Helicobacter Pylori Infection is Associated with an Increased Stress Ulcer Risk in Brainstem Hemorrhage Patients with Robot-Aided Stereotactic Hematoma Aspiration

Background: Whether H. pylori infection in brainstem hemorrhage patients is related to the occurrence of SU has not been reported. The purpose of this study is to explore the relationship between H. pylori infection and the occurrence of SU, and whether it is necessary to eradicate H. pylori infection during treatment. Methods: This retrospective study was conducted in our patients in Neurocritical Care Unit (NICU), Intensive Care Unit (ICU), and Emergency Intensive Care Unit (EICU) between May, 2017-July, 2020. Patients were eligible for the study if they were admitted to a participating ICU for brainstem hemorrhage with gastrointestinal bleeding and with an ICU stay of at least 3 days. Patients were ineligible if their ICU stay was less than 72 hours, and patients with a previous history of gastric or duodenal ulcer were excluded from the study. All patients were performed with robot-aided stereotactic hematoma aspiration and gastric tube indwelling. Results: In the study, 65 patients were enrolled. Of these, 7 patients were excluded because their ICU stay lasted less than 72 hours or because they had previous history of gastric or duodenal ulcer. A further 5 patients were excluded because they required blood transfusion for bleeding on admission. Thus, 53 patients constituted the study group. Conclusions: This study showed brainstem hemorrhage patients infected by H. pylori were at increased risk of gastrointestinal bleeding, suggesting that H. pylori has a major role in the pathogenesis of acute SU in brainstem hemorrhage patients.


Background
Primary brainstem hemorrhage (PBSH) has the worst outcome among all types of spontaneous intracerebral hemorrhage (SICH) [1][2][3]. There was no standardized criteria to diagnose PBSH. Generally, the diagnosis of PBSH is based on the history of hypertension, the clinical and radiological features after excluding other bleeding etiologies such as aneurysm, arteriovenous malformation (AVM), cavernomas and tumor apoplexy within brainstem [3,4]. The management of PBSH remains controversial [1,2].
Stress ulcer (SU) caused by brain injury is also called Cushing ulcer, which was rst reported by Cushing in 1932 [5,6]. SU is one of the common complications of patients with brain injury, with an incidence rate from 16-49%, as high as 40%-80% of patients with severe brain injury, increasing the mortality of patients [7]. William et al reported that endoscopic gastric mucosal injury after brain injury can appear within 24 hours, and 17% of patients can progress to clinically signi cant bleeding [8]. Although the incidence of upper gastrointestinal lesions in patients with brain injury is high, most of them are in the subclinical stage, and bleeding generally does not occur. However, once hemorrhage occurs, the condition can quickly deteriorate and severely affect the prognosis. It can also directly lead to death due to hemorrhagic shock. It is generally believed that the occurrence of SU after PBSH is due to various factors such as increased sympathetic nerve excitability under stress [9][10][11][12][13].
Helicobacter pylori (H. pylori) is a spiral-shaped G-bacterium that lives in the human stomach and duodenum. The infection rate of H. pylori in the population is related to the socio-economic development of the country or region where the patient lives. The infection rate within 10 years in developed countries is between 25%-50%, however, more than 90% people are infected with H. pylori in developing countries [14]. The H. pylori infection rate in the Chinese population is close to the world average which ranging from 42-84% in different regions in China. Studies have shown that aggravated H. pylori infection can directly lead to stress gastrointestinal mucosal lesions [15,16]. Conversely, other studies have shown that there was no relationship between H. pylori seropositivity and gastric bleeding [17][18][19].
Whether H. pylori infection in PBSH patients is related to the occurrence of SU has not been reported. The purpose of this study is to explore the relationship between H. pylori infection and the occurrence of SU, and whether it is necessary to eradicate H. pylori infection during treatment.

Methods
This retrospective study was conducted in our patients in Neurocritical Care Unit (NICU), Intensive Care Unit (ICU), and Emergency Intensive Care Unit (EICU) between May, 2017-July, 2020. Patients were eligible for the study if they were admitted to a participating ICU for PBSH with gastrointestinal bleeding and with an ICU stay of at least 3 days. Patients were ineligible if their ICU stay was less than 72 hours, and patients with a previous history of gastric or duodenal ulcer were excluded from the study. Because the aim of the study was to analyze the potential role of H. pylori infection for SU occurring in PBSH patients during treatments, patients who had hemorrhagic shock on admission or who received more than two units of red blood cell transfusion before or during the rst 72 hours after admission to the ICU were also excluded from the study. Blood sample for serum H. pylori urease antibody detection was done within 6 hours after admission. All patients were performed with robot-aided stereotactic hematoma aspiration

Clinical data
The following clinical characteristics were recorded: age, gender, previous signi cant disease, history of upper gastrointestinal bleeding. Upper gastrointestinal bleeding was suspected at 1, 3, and 7 days after operation.

Detection of H. pylori antigen
Serological antibody detection uses the colloidal gold method H. pylori urease antibody detection kit (Beijing Kangmei Tianhong Biotechnology Co., Ltd.). The blood sample was collected at 12 hours after admission.

Detection of gastric occult blood test
Gastric occult blood (OB) gold gel stripe is used. The gastric juice specimens were collected with sterile plastic tubes, and were collected three times at 1, 3, and 7 days after operation, and were submitted for inspection and completed within 1 hour after collection. Immunoassay hemoglobin colloidal gold test strip: product of Wanhua Bioengineering Co., Ltd., batch number 20407002, detection range 0.2-2000µg/ml. A red positive reaction line was showed within 5 minutes a red reaction line is positive.

Statistical analysis
All the data were presented as mean ± standard deviation (SD). Comparisons between data groups were performed with SPSS for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA). Qualitative values were compared by using the χ2 test or Fisher's exact test, as appropriate. Chi-square tests of independence for categorical variables and two-sample t-tests for continuous variables were used to compare unadjusted data; Mann-Whitney U-tests were used for continuous variables that were not normally distributed. Pvalue of less than 0.05 was considered to indicate statistical signi cance.

Results
In the study, 65 patients were enrolled. Of these, 7 patients were excluded because their ICU stay lasted less than 72 hours or because they had previous history of gastric or duodenal ulcer. A further 5 patients were excluded because they required blood transfusion for bleeding on admission. Thus, 53 patients constituted the study group. The clinical characteristics of the patients are summarized in Table 1.

Discussion
We found the correlation between H. pylori infection diagnosed by serum H. pylori urease antibody detection and the occurrence of upper gastrointestinal bleeding in PBSH patients.
PBSH has been con rmed that it was associated with increased gastric acid secretion and the risk of SU. Both proton pump inhibitors (PPI) and histamine-2 receptor antagonists (H2) have been shown to reduce the incidence of upper gastrointestinal bleeding the similar as that in brainstem patients [1,2,20,21].
The infection rate of H. pylori in China is relatively high, but not all infected patients have the same clinical outcome. In 1983, Australian scholars successfully isolated H. pylori from gastric mucosal tissue for the rst time. The concept of "sterile zone in the stomach" in the past of mankind. Since then, a large number of studies have shown that H. pylori has serious pathogenicity, and its infection is closely related to a variety of upper gastrointestinal diseases [22]. H. pylori is a spiral, microaerobe bacterium that shuttles through agella and spiral structures and colonizes between the surface and mucosal layers of the gastric mucosa. H. pylori infection is globally distributed, and there are differences in the infection rate in various regions; the infection rate in my country is about 50%, of which the infection rate in rural population is about 66%, and the infection rate in urban population is about 47% [22]. At present, H. pylori has been recognized as the main pathogenic factor of chronic gastritis, atrophic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. However, not all people infected with H. pylori have clinical symptoms.
The pathogenicity of H. pylori depends on colonization factors ( agella and helical structure) and virulence factors urease (Ure), adhesin, lipopolysaccharide, cytotoxin-related protein and cell vacuolar toxin (VacA). Colonization, in ammation and immune response damage the gastric mucosa, leading to disease [23]. At present, H. pylori has been rated as "the rst type of carcinogen" and is an important pathogen causing gastric diseases [22], and many studies have shown that H. pylori positive and peptic ulcer, chronic Gastrointestinal diseases such as gastritis and gastric cancer have a strong correlation [23,24]. Data show that 40% of the population in China has been infected with H. pylori, which is the main cause of gastric disease. In order to implement effective treatment for patients with gastric disease as soon as possible, it is necessary to diagnose the cause as soon as possible [24].
Bacterial culture method is currently recognized as the gold standard for the diagnosis of H. pylori infection, but the operation of bacterial culture method is very complicated, the detection time is relatively long, and the method is susceptible to external factors, which brings a large workload to clinical testing. The e ciency is low, so it is necessary to nd a quick and easy detection method [25]. 14-urea breath test method (14C-UBT), serum H. pylori urease antibody enzyme-linked immunosorbent assay (ELISA), and silver staining method are currently commonly used methods for detecting H. pylori infection. The rst two are non-invasive methods and the latter one is invasive. Studies have shown that the serum H. pylori urease antibody ELISA detection method can achieve a similar effect to the silver staining method, and has a better effect than the 14C-UBT detection. Therefore, for coma patients, we choose serum H. pylori urease antibody test to assess H. pylori infection. Robert [19]. However, the detection of H. pylori infection with rectal swab sampling was not reliable.
In recent years, H. pylori infection has been con rmed as an independent risk factor for cardiovascular and cerebrovascular diseases [26]. The possible mechanism is blood lipid metabolism disorder, blood oxygen free radical levels signi cantly increase, affect the immune system, and make vascular endothelium hyperplasia, injury, changes in blood composition, atherosclerotic plaque formation, and at the same time can increase the concentration of TNF-α and IL-6 in plasma. In recent years, some studies have discussed the relationship between H. pylori and SU, and the results are not consistent, and even many experimental results are completely opposite. Comparison of the positive rate of plasma H. pylori-IgG antibody in ischemic stroke patients and plasma IgG antibody concentration to verify whether H. pylori increases the occurrence of SU [26].

Conclusion
This study showed PBSH patients infected by H. pylori were at increased risk of gastrointestinal bleeding, suggesting that H. pylori has a major role in the pathogenesis of acute SU in PBSH patients, maybe it is necessary to eradicate H. pylori infection during treatment.

Limitation
The number of cases was small, and non-invasive detection methods have false positives or false negatives. Subsequent clinical sample size needs to be expanded in the future. Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. All patients were performed with robot-aided stereotactic hematoma aspiration