The Prevalence, Etiology and Treatment of Gastroduodenal Ulcers and Perforation: A Systematic Review

(1) Background: Gastroduodenal perforation (GDP) is a life-threatening condition caused by a spontaneous or traumatic event. Treatment should be based on the mechanism of damage, timing, location, extent of the injury, and the patient’s clinical condition. We aimed to examine several etiologic factors associated with gastroduodenal perforation and to search for the best method(s) for its prevention and treatment. (2) Methods: We conducted extensive literature reviews by searching numerous studies obtained from PubMed, Science Direct, and Cochrane for the following keywords: gastroduodenal perforation, Helicobacter pylori, NSAIDs’ use, side effects of GDP, laparoscopy, and surgery. The primary outcome was the reported occurrence of GDP. (3) Results: Using keywords, 883 articles were identified. After applying the inclusion and exclusion criteria, 53 studies were eligible for the current analyses, with a total number of 34,692 gastroduodenal perforation cases. Even though the risk factors of gastroduodenal perforation are various, the prevalence of H. pylori among patients with perforation is considerably high. As technology develops, the treatment for gastric perforation will also improve, with laparoscopic surgery having a lower mortality and complication rate compared to open surgery for GDP treatment. (4) Conclusions: H. pylori infection plays the most significant role in GDP, more than NSAIDs, surgery, chemotherapy, or transplantation. Treatment of H. pylori infection is essential to decrease the prevalence of GDP and speed up its recovery. However, urgent cases require immediate intervention, such as laparoscopic or open surgery.


Introduction
Duodenal and gastric ulcers remain the two most common perforations of the gastrointestinal tract.A gastric ulcer refers to a specific area of inflammation or damage on the lining of the stomach, whereas gastric perforation is a more serious issue characterized by the development of a hole or tear in the wall of the stomach.Gastric perforation commonly occurs as a consequence of untreated or inadequately controlled gastric ulcers.Both disorders necessitate medical intervention, but stomach perforation is regarded as a medical emergency owing to its capacity for severe consequences [1].Risk factors of gastroduodenal perforation (GDP) vary based on the geographical area associated with sociodemographic and environmental factors, such as overcrowding and poor hygiene in developing countries, and it mostly occurs spontaneously due to peptic ulcer disease [2].The mean prevalence of H. pylori infection in patients with perforated peptic ulcers is roughly around 65-70%, and this might indicate that there are more factors involved in its pathology [3].In many countries, the incidence of H. pylori infection has been decreasing in association with an improved standard of living [4].Patients often fails to perceive the symptoms and indicators of GDP, resulting in delayed treatment and jeopardizing their lives.Therefore, the use of CT scans is very important and needs to be considered as an effort to improve the ability to detect perforation [5].
The incidence and prevalence of GDP in recent years have attracted the attention of researchers in the medical field.Interest has always focused on H. pylori eradication as a strategy for eliminating gastroduodenal perforation.The objective of this study is to determine the most efficacious approach(es) for preventing and treating gastroduodenal perforation while also examining several etiological factors associated with this illness.Our research carries out further efforts into realizing the Sustainable Development Goals (SDGs) in Indonesia and ensuring a healthy life and good welfare for all people of all ages.

Literature Search and Study Selection
This systematic review was performed using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines [6].A search was completed in January 2022 using keywords from a combination of Medical Subject Headings in PubMed, Cochrane, and Science Direct with several inclusion and exclusion criteria (Table 1).The search terms used were "Gastroduodenal" and "Perforation" filtered with clinical trials and randomized controlled trial studies.Additionally, the reference lists of the selected articles were manually reviewed to obtain other potentially relevant articles.Selected publications were all in the English language.

2.
The necessary data were provided.
Patients were followed up, and results were reported.

Criteria
Exclusion Criteria

1.
The literature was not the original article (such as meta-analysis, review), or a literature duplication.

2.
The object of the study was cellular-based or animal-based.

3.
The evidence occurred other than in the gastric or duodenal area.4.
The articles were not in English.

Data Extraction and Quality Appraisal
The flowchart of the articles obtained in this study is shown in Figure 1.There were 883 articles identified after applying the keywords, of which 597 articles were excluded after screening because they did not meet the criteria.Abstract and full-text assessments were conducted to obtain relevant data; the final 53 eligible articles were used in this study.
1. Retrospective and prospective studies.2. The necessary data were provided.3. Evidence comprises gastroduodenal perforation, bleeding, and ulcers.4. Treatment of gastroduodenal perforation.5. Patients were followed up, and results were reported.
Exclusion Criteria 1.The literature was not the original article (such as meta-analysis, review), or a literature duplication.2. The object of the study was cellular-based or animal-based.3. The evidence occurred other than in the gastric or duodenal area.4. The articles were not in English.

Data Extraction and Quality Appraisal
The flowchart of the articles obtained in this study is shown in Figure 1.There were 883 articles identified after applying the keywords, of which 597 articles were excluded after screening because they did not meet the criteria.Abstract and full-text assessments were conducted to obtain relevant data; the final 53 eligible articles were used in this study.

Data Analysis
We divided the eligible articles for the current analysis into three categories based on the cause of perforation: H. pylori infection, NSAID treatment, and other risk factors for GDP.We extracted the total number of patients and calculated the prevalence of the perforation among each of the three groups independently.

Data Analysis
We divided the eligible articles for the current analysis into three categories based on the cause of perforation: H. pylori infection, NSAID treatment, and other risk factors for GDP.We extracted the total number of patients and calculated the prevalence of the perforation among each of the three groups independently.

Gastroduodenal Perforation Event and Prevalence
A total of 53 studies were qualified to acquire data, with a total of 118,600 patients obtained in this study.Out of a total of 118,600 patients included in this study, 34,692 individuals experienced gastroduodenal perforation, and 4666 patients passed away.Moreover, 12 of the 53 articles obtained tested participating patients for H. pylori, while the other studies did not disclose the infection.

The Prevalence of H. pylori Infection among Patients with Gastroduodenal Perforation
The overall prevalence of H. pylori infection among the total 1653 cases of perforation was 58% (Table 2).That prevalence varied between the studies from 3% to 100%, and this difference could be due to the wide variation of the sample size and/or the differences in the diagnostic methods used.There were 5 studies with a sample size greater than 100 patients vs. 7 studies with less than 100 patients.The overall prevalence of H. pylori was significantly higher among the group that participated in the larger sample size studies (61% vs. 39%, respectively, p = 0.0001).Studies by Pescatore et al. [7] and Tokunaga et al. [8] showed the highest H. pylori prevalence among patients with GDP and ranged from 92% to 100% (n = 119 patients), compared to the other studies that showed a prevalence of infection between 20 and 84.6% (n = 1457) [9][10][11][12][13][14][15][16].Two of the studies reported the lowest prevalence of H. pylori infection, with 12.5% among a total number of 48 patients and 13.8% among 29 patients with a perforated peptic ulcer, which could be due to the small sample size of both studies [3,17].2020) [3] The association between H. pylori and a perforated gastroduodenal ulcer.48 12.5% (6) Ha et al. ( 2016) [11] The gastrointestinal safety of herbal medicine in patients with osteoarthritis.761 53% (403) Vonkeman et al. (2007) [12] PPI reduced the risk of NSAID ulcer complications.104 20% (21) Köninger et al. (2004) [13] Laparoscopic repair of a perforated gastroduodenal ulcer.20 65% (13) Agaba et al. (2016) [14] The incidence of complicated PUD and analyses changes in surgical management.400 84% (336) Pescatore et al. (1998) [3] A new method combining laparoscopy and endoluminal endoscopy was designed to ensure complete closure of the perforation.

NSAIDs' Use among Gastroduodenal Perforation
Non-steroidal anti-inflammatory medicines (NSAIDs) are a pharmacological category frequently used for pain relief, inflammation reduction, and fever reduction.They function by suppressing the activity of an enzyme known as cyclooxygenase (COX), which has a crucial role in the synthesis of prostaglandins, which have a role in the promotion of inflammation, pain, and fever inside the body [18].Table 3 shows the prevalence of GDP among NSAID users according to the type of NSAID used.Among the total number of 8076 patients who used rofecoxib and naproxen, the risk ratio for perforation was 0.40 [19].The reported risk ratios among patients using celecoxib, ibuprofen, naproxen, and other NSAIDs slightly differ: 0.44, 0.48, and 0.49, respectively [12,20,21].The risk ratio below 1 indicates that the risk of GDP among the exposed group was relatively low [19].However, studies of NSAIDs in Japan demonstrated a very high risk ratio of 1.715 [21].In patients with rheumatoid arthritis, rofecoxib, a selective cyclooxygenase-2 inhibitor, shows fewer upper gastrointestinal events than naproxen.Celecoxib, compared to ibuprofen and naproxen, reduces clinically significant gastrointestinal events, but its benefits decrease with low-dose aspirin.Long-term NSAID use increases the prevalence of gastroduodenal ulcers, especially in those with a history of gastric ulcers.Serious comorbidities, particularly cardiovascular, raise in-hospital mortality risk from NSAID ulcer complications, mitigated by proton pump inhibitors.Approximately 50% of Japanese gastroduodenal ulcers with complications are NSAID-related, emphasizing the need for preventive measures based on risk factors [12,[20][21][22].

Other Causes of Gastroduodenal Perforation
There are other factors recognized to be the cause of GDP, as shown in Table 4.Among the 1558 patients who had a renal transplant, the prevalence of developing GDP ranged from 4.7% to 37% [23][24][25][26].Furthermore, 7.1% and 2.4% of patients undergoing major abdominal surgery and neurosurgery had GDP as postoperative complications [27,28].In patients with cardiovascular disease, GDP was one complication that occasionally occurred, with 1.2 percent of 17,598 patients having upper gastrointestinal complications such as bleeding, ulcer, or perforation for both the placebo and pantoprazole treatment groups [29][30][31].Complications also occurred after cardiovascular surgery with cardiopulmonary bypass, and gastroduodenal ulcer perforation occurred in 27.3% of 2349 patients [29].Among 39 patients who had laparoscopic surgery due to hernia; 35% of patients experienced GDP [32], and it also developed in 23% of patients with colorectal cancer as the side effect of chemotherapy [33].In intestinal transplantation cases, six children out of fifty-nine had spontaneous bowel rupture (13%) [34].Among other causes, such as burn, opiate addiction, and smoking, gastroduodenal perforation occurred as a side effect [35][36][37].However, prophylaxis was deemed important to prevent a more severe gastroduodenal event [11,38].The frequency of laparoscopy's success rate is shown in Table 5.
When compared to open surgery, laparoscopic procedures have a much higher success rate, with approximately a mean of 94.4% from a total of 555 patients.Success rates were obtained from the difference between total patients and mortality.Most of the time, the laparoscopic treatment showed no or little complications, wound infections, sepsis, stenosis, and extra-abdominal issues [13,15,[40][41][42][43][44][45][46].Despite the great result of laparoscopic outcomes, some failures, morbidity, and mortality occur in small numbers of patients due to delayed treatment, old age, comorbidity, and other reasons that are unrelated to gastroduodenal perforation [14,16].However, in a few instances where there was immediate leakage and bleeding, reoperations were also performed [47].The laparoscopic treatment of patients with ulcers resulted in good cicatrisation, and no pyloric stenosis remained [40].
If morbidity and death rates are to be reduced, an early surgical intervention is advised.In the majority of cases, simple closure with H. pylori eradication and acid suppression will be sufficient.Early treatment of cancer patients with spontaneous gastroduodenal perforation with a high index of suspicion of the illness may enhance survival.
Even though laparoscopic surgery has shown a greater success rate, open surgical procedures are still widely used to treat perforated gastroduodenal ulcers.As many as 30,919 patients in this study were treated with open surgery, with an average success rate of 85.03% (Table 5).Even though open surgery was more frequently performed, open surgery has a higher risk of mortality compared to laparoscopic surgery.The Ohene-Yeboah study showed that the incidence of mortality was 9.9% after surgery as a result of severe intra-abdominal sepsis and multi-organ failure [49].Another study also showed that the mortality rate in perforated gastric cancer after surgery was 13.8% [50].Other contributing factors, such as the buildup of fat, advancing age, the presence of other medical conditions, lack of appropriate therapy, and impaired liver function, have been found to elevate the risk of postoperative complications and mortality [48,52,56,58,59].

Discussion
Previous studies showed that H. pylori's urease, flagella, chemotaxis system, and adhesins are responsible for establishing colonization and exacerbated clinical outcomes [60].Moreover, studies showed that several virulence factors such as outer inflammatory protein (OipA), epithelial gene A1 (iceA1), babA2-gene positive (encodes BabA protein), duodenal ulcer promoting gene cluster (dupA cluster), vacA s1/m1 genotype, and cagA-gene positive expression are associated with peptic ulcer disease [61].Our study showed that approximately 58% of patients with gastroduodenal perforation were infected with H. pylori, which is consistent with previously reported studies [62].Patients afflicted with H. pylori should undergo treatment to eradicate infection and avoid its reoccurrence, hence averting the development of gastrointestinal diseases [2].The simultaneous administration of many antibiotics, including amoxicillin, clarithromycin, and ceftriaxone, is typically employed to eliminate H. pylori bacteria.This treatment is sometimes combined with a proton pump inhibitor (PPI) and omeprazole [7,13,17].The length of antibiotic treatment and abdominal drainage was contingent upon the clinical results.The duration of antibiotic medication may be extended due to a persistent fever, stomach discomfort, and intestinal paralysis [13].Perforated, H. pylori-negative chronic duodenal ulcers or recurrent ulcers may be treated with final anti-ulcer surgery (parietal cell vagotomy anterior linear gastrectomy).Surgeries are often the first line of treatment for perforations, especially for patients who are in a critical condition and need immediate medical attention [16].
Helicobacter pylori infection is a major contributor to developing GDP, although other variables, such as the utilization of NSAIDs, also play a part in this process.Non-steroidal anti-inflammatory drugs are characterized by their selectivity in inhibiting COX enzymes.Ibuprofen, naproxen, and diclofenac, which suppress both COX-1 and COX-2, can interfere with COX-1's protective mechanisms in the stomach lining, increasing the risk of perforation and ulcers [63].Selective COX-2 inhibitors like celecoxib and rofecoxib were developed to minimize gastrointestinal problems from non-selective NSAIDs.They reduce stomach ulcers and perforation risk compared to non-selective NSAIDs [19].However, certain COX-2 inhibitors may increase cardiovascular risks.The company took rofecoxib off the market on its own in September 2004 because of worries about the higher chance of heart attacks and strokes that came with its long-term, high-dose use.This is said to have caused between 88,000 and 140,000 cases of serious heart disease [64].
Our study showed that the overall prevalence of GDP among NSAID users was considerably low, while the prevalence of H. pylori among patients with GDP was relatively high.This finding is consistent with earlier studies that reported, despite the risk of gastroduodenal damage among NSAID users, the chance of perforation being low when taking a low dose of NSAIDs [65].Gastroduodenal perforation can also occur as a side effect of other medical therapies and/or surgeries.Nevertheless, the prevalence of GDP among such patients remains low, except for those who engage in smoking and suffer from opiate addiction since they are more vulnerable to GDP [35,36].Although NSAIDs and other therapies may play a role in the development of peptic ulcer disease, gastric cancer, malt lymphoma, and gastroduodenal perforation, the infection of H. pylori should not be overlooked.
Patients with gastric perforation need prompt treatment to prevent mortality.Surgical interventions are often undertaken as an emergency to seal leakages, followed by an additional regimen for treating the H. pylori infection.Open surgery and laparoscopic procedures are the most frequently performed for gastric perforation treatment.However, open surgery and laparoscopy trends are shifting.The 1998-2012 investigation revealed that the number of patients that underwent open surgery decreased after 2004, while the number of patients who underwent laparoscopy increased [46].Although the use of laparoscopic procedures is growing, open surgery is still often employed to treat patients with perforated gastroduodenal conditions for several reasons [15,17].Open surgeries may still be necessary to treat patients with gastric perforation based on circumstances such as the severity of the perforation, hemodynamic instability, or the presence of significant contamination.Open surgery enables a comprehensive examination of the abdominal cavity, which helps in effectively preventing contamination and managing difficult perforations optimally [66].
Taken together, this study acknowledges that the collective impact of various causes may contribute to stress on the gastrointestinal system, leading to ulcer perforation.However, H. pylori infection also plays a significant role in gastroduodenal perforation with or without NSAID use or due to the consequence of surgeries or the use of chemotherapy and transplantation.To prevent gastric perforation, it is necessary to identify and manage risk factors while implementing evidence-based therapy.Peptic ulcers, which can lead to stomach ruptures, can be averted by specifically addressing the H. pylori infection using medicines.Non-steroidal anti-inflammatory drug utilization necessitates meticulous management, encompassing the evaluation of potential risks and the prescrip-tion of prophylactic medications or other methods of pain management.Restricting the consumption of alcohol and tobacco; adhering to a diet abundant in nutrients from fruits, vegetables, and whole grains; and controlling portion sizes might enhance the wellbeing of the stomach.Meditation and yoga alleviate chronic stress, a potential trigger for stomach ulcers.Proton pump inhibitors (PPIs) and histamine-2 blockers aid in the healing and prevention of ulcers by maintaining the integrity of the mucosal lining.Regular medical examinations aid in the identification and treatment of disorders that can lead to stomach perforation.Preventive strategies for maintaining a healthy weight include engaging in regular exercise, following a balanced diet, and refraining from the use of gastric-irritating medications.Timely identification and management of gastrointestinal symptoms is crucial in order to prevent stomach perforation.Healthcare experts can avoid gastric perforation by applying these scientific principles in a customized manner.However, if gastric perforation occurs, certain procedures, such as laparoscopic or open surgery, are necessary to be performed immediately.

Study Limitation
It is imperative to recognize specific constraints in our research that could potentially impact the interpretation of our findings.An initial consideration must be given to the possibility that potential biases, such as recall bias or selection bias, may compromise the validity of our findings.Furthermore, discrepancies in study designs across various research components could potentially introduce variability in the collected data.The potential impact of data acquisition limitations, including insufficient sample size or missing data points, on the applicability of our findings should not be overlooked.Despite our best efforts to mitigate these constraints, it is important to acknowledge their existence when interpreting the results of this study.It is advisable that future investigations incorporate more substantial and varied sample sizes, as well as rigorous study designs, in order to augment the validity and applicability of our results.

Table 2 .
The prevalence of H. pylori infection among patients with gastroduodenal perforation.

Table 3 .
Gastroduodenal events induced by non-steroidal anti-inflammatory drugs.

Table 4 .
Other risk factors associated with a gastroduodenal event.

Table 5 .
Laparoscopic and open surgery treatment for gastroduodenal perforation incidence.