Low incidence of hyperamylasemia after proximal double-balloon enteroscopy: has the insertion technique improved?

• Introduction
• Patients and methods
• Study design
• Definition of hyperamylasemia and pancreatitis
• DBE procedure
• Statistical analysis
• Results
• Patient characteristics
• DBE procedure
• Findings and therapy during DBE procedures
• Laboratory results
• Hyperamylasemia and clinical outcome
• Discussion
• References

Background and study aim: Reported complications of double-balloon enteroscopy (DBE) include post-enteroscopy pancreatitis. Hyperamylasemia after proximal DBE is reported frequently, but the relationship to development of pancreatitis remains unclear. Hyperamylasemia may be related to balloon inflation in the pancreatic head region. The aims of the study were to identify risk factors for hyperamylasemia and to determine the incidence of hyperamylasemia and pancreatitis when a modified cautious DBE insertion protocol was used.

Patients and methods: In a prospective study, involving consecutive patients undergoing a proximal DBE, serum amylase activity was assessed immediately before and after the procedure.

Results: 135 patients were included (men 78, women 57; mean age 49 years [range 17 – 88]). The mean total procedure time was 73 minutes (range 30 – 150 minutes), and mean number of passes during the proximal DBE was 14 (6 – 24). While patients (17 %) developed hyperamylasemia after the DBE procedure, only one patient with hyperamylasemia had clinical symptoms indicating a mild acute pancreatitis (0.7 %). Total procedure time and number of passes correlated significantly with the occurrence of hyperamylasemia.

Conclusions: We found a low incidence of hyperamylasemia and pancreatitis post-DBE. Theoretically, this could result from the modified insertion technique, with local strain and friction of the small bowel as remaining causes of hyperamylasemia, a notion supported by the significant relation between hyperamylasemia and duration of DBE and total number of passes. We therefore advise use of the cautious insertion technique and, if possible, reduction of duration and of number of passes in every proximal DBE.

Introduction

Double balloon enteroscopy (DBE) is currently the standard endoscopic technique for visualization of the small bowel [1] [2] [3]. The main advantages of DBE are its sensitivity for the detection of mucosal abnormalities, and the abilities to take biopsies for histological confirmation and to perform therapeutic endoscopic interventions [4]. In general DBE has been shown to be safe, but a few severe complications have been reported. The most frequently reported complication after diagnostic DBE is acute pancreatitis [5] [6].

The pathophysiologic mechanism leading to post-DBE pancreatitis is debated. One hypothesis is that the inflation of the DBE balloons in the duodenum leads to an increase in the intraduodenal pressure that subsequently promotes reflux of duodenal contents into the pancreatic duct [7]. Another hypothesis is that local straining of small intestine during proximal DBE activates pancreatic enzymes [8]. In our department, the occurrence of severe post-DBE pancreatitis led to modification of the insertion protocol for proximal procedures so that during insertion balloons were only inflated after the overtube was distal to the ligament of Treitz [7].

The aim of this study was to determine the risk factors for hyperamylasemia, and to measure the incidence of hyperamylasemia and pancreatitis after proximal DBE procedures that were done using this amended insertion technique.

Patients and methods

Study design

Consecutive patients referred for proximal DBE were included in the study. All patients gave written informed consent.

At DBE, the insertion depth and the duration were noted for each procedure. Blood samples were collected before and 2 – 5 hours after the proximal DBE procedure, for measurement of serum amylase and C-reactive protein (CRP). The normal values for serum amylase and CRP levels were taken to be 0 – 99 U/L and < 9 mg/L, respectively.

After the inclusion of the first 50 patients, the study design was extended, with additional recording of number of passes and of post-procedural abdominal complaints. A pass was defined as every combined insertion and drawback of the endoscope and overtube (”push-and-pull”). Abdominal complaints were scored 2 – 5 hours after the procedure, using a 4-point scale, with pain scored as: absent (grade 0), mild (grade 1), moderate (grade 2) or severe (grade 3). If grade 2 or 3 abdominal complaints were reported, patients had a follow-up interview after 1 day, up to 1 week after the procedure until symptoms had completely resolved.

Definition of hyperamylasemia and pancreatitis

Hyperamylasemia was defined as an increase of serum amylase to above the normal upper limit (> 99 U/L), or to three times the baseline level before the procedure. Clinical (acute) pancreatitis was defined as typical pancreatic abdominal pain (mid-epigastric with radiation to the back), persisting for several hours, in association with hyperamylasemia.

DBE procedure

All patients had bowel preparation with 4 L polyethylene glycol solution. The enteroscopes used were the Fujinon EN-450P5 or the Fujinon EN-450T5 (Fujinon Inc., Saitama, Japan). Most procedures were performed using conscious sedation (midazolam and fentanyl). In selected cases, deep sedation with propofol was employed.

Statistical analysis

Numerical data were reported by using means and range. Continuous variables were compared using the unpaired or paired t test or the Wilcoxon rank-sum test. Qualitative variables were compared using chi-squared testing. A two-sided P value of < 0.05 was considered statistically significant.

Results

Patient characteristics

Over a period of 16 months 135 patients were included (78-males; mean age 49 years, [range 17 – 88]). The main indications for DBE were iron-deficiency anemia and (suspected) small-bowel Crohn’s disease; for patient characteristics see [Table 1].

DBE procedure

Conscious sedation was used in 87 % of the patients. The P- and T-type enteroscopes were used in 94 (70 %) and 41 patients (30 %), respectively. The mean total procedure time was 73 minutes (range 30 – 150). A total of 80 patients (59 %) underwent a combined proximal and distal DBE procedure; in 55 patients (41 %) only a proximal DBE procedure was performed. Complete visualization of the small intestine was achieved in 13 (10 %) patients; in four patients this was completely achieved via the proximal approach. The mean insertion depth for the proximal DBE procedure was 264 cm (range 100 – 420). The mean number of passes during the proximal DBE procedure was 14 (range 6 – 24). Grade 1 abdominal complaints were reported after the procedure by 11 patients (13 %), grade 2 by one patient (1 %), and no grade 3 complaint was reported. In only one patient, with grade 2 abdominal complaints, did these persist > 1 day after the procedure.

Findings and therapy during DBE procedures

Pathologic findings were reported in 73 patients (54 %), comprising ulcerations in 30 (22 %), angiodysplasia in 15 (11 %), polyps in 11 (8 %), tumors in 3 (2 %), and other findings in 14 (10 %) patients. Therapeutic procedures were carried out in 21 patients (16 %), being argon plasma coagulation in 11 (52 % of therapeutic procedures), dilation in 5 (24 %), and polypectomy in 5 (24 %).

Laboratory results

Serum samples were taken at a mean of 150 minutes after the DBE procedure (range 90 – 300 minutes). Ten patients had an elevated serum amylase at baseline (mean 122 U/L, range 100 – 231), without clinical signs or symptoms of pancreatitis. One of these patients developed post-procedural hyperamylasemia defined as three times the baseline level before procedure. The other nine patients (7 %) were defined as having possible macroamylasemia and showed no elevation of serum amylase post procedure (mean 136 U/L, range 112 – 215). These nine patients were excluded from further analysis.

In 22 patients (17 %) hyperamylasemia was found after the procedure (mean 191 U/L, range 101 – 468). The mean CRP levels after proximal DBE did not differ significantly between patients with or without hyperamylasemia, at 6 mg/L (range 1 – 24) and 7 mg/L (range 1 – 126), respectively.

Hyperamylasemia and clinical outcome

Out of 22 patients with hyperamylasemia, 18 (82 %) reported no complaints after the procedure. Of the four patients with complaints, three reported grade 1 abdominal complaints that resolved spontaneously within 24 hours after the procedure. Only one patient reported grade 2 abdominal complaints directly after the procedure. This patient had persistent complaints, which resolved after 3 days with conservative treatment. Because of the mild course of the pancreatitis, no additional radiological imaging or repeat measurement of serum amylase or lipase was done.

When total procedure time and number of passes were compared between the patient groups with hyperamylasemia and those with normal amylase levels, statistically significant differences were found. (Regarding procedure duration, mean [range] for the hyperamylasemia group was 82 minutes [50 – 150] and for the normal amylase group it was 71 minutes [30 – 120], P = 0.048. Regarding number of passes, the mean [range] for the hyperamylasemia group was 16 [12 – 23], and for the normal amylase group it was 13 [6 – 24], P = 0.006). No other associations with the occurrence of hyperamylasemia were found (see [Table 2]).

Discussion

Recently, two large retrospective cohort studies on complications after DBE reported an incidence of 0.3 % of acute pancreatitis following diagnostic proximal DBE procedures [5] [6], while two prospective studies reported a surprisingly high frequency of hyperamylasemia post DBE, with no clear association with the development of acute pancreatitis [9] [10]. In the present prospective study, involving a large number of consecutive DBE procedures, relatively low incidences of hyperamylasemia and pancreatitis were found following DBE. The total procedure time and number of passes were significantly correlated with development of hyperamylasemia post-DBE.

The actual mechanism causing post-DBE hyperamylasemia and acute pancreatitis is unknown, and there is an ongoing discussion concerning this issue [7] [8]. Our center was the first to report two cases of pancreatitis after proximal DBE [7]. We hypothesized that inflation of two balloons in the duodenum (distal before the ligament of Treitz and proximal in the duodenal bulb) can cause an increase in duodenal intraluminal pressure, leading to reflux of duodenal fluids into the pancreatic duct. Others hypothesized that prolonged mechanical stress on the upper abdominal organs due to the repeated ”push-and-pull,” or the direct trauma by compression of the papillary area, or direct obstruction of the pancreatic duct by the insufflated balloon(s) could cause acute pancreatitis [8] [11] [12] [13].

Earlier studies showed a large discrepancy between the incidence of procedure-related hyperamylasemia and the actual development of clinical acute pancreatitis. In our study, both the incidence of hyperamylasemia and of post-DBE pancreatitis were lower compared with those reported by these other prospective studies. The incidences of post-DBE hyperamylasemia were 46 %, 51 % and 17 %, and those of pancreatitis were 8 %, 3 % and 1 %, as reported by Honda et al. [9], Kopacova et al. [10], and in the present study. From these data, one might conclude that there seems to be a trend for an association between the incidences of hyperamylasemia and pancreatitis, but nevertheless there still remains a discrepancy between the incidences of post-procedural hyperamylasemia and acute pancreatitis.

In theory, the lower incidence found in our study might be due to the modification of the insertion technique at the start of the DBE procedure, and the remaining cases of hyperamylasemia might be caused by local friction and strain of the small bowel by the repeated push-and-pulls during the DBE procedure. The latter theory is supported by our findings of a positive relation between presence of hyperamylasemia and duration of the procedure, also shown by Honda et al., and between hyperamylasemia and number of passes during the DBE procedure. These findings may indicate that post-DBE pancreatitis can be prevented by shortening the duration of the procedure, and minimizing the number of passes. This is in line with the advice of the guidelines from the 2nd International Conference on DBE that total enteroscopy should be attempted in only selected cases [14].

A drawback of the present study is that patients’ serum amylase levels were only measured after the change in the insertion technique had been implemented. A randomized controlled trial would have given more insight, but this was considered to be unethical because of the theoretical relation to the development of acute pancreatitis. Considering this, we have to be careful with our conclusions about the impact of the modification of the insertion technique.

Secondly, serum lipase levels were not measured in combination with serum amylase. In general, serum lipase is thought to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis [15]. At our institution serum amylase is generally used as the first choice serum marker for pancreatitis. Also, recent series concerning DBE and hyperamylasemia have shown an excellent correlation between serum amylase and lipase measurements [9] [10]. Therefore we decided only to measure serum amylase in the present study.

We found relatively low incidences of hyperamylasemia and acute pancreatitis compared with other prospective studies. This different finding might be related to the modification in the insertion technique, but nevertheless this change does not seem to prevent the development of post-DBE hyperamylasemia and pancreatitis. These might also be caused by local friction and small-bowel strain, especially in DBEs with a high number of total passes and of longer duration. Considering these findings, we suggest that duration and number of passes for each DBE procedure should be minimized. Furthermore, we do not recommend routine serum amylase determination following DBE, but that it should be done only in patients with prolonged abdominal pain after the procedure.

Competing interests: The authors have no conflict of interest to report. No funding was received.

References

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P. B. F. MensinkMD, PhD 

Erasmus MC-University Medical Center
Department of Gastroenterology and Hepatology

’s Gravendijkwal 230
3015 CE Rotterdam
The Netherlands

Fax: +31-10-7034682

Email: p.mensink@erasmusmc.nl

References

• 1 Yamamoto H, Yano T, Kita H. et al . New system of double-balloon enteroscopy for diagnosis and treatment of small intestinal disorders.  Gastroenterology. 2003;  125 1556-1557
  PubMedSearch in Google Scholar
• 2 Yamamoto H, Sugano K. A new method of enteroscopy: the double-balloon method.  Can J Gastroenterol. 2003;  17 273-274
  PubMedSearch in Google Scholar
• 3 Yamamoto H, Sekine Y, Sato Y. et al . Total enteroscopy with a nonsurgical steerable double-balloon method.  Gastrointest Endosc. 2001;  53 216-220
  Search in Google Scholar
• 4 May A, Nachbar L, Ell C. Double-balloon enteroscopy (push-and-pull enteroscopy) of the small bowel: feasibility and diagnostic and therapeutic yield in patients with suspected small bowel disease.  Gastrointest Endosc. 2005;  62 62-70
  CrossrefPubMedSearch in Google Scholar
• 5 Mensink P B, Haringsma J, Kucharzik T. et al . Complications of double balloon enteroscopy: a multicenter survey.  Endoscopy. 2007;  39 613-615
  Thieme ConnectPubMedSearch in Google Scholar
• 6 Möschler O, May A D, Müller M K. et al . Complications in double-balloon-enteroscopy: results of the German DBE register.  Z Gastroenterol. 2008;  46 266-270 [in German]
  Thieme ConnectPubMedSearch in Google Scholar
• 7 Groenen M J, Moreels T G, Orlent H. et al . Acute pancreatitis after double-balloon enteroscopy: an old pathogenetic theory revisited as a result of using a new endoscopic tool.  Endoscopy. 2006;  38 82-85
  Thieme ConnectPubMedSearch in Google Scholar
• 8 Heine G D, Hadithi M, Groenen M J. et al . Double-balloon enteroscopy: indications, diagnostic yield, and complications in a series of 275 patients with suspected small-bowel disease.  Endoscopy. 2006;  38 42-48
  Thieme ConnectPubMedSearch in Google Scholar
• 9 Honda K, Itaba S, Mizutani T. et al . An increase in the serum amylase level in patients after peroral double-balloon enteroscopy: an association with the development of pancreatitis.  Endoscopy. 2006;  38 1040-1043
  Thieme ConnectPubMedSearch in Google Scholar
• 10 Kopacova M, Rejchrt S ;. et al . Hyperamylasemia of uncertain significance associated with oral double-balloon enteroscopy.  Gastrointest Endosc. 2007;  66 1133-1138
  CrossrefPubMedSearch in Google Scholar
• 11 Barkin J S, Lewis B S, Reiner D K. et al . Diagnostic and therapeutic jejunoscopy with a new, longer enteroscope.  Gastrointest Endosc. 1992;  38 55-58
  PubMedSearch in Google Scholar
• 12 Taylor A C, Buttigieg R J, McDonald I G, Desmond P V. Prospective assessment of the diagnostic and therapeutic impact of small-bowel push enteroscopy.  Endoscopy. 2003;  35 951-956
  Thieme ConnectPubMedSearch in Google Scholar
• 13 Honda K, Mizutani T, Nakamura K. et al . Acute pancreatitis associated with peroral double-balloon enteroscopy: a case report.  World J Gastroenterol. 2006;  12 1802-1804
  PubMedSearch in Google Scholar
• 14 Pohl J, Blancas J M, Cave D. et al . Consensus report of the 2nd International Conference on Double-Balloon Endoscopy.  Endoscopy. 2008;  40 156-160
  Thieme ConnectPubMedSearch in Google Scholar
• 15 Banks P, Freeman M. Practice guidelines in acute pancreatitis.  Am J Gastroenterol. 2006;  101 2379-2400
  CrossrefPubMedSearch in Google Scholar

P. B. F. MensinkMD, PhD 

Erasmus MC-University Medical Center
Department of Gastroenterology and Hepatology

’s Gravendijkwal 230
3015 CE Rotterdam
The Netherlands

Fax: +31-10-7034682

Email: p.mensink@erasmusmc.nl