MESTRADO INTEGRADO EM MEDICINA GASTRENTEROLOGIA
Antibiotic prophylaxis in patients with acute variceal bleeding
Rita Duarte Soares Bianchi de Aguiar
M
2022
Antibiotic prophylaxis in patients with acute variceal bleeding
Dissertação de candidatura ao grau de Mestre em Medicina, submetida ao Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto
Rita Duarte Soares Bianchi de Aguiar
Aluna do 6º ano profissionalizante de Mestrado Integrado em Medicina
Afiliação: Instituto de Ciências Biomédicas Abel Salazar – Universidade do Porto Endereço: Rua Jorge de Viterbo Ferreira nº228, 4050-313 Porto
Endereço eletrónico: rita.bianchi.aguiar@gmail.com
Orientador: Professora Doutora Isabel Maria Teixeira de Carvalho Pedroto
Professora Catedrática convidada do Instituto de ciências Biomédicas Abel Salazar, Universidade do Porto
Assistente Graduada Sénior de Gastrenterologia – Centro Hospitalar Universitário do Porto
Coorientador: Doutora Sara Rita e Sousa de Oliveira Barreto Archer
Mestre em Medicina
Colaboradora externa de Gastrenterologia – Centro Hospitalar Universitário do Porto
Maio 2022
Porto, 1 de Junho de 2022
Autor: Rita Duarte Soares Bianchi de Aguiar
Orientadora: Professora Doutora Isabel Pedroto
Coorientadora: Doutora Sara Archer
Assinado por : Isabel Maria Teixeira de Carvalho Pedroto
Num. de Identificação: 03964313 Data: 2022.06.01 15:33:56+01'00'
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Agradecimentos
"The key to success is not where you start, but how high you aim."
Nelson Mandela
À Professora Doutora Isabel Pedroto, uma referência na minha formação, pela dedicação, rigor e confiança. Pela orientação, ajuda e disponibilidade ao longo da realização desta dissertação.
Toda a partilha de conhecimentos e aprendizagens foram fulcrais para tornar esta investigação possível.
À Doutora Sara Archer, pelo empenho, ajuda e motivação ao longo da elaboração deste trabalho.
Aos meus pais, os meus pilares, pelo exemplo de vida maravilhoso, pelos valores que me incutiram e pelo apoio incondicional ao longo de todo o meu percurso académico.
Por fim, o meu sincero agradecimento à minha família e amigos por todo o apoio e companheirismo.
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Resumo
Introdução:
A hemorragia varicosa aguda é uma complicação comum nos doentes cirróticos. As diretrizes clínicas atuais recomendam que a profilaxia antibiótica seja instituída em todos os doentes cirróticos com hemorragia gastrointestinal alta, pois reduz a incidência de infeções bacterianas, melhora o controlo da hemorragia, diminui a recidiva hemorrágica e a mortalidade.
O principal objetivo deste estudo foi analisar a incidência das infeções bacterianas e a eficácia da profilaxia antibiótica nos doentes cirróticos com hemorragia varicosa aguda admitidos no Centro Hospitalar e Universitário do Porto.
Métodos:
Este estudo de investigação retrospetivo incluiu os doentes cirróticos admitidos com hemorragia varicosa aguda no Centro Hospitalar Universitário do Porto desde Janeiro de 2016 até Abril de 2019. A recolha dos dados foi realizada através de consulta do processo clínico eletrónico, incluindo informação clínica e resultados laboratoriais. O objetivo primário foi analisar a incidência das infeções bacterianas e a eficácia da profilaxia antibiótica neste grupo de doentes. Os objetivos secundários incluíram a identificação dos fatores de risco associados à infeção e a mortalidade às 6 semanas.
Resultados:
Foram incluídos 195 doentes: a maioria realizou profilaxia antibiótica, com ceftriaxone (115; 59.0%) ou ciprofloxacina (60; 30.8%). Apesar da profilaxia antibiótica, 21 doentes desenvolveram infeção bacteriana (10.8%) durante a hospitalização. Não se observaram diferenças no desenvolvimento de infeção entre os doentes com e sem profilaxia antibiótica, bem como entre a ceftriaxone ou ciprofloxacina. As infeções respiratórias representaram mais de 50% dos casos de infeção. A presença de infeção associou-se a uma maior necessidade de escalada terapêutica, com recurso aos cuidados intensivos, a doença hepática crónica avançada, com um score de Child-Pugh mais alto e à presença de hemorragia ativa. A mortalidade intra- hospitalar e às 6 semanas foi respetivamente de 11% e 17%. Nos doentes que infetaram, a mortalidade foi mais elevada, quer intra-hospitalar (29% vs 9% sem infeção), quer às 6 semanas (21% vs 9% sem infeção).
Conclusão:
A taxa de infeção foi de 10.8% nos doentes cirróticos com hemorragia varicosa aguda durante os 14 dias de hospitalização, apesar da profilaxia antibiótica. Por cada ponto adicional
iii no score de Child-Pugh, o risco de desenvolver infeção após a hemorragia aumentava 1.368 vezes. Os doentes classificados com um Child-Pugh Classe A tiveram taxas de infeção mais baixas comparando com os doentes categorizados como Classe B ou C. São necessários mais estudos para investigar se a realização de antibioterapia profilática após hemorragia varicosa aguda deveria ser aplicada só a um subgrupo de doentes com risco mais alto e se a estratificação através do score de Child-Pugh poderia definir esse grupo alvo.
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Abstract
Introduction:
Acute variceal bleeding is one of the most common complications in patients with cirrhosis and is still a life-threatening emergency. Current guidelines consider that antibiotic prophylaxis is a fundamental part of therapy for patients with cirrhosis presenting with upper gastrointestinal bleeding as it reduces the incidence of bacterial infections, improves bleeding control, decreases rebleeding and mortality. The aim of this study was to assess the incidence of bacterial infections and efficiency of antibiotic prophylaxis in cirrhotic patients with acute variceal bleeding admitted to the Centro Hospitalar e Universitário do Porto.
Methods:
In this study, a retrospective data analysis concerning all patients admitted Centro Hospitalar e Universitário do Porto with acute variceal bleeding who underwent esophagogastroduodenoscopy between January 2016 and April 2019 was conducted. Data collection was performed on electronic medical records of all eligible patients, including clinical data and laboratory examination results. The primary outcome of this study was to assess the incidence of bacterial infection and efficacy of antibiotic prophylaxis during hospitalization in cirrhotic patients with acute variceal hemorrhage. Secondary conclusions included predictive factors of bacterial infection and 6-week mortality.
Results:
195 patients were included: most patients were under antibacterial prophylaxis, either ceftriaxone (115; 59.0%) or ciprofloxacin (60; 30.8%). Despite the antibiotic prophylaxis, 21 patients developed a bacterial infection (10.8%) during hospitalization. There was no difference in infection rates between patients with or without antibacterial prophylaxis whether it was ceftriaxone or ciprofloxacin. Respiratory infections accounted for more than 50% of infections.
The presence of infection after acute variceal bleeding was associated with increased necessity for intensive care, advanced liver disease with higher/more severe Child-Pugh score/class and active bleeding. The in-hospital and 6-week mortality rates were 11% and 17% respectively.
Patients who developed infection had higher rates of both in-hospital mortality (29% vs 9%
without infection) and 6-week mortality (21% vs 9% without infection).
Conclusion:
The infection rate was 10.8% in patients with cirrhosis and Acute Variceal Bleeding within 14 days of admission, despite the use of antibiotic prophylaxis. For each additional point
v in the Child-Pugh score, the risk of developing post-acute variceal bleeding infection increased 1.368-fold. Consequently, patients categorized as Child-Pugh class A had lower rates of bacterial infection than patients categorized as classes B or C. Prospective studies should investigate whether prophylactic antibiotics should be targeted only at a subgroup of patients who are at a particular high risk of bacterial infection and whether Child-Pugh risk stratification can be used to define the target.
Keywords (MeSH from Index Medicus): Cirrhosis; Acute variceal bleeding; Antibiotic prophylaxis;
Bacterial infection; Respiratory infections; Gastrointestinal Hemorrhage.
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Abbreviations and acronyms
AAT – Alpha1-Antitrypsin AVB - Acute Variceal Bleeding
CHUPorto - Centro Hospitalar Universitário do Porto CLD - Chronic liver disease
CSPH - “Clinically significant portal hypertension”
CTP- Child-Turcotte-Pugh
EGD - Esophagogastroduodenoscopy GV - Gastric varices
GOV - Gastreoesophageal varices HBV - Hepatitis B virus
HCV – Hepatitis C virus
HVPG - Hepatic venous pressure gradient MDR - Multidrug-resistant
MTS - Manchester Triage System
MELD - model for end stage liver disease score NASH - Non-Alcoholic SteatoHepatitis
NIEC - North Italian Endoscopic Club OI- Orotracheal intubation
OV - Oesophageal varices PBC – Primary Biliary Cirrhosis PSC - Primary sclerosing cholangitis SBP- Spontaneous bacterial peritonitis SD - Standard deviation
TIPS - Transjugular intrahepatic portosystemic shunt UGIB - Upper gastrointestinal bleeding
URGE- Regional Gastroenterology Emergency
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Index
1. Introduction ...1
2. Materials and Methods ...4
2.1. Patients, study Design and outcomes ... 4
2.2. Definitions ... 5
2.3 Management program ... 6
2.4. Statistical analysis ... 6
2.5. Ethics Review ... 7
3. Results ...8
4. Discussion ... 11
5. Conclusion ... 15
6. Appendix ... 16
7. References ... 27
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List of Tables:
Table 1 - Clinical characterization of the study sample ………....16 Table II - Characterization of liver disease and complications in the study sample ……….17 Table III - Comparison of demographic and bleeding episode-related factors between patients with and without post-AVB infection ………...18 Table IV - Comparison of the liver disease scores and prophylaxis-related factors between patients with and without post-AVB infection……….……...….19 Table V - Endoscopic findings and management of patients with variceal bleeding ……...20 Table VI - Binary logistic regression model of predictors of post-AVB infection using the Child- Pugh raw score ………21 Table VII - Binary logistic regression model of predictors of post-AVB infection using the Child- Pugh class ………..……….22 Table VIII - Characterization of post-AVB infections ………..………23 Table IX - Comparison of the median required days of hospitalization between significant predictors of post-AVB infection ………24
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List of Figures:
Figure 1 - Comparison of Child-Pugh classes between patients with and without post-AVB infection ……….………....25 Figure 2 - (A) Association between the MELD and Child-Pugh Scores, and (B) Child-Pugh categories ………..……….26
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1. Introduction
Acute Variceal Bleeding (AVB) is one of the most common complications in patients with cirrhosis and is still a life-threatening emergency responsible for about one-third of cirrhosis- related deaths.(1) At the time of diagnosis of cirrhosis, it is estimated that 50% of the patients already have esophageal varices. Furthermore, new varices appear and/or pre-existing varices worsen every year. Once developed, varices progressively increase in size with an annual bleeding rate of 12%.(2,3)
Ruptured esophageal varices are responsible for 70% of all upper gastrointestinal bleeding (UGIB) episodes in cirrhotic patients.(4) Gastric varices are the source of UGIB in only 5 to 10% as they only appear in 20% of patients with portal hypertension.(5) The risk of gastric variceal bleeding is lower than that of esophageal variceal bleeding. However, gastric variceal bleeding, in particular from fundal varices, tends to be more severe with a higher mortality rate.(6)
The risk of hemorrhage in a cirrhotic patient with esophageal varices depends upon several factors. The 2 most relevant ones are variceal size and the severity of liver dysfunction as measured by the Child-Turcotte-Pugh (CTP) classification.(6) As varices are more common in CTP class C patients (85%) compared to CTP class A patients (40%), the bleeding risk is consequently higher in CTP class C patients.(7) Additionally, local factors such as the presence of red wale marks (“red signs”) and the bluish tone are indicative of a higher risk of varicose vein rupture. These predictors have been included in the North Italian Endoscopic Club (NIEC) index and are divided into groups with predicted 1-year bleeding risk ranging from 6% to 76%.(8) Overall, the size of the varices remains the most important predictor.(9) The presence or absence of known etiological factor or cofactors of liver cirrhosis and the hepatic venous pressure gradient (HVPG) are also related to the risk of bleeding. The measurement of HVPG, that is the difference between the wedged and free hepatic venous pressure, is the gold-standard method to determine the presence of “clinically significant portal hypertension” (CSPH). CSPH is defined as an HVPG above 10 mmHg which can result in multiple complications including gastroesophageal varices (GOV).(10) However, bleeding risk is only significantly increased when HVPG is higher than 12mmHg.(11–13)
The highest mortality peak is observed during the first 6 weeks after the bleeding episode.(12,14,15) Due to the improvement of management and treatment of portal hypertension and AVB, the associated mortality rate has decreased in the last 2 decades from 42% quoted in the 1981 Graham and Smith’s study to around 15% to 20% today.(6,16–18) This reduction in number
2 of deaths is a result of several advances such as: better access and quality of emergency care;
early use of vasopressors, including terlipressin and octreotide, and adequate antibiotic prophylaxis; access to out-of-hours emergency endoscopy; early involvement a multidisciplinary team and improved access to interventional radiology for transjugular intrahepatic portosystemic shunt (TIPS).(12,19,20)
Cirrhosis patients have an increased risk of bacterial infections due to innate and adaptive immune dysfunction, increased intestinal permeability, and pathogenic bacterial translocation.(21,22) Moreover, variceal bleeding conducts to other complications such as bacterial infections or hepatorenal syndrome.(6) In the absence of antibiotic prophylaxis, approximately 20% of patients have an infection detected on the day of admission, while 35- 66% develop an infection within the first 5 to 7 days after admission.(15,23)This risk is increased in patients with advanced liver failure, with Child-Pugh C disease and/or history of severe hemorrhage.(24) Bacterial infections have important clinical consequences, including hemostasis dysfunction, greater failure to control UGIB within 5 days, increased bleeding-event-related mortality, and increased rebleeding.(21,23)Consequently, current clinical guidelines consider that antibiotic prophylaxis is a fundamental part of therapy for patients with cirrhosis presenting with UGIB. It should be administered as early as possible after AVB and continued for 5 to 7 days in all patients(13,23). Antibiotic prophylaxis reduces the incidence of bacterial infections by 10-20%, improves bleeding control, decreases rebleeding and mortality.(15,23,25,26) Initially, when antibiotic prophylaxis was proposed, the most frequent infections were spontaneous bacterial peritonitis and bacteremia caused by enteric Gram-negative bacilli.(27) For this reason, non-absorbable antibiotics and oral quinolones, like norfloxacin, were preferably used.(23,28,29) Currently, due to the increased prevalence of Gram-negative bacilli and quinolone-resistant non-enteric Streptococcus, the use of 3rd generation intravenous cephalosporins is recommended.
Intravenous ceftriaxone (1g/24h) for a maximum of 7 days should be considered the treatment of choice in populations with advanced cirrhosis, hospital settings with high prevalence of quinolone-resistant bacterial infections and history of prior quinolone prophylaxis.(13,30,31)
Despite antibiotic prophylaxis, studies report rates of bacterial infections in almost 20- 40% of patients. Some studies show that spontaneous bacterial peritonitis is the most common bacterial infection, followed by bacteremia, urinary tract infection and respiratory infections.(6,11,27)
The outcomes of AVB have improved significantly in recent decades. However, despite the such advances, antibiotic prophylaxis and management of early infections are still important areas with potential for optimization. We therefore considered relevant to continue addressing this topic.
3 The objective of this study was to assess the incidence of bacterial infections and efficiency of antibiotic prophylaxis in cirrhotic patients with AVB admitted to the Centro Hospitalar e Universitário do Porto (CHUPorto). Secondary study endpoints included rebleeding rates, risk factors for infection and 6-week mortality.
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2. Materials and Methods
2.1. Patients, study Design and outcomes
In this study, a retrospective analysis of data concerning all patients admitted to CHUPorto with acute variceal bleeding who underwent esophagogastroduodenoscopy (EGD) between January 2016 and April 2019 was performed. This was an observational cross- sectional study in which patients who met the following inclusion criteria were assessed: (1) age
≥ 18 years; (2) diagnosis of chronic liver disease (CLD) based upon the clinician’s assessment using standard criteria including clinical evaluation, laboratory results, radiological data and/or histological findings, (3) AVB defined as at least one of the following: bleeding from an oesophageal varices (OV), gastreoesophageal varices (GOV), or gastric varices (GV) at the time of endoscopy; signs of recent bleeding noted on varices; presence of high-risk stigmata (clot, white nipple sign); presence of large OV with blood in the stomach and no other recognizable cause of bleeding.
Exclusion criteria included: (1) patients with an active bacterial infection on admission, whose onset was prior to admission; (2) patients with no documented liver disease at the time of admission.
Data collection was performed on electronic medical records of all eligible patients, including clinical data and laboratory examination results. The following variables were obtained for each patient: age and sex; etiology of liver disease; presence of liver carcinoma; comorbid illnesses (based on the Charlson index);(32) model for end stage liver disease score (MELD) at admission;(33) Child-Pugh score at admission;(34) previous AVB; primary or secondary prophylaxis for portal hypertensive bleeding; use of vasoactive drugs (octreotide or terlipressine); use of prophylactic antibiotics; antibiotic class used; timing of EGD; bleeding characteristics (location of varices, active bleeding at the time of endoscopy); endoscopic treatment; need for orotracheal intubation (OI) and/or sedation; type of required care.
The primary objective of this study was to assess the incidence of bacterial infection and efficacy of antibiotic prophylaxis during hospitalization in cirrhotic patients with acute variceal hemorrhage admitted in CHUPorto. Secondary outcomes included predictive factors of bacterial infection and 6-week mortality.
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2.2. Definitions
Antibiotic prophylaxis was defined as an antibiotic prescription following AVB in the absence of clinical signs of bacterial infection.
Non-oesophageal varices were categorized according to the Sarin classification.
Haemodynamic instability was defined as a decrease in systolic blood pressure below 80 mmHg
along with signs of hypoperfusion.
The timing of endoscopy was defined as the time interval since the arrival at the first hospital until the start of the endoscopic procedure.
Second look endoscopy was defined as a second EGD performed during the hospital stay. The reasons for its occurrence were defined as (1) rebleeding, (2) inconclusive etiology after the first endoscopy, (3) inefficiency of the procedure (non-hemostatic endoscopy), or (4) follow-up (mainly to confirm adequate hemostasis).
The diagnosis of bacterial infection was based on clinical and laboratory finding at admission and during hospitalization. The type and the timing of bacterial infection were analyzed. Bacterial infections which occurred up to 14 days of hospitalization were included.
Isolation of a causal microorganism was not a mandatory condition. High body temperature without an identified infectious source was not considered as a bacterial infection. In addition, spontaneous bacterial peritonitis (SBP) was defined as an ascites polymorphonuclear cell count
≥250 cells/mm3 and/or positive ascitic fluid culture. The diagnosis of a respiratory infection was based on clinical symptoms of infection and new or progressive infiltrates on chest X-ray. Urinary tract infection was defined either as abnormal urinary sediment (>10 leukocytes/field) and positive urine culture or uncountable leukocytes per field if cultures prove negative, and presence of urinary tract infection symptoms or positive blood culture. Skin and soft tissue infections were defined as clinical signs of infection associated with swelling, erythema, heat and tenderness in the skin. The diagnosis of bacteremia was determined by positive blood cultures and clinical signs of infection (such as fever >38ºC; hypothermia <36ºC; change in mental status; hemodynamic instability and oliguria) without other recognized cause. Common skin flora were considered contaminants unless blood cultures were positive on 2 or more separate occasions or in the presence of clinical signs of relevant infection.
There are several comorbidity scoring systems developed and in use, of which the Charlson Comorbidity Index is among the oldest and most widely used. This is a method for predicting mortality by classifying comorbid conditions (comorbidities).(32,35,36)
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2.3 Management program
In CHUPorto, EGD is available 24 hours a day. During daytime, a gastroenterologist from the unit is present seven days a week. During night shifts, from 8pm to 8am, there is a settled regional out-of-hours endoscopy model of care (Regional Gastroenterology Emergency - URGE) made up of specialists from six institutions. There are two different types of admissions: direct admissions, where patients can be directly admitted to this hospital’s emergency service; or indirect admissions where patients are transferred from another hospital (tertiary and non- tertiary care settings) after initial assessment and emergency care to perform EGD. Patient transference is performed in a medical vehicle with a medical team. The furthest hospital is located 200km away.
The Manchester Triage System is used in the emergency department to triage patients.(37) Usually, patients with AVB are attributed colours orange or red, the most critical categories. These patients are immediately transferred to the emergency department and evaluated by a team of intensive care and/or internal medicine physicians. Initial resuscitation and AVB protocol – namely vasoactive agents (terlipressin or octreotide) and prophylactic antibiotics – follow the classic ABC scheme (airway, breathing, circulation). This emergency team also contacts the on-duty gastroenterologist. After hemodynamic resuscitation, patients with suspected AVB should undergo upper endoscopy within 12 hours of presentation. If the patient is unstable, endoscopy is performed safely as soon as possible. After EGD, stable patients are transferred back to the hospital of origin.
2.4. Statistical analysis
Regarding the statistical treatment, a descriptive analysis was performed to summarize the collected data. Categorical variables are presented as absolute (n) and relative (%) frequencies and quantitative variables as mean and standard deviation (SD), or median and interquartile range.
For all analyses, a 95% confidence interval was assumed. For the comparison of proportions in categorical variables, a Chi-square test was performed; alternatively, a Fisher’s exact test was used when predicted cell count for at least one cell was below the value of 5.
Regarding continuous variables, normality and homoscedasticity were assessed prior to all tests using the Shapiro-Wilk and Levene tests, respectively.
For the comparison of means between 2 groups, an independent sample Student’s t-
7 test was used. For the comparison of medians of discrete variables among 2 or more groups, a Mann-Whitney or Kruskal-Wallis tests were used respectively. A binary logistic regression model was used to assess for independent predictors of a desired outcome. Non-parametric correlations (between discrete numerical variables) were assessed using Kendall’s τ. Adequate effect size statistics were reported for all tests (Cramer’s V for proportion analysis, Hedge’s g for Student’s t-test, Kendall’s τ for correlation, r for non-parametric tests and the odds ratio (OR) for logistic regression). Effect size cutoffs for Cramer’s V, Kendall’s τ and r were 0.1, 0.3 and 0.5 for small, medium and large effects, respectively. Effect sizes for Hedge’s g were 0.2, 0.5 and 0.8 as a small, medium and large effect, respectively. All statistical analyses were processed using IBM SPSS Statistics® version 27.0.1.0 for Windows (SPSS Inc., Chicago, IL, USA).
2.5. Ethics Review
The study’s protocol was approved by the hospital’s Ethics Committee (reference:
2021.298 (244-DEFI/252-CE)). Informed consent was waived due to the retrospective nature of the analysis without specific interventions for the patients assessed.
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3. Results
The study’s sample was comprised of 195 patients, 146 (74.9%) of which were males, with a median age of 58 years old. Admissions of patients with acute variceal bleeding (AVB) were more common on weekend days and during the night (Table 1), and for most patients this was the first AVB episode (132; 67.7%). Almost all patients were neither under antiaggregating nor anticoagulating drugs (176; 90.3%). The in-hospital and 6-week mortality rates were respectively 11% and 17%.
All patients presenting with AVB had a prior history of liver cirrhosis (Table 2), with the most common etiologies being alcoholic (101; 51.8%), or an overlap between alcoholic and an additional cause (42; 21.5%). Liver disease staging was distributed between different Child-Pugh categories (Table 2). Most patients were under antibacterial prophylaxis, either ceftriaxone (115; 59.0%) or ciprofloxacin (60; 30.8%), and under vasoconstrictor therapy (170; 87.2%). About half of the patients were under portal hypertension prophylaxis (pharmacologic or endoscopic or both).
After the AVB event, 21 patients developed a bacterial infection (10.8%). It was firstly assessed whether demographic (sex and age) and bleeding event-related factors (time of day, origin, first or subsequent episode, use of antiaggregant or anticoagulant drugs) were different between patients that developed or did not develop a post-AVB infection. None of these factors were significantly different between patients (Table 3) and were, therefore, unlikely to be predictors of infection development following an AVB. However, a significant effect regarding the required degree of care was observed, with patients requiring intensive care having developed a higher proportion of post-AVB infection (Table 3). Finally, it was also observed that patients that developed infection had higher rates of both in-hospital mortality (29% vs 9%
without infection) and 6-week mortality (21% vs 9% without infection).
Next, it was assessed whether classic liver disease stating scores (MELD and Child-Pugh) were different between patients with and without infection. The MELD score tended to be higher in patients who developed infection, albeit not reaching statistical significance (Table 4).
However, both the Child-Pugh score (Table 4) and class (Figure 1) were significantly higher/more severe in patients who developed infection. Specifically, 83% of patients that did not develop infection were categorized in Child-Pugh classes A or B (35% and 48%, respectively), while 81%
patients that had an infection were mostly class B or C (38% and 43%, respectively). No differences were found between the Charlson Comorbidity Index between patients with and without infection (Table 4).
9 Then, it was assessed whether patients undergoing different prophylaxis for cirrhosis- related complications had a different rate of post-AVB infection, when compared to those that were not under the respective prophylactic measure. Surprisingly, there was no difference in infection development between patients with or without antibacterial prophylaxis (Table 4). In those undergoing antibiotics, no difference was found in the rate of infection regarding the choice between ceftriaxone and ciprofloxacin. Finally, no differences were also found between the proportion of patients undergoing neither portal hypertension nor vasoconstrictor therapy (Table 4).
As expected, all AVB patients underwent upper endoscopy at some point. When comparing patients with and without post-AVB infection (Table 5), no difference in several endoscopy-related factors was observed, namely in the following: type of varices (χ2(4) = 1.554, p = 0.817, V = 0.089), hemodynamic instability (χ2(1) = 0.042, p = 0.837, V = 0.015), timing of endoscopy (χ2(1) = 2.040, p = 0.153, V = 0.102), need for endoscopic treatment (χ2(1) = 1.007, p
= 0.316, V = 0.072), type of endoscopic treatment at the 1st endoscopy (χ2(4) = 3.810, p = 0.283, V = 0.151), and origin of bleeding (χ2(2) = 2.165, p = 0.339, V = 0.105). However, a significantly higher proportion of patients with active bleeding had post-AVB infection (χ2(1) = 4.616, p = 0.032, V = 0.154).
After assessing for potential predicting factors of post-AVB infection, scores that differed between patients with and without infection were selected with the aim of developing a predictive model for post-AVB infection. Since both liver disease staging scores (MELD and Child- Pugh) were potential candidates, the association between them was evaluated. As expected, the MELD and Child-Pugh raw scores showed a significant correlation (τ = 0.386, p < 0.001), albeit with a moderate effect (Figure 2A), which indicates that both scores might be relevant as individual predictors. Similarly, differences in the median MELD score were observed between different Child-Pugh classes (H (2) = 41.492, p < 0.001) (Figure 2B).
Afterwards, binary logistic regression models were generated to assess the MELD score, Child-Pugh score/class, presence of active bleeding and degree of care as predictors of post-AVB infection. Both models had similar effect sizes/proportion of explained variance, with the one using the Child-Pugh raw score (Table 6) being slightly superior to the one using the Child-Pugh class (Table 7) (Nagelkerke pseudo-R2 of 0.149 vs 0.133, respectively). When looking for significant predictors within each model, only the Child-Pugh score reached statistical significance. This indicates that, when all of the predictors are combined together, only the Child-Pugh score provides individual information to the model, while other factors contribute with predictive information that is similar among them. This also leads us to conclude that the Child-Pugh score is the best predictor of post-AVB infection in the model. Finally, it can be
10 observed that for each additional point in the Child-Pugh score, the risk of developing post-AVB infection increases 1.368-fold.
Regarding the 21 patients that developed post-AVB infection, the most common affected organ system was the respiratory system (Table 8). In most cases, there was no isolation of a microorganism in bacterial cultures, and no specific bacteria was more common when isolated. The degree of antibacterial resistance was assessed only for a small proportion of patients, with half of them showing antibacterial resistance. In general, most hospital stays were short, with a median of 5 days of hospitalization.
As expected, the median days of hospitalization were smaller for patients that did not develop an infection (4.5 ± 6.0 days), and much longer for those that did (14.0 ± 11.0 days) (U = 3234.0, p < 0.001, r = 0.414).
Finally, it was assessed whether these predicting factors of post-AVB infection were also associated with the number of days of hospitalization that patients with infection required. No correlation between the MELD score and days of hospitalization (τ = -0.028, p = 0.607) was observed, and neither between the Child-Pugh score and day of infection (τ = 0.011, p = 0.851).
Furthermore, no difference in the median days of hospitalization was found between patients with and without active bleeding upon admission, nor between patients with intermediate or intensive care requirements (Table 9).
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4. Discussion
Antibiotic overuse is becoming a public health issue in current medical practices.
Therefore, it is relevant to have a restrictive and effective antibiotic stewardship program for populations in high risk of bacterial infection and avoid inappropriate antibiotic use.(38) Current clinical guidelines consider that antibiotic prophylaxis is a fundamental part of therapy for patients with cirrhosis presenting with AVB, as they have a higher risk of infections and severe complications.(39) Over the last decades, studies have demonstrated that antibiotic prophylaxis reduces the risk of bacterial infection, rebleeding, and mortality in patients with cirrhosis and UGI bleeding.(15,23)
In this study, the incidence of bacterial infections, predictive factors and efficiency of antibiotic prophylaxis were evaluated in cirrhotic patients admitted to the CHUP with AVB who underwent EGD during a 3-year period. For most of the patients, this was the first AVB episode and almost 11% of them developed a bacterial infection within 14 days of admission, despite the use of antibiotic prophylaxis. Respiratory infections accounted for more than 50% of infections. The presence of infection after AVB was associated with increased necessity for intensive care; advanced liver disease with higher/more severe Child-Pugh score/class and active bleeding upon admission. The in-hospital and 6-week mortality rates were respectively 11% and 17%. Patients that developed infection had higher rates of both in-hospital mortality (29% vs 9% without infection) and 6-week mortality (21% vs 9% without infection).
Antibiotics represent a major step forward in the AVB management and, as a result, they are currently recommended as empiric therapy in all patients.(40,41) Studies that evaluated the efficacy of antibiotic prophylaxis for cirrhotic patients with AVB reported lower rates of bacterial infection with prophylaxis.(15,27) Most patients were under antibacterial prophylaxis, either ceftriaxone (59.0%) or ciprofloxacin (30.8%). However, no difference was found in the rate of infection regarding the choice between the two. This study showed a rate of bacterial infection of 11% which is slightly lower than reported rates from previous meta-analyses in patients with AVB. (15,27,42) Respiratory infections were the most common infection identified within 14 days of AVB, accounting for more than half of all infections (57%), similar to rates reported in other recently published series.(27,42) In the pre-prophylaxis era, spontaneous bacterial peritonitis was the most frequent infection, but, in this study, only represented 10% of the infections, which suggests the efficacy of current prophylaxis against gut microbes.(42)
Surprisingly, there was no difference in infection development between patients with or without antibacterial prophylaxis. These results were observed indistinctly of the antibiotic assessed. This may be due to the sample size of 21 patients who developed bacterial infection
12 not being large enough, but also to multi-drug resistance. In this study, in those undergoing antibacterial drugs, no difference was found in the rate of infection regarding the choice between ceftriaxone and ciprofloxacin. In contrast, other studies show that patients who received norfloxacin had a higher rate of bacterial infections than those receiving cephalosporin, due to quinolone resistance.(30) Although the degree of antibacterial resistance was assessed only for a small proportion of patients, half of them showed antibiotic resistance. Worldwide, the most serious concern associated with antibiotic use is the development of antibiotic resistance. Multidrug-resistant (MDR) organisms are, by definition, resistant to three or more antibiotic classes and the prevalence of infections with MDR bacteria in cirrhosis is increasing alarmingly.(27,43–45) In addition, the spectrum of pathogens from local epidemiology (potentially different between hospitals, regions and countries) as well as the patient’s individual characteristics, such as previous use of antibiotic and previous known infections, should also be considered. (38,43)
Since we live in an era of risk stratification patient strategies, it is important to reconsider current recommendations and assess the balance of benefits and risks of antibiotic prophylaxis in AVB using risk-stratified strategies.(43,46,47) In this study, the required degree of care was an independent risk factor for bacterial infection. This study´s data identified that patients who required intensive care developed a higher proportion of post-AVB infection, probably due to the vulnerability of this population and to the wide-ranging complications of the disease.(48,49) This study also demonstrated that demographic (sex and age) and bleeding event-related factors (time of day, type of patient’s admission, first or subsequent episode, use of antiaggregant or anticoagulant drugs) were not significantly different among patients and were not useful predictors of infection development following an AVB.
In the current series, a significantly higher proportion of patients with active bleeding upon admission had post-AVB infection. Therefore, this suggests that the severity of the variceal hemorrhage episode contributes to the risk of infection as patients with a more severe AVB have a higher risk of infection afterwards. Some studies show that the presence of active bleeding at index endoscopy is predictive of both 5-day and 6-week mortality.(4,50) Another possible explanation is that the higher volumes of blood lost during hemorrhage increased the bacterial translocation to the blood circulation and the chance of infection. Due to multilevel immunodeficiency, high concentrations of endotoxin and increased intestinal permeability, cirrhotic patients are at increased risk of bacterial infections.(21,22) Moreover, variceal hemorrhage is a well-established risk factor for bacterial infection.(23) In addition, and, although this hypothesis needs to be confirmed by future studies, it has been suggested that bacterial infection can also trigger variceal hemorrhage. This happens mainly because of the increase in
13 intrahepatic resistance by the release of endothelin and the defect of primary haemostasis through the antiplatelet effects of nitric oxide or prostacyclin.(51) Bacterial infections and/or endotoxaemia have been associated with worse control of variceal bleeding, more early variceal rebleeding, abnormalities in coagulation, vasodilatation of the systemic vasculature, and worsening liver function.(52)
As the outcome of cirrhotic patients is not only influenced by the severity of the bleeding episode itself, but also by the underlying liver disease, the prognosis is difficult to predict. In a recent systematic review of 118 studies outlining the natural history and prognostic indicators of survival in cirrhosis, the MELD and CTP scores were recognized as accurate predictors of liver disease severity and long-term survival in patients with decompensated cirrhosis.(53) With the aim of developing a predictive model for post-AVB infection, the association between MELD and Child-Pugh score was evaluated, since both are liver disease staging scores. As expected, these two scores showed a significant correlation, albeit with a moderate effect. Therefore, both scores might be relevant as individual predictors.
On one hand, the MELD score tended to be higher in patients who developed infection, albeit not reaching statistical significance. However, some studies confirm that patients with a high MELD score are either more likely to have an infection or to die as a result of spontaneous bacterial peritonitis (SBP). (54)
On the other hand, this study supports what is already well established: that increasing Child-Pugh class is a strong predictor of bacterial infection in patients with cirrhosis.(24,40,55) Both the Child-Pugh score and class were significantly higher/more severe in patients who developed infection. For each additional point in the Child-Pugh score, the risk of developing post-AVB infection increased 1.368-fold. Specifically, only 19% of patients that developed infection were categorized in Child-Pugh classes A while 81% were mostly class B (38%) or C (43%). With these results, it would be useful to evaluate which Child-Pugh class specific benefits of antibiotic prophylaxis and determine whether there was evidence to limit antibiotic use to select high-risk subgroup. (26) Patients with Child–Pugh class C cirrhosis have an extremely high risk of bacterial infection, so prophylactic antibiotic use is justified
Child-Pugh class A/B are at a relatively lower risk of bacterial infection, and such infections are generally less severe. (24,38) Patients with Child–Pugh class A cirrhosis with AVB had low bacterial infection and mortality rates without receiving antibiotic prophylaxis as demonstrated by a recent study in Canada.(56) This suggests that the role of antibiotic prophylaxis is less important in the patients with Child–Pugh class A/B cirrhosis and UGI bleeding. Therefore, the identification of subpopulations that clearly benefit from antibiotic prophylaxis is a key strategy to prevent bacterial infections but also bacterial resistance and other adverse
14 complications from the antibiotic overuse. This issue has been discussed in the last Baveno meeting, Baveno VII, in November 2021.The statement was: “The risk of bacterial infection and mortality are very low in patients with Child-Pugh A cirrhosis, but more prospective studies are still needed to assess whether antibiotic prophylaxis can be avoided in this subgroup of patients.” (13)
Different binary logistic regression models were generated to assess for the MELD score, Child-Pugh score/class and presence of active bleeding as predictors of post-AVB infection. It was observed that both models had similar effect sizes and that the one using the Child-Pugh raw score is slightly superior to the one using the Child-Pugh class. That said, the Child-Pugh score can allow an earlier identification of patients with substantially increased risk of infection.
Furthermore, the only significant predictor variable in either model was the Child-Pugh classification when used as a score, suggesting that this classification system is a better predictor of bacterial infection in cirrhotic patients after AVB than MELD score. Although there may be other reasons, this could be explained by the fact that Child-Pugh score includes more parameters (e.g. albuminemia, encephalopathy and ascites).(40)The present version of MELD score incorporates only 3 objective variables, including total bilirubin, creatinine, and INR and it has been used to rank the priority of liver transplantation candidates. The literature is in line with the fact that Child–Pugh and MELD scores have similar prognostic values in most of cases, their benefits might be heterogeneous in some specific conditions. Therefore, the indications for Child–Pugh and MELD scores should be further identified.(25–27)
Finally, it was determined that there is no association between these predicting factors of post-AVB infection and the number of days of hospitalization that patients with infection required. The lack of influence is likely the result of infection not being an independent predictive factor for the hospitalization length. The median length of hospitalization was 5 days and several factors may explain this. Besides that, as already mentioned, patients with bacterial infection required a higher degree of care, mainly intensive care. However, there was no significant difference between the length of hospitalization and the level of care, Intermediate or Intensive care unit.
Possible limitations in this study were identified. First of all, hidden confounders could have influenced the results. Second, the sample size of 196 patients might not be large enough.
Third, minor episodes of bacterial infection may not have been detected. However, overall, this study´s findings have significant implications for possible Child Pugh risk stratification to target the patients who benefit more from antibiotic prophylaxis.
15
5. Conclusion
In this retrospective analysis of patients with cirrhosis and AVB, the infection rate was 10.8% within 14 days of admission, despite the use of antibiotic prophylaxis. Respiratory infections accounted for more than 50% of infections. The presence of infection after AVB was associated with increased need for intensive care; advanced liver disease with higher/more severe Child-Pugh score/class and active bleeding. For each additional point in the Child-Pugh score, the risk of developing post-AVB infection increased 1.368-fold. Consequently, patients categorized as Child-Pugh class A had lower rates of bacterial infection than patients categorized as classes B or C.
Although current guidelines recommend antibiotic prophylaxis for all cirrhotic patients with AVB, prospective studies should investigate whether prophylactic antibiotics should be targeted only to a subgroup of patients who are particularly at high risk for bacterial infection and if Child-Pugh risk stratification can be used to define the target.
16
6. Appendix
Table 1. Clinical characterization of the study sample.
Variable Sample (N = 195)
Sex Male 146 (74.9%)
Female 49 (25.1%)
Age 58 (33 – 92)
Weekday
Monday 24 (12.3%)
Tuesday 22 (11.3%)
Wednesday 25 (12.8%)
Thursday 27 (13.8%)
Friday 25 (12.8%)
Saturday 41 (21.0%)
Sunday 31 (15.9%)
Time of Day Day 67 (34.4%)
Night 128 (65.6%)
Origin CHUPorto 93 (47.7%)
Other 102 (52.3%)
First Bleeding Episode Yes 132 (67.7%)
No 63 (32.3%)
Antiaggregant/ Anticoagulant
None 176 (90.3%)
Antiaggregant 13 (6.6%)
Anticoagulant 5 (2.6%)
Both 1 (0.5%)
Degree of Required Care
General 39 (20.2%)
Intermediate 108 (56.0%)
Intensive 46 (23.8%)
In-Hospital Mortality 21 (10.8%)
6-Week Mortality 33 (16.9%)
For the variable “Age”, the median (range) is shown. For the remaining variables, the frequency (proportion) is shown.
CHUPorto, Centro Hospitalar Universitário do Porto.
17 Table II. Characterization of liver disease and complications in the study sample.
Variable Sample (N = 195)
Etiology of Cirrhosis
HBV 4 (2.1%)
HCV 15 (7.7%)
Alcohol 101 (51.8%)
NASH 6 (3.1%)
Autoimmune 2 (1.0%)
PBC 3 (1.5%)
PSC 1 (0.5%)
AAT Deficiency 2 (1.0%)
Autoimmune and PBC
overlap 4 (2.1%)
Multiple Causes 38 (19.5%)
Other 14 (7.2%)
Unknown 5 (2.6%)
MELD 15 (8 – 32)
Charlson Index 6 (3 – 14)
Child-Pugh (N = 173) 7 (0 – 13)
Child-Pugh Category
A 57 (33.0%)
B 81 (46.8%)
C 35 (20.2%)
Antibiotic Prophylaxis
None 20 (10.3%)
Ceftriaxone 115 (59.0%)
Ciprofloxacin 60 (30.8%)
Portal Hypertension Prophylaxis
None 96 (49.2%)
Primary 41 (21.0%)
Secondary 58 (29.7%)
Vasoconstrictor No 25 (12.8%)
Yes 170 (87.2%)
Post-Bleeding Infection
No 174 (89.2%)
Yes 21 (10.8%)
For the variables “MELD”, “Charlson Index” and “Child-Pugh” the median (interquartile range) is shown. For the remaining variables, the frequency (proportion) is shown.
AAT - Alpha1-antitrypsin; HBV - Hepatitis B virus; HCV - Hepatitis C virus; MELD - model for end-stage liver disease;
NASH – Non-alcoholic steatohepatitis; PBC – primary biliary cholangitis; PSC – primary sclerosing cholangitis.
18 Table III. Comparison of demographic and bleeding episode-related factors between patients with and without post-AVB infection.
Variable No
Infection (n=174)
Infection (n=21)
Statistical Test
Sig.
(p)
Effect size
Sex Female 44 (90%) 5 (10%) χ2(1) =
0.022
0.883 V=0.011 Male 130 (89%) 16 (11%)
Age 59.3
(11.6)
58.5 (10.3)
t(193) = 0.300
0.765 g=0.097 Time of Day Day 61 (91%) 6 (9%) χ2(1) =
0.350
0.554 V=0.042 Night 113 (88%) 15 (12%)
Origin CHUPorto 80 (86%) 13 (14%) χ2(1) = 1.906
0.167 V=0.099 Other 94 (92%) 8 (8%)
First Bleeding Episode
Yes 118 (89%) 14 (11%) χ2(1) = 0.011
0.915 V=0.008 No 56 (89%) 7 (11%)
Antiaggregant Yes 13 (93%) 1 (7%) χ2(1) = 0.206
0.650 V=0.033 No 161 (89%) 20 (11%)
Anticoagulant Yes 4 (67%) 2 (33%) χ2(1) = 3.280
0.070 V=0.130 No 170 (90%) 19 (10%)
Degree of Required Care
General 38 (97%) 1 (3%)
Intermediate 98 (91%) 10 (9%) χ2(2) = 6.889
0.032 V=0.189 Intensive 37 (80%) 9 (20%)
Died In-Hospital
Yes 15 (71%) 6 (29%) χ2(1) = 7.762
0.005 V=0.200 No 159 (91%) 15 (9%)
Died In 6 Weeks
Yes 26 (79%) 6 (21%) χ2(1) = 4.508
0.034 V=0.152 No 148 (91%) 14 (9%)
CHUPorto, Centro Hospitalar Universitário do Porto.
19 Table IV. Comparison of liver disease scores and prophylaxis-related factors between patients with and without post-AVB infection.
Variable
No Infection
(n=174)
Infection (n=21)
Statistical Test
Sig.
(p)
Effect size
MELD 15.0 (6.0) 18.0
(3.5) U = 2299.0 0.053 0.139 Child-Pugh 7.0 (3.0) 9.0 (4.0) U = 2170.5 0.008 0.200 Charlson Index 6.0 (3.0) 6.0 (3.0) U = 1795.0 0.895 g=0.009 Antibiotic
Prophylaxis
Yes 154 (88%) 21 (12%) χ2(1) =
2.690 0.101 V=0.117 No 20 (100%) 0 (0%)
Type of Antibiotic
Ceftriaxone 101 (88%) 14 (12%) χ2(1) =
0.010 0.922 V=0.003 Ciprofloxacin 53 (88%) 7 (12%)
Portal Hypertension
Prophylaxis
None 84 (88%) 11 (12%)
χ2(2) =
0.672 0.715 V=0.059 Primary 38 (93%) 3 (7%)
Secondary 51 (88%) 7 (12%)
Vasoconstrictor
Yes 153 (90%) 17 (10%) χ2(1) =
0.817 0.366 V=0.065 No 21 (84%) 4 (16%)
MELD - model for end-stage liver disease.
20 Table V. Endoscopic findings and management of patients with variceal bleeding.
Variable Sample (N=195) No Infection
(N=174)
Infection (N=21)
Type of Varices
Esophageal 141 (72%) 125 (89%) 16 (11%)
GOV1 42 (22%) 37 (88%) 5 (12%)
GOV2 6 (3%) 6 (100%) 0 (0%)
IGV1 5 (3%) 5 (100%) 0 (0%)
IGV2 1 (1%) 1 (100%) 0 (0%)
Active Bleeding No 125 (64%) 116 (93%) 9 (7%)
Yes 70 (36%) 58 (83%) 12 (17%)
Hemodynamic Instability
No 152 (78%) 136 (90%) 16 (10%)
Yes 43 (22%) 38 (88%) 5 (12%)
Timing of Endoscopy
< 12h 165 (85%) 145 (88%) 20 (12%)
12-24h 30 (15%) 29 (97%) 1 (3%)
Endoscopic Treatment
No 8 (4%) 8 (100%) 0 (0%)
Yes 187 (96%) 166 (89%) 21 (11%)
Treatment on 1st Endoscopy
(N = 187)
EVL 97 (50%) 88 (91%) 9 (9%)
Polidocanol 40 (21%) 34 (85%) 6 (15%)
Cyanoacrylate 25 (13%) 21 (84%) 4 (16%)
Blakemore Tube 6 (3%) 4 (67%) 2 (33%)
Treatment on 2nd Endoscopy
(N = 29)
EVL 17 (9%) 16 (94%) 1 (6%)
Polidocanol 3 (2%) 1 (33%) 2 (67%)
Cyanoacrylate 7 (4%) 7 (100%) 0 (0%)
Blakemore Tube 2 (1%) 2 (100%) 0 (0%)
Endoscopy
Un-sedated 23 (12%) 22 (96%) 1 (4%)
Sedated, no OI 94 (50%) 81 (86%) 13 (14%) Sedated, with OI 78 (40%) 71 (91%) 7 (9%)
For all variables, the frequency (proportion) is shown.
EVL – endoscopic variceal ligation; GOV 1 - type 1 gastroesophageal varix; GOV 2 - type 2 gastroesophageal varix; IGV - type 1 Isolated gastric varix; IGV 2 - Type 2 Isolated gastric varix; OI -orotracheal intubation.
21 Table VI. Binary logistic regression model of predictors of post-AVB infection using the Child- Pugh raw score.
Variable b Wald Sig. (p) OR 95% CI
Constant -5.313 13.819 < 0.001
MELD -0.027 0.223 0.637 0.973 [0.868, 1.090]
Child-Pugh (Score) 0.313 4.731 0.030 1.368 [1.031, 1.813]
Active Bleeding -0.810 2.529 0.112 0.445 [0.164, 1.207]
Degree of Care 0.688 2.652 0.103 1.989 [0.869, 4.549]
Nagelkerke pseudo-R2 = 0.149.
MELD - model for end-stage liver disease.
22 Table VII. Binary logistic regression model of predictors of post-AVB infection using the Child- Pugh class.
Variable b Wald Sig. (p) OR 95% CI
Constant -3.000 5.218 0.022
MELD -0.003 0.003 0.958 0.997 [0.896, 1.110]
Child-Pugh (Class) 3.627 0.163
A vs B 0.128 0.035 0.851 1.137 [0.297, 4.343]
A vs C 1.201 2.425 0.119 3.323 [0.733, 15.064]
Active Bleeding -0.796 2.436 0.119 0.451 [0.166, 1.226]
Degree of Care 0.651 2.409 0.121 1.918 [0.843, 4.364]
Nagelkerke pseudo-R2 = 0.149.
MELD - model for end-stage liver disease.
23 Table VIII. Characterization of post-AVB infections.
Variable Sample (N=21)
Type of Infection Respiratory 12 (57%)
Bacteriemia 4 (19%)
Urinary 2 (10%)
Peritonitis 2 (10%)
Cutaneous 1 (4%)
Infectious Agent (N=17) No Isolation 9 (52%)
Pseudomonas aeruginosa 2 (12%)
Escherichia coli 1 (6%)
Enterococcus faecalis 1 (6%) Staphylococcus epidermidis 1 (6%) Staphylococcus aureus 1 (6%)
Streptococcus mitis 1 (6%)
Streptococcus salivarius 1 (6%) Antibacterial Resistance
(N=8)
No resistance 4 (50%)
Resistant 4 (50%)
Day of Infection Diagnosis 2.0 (1.0 – 7.5)
Days of Hospitalization 5.0 (2.0 – 8.0)
For “Day of Infection Diagnosis” and “Days of Hospitalization”, the median (interquartile range) is shown. For the remaining variables, the frequency (proportion) is shown.
24 Table IX. Comparison of the median required days of hospitalization between significant predictors of post-AVB infection.
Variable N Days of
Hospitalization
Statistical Test
Sig.
(p)
Effect size Active Bleeding
No 9 15.0 (17.3)
U = 39.0 0.285 0.233
Yes 12 15.0 (5.0)
Degree of Required Care
Intermediate 10 13.0 (11.3)
U = 41.0 0.743 0.075 Intensive 9 13.0 (11.0)
25 Figure 1. Comparison of Child-Pugh classes between patients with and without post-AVB infection (χ2(3) = 11.692, p = 0.009, V = 0.245).
26 Figure 2. (A) Association between the MELD and Child-Pugh Scores, and (B) Child-Pugh categories.
MELD - model for end-stage liver disease.
27
7. References
1. de Franchis R, Primignani M. Natural history of portal hypertension in patients with cirrhosis. Clin Liver Dis. 2001 Aug;5(3):645–63.
2. Albillos A. Preventing first variceal hemorrhage in cirrhosis. J Clin Gastroenterol. 2007 Dec;41 Suppl 3:S305-311.
3. Kim YD. Management of Acute Variceal Bleeding. Clin Endosc. 2014 Jul;47(4):308–14.
4. D’Amico G, De Franchis R, Cooperative Study Group. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology. 2003 Sep;38(3):599–612.
5. Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology. 1992 Dec;16(6):1343–9.
6. García-Pagán JC, Reverter E, Abraldes JG, Bosch J. Acute variceal bleeding. Semin Respir Crit Care Med. 2012 Feb;33(1):46–54.
7. Al-Busafi SA, McNabb-Baltar J, Farag A, Hilzenrat N. Clinical manifestations of portal hypertension. Int J Hepatol. 2012;2012:203794.
8. North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices.
Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med. 1988 Oct 13;319(15):983–9.
9. D’Amico G. Esophageal varices: from appearance to rupture; natural history and prognostic indicators. Portal Hypertension in the 21st Century. 2004 Jan 1;147–54.
10. D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology. 2006 Nov;131(5):1611–24.
11. Tayyem O, Bilal M, Samuel R, Merwat SK. Evaluation and management of variceal bleeding. Dis Mon. 2018 Jul;64(7):312–20.
12. Haq I, Tripathi D. Recent advances in the management of variceal bleeding.
Gastroenterol Rep (Oxf). 2017 May;5(2):113–26.
13. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, Abraldes JG, et al. Baveno VII – Renewing consensus in portal hypertension. Journal of Hepatology. 2022 Apr;76(4):959–74.
14. El-Tawil AM. Trends on gastrointestinal bleeding and mortality: Where are we standing?
World J Gastroenterol. 2012 Mar 21;18(11):1154–8.
15. Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, Soares-Weiser K, Uribe M.
Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding. Cochrane Database Syst Rev. 2010 Sep 8;(9):CD002907.
16. de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol.
2005 Jul;43(1):167–76.
17. Graham DY, Smith JL. The course of patients after variceal hemorrhage.
Gastroenterology. 1981 Apr 1;80(4):800–9.
28 18. Gunarathne LS, Rajapaksha H, Shackel N, Angus PW, Herath CB. Cirrhotic portal hypertension: From pathophysiology to novel therapeutics. World Journal of Gastroenterology.
2020 Oct 28;26(40):6111–40.
19. Boyer TD, Haskal ZJ, American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension.
Hepatology. 2005 Feb;41(2):386–400.
20. McCormick P, O’Keefe C. Improving prognosis following a first variceal haemorrhage over four decades. Gut. 2001 Nov;49(5):682–5.
21. Rimola A, Soto R, Bory F, Arroyo V, Piera C, Rodes J. Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis. Hepatology.
1984 Feb;4(1):53–8.
22. Garcia-Tsao G, Lee FY, Barden GE, Cartun R, West AB. Bacterial translocation to mesenteric lymph nodes is increased in cirrhotic rats with ascites. Gastroenterology. 1995 Jun;108(6):1835–41.
23. Bernard B, Grangé JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: A meta- analysis: Antibiotic Prophylaxis for the Prevention of Bacterial Infections in Cirrhotic Patients With Gastrointestinal Bleeding: A Meta-Analysis. Hepatology. 1999 Jun;29(6):1655–61.
24. Pauwels A, Mostefa-Kara N, Debenes B, Degoutte E, Levy V. Systemic antibiotic prophylaxis after gastrointestinal hemorrhage in cirrhotic patients with a high risk of infection.
Hepatology. 1996;24(4):802–6.
25. Hou MC, Lin HC, Liu TT, Kuo BIT, Lee FY, Chang FY, et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial.
Hepatology. 2004 Mar;39(3):746–53.
26. Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila F, Soares-Weiser K, Mendez- Sanchez N, Gluud C, et al. Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding - an updated Cochrane review. Aliment Pharmacol Ther. 2011 Sep;34(5):509–18.
27. Martínez J, Hernández-Gea V, Rodríguez-de-Santiago E, Téllez L, Procopet B, Giráldez Á, et al. Bacterial infections in patients with acute variceal bleeding in the era of antibiotic prophylaxis. Journal of Hepatology. 2021 Aug 1;75(2):342–50.
28. Franchis R de. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. Journal of Hepatology. 2015 Sep 1;63(3):743–52.
29. Rimola A, Salmerón JM, Clemente G, Rodrigo L, Obrador A, Miranda ML, et al. Two different dosages of cefotaxime in the treatment of spontaneous bacterial peritonitis in cirrhosis: results of a prospective, randomized, multicenter study. Hepatology. 1995 Mar;21(3):674–9.
30. Fernández J, Arbol LR del, Gómez C, Durandez R, Serradilla R, Guarner C, et al.
Norfloxacin vs Ceftriaxone in the Prophylaxis of Infections in Patients With Advanced Cirrhosis and Hemorrhage. Gastroenterology. 2006 Oct 1;131(4):1049–56.
31. Zanetto A, Garcia-Tsao G. Management of acute variceal hemorrhage. F1000Res. 2019 Jun 25;8:F1000 Faculty Rev-966.
