*2.1. General Measures*

In combination with initial systemic stabilization (i.e., protection of circulatory and respiratory status) and start of intravenous proton pump inhibitors (PPIs), as in any patient hospitalized with upper GI bleeding, specific nuances in the management of patients with cirrhosis include a *restrictive* transfusion strategy and the use of prophylactic antibiotic therapy [5–8]. Additional measures include management of both coagulopathy and therapy with PPIs. For patients with alcohol-related liver disease, immediate and sustained cessation of alcohol consumption is particularly important to improve liver function and reduce risks of further bleeding, decompensation and mortality by reducing liver damage and portal pressure [9].

#### 2.1.1. Blood Transfusion Strategy

The main driver for development of esophageal VH is clinically significant portal hypertension [10]. In a way, the acute loss of intravascular volume due to bleeding reduces splanchnic pressure and may lead to self-limitation or self-interruption of active hemorrhage. By contrast, a sudden restitution of intravascular volume is associated with a rebound increase in portal pressure, which in turn may lead to failure to control bleeding and/or early rebleeding [11]. In a seminal randomized control trial (RCT), a "restrictive" transfusion strategy (hemoglobin threshold for transfusion of 7 g/dL with target range of 7–9 g/dL) was associated with a significantly higher probability of survival compared with a "liberal" strategy (hemoglobin threshold for transfusion of 9 g/dL with target range of 9–11 g/dL) [12]. Therefore, current guidelines recommend initiating transfusions in cirrhosis when hemoglobin levels decrease to <7 g/dL, with a target level of 7–9 g/dL [5–8].

Restitution of intravascular volume should be managed with large peripheral lines (16–18 gauges), and blood loss has to be replaced by red blood packed cells [8]. Replacement of fluids and electrolytes is important to prevent pre-renal acute kidney injury, which is common in cirrhosis with GI bleeding and is associated with increased mortality [13]. Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs, non-selective betablockers (NSBBs), and other hypotensive drugs may be suspended during the acute course of VH [6]. As occurrence of acute decompensation may be associated with instability in the feeble hemostatic balance of decompensated cirrhosis, the need for invasive procedures should be evaluated carefully on an individual basis. As discussed below, clotting factors may be replaced only to correct an eventual dilutional coagulopathy, whereas there is no indication to prophylactically correct a prolonged prothrombin time or a low platelet count [5–8].

#### 2.1.2. Antibiotic Prophylaxis

Bacterial infections are observed in up to 50% patients with cirrhosis hospitalized for GI bleeding, and are associated with strong risks of failure to control bleeding, early re-bleeding and mortality [14–16]. A recent meta-analysis including 12 studies comparing antibiotic prophylaxis vs. either placebo or no intervention demonstrated that the administration of prophylactic antibiotics was associated with reduced all-cause mortality (relative risk (RR): 0.79, 95% CI: 0.63–0.98), infection-driven mortality (RR: 0.43, 95% CI: 0.19–0.97), risk of bacterial infection (RR: 0.35, 95% CI: 0.26–0.47), rebleeding (RR: 0.53, 95% CI: 0.38–0.74), and length of stay (mean difference −1.9 days, 95% CI: −3.8–0.02) [17]. Therefore, a timely, short-term course of prophylactic antibiotics is an important step in the management of patients with cirrhosis and VH, and shall be instituted as early as possible upon admission, before upper endoscopy [5–8].

Whether severity of cirrhosis affects the importance of prophylaxis is unclear. In fact, while the role of prophylaxis is incontrovertible in patients with most advanced liver dysfunction (Child B and C), in those with less advanced liver disease conflicting data have been reported. In one retrospective analysis, Child A patients had lower risks of infection in the absence of prophylaxis (2%), and no difference in mortality was observed in treated vs. non treated patients [18]. The same study showed that the use of antibiotics was associated with a substantial reduction in mortality in Child C class [18]. However, prospective data are required to evaluate whether antibiotic prophylaxis can be avoided in Child A and current recommendation is to administer prophylaxis in all patients with cirrhosis presenting with VH, independent of child [5–8].

Intravenous ceftriaxone (1 g/24 h) for 7 days is the first choice in patients belonging to Child B and C classes, in those who were on quinolone prophylaxis, and in hospitals in which there is a high frequency of quinolone-resistant bacteria. Norfloxacin 400 mg twice daily may be used in the other patients. However, due to widespread quinolone resistance, ceftriaxone (a third-generation cephalosporin) has become the antibiotic of choice [5–7]. As approximately 30% of infection are from multidrug resistance antibiotics bacteria [19], evaluation of local resistance, if doable, may further improve definition of antibiotic regimen and should be considered [8]. Prophylactic antibiotics should be administered for a maximum of seven days, and their use should not be extended after discharge from the hospital [5–7]. In patients discharged before Day 7, transition to an oral antibiotic with the goal of completing seven days of treatment may be considered [8].

In a recent, nationwide study from Spain including 1656 patients with cirrhosis hospitalized for VH between 2013 and 2015, Martinez et al. investigated current epidemiology and trends of bacterial infections in these patients [20]. Interestingly, despite prophylaxis as currently recommended by international guidelines [5–7], 20% of patients developed bacterial infections, particularly respiratory tract infection. Development of infection was observed early (median time from admission 3 days) and was independently associated with Child C class (odds ratio (OR): 3.1; 95% CI: 1.4–6.7), Grade III–IV encephalopathy at admission (OR: 2.8; 95% CI: 1.8–4.4), orotracheal intubation for endoscopy (OR: 2.6; 95% CI: 1.8–3.8), and placement of nasogastric tube/balloon tamponade (OR: 1.7; 95% CI: 1.2–2.4 and 2.4; 95% CI: 1.2–4.9, respectively) [20]. Such procedures should, therefore, be minimized whenever possible, particularly in patients with additional risk factors, and active screening for respiratory infections shall be performed in case of early clinical deterioration. Whether patients at risk for respiratory infection would benefit from tailored regiments of antibiotic prophylaxis, particularly in settings with high risk of resistant strains bacteria, it remains to be evaluated in further studies.
