Ileal Free Perforation with Nonspecific Etiology such as Simple Inflammation or Ulcer
*Corresponding author:Seung-Jin Kwag, MD PhD, Department of General Surgery, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, 79, Gangnam-ro, Jinju-si, Gyeongsangnam-do, Korea-52727; E-mail: firstname.lastname@example.org
Ileal free perforation in adults is rare. However, peritonitis from ileal perforation is associated with excessively high morbidity and mortality rates . Patients with ileal perforation often visit a hospital late, with purulent peritonitis and in poor general condition. Peritonitis following intestinal perforation may lead to multi-organ failure and death even if it is treated promptly and vigorously.
Patients with ileal free perforation caused by simple inflammation or ulcer are rare. The origin of ileal ulcer is mostly unclear. Suggested causes include local ischemia of mucosa due to vascular changes in mesentery, damage after passing of a foreign body, NSAIDs use, and inflammation of bacterial origin[3, 4].
Typhoid fever and tuberculosis are common causes of such perforation in developing countries whereas non-infectious pathology is more common in industrial countries. For this reason, there are many reports of perforation of the ileum. The cause of infection (such as typhoid fever, tuberculosis, or CMV infection) and underlying disease (such as Crohn’s disease or ulcerative colitis) have been confirmed in developing countries [6-10].
However, to the best of our knowledge, ileal perforation due to simple inflammation or ulcer has not been reported yet. Therefore, the purpose of this study was to review patients with ileal free perforation and determine their clinical characteristics and outcomes.
A total of 359 patients underwent emergency surgery because of small-bowel perforation from October 2009 to March 2018 at our hospital. Small-bowel free perforation was defined as perforation of the small intestine with intestinal content spilling into the general peritoneal cavity. We excluded a total of 329 patients from this study because they had surgical trauma such as foreign bodies, malignancy, diverticula, or problems caused by medical and surgical operations. Those with perforation in the duodenum or jejunum were also excluded. Typhoid enteritis, a common cause of small-bowel perforation in developing countries, was absent. There were three cases of inflammatory bowel disease (one case of Crohn’s disease, one case of Cytomegalovirus infection, and one case of tuberculosis). Of patients with ileal perforation who did not meet the exclusion criteria, 30 patients had perforation caused by simple chronic inflammation regardless of ulcer formation. Causes of small intestinal perforation are shown in Table 1.
Data collected included age, gender, American Society of Anesthesiologists score, comorbidity, presenting signs and symptoms, complete blood count, c-reactive protein, blood urea nitrogen, blood creatinine, and serum electrolytes. Abdominal enhanced computed tomography scan was reviewed by a radiological specialist to detect the presence of fecal impaction or bowel ischemia around the perforation site.
In this study, the decision for surgery was based on clinical examination with the aid of plain radiographs and CT scans. All patients received emergency operations under general anesthesia. The chosen surgical procedure and the necessity of stoma depended on the surgeons’ operative assessment. All intestinal anastomoses were either hand-sewn or stapled. After the operation, all patients received empiric antibiotics and fluid resuscitation treatment.
All clinical data were analyzed with the Statistical Package for the Social Science version 18.0 (SPSS, Chicago, IL, USA). Categorical variables are presented in percentages while continuous scaled variables are presented as mean ± SD. Univariate analysis was performed using a Chi-square test for categorical variables. Multivariate linear analysis was performed with backward elimination. The criterion to include variables in the multivariate analysis was a liberal p value of < 0.15 in univariate analysis. The study protocol was approved by the Institutional Review Board of the Gyeongsang National University Hospital (approval number: 2018-07-022-001).
Of the 30 subjects with ileal free perforation, 16 (53.3%) were males and 14 (46.7%) were females. Of these cases, 12 (40%) patients were diagnosed with ileal perforation caused by ulcer (Fig. 1A) and 18 (60%) patients were diagnosed with simple inflammation such as transmural infarction (Fig. 1B) or acute serositis (Fig. 1C). In this study, the mean age of patients was 70.7 years. Thirteen (43.4%) patients were in their 70s. Their average BMI was 21.6 kg / m2. Among these patients, 21 (70%) had an underlying disease. Of these underlying diseases, hypertension was the most common (n = 11), followed by coronary disease (n = 7), diabetic mellitus (n = 4), and malignancy (n = 4). Eight patients underwent abdominal surgery before ileal perforation. Twelve patients continued to use nonsteroidal anti-inflammatory drugs before surgery. Their baseline demographic and clinical characteristics are shown in Table 2.
Figure 1: Various pathologic findings of cases with spontaneous ileal perforation. (A) An excavated lesion without mucosa extends proper muscle (ulcer, x20). (B) The mucosa is denuded and ischemic necrosis is shown through the whole intestinal wall. (transmural infarction, x40). (C) Neutrophilic infiltration (left upper corner) is found in the serosa and sub serosal tissue. (acute serositis, x40 and x200).
Clinical parameters and laboratory investigations of patients before surgery are shown in Table 3.
Patients were classified according to Systemic Inflammatory Response Syndrome (SIRS) criteria. Cases with tachycardia (n = 17) and those with less than 32 mm Hg of serum CO2 (n = 16) were more than half of the total. A total of 76.7% of patients had leukocytosis or leukopenia. In most patients, C-reactive protein levels were elevated. However, few patients had hypotension or high fever. All patients underwent abdominal or chest X-rays and computed tomography before surgery. Only nine (30%) of these patients were found to have free air on X-ray. All abdominal computed tomography (CT) scans of patients were reviewed by a radiology specialist. Four patients had ischemic enteritis (Fig. 2A) while nine patients had fecal impaction (Fig. 2B). Five patients showed a definite wall defect of the ileum (Fig. 2C). Thickening of the ileal wall was observed in almost all patients. Only two patients showed normal bowel wall. Data are summarized in Table 4.
Figure 2: Abdominal computed tomography of ileal perforation patients is seen in various forms.
(A) Ischemic enteritis (thin arrow), (B) Fecal impaction (thick arrow), (C) Ileal wall defect (thin arrow).
The average operation time was 123.3 minutes. Resection and anastomosis were performed in 15 (50%) patients and primary repair was performed for seven patients. Right hemicolectomy or ileostomy was performed for five cases. Fifteen patients underwent open laparotomy. The remaining patients underwent laparoscopy. Of these, 13 patients underwent open conversion. Transfusion was performed in 15 (50%) patients during operation. Additional details are shown in Table 5.
Gas out was achieved for patients after an average of 4.7 days postoperatively. The first diet was started after 8.0 days. Morbidity occurred in 19 (63.3%) cases. Wound dehiscence and atelectasis or pulmonary edema were found in 12 (40%) cases. Ileus was found in three cases and leakage was found in one case. Eight (26.7%) patients died, with pneumonia being the most common cause (three cases). The other five died because of leakage, sepsis, pulmonary thromboembolism, heart failure, or pancreas cancer aggravation (Table 6). In the patient with pancreatic cancer, perforation of the ileum was not associated with pancreatic cancer.
Univariate and multivariate analyses were performed to identify factors associated with morbidity and mortality. In the univariate analysis of morbidity, only postoperative ICU care was statistically significant (OR, 12.6; p = 0.003). Other factors were not statistically significant. There was morbidity in all patients with heart disease, malignancy, or more than two underlying diseases. Thus, univariate analysis was not performed. On univariate analysis, mortality was associated with more than two underlying diseases (OR, 10.6; p = 0.016), previous use of non-steroidal anti-inflammatory drugs (OR, 8.0; p = 0.039), postoperative ICU care (OR, 10.1; p = 0.039), and use of inotropes such as norepinephrine or dopamine (OR, 15.0; p = 0.012). On multivariate analysis, having more than two underlying diseases was found to be the only significant predictor of mortality (OR, 21.8; p = 0.037) (Table 7).
Peritonitis due to non-traumatic ileal perforation is rare. Its etiologies are diverse. Infections including tuberculosis and typhoid fever are the most common causes of ileal perforation in developing countries. In developed countries, noninfectious etiology such as Crohn’s disease is predominant ,. In our hospital, many cases of ileal perforation were due to simple inflammation or ulcer based on pathologic examination after surgery.
In this study, five patients who were excluded from this study were found to have gross or pathological ulcer after surgery because of small intestinal perforation. They had clear causes: Crohn’s disease in three patients, tuberculosis in one patient, and CMV infection in one patient. Crohn’s disease was announced in 1932 by Burrill Crohn, a gastroenterologist at Mt. Sanai hospital in New York . This disease is typically a process of progressive transmural intestinal inflammation. As a result, a deep ulcer is formed, leading to perforation. Free perforation of the small bowel is rare in Crohn’s disease. It must penetrate the full thickness of the bowel in order for it to be perforated. The incidence of this complication is 1-2% in all cases of Crohn’s disease [5, 13]. In addition, Crohn’s disease involves terminal ileum in 76.8% of patients. It also involves the colon . In our study, perforation sites within 50 cm of the IC valve were present whenever there was small intestinal perforation due to Crohn’s disease, consistent with previous studies.
Perforation by a tuberculous ulcer is also rare. Tuberculous ulcers in the small intestine might grow slowly to allow proper fibrous tissue to form on the base of the ulcer. Therefore, stricture formation is a common complication . About 36-90% of all cases of abdominal tuberculosis involve the ileocecal junction and/or jejunum and ileum [16, 17]. In our study on perforations of the small intestine caused by tuberculosis, the perforation site was located in the upper jejunum, 25 cm below the Treitz ligament.
Cytomegalovirus (CMV) is a member of the herpes virus group which also includes herpes simplex, Epstein–Barr, and varicella zoster. CMV infection is usually acquired during the neonatal period. It can present subclinical symptoms. However, if the patient is in a state of immune deprivation, CMV infection can become serious[18, 19]. Gastrointestinal tract CMV disease is an erosive or ulcerative process that can occur anywhere from the esophagus to the rectum . The colon and esophagus are commonly involved sites whereas involvement of the small intestine is relatively rare. However, in this study, some patients had small bowel perforation due to CMV involvement in the upper jejunum.
The definitive cause of the ulcer and simple inflammation in the 30 small bowel intestinal perforation patients included in this study is unknown. It might be acute ischemic change of the ileum caused by general deterioration of the patient or occurrence of stercoral ulcer due to fecal impaction. It could also be due to NSAID use. However, it is almost impossible to prove a clear cause-and-effect relationship given preoperative imaging, visualization at the time of surgery, and postoperative pathology results.
It has been reported that NSAIDs are associated with a wide range of intestinal pathological changes, including ulcer and stenosis formation[4, 21]. Although we could not conclude that ileal perforation resulted from the use of NSAIDs, 40% of patients in this study had a history of continued use of NSAIDs. In our study, univariate analysis showed that death was significantly more frequent for patients who used NSAIDs than for those who did not, with odds ratio of 8.0 and p < 0.039. Thus, the use of NSAIDs should be considered as a risk factor for ileal perforation.
After surgery with ileal perforation, two past medical histories, ICU care after surgery, and IV inotropes were also found to be factors significantly associated with mortality in univariate analysis. Multivariate analysis was performed by collecting factors with p values less than 0.1 in univariate analysis. Results showed that having more than two underlying disease (odds ratio: 22.1) was the only significant factor associated with mortality.
In addition, the probability of finding free air in patients with ileal perforation on simple x-rays was 30% in this study. If perforation occurs with inflammation of the small intestine, the perforation site might be covered by fibrin, omentum, adjacent small intestine, and large intestine loops due to decreased intestinal motility. Therefore, in preoperative diagnosis, a simple x-ray has limited contribution and accuracy. Imaging with computed tomography is a better diagnostic method. It is not uncommon for CT to show a definite perforation site[22, 23]. However, most cases are accompanied by wall thickening of the ileum, occasionally with fecal impaction or ileal-wall ischemic change. If there are imaging or laboratory results as described above, ileal perforation should be suspected. Diagnostic laparotomy should be performed if necessary.
The best type of surgery will depend on the time of onset, degree of peritonitis, general physical condition, and lesion of the small bowel. The following types of surgery are common: primary repair, resection and anastomosis, right hemicolectomy when terminal ileal peroration is severe, and stoma formation if needed. General conditions of our patients were almost all poor and peritonitis was severe when they came to the hospital. Hence, the rate of laparoscopic surgery was low. Most cases were converted to open surgery after laparoscopy or open only.
This study has some limitations. First, our study sample was small. Collection of ileal ulcer perforation cases by literature review or collecting cases for a longer period may be helpful to address this limitation. Second, there was no comparison between ileal perforations due to typhoid enteritis, tuberculosis, and CMV infection known to be common in developing countries. Due to geographical characteristics of the Republic of Korea, the limited patient population did not have a comparable ileal perforation resulting from typhoid enteritis or tuberculosis. Therefore, it is necessary to compare these indirectly by carrying out meta-analysis in the future.
Ileal perforation due to simple inflammation or ulcer is rare. Causes underlying nonspecific small bowel ulcer perforation remain obscure. Most of our patients were older than 70 years with an underlying disease. They did not have good overall clinical parameters or laboratory findings. Thus, they had high rates of morbidity and mortality. Patients with at least two underlying disease and those who had used NSAIDs had higher mortality rate. Simple x-ray imaging by itself often cannot provide a good diagnosis before surgery. However, almost all cases of ileal perforation can be predicted by an abdominal CT scan. Besides, recent advances in laparoscopy techniques have replaced many open surgeries with laparoscopic surgeries. However, most patients are still undergoing open surgery because of severe ileus, bowel edema, and severe intraabdominal contamination. Further studies are needed to understand the mechanism of ileal perforation with unexplained ulcer or simple inflammation.
This study was supported by a grant (NRF-2015R1C1A1A01054857) of the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning.
Conflict of Interest The authors declare that they have no conflict of interest.
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