Efficacy and timing of gastrografin administration after ileus tube insertion in patients with adhesive small bowel obstruction.

BACKGROUND AND STUDY AIMS
Gastrografin administration (GA) is performed for adhesive small bowel obstruction (ASBO) in cases when decompression therapy using an ileus tube fails to relieve the obstruction. This study evaluated the efficacy of GA and optimized its timing after ileus tube insertion.


PATIENTS AND METHODS
In this retrospective study, we evaluated data from patients with ASBO admitted between January 2014 and August 2018 and included patients who underwent ileus tube intubation and GA. The patients were classified as those treated with GA within 48 h after admission (early GA [EGA]) and those treated later with GA (delayed GA [DGA]). Propensity score matching was performed to compensate for differences between the groups. Short-term outcomes were compared between the two groups.


RESULTS
We included 67 and 80 patients in the EGA and DGA groups, respectively, and 55 pairs with similar background characteristics were matched. The rates of successful conservative management were 87.3% (48/55) in the EGA group, 96.4% (53/55) in the DGA group, and 91.8% (101/110) in the entire sample. The median period of ileus tube insertion in the DGA group was significantly lower than that in the EGA group, whereas other outcomes did not significantly differ between the groups. Aspiration pneumonia occurred in one patient in the EGA group.


CONCLUSIONS
GA with an ileus tube achieved a high rate of successful conservative management. Follow-up using decompression with an ileus tube for at least 48 h after admission is recommended in patients with ASBO.

administration with ileus tube achieved a high rate of successful conservative management. Follow-up by decompression with ileus tube for at least 48 h after admission is required in patients with ASBO, which may avoid unnecessary gastrografin administration and consequently reduce the total cost of treatment.

Background
Acute small bowel obstruction is usually associated with postoperative adhesion. Patients with clinical evidence of adhesive small bowel obstruction (ASBO), except those with suspected strangulation, have been treated conservatively [1]. Gastrointestinal decompression using an ileus tube or a nasogastric tube is considered to be an effective treatment in such patients [2]. A previous randomized controlled trial showed that the relief of clinical symptoms and improvement in the findings of abdominal radiography were quicker with an ileus tube than with a nasogastric tube [3]. Therefore, gastrointestinal decompression using an ileus tube is the first treatment choice in patients with ASBO at our hospital. Ileus tube insertion is usually performed on the first day of hospital admission in these patients.
However, we sometimes experience failure in relieving obstruction with only gastrointestinal decompression using an ileus tube. Surgery is considered in these patients, but this approach might have high burden among patients. If gastrointestinal decompression fails to relieve obstruction, gastrografin is often administered through the ileus tube [4]. Gastrografin is a hyperosmolar water-soluble contrast medium; therefore, the status of small bowel obstruction can be evaluated with gastrografin administration.
The ileus tube can be inserted deeper because gastrografin administration is usually performed under continuous radiography. Furthermore, gastrografin administration has been suggested to have a therapeutic effect, which was reported to reduce the need for surgery in some previous reports [4][5][6]. In addition to gastrointestinal decompression 4 using an ileus tube, gastrografin administration could be effective for treatment when conservative therapy fails [4]. Therefore, we usually administer gastrografin via the ileus tube if the obstruction does not improve over 12-24 h after ileus tube intubation.
However, the evidence of gastrografin administration as a treatment for ASBO is insufficient. Furthermore, the appropriate timing of gastrografin administration is unknown. Gastrografin administration at an early stage might be associated with earlier improvement compared with insufflation at a later stage or no insufflation. In contrast, gastrografin administration at an early stage might be considered as excessive treatment because some patients might show relief of obstruction with only ileus tube intubation. Therefore, the present study aimed to evaluate therapeutic outcomes of gastrografin administration at an early stage within 48 h after admission, with a propensity-score matching analysis to compensate for the confounding bias [7,8].

Patients and study approval
This retrospective study used the data of patients older than 18 years with acute small bowel obstruction admitted to the Division of Gastroenterology, Department of Internal Medicine, Nihon University School of Medicine between January 2014 and August 2018.
The inclusion criteria were as follows: (1) presence of clinical symptoms and physical signs associated with acute small bowel obstruction such as abdominal pain, distention, nausea, and vomiting without stool production; (2) diagnosis of ASBO on radiography with computed tomography (CT), which was confirmed by no less than two clinicians or radiologists (Figure 1a, b); and (3) admission to the Department of Gastroenterology at our hospital within one day after symptom onset. The exclusion criteria were as follows: (1) emergency surgery for suspected strangulation; (2) large bowel obstruction, cancer peritonitis, obstructed abdominal wall, groin hernia, active inflammatory bowel disease 5 including suspected Crohn's disease; (3) early postoperative small bowel obstruction within 4 weeks after surgery; (4) successful treatment without any decompression therapy; (5) successful treatment using a nasogastric tube; and (6) successful treatment using an ileus tube without gastrografin administration within 24 h after admission. If patients had two or more admissions during the study period, the first admission was considered. Patients were classified into the following two groups: (1) those treated with gastrografin administration within 48 h after admission (early gastrografin administration group; EGA group) and (2) those treated without gastrografin administration within 48 h after admission (nonearly gastrografin administration group; NEGA group). Some patients were treated with gastrografin administration after 48 h following admission and others were treated without gastrografin administration during the entire hospital stay.

Ileus tube insertion and gastrografin administration
All enrolled patients underwent gastrointestinal decompression within 24 h after admission. The CLYNY single or double-balloon type tube (Create Medic, Tokyo, Japan) was used as an ileus tube for decompression of the gastrointestinal tract. The length and outer diameter were 300 cm and 5.3 mm (16 Fr), respectively. The ileus tube was inserted using endoscopy and/or continuous radiography with a guidewire (350 cm or 500 cm in length and 1.32 mm in diameter). In the endoscopic insertion method, the guidewire was inserted into the duodenum through the main channel of a trans-nasal ultrathin endoscope (GIF-XP260N; Olympus, Tokyo, Japan). After removal of the endoscope, the ileus tube was inserted through the guidewire, reaching at least the upper jejunum ( Figure 2). A small amount of gastrografin was used to obtain contrast images of the small intestinal tract during ileus tube intubation. Patients who failed to insert ileus tube were switched to the treatment with nasogastric tube. Such patients were excluded from this study. After insertion, gastrointestinal decompression was performed via the ileus tube, without any 6 oral intake. Gastrografin was administered if clinical remission could not be achieved; the ileus tube could not be removed because no clinical improvement was identified, which was considered as the disappearance of abdominal symptoms with stool production.
Administration was preformed through the ileus tube ( Figure 3). The amount of gastrografin at one administration was 150 ml. If possible, the ileus tube was advanced to the anal side. It was then clamped for 1-2 h after gastrografin administration.
Gastrografin administration was sometimes repeated when improvement was not achieved over 24 h after the previous administration. In the EGA group, the first gastrografin administration was performed within 24-48 h after hospital admission. In the NEGA group, decompression was continued using an ileus tube without gastrografin administration for at least 48 h after admission. If clinical improvement was not achieved for over 48 h, gastrografin administration was considered, as in the EGA group.

Outcome measures
The aim of decompression therapy or gastrografin administration was clinical remission without surgery due to ASBO. Therefore, the study outcomes were the rate of successful conservative management without surgery, the period until the first stool, the period of ileus tube intubation, and the total period of hospital admission. Clinical improvement was defined as disappearance of abdominal symptoms with stool production. After confirming clinical improvement, the ileus tube was clamped and then drinking or liquid food was 7 started. Thereafter, the ileus tube was removed after confirming the absence of symptom recurrence over 24 h. Clinical remission was considered if the ileus tube could be removed. Discharge criterion was the achievement of remaining clinical improvement with taking soft or normal food over 48 h after tube removal. In contrast, patients eventually underwent surgery if clinical improvement was not achieved with decompression therapy and gastrografin administration during admission. Patients who showed no clinical improvement in the initial 48 h after admission were consulted by surgeons. Surgery was finally performed if the clinical symptoms worsened or strangulation was suspected. If allergic reaction, aspiration pneumonia, and renal failure occurred after gastrografin administration, they were considered as adverse events related to gastrografin administration [4,5,9].

Statistical analysis
The sample size was calculated based on the expected rate of successful conservative management, which was the primary outcome. We estimated 70% in the NEGA group according to the previous reports. We hypothesized that an additional effect of 20% in the EGA group constituted a clinically relevant improvement of EGA over NEGA. A required sample size of 98 patients was then calculated considering a 2-sided α error of 0.05 and β error of 0.2. There were confounding biases between the two study groups, as this was a nonrandomized study. Thus, propensity-score matching analysis, which has been used to compensate for confounding factors, was adopted in this study [10][11][12]. Logistic regression of factors, including background characteristics, and propensity score were calculated.

Background characteristics before matching
A total of 169 patients were treated using ileus tube insertion as first-line therapy in this study. Of these, 17 patients immediately achieved relief of obstruction within 24 h after admission. Therefore, 152 patients were included in this study. Flowchart of patient enrollment is shown in Figure 4. The background characteristics of the enrolled patients are presented in Table 1 time was 37 (IQR, 29.4-46.5) min. There were no significant differences in the factors between the two groups.
One patient, a 79-year-old female in the EGA group experienced fever on the next day after gastrografin administration. She was diagnosed with aspiration pneumonia based on X-ray and blood test results. She was treated with antibiotic therapy. No aspiration pneumonia occurred in the NEGA group. In addition, no other adverse events occurred in both groups.

Propensity-score matching and matching factors between the study groups
Propensity-score matching was performed, and 55 pairs were obtained in this study. The C-statistic was estimated to be 0.64, indicating good predictive power. The matching factors after propensity-score matching are shown in Table 3. No factor was significantly different between the two groups. In addition, all absolute standardized difference ranges were within 1.96√2/n, which indicated that the characteristics were well balanced.

Study outcomes after propensity-score matching
Therapeutic outcomes after propensity-score matching are presented in Table 4. The rates of successful conservative management without surgery were 89.1% (49/55) in the matched EGA group and 94.5% (52/55) in the matched NEGA group, and there was no significant difference between the groups (P = 0.49). In the matched NEGA group, 5.5%

Discussion
This was the first study to evaluate the efficacy of early gastrografin administration after ileus tube insertion. The present study found that gastrografin administration with gastrointestinal decompression by ileus tube achieved quite a high rate of successful conservative management without surgery in patients with ASBO. However, early gastrografin administration was not superior to nonearly gastrografin administration with regard to the improvement in clinical outcomes among patients with ASBO.
With regard to the treatment of acute small bowel obstruction, the most important factor is the exclusion of bowel strangulation, which requires immediate surgery [4], and the mortality rate in such patients has been reported to be over 30% when the period from onset to surgery is over 36 h. Thus, overlooking strangulation can result in a very serious situation. Enhanced CT is useful to assess the blood flow in the ileum. Emergency surgery was performed in 37 patients with acute small bowel obstruction at our hospital during study period; 33 patients were suspected of strangulation and 4 patients were at the discretion of the surgeons. Strangulation was observed in 16 patients during surgery. Gastrografin reduces the edema of the gastrointestinal wall thorough absorption of water owing to its high osmotic pressure. Its therapeutic efficacy for ASBO was expected when conservative therapy using an ileus tube failed. Two recent meta-analyses have reported the therapeutic efficacy of gastrografin administration [6,19]. One meta-analysis suggested the efficacy of gastrografin administration in reducing the need of surgery in patients with ASBO as well as predicting the need of surgery. While, another meta-analysis showed that gastrografin administration could not reduce the need of surgery. Therefore, its efficacy was controversial according to the previous meta-analysis. In this study, 147 of the 152 included patients underwent gastrografin administration before matching.
Although 11 patients finally underwent surgery because of conservative therapy failure, successful conservative management was achieved in 141 patients (92.8%). Therefore, gastrografin administration with the gastrointestinal decompression by ileus tube contributed to a low rate of surgery. Furthermore, if 17 excluded patients who had successful treatment using an ileus tube alone without gastrografin administration within 24 h after admission were added to the included patients in this study, the rate of successful conservative management without surgery increased up to 93.5% (158/169).
Previous studies reported that the success rate with conservative management using an ileus tube was 74%-81.1% [16,20]. The success rate in the present study was higher than that in these previous studies, and this might be because of the increased efficacy with the addition of gastrografin administration.
We hypothesized that gastrografin administration at an early stage might contribute to better outcomes of conservative therapy for small bowel obstruction. However, in this study, the final surgical rate did not differ between the EGA and NEGA groups. The period until the first stool and total period of hospital admission were not significantly different between the two groups. In contrast, the period of ileus tube intubation was significantly longer in the EGA group than in the NEGA group. Furthermore, 5.5% (3/55) of patients in the NEGA group after matching (5.9%, 5/85 before matching) were successfully treated without gastrografin administration. Therefore, we could not confirm the superiority of early gastrografin administration within 48 h after admission. On the contrary, early gastrografin administration, the opportunity to relieve ileus without gastrografin administration might be missed. The results suggest that gastrografin administration might not be as important as gastrointestinal decompression in the early stage of small 13 bowel obstruction. Gastrografin has a high osmolarity (1900 mOsm/l), and it induces water movement from the gastrointestinal wall to the lumen. Although gastrografin administration reduces edema, it increases the amount of fluid in the lumen, which might reduce the efficacy of decompression by an ileus tube. Gastrografin administration might be performed after sufficient decompression by an ileus tube, which might contribute to a reduction in the total cost, including the cost of materials and staff for gastrografin administration.
With regard to the adverse events, aspiration pneumonia occurred in one patient of the EGA group. Gastrografin might have been vomited and aspirated as a result of administration without relieve of small bowel obstruction, although gastrografin could assist in releasing its obstruction. This patient was treated with conservative therapy, and no other patients showed adverse events. Considering the low rate of adverse events in this study, gastrografin administration through the ileus tube was considered as a safe treatment for patients with ASBO.
During the study period, overall, 48 patients underwent surgery, and 37 of these patients underwent surgery without conservative therapy mainly because strangulation was suspected at the initial diagnosis. The remaining 11 patients were included in this study and underwent surgery because consecutive treatment using ileus tube did not achieve clinical remission. Of these 11 patients, 9 only required adhesion dissection and 2 required not only adhesion dissection but also partial small intestine resection owing to strangulation. The average (median) period of conservative therapy was 5 (8.9) days. Only one patient showed relapse of acute small bowel obstruction after surgery, but the obstruction was relieved with conservative therapy. Other patients were followed-up without recurrence of small bowel obstruction. Surgical treatment should be considered in patients who do not achieve clinical remission with only conservative therapy, including 14 gastrointestinal decompression by an ileus tube and gastrografin administration.
The present study has some limitations. First, this was a retrospective study without randomization. Therefore, there might have been bias with regard to the selection of the treatment strategy. There was a possibility that early gastrografin administration was conducted for patients with severe condition. To reduce this bias, propensity-score matching was performed, and it was found that the treatment outcomes did not differ between before and after matching. Second, two types of ileus tubes were used in this study. One has only one balloon attached to the edge to the tube sheath, whereas the other has two balloons. Thus, the efficacy of gastrointestinal decompression might differ between the two types of tubes, and such a difference might affect the treatment outcomes. Third, the length of insertion and the amount of output from ileus tube were not evaluated in this study. These factors might affect the treatment outcomes. Fourth, patients with ASBO just after no clinical improvement in the initial 48 h after admission was consulted by surgeons and surgery was considered in this study. This strategy was similar to the previous studies [4,9]. However, a recent study suggested a significant proportion of small bowel obstructions require >48 h to resolve after gastrografin administration [21]. Although some patients continued to take conservative treatment before surgery, others underwent surgery soon after their consultation with surgeons.
Continuation of conservative management for >48 h might have helped avoid surgery. The efficacy of gastrografin administration might not have been fully evaluated. Fifth, we aimed to evaluate the efficacy of adding gastrografin administration with an ileus tube and its appropriate timing for patients who did not have successful treatment using an ileus tube. Therefore, we excluded those patients who had successful treatment using ileus tube without gastrografin administration within 24 h after admission. As a result of exclusion, we might have underestimated the rate of successful conservative management 15 especially for the NEGA group. We additionally showed the rate of successful conservative management for all patients adding excluded patients. The direct comparison of the treatment outcomes of included patients with those of other study should be taken care of. Sixth, we could not evaluate the presence of the contrast agent in the colon after gastrografin administration because this study was a retrospective one without a definite protocol for evaluation. It is a good prediction marker for the need of surgery in patients with ASBO. Therefore, a prospective randomized controlled trial should be performed in the future to clarify the efficacy and the most appropriate timing of gastrografin administration after ileus tube insertion.

Conclusions
Conservative approaches, including gastrointestinal decompression using an ileus tube and reduction of edema of the gastrointestinal wall through gastrografin administration, can help relieve acute small bowel obstruction without strangulation, which might contribute to a high rate of successful conservative management without surgery.

Consent for publication: Not applicable
Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.    Flowchart of patient enrollment in this study