmissions were cardiological and vascular diseases (6%), traumatic injuries (6%), gastrointestinal illness excluding complications related to portal hypertension (6%), neurological disorders excluding HE (3%), pulmonary diseases excluding infections (2%), metabolic and endocrinological diseases (2%), and urinary disorders excluding infections (2%).
Figure 2Panel A: Number of patients with 1, 2, 3 and 4 or more readmissions during the follow-up period. Panel B: Kaplan-Meier estimate of the cumulative incidence of all cause readmissions during follow-up (blue line, death and transplant considered as censoring events) and cumulative incidence of all cause readmission or death (red line, transplant considered as censoring event).
Cumulative incidence of any-cause of first readmission was 20% (95% CI: 16-25%) at 30 days, 39% (95% CI: 34-45%) at 90 days and 63% (95% CI: 57-68%) at the end of follow-up (Figure 2B). Cumulative incidence of any-cause of first readmission or death was 25% (95% CI: 21-30%) at 30 days, 47% (95% CI: 42-53%) at 90 days and 71% (95% CI: 64-73%) at the end of follow-up (Figure 2B). The median time between discharge from the index hospitalization and first readmission was 56 days (range 9-159).
Of the 63 readmissions occurring within 30 days, 54 were liver-related with a cumulative incidence of 17% (95% CI: 13-21%) (Figure 3A). No differences were detected in the frequency of causes responsible for readmissions occurring within or after 30 days except for GI bleeding which was more frequent in late readmissions (Table 1).
Figure 3Panel A: 30-day cumulative incidence of liver-related early readmissions. Panel B: Cumulative incidence function of mortality considering liver transplantation as competing event in patients readmitted within 30 days (early readmission) for liver-related causes as compared to those not early readmitted. The cumulative incidence was compared by the Grey’s test.
Overall, during the whole post-discharge follow-up, 113 patients died and 28 received a liver graft. In particular, in the first 30 days after discharge, 26 patients died and 4 were transplanted. The cumulative incidence of death considering transplantation as a competing risk event was significantly higher in patients who experienced at least one liver-related readmission within 30 days as compared to that of the remaining patients (47% [95% CI: 33-59%] vs 32% [95% CI: 27-38%]; p=0.037) (Figure 3B).
Clinical characteristics of patients readmitted or not within 30 days
Patients who were readmitted within 30 days for liver-related causes did not differ from those who did not present early readmissions in terms of demographic data, etiology of cirrhosis and clinical features at admission of the index hospitalization, except for type 2 diabetes which was more frequent in the former group.
Among baseline biochemical parameters, patients early readmitted presented lower serum sodium and higher bilirubin levels at admission. As a result, MELD-Na score at admission was significantly higher (Table 2).
Table 2Demographic, biochemical and clinical characteristics at baseline and discharge from index hospitalization and events during the index hospitalization in patients readmitted for liver-related causes within 30 days or not readmitted within 30 days.
Readmitted within 30 days (n=54)
Not readmitted within 30 days (n=275)
P value
Anthropometric data
Age (years)
60 ± 15
63 ± 14
0.134
Male sex (n, %)
38 (70)
166 (60)
0.220
Etiology of cirrhosis
Viral (n, %)
19 (35)
114 (41)
0.449
Alcohol (n, %)
10 (19)
51 (19)
1.000
NASH (n, %)
2 (4)
21 (8)
0.393
Mixed (n, %)
13 (24)
49 (18)
0.340
Other (n, %)
10 (19)
40 (15)
0.533
Clinical and biochemical and hemodynamic data at admission
Ascites (n, %)
35 (65)
151 (55)
0.230
Encephalopathy III/IV grade (n, %)
13 (24)
42 (15)
0.115
Renal dysfunction (n, %)
11 (20)
48 (17)
0.567
Gastrointestinal bleeding (n, %)
3 (6)
21 (8)
0.778
Bacterial infection at admission (n, %)
11 (20)
62 (23)
0.858
ACLF at admission (n, %)
14 (26)
47 (17)
0.129
Active alcohol consumption (n, %)
9 (17)
61 (22)
0.468
Hb (g/dL)
10.4 ± 1.5
10.7 ± 2.07
0.281
WBC (109/L)
5.64 (3.78 – 8.16)
5.2 (3.6 – 8.2)
0.471
CRP (mg/dL)
1.23 (0.35 – 2.66)
1.12 (0.38 – 3.17)
0.743
Platelets (109/L)
84 (55 – 124)
92 (59 – 143)
0.324
Sodium (mmol/L)
136 (132 – 139)
137 (134 – 140)
0.015
Bilirubin (mg/dL)
2.96 (1.37 – 5.82)
2.0 (1.1 – 3.5)
0.013
Creatinine (mg/dL)
0.92 (0.79 – 1.36)
0.95 (0.75 – 1.27)
0.463
Albumin (mg/dL)
3.08 ± 0.57
3.24 ± 0.61
0.089
INR
1.46 (1.33 – 1.58)
1.34 (1.23 – 1.56)
0.058
MAP (mmHg)
85 (76 – 93)
85 (79 – 93)
0.526
HR (bpm)
74 (66 – 85)
77 (68 – 86)
0.488
Prognostic scores at admission
Child–Pugh score
9 (7 – 10)
8 (7 – 9)
0.088
Child–Pugh class
Class A (n, %)
9 (17)
68 (25)
0.223
Class B (n, %)
28 (52)
139 (51)
0.883
Class C (n, %)
17 (32)
68 (25)
0.310
MELD
16 (11 – 21)
15 (10 – 19)
0.097
MELD-Na
20 (15 – 23)
17 (13 – 21)
0.008
CLIF-C AD
53 ± 9
51 ± 9
0.226
Comorbidities
Charlson comorbidity index
6.00 (4.55 – 8.15)
6.10 (4.95 – 7.30)
0.825
HCC (n, %)
11 (20)
58 (21)
1.000
Diabetes (n, %)
26 (48)
91 (33)
0.043
Events occurring during index hospitalization
Hospital–related infection (n, %)
8 (15)
29 (11)
0.351
ACLF during hospital–stay (n, %)
10 (19)
21 (8)
0.020
Blood transfusion (n, %)
19 (35)
78 (29)
0.203
Length of index hospitalization (days)
14 (8 – 21)
10 (7 – 18)
0.010
Clinical, biochemical and hemodynamic data at discharge from index admission
Hb (g/dL)
9.9 (8.9 – 10.8)
10.3 (9.5 – 11.6)
0.010
WBC (109/L)
4.9 (3.5 – 6.9)
4.72 (3.39 – 6.55)
0.739
CRP (mg/dL)
0.91 (0.39 – 1.65)
0.86 (0.33 – 1.79)
0.519
Platelets (109/L)
74 (55 – 110)
92 (58 – 145)
0.108
Sodium (mmol/L)
137 (135 – 139)
139 (136 – 141)
0.014
Bilirubin (mg/dL)
3.2 (1.4 – 5.7)
1.8 (0.9 – 3.4)
0.003
Creatinine (mg/dL)
1.02 (0.80 – 1.25)
0.93 (0.71 – 1.27)
0.171
Albumin (mg/dL)
3.40 (3.30 – 3.90)
3.50 (3.10 – 3.90)
0.349
INR
1.42 (1.26 – 1.64)
1.35 (1.21 – 1.54)
0.096
MAP (mmHg)
83 (78 – 90)
83 (77 – 93)
0.606
HR (bpm)
70 (64 – 80)
70 (60 – 80)
0.548
MELD
16 (12 – 20)
14 (10 – 18)
0.018
MELD-Na
18 (12 – 21)
15 (11 – 19)
0.011
CLIF-C AD
50 ± 8
49 ± 9
0.298
Data is reported by mean and standard deviation, median and interquartile range or absolute frequency and percentage (%) as appropriate. Comparisons between groups were performed by means of Student’s t Test, Mann-Whitney U test or the χ2 test when appropriate. NASH: non-alcoholic steatohepatitis; ACLF: acute-on-chronic liver failure; Hb: hemoglobin; WBC: white blood cells; CRP: C-reactive protein; INR: international normalized ratio; MAP: mean arterial pressure; HR: heart rate; MELD: model for end-stage liver disease; CLIF-C AD: CLIF consortium acute decompensation score; HCC: hepatocellular carcinoma; RBC: red blood cell.
Patients re-hospitalized within 30 days more frequently developed ACLF during the index hospitalization, while no differences were recorded in the incidence of nosocomial bacterial infections and number of blood transfusion. Moreover, the length of the index hospitalization was significantly higher in patients with early readmission (Table 2).
Finally, among the biochemical data recorded at discharge, patients with early readmission were characterized by lower hemoglobin and serum sodium and higher bilirubin levels. Overall, the severity of cirrhosis at discharge was higher in patients re-hospitalized within 30 days, as assessed by the MELD and MELD-Na scores (Table 2).
Risk factors for liver-related re-admission within 30 days
We then performed a multivariable Cox regression analysis to identify the independent predictors of early readmission. The parameters significantly associated with early-readmission at univariate analysis (Table 2) included in the initial model were the presence of diabetes, length of the index hospitalization, nACLF, MELD-Na and hemoglobin level at discharge. Diabetes and nACLF were considered dichotomous variables, while length of hospital stay, MELD-Na and hemoglobin level at discharge were categorized according to their best cut-off as determined by ROC curve analysis. As reported in Table 3, MELD-Na >16 (HR 2.234 [95% CI: 1.268 – 3.934], p=0.005) and hemoglobin ≤ 8.7 g/dl (HR 2.629 [95% CI: 1.379 – 5.017], p=0.003) at discharge were identified as independent predictors of early liver-related readmission. The internal validity of the Cox regression model was also evaluated by using bootstrap resampling in which 1000 replications were generated by sampling with replacement from the original dataset. This model confirmed MELD-Na>16 (HR 2.23, 95%CI 1.25- 3.99, p=0.007) and Hb ≤ 8.75 g/dl (HR 2.63, 95%CI 1.32- 5.24, p=0.006) as independent predictors of hospital readmission.
Table 3Cox Regression analysis of factors associated with early unplanned readmission liver-related. Unscheduled non-liver related readmission and death without admission to the hospital were considered censoring events. Data is reported as Hazard Ratio (HR) and 95% confidence interval (CI).
As a further sensitivity analysis, we also performed a multivariable competing risk regression model, considering death, liver transplantation not preceded by admission for AD and non-liver related readmission as competing events (Supplementary Table 3). This model confirms MELD-Na >16 (sHR 2.25 [95% CI: 1.27-3.99], p=0.005) and hemoglobin ≤ 8.7 g/dl (sHR 2.38 [95% CI: 1.22-4.64], p=0.011) as independent predictors, and identified the presence of diabetes (sHR 1.74 [95% CI: 1.02-2.99], p=0.044) as additional risk factor for early readmission.
Overall, a MELD-Na score >16 was found in 134 subjects, while patients with Hb ≤ 8.7 g/dl at discharge were 33 (10%). In the latter group, the main cause of anemia was acute gastrointestinal bleeding (3 subjects), iron deficiency (10 subjects of whom 6 with evidence of occult chronic gastrointestinal bleeding), folate deficiency (2 subjects), and malnutrition in patients with chronic alcohol abuse (2 subjects). In the remaining 18 patients, the low hemoglobin level was attributed to multifactorial factors (i.e., hypersplenism, hyporegenerative bone marrow, chronic inflammation). Interestingly, patients with Hb ≤8.7 g/dl presented higher levels of CRP at discharge than those with Hb >8.7 g/dL (1.72 g/dL [IQR 0.47-2.95] vs 0.79 g/dL [IQR 0.33-1.6], p=0.016).
We then analyzed the cumulative incidence of early readmission in patients presenting none, 1 or 2 of these risk factors. As shown in Figure 4A, the cumulative incidence of early readmission due to liver-related causes was 10% (95% CI: 6-13) in patients presenting no risk factors, 23% (95% CI: 16-32) in those with one risk factor and 44% (95% CI: 26-66) in those with two risk factors (p<0.001). Furthermore, we analyzed the sub-population with MELD-Na >16 at discharge: in this subgroup of patients, the additional presence of Hb ≤8.7 g/dl at discharge doubled the cumulative incidence of 30-day readmission (44% [95% CI 26-66%] vs 22% [95% CI 15-31]: p=0.023) (Figure 4B).
Figure 4Panel A. 30-day cumulative incidence of liver-related early readmissions in patients presenting none, one or two of the following independent risk factors: hemoglobin ≤8.7 g/dL and MELD-Na > 16 at discharge of the index hospitalization. Panel B. 30-day cumulative incidence of liver-related early readmissions in patients with MELD-Na>16 presenting a hemoglobin level of at least or lower than 8.7 g/dL at discharge. Comparisons were made by the Log-Rank test.
Finally, the cumulative incidence of liver-related early readmission was similar in patients receiving or not blood transfusion during index hospitalization (20% [95%CI 12-28%] vs 15 [95%CI 11-20%]; p=0.289).
Discussion
Recurrent emergent hospitalizations represent a major clinical and socio-economic problem in patients with decompensated cirrhosis. The major findings of the present study can be synthetized as follows: 1. The cumulative incidence of readmissions increases progressively over the year following discharge from an index hospitalization due to AD, with a greater rate during the initial weeks; and 2. Low hemoglobin levels independently predict liver-related 30-day readmission.
The majority of available studies on readmissions have evaluated retrospective cohorts of patients and large national registries
Based on the results of our study performed in a relatively large prospective cohort, a patient discharged after AD of cirrhosis carries about 50% chance of being re-hospitalized at least once in the following year. Even more important, more than 50% of these patients had more than one readmission and almost 30% at least three over a year. This means that a relatively high number of patients with decompensated cirrhosis is at high risk of multiple readmissions, thus representing a heavy burden for healthcare systems.
Three out of four of all readmissions were due to liver-related causes with ascites and HE responsible for almost 60% of them. This implies that improving the management of these two complications will likely reduce the disease burden. At this regard, in addition to optimization of drug therapy, early contacts with nurses or doctors after discharge, the education of patients and their caregivers or telemedicine (i.e., smartphone apps) have shown encouraging results to reduce readmissions.
Implementation of long-term albumin administration in the outpatient setting may represent a further option, as it has been reported that this approach reduces HE, ascites, infections, and hospitalization.
Early Hospital Readmissions and Mortality in Patients With Decompensated Cirrhosis Enrolled in a Large National Health Insurance Administrative Database.
as also confirmed by our study. Second, being rapidly re-admitted is a psychological stressful event a rapid deterioration of the patient’s quality of life. Third, early readmissions are considered an outcome indicator of in-hospital management of patients driving to reduced reimbursement to hospitals.
Thus, many efforts have been made for identifying parameters able to stratify patients for their risk of early readmission. We found that MELD-Na and hemoglobin level at discharge independently predict 30-day liver-related readmission. While the association between either severity of cirrhosis with the risk of early readmission has been already reported,
the independent predicting role of the hemoglobin level represents, at the best of our knowledge, a novel finding.
In our cohort, hemoglobin levels equal or below 8.7 g/dL at discharge were associated with more than a double risk of early readmission. Thus, a simple inexpensive parameter available in all care settings can help to identify, among those with advanced cirrhosis (i.e., with MELD-Na >16), a sub-group of patients who have almost a 50% probability to be readmitted within 30 days and therefore should be included in a close surveillance outpatient program.
Up to now, anemia has been related to the severity of cirrhosis, as assessed by MELD and Child-Pugh scores,
More recently, a retrospective study in almost 5.000 outpatients with advanced chronic liver disease found a significant association between anemia and incidence of hepatic decompensation, hospitalization, ACLF and long-term overall survival.
Therefore, considering these data, we could hypothesize that a low hemoglobin level can act as surrogate marker of disease severity and, among the multiple possible causes, the role of systemic inflammation that characterizes advanced cirrhosis may be predominant, as also suggested by the higher level of CRP at discharge in patients with Hb ≤ 8.7 d/dL.
The last issue to discuss is whether our finding should prompt clinical interventions aimed at improving the circulating hemoglobin level before discharge. Several considerations can be made. First, the cut-off we identified (8.7 g/dL) is a value for which current guidelines do not recommend red blood cell transfusion.
Second, the incidence of liver related early-readmission was similar in transfused and non-transfused patients and no difference was found in the number of blood transfusion received by early-readmitted or not early-readmitted patients during index hospitalization. Third, even in presence of an apparent depletion, iron supplementation may not be appropriate in patients with AD and even less in case of ACLF. Indeed, in these patients, who present a complex and still not fully clarified alteration of the iron metabolism,
Thus, studies are still needed before an indication to correct anemia beyond the current recommendation can be proposed.
Some limitations of our study must be acknowledged. First, our study is a secondary analysis of a cohort of patients with prospectively collected data and the original study was not designed to study anemia and related parameters,
Prognostic Role of Bacterial and Fungal Infections in Patients With Liver Cirrhosis With and Without Acute-on-Chronic Liver Failure: A Prospective 2-Center Study.
therefore a comprehensive characterization of the etiology of anemia was not possible. Second, the number of patients enrolled is significantly lower compared to the large retrospective registry studies already published.
However, we believe that the prospective collection of the data in a relatively large cohort provides more robust and reliable information as compared to pure retrospective analysis. Finally, the number of discharged patients who could not be included in the analysis due to the lack of complete data on hospitalization during follow-up was relatively high (28%). However, baseline characteristics and 1-year mortality of these patients were comparable to those included in the analysis, thus mitigating the risk of a selection bias.
In conclusion our study shows that multiple readmissions to hospital are frequent and distributed over a period of 1 year in patients with decompensated cirrhosis discharged after an index hospitalization for AD. Furthermore, a low hemoglobin level (≤8.7 g/dl) has been identified for the first time as independent predictor of early liver-related readmission, contributing to identify the subgroup of patients (about 10% of our entire cohort) who deserves a closer surveillance by their inclusion in transitional care programs with the objective of preventing rehospitalizations and saving healthcare resources.
Appendix A. Supplementary data
The following is/are the supplementary data to this article:
Author names in bold designate shared co-first authorship
Sepanlou S.G.
Safiri S.
Bisignano C.
Ikuta K.S.
Merat S.
Saberifiroozi M.
et al.
The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.
Prognostic Role of Bacterial and Fungal Infections in Patients With Liver Cirrhosis With and Without Acute-on-Chronic Liver Failure: A Prospective 2-Center Study.
Early Hospital Readmissions and Mortality in Patients With Decompensated Cirrhosis Enrolled in a Large National Health Insurance Administrative Database.
00029-0&id=ga1.jpg){kind=link}
00029-0&id=gr1.jpg){kind=link}
00029-0&id=gr2.jpg){kind=link}
00029-0&id=gr3.jpg){kind=link}
00029-0&id=gr4.jpg){kind=link}