j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e7
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Dysmotility by mechanical bowel preparation using polyethylene glycol Takeshi Yamada, MD, PhD,* Hayato Kan, MD, PhD, Satoshi Matsumoto, MD, PhD, Michihiro Koizumi, MD, PhD, Akihisa Matsuda, MD, PhD, Seiichi Shinji, MD, PhD, Junpei Sasaki, MD, PhD, and Eiji Uchida, MD, PhD Department of Gastrointestinal and Hepato-Billiary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
article info
abstract
Article history:
Background: The effects of mechanical bowel preparation (MBP) on morbidity (e.g., anas-
Received 6 July 2013
tomotic leakage and surgical site infection) have been evaluated. Its effect on early re-
Received in revised form
covery after surgery has drawn renewed attention, and its use is discouraged in the
29 January 2014
postsurgical management of enhanced recovery. However, most surgeons in Japan prefer
Accepted 3 March 2014
polyethylene glycol (PEG) for MBP. We investigated the effect of MBP with PEG on post-
Available online xxx
operative intestinal motility. Materials and methods: We prospectively evaluated a consecutive series of 258 colon cancer
Keywords:
patients who underwent colonic resection and primary anastomosis. We orally adminis-
Mechanical bowel preparation (MBP)
tered 2000 mL of PEG in the PEG group and did not administer PEG to patients in the no-PEG
Polyethylene glycol
group. Postoperative gastrointestinal motility was assessed with radiopaque markers. All
Colon cancer
patients ingested radiopaque markers 2 h before surgery. Postoperative intestinal motility
Enhanced recovery after surgery
was radiologically assessed by counting the number of residual markers. Abdominal radiography was conducted on postoperative days 1, 3, and 5 to count residual markers in
(ERAS)
the large and small intestines. Results: The total number of residual markers in the no-PEG group was less than that in the PEG group on day 5 (P < 0.01) but not on days 1 and 3. On all 3 d, the numbers of residual markers in the small intestine were significantly less in the no-PEG group than in the PEG group (P < 0.001). There were no differences in postoperative complications between the no-PEG and PEG groups. Conclusions: PEG can negatively affect postoperative intestinal motility, and MBP using PEG is unnecessary in elective colon cancer surgery. ª 2014 Elsevier Inc. All rights reserved.
1.
Introduction
The use of mechanical bowel preparation (MBP) for colorectal surgery is controversial. MBP has been expected to decrease the prevalence of surgical site infection (SSI). However, MBP
has not been reported to influence the risk of SSI and anastomotic leakage in large clinical trials [1,2]. A meta-analysis also indicated that MBP does not decrease the prevalence of SSI and anastomotic leakage [3]. Nonetheless, many surgeons in Japan continue to undertake MBP with polyethylene glycol
* Corresponding author. Department of Gastrointestinal and Hepato-Billiary-Pancreatic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Tel.: þ81 3 3822 2131; fax: þ81 3 5685 0989. E-mail address: [email protected] (T. Yamada). 0022-4804/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.03.001
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(PEG) for colorectal surgery because they consider PEG to substantially decrease intestinal residues and help them to carry out the surgical procedure more easily. In the past, the significance of MBP was discussed from the viewpoint of whether it could affect morbidity (e.g., anastomotic leakage, SSI). Considering that early recovery of intestinal motility may allow for early recovery of the general condition of the patient and early discharge from hospital, whether MBP affects postoperative intestinal motility is clinically important. In addition, there are technical reasons for MBP that are independent from the need to decrease the risk of SSI or leakage. These include a laparoscopic approach (bowel can be easier to handle) and the requirement for intraoperative localization (e.g., colonoscopy) of the lesion. Fast-track surgery combines various methods used in the care of patients undergoing elective surgery. The methods used include epidural anesthesia, minimally invasive methods, optimal pain control, aggressive postoperative rehabilitation, and early oral nutrition. The combination of these approaches reduces the stress response and organ dysfunction, thereby greatly shortening the time required for full recovery. Particularly, in colon surgery, this concept is recognized widely as enhanced recovery after surgery (ERAS), which comprises 17 elements [4]. As a part of perioperative management, ERAS can reduce morbidity [5], and MBP is discouraged in ERAS management. However, in many ERAS studies, not all 17 elements were used, and MBP was not omitted in some studies [6,7]. Previously, we undertook a small, randomized controlled trial to evaluate the influence of PEG. We showed that PEG negatively affected postoperative intestinal motility in open colon surgery but not in laparoscopic surgery [8]. However, that trial involved only 79 patients and conclusive results could not be drawn. We considered conducting a randomized controlled trial of 300 patients, but many Japanese surgeons were concerned about the omission of PEG at that time. Therefore, we conducted an observational study to test the hypothesis that PEG can negatively affect postoperative intestinal motility and that omission of PEG may not increase the prevalence of postoperative complications.
2.
Materials and methods
2.1.
Patient selection
75 mg of sodium picosulfate hydrate (Laxoberon; Teijin Pharma Limited, Tokyo, Japan) if it was deemed necessary. Inclusion criteria were patients (1) with a primary tumor located somewhere between the cecum and sigmoid colon, (2) who could undergo elective surgery, (3) who had an American Society of Anesthesiologists grades of 1e3, and (4) aged 20e85 y. Exclusion criteria were as follows: (1) 2 anastomoses, (2) intestinal obstruction, (3) having undergone colostomy or ileostomy, (4) having undergone any additional procedures, and (5) need for admission to the intensive care unit after surgery. If we intended to carry out a colectomy with a colostomy or an ileostomy before the procedure, we excluded these patients before surgery. If we decided to create a stoma during the procedure for various reasons (e.g., edema of the colon or ileum, peritoneal dissemination), we excluded these patients after surgery. This study was carried out in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethics Review Committee of Nippon Medical School (Tokyo, Japan). The written informed consent was obtained from each patient.
2.2.
All patients began a low-residue diet 2 d before the procedure. They were prohibited from eating from the morning of the day before surgery. We administered 2000 mL of an oral agent consisting of PEG (Niflec; Ajinomoto, Tokyo, Japan) in the morning of the day before surgery to patients in the PEG group. All patients scheduled to undergo colorectal anastomoses received 120 mL of glycerin in the form of an enema.
2.3.
Anesthesia and postoperative analgesia
General anesthesia and epidural anesthesia was induced in all participants. If the anesthetist judged that the risk of epidural anesthesia was high, patients underwent only general anesthesia. Patients in whom epidural anesthesia was induced received continuous epidural analgesia containing fentanyl (0.4e1.2 mg every 2 d) and bupivacaine hydrochloride for postoperative analgesia. Patients in whom epidural analgesia was not induced received intravenous fentanyl (0.4e1.2 mg every 2 d).
2.4. This was a single-center, prospective observational study. We evaluated a consecutive series of patients who underwent resection and primary anastomosis of the colon. All patients undergoing elective surgery for colon cancer (International Classification of Diseases, 10th revision, C18) between January 2010 and June 2012 were considered eligible for this study. This study involved patients who underwent elective open or laparoscopic resection of the colon. Patients registered between January 2010 and June 2011 belonged to the PEG group. Those registered between July 2011 and June 2012 belonged to the no-PEG group. Patients in the PEG group were administered PEG. We prohibited the administration of PEG to patients in the no-PEG group. We permitted the administration of only
Preoperative management
Surgical procedure and postsurgical management
Open abdominal surgery was done through a midline laparotomy. For laparoscopic colon resection, the abdomen was entered via an incision of z4e6 cm in the appropriate area. D2 or D3 lymphadenectomy was conducted. Bowel reconstructions were undertaken by hand sewing or a functional end-to-end anastomosis in a right colectomy and by hand sewing or a double-stapled end-to-end anastomosis in a left colectomy. All procedures were undertaken by one of five staff surgeons in the Section of Colorectal Surgery at the Department of Digestive Surgery of Nippon Medical School. We inserted suction drains in patients who had suffered large volumes of blood loss or intraoperative contamination.
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We did not prohibit insertion of suction drains and inserted them if they were needed. Nasogastric tubes were removed before the patient awoke from anesthesia or before leaving the operating room. Patients began taking oral fluids on postoperative day (POD) 1 and a fluid diet on POD 2. They were allowed a regular diet on POD 4. Patients in both groups received an intravenous infusion of 1 g of the prophylactic antibiotic flomoxef at the induction of anesthesia and every 3 h during surgery.
2.5. End points and assessment of postoperative intestinal motility To assess postoperative intestinal motility, we used the radiopaque marker Sitzmarks (Konsyl, Easton, MD), which contains 20 radiopaque ring markers (diameter: 4.5 mm) per capsule. All patients ingested one Sitzmarks capsule 2 h before surgery. Postoperative intestinal motility was assessed by radiological means by counting the number of residual markers on abdominal radiography (PODs 1, 3, and 5). The total number of residual markers and the number of residual markers in the small intestine were counted by two physicians blinded to the study protocol. The primary end point of our study was demonstration that the total number of residual markers and the number of residual markers in the small intestine in the no-PEG group were smaller than those in the PEG group. Such a finding would indicate that PEG can negatively affect postoperative intestinal motility.
2.6.
Postoperative complications
Postoperative complications were recorded prospectively every day during the hospital stay and at the first visit to the outpatient clinic z4 wk after surgery. Anastomotic leakage, ileus, wound infection, formation of an intra-abdominal abscess, postoperative bleeding, postoperative nausea (PON), and postoperative vomiting (POV) were recorded as complications. Ileus was identified as a patient who needed a stomach tube or who could not tolerate a fluid diet >4 d after surgery. Formation of an intra-abdominal abscess was defined as a fluid collection identified by computed tomography in conjunction with a raised temperature and increased white blood cell count that required antibiotic treatment or was documented at the time of reoperation. The secondary end point of this study was demonstration that omission of PEG may not increase the prevalence of postoperative complications.
2.7.
Calculation of sample size and statistical analyses
Sample size was calculated for patients scheduled to be in one of the two study groups. Power calculations indicated that 248 patients (124 for each group) were required to achieve a power of 90% with a two-sided a ¼ 0.05 based on the ability to demonstrate that the number of residual markers in the noPEG group was smaller than that in the PEG group. This investigation was based on the assumption that the margin between the two groups was four markers (20%), which was expected from our previous study. Statistical analyses to compare the background factors and the prevalence of postoperative complications in the PEG and no-PEG groups were conducted using the chi-square test. The total number of residual markers and the number of residual markers in the small intestine were expressed as the mean þ standard error, and the ManneWhitney U-test was used to compare the groups. This analysis was conducted in two subgroups: laparoscopic surgery group (laparoscopic group) and open surgery group (open group). P < 0.05 was considered significant. All analyses were conducted using SPSS version 20 Base System (SPSS Japan, Tokyo, Japan).
3.
Results
3.1.
Characteristics of the patients
We enrolled 282 patients aged 20e85 y with colon cancer who had undergone elective surgery and had an American Society of Anesthesiologists grades of 1e3 in a defined period. Twenty-four patients were excluded because of having two anastomoses (n ¼ 3), intestinal obstruction (n ¼ 4), undergone colostomy or ileostomy (n ¼ 6), undergone excision in another organ (n ¼ 9), and the need for admission to the intensive care unit (n ¼ 2). Finally, 258 patients were included (PEG ¼ 152 and no-PEG ¼ 106). Originally, we planned to administer PEG to 150 patients and not administer PEG to another 150 patients. However, when >100 participants had been registered in the no-PEG group, we had a strong impression that postoperative dysmotility recovered earlier in the no-PEG group than in the PEG group. Therefore, we terminated participant recruitment. Finally, the actual statistical power in our study was 86%. A left colectomy was carried out significantly more frequently in the PEG group than in the no-PEG group (P ¼ 0.03). There were no significant differences in the other
Table 1 e Baseline characteristics of patients, tumor locations, and surgical procedures. Characteristics Age (y) Male:female Right:left Laparoscopic:open Operation time (min) Bleeding (mL)
All
PEG (N ¼ 152)
No-PEG (N ¼ 106)
P
69.5 (36e85) 157:101 114:144 161:97 236 (112e597) 193 (0e2510)
69.1 (36e85) 92:60 59:93 97:55 235 (112e597) 218 (0e2510)
70.1 (36e85) 65:41 55:51 64:42 237 (116e470) 159 (0e1600)
0.26 0.97 0.03 0.51 0.41 0.13
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Table 2 e Comorbidities. Comorbidity Hypertension Diabetes Anemia (HB 200 patients with colon cancer to evaluate the influence of MBP objectively using PEG on intestinal motility in the postoperative recovery phase. We clearly demonstrated that PEG can increase the number of residual markers, which indicates that PEG can negatively affect postoperative intestinal motility. As described previously, our previous small randomized study showed that PEG negatively affected postoperative intestinal motility only in open colectomies. However, in the present large study, the numbers of residual markers in the small intestine were significantly less in the no-PEG group than in the PEG group in analyses of all patients and the two surgical approaches. This finding suggests that PEG could negatively affect motility in the small intestine. We also showed that the total numbers of residual markers were significantly less in the no-PEG group than in the PEG group in all surgeries and in the two subgroups on day 5. We evaluated not only all intestinal motility but also small intestinal motility after surgery using a simple method: plastic markers. In terms of early recovery of intestinal motility, the motility of the small intestine is more important than that of the large intestine because nutrient absorption occurs mainly in the small intestine. It has been reported that MBP prolongs the time to first bowel emptying after colon surgery. Jung et al. [9] reported that MBP delayed the first postoperative bowel movement in open colon surgery. Bucher et al. [10] reported that PEG delayed the first postoperative bowel movement in left-sided colon surgery. The first bowel movement may be affected by the motility of the small and large bowels. Large bowel motility may be decreased before surgical intervention for reasons such as constipation. There are great differences among individuals with respect to this parameter. Early recovery from postoperative intestinal hypomotility can enable early oral feeding, thereby reducing the risk of anastomotic leakage, wound infection, pneumonia, and formation of intra-abdominal abscesses [11]. However, the reason why MBP is omitted from ERAS management is that MBP can result in dehydration and electrolyte abnormalities and can increase the risk of anastomotic leakage. Previous studies have not referred to the effect of MBP on postoperative intestinal motility [4,12]. As shown in the present study, omission of MBP may be one of the most important elements of ERAS, which allows for early intestinal recovery after surgery.
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Fig. 1 e Numbers of residual markers. The total number of residual markers in the no-PEG group is less than that in the PEG group on day 5 (*P < 0.01) but not on day 1 (P [ 0.46) and day 3 (P [ 0.34). On all 3 d, the numbers of residual markers in the small intestine are significantly less in the no-PEG group than in the PEG group (**P < 0.001). Data represent the mean ± standard error.
Why MBP using PEG negatively affects postoperative intestinal motility is not clear. In rats, PEG increases bile secretion and induces mild congestion, edema, and inflammation in the small and large bowels but not in the stomach [13]. Congestion, edema, and inflammation can negatively affect not only the wound healing of anastomoses but also intestinal motility. Moreover, even a relatively small amount of PEG (500e750 mL) causes the small intestine to dilate for many hours in humans [14]. These actions of PEG can negatively affect postoperative intestinal motility. Various laxatives have been administered for MBP in studies, and several methods of MBP were mixed in some studies, especially large studies and meta-analyses [1,2,3]. Postoperative complications appeared to be less common with sodium phosphate than with sodium picosulfate [15]. In addition, SSI was less common with sodium phosphate than with PEG [16]. Likewise, the influence of each laxative on
intestinal motility can differ according to its mechanism of action. PEG can negatively affect intestinal motility because it increases intestinal fluid and dilates the small intestine. Conversely, stimulant laxatives (e.g., sodium phosphate, sodium phosphate, and senna) may not increase intestinal fluid or dilate the small intestine [17]. There were no differences in the operation time or blood loss between PEG and no-PEG groups, indicating that omission of PEG does not make the procedure more difficult. The prevalence of POV was greater in the PEG group, but there were no differences in the prevalence of morbidity with the exception of POV between the two groups. The difference in the prevalence of POV could not be caused by opioids because 98.7% of patients were administered fentanyl in the PEG group and 99.2% in the no-PEG group. Thus, omission of PEG does not increase morbidity. These findings are in accordance with the results of other recent studies that evaluated the role of PEG
Fig. 2 e Numbers of residual markers in open surgery. In the open subgroup, the total number of residual markers in the noPEG group is less than that in the PEG group on day 5 (*P [ 0.02) but not on day 1 (P [ 0.23) and day 3 (P [ 0.14). On all 3 d, the numbers of residual markers in the small intestine are significantly less in the no-PEG group than in the PEG group (**P < 0.01). Data represent the mean ± standard error.
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Fig. 3 e Numbers of residual markers in laparoscopic surgery. In the laparoscopic subgroup, the total number of residual markers in the no-PEG group is less than that in the PEG group on day 5 (*P [ 0.01) but not on day 1 (P [ 0.31) and day 3 (P [ 0.35). On all 3 d, the numbers of residual markers in the small intestine are significantly less in the no-PEG group than in the PEG group (**P < 0.01). Data represent the mean ± standard error.
before elective colon surgery. Omission of MBP did not affect the operation time [1,2,17,18], bleeding volume [1,18], prevalence of anastomotic leakage [1,2,3,18,19], or prevalence of SSI [1,2,18,19] in such studies. POV was induced not only by PEG but also by postoperative analgesia with fentanyl. Fearon et al. [4] recommended that postoperative opioid use should be avoided to prevent PON and POV. Several studies have been carried out to evaluate intestinal motility in patients with constipation or neurologic disorders. However, only our previous study evaluated intestinal motility objectively. To date, a suitable method to evaluate postoperative intestinal motility has not been developed. Therefore, a new method to evaluate intestinal motility that was suitable for surgical patients needed to be developed. The method needed to be less invasive for patients who had undergone digestive surgery. It also needed be inexpensive because z300 patients had to be evaluated. To evaluate intestinal motility, three methods have been used: transit of plastic markers viewed by radiography, transit of a radioisotope viewed by a gamma camera (scintigraphy), and the hydrogen breath test. Scintigraphy requires a long period and is less expensive than plastic markers. The hydrogen breath test is less invasive for healthy subjects and
Table 4 e Postoperative complications. Complication Leakage Ileus Wound infection Abscess Bleeding PON POV Mortality
All, n (%)
PEG, n (%)
No-PEG, n (%)
P
10 (4.2) 9 (3.8) 7 (2.9)
8 (5.4) 4 (2.7) 5 (3.4)
2 (2.2) 5 (5.5) 2 (2.2)
0.23 0.27 0.60
8 (3.3) 3 (1.3) 34 (14.2) 19 (7.9) 0 (0.0)
6 (4.1) 2 (1.4) 24 (16.2) 16 (10.3) 0 (0.0)
2 (2.2) 1 (1.1) 10 (11.0) 3 (3.3) 0 (0.0)
0.44 0.86 0.26 0.04
involves measuring hydrogen in exhaled breath every 5 min during z180 min [20]. However, it may be difficult to conduct this test for surgical patients because it requires a long period. Plastic markers are easy to use, widely available, and have a longer history of use than scintigraphy [21]. We selected plastic markers because only a short time is required to carry out radiography. Among the three methods, this may impose the least strain to patients. However, validating the method of plastic markers has major drawbacks. Bouchoucha et al. [22] reported a method to calculate the colonic transit time of nonsurgical patients using plastic markers, and this method is used widely. However, patients must ingest plastic markers for 6 d using this method, placing a heavy burden on patients undergoing surgery (especially digestive surgery). Moreover, it can be used to evaluate motility only for 1 wk. Therefore, it is an inadequate method because postoperative intestinal motility can show daily improvement. Intestinal motility should be measured for 5 PODs to evaluate the effect of PEG. This period enables the development of postoperative ileus and other postoperative complications. In the radiological method described here, patients had to ingest plastic markers only once preoperatively. This method imposed the least strain on participants. Evaluation of intestinal motility (especially in the small intestine) by counting residual markers has not been validated. In five healthy subjects, all radiopaque plastic markers (Sitzmarks) passed through the small intestine and proceeded into the colon 48 h after surgery). In patients in the no-PEG group who had undergone laparoscopic surgery (considered to have the earliest recovery), all markers passed through the small intestine in only 37 patients (57.8%). The finding could indicate that the negative affect caused by colon surgery could extend the retention of markers in the small intestine. By counting the total number of residual markers and the numbers of residual markers in the small intestine,
j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e7
we could evaluate not only the total intestinal motility but also the motility of the small intestine. This study had several limitations. First, it was not a randomized controlled study. We intended to overcome bias by including consecutive cases and undertaking prospective observations. The second limitation was that rectal procedures were not included. We excluded rectal surgery cases because poorer outcomes have been demonstrated when MBP is omitted before rectal surgery [23]. We also did not include patients with colonic diverticulitis because these patients are considered to be poor surgical candidates in Japan. The third limitation was that we evaluated the influence of MBP using only PEG. Another study is needed to evaluate the influence of MBP using sodium phosphate or another laxative. The fourth limitation was based on demographics. The results were derived only from univariate analyses. Moreover, the sample size was small, which was not sufficient to test differences in the prevalence of postoperative complications.
5.
Conclusions
We demonstrated that PEG can negatively affect postoperative intestinal motility and that omitting PEG administration may not increase morbidity in patients with colon cancer. Both these findings increase the incentive to omit MBP using PEG for elective surgery for colon cancer.
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
Acknowledgment Author contributions: T.Y. and E.U. contributed to the study conception and design. T.Y., H.K., S.M., and A.M. did the analysis and interpretation of data. M.K., S.S., and J.S. did the data collection. T.Y. wrote the article.
[15]
[16]
Disclosure [17]
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
[18]
references [19] [1] Jung B, Pahlman L, Nystrom PO. Multicentre randomized clinical trial of mechanical bowel preparation in elective colonic resection. Br J Surg 2007;94:689. [2] Contant CM, Hop WC, van’t Sant HP, et al. Mechanical bowel preparation for elective colorectal surgery: a multicentre randomized trial. Lancet 2007;370:2112. [3] Slim K, Vicaut E, Launay-Savary MV, et al. Updated systematic review and meta-analysis of randomized clinical trials on the role of mechanical bowel preparation before colorectal surgery. Ann Surg 2009;249:203. [4] Fearon KC, Ljungqvist O, Von Meyenfeldt M, et al. Enhanced recovery after surgery: a consensus review of clinical care for patients undergoing colonic resection. Clin Nutr 2005;24:466. [5] Kehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. Ann Surg 2008;248:189. [6] Nygren J, Soop M, Thorell A, Hausel J, Ljungqvist O. An enhanced-recovery protocol improves outcome after
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colorectal resection already during the first year: a singlecenter experience in 168 consecutive patients. Dis Colon Rectum 2009;52:978. Khoo CK, Vickery CJ, Forsyth N, Vinall NS, Eyre-Brook IA. A prospective randomized controlled trial of multimodal perioperative management protocol in patients undergoing elective colorectal resection for cancer. Ann Surg 2007;245:867. Sasaki J, Matsumoto S, Kan H, et al. Objective assessment of postoperative gastrointestinal motility in elective colonic resection using a radiopaque marker provides an evidence for the abandonment of preoperative mechanical bowel preparation. J Nippon Med Sch 2012;79:259. Jung B, Lannerstad O, Pahlman L, Arodell M, Unosson M, Nilson E. Preoperative mechanical preparation of the colon: the patient’s experience. BMC Surg 2007;7:5. Bucher P, Gervaz P, Soravia C, et al. Randomized clinical trial of mechanical bowel preparation versus no preparation before elective left-sided colorectal surgery. Br J Surg 2005; 92:409. Lewis SJ, Egger M, Sylvester PA, Thomas S. Early enteral feeding versus “nil by mouth” after gastrointestinal surgery: systematic review and meta-analysis of controlled trials. BMJ 2001;323:773. Lassen K, Soop M, Nygren J, et al. Consensus review of optimal perioperative care in colorectal surgery. Arch Surg 2009;144:961. Bingol-Kologlu M, Senocak ME, Talim B, Kale G, Ocal T, Buyukpamukcu N. A comparative histopathologic evaluation of the effects of three different solutions used for whole bowel irrigation: an experimental study. J Pediatr Surg 2000; 35:564. McKenna DA, Roche CJ, Murphy JM, et al. Polyethylene glycol solution as an oral contrast agent for MRI of the small bowel in a patient population. Clin Radiol 2006;61:966. Yoshioka K, Connolly AB, Ogunbiyi OA, et al. Randomized trial of oral sodium phosphate compared with oral sodium picosulphate (Picolax) for elective colorectal surgery and colonoscopy. Dig Surg 2000;17:66. Itani KM, Wilson SE, Awad SS, et al. Polyethylene glycol versus sodium phosphate mechanical bowel preparation in elective colorectal surgery. Am J Surg 2007;193:190. Valverde A, Hay JM, Fingerhut A, et al. Senna vs polyethylene glycol for mechanical preparation the evening before elective colonic or rectal resection. Arch Surg 1999;134:514. Fa-Si-Oen P, Roumen R, Buitenweg J, et al. Mechanical bowel preparation or not? Outcome of a multicenter, randomized trial in elective open colon surgery. Dis Colon Rectum 2005; 48:1509. Miettinen RP, Laitinen ST, Makela JT, et al. Bowel preparation with oral polyethylene glycol electrolyte solution vs. no preparation in elective open colorectal surgery: prospective, randomized study. Dis Colon Rectum 2000;43:669. Sciarretta G, Furno A, Mazzoni M, et al. Lactulose hydrogen breath test in orocecal transit assessment: critical evaluation by means of scintigraphic method. Dig Dis Sci 1994;39:1505. Southwell BR, Clarke MC, Sutcliffe J, et al. Colonic transit studies: normal values for adults and children with comparison of radiological and scintigraphic methods. Pediatr Surg Int 2009;25:559. Bouchoucha M, Devroede G, Ahran P, et al. What is the meaning of colorectal transit time measurement? Dis Colon Rectum 1992;35:773. Bretagnol F, Panis Y, Rullier E, et al. Rectal cancer surgery with or without bowel preparation. The French GRECCAR III multicenter single-blinded randomized trial. Ann Surg 2010; 252:863.
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Dysmotility by mechanical bowel preparation using polyethylene glycol Takeshi Yamada, MD, PhD,* Hayato Kan, MD, PhD, Satoshi Matsumoto, MD, PhD, Michihiro Koizumi, MD, PhD, Akihisa Matsuda, MD, PhD, Seiichi Shinji, MD, PhD, Junpei Sasaki, MD, PhD, and Eiji Uchida, MD, PhD Department of Gastrointestinal and Hepato-Billiary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
article info
abstract
Article history:
Background: The effects of mechanical bowel preparation (MBP) on morbidity (e.g., anas-
Received 6 July 2013
tomotic leakage and surgical site infection) have been evaluated. Its effect on early re-
Received in revised form
covery after surgery has drawn renewed attention, and its use is discouraged in the
29 January 2014
postsurgical management of enhanced recovery. However, most surgeons in Japan prefer
Accepted 3 March 2014
polyethylene glycol (PEG) for MBP. We investigated the effect of MBP with PEG on post-
Available online xxx
operative intestinal motility. Materials and methods: We prospectively evaluated a consecutive series of 258 colon cancer
Keywords:
patients who underwent colonic resection and primary anastomosis. We orally adminis-
Mechanical bowel preparation (MBP)
tered 2000 mL of PEG in the PEG group and did not administer PEG to patients in the no-PEG
Polyethylene glycol
group. Postoperative gastrointestinal motility was assessed with radiopaque markers. All
Colon cancer
patients ingested radiopaque markers 2 h before surgery. Postoperative intestinal motility
Enhanced recovery after surgery
was radiologically assessed by counting the number of residual markers. Abdominal radiography was conducted on postoperative days 1, 3, and 5 to count residual markers in
(ERAS)
the large and small intestines. Results: The total number of residual markers in the no-PEG group was less than that in the PEG group on day 5 (P < 0.01) but not on days 1 and 3. On all 3 d, the numbers of residual markers in the small intestine were significantly less in the no-PEG group than in the PEG group (P < 0.001). There were no differences in postoperative complications between the no-PEG and PEG groups. Conclusions: PEG can negatively affect postoperative intestinal motility, and MBP using PEG is unnecessary in elective colon cancer surgery. ª 2014 Elsevier Inc. All rights reserved.
1.
Introduction
The use of mechanical bowel preparation (MBP) for colorectal surgery is controversial. MBP has been expected to decrease the prevalence of surgical site infection (SSI). However, MBP
has not been reported to influence the risk of SSI and anastomotic leakage in large clinical trials [1,2]. A meta-analysis also indicated that MBP does not decrease the prevalence of SSI and anastomotic leakage [3]. Nonetheless, many surgeons in Japan continue to undertake MBP with polyethylene glycol
* Corresponding author. Department of Gastrointestinal and Hepato-Billiary-Pancreatic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Tel.: þ81 3 3822 2131; fax: þ81 3 5685 0989. E-mail address: [email protected] (T. Yamada). 0022-4804/$ e see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.03.001
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(PEG) for colorectal surgery because they consider PEG to substantially decrease intestinal residues and help them to carry out the surgical procedure more easily. In the past, the significance of MBP was discussed from the viewpoint of whether it could affect morbidity (e.g., anastomotic leakage, SSI). Considering that early recovery of intestinal motility may allow for early recovery of the general condition of the patient and early discharge from hospital, whether MBP affects postoperative intestinal motility is clinically important. In addition, there are technical reasons for MBP that are independent from the need to decrease the risk of SSI or leakage. These include a laparoscopic approach (bowel can be easier to handle) and the requirement for intraoperative localization (e.g., colonoscopy) of the lesion. Fast-track surgery combines various methods used in the care of patients undergoing elective surgery. The methods used include epidural anesthesia, minimally invasive methods, optimal pain control, aggressive postoperative rehabilitation, and early oral nutrition. The combination of these approaches reduces the stress response and organ dysfunction, thereby greatly shortening the time required for full recovery. Particularly, in colon surgery, this concept is recognized widely as enhanced recovery after surgery (ERAS), which comprises 17 elements [4]. As a part of perioperative management, ERAS can reduce morbidity [5], and MBP is discouraged in ERAS management. However, in many ERAS studies, not all 17 elements were used, and MBP was not omitted in some studies [6,7]. Previously, we undertook a small, randomized controlled trial to evaluate the influence of PEG. We showed that PEG negatively affected postoperative intestinal motility in open colon surgery but not in laparoscopic surgery [8]. However, that trial involved only 79 patients and conclusive results could not be drawn. We considered conducting a randomized controlled trial of 300 patients, but many Japanese surgeons were concerned about the omission of PEG at that time. Therefore, we conducted an observational study to test the hypothesis that PEG can negatively affect postoperative intestinal motility and that omission of PEG may not increase the prevalence of postoperative complications.
2.
Materials and methods
2.1.
Patient selection
75 mg of sodium picosulfate hydrate (Laxoberon; Teijin Pharma Limited, Tokyo, Japan) if it was deemed necessary. Inclusion criteria were patients (1) with a primary tumor located somewhere between the cecum and sigmoid colon, (2) who could undergo elective surgery, (3) who had an American Society of Anesthesiologists grades of 1e3, and (4) aged 20e85 y. Exclusion criteria were as follows: (1) 2 anastomoses, (2) intestinal obstruction, (3) having undergone colostomy or ileostomy, (4) having undergone any additional procedures, and (5) need for admission to the intensive care unit after surgery. If we intended to carry out a colectomy with a colostomy or an ileostomy before the procedure, we excluded these patients before surgery. If we decided to create a stoma during the procedure for various reasons (e.g., edema of the colon or ileum, peritoneal dissemination), we excluded these patients after surgery. This study was carried out in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethics Review Committee of Nippon Medical School (Tokyo, Japan). The written informed consent was obtained from each patient.
2.2.
All patients began a low-residue diet 2 d before the procedure. They were prohibited from eating from the morning of the day before surgery. We administered 2000 mL of an oral agent consisting of PEG (Niflec; Ajinomoto, Tokyo, Japan) in the morning of the day before surgery to patients in the PEG group. All patients scheduled to undergo colorectal anastomoses received 120 mL of glycerin in the form of an enema.
2.3.
Anesthesia and postoperative analgesia
General anesthesia and epidural anesthesia was induced in all participants. If the anesthetist judged that the risk of epidural anesthesia was high, patients underwent only general anesthesia. Patients in whom epidural anesthesia was induced received continuous epidural analgesia containing fentanyl (0.4e1.2 mg every 2 d) and bupivacaine hydrochloride for postoperative analgesia. Patients in whom epidural analgesia was not induced received intravenous fentanyl (0.4e1.2 mg every 2 d).
2.4. This was a single-center, prospective observational study. We evaluated a consecutive series of patients who underwent resection and primary anastomosis of the colon. All patients undergoing elective surgery for colon cancer (International Classification of Diseases, 10th revision, C18) between January 2010 and June 2012 were considered eligible for this study. This study involved patients who underwent elective open or laparoscopic resection of the colon. Patients registered between January 2010 and June 2011 belonged to the PEG group. Those registered between July 2011 and June 2012 belonged to the no-PEG group. Patients in the PEG group were administered PEG. We prohibited the administration of PEG to patients in the no-PEG group. We permitted the administration of only
Preoperative management
Surgical procedure and postsurgical management
Open abdominal surgery was done through a midline laparotomy. For laparoscopic colon resection, the abdomen was entered via an incision of z4e6 cm in the appropriate area. D2 or D3 lymphadenectomy was conducted. Bowel reconstructions were undertaken by hand sewing or a functional end-to-end anastomosis in a right colectomy and by hand sewing or a double-stapled end-to-end anastomosis in a left colectomy. All procedures were undertaken by one of five staff surgeons in the Section of Colorectal Surgery at the Department of Digestive Surgery of Nippon Medical School. We inserted suction drains in patients who had suffered large volumes of blood loss or intraoperative contamination.
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We did not prohibit insertion of suction drains and inserted them if they were needed. Nasogastric tubes were removed before the patient awoke from anesthesia or before leaving the operating room. Patients began taking oral fluids on postoperative day (POD) 1 and a fluid diet on POD 2. They were allowed a regular diet on POD 4. Patients in both groups received an intravenous infusion of 1 g of the prophylactic antibiotic flomoxef at the induction of anesthesia and every 3 h during surgery.
2.5. End points and assessment of postoperative intestinal motility To assess postoperative intestinal motility, we used the radiopaque marker Sitzmarks (Konsyl, Easton, MD), which contains 20 radiopaque ring markers (diameter: 4.5 mm) per capsule. All patients ingested one Sitzmarks capsule 2 h before surgery. Postoperative intestinal motility was assessed by radiological means by counting the number of residual markers on abdominal radiography (PODs 1, 3, and 5). The total number of residual markers and the number of residual markers in the small intestine were counted by two physicians blinded to the study protocol. The primary end point of our study was demonstration that the total number of residual markers and the number of residual markers in the small intestine in the no-PEG group were smaller than those in the PEG group. Such a finding would indicate that PEG can negatively affect postoperative intestinal motility.
2.6.
Postoperative complications
Postoperative complications were recorded prospectively every day during the hospital stay and at the first visit to the outpatient clinic z4 wk after surgery. Anastomotic leakage, ileus, wound infection, formation of an intra-abdominal abscess, postoperative bleeding, postoperative nausea (PON), and postoperative vomiting (POV) were recorded as complications. Ileus was identified as a patient who needed a stomach tube or who could not tolerate a fluid diet >4 d after surgery. Formation of an intra-abdominal abscess was defined as a fluid collection identified by computed tomography in conjunction with a raised temperature and increased white blood cell count that required antibiotic treatment or was documented at the time of reoperation. The secondary end point of this study was demonstration that omission of PEG may not increase the prevalence of postoperative complications.
2.7.
Calculation of sample size and statistical analyses
Sample size was calculated for patients scheduled to be in one of the two study groups. Power calculations indicated that 248 patients (124 for each group) were required to achieve a power of 90% with a two-sided a ¼ 0.05 based on the ability to demonstrate that the number of residual markers in the noPEG group was smaller than that in the PEG group. This investigation was based on the assumption that the margin between the two groups was four markers (20%), which was expected from our previous study. Statistical analyses to compare the background factors and the prevalence of postoperative complications in the PEG and no-PEG groups were conducted using the chi-square test. The total number of residual markers and the number of residual markers in the small intestine were expressed as the mean þ standard error, and the ManneWhitney U-test was used to compare the groups. This analysis was conducted in two subgroups: laparoscopic surgery group (laparoscopic group) and open surgery group (open group). P < 0.05 was considered significant. All analyses were conducted using SPSS version 20 Base System (SPSS Japan, Tokyo, Japan).
3.
Results
3.1.
Characteristics of the patients
We enrolled 282 patients aged 20e85 y with colon cancer who had undergone elective surgery and had an American Society of Anesthesiologists grades of 1e3 in a defined period. Twenty-four patients were excluded because of having two anastomoses (n ¼ 3), intestinal obstruction (n ¼ 4), undergone colostomy or ileostomy (n ¼ 6), undergone excision in another organ (n ¼ 9), and the need for admission to the intensive care unit (n ¼ 2). Finally, 258 patients were included (PEG ¼ 152 and no-PEG ¼ 106). Originally, we planned to administer PEG to 150 patients and not administer PEG to another 150 patients. However, when >100 participants had been registered in the no-PEG group, we had a strong impression that postoperative dysmotility recovered earlier in the no-PEG group than in the PEG group. Therefore, we terminated participant recruitment. Finally, the actual statistical power in our study was 86%. A left colectomy was carried out significantly more frequently in the PEG group than in the no-PEG group (P ¼ 0.03). There were no significant differences in the other
Table 1 e Baseline characteristics of patients, tumor locations, and surgical procedures. Characteristics Age (y) Male:female Right:left Laparoscopic:open Operation time (min) Bleeding (mL)
All
PEG (N ¼ 152)
No-PEG (N ¼ 106)
P
69.5 (36e85) 157:101 114:144 161:97 236 (112e597) 193 (0e2510)
69.1 (36e85) 92:60 59:93 97:55 235 (112e597) 218 (0e2510)
70.1 (36e85) 65:41 55:51 64:42 237 (116e470) 159 (0e1600)
0.26 0.97 0.03 0.51 0.41 0.13
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Table 2 e Comorbidities. Comorbidity Hypertension Diabetes Anemia (HB 200 patients with colon cancer to evaluate the influence of MBP objectively using PEG on intestinal motility in the postoperative recovery phase. We clearly demonstrated that PEG can increase the number of residual markers, which indicates that PEG can negatively affect postoperative intestinal motility. As described previously, our previous small randomized study showed that PEG negatively affected postoperative intestinal motility only in open colectomies. However, in the present large study, the numbers of residual markers in the small intestine were significantly less in the no-PEG group than in the PEG group in analyses of all patients and the two surgical approaches. This finding suggests that PEG could negatively affect motility in the small intestine. We also showed that the total numbers of residual markers were significantly less in the no-PEG group than in the PEG group in all surgeries and in the two subgroups on day 5. We evaluated not only all intestinal motility but also small intestinal motility after surgery using a simple method: plastic markers. In terms of early recovery of intestinal motility, the motility of the small intestine is more important than that of the large intestine because nutrient absorption occurs mainly in the small intestine. It has been reported that MBP prolongs the time to first bowel emptying after colon surgery. Jung et al. [9] reported that MBP delayed the first postoperative bowel movement in open colon surgery. Bucher et al. [10] reported that PEG delayed the first postoperative bowel movement in left-sided colon surgery. The first bowel movement may be affected by the motility of the small and large bowels. Large bowel motility may be decreased before surgical intervention for reasons such as constipation. There are great differences among individuals with respect to this parameter. Early recovery from postoperative intestinal hypomotility can enable early oral feeding, thereby reducing the risk of anastomotic leakage, wound infection, pneumonia, and formation of intra-abdominal abscesses [11]. However, the reason why MBP is omitted from ERAS management is that MBP can result in dehydration and electrolyte abnormalities and can increase the risk of anastomotic leakage. Previous studies have not referred to the effect of MBP on postoperative intestinal motility [4,12]. As shown in the present study, omission of MBP may be one of the most important elements of ERAS, which allows for early intestinal recovery after surgery.
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Fig. 1 e Numbers of residual markers. The total number of residual markers in the no-PEG group is less than that in the PEG group on day 5 (*P < 0.01) but not on day 1 (P [ 0.46) and day 3 (P [ 0.34). On all 3 d, the numbers of residual markers in the small intestine are significantly less in the no-PEG group than in the PEG group (**P < 0.001). Data represent the mean ± standard error.
Why MBP using PEG negatively affects postoperative intestinal motility is not clear. In rats, PEG increases bile secretion and induces mild congestion, edema, and inflammation in the small and large bowels but not in the stomach [13]. Congestion, edema, and inflammation can negatively affect not only the wound healing of anastomoses but also intestinal motility. Moreover, even a relatively small amount of PEG (500e750 mL) causes the small intestine to dilate for many hours in humans [14]. These actions of PEG can negatively affect postoperative intestinal motility. Various laxatives have been administered for MBP in studies, and several methods of MBP were mixed in some studies, especially large studies and meta-analyses [1,2,3]. Postoperative complications appeared to be less common with sodium phosphate than with sodium picosulfate [15]. In addition, SSI was less common with sodium phosphate than with PEG [16]. Likewise, the influence of each laxative on
intestinal motility can differ according to its mechanism of action. PEG can negatively affect intestinal motility because it increases intestinal fluid and dilates the small intestine. Conversely, stimulant laxatives (e.g., sodium phosphate, sodium phosphate, and senna) may not increase intestinal fluid or dilate the small intestine [17]. There were no differences in the operation time or blood loss between PEG and no-PEG groups, indicating that omission of PEG does not make the procedure more difficult. The prevalence of POV was greater in the PEG group, but there were no differences in the prevalence of morbidity with the exception of POV between the two groups. The difference in the prevalence of POV could not be caused by opioids because 98.7% of patients were administered fentanyl in the PEG group and 99.2% in the no-PEG group. Thus, omission of PEG does not increase morbidity. These findings are in accordance with the results of other recent studies that evaluated the role of PEG
Fig. 2 e Numbers of residual markers in open surgery. In the open subgroup, the total number of residual markers in the noPEG group is less than that in the PEG group on day 5 (*P [ 0.02) but not on day 1 (P [ 0.23) and day 3 (P [ 0.14). On all 3 d, the numbers of residual markers in the small intestine are significantly less in the no-PEG group than in the PEG group (**P < 0.01). Data represent the mean ± standard error.
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Fig. 3 e Numbers of residual markers in laparoscopic surgery. In the laparoscopic subgroup, the total number of residual markers in the no-PEG group is less than that in the PEG group on day 5 (*P [ 0.01) but not on day 1 (P [ 0.31) and day 3 (P [ 0.35). On all 3 d, the numbers of residual markers in the small intestine are significantly less in the no-PEG group than in the PEG group (**P < 0.01). Data represent the mean ± standard error.
before elective colon surgery. Omission of MBP did not affect the operation time [1,2,17,18], bleeding volume [1,18], prevalence of anastomotic leakage [1,2,3,18,19], or prevalence of SSI [1,2,18,19] in such studies. POV was induced not only by PEG but also by postoperative analgesia with fentanyl. Fearon et al. [4] recommended that postoperative opioid use should be avoided to prevent PON and POV. Several studies have been carried out to evaluate intestinal motility in patients with constipation or neurologic disorders. However, only our previous study evaluated intestinal motility objectively. To date, a suitable method to evaluate postoperative intestinal motility has not been developed. Therefore, a new method to evaluate intestinal motility that was suitable for surgical patients needed to be developed. The method needed to be less invasive for patients who had undergone digestive surgery. It also needed be inexpensive because z300 patients had to be evaluated. To evaluate intestinal motility, three methods have been used: transit of plastic markers viewed by radiography, transit of a radioisotope viewed by a gamma camera (scintigraphy), and the hydrogen breath test. Scintigraphy requires a long period and is less expensive than plastic markers. The hydrogen breath test is less invasive for healthy subjects and
Table 4 e Postoperative complications. Complication Leakage Ileus Wound infection Abscess Bleeding PON POV Mortality
All, n (%)
PEG, n (%)
No-PEG, n (%)
P
10 (4.2) 9 (3.8) 7 (2.9)
8 (5.4) 4 (2.7) 5 (3.4)
2 (2.2) 5 (5.5) 2 (2.2)
0.23 0.27 0.60
8 (3.3) 3 (1.3) 34 (14.2) 19 (7.9) 0 (0.0)
6 (4.1) 2 (1.4) 24 (16.2) 16 (10.3) 0 (0.0)
2 (2.2) 1 (1.1) 10 (11.0) 3 (3.3) 0 (0.0)
0.44 0.86 0.26 0.04
involves measuring hydrogen in exhaled breath every 5 min during z180 min [20]. However, it may be difficult to conduct this test for surgical patients because it requires a long period. Plastic markers are easy to use, widely available, and have a longer history of use than scintigraphy [21]. We selected plastic markers because only a short time is required to carry out radiography. Among the three methods, this may impose the least strain to patients. However, validating the method of plastic markers has major drawbacks. Bouchoucha et al. [22] reported a method to calculate the colonic transit time of nonsurgical patients using plastic markers, and this method is used widely. However, patients must ingest plastic markers for 6 d using this method, placing a heavy burden on patients undergoing surgery (especially digestive surgery). Moreover, it can be used to evaluate motility only for 1 wk. Therefore, it is an inadequate method because postoperative intestinal motility can show daily improvement. Intestinal motility should be measured for 5 PODs to evaluate the effect of PEG. This period enables the development of postoperative ileus and other postoperative complications. In the radiological method described here, patients had to ingest plastic markers only once preoperatively. This method imposed the least strain on participants. Evaluation of intestinal motility (especially in the small intestine) by counting residual markers has not been validated. In five healthy subjects, all radiopaque plastic markers (Sitzmarks) passed through the small intestine and proceeded into the colon 48 h after surgery). In patients in the no-PEG group who had undergone laparoscopic surgery (considered to have the earliest recovery), all markers passed through the small intestine in only 37 patients (57.8%). The finding could indicate that the negative affect caused by colon surgery could extend the retention of markers in the small intestine. By counting the total number of residual markers and the numbers of residual markers in the small intestine,
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we could evaluate not only the total intestinal motility but also the motility of the small intestine. This study had several limitations. First, it was not a randomized controlled study. We intended to overcome bias by including consecutive cases and undertaking prospective observations. The second limitation was that rectal procedures were not included. We excluded rectal surgery cases because poorer outcomes have been demonstrated when MBP is omitted before rectal surgery [23]. We also did not include patients with colonic diverticulitis because these patients are considered to be poor surgical candidates in Japan. The third limitation was that we evaluated the influence of MBP using only PEG. Another study is needed to evaluate the influence of MBP using sodium phosphate or another laxative. The fourth limitation was based on demographics. The results were derived only from univariate analyses. Moreover, the sample size was small, which was not sufficient to test differences in the prevalence of postoperative complications.
5.
Conclusions
We demonstrated that PEG can negatively affect postoperative intestinal motility and that omitting PEG administration may not increase morbidity in patients with colon cancer. Both these findings increase the incentive to omit MBP using PEG for elective surgery for colon cancer.
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
Acknowledgment Author contributions: T.Y. and E.U. contributed to the study conception and design. T.Y., H.K., S.M., and A.M. did the analysis and interpretation of data. M.K., S.S., and J.S. did the data collection. T.Y. wrote the article.
[15]
[16]
Disclosure [17]
The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
[18]
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