Association Between Gastrointestinal Bleeding With Clinical Outcome On Acute Ischemic Stroke Patient

Gastrointestinal bleedingis one of the complication of acute ischemic stroke and cause of increased mortality and length of stay. This is caused by a delay in the administration of antiplatelet or anticoagulant.Objective.To find the association between gastrointestinal bleeding with clinical outcome in acute ischemic stroke patient.Methods.This study was a prospective observational, conducted at Hasan Sadikin Hospital Bandung for 4 months (November 2017-February 2018). Acute ischemic stroke patients that fulfill the inclusion and exclusion were observed while being inpatients to observe their mortality and length of stay.This study used univariat, bivariat, multivariat, and stratification analysis.Results. A total of 100 acute ischemic stroke patients were found, and 24 patients had gastrointestinal bleeding. A history of previous peptic ulcer/gastrointestinal bleeding was found most often in patient with gastrointestinal bleeding (20.8%/p=0.003).Median NIHSS score is higher (16 vs 7/p<0.001) and GCS score was lower (12 vs 15/p<0.001) in patients with gastrointestinal bleeding. Multivariate analysis showed that gastrointestinal bleeding were significantly associated with survival (p = 0.021) and length of stay (p = 0.008). The analysis of stratification showed subjects with infections who later experienced gastrointestinal bleeding had a lower risk of death and length of stay than subjects without infection who experienced gastrointestinal bleeding (1.7 vs 22.5 times and 1.5 vs 2 times).Conclusion.Gastrointestinal bleeding had more increased mortality and length of stay than without gastrointestinal bleeding in acute ischemic stroke patient.


Abstract Background
Gastrointestinal bleedingis one of the complication of acute ischemic stroke and cause of increased mortality and length of stay. This is caused by a delay in the administration of antiplatelet or anticoagulant.Objective.To find the association between gastrointestinal bleeding with clinical outcome in acute ischemic stroke patient.Methods.This study was a prospective observational, conducted at Hasan Sadikin Hospital Bandung for 4 months (November 2017-February 2018). Acute ischemic stroke patients that fulfill the inclusion and exclusion were observed while being inpatients to observe their mortality and length of stay.This study used univariat, bivariat, multivariat, and stratification analysis.Results.
A total of 100 acute ischemic stroke patients were found, and 24 patients had gastrointestinal bleeding. A history of previous peptic ulcer/gastrointestinal bleeding was found most often in patient with gastrointestinal bleeding (20.8%/p=0.003).Median NIHSS score is higher (16 vs 7/p<0.001) and GCS score was lower ( Gastrointestinal bleeding has been reported since 1800. 5 In patients with haemorrhagic stroke, gastrointestinal bleeding occurs in about 26.7%, the incidence is related to age and volume of bleeding. 6 The incidence of gastrointestinal bleeding in ischemic stroke patients is lower, ie 0.1 -8%. The report on the incidence of gastrointestinal bleeding in ischemic stroke in Asia ranges from 1.4 -7.8% . 7,8 Gastrointestinal bleeding is still a serious problem in both stroke and ischemic stroke.
Pathophysiologically, there are different mechanisms for the occurrence of gastrointestinal bleeding in both types of stroke. Gastrointestinal bleeding in bleeding strokes occurs due to suppression of the pituitary gland by a hematoma. This causes an increase in cortisol resulting in the release of stomach acid. Gastrointestinal bleeding in ischemic stroke is caused more by the neuroinflamasi process that occurs after ischemic in the brain then stimulates vagal hyperactivity resulting in an increase in stomach acid.
In addition to gastrointestinal bleeding, infection is a non-neurological complication that is often found. The incidence of infection is around 23% -50% in patients with acute ischemic stroke. Extensive ischemic stroke causes an increase in catecholamines through the sympathetic system. The increase in catecholamines causes suppression of the immune system through neutrophil malfunction, making it easier to get infected.
The incidence of gastrointestinal bleeding and infection in acute ischemic stroke patients is associated with poor outcomes. The output includes increased disability after stroke, death, and prolonging hospital care. One of the factors that influence the outcome is the cessation of antiplatelet or anticoagulant therapy which can cause a thrombotic state that can aggravate brain ischemic conditions. The results of this study are expected to provide clinical consideration for the provision of prophylactic treatment for gastrointestinal bleeding in patients with acute ischemic stroke.

Methods
This was a prospective observational study conducted in neurology ward Dr. Hasan Sadikin The exclusion criteria were gastrointestinal bleeding before treatment at Hasan Sadikin Hospital. Data analysis used was univariate, bivariate, multivariate, and statistical stratification data analysis.

Results
A total of 100 acute ischemic stroke patients who met the inclusion and exclusion criteria.
During treatment, the subjects were observed until they were discharged from the hospital or died, then the length of time the subject was treated. The characteristics of the research subject can be seen in Table 1. Table 1 shows the mean age of subjects with older gastrointestinal bleeding compared with no gastrointestinal bleeding (61 ± 13 vs 58 ± 10 years). Hypertension is the most risk factor in all subjects (87.5% vs 85.5%). Embolic type strokes are more common in subjects with gastrointestinal bleeding, which is 66.7%. In contrast, the type of atherothrombosis was more common in subjects without bleeding, which was 57.9%. This was statistically significant (p = 0.036).
Other characteristics that differed significantly in the two groups were atrial fibrillation In addition, this study looks at the characteristics of subjects with infections as confounding variables. The number of subjects with infection in this study were 27 subjects. The average age of subjects with infection is 61 years with more women than men (17 vs 10). Subjects with more infections in embolic type strokes than atherothrombotic types (18 vs 9). Median GCS and NIHSS scores respectively 12 and 17. Table 2 shows that of the 24 subjects with gastrointestinal bleeding half died, while without bleeding only 7.9%. This is significantly different (p <0.001). In addition, subjects with bleeding died within a median time of 3 days (Quartile Range interval / IQR: 2-7) and most of the causes of death were neurological causes in this case cerebral herniation (8 subjects / 66%). Meanwhile, subjects without bleeding died within a median of 8 days (IQR 3-10) and fewer died of neurological causes (2 subjects / 33%).

Relationship to Survival of Gastrointestinal Bleeding
Of the 27 patients diagnosed with infection during treatment, almost half died, while without infection only 6.8%. This is significantly different (p <0.001). Infection in this study was pneumonia and urinary tract infections. In addition, it was found that subjects with infections died within a median of 8 days (IQR: 3-10) and fewer died of neurological causes (6 subjects / 46%; meanwhile subjects without infection died within a median of 3 days (IQR 2-3 ) and most died of neurological causes (4 subjects / 80%).
Based on bivariate analysis, subjects with gastrointestinal bleeding were 6.3 times more likely to die than without bleeding. Then multivariate analysis showed that subjects with gastrointestinal bleeding had a risk of dying 3.2 times greater than without bleeding after being controlled by confounding infection variables (p = 0.021) ( Table 3). Table 3 shows that there were 13 subjects with infections who had gastrointestinal bleeding more than half (8 subjects) died, while those who did not bleed only 5 subjects (38.5%). Uninfected subjects who experienced gastrointestinal bleeding as many as 4 subjects (36.4%) died, while those who did not bleed only 1 subject (1.6%).
Subjects with infections then experiencing gastrointestinal bleeding have a risk of dying of 1.7 times. Whereas subjects without infection then experienced gastrointestinal bleeding at a risk of death of 22.5 times. Table 4 shows that in the group of living subjects the length of stay> 7 days was greater in gastrointestinal bleeding than without bleeding (75% vs 32.9%). This is significantly different (p = 0.009). Living subjects who were diagnosed with infection had more than 7 days of treatment compared to those without infection (78.6% vs 30.9%). This is significantly different (p <0.001). From these results it was found that subjects with gastrointestinal bleeding were 2.3 times more likely to be treated for> 7 days than without bleeding.

Relationship to Gastrointestinal Bleeding with Length of Stay
After multivariate analysis, it was found that subjects living with gastrointestinal bleeding had a risk of length of stay of> 7 days, 1.8 times rather than without bleeding after being controlled by confounding infection variables (p = 0.008) ( Table 4).
Research in Taiwan says Asian races have more bleeding than Caucasians associated with Helicobacter pylori infection. Research in Indonesia, Taiwan, the Philippines, and Malaysia was only in one hospital, while in the United States, Japan, Canada, and China multicentre studies so that there were differences in the number of subjects. In addition, this difference may be due to differences in the operational definition of gastrointestine bleeding l. In developed countries, endoscopic examination is the gold standard for the diagnosis of gastrointetinal bleeding, whereas in this study only based on clinical findings. 7,11,12 This study showed the proportion of women who experienced gastrointestinal bleeding was slightly more than men (54.2% vs 45.8%), but no significant difference was found.
Conversely there was a significant difference in China and Taiwan where men were more at risk of developing gastrointestinal bleeding. This might be due to differences in the characteristics and number of research subjects. 10,12 The average age of the study subjects was younger (58 years) compared to the stroke register in Indonesia (65 years), Chinese (66 years), Taiwan (69 years). This might be due to differences in the characteristics and number of research subjects. Another reason is that Indonesia is a developing country that experiences unhealthy lifestyle changes that increases risk factors for stroke such as hypertension and diabetes mellitus. The age of subjects with gastrointestinal bleeding was older compared to those without gastrointetinal bleeding (61 vs 58 years) according to the study in Taiwan (74 vs 69 years), Japanese (76 vs 73 years), Canada (75 vs 72 years). This is because at an older age the physiological function of the gastrointestinal system decreases. This causes a decrease in the function of protective cells in the gastrointestinal system so that bleeding occurs more easily. 7,13,14 This study showed the risk factors for dyslipidemia were slightly lower in subjects with gastrointestinal bleeding (54.1%) compared to those without gastrointestinal bleeding (60.5%). This is consistent with previous studies in Japan (29.2% vs 49.6%), Canada (18% vs 34%). The cause of this event is not yet fully known, but previous studies say it might be due to the use of antibiotics for eradicating bacteria, especially Helicobacter pylori.
Such eradication may be related to an increase in serum cholesterol or triglycerides. Subjects with gastrointestinal bleeding had atrial fibrillation risk factors and embolic stroke type than those without gastrointestinal bleeding (25% vs 5.2% and 66.7% vs.

42.1%
). This is because in embolic strokes there is a widespread brain ischemic so that the neuroinflammation in the brain gets more intense. The inflammatory mediator involves activating the cervico-vagal nerve pathway which will activate parasympathetic pathway to produce acetylcholine vagal hyperactivity. This vagal hyperactivity stimulates production of acid chloride in gastric causing gastrointestinal bleeding. Previous research in Japan (36%) and Canada (20%) showed the same cases.

Subjects with gastrointestinal bleeding had a history of peptic ulcer / gastrointestinal
bleeding and the use of antiplatelet / anticoagulant therapy before admission was slightly more than without gastrointestinal bleeding (20.8% vs 0 and 29.2% vs. 11.8%). These results are in line with previous studies in Taiwan, Japan, the United States, and Canada. This is because the use of antiplatelet is associated with damage to the gastric epithelium directly and inhibits the production of prostaglandin by the gastric mucosa, causing gastric ulcers. The use of anticoagulants is related to the systemic effects caused by inhibition of clotting factors involving vitamin K. 11,15,16 Subjects with gastrointestinal bleeding had a higher NIHSS score at admission compared to those without gastrointestinal bleeding (16 vs 7). The results of this study are in accordance with other studies in Japan. GCS scores at admission are lower in subjects with gastrointestinal bleeding (12) compared to those without gastrointestinal bleeding (15). This is related to the severity of the ischemic stroke that occurs. The median mRS score before admission did not differ between subjects with bleeding and without bleeding. This is caused by the severity of the stroke that occurred before is relatively mild. There are several hypotheses which state that the severity of ischemic stroke causes gastrointestinal bleeding. Nosocomial infections that occur due to disability in the stroke.
Another opinion said the infection caused gastrointestinal bleeding due to changes in faktor coagulation due to inflammation that occurs. 11,17

Relationship to Gastrointestinal Bleeding with Survival
This study showed gastrointestinal bleeding significantly affected the incidence of death Infection is considered to be a confounding variable because in several studies in Taiwan, the United States, Brazil and Poland, infection significantly affected mortality in acute ischemic stroke patients. Extensive ischemic stroke causes an increase in catecholamines through the sympathetic system. The increase in catecholamines causes suppression of the immune system through neutrophil malfunction, making it easier to get an infection. 9,11,18 Research in Japan said the mortality of subjects with gastrointestinal bleeding was higher than without bleeding (15.7% vs 1.9%) with a risk of death 8.7 times. In Canada, the mortality of subjects with gastrointestinal bleeding was 28% with a risk of death 1.5 times greater than without bleeding. Research in the United States showed that as many as 16.1% of subjects with gastrointestinal bleeding died with a risk of death 1.8 times greater than without bleeding. Based on these data, gastrointestinal bleeding significantly affected death in patients with acute ischemic stroke. 11 Stratification analysis based on the presence or absence of infection diagnosis showed that subjects with infections who subsequently had gastrointestinal bleeding had a lower risk of death than those without infection and then had gastrointestinal bleeding (1.7 times vs. 22.5 times).
In addition there were 10 patients without gastrointestinal bleeding who were given prophylactic therapy (PPI, histamine H2 antagonist, or cytoprotectic agent), where only 1 subject died due to sepsis.

Relationship to Gastrointestinal Bleeding with Length of Stay
This study showed subjects with gastrointestinal bleeding were treated more than 7 days (75%) compared with no gastrointestinal bleeding (32.9%). The risk of treatment is 1.8 times longer in subjects with gastrointestinal bleeding than without bleeding after being controlled by confounding infection variables. Although the risk of long-term treatment for infection is higher (2.2 times), the focus of this study is gastrointestinal bleeding. Based on these results, gastrointestinal bleeding plays an important role in the length of care without infection. Infection is considered a confounding variable because previous studies in Taiwan, the United States, Denmark, and the United Kingdom mentioned infection affecting the length of stay in acute ischemic stroke patients. 11,19 The results of this study are in accordance with previous studies in the United States.
Research in the United States found that ischemic stroke patients with gastrointestinal bleeding had a longer average length of stay (11 days) than without gastointestinal bleeding (5 days) with a 2.3 times longer risk of treatment. Patient care was longer due to examination and therapy. additions were made to patients with gastrointestinal bleeding such as delaying antiplatelet / anticoagulant initial therapy, blood transfusion, and endoscopy to find gastrointestinal bleeding sources. Based on these data, gastrointestinal bleeding has a significant effect on prolonging the length of treatment in acute ischemic stroke patients (p = 0.008) . 11 Stratification analysis based on the presence or absence of infection diagnosis showed that subjects with infections who subsequently experienced gastrointestinal bleeding had a long risk of treatment not much different than those without infection and then had gastrointestinal bleeding (1.5 times vs. 2 times).

Research Limitations
This study used clinical symptoms to diagnose gastrointestinal bleeding from brownish NGT hose, not confirmed by endoscopy to find the source of bleeding and Helicobacter pylori infection. This study did not take into account antiplatelet administration, anticoagulants, or other drugs that might affect the gastrointestinal tract during hospital treatment.

Conclusions
Acute ischemic stroke that has gastrointestinal bleeding has a higher risk of death and longer treatment duration than without gastrointestinal bleeding. Infection events during treatment affect mortality and length of stay in subjects with acute ischemic stroke.
Embolic stroke type, having atrila fibrillation, low GCS scoe, higher NIHSS score, history of peptic ulcer, history of antiplatelet/anticoagulant therapy and infection during hospitalization in acute ischemic stroke patients had tendency towards gastrointestinal bleeding. Prophylactic treatment using PPI, histamine H2 antagonist, or cytoprotectic agent can reduce mortality in acute ischemic stroke patients.

Competing Interest
There is no competing interest.

Funding
There is no funding for this research

Consent for Publication
This publication is one of the requirements to pursue doctoral title from Faculty of Medicine, University of Padjadjaran Bandung, Indonesia.

Availability of Data and Material
The full data showed in supplementary material.