Patients’ baseline characteristics and outcomes
A total of 2259 records of cirrhotic patients admitted for acute GIB were selected, among whom 20 cases were excluded for the incomplete data. There were 736 patients with PVT or HCC were excluded. Overall, 1503 records were included in this study. The mean age was 53.1 ± 13.1, 1005 (66.9%) were male. Except for 190 (12.6%) cases without identified etiology, the other etiologies for cirrhosis were: 867 (57.7%) HBV infections; 197 (13.1%) alcoholic liver diseases; 135 (9.0%) autoimmune liver diseases; 59 (3.9%) HCV infections; 22 (1.5%) secondary cholestatic liver diseases; 10 (0.7%) vascular disorders, 23 (1.5%) others. According to the Child-Pugh classification, there were 474 (31.5%) patients classified as class A, 715 (47.6%) as class B, and 314 (20.9%) as class C. At admission, 123 patients were concomitant with encephalopathy, and 750 patients had ascites. In terms of the rebleeding sources, there were 128 (8.5%) patients who did not receive endoscopy examinations to identify the bleeding lesion. Because they could not tolerate interventions due to comorbidities or patients avoid endoscopic interventions. There were 1375 (91.5%) cases presented upper GI tract bleeding lesion (variceal or non-variceal lesions) and 47 (3.1%) had lower GI tract bleeding lesions (jejunoileal or colonic lesion). Variceal lesion were observed in 1275 cases (84.8%), while non-variceal lesion in 100 patients (6.7%). In variceal bleeding, balloon tamponade was initially applied in 169 cases to control active bleeding, 21 emergent transjugular intrahepatic portosystemic shunts (TIPS) were performed as rescue therapy. During hospitalization, 511 (34.0%) patients received endoscopic treatments, including 491 cases of endoscopic band ligation with/without injection of tissue adhesive, 19 cases of endoscopic sclerotherapy/injection of tissue adhesive, 1 cases endoscopic treatment for ulcer lesions. About half of the endoscopic treatments (251, 49.1%) were performed within 5 days to prevent early rebleeding. There were 10 cases underwent additional radiological interventional treatment due to the failure of endoscopic treatments, while 372 (25.0%) patients only underwent radiological interventional treatment. The majority of the radiological interventions were TIPS (352, 92.1%) for the failure of previous endoscopic treatment prevention. The other interventions including balloon-occluded retrograde obliteration (20, 5.2%), embolization of non-variceal lesion (8, 2.1%), and partial splenic embolization (2, 0.5%).
Overall, there were 146 (9.7%) patients for whom in-patient rebleeding occurred, with an average of 12.2±6.5 hospitalization days. As regards the in-hospital mortality, a total of 81 (5.4 %) patients died during hospitalization and 67 of them experienced in-patient rebleeding before death. The reasons of deaths were as followed: hemorrhagic shock (n=57), hepatorenal syndrome (n=11), hepatic encephalopathy (n=1), multiple organ failure (n=6), infection (n=2), cerebrovascular event (n=3), and acute myocardial infarction (n=1).
The association between albumin/RBC infusion for in-patient rebleeding
Univariate variables associated with rebleeding were displayed in Table 1. Patients suffered rebleeding were more likely to have hepatic encephalopahty (6.9% vs 19.9%, p <0.001), higher Child-Pugh classification (Child A 33.5% vs 13.0%，Child B 47.1% vs 52.1%, Child C 19.4% vs 34.9%, p<0.001), higher bilirubin level (32.5 vs 48.4 umol/L, p<0.001), lower albumin level (31.0 vs 27.8 g/L, p<0.001), and deteriorated prothrombin time at baseline (16.6 vs 18.3 s, p=0.038). More rebleeding occurs in cases with unidentified lesions (8.0% vs 13.7%, p=0.027) and patients without ascites (51.5% vs 34.9%, p<0.001). Rebleeding was more likely to occur in patients rescued by balloon tamponade at admission (7.0% vs 50.7%, p<0.001), while subsequent endoscopic treatment effectively prevents rebleeding (36.0% vs 15.1%, p<0.001) (Table 1).
An average of 2.3 ± 3.3 units of RBC and 14.2 ± 32.3 g albumin were administrated to patients presented anemia or hypoalbuminemia. During hospitalization, the average minimum value of HGB and albumin were significantly higher in those patients without rebleeding (Table 2). Hence, more total-RBC (1.9±2.5 vs 6.7±5.9 units, p<0.001) and total-ALB (12.7±28.7 vs 28.5±53.3 g, 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 (1.9±2.5 vs 4.1±3.9 units, p<0.001), while the pre-ALB infusion was comparable (12.7±28.7 vs 10.5±34.4 g, p=0.395). In particular, in patients with Child-Pugh C class, the pre-ALB infusion was lower in those with rebleeding (14.1 vs 29.9g, p=0.021). (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, 0.500 [0.312-0.800], p=0.004; OR for > 40g vs 0g, OR 0.279 [0.134-0.580], p<0.001).(Table 3)
Furthermore, in another multivariate model adjusted for all confounders (Child-Pugh class, presence of hepatic encephalopathy and ascites, bleed from 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. There was a negative dose-effect relationship between albumin and rebleeding risk (adjusted OR for ≤40g vs 0g, 0.469 [0.274-0.805], p=0.006; adjusted OR for >40g vs 0g, 0.272 [0.122-0.604], p=0.001) . Other independent factors in this model included Child-Pugh classification (adjusted OR for Child B vs A, 1.935 [1.073-3.490], p=0.028; Child C vs A, 2.253 [1.086-4.673], p=0.029), presence of encephalopathy (adjusted OR 1.951 [1.042-3.656], p=0.037) and ascites (adjusted OR 0.526 [0.345-0.802], p=0.003), rescue therapy with balloon tamponade (adjusted OR 13.996 [8.964-21.758], p<0.001) and endoscopic treatment (adjusted OR 0.337 [0.199-0.571], 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 3.556 [2.369-5.338], p<0.001; OR for >8 vs <4 units 5.654 [2.913-10.975], 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 1.888 [1.154-3.088], p=0.011; adjusted OR for >8 vs <4 units 2.634 [1.171-5.923], p=0.019) (Figure 1B).
When the multivariate analysis were further performed stratified by Child-Pugh class, the benefit effect of pre-ALB infusion was only observed in patients of Child-Pugh C class (adjusted OR for ≤40g vs 0g, 0.185 [0.057-0.520], p=0.002; adjusted OR for >40g vs 0g, 0.198 [0.047-0.668], p=0.015). While, the negative impact of pre-RBC infusion was shown in patients of Child-Pugh B class (adjusted OR for 4-8 vs <4 units 2.235 [1.168-4.180], p=0.013; adjusted OR for >8 vs <4 units 3.495 [1.254-9.373], p=0.014).
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), prensece of encephalopathy, bleed from varices or unidentified lesion, initial rescue therapy with tamponade and occurrence of rebleeding. The presence of ascites, the uses of endoscopic and radiological interventions decreased mortality risk (Table 4). A higher amount of total-RBC (2.2±3.1 vs 5.5±5.3 units, p<0.001) and similary amount of total-ALB (13.9±31.0g vs 19.8±49.1g, p=0.114) infused to patients who died during hospitalization. However, after adjusted for baseline albumin level and Child-Pugh class (OR for ≤ 40g vs 0g, 0.485 [0.265-0.888], p=0.019; OR for > 40g vs 0g, 0.432 [0.206-0.903], p=0.026), there was a significant correlation between total-ALB infusion and mortality. In another multivariate model adjusted for all confounders (Child-Pugh classification, presence of encephalopathy and ascites, the 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 albumin does not correlated with in-hospital mortality . (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, 2.583 [1.448-4.608, p=0.001; OR for >8 vs ＜4 units, 8.350 [4.550-15.325], p<0.001) and a multivariate model adjusted for baseline hemoglobin level and Child-Pugh class (OR for 4-8 vs ＜4 units, 2.373 [1.253-4.493], p=0.008; OR for >8 vs ＜4 units, 8.399 [4.256-16.577], 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, 1.198 [0.412-3.478], p=0.740; adjusted OR for >8 vs ＜4 units, 1.526 [0.422-5.526], p=0.520) (Figure 2B).
Similarly, the multivariate analysis was performed in each Child-Pugh Class, the beneficial effect of total-ALB infusion was only observed in patients of C class (adjusted OR for ≤40g vs 0g, 0.653 [0.111-3.404], p=0.618; adjusted OR for >40g vs 0g, 0.136 [0.019-0.741], p=0.031). Meanwhile, the total-RBC infusion was still not correlated with in-hospital mortality.