Albumin infusion reduces the risk of rebleeding and in-hospital mortality in cirrhotic patients admitted for acute gastrointestinal bleeding: retrospective analysis of a single institute

doi:10.21203/rs.2.20564/v1

Background

To investigate the effect of albumin infusion in cirrhotic patients admitted for acute gastrointestinal bleeding.

Methods

Medical records of cirrhotic patients who admitted due to acute gastrointestinal bleeding through January 2009 to December 2018 were systemically reviewed. Clinical data and the total amount of albumin and red blood cell used during hospitalization were recorded. For patients with rebleeding, the amount of albumin and red blood cell used before rebleeding was also documented. The primary outcome was the occurrence of rebleeding and the second outcome was in-hospital mortality. Univariate and multivariate logistic analysis were performed to identify risk factors associated with rebleeding and in-hospital mortality.

Results

A total of 2239 cirrhotic patients were included in the analysis. There were 245 episodes of in-patient rebleeding occurred, while 135 patients died. Overall, more red blood cells and albumin were prescribed to patients who suffered rebleeding. In terms of the amount before rebleeding, the red blood cell was higher in patients with rebleeding, but the albumin infusion were similar. In the multivariate model, the albumin infusion was an independent risk factor associated with rebleeding (adjusted OR for ≤40g, 0.385 [0.252-0.588], p<0.001; OR for >40g, 0.295 [0.169-0.514], p<0.001). The use of albumin more than 40g during hospitalization reduces the risk of in-patient mortality (adjusted OR for ≤40g, 0.730 [0.375-1.423], p=0.356; OR for >40g, 0.389 [0.180-0.838], p=0.016).

Conclusions

Albumin infusion could reduce risk of in-hospital rebleeding. Moreover, more than 40g albumin infusion decrease numbers of mortality in cirrhosis admitted for acute gastrointestinal bleeding.

Internal Medicine

albumin

cirrhosis

gastrointestinal bleeding

portal hypertension

Gastrointestinal bleeding (GIB) accounts for nearly one-third of all death in cirrhotic patients. Hypoalbuminemia, frequently caused by the impaired synthesis in the scenario of advanced cirrhosis, may further deteriorate after GIB due to the direct loss of albumin in the gastrointestinal tract and short-term fast. As an established risk factor for sepsis and mortality in critical ill patients, hypoalbuminemia needs to be corrected by albumin treatment[1]. In patients with cirrhosis, the use of albumin prevents circulatory dysfunction after paracentesis, improves the outcomes in patients with refractory ascites, spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS)[2, 3]. However, no studies thus far have elucidated its role in the management of GIB in cirrhotic patients.

The antibiotic prophylaxis has been accepted by international consensus for its role in reducing rebleeding risk in cirrhotic patients[4]. The therapeutic effect of antibiotics in cirrhosis is attributed to the improvement of the inflammatory state caused by bacterial infection[5]. Meanwhile, emerging evidence supports the anti-inflammatory property of albumin, which contributes to reducing the risk of complications and mortality rate in cirrhotic patients[6, 7]. On the contrary, albumin infusion, noted as a volume expander, may increase portal pressure and induce rebleeding due to deteriorated pre-existing portal hypertension[8]. Therefore, our study aims to investigate whether the albumin infusion would affect the prognosis of cirrhotic patients admitted for GIB.

Study design

Medical records of cirrhotic patients who admitted to West China Hospital due to GIB through Jan 2009 to Dec 2018 were systemically reviewed. Data of patients’ demographics, cause of cirrhosis, Child-Pugh classification, laboratory tests, days of hospital stay, sources of bleeding, initial rescue therapy with balloon tamponade, endoscopic and radiological interventions, concomitant of hepatic carcinoma (HCC) and portal vein thrombosis (PVT), occurrence of in-hospital rebleeding and deaths were collected based on the medical records.

The sources of bleeding were classified into upper or lower GI tract according to endoscopic findings. The upper GI bleeding was further divided into variceal bleeding and non-variceal bleeding lesions as determined by esophagogastroduodenoscopy. Variceal bleeding was defined as active hemorrhage from varices, or the presence of a clot over varices, or varices as the only potential source of bleeding. The presence of HCC or PVT was confirmed by radiological imaging records or discharge diagnosis. The baseline level of hemoglobin, bilirubin, albumin, creatine, and prothrombin time were obtained from the laboratory results at admission.

Clinical outcomes

The primary outcome was the in-hospital rebleeding event, defined as the following symptoms that occurred after initial hemostasis achieved: 1) newly occurrence of hematemesis or bloody nasogastric aspirate; 2) recurrence of hematochezia or melena. The secondary outcome was in-hospital mortality. The death reasons were derived from the discharge diagnosis.

Infusion of albumin and red blood cell

The amount of albumin and red blood cell (RBC) infusion during hospitalization was collected from the hospital database. The total amount of albumin and RBC used during hospitalization were recorded as total-ALB and total-RBC. For patients with rebleeding occurred, the amount of albumin and RBC used before rebleeding was recorded as pre-ALB and pre-RBC. For patients without rebleeding, the amount of pre-ALB and pre-RBC was equivalent to the total-ALB and total-RBC.

Statistical analysis

Continuous variables were displayed as means ± standard deviation and compared using the Student’s t test. Categorical variables were displayed as frequencies and percentages and compared by Chi-square or Fisher exact tests. Baseline characteristics and other associated covariates with outcomes were estimated with univariate and multivariate logistic regression models and reported as odds ratios (OR) with 95% confidence intervals (CI). Statistics are calculated using R version 3.2.0 (R Foundation for Statistical Computing, Vienna, Austria).

Patients’ baseline characteristics and outcomes

A total of 2259 cirrhotic patients who admitted for acute GIB were selected, among whom 20 cases were excluded for incomplete data. Overall, 2239 records were included in this analysis. The mean age was 53.0±13.1, 1568 (70%) were male. Except for 273 (12.2%) cases without identified etiology, the other etiologies for cirrhosis were: 1385 (61.9%) HBV infections; 264 (11.8%) alcoholic liver diseases; 159 (7.1%) autoimmune liver diseases; 82 (3.7%) HCV infections; 26 (1.2%) secondary cholestatic liver diseases; 15 (0.7%) vascular disorders, 35 (1.6%) others. According to the Child-Pugh classification, there were 636 (28.4%) patients classified as class A, 1096 (49%) as class B , and 507 (22.6%) as class C. PVT and HCC were present in 407 (18.2%) and 414 (18.5%) patients, respectively. In terms of the rebleeding sources, there were 1960 (87.5%) cases with upper GI tract bleeding and 71 (3.2%) with lower GI tract bleeding (jejunoileal or colonic lesion). There were 208 (9.3%) patients who did not receive endoscopy interventions because of massive hemorrhage with rapid deterioration conditions, or patients avoid endoscopic interventions. Variceal lesion causes bleeding in 1901 cases (84.9%), among which 44 cases were concomitant with healing ulcer lesion. Non-variceal lesion only causes 124 cases (5.5%) of bleeding. In variceal bleeding, balloon tamponade was initially applied in 273 cases to control active bleeding, 33 emergent transjugular intrahepatic portosystemic shunt (TIPS) were performed as rescue therapy. During hospitalization, 691 (30.9%) patients received endoscopic treatment, among whom 16 cases underwent additional radiological interventional treatment due to the failure of control bleeding, while 535 (23.9%) patients only underwent radiological interventional treatment.

Overall, there were 245 (10.9%) patients for whom in-patient rebleeding occurred, with an average of 12.3±6.6 hospitalization days. As regards the in-hospital mortality, a total of 135 (6%) patients died during hospitalization and 110 of them experienced in-patient rebleeding. The reasons of deaths were as followed: hemorrhagic shock (n=95), hepatorenal syndrome (n=18), hepatic encephalopathy (n=7), liver failure (n=6), infection (n=4), cerebrovascular event (n=3), metastasis (n=1), acute myocardial infarction (n=1).

The association between albumin/RBC infusion for in-patient rebleeding

Univariate variables association with rebleeding were displayed in Table 1. Patients suffered rebleeding were more likely to have HCC (17.6% vs 26.1%, p=0.002), higher Child-Pugh classification (Child A 30.6% vs 10.6%，Child B 48.8% vs 50.2%, Child C 20.6% vs 39.2%, p<0.001), higher bilirubin level (32.5±39.7 vs 47.8±78.8, p<0.001), lower albumin level (30.8±6.0 vs 28.2±6.6, p<0.001), and deteriorated prothrombin time at baseline (16.3±8.8 vs 17.7±8.6, p=0.026). The risk of rebleeding also varies depending on the bleeding sources, with more rebleeding occurs in cases with unidentified lesions (8.6% vs 14.7%, p=0.003) and less in non-variceal lesion (5.9% vs 2.0%, p=0.018). Rebleeding was more likely to occur in patients rescued by balloon tamponade at admission (7.3% vs 52.2%, p<0.001), while subsequent endoscopic treatment effectively prevents rebleeding (32.9% vs 13.9%, p<0.001) (Table 1).

An average of 2.4±3.4 units of RBC and 15.3 ± 36.1g albumin were administrated to all included patients. More total-RBC (1.8±2.5 vs 6.7±6.0 units, p<0.001) and total-ALB (13.6±32.6 vs 29.6±54.9g, p<0.001) were prescribed to patients who had rebleeding, compared to those without rebleeding. Nevertheless, the pre-RBC transfusion was higher in rebleeding patients (1.8±2.5 vs 4.2±4.4 units, p<0.001), while the pre-ALB infusion was comparable (13.6±32.6 vs 12.3±34.1g, p=0.630). Moreover, in patients with Child-Pugh A and B class, both the pre-ALB and pre-RBC infusion were higher in those with rebleeding in contrast with Child-Pugh C patients in which pre-ALB infusion was substantially lower in those with rebleeding (15.2 vs 30.6g, p=0.009). (Table 2)

To explore the association between the dose and risk of rebleeding, the amount of pre-ALB was further classified into two subgroups as ≤40g and > 40g. The use of pre-ALB was not linked to rebleeding in univariate analysis. In the multivariate model adjusted for baseline albumin and Child-Pugh class, however, the use of an increased dose of albumin reduces the risk of rebleeding (OR for ≤40g vs 0g, 0.463 [0.319-0.672], p<0.001; OR for > 40g vs 0g, OR 0.374 [0.226-0.619], p<0.001).(Table 3)

Furthermore, in another multivariate model adjusted for all confounders (HCC, bleed from non-varices lesion, unidentified lesion, the initial application of balloon tamponade, level of bilirubin, albumin and prothrombin time, endoscopic treatments), the pre-ALB infusion was still associated with a lower risk of rebleeding, with a negative dose-effect relationship between albumin use and rebleeding risk observed (adjusted OR for ≤40g vs 0g, 0.385 [0.252-0.588], p<0.001; adjusted OR for >40g vs 0g, 0.295 [0.169-0.514], p<0.001) (Table 3). Other independent factors in this model included Child-Pugh classification (adjusted OR for Child B vs A, 1.819 [1.123-2.948], p=0.015; adjusted OR for Child C vs A, 2.834 [1.613-4.980], p<0.001), bleed form non-variceal lesion (adjusted OR 0.362 [0.137-0.954], p=0.040), rescue therapy with balloon tamponade (adjusted OR 14.001 [10.007-19.589], p<0.001) and endoscopic treatment (adjusted OR 0.339 [0.223-0.516], p<0.001) (Figure 1A).

Regarding RBC infusion before rebleeding, the pre-RBC infusion remained associated with more occurrences of rebleeding in univariate (OR for 4-8 vs < 4 units 3.569 [2.591-4.918], p<0.001; OR for >8 vs <4 units 7.837 [4.633-13.257], p<0.001).In the multivariate analysis adjusted for the confounders above, the risk was positively correlated with the infused RBC units (adjusted OR for 4-8 vs <4 units 1.835 [1.249-2.695], p=0.002; adjusted OR for >8 vs <4 units 4.253 [2.242-8.071, p<0.001) (Figure 1B).

The association between albumin/RBC infusion and in-hospital mortality

In the univariate analysis, the in-hospital mortality was more probable in patients with compromised liver function (i.e. higher Child-Pugh classification, lower levels of albumin, higher values of bilirubin, creatine and prothrombin time), concomitant with HCC, bleed from varices or unidentified lesion, initial rescue therapy with tamponade and occurrence of rebleeding. The uses of endoscopic and radiological interventions, however, decreased mortality risk (Table 4). More total-RBC (2.2±3.2 vs 5.6±5.4 units, p<0.001) and total-ALB (15.0±35.2g vs 21.6±47.6g, p=0.004) infusion were observed in patients who died during hospitalization than in those who recovered. The number of death between patients administrated with ≤ 40g compared with those with ＞ 40g was not statistically different (115/1975 vs 20/264, p=0.15). However, after adjusted for baseline albumin level and Child-Pugh class (OR for ≤ 40g vs 0g, 0.557 [0.366-0.908], p=0.017; OR for > 40g vs 0g, 0.525 [0.304-0.906], p=0.021), there was a significant correlation between total-ALB infusion and mortality. In another multivariate model adjusted for all confounders (Child-Pugh classification, presence of HCC, occurrence of rebleeding, bleed from variceal lesion or unidentified lesion, the initial therapy of tamponade, level of bilirubin, creatine, albumin and prothrombin time, endoscopic and radiological interventions), the infusion of more than 40g albumin decreased the risk of in-hospital mortality (adjusted OR for ≤40g vs 0g, 0.730 [0.375-1.423], p=0.356; adjusted OR for >40g vs 0g, 0.389 [0.180-0.838], p=0.016) (Table 5 and Figure 2A).

On the other hand, the infusion of total-RBC increased the mortality risk in the univariate analysis (OR for 4-8 vs ＜4 units, 2.816 [1.807-4.387, p<0.001; OR for >8 vs ＜4 units, 9.097 [5.628-14.706], p<0.001) and a multivariate model adjusted for baseline hemoglobin level and Child-Pugh class (OR for 4-8 vs ＜4 units, 2.626 [1.613-4.276], p<0.001; OR for >8 vs ＜4 units, 9.559 [5.535-16.509], p<0.001). However, this association between RBC use and in-hospital mortality risk was not observed in another multivariate model adjusted for all confounders described above (adjusted OR for 4-8 vs ＜4 units, 0.735 [0.357-1.517], p=406; adjusted OR for >8 vs ＜4 units, 1.156 [0.522-2.562], p=0.721) (Figure 2B).

Gastrointestinal bleeding (GIB) is a fatal complication of cirrhosis, especially for those with rupture of varices. The application of endoscopic and radiological interventions has greatly improved the prognosis of patients with acute GIB[9]. In addition to the advances of invasive treatments, the conservative treatments remain an integral part of the management of this medical emergency and is increasingly standardized. The therapeutic value of prophylactic antibiotics and restrict blood transfusion strategy has recently been proved by several clinical studies[5, 8]. However, the role of albumin in the management of GIB in patients with decompensated cirrhosis has not yet been assessed. This study demonstrated that albumin infusion was associated with a lower risk of rebleeding and in-hospital mortality in cirrhotic patients.

Our study revealed a rebleeding rate of 10.8% and overall mortality of 6.0%, which were lower than those described in previous studies possibly due to a shorter follow-up period in our study[10, 11]. Despite the risk factors that are already known for rebleeding, our study found that the unidentified lesion also increased the risk of rebleeding and in-hospital mortality in cirrhotic patients[5, 11]. Current consensus recommended endoscopic intervention for non-variceal upper gastrointestinal bleeding within 24 hours since hemodynamic homeostasis, while the timing of endoscopy in cirrhosis suspected variceal bleeding seems not correlated to the outcomes[12]. Given the unclear urgency of endoscopic intervention and its requirement of technical expertise, endoscopy examinations for suspected variceal bleeding were only delivered after hemodynamic hemostasis in our institute. However, based on our results, we advocated that appropriate endoscopic therapies for variceal lesion should be given within 5 days as most experts suggested. In consideration of the negative impact of unidentified lesion on the outcomes possible due to the rapid disease deterioration and passive surveillance to invasive treatments, we believe early identification of bleeding lesion is crucial for the management of acute GIB.

Our study aims to explore whether albumin infusion influences the outcomes of cirrhotic patients admitted for GIB. Theoretically, abundant albumin infusion in patients with GIB may cause rebleeding by increased portal pressure in a similar manner of liberal transfusion strategy[13]. Interestingly, we found that albumin infusion reduces the risk of in-hospital rebleeding. Particularly, this beneficial effect was predominately observed in patients with Child-Pugh C class, most of whom had high portal pressure.

In our study, the mean amount of pre-ALB was just 12.3 g, which is much lower than those recommended for ascites treatment (1-1.5 g/kg). Also, the dose-dependent effect of albumin in reducing rebleeding does not support the view that a higher dose leads to more bleeding. In fact, a recent study suggests that the portal pressure was not affected after the infusion of albumin (1.5 g/kg, every week)[6]. Hence, the concern that albumin infusion increases the risk of rebleeding due to deterioration of portal pressure seems unnecessary. On the other hand, albumin is used in cirrhosis for the treatment of SBP and was widely discussed in the sepsis treatment for its immunomodulatory and anti-inflammatory properties[14, 15]. As bacterial infection was identified as a critical determinant of rebleeding in cirrhosis by increasing portal pressure through vasoactive substances[5], the effect of albumin on systemic inflammation provides a potential theoretical basis for its role in reducing bleeding. Moreover, albumin may also control the bleeding risk by promoting the transportation of drugs such as proton pump inhibitor and antibiotics, two essential agents in the management of acute GIB. Indeed, a recent clinical study found that the combination of albumin and antibiotics is superior to antibiotics alone in the control of inflammation[6]. Collectively, the mechanisms involved the benefit of albumin is attribute to its effect on systemic inflammation and pharmacokinetic process, although its other properties may also play a role[16, 17].

The association between albumin infusion and in-hospital mortality was also evaluated. In our study, infection, HRS and liver failure are the main non-bleeding cause of death in cirrhotic patients with acute GIB[10]. It is thus reasonable to assume that albumin treatment may ameliorate the number of deaths from infection or infection-related organ failures. Although the results showed that more than 40 g of albumin infusion reduce mortality in multivariate regression, we failed to demonstrate the beneficial results of its effect on non-bleeding deaths since most patients dead from hemorrhagic shock. However, based on current evidence supporting its efficacy in these complications, we believe that the infusion of albumin for cirrhosis with GIB is favorable to improve the in-hospital prognosis in those with high-risk for non-bleeding death[14]. Further studies on GIB patients with a high risk of infection and HRS are needed to address this issue.

In this study, the pre-RBC infusion was positively correlated with the occurrence of rebleeding. It is not surprising that patients with rebleeding present severe bleeding at admission, thus require more RBC transfusion. Although the causal relationship between pre-RBC infusion and rebleeding cannot be determined based on current data, this issue has already been described by many well-designed studies[8, 18, 19]. A limited RBC transfusion reduces the occurrence of rebleeding, the survival benefit was not observed in our study. Its effect on survival was not inconsistent in previous reports probably due to the different enrollment criteria[8, 19–22]. Nevertheless, the restrictive RBC transfusion is a cost-effective strategy as most studies show that less RBC transfusion does not correlated with poor prognosis.

As a retrospective study, the limitations were inevitable. First, the time of albumin infusion before rebleeding was not evaluated. Normally, the albumin is not recommended in the initial resuscitation of hemorrhagic shock. Whether albumin should be applied in the resuscitation stage or after hemostasis achieved needs to be explored; Second, the average dose of albumin used in our study is low compared with previous studies. The lower dose may be due to the conventional view of its limited effect on GIB, as well as its high cost. Hence, the appropriate dose needs to be evaluated by further studies focused on this issue. Third, the rebleeding was associated with many confounding variables, we cannot exclude the existence of selection bias due to our retrospective design. Although our result has been statistically adjusted by confounders, the applicability of the conclusion requires evaluation in the target population. Last, the 12-day follow-up period was shorter than those described in prior studies. However, as the rebleeding usually occurs within the first two weeks, we believe our analysis was still persuasive[8].

Gastrointestinal bleeding (GIB) is a fatal complication of cirrhosis, especially for those with rupture of varices. The application of endoscopic and radiological interventions has greatly improved the prognosis of patients with acute GIB[9]. In addition to the advances of invasive treatments, the conservative treatments remain an integral part of the management of this medical emergency and is increasingly standardized. The therapeutic value of prophylactic antibiotics and restrict blood transfusion strategy has recently been proved by several clinical studies[5, 8]. However, the role of albumin in the management of GIB in patients with decompensated cirrhosis has not yet been assessed. This study demonstrated that albumin infusion was associated with a lower risk of rebleeding and in-hospital mortality in cirrhotic patients.

Our study revealed a rebleeding rate of 10.8% and overall mortality of 6.0%, which were lower than those described in previous studies possibly due to a shorter follow-up period in our study[10, 11]. Despite the risk factors that are already known for rebleeding, our study found that the unidentified lesion also increased the risk of rebleeding and in-hospital mortality in cirrhotic patients[5, 11]. Current consensus recommended endoscopic intervention for non-variceal upper gastrointestinal bleeding within 24 hours since hemodynamic homeostasis, while the timing of endoscopy in cirrhosis suspected variceal bleeding seems not correlated to the outcomes[12]. Given the unclear urgency of endoscopic intervention and its requirement of technical expertise, endoscopy examinations for suspected variceal bleeding were only delivered after hemodynamic hemostasis in our institute. However, based on our results, we advocated that appropriate endoscopic therapies for variceal lesion should be given within 5 days as most experts suggested. In consideration of the negative impact of unidentified lesion on the outcomes possible due to the rapid disease deterioration and passive surveillance to invasive treatments, we believe early identification of bleeding lesion is crucial for the management of acute GIB.

Our study aims to explore whether albumin infusion influences the outcomes of cirrhotic patients admitted for GIB. Theoretically, abundant albumin infusion in patients with GIB may cause rebleeding by increased portal pressure in a similar manner of liberal transfusion strategy[13]. Interestingly, we found that albumin infusion reduces the risk of in-hospital rebleeding. Particularly, this beneficial effect was predominately observed in patients with Child-Pugh C class, most of whom had high portal pressure.

In our study, the mean amount of pre-ALB was just 12.3g, which is much lower than those recommended for ascites treatment (1-1.5 g/kg). Also, the dose-dependent effect of albumin in reducing rebleeding does not support the view that a higher dose leads to more bleeding. In fact, a recent study suggests that the portal pressure was not affected after the infusion of albumin (1.5g/kg, every week)[6]. Hence, the concern that albumin infusion increases the risk of rebleeding due to deterioration of portal pressure seems unnecessary. On the other hand, albumin is used in cirrhosis for the treatment of SBP and was widely discussed in the sepsis treatment for its immunomodulatory and anti-inflammatory properties[14, 15]. As bacterial infection was identified as a critical determinant of rebleeding in cirrhosis by increasing portal pressure through vasoactive substances[5], the effect of albumin on systemic inflammation provides a potential theoretical basis for its role in reducing bleeding. Moreover, albumin may also control the bleeding risk by promoting the transportation of drugs such as proton pump inhibitor and antibiotics, two essential agents in the management of acute GIB. Indeed, a recent clinical study found that the combination of albumin and antibiotics is superior to antibiotics alone in the control of inflammation[6]. Collectively, the mechanisms involved the benefit of albumin is attribute to its effect on systemic inflammation and pharmacokinetic process, although its other properties may also play a role[16, 17].

The association between albumin infusion and in-hospital mortality was also evaluated. In our study, infection, HRS and liver failure are the main non-bleeding cause of death in cirrhotic patients with acute GIB[10]. It is thus reasonable to assume that albumin treatment may ameliorate the number of deaths from infection or infection-related organ failures. Although the results showed that more than 40g of albumin infusion reduce mortality in multivariate regression, we failed to demonstrate the beneficial results of its effect on non-bleeding deaths since most patients dead from hemorrhagic shock. However, based on current evidence supporting its efficacy in these complications, we believe that the infusion of albumin for cirrhosis with GIB is favorable to improve the in-hospital prognosis in those with high-risk for non-bleeding death[14]. Further studies on GIB patients with a high risk of infection and HRS are needed to address this issue.

In this study, the pre-RBC infusion was positively correlated with the occurrence of rebleeding. It is not surprising that patients with rebleeding present severe bleeding at admission, thus require more RBC transfusion. Although the causal relationship between pre-RBC infusion and rebleeding cannot be determined based on current data, this issue has already been described by many well-designed studies[8, 18, 19]. A limited RBC transfusion reduces the occurrence of rebleeding, the survival benefit was not observed in our study. Its effect on survival was not inconsistent in previous reports probably due to the different enrollment criteria[8, 19-22]. Nevertheless, the restrictive RBC transfusion is a cost-effective strategy as most studies show that less RBC transfusion does not correlated with poor prognosis.

As a retrospective study, the limitations were inevitable. First, the time of albumin infusion before rebleeding was not evaluated. Normally, the albumin is not recommended in the initial resuscitation of hemorrhagic shock. Whether albumin should be applied in the resuscitation stage or after hemostasis achieved needs to be explored; Second, the average dose of albumin used in our study is low compared with previous studies. The lower dose may be due to the conventional view of its limited effect on GIB, as well as its high cost. Hence, the appropriate dose needs to be evaluated by further studies focused on this issue. Third, the rebleeding was associated with many confounding variables, we cannot exclude the existence of selection bias due to our retrospective design. Although our result has been statistically adjusted by confounders, the applicability of the conclusion requires evaluation in the target population. Last, the 12-day follow-up period was shorter than those described in prior studies. However, as the rebleeding usually occurs within the first two weeks, we believe our analysis was still persuasive[8].

GIB: gastrointestinal bleeding; SBP: spontaneous bacterial peritonitis; HRS: hepatorenal syndrome; HCC: hepatocellular carcinoma; PVT: portal vein thrombosis; RBC: red blood cell; ALB: albumin

Acknowledgment: Not applicable

Author contributions: WZ and YJL designed the research. XYW, LQ, YHL and LXB collected the research data. LY and ZX analyzed the data.

Funding: This work was granted by Key project of Sichuan Science and Technology Department (No. 2017FZ0091).

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate: This research protocol was approved by the Ethics Committee of the West China Hospital of Sichuan University.

Consent for publication: Not applicable
Competing interests: All authors declare no conflicts of interest.

Xu JY, Chen QH, Xie JF, Pan C, Liu SQ, Huang LW, Yang CS, Liu L, Huang YZ, Guo FM et al: Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. Crit Care 2014, 18(6):702.
Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R: Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology 2013, 58(5):1836-1846.
Guevara M, Terra C, Nazar A, Sola E, Fernandez J, Pavesi M, Arroyo V, Gines P: Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. J Hepatol 2012, 57(4):759-765.
de Franchis R, Baveno VF: Revising consensus in portal hypertension: report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010, 53(4):762-768.
Hou MC, Lin HC, Liu TT, Kuo BI, Lee FY, Chang FY, Lee SD: Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology 2004, 39(3):746-753.
Fernandez J, Claria J, Amoros A, Aguilar F, Castro M, Casulleras M, Acevedo J, Duran-Guell M, Nunez L, Costa M et al: Effects of Albumin Treatment on Systemic and Portal Hemodynamics and Systemic Inflammation in Patients With Decompensated Cirrhosis. Gastroenterology 2019, 157(1):149-162.
Thevenot T, Bureau C, Oberti F, Anty R, Louvet A, Plessier A, Rudler M, Heurgue-Berlot A, Rosa I, Talbodec N et al: Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. J Hepatol 2015, 62(4):822-830.
Villanueva C, Colomo A, Bosch A, Concepcion M, Hernandez-Gea V, Aracil C, Graupera I, Poca M, Alvarez-Urturi C, Gordillo J et al: Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013, 368(1):11-21.
Nevens F, Bittencourt PL, Coenraad MJ, Ding H, Hou MC, Laterre PF, Mendizabal M, Ortiz-Olvera NX, Vorobioff JD, Zhang W et al: Recommendations on the Diagnosis and Initial Management of Acute Variceal Bleeding and Hepatorenal Syndrome in Patients with Cirrhosis. Dig Dis Sci 2019, 64(6):1419-1431.
D'Amico G, De Franchis R, Cooperative Study G: Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 2003, 38(3):599-612.
Garcia-Pagan JC, Reverter E, Abraldes JG, Bosch J: Acute variceal bleeding. Semin Respir Crit Care Med 2012, 33(1):46-54.
Cheung J, Soo I, Bastiampillai R, Zhu Q, Ma M: Urgent vs. non-urgent endoscopy in stable acute variceal bleeding. Am J Gastroenterol 2009, 104(5):1125-1129.
China L, Skene SS, Shabir Z, Maini A, Sylvestre Y, Bennett K, Bevan S, O'Beirne J, Forrest E, Portal J et al: Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial. Clin Gastroenterol Hepatol 2018, 16(5):748-755 e746.
Salerno F, Navickis RJ, Wilkes MM: Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials. Clin Gastroenterol Hepatol 2013, 11(2):123-130 e121.
Artigas A, Wernerman J, Arroyo V, Vincent J-L, Levy M: Role of albumin in diseases associated with severe systemic inflammation: Pathophysiologic and clinical evidence in sepsis and in decompensated cirrhosis. Journal of Critical Care 2016, 33:62-70.
Cheng HC, Chang WL, Chen WY, Tsai YC, Yeh YC, Sheu BS: Intravenous albumin shortens the duration of hospitalization for patients with hypoalbuminemia and bleeding peptic ulcers: a pilot study. Dig Dis Sci 2013, 58(11):3232-3241.
Matsuda S, Niihara M, Tsubosa Y, Sato H, Takebayashi K, Kawamorita K, Mori K, Tsushima T, Yasui H, Takeuchi H et al: Clinical significance of postoperative recovery of serum albumin levels in patients with esophageal cancer who underwent transthoracic esophagectomy. Surg Today 2016, 46(10):1138-1145.
Sung JJ, Chiu PW, Chan FKL, Lau JY, Goh KL, Ho LH, Jung HY, Sollano JD, Gotoda T, Reddy N et al: Asia-Pacific working group consensus on non-variceal upper gastrointestinal bleeding: an update 2018. Gut 2018, 67(10):1757-1768.
Chen Y-C, Hsiao C-T, Lin L-C, Hsiao K-Y, Hung M-S: The association between red blood cell transfusion and outcomes in patients with upper gastrointestinal bleeding. Clinical and Translational Gastroenterology 2018, 9(3).
Mirski MA, Frank SM, Kor DJ, Vincent J-L, Holmes DR: Restrictive and liberal red cell transfusion strategies in adult patients: reconciling clinical data with best practice. Critical Care 2015, 19(1).
Odutayo A, Desborough MJR, Trivella M, Stanley AJ, Dorée C, Collins GS, Hopewell S, Brunskill SJ, Kahan BC, Logan RFA et al: Restrictive versus liberal blood transfusion for gastrointestinal bleeding: a systematic review and meta-analysis of randomised controlled trials. The Lancet Gastroenterology & Hepatology 2017, 2(5):354-360.
Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, James MW, Stanley AJ, Everett SM, Bailey AA, Dallal H et al: Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial. The Lancet 2015, 386(9989):137-144.

Table 1. Univariate analysis of baseline characteristics between patients with and without rebleeding.

	No rebleeding (n=1994)	Rebleeding (n=245)	P value
Age	53.0±13.0	53.4±13.8	0.644
Gender (M)	1396 (70.0)	172 (70.2)	1
Child-Pugh class			<0.001
A	610 (30.6)	26 (10.6)
B	973 (48.8)	123 (50.2)
C	411 (20.6)	96 (39.2)
Hepatocellular carcinoma	350 (17.6)	64 (26.1)	0.002
Portal vein thrombosis	358 (18.0)	49 (20.0)	0.486
Source of Bleeding
Varices lesion	1698 (85.2)	203 (82.9)	0.393
Non-varices lesion	118 (5.9)	5(2.0)	0.018
Lower gastrointestinal lesion	64 (3.2)	7 (2.9)	0.917
Unidentified lesion	172 (8.6)	36 (14.7)	0.003
Bilirubin (umol/L) †	32.5±39.7	47.8±78.8	<0.001
Albumin (g/L) †	30.8±6.0	28.2±6.6	<0.001
Creatine (mol/L)†	79.8±56.3	84.5±49.3	0.206
Hemoglobin (g/L) †	76.7±23.2	76.4±24.2	0.814
Prothrombin time (s)†	16.3±8.8	17.7±8.6	0.026
Balloon tamponade	145 (7.3)	128 (52.2)	<0.001
Endoscopic treatment	657 (32.9)	34 (13.9)	<0.001
Radiological intervention	481 (24.1)	70 (28.6)	0.148

† values were obtained at admission

Table 2. The amount of albumin and RBC infusion in cirrhosis with and without in-patient rebleeding

	Child-Pugh A				Child-Pugh B					Child-Pugh C
		No rebleeding		rebleeding		P value	No rebleeding	rebleeding	P value		No rebleeding	rebleeding	P value
Total-ALB (g) †			3.3	15.4		<0.001	12.8	30.8	<0.001		30.6	32.1	0.805
Pre-ALB (g) §			3.3	3.7		0.876	12.8	11.8	0.695		30.6	15.2	0.009
Total-RBC (unit)†			1.3	5.7		<0.001	2.0	7.4	<0.001		2.3	6.0	<0.001
Pre-RBC (unit) §			1.3	3.0		<0.001	2.0	4.7	<0.001		2.3	3.8	<0.001

† Total-ALB and total-RBC: the total amount of albumin/RBC infusion during hospitalization;

§ Pre-ALB and pre-RBC: the amount of albumin infusion before rebleeding occurrence. In patients without bleeding, the pre-ALB and pre-RBC equals the total-ALB and total-RBC.

Table 3. Multivariate Hazards regression analysis of the relationship between different dose of albumin/red blood cell infusion before rebleeding and rebleeding.

Pre-ALB infusion
	( 0, 40 g]	P value	＞ 40 g	P value
Unadjusted	0.791(0.555-1.126)	0.1929	0.759(0.472-1.219)	0.2541
Adjusted for albumin, Child-Pugh class	0.463(0.319-0.672)	<0.001	0.374(0.226-0.619)	<0.001
Multivariable †adjusted	0.385(0.252-0.588)	<0.001	0.295(0.169-0.514)	<0.001
Pre-RBC infusion
	( 4-8 units]	P value	> 8 units	P value
Unadjusted	3.569(2.591-4.918)	<0.001	7.837(4.633-13.257)	<0.001
Adjusted for hemoglobin, Child-Pugh class	3.724(2.612-5.310)	<0.001	8.808(5.044-15.381)	<0.001
Multivariable† adjusted	1.835(1.246-2.688)	0.002	4.052(2.134-7.694)	<0.001

† adjust for Child-Pugh classification, HCC, bleed from non-varices lesion, unidentified lesion, the initial application of tamponade, level of bilirubin,

albumin and prothrombin time, endoscopic treatments

Table 4 . Univariate analysis of baseline characteristics and between patients with and without rebleeding

	No death (n=2104)	Death (n=135)	P value
Age	52.9±13.0	53.7±14.0	0.536
Gender (M)	1469 (69.8)	99 (73.1)	0.443
Child-Pugh classification			<0.001
A	630 (29.9)	6 (4.5)
B	1055 (50.1)	41 (30.6)
C	419 (20.0)	88 (64.9)
Hepatocellular carcinoma	369 (17.5)	45 (33.6)	<0.001
Portal vein thrombosis	391 (18.6)	16 (11.9)	0.064
Rebleeding	135 (6.4)	110 (81.5)	<0.001
Sources of bleeding
Varies lesion	1803 (85.7)	98 (72.6)	<0.001
Non-varices lesion	121 (5.8)	2 (1.5)	0.055
Lower gastrointestinal lesion	68 (3.2)	3 (2.2)	0.692
Unidentified lesion	175 (8.3)	33 (24.6 )	<0.001
Bilirubin (umol /L)†	31.9±38.3	69.2±103.8	<0.001
Albumin (g/L)†	30.7±6.0	26.9±6.5	<0.001
Creatine (mol/L)†	78.7±53.4	104.8±78.0	<0.001
Hemoglobin (g/L)†	76.7±23.16	76.5±25.90	0.910
Prothrombin time (s)†	16.28±8.6	19.72±10.94	<0.001
Balloon tamponade	207 (9.8)	66 (48.9)	<0.001
Endoscopic treatment	684 (32.5)	7 (5.2)	<0.001
Radiological intervention	547 (26)	4 (3)	<0.001

† values were obtained at admission

Table 5. Multivariate Hazards regression analysis of different dose of albumin/red blood cell and death.

Total-ALB infusion
	( 0, 40 g]	P value	> 40 g	P value
Unadjusted	1.254(0.819-1.919)	0.298	1.402(0.845-2.326)	0.191
Adjusted for albumin, Child-Pugh class	0.577(0.366-0.908)	0.017	0.525(0.304-0.906)	0.021
Multivariable †adjusted	0.739(0.375-1.423)	0.356	0.389(0.180-0.838)	0.016
Total-RBC infusion
	( 4, 8 units ]	P value	> 8 units	P value
Unadjusted	2.816(1.807-4.387)	<0.001	9.097(5.628-14.706)	<0.001
Adjusted for hemoglobin, Child-Pugh class	2.626(1.613-4.276)	<0.001	9.559(5.535-16.509)	<0.001
Multivariable †adjusted	0.736(0.357-1.517)	0.406	1.156(0.522-2.562)	0.721

† adjust for Child-Pugh classification, HCC, occurrence of rebleeding, bleed from varices lesion and unidentified lesion,

the initial application of tamponade, level of bilirubin creatine, albumin and prothrombin time, endoscopic and radiological treatment.

Albumin infusion reduces the risk of rebleeding and in-hospital mortality in cirrhotic patients admitted for acute gastrointestinal bleeding: retrospective analysis of a single institute

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