Surg Endosc DOI 10.1007/s00464-014-3463-4
and Other Interventional Techniques
The efficacy of single-dose postoperative intravenous dexamethasone for pain relief after endoscopic submucosal dissection for gastric neoplasm Hye Won Lee • Hyuk Lee • Hyunsoo Chung • Jun Chul Park • Sung Kwan Shin Sang Kil Lee • Young Chan Lee • Jung Hwa Hong • Dong Wook Kim
•
Received: 1 November 2013 / Accepted: 24 January 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Endoscopic submucosal dissection (ESD) is the gold standard technique for en bloc resection of large superficial tumors in the upper and lower gastrointestinal tract. Little is known about the management of epigastric pain after ESD of gastric neoplasms. This study investigated the utility and safety of single-dose, perioperative, intravenous dexamethasone for epigastric pain relief following ESD. Methods The efficacy of intravenous dexamethasone 0.15 mg/kg (DEXA group) compared with saline-only placebo (placebo) for epigastric pain after ESD of early gastric neoplasms was assessed in a double-blinded, placebo-controlled trial. Patients completed a questionnaire about present pain intensity (PPI) and short-form McGill pain (SF-MP) categories for immediate and 6-, 12-, and 24-h postoperative periods. The primary outcome variable was PPI at 6 h following ESD. Secondary outcome variables included pain medication, SF-MP scores, complications, second-look endoscopic findings, and length of stay. Results A total of 36 patients participated in the study. The mean 6-h PPI value was lower (p \ 0.001) in the H. W. Lee H. Lee (&) H. Chung J. C. Park S. K. Shin S. K. Lee Y. C. Lee Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120–752, Korea e-mail: [email protected] H. Lee H. Chung J. C. Park S. K. Shin S. K. Lee Y. C. Lee Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea J. H. Hong D. W. Kim Department of Research Affairs, Biostatics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea
DEXA group (1.61 ± 0.21) than in the placebo group (2.66 ± 0.19). The total 6-h SF-MP score, especially the sensory domain, was higher (p = 0.054) in the placebo group (11.56 ± 0.75) than in the DEXA group (8.89 ± 0.75). Tramadol for epigastric pain relief was more frequent (p = 0.026) in the placebo group (44.4 %) than in the DEXA group (11.1 %). No differences were noted between groups in length of stay or complications, including acute or delayed bleeding. The distribution of artificial ulcer patterns at 48-h post-ESD as determined by second-look endoscopy was similar in both groups. Conclusion Single-dose perioperative intravenous dexamethasone after ESD effectively relieved epigastric pain 6 h postoperatively. Keywords Endoscopic submucosal dissection Early gastric cancer Pain relief Intravenous dexamethasone Present pain intensity Endoscopic submucosal dissection (ESD) is an effective treatment for early gastric cancer or premalignant lesions in the stomach [1]. ESD enables en bloc resection of gastrointestinal neoplasms and increases the rates of histologically complete resections. ESD also reduces local recurrence rates compared with endoscopic mucosal resection (EMR) [2]. Despite these advantages, ESD is thought to be technically more difficult and to induce various complications. Wellknown ESD-related complications include perforation and postoperative bleeding or stricture [3–5]. Many studies have investigated the major complications of ESD and their risk factors [6–8]. In addition to major ESD-related complications, minor adverse events after ESD are also commonly noticed. Pain is one of these frequently noticed minor ESDrelated complications, is the main reason for prolongation of
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the hospital stay, and is related to patients’ compliance; however, there is a tendency to neglect or underestimate post-ESD pain. The causes of pain associated with ESD or gastric polypectomy are thought to be associated with transmural burn or transmural air leak [9–11]. There are only a few studies on management strategies for pain after ESD. However, how to control localized pain following ESD is emerging as a new medical interest. Some studies have tried to control localized pain during and after ESD using local lidocaine or a transdermal fentanyl patch [12, 13]. Glucocorticoids are used to reduce inflammation and tissue damage in various clinical settings, including inflammatory disease, rheumatic disease, etc. [14]. Recently, the efficacy of glucocorticoids for reducing pain after surgery has been investigated [15, 16]. Glucocorticoids are thought to inhibit collagen deposition and fibrosis locally, thereby reducing scar-tissue formation. In particular, systemic steroids easily achieve a continuous effect with stable serum concentrations. Based on previous studies [14–17], we proposed that intravenous dexamethasone could be helpful in relieving pain following ESD if the pain was partially associated with acute inflammation. In a meta-analysis of about 2,500 patients who received surgery, dexamethasone at doses of[0.1 mg/kg effectively reduced postoperative pain [16]. The results of many studies have shown that intravenous dexamethasone reduces postoperative acute pain after laparoscopic cholecystectomy, tonsillectomy, or thyroidectomy [14–16]. There have been no previous trials on the use of dexamethasone specifically for pain control following ESD. Thus, the purpose of this study was to assess the efficacy of single-dose postoperative intravenous dexamethasone for pain relief after ESD.
Materials and methods Study participants Patients who needed ESD for a diagnosis of early gastric neoplasm and who were admitted from October 2012 to March 2013 at Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, were considered as participants in this double-blind, placebo-controlled study. Inclusion criteria were (i) 20 years of age or older, (ii) pathologically diagnosed gastric adenoma or cancer that was eligible for ESD, and (iii) written informed consent given by the patient or a responsible family member. Exclusion criteria were (i) administration of a painkiller on a regular basis or within 48 h of enrollment, (ii) confirmation of any other disease that could induce epigastric pain, such as peptic ulcer disease and gastroesophageal reflux disease, (iii) presence of multiple gastric lesions for
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ESD, (iv) history of gastric surgery at enrollment, and (v) presence of a severe underlying disease, including infection, cardiopulmonary disease, and diabetes. The standard criteria used to determine a patient’s eligibility for ESD included (i) histological diagnosis of a well- or moderately differentiated adenocarcinoma or dysplasia (adenoma), (ii) tumor invasion of the mucosa or minute submucosal layers defined by endoscopic ultrasonography, (iii) tumor size of B3 cm if minute submucosal invasion or a tumor with ulceration was suspected, and (iv) a tumor of any size if it was a differentiated adenocarcinoma without ulceration or submucosal invasion. Fifty consecutive patients with the aforementioned characteristics were screened to determine eligibility for this study. Ten of these patients were excluded because they did not provide informed consent (N = 3), had multiple lesions (N = 3), or were taking a nonsteroidal anti-inflammatory drug (NSAID) (N = 4). The remaining 40 patients were randomized to receive intravenous dexamethasone (0.15 mg/ kg) immediately after ESD (DEXA group) or saline only (placebo group). This study was approved by the Independent Institutional Review Board of Severance Hospital and conformed to the ethical guidelines of the 1975 Helsinki Declaration. Study design Patients were enrolled in outpatient settings after evaluation of appropriate ESD indications. A single study coordinator performed a randomization process, using a table of random numbers, to randomly allocate the patients to receive either intravenous dexamethasone (0.15 mg/kg) or normal saline as placebo immediately after ESD (patients with an odd number were assigned into the DEXA group, and patients with an even number were assigned into the placebo group). The syringes for dexamethasone and placebo were completely covered with a paper sticker to mask treatment assignment. The operator and assisting nurse were both blinded to the study. To prevent bleeding and other complications, patients routinely received an intravenous injection of the proton pump inhibitor pantoprazole [40 mg twice daily (bid)] on the day of the ESD and on the following day. On the third day following ESD, a medication regimen was started for all patients that consisted of oral lansoprazole (40 mg) once a day and sucralfate suspension three times a day for a period of 28 days. Standardization of ESD A single experienced operator (HL) performed the ESD according to a standard ESD procedure. Sedation was accomplished with either midazolam (0.05–1 mg/kg) or
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propofol (2 mg/kg/h), and electrocardiography, heart rate, oxygen saturation, and blood pressure were closely monitored. Each patient received oxygen continuously via a nasal cannula. The ESD procedure consisted of marking, incision, and submucosal dissection with hemostasis. After the target lesion was identified, marking dots were made at a circumference of about 5 mm lateral to the margin of the lesion, using a needle knife (KD-1L-1; Olympus Optical, Tokyo, Japan). After marking, submucosal injections of normal saline solution and an epinephrine mixture (0.1 % epinephrine 1 cc plus sodium chloride 9 cc) were administered to lift the lesion. An initial incision in the mucosa was then made with a needle knife, and a circumferential mucosal incision was made outside the marking dots to separate the lesion from the surrounding non-neoplastic mucosa. Complete en bloc resection was defined as negative tumor from the resection margin. The size of the ulcer that developed after ESD was measured by multiplying the maximal diameter of the specimen and the tumor size equally [18]. The degree of bleeding (minimal, moderate, severe) and the degree of fibrosis (minimal, moderate, severe) were evaluated in all patients during the procedure. A second-look endoscopy was performed between the day of and 2 days after the ESD procedure to check for the presence of bleeding and the status of any iatrogenic ulcer. The second-look endoscopic finding was categorized into six patterns based on Forrest’s classification (i.e., spurting bleeding, oozing bleeding, non-bleeding visible vessel, adherent clot, black spot, and adherent clot) [19]. Evaluation of primary and secondary outcomes Postoperative pain was monitored during hospitalization. To evaluate abdominal pain after ESD, patients completed a questionnaire about their degree of abdominal pain using the present pain intensity (PPI) and short-form McGill pain (SF-MP) score during the immediate postoperative period and 6, 12, and 24 h after surgery on the day of the ESD. The PPI is based on a scale of 0–5, in which 0 = no pain and 5 = pain as bad as it could be [20]. The 15-adjective checklist for the SF-MP score includes 11 sensory and four affective dimensions of pain. Each dimension of pain is rated on a four-point intensity scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). The SF-MP score also includes one item for PPI and one item for a visual analog scale from 0 to 10. Total SF-MP scores range from 0 to 60, with a higher score indicating worse pain [20, 21]. A trained research assistant recorded the pain scores. The primary outcome of this study was PPI measured at 6 h after ESD. This parameter was chosen because maximum pain was observed in patients at 6 h after ESD in our pilot study. The secondary outcomes included the need for an additional painkiller, SF-MG pain score, the presence of
complications, a second-look endoscopic finding, and the length of hospital stay. If a patient needed additional painkillers due to severe pain after ESD, tramadol HCl (TridolÒ, 50 mg/vial, Yuhan, Korea) was given once intramuscularly. Patients who suffered from sustained pain after the first tramadol injection were given one more injection, regardless of time. Data collection also included age, sex, body mass index (BMI), the presence of Helicobacter pylori infection, tumor size, tumor location, degree of bleeding, and degree of fibrosis. These variables were compared between the DEXA and placebo groups. Statistical analysis The sample size was calculated on the basis of results of a two-arm pilot study that was performed with ten patients in each group and that showed 6-h PPI scores of 1.4 [standard deviation (SD) 1.8] for the DEXA group and 3.3 (SD 2.2) for the placebo group. Based on a power of 80 % and a two-tailed alpha of 0.05, the sample size required for the present study was determined to be 18 per group, for a total of 36 patients. The final sample size required was 40 patients to accommodate a dropout rate of 10 %. The data for all variables with normal distributions were expressed as mean ± SD. Comparisons between variables were analyzed by the t test. Categorical variables were expressed as percentages and compared using the Chisquared test or Fisher’s exact test. Binary logistic regression tests were used for multivariate analysis. Characteristics with a univariate significance of p \ 0.05 were candidates for multivariate analysis. Repeated measured variables, such as the total SF-MP score, sensory SF-MP score, affective SF-MP score, and PPI, were analyzed using a linear mixed model (LMM) and generalized estimating equations (GEE) for numerical and categorical measures, respectively, with fixed effect and random effect. When the interaction of group, time, and group by time of the variables showed statistical significance, post hoc analysis was carried out with Bonferroni correction for the adjustment for multiple comparisons. All probabilities were two-tailed, and the level of statistical significance was defined as p \ 0.05. Statistical analysis was performed using SPSS software (SPSS version 20.0, IMB, Armonk, NY, USA).
Results Patients and tumor characteristics A total of 20 patients were randomized to receive intravenous dexamethasone and 20 patients received placebo. Among these 40 patients, two patients from the DEXA group were eliminated because of failure to complete the
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Surg Endosc Table 1 Baseline characteristics Variable
Dexamethasone (N = 20, %)
Placebo (N = 20, %)
Age
54.20 ± 9.34
53.90 ± 7.33
Male gender
13 (65)
10 (50)
BMI
22.25 ± 2.83
22.10 ± 1.80
0.150
H. pylori infection
3 (15)
6 (30)
0.256
Size (mm)
914 ± 269.30
1063 ± 356.90
0.144
Upper
2
3
Middle
7
8
Lower
11
9
40.35 ± 10.69
36.80 ± 12.54
Location
Procedure time (min) Fig. 1 Recruitment algorithm. A total of 20 patients were randomized to receive intravenous dexamethasone and 20 patients received a placebo. Four patients dropped out, leaving a total of 36 patients for the final statistical analysis. NSAID non-steroidal anti-inflammatory drug
questionnaire and two patients from the placebo group were eliminated because of an ESD-related complication (N = 1) and the presence of unexpected multiple lesions (N = 1). A total of 36 patients were, therefore, enrolled in the study (Fig. 1). There were no significant differences between the two groups in baseline characteristics (Table 1). All the patients underwent complete and en bloc resection. Primary and secondary efficacy variables Analysis by LMM showed (Fig. 2) a significant difference (p \ 0.001) between the mean value of 6-h PPI in the DEXA group (1.67 ± 1.03) and that in the placebo group (2.67 ± 1.03),. The 12-h PPI was also significantly lower (p = 0.011) in the DEXA group (1.56 ± 0.78) than in the placebo group (2.11 ± 0.83). After post hoc analysis with Bonferroni correction, PPI values were significantly lower in the DEXA group at both 6 and 12 h. However, there were no differences between the two groups in immediate PPI and delayed PPI (24-h PPI) after ESD. We also identified a dramatic reduction in the total SFMP score, which was significantly lower in the DEXA group than in the placebo group (9.39 ± 2.75 vs. 12.11 ± 4.14, respectively; p = 0.086) (Fig. 3). In particular, the sensory SF-MP score at 6 h after ESD was much lower in the DEXA group than in the placebo group (8.89 ± 2.30 vs. 11.56 ± 3.90, respectively; p = 0.054). In contrast, there was no meaningful difference in the affective SF-MP score, even at 6 h following the ESD procedure. Tramadol, as an extra painkiller, was more frequently used in the placebo group than in the DEXA group (44.4
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0.792
Bleeding 13 (65)
14 (70)
Moderate
5 (25)
4 (20)
2 (10)
2 (10)
Minimal
14
15
Moderate
5
3
Severe
0.341 0.148
Minimal Severe Fibrosis
p value
0.955
1
2
En block resection
20 (100)
18 (90)
Complete resection
20 (100)
20 (100)
Dysplasia LGD
7
9
HGD
5
2
0.147
0.866
EGC
8 (40)
9 (45)
0.451
Differentiated cancer
7 (87.5)
8 (88.9)
0.929
SM invasion
2 (10)
2 (10)
Variables are expressed as median (range) or N (%) BMI body mass index, EGC early gastric cancer, HGD high-grade dysplasia, LGD low-grade dysplasia, SM submucosa
vs. 11.1 %, respectively; p = 0.026). In the DEXA group, two patients (11.1 %) were given tramadol once and 16 patients (88.9 %) were given the painkiller twice. In the placebo group, eight patients (44.4 %) received tramadol once and ten patients (55.6 %) received it twice. A secondlook endoscopy performed on 33 patients (91.7 %) revealed a similar distribution of artificial ulcer patterns. There were no visible non-bleeding vessels noted on second-look endoscopy in DEXA group patients and only one case (5.9 %) in the placebo group patients. There was no evidence of acute or delayed bleeding, which is known as one of the major complications after ESD. The mean hospital stay did not differ between the DEXA and placebo groups (3.89 ± 0.47 vs. 3.78 ± 0.55 days, respectively).
Surg Endosc Table 2 The clinical outcome after ESD
Fig. 2 The trend of PPI scores according to time. The 6- and 12-h PPIs were significantly reduced in the DEXA group compared with the placebo group. DEXA dexamethasone, Group 1 DEXA group, Group 2 placebo group, PPI present pain intensity
Variables
Dexamethasone (N = 18, %)
Placebo (N = 18, %)
p value
En block resection
18 (100)
18 (100)
0.147
Complete resection
18 (100)
18 (100)
Complication
0
0
Additional need of painkiller
2 (11.1)
8 (44.4)
Once
1 (10)
7 (70)
Twice
1 (10)
1 (10)
Second look EGD finding
0.544
Clean base
4 (25.0)
2 (11.8)
Black spot
9 (56.3)
9 (52.9)
Adherent clot
3 (18.8)
5 (29.4)
Non-bleeding visible vessel
0
1 (5.9)
3.89 ± 0.47
3.78 ± 0.55
Length of hospital stay (days)
0.026
0.519
EGD esophagogastroduodenoscopy
procedure time, severity of bleeding, degree of fibrosis, differentiated cancer, and submucosa invasion were included in univariate analyses. Among these factors, postoperative intravenous dexamethasone [odds ratio (OR) 0.127, 95 % confidence interval (CI) 0.027–0.606, p = 0.010) and tumor size (OR 1.005, 95 % CI 1.001–1.008, p = 0.004) were selected as significant factors for lowering the 6-h PPI score after ESD in univariate analysis. Larger tumor size was associated with a higher 6-h PPI score. Multivariate analysis identified postoperative intravenous dexamethasone (OR 0.109, 95 % CI 0.016–0.768, p = 0.026) and tumor size (OR 1.005, 95 % CI 1.001–1.008, p = 0.007) as independent factors of predicting development of pain after ESD. Fig. 3 Trend of the SF-MP score. A Total SF-MP score. The 6-h total SF-MP score was lower in the DEXA group than in the placebo group. B Sensory SF-MP score. The 6-h sensory SF-MP score was much lower in the DEXA group than in the placebo group. Group 1 DEXA group, Group 2 placebo group, SF-MP short-form McGill pain
Laboratory tests on parameters, including hemoglobin and glucose levels, performed the day after ESD, were within normal limits. Multivariate analysis for predictive factors To investigate the factors affecting the 6-h PPI score, we performed univariate and multivariate linear regression analyses (Table 2). Factors including dexamethasone protocol, age, sex, BMI, H. pylori infection, tumor size,
Discussion The results of this study indicate for the first time that an intravenous dexamethasone protocol was effective in managing postoperative pain after ESD for early gastric neoplasm. Well-known major complications of ESD are bleeding (7–15.6 %) and perforation (1.2–4 %) [6]. In addition, there are various minor complications, including abdominal pain for 1–2 days and intermittent fever of unknown origin. Because postoperative pain was detected only during 3–4 days of a hospital stay and was usually self-limited, pain has not been of high interest to doctors. Recently, there have been various efforts to aggressively control pain after ESD. Acute inflammatory response starts immediately after ESD, and this inflammatory process causes severe complications, such as stricture. Several
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Surg Endosc Table 3 The univariate and multivariate analysis Variables
Univariate
Multivariate
OR (95 % CI)
p value
OR (95 % CI)
p value
0.109 (0.016–0.768)
0.026
1.005 (1.001–1.008)
0.007
Dexamethasone
0.127 (0.027–0.606)
0.010
Age
0.998 (0.920–1.082)
0.962
Sex
1.083 (0.279–4.210)
0.908
BMI
1.227 (0.230–6.548)
0.811
Helicobacter pylori infection
0.927 (0.184–4.685)
0.927
Tumor size
1.005 (1.001–1.008)
0.004
Procedure time Severity of bleeding
0.995 (0.935–1.058) 1.172 (0.413–3.323)
0.865 0.766
Fibrosis
1.581 (0.500–5.002)
0.436
Differentiated cancer
2.550 (0.124–50.444)
0.550
SM invasion
0.175 (0.016–1.882)
0.150
BMI body mass index, CI confidence interval, OR odds ratio, SM submucosa
studies suggest that immediate anti-inflammatory treatment might be effective, especially for stricture, by suppressing inflammation at the outset during the initial phase [22, 23]. Steroids are well known as regulating wound healing through anti-inflammatory effects. Based on this effect, some studies have tried to prevent stricture after ESD for esophageal carcinoma by direct intralesional steroid injection [24, 25]. However, the effects of anti-inflammatory treatment on relieving pain are not clear. Even though it is not a critical complication, development of pain after ESD due to various degrees of inflammatory response is very common in the clinical setting. In our previous study of post-ESD electrocoagulation syndrome, we reported that the rate of development of pain after ESD combined with fever was 7 % [9]. The pain that develops after ESD was not somatic pain, but visceral pain. This visceral signal developed via the enteric nervous system. Various attempts to control postoperative pain have been published. For example, two studies for visceral pain control associated with ESD examine local lidocaine injections and transdermal fentanyl patches for pain relief [12, 13]. The pilot study of lidocaine injections shows that fewer patients in the lidocaine treatment group suffered from pain than in the control group [12]. The use of fentanyl patches has also been shown to be effective in controlling postoperative pain after ESD [13]. The transdermal fentanyl patch has the advantage of continuous pain-relief effects. However, these studies of local lidocaine injections and transdermal fentanyl patch deal with the regulation of pain itself and not with preventive management of causes of pain, such as inflammation around a residual ulcer. In the surgery domain, the effects of steroid injection for postoperative pain control are inconsistent, depending on the study. Nevertheless, steroids have been proven to
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provide strong relief for postoperative pain in many studies. In a representative meta-analysis of 2,500 patients, systemic dexamethasone ([0.1 mg/kg) was shown to be effective in reducing not only postoperative pain, but also postoperative opioid consumption for pain control [17]. There are concerns about adverse events with intravenous dexamethasone, such as the risk of infection, delayed wound healing, or an increase in glucose level. However, a previous meta-analysis showed that adverse events related to the use of intravenous steroids were minimal [14]. Our study investigated the effects of intravenous dexamethasone following ESD on pain, as assessed with PPI and SF-MP scores, and on various additional factors associated with post-ESD patient recovery, including the development of complications, second-look endoscopic findings, and length of hospital stay. Our results indicate that there were no serious complications associated with healing of the residual ulcer and no bleeding, infection, or increases in glucose level. Subsequent multivariate analysis identified the size of gastric lesion as well as the intravenous dexamethasone protocol as independent factors of pain development after ESD. The reason that the size of the gastric lesion is an independent factor in pain development is thought to be the repetitive electrical stimuli used during the procedure in cases of larger-sized gastric lesions. Thus, aggressive pain control should be considered for patients undergoing ESD for larger-sized gastric lesions. However, the degree of pain was not associated with the duration of the procedure or with submucosal invasion (Table 3). This study had some limitations. First, the mechanism involved in the pain relief by the intravenous steroids was not clarified in our study. Efforts for analyzing surrogate markers of various forms of pain or inflammation are needed in future studies. Second, the best time and best
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dose for pain relief by steroid injection was not determined in this study. A previous study showed that preoperative administration of dexamethasone was more effective than intraoperative administration [17]. Another study reported that high-dose dexamethasone ([0.2 mg/kg) reduced pain considerably later (24 h after ESD) than an intermediate dose of dexamethasone (0.11–0.2 mg/kg) [16]. Further investigation of the appropriate time and dose for steroid injection is recommended. Also, a randomized control study will be needed in the future to assess the effectiveness and safety of systemic steroids for pain control. Nonetheless, our study is important because it is the first to consider intravenous dexamethasone for the management of pain after gastric ESD. The anti-inflammatory mechanism of systemic steroids had strong effects on relieving pain after ESD. In conclusion, our study showed that intravenous dexamethasone was effective as an aggressive postoperative modality for pain control after ESD for early gastric neoplasm that takes into consideration the pathophysiology of the inflammatory response.
Disclosures Drs. Hye Won Lee, Hyuk Lee, Hyunsoo Chung, Jun Chul Park, Sung Kwan Shin, Sang Kil Lee, Yong Chan Lee, and Ms. Jung Hwa Hong and Mr. Dong Wook Kim have no conflicts of interest or financial ties to disclosure.
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24. Sato H, Inoue H, Kobayashi Y, Maselli R, Santi EG, Hayee B, Igarashi K, Yoshida A, Ikeda H, Onimaru M, Aoyagi Y, Kudo SE (2013) Control of severe strictures after circumferential endoscopic submucosal dissection for esophageal carcinoma: oral steroid therapy with balloon dilation or balloon dilation alone. Gastrointest Endosc 78(2):250–257 25. Deprez PH (2013) Esophageal strictures after extensive endoscopic resection: hope for a better outcome? Gastrointest Endosc 78(2):258–259
and Other Interventional Techniques
The efficacy of single-dose postoperative intravenous dexamethasone for pain relief after endoscopic submucosal dissection for gastric neoplasm Hye Won Lee • Hyuk Lee • Hyunsoo Chung • Jun Chul Park • Sung Kwan Shin Sang Kil Lee • Young Chan Lee • Jung Hwa Hong • Dong Wook Kim
•
Received: 1 November 2013 / Accepted: 24 January 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Endoscopic submucosal dissection (ESD) is the gold standard technique for en bloc resection of large superficial tumors in the upper and lower gastrointestinal tract. Little is known about the management of epigastric pain after ESD of gastric neoplasms. This study investigated the utility and safety of single-dose, perioperative, intravenous dexamethasone for epigastric pain relief following ESD. Methods The efficacy of intravenous dexamethasone 0.15 mg/kg (DEXA group) compared with saline-only placebo (placebo) for epigastric pain after ESD of early gastric neoplasms was assessed in a double-blinded, placebo-controlled trial. Patients completed a questionnaire about present pain intensity (PPI) and short-form McGill pain (SF-MP) categories for immediate and 6-, 12-, and 24-h postoperative periods. The primary outcome variable was PPI at 6 h following ESD. Secondary outcome variables included pain medication, SF-MP scores, complications, second-look endoscopic findings, and length of stay. Results A total of 36 patients participated in the study. The mean 6-h PPI value was lower (p \ 0.001) in the H. W. Lee H. Lee (&) H. Chung J. C. Park S. K. Shin S. K. Lee Y. C. Lee Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120–752, Korea e-mail: [email protected] H. Lee H. Chung J. C. Park S. K. Shin S. K. Lee Y. C. Lee Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea J. H. Hong D. W. Kim Department of Research Affairs, Biostatics Collaboration Unit, Yonsei University College of Medicine, Seoul, Korea
DEXA group (1.61 ± 0.21) than in the placebo group (2.66 ± 0.19). The total 6-h SF-MP score, especially the sensory domain, was higher (p = 0.054) in the placebo group (11.56 ± 0.75) than in the DEXA group (8.89 ± 0.75). Tramadol for epigastric pain relief was more frequent (p = 0.026) in the placebo group (44.4 %) than in the DEXA group (11.1 %). No differences were noted between groups in length of stay or complications, including acute or delayed bleeding. The distribution of artificial ulcer patterns at 48-h post-ESD as determined by second-look endoscopy was similar in both groups. Conclusion Single-dose perioperative intravenous dexamethasone after ESD effectively relieved epigastric pain 6 h postoperatively. Keywords Endoscopic submucosal dissection Early gastric cancer Pain relief Intravenous dexamethasone Present pain intensity Endoscopic submucosal dissection (ESD) is an effective treatment for early gastric cancer or premalignant lesions in the stomach [1]. ESD enables en bloc resection of gastrointestinal neoplasms and increases the rates of histologically complete resections. ESD also reduces local recurrence rates compared with endoscopic mucosal resection (EMR) [2]. Despite these advantages, ESD is thought to be technically more difficult and to induce various complications. Wellknown ESD-related complications include perforation and postoperative bleeding or stricture [3–5]. Many studies have investigated the major complications of ESD and their risk factors [6–8]. In addition to major ESD-related complications, minor adverse events after ESD are also commonly noticed. Pain is one of these frequently noticed minor ESDrelated complications, is the main reason for prolongation of
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the hospital stay, and is related to patients’ compliance; however, there is a tendency to neglect or underestimate post-ESD pain. The causes of pain associated with ESD or gastric polypectomy are thought to be associated with transmural burn or transmural air leak [9–11]. There are only a few studies on management strategies for pain after ESD. However, how to control localized pain following ESD is emerging as a new medical interest. Some studies have tried to control localized pain during and after ESD using local lidocaine or a transdermal fentanyl patch [12, 13]. Glucocorticoids are used to reduce inflammation and tissue damage in various clinical settings, including inflammatory disease, rheumatic disease, etc. [14]. Recently, the efficacy of glucocorticoids for reducing pain after surgery has been investigated [15, 16]. Glucocorticoids are thought to inhibit collagen deposition and fibrosis locally, thereby reducing scar-tissue formation. In particular, systemic steroids easily achieve a continuous effect with stable serum concentrations. Based on previous studies [14–17], we proposed that intravenous dexamethasone could be helpful in relieving pain following ESD if the pain was partially associated with acute inflammation. In a meta-analysis of about 2,500 patients who received surgery, dexamethasone at doses of[0.1 mg/kg effectively reduced postoperative pain [16]. The results of many studies have shown that intravenous dexamethasone reduces postoperative acute pain after laparoscopic cholecystectomy, tonsillectomy, or thyroidectomy [14–16]. There have been no previous trials on the use of dexamethasone specifically for pain control following ESD. Thus, the purpose of this study was to assess the efficacy of single-dose postoperative intravenous dexamethasone for pain relief after ESD.
Materials and methods Study participants Patients who needed ESD for a diagnosis of early gastric neoplasm and who were admitted from October 2012 to March 2013 at Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, were considered as participants in this double-blind, placebo-controlled study. Inclusion criteria were (i) 20 years of age or older, (ii) pathologically diagnosed gastric adenoma or cancer that was eligible for ESD, and (iii) written informed consent given by the patient or a responsible family member. Exclusion criteria were (i) administration of a painkiller on a regular basis or within 48 h of enrollment, (ii) confirmation of any other disease that could induce epigastric pain, such as peptic ulcer disease and gastroesophageal reflux disease, (iii) presence of multiple gastric lesions for
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ESD, (iv) history of gastric surgery at enrollment, and (v) presence of a severe underlying disease, including infection, cardiopulmonary disease, and diabetes. The standard criteria used to determine a patient’s eligibility for ESD included (i) histological diagnosis of a well- or moderately differentiated adenocarcinoma or dysplasia (adenoma), (ii) tumor invasion of the mucosa or minute submucosal layers defined by endoscopic ultrasonography, (iii) tumor size of B3 cm if minute submucosal invasion or a tumor with ulceration was suspected, and (iv) a tumor of any size if it was a differentiated adenocarcinoma without ulceration or submucosal invasion. Fifty consecutive patients with the aforementioned characteristics were screened to determine eligibility for this study. Ten of these patients were excluded because they did not provide informed consent (N = 3), had multiple lesions (N = 3), or were taking a nonsteroidal anti-inflammatory drug (NSAID) (N = 4). The remaining 40 patients were randomized to receive intravenous dexamethasone (0.15 mg/ kg) immediately after ESD (DEXA group) or saline only (placebo group). This study was approved by the Independent Institutional Review Board of Severance Hospital and conformed to the ethical guidelines of the 1975 Helsinki Declaration. Study design Patients were enrolled in outpatient settings after evaluation of appropriate ESD indications. A single study coordinator performed a randomization process, using a table of random numbers, to randomly allocate the patients to receive either intravenous dexamethasone (0.15 mg/kg) or normal saline as placebo immediately after ESD (patients with an odd number were assigned into the DEXA group, and patients with an even number were assigned into the placebo group). The syringes for dexamethasone and placebo were completely covered with a paper sticker to mask treatment assignment. The operator and assisting nurse were both blinded to the study. To prevent bleeding and other complications, patients routinely received an intravenous injection of the proton pump inhibitor pantoprazole [40 mg twice daily (bid)] on the day of the ESD and on the following day. On the third day following ESD, a medication regimen was started for all patients that consisted of oral lansoprazole (40 mg) once a day and sucralfate suspension three times a day for a period of 28 days. Standardization of ESD A single experienced operator (HL) performed the ESD according to a standard ESD procedure. Sedation was accomplished with either midazolam (0.05–1 mg/kg) or
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propofol (2 mg/kg/h), and electrocardiography, heart rate, oxygen saturation, and blood pressure were closely monitored. Each patient received oxygen continuously via a nasal cannula. The ESD procedure consisted of marking, incision, and submucosal dissection with hemostasis. After the target lesion was identified, marking dots were made at a circumference of about 5 mm lateral to the margin of the lesion, using a needle knife (KD-1L-1; Olympus Optical, Tokyo, Japan). After marking, submucosal injections of normal saline solution and an epinephrine mixture (0.1 % epinephrine 1 cc plus sodium chloride 9 cc) were administered to lift the lesion. An initial incision in the mucosa was then made with a needle knife, and a circumferential mucosal incision was made outside the marking dots to separate the lesion from the surrounding non-neoplastic mucosa. Complete en bloc resection was defined as negative tumor from the resection margin. The size of the ulcer that developed after ESD was measured by multiplying the maximal diameter of the specimen and the tumor size equally [18]. The degree of bleeding (minimal, moderate, severe) and the degree of fibrosis (minimal, moderate, severe) were evaluated in all patients during the procedure. A second-look endoscopy was performed between the day of and 2 days after the ESD procedure to check for the presence of bleeding and the status of any iatrogenic ulcer. The second-look endoscopic finding was categorized into six patterns based on Forrest’s classification (i.e., spurting bleeding, oozing bleeding, non-bleeding visible vessel, adherent clot, black spot, and adherent clot) [19]. Evaluation of primary and secondary outcomes Postoperative pain was monitored during hospitalization. To evaluate abdominal pain after ESD, patients completed a questionnaire about their degree of abdominal pain using the present pain intensity (PPI) and short-form McGill pain (SF-MP) score during the immediate postoperative period and 6, 12, and 24 h after surgery on the day of the ESD. The PPI is based on a scale of 0–5, in which 0 = no pain and 5 = pain as bad as it could be [20]. The 15-adjective checklist for the SF-MP score includes 11 sensory and four affective dimensions of pain. Each dimension of pain is rated on a four-point intensity scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). The SF-MP score also includes one item for PPI and one item for a visual analog scale from 0 to 10. Total SF-MP scores range from 0 to 60, with a higher score indicating worse pain [20, 21]. A trained research assistant recorded the pain scores. The primary outcome of this study was PPI measured at 6 h after ESD. This parameter was chosen because maximum pain was observed in patients at 6 h after ESD in our pilot study. The secondary outcomes included the need for an additional painkiller, SF-MG pain score, the presence of
complications, a second-look endoscopic finding, and the length of hospital stay. If a patient needed additional painkillers due to severe pain after ESD, tramadol HCl (TridolÒ, 50 mg/vial, Yuhan, Korea) was given once intramuscularly. Patients who suffered from sustained pain after the first tramadol injection were given one more injection, regardless of time. Data collection also included age, sex, body mass index (BMI), the presence of Helicobacter pylori infection, tumor size, tumor location, degree of bleeding, and degree of fibrosis. These variables were compared between the DEXA and placebo groups. Statistical analysis The sample size was calculated on the basis of results of a two-arm pilot study that was performed with ten patients in each group and that showed 6-h PPI scores of 1.4 [standard deviation (SD) 1.8] for the DEXA group and 3.3 (SD 2.2) for the placebo group. Based on a power of 80 % and a two-tailed alpha of 0.05, the sample size required for the present study was determined to be 18 per group, for a total of 36 patients. The final sample size required was 40 patients to accommodate a dropout rate of 10 %. The data for all variables with normal distributions were expressed as mean ± SD. Comparisons between variables were analyzed by the t test. Categorical variables were expressed as percentages and compared using the Chisquared test or Fisher’s exact test. Binary logistic regression tests were used for multivariate analysis. Characteristics with a univariate significance of p \ 0.05 were candidates for multivariate analysis. Repeated measured variables, such as the total SF-MP score, sensory SF-MP score, affective SF-MP score, and PPI, were analyzed using a linear mixed model (LMM) and generalized estimating equations (GEE) for numerical and categorical measures, respectively, with fixed effect and random effect. When the interaction of group, time, and group by time of the variables showed statistical significance, post hoc analysis was carried out with Bonferroni correction for the adjustment for multiple comparisons. All probabilities were two-tailed, and the level of statistical significance was defined as p \ 0.05. Statistical analysis was performed using SPSS software (SPSS version 20.0, IMB, Armonk, NY, USA).
Results Patients and tumor characteristics A total of 20 patients were randomized to receive intravenous dexamethasone and 20 patients received placebo. Among these 40 patients, two patients from the DEXA group were eliminated because of failure to complete the
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Surg Endosc Table 1 Baseline characteristics Variable
Dexamethasone (N = 20, %)
Placebo (N = 20, %)
Age
54.20 ± 9.34
53.90 ± 7.33
Male gender
13 (65)
10 (50)
BMI
22.25 ± 2.83
22.10 ± 1.80
0.150
H. pylori infection
3 (15)
6 (30)
0.256
Size (mm)
914 ± 269.30
1063 ± 356.90
0.144
Upper
2
3
Middle
7
8
Lower
11
9
40.35 ± 10.69
36.80 ± 12.54
Location
Procedure time (min) Fig. 1 Recruitment algorithm. A total of 20 patients were randomized to receive intravenous dexamethasone and 20 patients received a placebo. Four patients dropped out, leaving a total of 36 patients for the final statistical analysis. NSAID non-steroidal anti-inflammatory drug
questionnaire and two patients from the placebo group were eliminated because of an ESD-related complication (N = 1) and the presence of unexpected multiple lesions (N = 1). A total of 36 patients were, therefore, enrolled in the study (Fig. 1). There were no significant differences between the two groups in baseline characteristics (Table 1). All the patients underwent complete and en bloc resection. Primary and secondary efficacy variables Analysis by LMM showed (Fig. 2) a significant difference (p \ 0.001) between the mean value of 6-h PPI in the DEXA group (1.67 ± 1.03) and that in the placebo group (2.67 ± 1.03),. The 12-h PPI was also significantly lower (p = 0.011) in the DEXA group (1.56 ± 0.78) than in the placebo group (2.11 ± 0.83). After post hoc analysis with Bonferroni correction, PPI values were significantly lower in the DEXA group at both 6 and 12 h. However, there were no differences between the two groups in immediate PPI and delayed PPI (24-h PPI) after ESD. We also identified a dramatic reduction in the total SFMP score, which was significantly lower in the DEXA group than in the placebo group (9.39 ± 2.75 vs. 12.11 ± 4.14, respectively; p = 0.086) (Fig. 3). In particular, the sensory SF-MP score at 6 h after ESD was much lower in the DEXA group than in the placebo group (8.89 ± 2.30 vs. 11.56 ± 3.90, respectively; p = 0.054). In contrast, there was no meaningful difference in the affective SF-MP score, even at 6 h following the ESD procedure. Tramadol, as an extra painkiller, was more frequently used in the placebo group than in the DEXA group (44.4
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0.792
Bleeding 13 (65)
14 (70)
Moderate
5 (25)
4 (20)
2 (10)
2 (10)
Minimal
14
15
Moderate
5
3
Severe
0.341 0.148
Minimal Severe Fibrosis
p value
0.955
1
2
En block resection
20 (100)
18 (90)
Complete resection
20 (100)
20 (100)
Dysplasia LGD
7
9
HGD
5
2
0.147
0.866
EGC
8 (40)
9 (45)
0.451
Differentiated cancer
7 (87.5)
8 (88.9)
0.929
SM invasion
2 (10)
2 (10)
Variables are expressed as median (range) or N (%) BMI body mass index, EGC early gastric cancer, HGD high-grade dysplasia, LGD low-grade dysplasia, SM submucosa
vs. 11.1 %, respectively; p = 0.026). In the DEXA group, two patients (11.1 %) were given tramadol once and 16 patients (88.9 %) were given the painkiller twice. In the placebo group, eight patients (44.4 %) received tramadol once and ten patients (55.6 %) received it twice. A secondlook endoscopy performed on 33 patients (91.7 %) revealed a similar distribution of artificial ulcer patterns. There were no visible non-bleeding vessels noted on second-look endoscopy in DEXA group patients and only one case (5.9 %) in the placebo group patients. There was no evidence of acute or delayed bleeding, which is known as one of the major complications after ESD. The mean hospital stay did not differ between the DEXA and placebo groups (3.89 ± 0.47 vs. 3.78 ± 0.55 days, respectively).
Surg Endosc Table 2 The clinical outcome after ESD
Fig. 2 The trend of PPI scores according to time. The 6- and 12-h PPIs were significantly reduced in the DEXA group compared with the placebo group. DEXA dexamethasone, Group 1 DEXA group, Group 2 placebo group, PPI present pain intensity
Variables
Dexamethasone (N = 18, %)
Placebo (N = 18, %)
p value
En block resection
18 (100)
18 (100)
0.147
Complete resection
18 (100)
18 (100)
Complication
0
0
Additional need of painkiller
2 (11.1)
8 (44.4)
Once
1 (10)
7 (70)
Twice
1 (10)
1 (10)
Second look EGD finding
0.544
Clean base
4 (25.0)
2 (11.8)
Black spot
9 (56.3)
9 (52.9)
Adherent clot
3 (18.8)
5 (29.4)
Non-bleeding visible vessel
0
1 (5.9)
3.89 ± 0.47
3.78 ± 0.55
Length of hospital stay (days)
0.026
0.519
EGD esophagogastroduodenoscopy
procedure time, severity of bleeding, degree of fibrosis, differentiated cancer, and submucosa invasion were included in univariate analyses. Among these factors, postoperative intravenous dexamethasone [odds ratio (OR) 0.127, 95 % confidence interval (CI) 0.027–0.606, p = 0.010) and tumor size (OR 1.005, 95 % CI 1.001–1.008, p = 0.004) were selected as significant factors for lowering the 6-h PPI score after ESD in univariate analysis. Larger tumor size was associated with a higher 6-h PPI score. Multivariate analysis identified postoperative intravenous dexamethasone (OR 0.109, 95 % CI 0.016–0.768, p = 0.026) and tumor size (OR 1.005, 95 % CI 1.001–1.008, p = 0.007) as independent factors of predicting development of pain after ESD. Fig. 3 Trend of the SF-MP score. A Total SF-MP score. The 6-h total SF-MP score was lower in the DEXA group than in the placebo group. B Sensory SF-MP score. The 6-h sensory SF-MP score was much lower in the DEXA group than in the placebo group. Group 1 DEXA group, Group 2 placebo group, SF-MP short-form McGill pain
Laboratory tests on parameters, including hemoglobin and glucose levels, performed the day after ESD, were within normal limits. Multivariate analysis for predictive factors To investigate the factors affecting the 6-h PPI score, we performed univariate and multivariate linear regression analyses (Table 2). Factors including dexamethasone protocol, age, sex, BMI, H. pylori infection, tumor size,
Discussion The results of this study indicate for the first time that an intravenous dexamethasone protocol was effective in managing postoperative pain after ESD for early gastric neoplasm. Well-known major complications of ESD are bleeding (7–15.6 %) and perforation (1.2–4 %) [6]. In addition, there are various minor complications, including abdominal pain for 1–2 days and intermittent fever of unknown origin. Because postoperative pain was detected only during 3–4 days of a hospital stay and was usually self-limited, pain has not been of high interest to doctors. Recently, there have been various efforts to aggressively control pain after ESD. Acute inflammatory response starts immediately after ESD, and this inflammatory process causes severe complications, such as stricture. Several
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Surg Endosc Table 3 The univariate and multivariate analysis Variables
Univariate
Multivariate
OR (95 % CI)
p value
OR (95 % CI)
p value
0.109 (0.016–0.768)
0.026
1.005 (1.001–1.008)
0.007
Dexamethasone
0.127 (0.027–0.606)
0.010
Age
0.998 (0.920–1.082)
0.962
Sex
1.083 (0.279–4.210)
0.908
BMI
1.227 (0.230–6.548)
0.811
Helicobacter pylori infection
0.927 (0.184–4.685)
0.927
Tumor size
1.005 (1.001–1.008)
0.004
Procedure time Severity of bleeding
0.995 (0.935–1.058) 1.172 (0.413–3.323)
0.865 0.766
Fibrosis
1.581 (0.500–5.002)
0.436
Differentiated cancer
2.550 (0.124–50.444)
0.550
SM invasion
0.175 (0.016–1.882)
0.150
BMI body mass index, CI confidence interval, OR odds ratio, SM submucosa
studies suggest that immediate anti-inflammatory treatment might be effective, especially for stricture, by suppressing inflammation at the outset during the initial phase [22, 23]. Steroids are well known as regulating wound healing through anti-inflammatory effects. Based on this effect, some studies have tried to prevent stricture after ESD for esophageal carcinoma by direct intralesional steroid injection [24, 25]. However, the effects of anti-inflammatory treatment on relieving pain are not clear. Even though it is not a critical complication, development of pain after ESD due to various degrees of inflammatory response is very common in the clinical setting. In our previous study of post-ESD electrocoagulation syndrome, we reported that the rate of development of pain after ESD combined with fever was 7 % [9]. The pain that develops after ESD was not somatic pain, but visceral pain. This visceral signal developed via the enteric nervous system. Various attempts to control postoperative pain have been published. For example, two studies for visceral pain control associated with ESD examine local lidocaine injections and transdermal fentanyl patches for pain relief [12, 13]. The pilot study of lidocaine injections shows that fewer patients in the lidocaine treatment group suffered from pain than in the control group [12]. The use of fentanyl patches has also been shown to be effective in controlling postoperative pain after ESD [13]. The transdermal fentanyl patch has the advantage of continuous pain-relief effects. However, these studies of local lidocaine injections and transdermal fentanyl patch deal with the regulation of pain itself and not with preventive management of causes of pain, such as inflammation around a residual ulcer. In the surgery domain, the effects of steroid injection for postoperative pain control are inconsistent, depending on the study. Nevertheless, steroids have been proven to
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provide strong relief for postoperative pain in many studies. In a representative meta-analysis of 2,500 patients, systemic dexamethasone ([0.1 mg/kg) was shown to be effective in reducing not only postoperative pain, but also postoperative opioid consumption for pain control [17]. There are concerns about adverse events with intravenous dexamethasone, such as the risk of infection, delayed wound healing, or an increase in glucose level. However, a previous meta-analysis showed that adverse events related to the use of intravenous steroids were minimal [14]. Our study investigated the effects of intravenous dexamethasone following ESD on pain, as assessed with PPI and SF-MP scores, and on various additional factors associated with post-ESD patient recovery, including the development of complications, second-look endoscopic findings, and length of hospital stay. Our results indicate that there were no serious complications associated with healing of the residual ulcer and no bleeding, infection, or increases in glucose level. Subsequent multivariate analysis identified the size of gastric lesion as well as the intravenous dexamethasone protocol as independent factors of pain development after ESD. The reason that the size of the gastric lesion is an independent factor in pain development is thought to be the repetitive electrical stimuli used during the procedure in cases of larger-sized gastric lesions. Thus, aggressive pain control should be considered for patients undergoing ESD for larger-sized gastric lesions. However, the degree of pain was not associated with the duration of the procedure or with submucosal invasion (Table 3). This study had some limitations. First, the mechanism involved in the pain relief by the intravenous steroids was not clarified in our study. Efforts for analyzing surrogate markers of various forms of pain or inflammation are needed in future studies. Second, the best time and best
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dose for pain relief by steroid injection was not determined in this study. A previous study showed that preoperative administration of dexamethasone was more effective than intraoperative administration [17]. Another study reported that high-dose dexamethasone ([0.2 mg/kg) reduced pain considerably later (24 h after ESD) than an intermediate dose of dexamethasone (0.11–0.2 mg/kg) [16]. Further investigation of the appropriate time and dose for steroid injection is recommended. Also, a randomized control study will be needed in the future to assess the effectiveness and safety of systemic steroids for pain control. Nonetheless, our study is important because it is the first to consider intravenous dexamethasone for the management of pain after gastric ESD. The anti-inflammatory mechanism of systemic steroids had strong effects on relieving pain after ESD. In conclusion, our study showed that intravenous dexamethasone was effective as an aggressive postoperative modality for pain control after ESD for early gastric neoplasm that takes into consideration the pathophysiology of the inflammatory response.
Disclosures Drs. Hye Won Lee, Hyuk Lee, Hyunsoo Chung, Jun Chul Park, Sung Kwan Shin, Sang Kil Lee, Yong Chan Lee, and Ms. Jung Hwa Hong and Mr. Dong Wook Kim have no conflicts of interest or financial ties to disclosure.
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