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Year : 2014  |  Volume : 7  |  Issue : 3  |  Page : 412-416

The effect of addition of neostigmine to epidural levobupivacaine/fentanyl mixture on return of intestinal motility in postoperative ICU

Department of Anesthesiology and Pain Management, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Web Publication27-Aug-2014

Correspondence Address:
Heba I.A. Nagy
Department of Anesthesiology and Pain Management, Faculty of Medicine, Cairo University, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1687-7934.139582

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Postoperative ileus is a major cause of morbidity and mortality. It has a direct correlation with pain and the use of narcotic analgesics. Neostigmine is an anticholine esterase. It acts as an adjuvant analgesic in the epidural space. This study aimed to demonstrate the effect of epidural neostigmine addition to levobupivacaine/fentanyl mixture on postoperative analgesia following abdominal hysterectomy.
Materials and methods
A total of 40 patients were divided into group N (the neostigmine group) and group C (the control group). In group N, neostigmine 1 μg/kg was added to the epidural infusion of levobupivacaine and fentanyl.
Both groups were comparable in demographic data, surgical time, and hemodynamic data. Group N had significantly lower visual analogue scale (P < 0.05). In addition, time to first analgesic request was significantly longer in group N (9.5+ or −1.3 vs. 8.1+ or −0.9 in group C). The number of patients requiring analgesia in group N was two (10%), whereas in group C the number was nine (45%), which was statistically significant. Total narcotic consumption was significantly less in group N (104 ± 21.6 vs. 218 ± 35.2 mg in group C) and return of intestinal sounds was significantly faster in group N (8.1 ± 0.7 vs. 10.5 ± 1.8 h in group C). Group N had less nausea and vomiting. However, the difference was nonsignificant.
Neostigmine addition to levobupivacaine and fentanyl in lumbar epidural analgesia reduces pain scores and helps early return of intestinal motility during the postoperative period following abdominal hysterectomy.

Keywords: epidural, intensive care unit, neostigmine

How to cite this article:
Nagy HI, El Zayyat NS, El Dahab HA. The effect of addition of neostigmine to epidural levobupivacaine/fentanyl mixture on return of intestinal motility in postoperative ICU. Ain-Shams J Anaesthesiol 2014;7:412-6

How to cite this URL:
Nagy HI, El Zayyat NS, El Dahab HA. The effect of addition of neostigmine to epidural levobupivacaine/fentanyl mixture on return of intestinal motility in postoperative ICU. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Dec 1];7:412-6. Available from:

  Introduction Top

Postoperative ileus is a transient interruption of gut function following surgical intervention. It is a major cause of increasing hospitalization period, morbidity, and mortality after major surgery [1]. It evolves because of impaired motility of the gastrointestinal tract in the absence of any mechanical obstruction [2]. Failure of coordinated propulsive action leads to accumulation of luminal gas and fluid. Clinically, it is manifested by abdominal distension, nausea, vomiting, and diet intolerance [3]. Many mechanisms are involved in the delay of gut motility during the postoperative period. Sympathetic nervous system inhibits the small bowel, whereas parasympathetic nervous system stimulates it [2]. Parasympathetic stimulation and sympathetic blockade promotes small bowel function. Normally, there is baseline predominant sympathetic inhibition. It is the balance that determines the amount of acetylcholine released by excitatory nerve fibers of the bowel. Epidural catheters can block sympathetic output, thus allowing small bowel function to return faster [2].

One of the side effects of using narcotic analgesics during the postoperative period to treat pain is increased incidence of postoperative ileus. Narcotics delay colonic transit in postoperative patients, an effect that can be reversed by the narcotic antagonists [4]; yet, it is a modifiable risk factor. Advances of anesthesia have played a role in the reduction of the rate of paralytic ileus following major surgeries [5].

Neostigmine (Prostigmine) is an anticholinesterase that increases acetylcholine available for muscarinic receptors. Neostigmine is the drug of choice in treating colonic ileus. Intravenous neostigmine must be given in a monitored setting to monitor for complications such as bradycardia and bronchospasm, which are rather common [6]. Several doses or infusion may be needed. Previous studies investigating the effect of adding neostigmine to epidural anesthesia concluded that it has analgesic effect during the perioperative period for several hours with no side effects [7]. Abdominal hysterectomy has been chosen for this study to demonstrate this effect. It is an abdominal procedure but it does not include intestinal resection, anastomosis, or intestinal ischemia. This study was designed to evaluate the efficacy of adding neostigmine to epidural levobupivacaine/fentanyl infusion on the time required for return of intestinal motility in patients undergoing abdominal hysterectomy. Its analgesic effect and possible side effects were also investigated.

  Materials and methods Top

This was a randomized double-blind controlled study conducted in the faculty of medicine, Cairo University during the period between June 2012 and October 2013. After approval of the local Ethical committee, informed written consent was obtained from all patients recruited for the study. Forty women ASA I or II scheduled for abdominal hysterectomy operation aged 45-60 years were included in this study. Randomization was performed using closed envelopes. Patients were allocated into two groups: group N was the study group, which received levobupivacaine 0.125% 15 ml + neostigmine 1 μg/kg + 50 μg fentanyl + saline to complete a total volume of 20 ml in the epidural catheter, whereas group C was the control group, which received levobupivacaine 0.125% 15 ml + 50 μg fentanyl+saline to complete a total volume of 20 ml in the epidural catheter. All syringes were prepared by an anesthesiologist who was blinded to the study and were given numbers.

Exclusion criteria included hypertension, diabetes, coexisting renal or liver disease, coagulopathies, electrolytes disturbance, neurological disorders, acute or chronic pain disorders, history of intestinal pathology, or any contraindication to regional anesthesia. Patients who had accidental dural puncture were also excluded. Patients who needed nasogastric tube insertion were also excluded.

On arrival to operating theater, all patients had basic monitors attached including noninvasive blood pressure, five-lead ECG (two channels), and pulse oximetry, and baseline readings were collected. Preoperatively, all patients were not premedicated and were given clear instructions about the visual analogue scale (VAS) for pain (10 cm long line, where 0 represented no pain at all and 10 represented the worst pain one can imagine). An 18-G intravenous peripheral cannula was inserted in the dorsum of the hand, and preload consisted of 10 ml/kg of Ringer's solution before epidural insertion. Patient was put in the sitting position. After sterilization and under complete aseptic conditions, 18-G epidural (Touhy) needle was inserted in the lumbar region at L4-L5 interspace under local anesthesia. Using the loss-of-resistance technique, epidural catheter was inserted, fixed with 4 cm in the epidural space, and then covered with a sterile dressing for protection. After aspiration was negative, injection of 3 ml lidocaine was given to all patients as an epidural test dose. General anesthesia was induced with fentanyl 2 μg/kg and propofol 2 mg/kg, and intubation was performed using Atracurium 0.5 mg/kg. All patients were mechanically ventilated to maintain the end-tidal carbon dioxide between 30 and 35 mmHg. Anesthesia was maintained with 1 MAC isoflurane and 100% oxygen and 0.1 mg/kg Atracurium top-ups every 25 min. Bradycardia (heart rate <55/min) was treated by atropine sulfate 1 mg, and if hypotension occurred (reduction of MAP by >20% of the preoperative value) it was treated by ephedrine 15 mg intravenously. Immediately following removal of the uterus and the initiation of hemostasis, the epidural activation was initiated by a loading bolus of 15 ml levobupivacaine 0.125% (Chirocaine 0.5%; Abbot Laboratories, Abbot Park, Illinois, USA) followed by infusion of the same preparation at a rate of 5 ml/h for all groups with all syringes of the same patient given the same number. For all patients, neuromuscular blockade was reversed and trachea was extubated in the operating room, and all patients were shifted to the PACU, where they were monitored, then after 2 h transferred to the postoperative ICU in the gynecology hospital where they were observed for 48 h. All patients received humidified O 2 by face mask at FiO 2 0.4 in the first 24 h and were nursed in 30° head-up position. All patients received 40 IU of low-molecular-weight heparin once daily (prophylactic dose); however, removal of catheters was performed 12 h after the final dose. The data measured included hemodynamics, MAP at the beginning and every 8 h. Times of bowel sounds were recorded postoperatively in the ICU. Times of first motion (passage of flatus and defecation) were also recorded. Tolerance to oral feeding and postoperative VAS were the methods of choice in this study for assessment of pain severity. The Time to first rescue analgesic request was recorded. Postoperative nausea and vomiting was also reported. Patients had an erect plain x-ray before discharge to exclude intestinal obstruction.

Measurements and data collection

Hemodynamics: It included measurement of heart rate and noninvasive mean arterial blood pressure.

Nausea and vomiting, abdominal cramps, and return of intestinal motility were recorded.

Clinically, sounds assessment was performed by stethoscope every hour and motions (flatus and stools) were recorded as reported by the patients.

Pain measurement: It was measured using the VAS.

Rescue analgesia in the form of intramuscular pethidine (0.5 mg/kg) was given when VAS was 4 or more. Time to first dose and the number of patients requiring rescue dose in the first 48 h in each group were recorded. Additional analgesia was administered by the attending nurse who was blinded to the study.

Intestinal motility was assessed by stethoscope by a gynecologist who was blinded to the study. Tolerance to oral feeding was defined as 24 h passed from the first meal without distension, flatulence, anorexia, nausea, or vomiting.

Statistical analysis

On the basis of publications, we assumed that the time of the studied patients' first bowel sounds decreased 50% after administering epidural neostigmine. If we assumed a two-tailed type one error of 0.05 and a power of 0.80, the necessary sample size was 16 patients at least. Hence, we included 20 patients in every group to abolish the effects of errors.

Statistical analysis was performed using SPSS for Windows. Collected data were expressed as mean ± SD, ranges, numbers, and ratios as appropriate. Categorical data (non-numerical) were analyzed using the Fischer exact test. Between-group differences were analyzed using an independent sample t-test or its nonparametric counterpart. Continuous data were analyzed using unpaired t-test. P value less than 0.05 was considered statistically significant.

  Results Top

Forty patients were enrolled in this study, each group containing 20 patients. Demographic characteristics of the two groups are presented in [Table 1]. There were no significant differences between the two groups with respect to age, sex, BMI, ASA physical status, and duration of surgery and anesthesia.
Table 1 Patients' characteristics

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As shown in [Table 2], hemodynamic data including heart rate and mean arterial blood pressure at regular intervals were not statistically significant between the two groups (P > 0.05).

Time to first motion (stools or flatus) was significantly shorter in group N than in group C. Time to intestinal sounds appearance was significantly shorter as well in group N compared with group C [Table 3].
Table 2 HR and MAP measurements throughout the study

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Table 3 Assessments of intestinal function

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There was also less consumption of intravenous opioid analgesics in group N when compared with group C as shown in [Table 4], with a statistically significant difference.

Patient pain scores were recorded at 6 hourly interval for 48 h, which were found lower in group N compared with group C; however, this was not statistically significant (P > 0.05). This is demonstrated in [Figure 1].
Figure 1: Visual analogue scale (VAS) during the postoperative period (mean ± SD). *P < 0.05 versus other group. Error bars repres ent ± SD.

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Table 4 Analgesia postoperative

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With respect to the time to first rescue analgesia, it was significantly longer in group N compared with group C (P < 0.05). Only two patients in group N (10%) needed rescue analgesia during the first 48 h compared with nine patients in group C (45%), which was statistically significant. This is shown in [Table 4].

The incidence of postoperative complications was comparable in both groups. In addition, no patients in the two groups showed bradycardia (heart rate <55/min), bronchospasm, or incontinence to stools. All patients had normal erect abdominal radiograph [Table 5].
Table 5 Postoperative complications

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  Discussion Top

As the exact treatment of postoperative ileus is still uncertain, the prevention of postoperative ileus is most effective [8]. The effect of epidural analgesia with local anesthetics was shown to promote intestinal functions and reduce the rate of postoperative ileus [9]; however, this study focuses on displaying the value of adding neostigmine. The current study demonstrated that lumbar epidural neostigmine added to levobupivacaine-fentanyl mixture shortened significantly the time required to return intestinal function measured clinically by intestinal sounds and motions. In addition, the neostigmine augmented the analgesic effect of the levobupivacaine-fentanyl combination in postoperative lumbar epidural analgesia. The time to first rescue analgesia was significantly longer and the number of patients requiring rescue analgesia was significantly less in the neostigmine group. In addition, the total consumption of intravenous narcotics in 48 h was also significantly less in the neostigmine group when compared with the control group. However, the incidence of PONV and other complications was comparable.

The concentration of levobupivacaine for analgesia has been chosen in agreement with a study conducted by De Cosmo et al. [10] who demonstrated the efficacy of 0.125% levobupivacaine in treatment of post-thoracotomy pain with a lower incidence of nausea and vomiting and no weakness due to motor block. The neostigmine (1 μg/kg) has been used in a previous study as the least effective analgesic dose [11,12]. This is different from the work conducted by Nakayama et al. [13] who used higher doses of neostigmine (5 and 10 μg/kg) as boluses and compared their analgesic effects and duration of analgesia [13].

Neostigmine is a cholinesterase inhibitor. It is used in the epidural space to augment the effect of analgesia of local anesthetics [13]. The exact mechanism how neostigmine prevents ileus remains uncertain; however, there are theories to explain the development of ileus, thus understanding the effect of neostigmine. The enteric nervous system especially in the colon depends on autonomic input [14]. Studies also showed that surgical manipulation of intestine decreases the response of smooth muscles to acetylcholine, therefore increasing acetylcholine effects on motility [15]. Studies demonstrated a correlation between nonsteroidal anti-inflammatory drugs and ileus [8]. Meanwhile, studies supported the evidence that excessive use of analgesics to treat postoperative pain increases the incidence of postoperative intestinal dysfunction [16]. Other studies present an explanation why the use of neostigmine enhances intestinal functions. This is due to its adjuvant analgesic effects, which decreases the need for narcotics in addition to the parasympathomimetic effect on intestinal motility [17]. The current study used female population following hysterectomy, excluding those who had any form of intestinal resection or excessive manipulation in addition to those who had nasogastric tube insertion, as some studies have demonstrated different susceptibility to ileus, which was significantly higher in male sex as well as in those with advancing age [18] and with intestinal manipulation and resection and with the use of nasogastric tubes [8,18].

The results in this study agreed with a previous study, which found that intrathecal neostigmine resulted in involuntary defecation, which was explained by direct stimulation of neostigmine in the medulla spinalis. In the current study, no patients developed involuntary defecation [19].

Time to motions as reported by the patients of this study was significantly shorter with the use of neostigmine. The results of this study also are in agreement with the results of Caliskan's study, which concluded that thoracic epidural neostigmine decreases the incidence of ileus after abdominal aortic surgeries [20]. Agarwal et al. [21] showed that some patients show rhythmic rectal contractions during rigid cystoscopy.

With respect to PONV, our results found that the difference between both groups was in favor of the neostigmine group as demonstrated by Caliskan et al.; [20]; however, in the current study the difference was not statistically significant.

The current study showed better pain score with the use of neostigmine. This could be explained by a study conducted by Roelants et al. [22], who demonstrated reduction of pain by neostigmine and differentiated between somatic and visceral pain. The results of this study agree also with other studies such as the study by Argawal et al. [21], who showed significantly lower pain score (VAS scale) in patients who received epidural neostigmine than in those who did not receive neostigmine in rigid cystoscopy procedures.

The limitations of this study are that the effect of the epidural neostigmine on the length of ICU and hospital stay was not studied. However, this study demonstrated the effect of neostigmine in a rather controlled setting where all patients are discharged at 48 h. In addition, another drawback is depending totally on clinical data to assess the intestinal motility. Recommendations include studying the effect of adding neostigmine on the development of ileus in conditions where there are different comorbid conditions in addition to assessing its combined effect with early feeding. A meta-analysis would also be beneficial in putting epidural neostigmine, local anesthetics, and low-dose narcotic use as a preventive protocol in ileus prevention in some surgeries. This could, in fact, acquire a special importance, as postoperative paralytic ileus is still without a definitive treatment; therefore, prevention could be the best solution.

  Conclusion Top

In conclusion, the addition of neostigmine to lumbar epidural Levobupivacaine and fentanyl enhances earlier recovery of bowel function and augments the analgesic effect without systemic complications.

  Acknowledgements Top

  References Top

1.Kehlet H, Holte K. Review of postoperative ileus. Am J Surg 2001; 182:3S-10S.  Back to cited text no. 1
2. Senagore AJ. Pathogenesis and clinical and economic consequences of postoperative ileus. Am J Health Syst Pharm 2007; 64:S3-S7.  Back to cited text no. 2
3. Lubawski J, Saclarides T. Postoperative ileus; strategies for reduction. Ther Clin Risk Manag 2008; 4:913-917.   Back to cited text no. 3
4. Becker G, Blum HE. Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus. Lancet 2009; 373:1198-1206.   Back to cited text no. 4
5. Patel S, Lutz JM, Panchagnula U, Bansal S. J Anaesthesiol Clin Pharmacol. 2012; 28:162-171.  Back to cited text no. 5
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8. Ay AA, Kutun S, Ulucanlar H, Tarcan O, Demir A, Cetin A. Risk factors for postoperative ileus. J Korean Surg Soc 2011; 81:242-249.  Back to cited text no. 8
9. Holte K, Kehlet H. Postoperative ileus progress towards effective management. Drugs 2002; 62:2603-2615.  Back to cited text no. 9
10.De Cosmo G, Mascia A, Clemente A, Congedo E, Aceto P. Use of levobupivacaine for the treatment of postoperative pain after thoracotomies. Minerva Anestesiol 2005; 71:347-351.  Back to cited text no. 10
11.Lauretti GR, de Oliveira R, Perez MV, Paccola CA. Postoperative analgesia by intraarticular and epidural neostigmine following knee surgery. J Clin Anesth 2000; 12:444-448.  Back to cited text no. 11
12.Lauretti GR, de Oliviera R, Reis MP, Juliao MC, Pereira NL. Study of three different doses of epidural neostigmine coadministered with lidocaine for postoperative analgesia. Anesthesiology 1999; 90:1534-1538.  Back to cited text no. 12
13.Nakayama M, Ichinose H, Nakabayashi KI, Satoh O,Yamamoto S, Namiki A. Analgesic effect of epiduralneostigmine after abdominal hysterectomy. J Clin Anesth 2001; 13:86-89.  Back to cited text no. 13
14.Zeinali F, Stulberg JJ, Delaney CP. Pharmacological management of postoperative ileus Can J Surg 2009; 52:153-157.  Back to cited text no. 14
15.Kalff JC, et al. Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus. Ann Surg 1998; 228:652-663.  Back to cited text no. 15
16.Millan M, Biondo S, Fraccalvieri D, Frago R, Golda T, Kreisler E. Risk factors for prolonged postoperative ileus after colorectal cancer surgery. World J Surg 2012; 36:179-185.  Back to cited text no. 16
17.Barletta JF, Asgeirsson T, Senagore AJ. Influence of intravenous opioid dose on postoperative ileus. Ann Pharmacother 2011; 45:916-923.   Back to cited text no. 17
18.Kronberg U, Kiran RP, Soliman MS, Hammel JP, Galway U, Coffey JC, Fazio VW. A characterization of factors determining postoperative ileus after laparoscopic colectomy enables the generation of a novel predictive score. Ann Surg 2011; 253:78-81.  Back to cited text no. 18
19.Chung CJ, Kim JS, Park HS, Chin YJ. The efficacy of lntrathecal neostigmine, intrathecal morphine, and their combination for post-cesarean section analgesia. Anesth Analg 1998; 87:341-346.  Back to cited text no. 19
20.Caliskan E, Turkoz A, Sener M, Bozdogan N, Gulcan O, Turkoz R. A prospective randomized double-blind study to determine the effect of thoracic epidural neostigmine on postoperative ileus after abdominal aortic surgery. Anesth Analg 2008; 106:959-964.  Back to cited text no. 20
21.Agarwal MM, Singh SK, Batra YK, Mavuduru R, Mandal AK. Effect of lumbar epidural administration of neostigmine on lower urinary tract function. Neurourol Urodyn 2010; 29:443-448.  Back to cited text no. 21
22.Roelants F, Rizzo M, Lavand'homme P. The effect of epidural neostigmine combined with ropivacaine and sufentanil on neuraxial analgesia during labor. Anesth Analg 2003; 96B:1161-1166.  Back to cited text no. 22


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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