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Section of Thoracic Surgery, Department of Surgery, Hospital of St. Raphael, New Haven, Connecticut
Accepted for publication January 26, 2009.
* Address correspondence to Dr Fabian, 330 Orchard St, Suite 300, New Haven, CT 06516 (Email: tfabian1{at}srhs.org).
Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Methods: Patient data were collected in a prospective fashion at a single institution. Forty-eight patients underwent intrapyloric botulinum toxin injection during esophagectomy during a 26-month period (October 2005 to January 2008). Three patients were excluded from analysis because of complications, which interfered with postoperative evaluation of emptying. Forty-five patients were evaluated clinically for signs of delayed gastric emptying. Objective assessment included a dysphagia score in 15, barium swallow in 43, and nuclear gastric emptying scans in 15 patients. The data were also reviewed for evidence of aspiration events leading to pulmonary complications.
Results: Forty-three of 45 patients (96%) had no clinical evidence of delayed gastric emptying in the immediate postoperative period. Four barium studies were interpreted as delayed gastric emptying; however, only 2 patients were symptomatic. These 2 patients underwent balloon pyloric dilation, which resulted in resolution of symptoms in 1. Three additional patients exhibited "late" delayed gastric emptying after initially doing well (mean of 3 months postoperatively) and required endoscopic intervention. No complications were identified in the study related to botulinum toxin injection.
Conclusions: Intrapyloric injection with botulinum toxin is a simple, safe, and effective means of avoiding delayed gastric emptying after esophagectomy. When necessary, reintervention may be performed endoscopically.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Pyloromyotomy and pyloroplasty are generally considered simple procedures; however, they may be complicated by stricture, leak, and even death [5]. Because of these complications, and the limited demonstrated benefit, some advocate not performing an emptying procedure during esophagectomy [6]. We sought an alternative, particularly in the minimally invasive setting, when these procedures can be time-consuming and difficult to perform during a complex operation. Previously, we published a pilot study on the off-label use of intrapyloric botulinum toxin (Botox) injection during esophagectomy [7]. Our analysis of the outcomes of 15 patients at two institutions found the technique to be feasible and safe.
Here we present our medium-term follow-up at a single high-volume center. The purpose of the study was to demonstrate continued safety and efficacy of botulinum toxin injection during esophagectomy and to document its effects on postoperative outcomes including delayed gastric emptying and aspiration.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Patients were assessed using a combination of clinical evaluation, radiographic studies, and a self-assessment dysphagia score [8]. Initial clinical evaluation looked for signs of delayed gastric emptying, which included inability to tolerate an adequate diet, regurgitation, vomiting, or aspiration. Routine barium esophagram was performed in the postoperative period to assess for evidence of leak and delayed gastric emptying. Follow-up outpatient evaluation included objective data, which were gathered from nuclear gastric emptying scans and a standardized dysphagia score.
Technique
Injection of botulinum toxin during esophagectomy
Botulinum toxin was administered during gastric mobilization at laparoscopy or laparotomy. A total dose of 200 U in 5 mL of 0.9% normal saline solution was injected into the pyloric musculature at four points using a 21-gauge needle. Although injection is primarily into the anterior wall, the needle is placed deep within the pyloric musculature at the superior and inferior injections to deliver Botox posteriorly.
Surgical technique
Patients who underwent esophagectomy during the study period were included regardless of surgical approach. The surgical approaches included minimally invasive esophagectomy, open esophagectomy, and hybrid procedures with either cervical or intrathoracic anastomosis. Briefly, our surgical techniques include a two-field lymph node dissection and creation of a 5-cm gastric conduit. Other specifics regarding our surgical technique have been published previously [9–11].
Postoperative Evaluation of Emptying
Esophagram
Patients underwent routine barium esophagram on postoperative day 6 unless physically unable to do so or contraindicated at the time. Forty-three barium esophagrams were evaluated by a radiologist and included evaluation of conduit emptying. The findings of these studies were categorized into two groups: Prompt emptying and minimal delay were distinguished from reports of profound delay.
Nuclear gastric emptying scan
Fifteen patients underwent a solid-food nuclear gastric emptying scan at an average of 4 months after the operation. In this study, 1 mCi of technetium 99 labeled with sulfur colloid was mixed with scrambled eggs and ingested. The time required for 50% of the radiotracer to empty from the gastric conduit (defined as t50) was recorded. Emptying of both solids and liquids was delineated.
Dysphagia Score
A standardized, validated, dysphagia score [8] was used to objectively evaluate patient symptoms 3 months postoperatively in 15 patients. Table 1
illustrates the scoring system. Points are awarded to food items with increasing viscosity. The maximum score of 45 indicates no perceived difficulty in swallowing.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Three patients were excluded as a result of complications precluding ability to evaluate gastric emptying. One patient had gastric tip necrosis requiring diversion, and 2 patients experienced respiratory failure not related to aspiration events.
Of the 45 patients clinically evaluated, 43 patients (96%) had no initial clinical symptoms of delayed gastric emptying (Fig 1). Two patients exhibited clinically significant delayed gastric emptying in the early postoperative period. These 2 patients had objective evidence of profound delay on their barium esophagram and required intervention before discharge. One of these patients required reintubation for an aspiration event. Both of these patients underwent balloon dilation of the pylorus in the immediate postoperative period, which resulted in complete resolution in 1 patient and no improvement in the second.
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Three patients (7%) who had no clinical or radiographic evidence of delayed gastric emptying in the immediate postoperative period presented at 3, 3, and 4 months postoperatively with symptoms consistent with delayed gastric emptying. All 3 were evaluated with barium esophagram, which demonstrated a change from their early postoperative study. These patients who experienced late-onset delayed gastric emptying underwent endoscopic treatment with botulinum injection (n = 2) or balloon dilation (n = 1) of the pylorus. All 3 had immediate and complete resolution of their symptoms (Table 2).
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The reintubation rate was 18% (8 of 45 patients). The cause of reintubation was delirium tremens in 4, anastomotic leak in 2, pulmonary embolism in 1, and aspiration event in 1. The one acute aspiration event occurred during postoperative recovery and resulted in pneumonia. This patient had both clinical and radiographic evidence of delay and was treated with endoscopic balloon dilation of the pylorus. No other aspiration events resulting in pneumonia, acute respiratory distress syndrome, or other clinically significant events were identified. The mortality rate in our study was 2% (1 of 48 patients). This single patient expired at 52 days after salvage esophagectomy, the result of an undiagnosed preoperative pneumonia that led to irreversible adult respiratory distress syndrome with subsequent withdrawal of life support. Median length of stay was 10 days (range, 7 to 52 days).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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The issue of pyloric obstruction is frequently discussed in the surgical literature. The largest randomized trial comparing drainage with no drainage was conducted by Fok and associates [15]. This study demonstrated a significant improvement in gastric transit time in patients who underwent an emptying procedure as documented by nuclear emptying scan at 6 months postoperatively (6.6 versus 24.3 minutes; p < 0.001). This study failed to demonstrate a significant reduction in respiratory complication in those patients undergoing emptying procedures versus those who did not (16% versus 23%; p = 0.15).
The clinical significance of delayed gastric emptying relates to symptoms of stasis and increased respiratory complications, primarily aspiration. In a recent review of the literature, Hagen and Peyre [17] document a growing body of evidence that suggests that the performance of a gastric emptying procedure is associated with decreased symptoms of gastric stasis, and thereby increased quality of life and possible earlier return to a normal diet. Urschel and colleagues [4] conducted a meta-analysis of the published data in 2002, which included 553 patients. Early complications related to delayed gastric emptying were reduced if pyloroplasty was performed. (relative risk, 0.018; p = 0.046). Like other reports [15], this study demonstrated a trend toward increased pulmonary complications in patients who did not undergo an emptying procedure; however, the difference was not statistically significant.
The literature suggests that gastric emptying procedures are likely beneficial, at least in terms of an earlier return to a normal diet and a possible reduction in respiratory complications. Performing them does not ensure avoidance of these issues and may be associated with complications related to the procedures themselves [4]. Leak, stricture, bleeding, and death have been reported as complications of pyloroplasty. Physiologic complications of an emptying procedure may include bile reflux, reflux esophagitis, and dumping syndrome. A recent publication found that routine performance of pyloromyotomy or pyloroplasty may be associated with increased incidence of these symptoms without demonstrable reduction in complications related to delayed gastric emptying [18].
The lack of clarity regarding emptying procedures is what constitutes the subject for continued debate. Proponents of the no drainage approach argue that the intrathoracic stomach is a passive conduit, with gravity being the most important factor in ensuring drainage [17]. Additionally, it has been argued that symptoms relating to delayed gastric emptying may be managed with medical and endoscopic measures when they do occur [13].
In our institution, minimally invasive esophagectomy is the preferred surgical approach to esophagectomy. We find that pyloromyotomy or pyloroplasty are technically challenging during this approach, and as such we developed an interest in the utility of intrapyloric botulinum toxin (Botox) as a potential substitute for the traditional approaches. Botox is a potent anticholinergic agent, inhibiting acetylcholine release from presynaptic nerve endings. The initial gastrointestinal tract application of Botox was in the treatment of achalasia to reduce lower esophageal sphincter resting pressure [19]. The success of this treatment was limited owing to recurrence of symptoms in up to 50% of patients. This is perhaps explained by regeneration of the affected receptors after a period of months [20, 21].
There is evidence to suggest that function of the gastric conduit improves with time [12, 22], and therefore an emptying procedure is most important in the early postoperative period. Theoretically, if pyloric activity is restored after a period of time subsequent to improved conduit function, this could reduce or eliminate bile reflux.
After our initial pilot study [7], which documented that the routine use of Botox was both safe and feasible as part of a minimally invasive approach to esophageal resection, we have adopted this technique as our standard of practice at our center. It has been our experience that routine administration of Botox during our open or minimally invasive approaches adds minimal operative time and appears to be effective.
In our series, barium studies were obtained as a routine evaluation during the early postoperative period. We documented an 91% rate of prompt emptying in these patients. Only 2 patients (4%) had symptomatic delayed gastric emptying. Both of these patients underwent pneumatic dilation in the early postoperative period and did well. One had an immediate and obvious improvement with complete resolution of symptoms. The second did not improve as a result of the intervention, suggesting that pyloric obstruction may not have been the source of his symptoms. This patient did improve with time and was able to resume a normal diet without significant symptoms.
Three patients exhibited late symptoms of delayed emptying at a mean follow-up of 3 months. These patients were managed successfully using either endoscopic injection of the pylorus with Botox (n = 2) or balloon dilation (n = 1). Although the number of patients with the development of late symptoms was low, the time frame of this occurrence may correspond with the duration of action of the Botox treatment [20, 21]. Other published data regarding Botox injection of the pylorus in diabetic gastroparesis noted a 5-month mean duration of response [23]. All patients who required intervention were successfully managed by endoscopic means.
Although not routinely performed, the radionuclide scintigraphic test provides additional objective information. We performed this test in 12 consecutive patients in our series and in a further 3 symptomatic patients. Normal values for this study are not known in the postesophagectomy patient population; however, some data are available from two randomized trials by Gupta and coworkers [24] and Kao and associates [14]. These two studies compared drainage versus no drainage and assessed patients using nuclear emptying studies (Table 3). The t50 in our series for emptying of both solids and liquids is comparable to available data for standard pyloroplasty. We documented a t50 of 154 minutes for solids, and 32 minutes for liquids. This is similar to the 175.9 minutes for solids and 161.21 minutes for liquids reported by Kao and colleagues [14] and Gupta and associates [24], respectively, in the pyloroplasty arms of their studies, and was substantially better than the no-drainage arms.
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Although there is growing experience with the use of Botox to promote emptying of the conduit after esophagectomy, further trials will be necessary to document efficacy and whether or not it should be recommended as a preferred approach. It has been estimated that to demonstrate a reduction in long-term foregut dysfunction from 30% to 20%, an appropriately powered study would require 581 patients [4]. The ideal trial would include a large prospectively randomized cohort with three arms, comparing no drainage, pyloroplasty, and Botox. Until such time it is likely that the debate surrounding the appropriate choice and recommendation of gastric emptying procedure will continue.
In conclusion, intrapyloric botulinum toxin injection is a simple, safe, and effective means of avoiding delayed gastric emptying after esophagectomy. Despite the technical advantages of Botox delivery, further studies will be necessary to investigate equivalence or superiority to standard gastric emptying procedures in the routine practice of esophagectomy.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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One of the issues regarding this particular question, which, as you pointed out, has been reviewed multiple times historically, is that every institution has their different approach to managing this situation. Many of us believe that the major issue of functional eating after esophagectomy has to do with conduit preparation and orientation. You presented this to your IRB (institutional review board), you identified that this might be an appropriate approach to improve outcomes, but we don't know what the standard results at your institution were before you instituted this particular procedure. Wouldn't this have been an ideal opportunity for a nonrandomized controlled trial to demonstrate the differences in results in your patient population?
DR MARTIN: That's a very good question. As far as our surgical technique at this institution, our use of Botox correlated with us starting the minimally invasive program, and it was the feeling of the surgeons at the time that this was a safe and effective approach and that we would continue doing this with all of our patients. I agree with you that we could have potentially tried to divide this down and have a control arm, but given our numbers, 48 patients, this is always difficult to have an adequately powered study, and I think we would have potentially further diluted our data. I think ultimately it goes back to the fact that the occurrence of delayed gastric emptying, particularly the aspiration events, can be such a comorbid factor that if this was something that could help them, we wanted to afford that benefit to all of our patients. I think to really answer this we are going to need a much larger study, significantly powered.
DR DANIEL L. MILLER (Atlanta, GA): Dr Martin, I enjoyed your presentation. We have been using this at Emory since 2002. What we use it for is more in regards to preventing dumping at a later date. First of all, do you have any information with regards to your dumping episodes at 6 and 12 months?
The other thing, too, in using the Botox, we have found that normally when we decompress the stomach for a standard pyloromyotomy and pyloroplasty, we leave the nasogastric (NG) tube in for about 48 hours; however, with the Botox, because you are creating a lot of edema there, we usually have to leave the NG tube in a little bit longer, maybe even up to 5 days sometimes, and that might be helping your delayed gastric emptying. Have you seen that problem?
DR MARTIN: Two very good questions. I'll address your second question first in regard to our NG tube management. Our standard of care is that we leave it in until postoperative day 5, so that would kind of correlate with your experience. I'm not sure. There may be some initial edema effect. That's a good comment.
Your first question again?
DR MILLER: In regards to dumping. That's the main reason that we use it. You know, when it resolves at 4 to 6 months, the patients usually don't complain of any dumping.
DR MARTIN: Right. Again, we didn't specifically look at dumping syndrome rates in our patients. In their follow-up evaluation, again, I can't quote you the numbers, but my impression is that the incidence was pretty low.
DR ROBERT J. CERFOLIO (Birmingham, AL): As usual, Dr Miller is a great setup man. I want to congratulate you, and of course Tom Fabian. Tom, this is outstanding work, and we are all aware of the great job you are doing up there and we appreciate all of your contributions in this field.
We just presented our experience of this at the Western in 2008 concerning our use of Botox over the last many years, in—I forgot the number of people—but there are two things in our experience that we can comment on: One, we thought there was less aspiration in the Botox group when compared retrospectively to a group that got pyloromyotomy and a group that didn't. You showed your aspiration rate, but you didn't show it for the other. Is it higher or lower?
DR MARTIN: The aspiration rate documented in the literature seems higher. Our single patient was, interestingly, a patient who had failed intraop botox management, was symptomatic, and got reintervened. That was a patient who had a complicated postop(erative) course. We had no other aspiration events.
DR CERFOLIO: So that was our conclusion as well—that it may decrease the aspiration rate, which is still our number one and most devastating postop(erative) complication. The number two thing we liked about it wasn't really the prevention of dumping as Dan suggested but rather the prevention of bile reflux. Instead of turning a valve that's supposed to be a one-way valve into an incompetent bidirectional valve that gives bile reflux. I was tired of patients coming back with that complaint and I had nothing to treat them with and would just say "Hey, you're cured of your cancer. Go home," because I had nothing else to treat them with. Since using Botox, which is why I started using it a long time ago, is that this really has reduced our incidence of bile reflux. What about you?
DR MARTIN: Certainly. We had a zero incidence of bile reflux, and I think that that touches on one very important advantage of Botox, that this is a transient effect in the immediate postop(erative) period where aspiration can be a life-threatening complication, yet doesn't leave the patient with an additional complication that can be lifelong.
DR CERFOLIO: And, finally, those are the reasons why I think it's the ideal solution. Yes, we need a prospective randomized study, but until we do it, I think Botox is the answer, not pyloromyotomy, pyloroplasty, or nothing. I think it's Botox because it reduces the early postop(erative) problems of aspirations. In 3 months it goes away and then reduces the late complication of biliary reflux for which there is no satisfactory therapy after esophagogastrectomy.
DR THOMAS J. WATSON (Rochester, NY): I really enjoyed your talk.
Do you have any experience using endoscopically administered Botox postoperatively for some of these failures or in patients whom you see without any sort of pyloric drainage at the time of their initial operation?
DR MARTIN: All of our patients had pyloric drainage using Botox. The patients who were reintervened, we had 3 patients who were reinjected, and the 2 patients who were reinjected with Botox did well. They had freedom from symptomatology. One of the difficulties with reinjecting endoscopically is are you definitely hitting the muscular layer as opposed to the risk of a submucosal injection, but in our 2 patients we had good outcomes with reinjection.
DR WATSON: Have you given any thought to just waiting to see who develops delayed gastric emptying and selectively injecting those people?
DR MARTIN: Again, that's a good question and I think that's something that will have to be answered in a larger trial.
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References |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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  M. Lanuti, P. DeDelva, C. R. Morse, C. D. Wright, J. C. Wain, H. A. Gaissert, D. M. Donahue, and D. J. Mathisen Management of Delayed Gastric Emptying After Esophagectomy With Endoscopic Balloon Dilatation of the Pylorus Ann. Thorac. Surg., April 1, 2011; 91(4): 1019 - 1024. [Abstract] [Full Text] [PDF]
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