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PAIN MEDICINE

A Prospective Randomized Double-Blind Study to Determine the Effect of Thoracic Epidural Neostigmine on Postoperative Ileus After Abdominal Aortic Surgery

Esra Caliskan, MD^*, Ayda Turkoz, MD^*, Mesut Sener, MD^*, Nesrin Bozdogan, MD^*, Oner Gulcan, MD, and Riza Turkoz, MD

From the Departments of *Anesthesiology and Reanimation, and Cardiovascular Surgery, Baskent University Faculty of Medicine, Ankara, Turkey.

Address correspondence and reprint requests to Esra Caliskan, MD, Baskent University, Faculty of Medicine, Adana Teaching and Medical Research Center, Anesthesiology Department, Dadaloglu Mahallesi, 39.sokak, No: 36, Yüregir 01250 Adana, Turkey. Address e-mail to esra_ertr{at}yahoo.com.

	Abstract

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BACKGROUND: Postoperative ileus is a major gastrointestinal complication of abdominal aortic surgery leading to increased rates of morbidity and mortality, longer lengths of hospital stay, and higher costs. In this study, we evaluated the effect of epidurally administered neostigmine on postoperative ileus after abdominal aortic surgery.

METHODS: We enrolled 45 patients who were scheduled for elective abdominal aortic surgery at our institution. All patients received identical general and epidural anesthesia. Before the induction of general anesthesia, an epidural catheter was placed at the T₇–T₈ intervertebral space, and 20 mL bupivacaine (0.5%) was injected over 15 min. Patients were randomized into two groups. Patients received a 5 mL bolus of neostigmine (1 µg/kg) diluted with normal saline (Group 1) or a 5 mL bolus of normal saline (Group 2) via an epidural catheter at the end of surgery and 8 h postoperatively. Times of bowel sounds were recorded postoperatively in the intensive care unit. Times of daily passage of flatus and defecation also were recorded.

RESULTS: Times to the first bowel sounds and the first flatus were significantly shorter in Group 1 than they were in Group 2 (11.6 ± 11.2 h vs 22.6 ± 12.8 h and 21.8 ± 15.6 h vs 36.6 ± 19.1 h, respectively, P < 0.05). The times to first defecation were similar in both groups (P > 0.05). Nausea was more frequent in patients in Group 2 than in Group 1 (P < 0.05). The incidence of postoperative complications was similar between the groups (P > 0.05).

CONCLUSIONS: Thoracic epidural neostigmine enables faster restoration of bowel sounds and shortens duration of postoperative ileus after abdominal aortic surgery.

	Introduction

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Postoperative ileus is a major complication of abdominal aortic surgery associated with prolonged hospital stay and higher rates of postoperative mortality and morbidity.1 The reported incidence of postoperative ileus ranges from 3.9% to 11%.1,2 The exact pathophysiologic basis of postoperative ileus is unknown. Traditionally, it is believed that the impairment of normal function of the autonomic nervous system is the most important factor that causes postoperative ileus.3 However, it is reported that neurogenic, inflammatory, and pharmacological factors contribute to the pathogenesis of postoperative ileus. It has been shown that surgical stress, extensive manipulation of the intestine and mesentery, and stimulation of nociceptive afferent and sympathetic efferent nerve pathways may cause gastrointestinal complications after abdominal surgery.4

A multimodality treatment, including continuous midthoracic epidural bupivacaine in addition to early enteral feedings, early ambulation, maintenance of normal hydration, laxatives, non-narcotic and antiinflammatory analgesics, has been shown to hasten recovery from postoperative ileus.5,6

Neostigmine is a reversible inhibitor of acetylcholinesterase and, when administrated IV, it stimulates gastrointestinal motility by increasing parasympathetic activity. Neostigmine has been investigated as a potential treatment of postoperative ileus.7,8 Because of the relatively frequent incidence of systemic adverse effects (abdominal cramps, blurred vision, and increased gastric acid secretion), IV use of neostigmine in postoperative ileus has been limited.5 However, the direct effects of epidural neostigmine on postoperative bowel function have not been studied.

Additionally, neostigmine has been used as an adjuvant drug to epidural local anesthetics intraoperatively and postoperatively.9 In dosages that enhance the analgesic effect of local anesthetics, nausea, vomiting, and involuntary defecation have been reported as adverse effects in studies using neostigmine as a neuroaxial adjuvant drug.10–15 Although neostigmine administered via the epidural route shows analgesic efficacy mediation with spinal cholinergic stimulation, it also may increase intestinal motility with the same mediation. Lauretti et al.'s study16 indicates that if neostigmine is administered via the epidural route, its analgesic effect is seen at least 1 µg/kg. In our study, we aimed to obtain spinal cholinergic stimulation using 1 µg/kg neostigmine (the minimal dose that provides analgesic effect with the least amount of adverse effects) administered via the epidural route. We evaluated the effects of epidurally administered neostigmine on restoring postoperative ileus after abdominal aortic surgery.

	METHODS

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The project was approved by the university research council and the local ethics committee. All patients provided written informed consent. This prospective, randomized, controlled, double-blind study enrolled 45 consecutive patients of ASA physical status II and III undergoing elective abdominal aortic surgery for aneurismal or occlusive disease between December 2003 and September 2006. Patients were randomly divided into two groups using a sealed envelope method.

Before the operation, patients were instructed how to evaluate pain using a visual analog scale (VAS; 0 = no pain, 10 = worst possible pain). All surgical and anesthetic procedures were performed by the same teams. All patients were operated on using open transabdominal aortic revascularization procedures. The treatment assignment was not revealed to the patient or any clinical personnel involved in the study. All patients were premedicated with midazolam (5 mg per oral (PO) 30 min before the operation. In the operating room, patients’ heart rates, mean arterial blood pressure, and pulse oximetry levels were monitored, and 5-channel electrocardiogram with continuous ST-segment analysis was performed. Before induction of general anesthesia, an epidural catheter was placed under local anesthesia at the T₇–T₈ intervertebral space using a loss-of-resistance technique. A test dose of 3 mL of 2% lidocaine with 1:200,000 epinephrine was injected to confirm correct positioning of the catheter. In both groups, 0.5% bupivacaine (20 mL) was injected through the epidural catheter, and patients’ hemodynamic status was carefully monitored for the next 15 min. The level of the block was tested by pinprick every 5 min. T₄–S₅ dermatomal desensitization was achieved in 20 min, and in both groups, general anesthesia was then induced with thiopental (5 mg/kg), fentanyl (1 µg/kg), and vecuronium (0.1 mg/kg). Anesthesia was maintained with isoflurane 0.5% end-tidal volume, a 50/50% oxygen/air combination, and continuous epidural infusion of 0.2% bupivacaine at the rate of 6–12 mL/h. The infusion rate of 0.2% bupivacaine was determined by means of clinical data, such as mean arterial blood pressure, heart rate, appearance of tears, sweating, and patient movement. All patients were followed-up by the same investigators (E.C. and N.B.) during and after surgery.

For fluid therapy, all patients received balanced salt solution at a rate of 6–10 mL · kg^–1 · h^–1 perioperatively and 2 mL · kg · h^–1 postoperatively. Additionally, after a bolus dose of epidural bupivacaine, when the heart rate decreased to <45 bpm, patients were treated with a 0.5-mg dose of atropine, and when decreases in systolic blood pressure of <100 mm Hg were seen, an infusion of dopamine ranging from 2 to 5 µg · kg^–1 · min^–1 was administered.

Additional bolus doses of vecuronium were injected if necessary. Patients’ lungs were ventilated at a tidal volume of 10 mL/kg; end-tidal carbon dioxide concentration was maintained at 35–40 mm Hg. All patients were placed on a water-warming blanket. Heart rate, mean arterial blood pressure, and partial oxygen saturation were monitored at baseline, induction, during tracheal intubation, during first incision, and measurements were taken at 15-min intervals during maintenance of anesthesia. Central venous pressure, end-tidal carbon dioxide concentration, nasopharyngeal temperature, urine output, blood gas analysis, and surgery times also were recorded during the procedure.

In the first group, patients received a 5-mL bolus of neostigmine (1 µg/kg) diluted with normal saline via an epidural catheter at the end of surgery and 8 h postoperatively. The decision about the dose of epidural neostigmine was based on a previous study of Lauretti et al.16 In that study, epidural neostigmine ranging from 1 to 4 µg/kg was used as an adjuvant drug to epidural local anesthetics in minor orthopedic procedures. That clinical study showed a dose-independent analgesic effect at 1, 2, or 4 µg/kg epidural neostigmine combined with 85 mg lidocaine. However, there were no differences among the three different dosages of neostigmine with regard to their analgesic effects, and the time of first analgesic requirement for patients was 8 h between groups. According to the Lauretti et al. study, we hypothesized that the small dose of epidural neostigmine (1 µg/kg) might be effective for recovery of bowel function and postoperative ileus after abdominal aortic surgery. In the current study, patients in Group 2 received 5 mL normal saline via an epidural catheter at the end of surgery and 8 h postoperatively.

All medications used in this study were prepared by a researcher (A.T.) not involved in the intraoperative and postoperative patient treatment. Postoperative data were collected by another researcher (M.S.) blinded to the study medications used.

At the end of surgery, patients were transferred to the intensive care unit (ICU). Bowel functions were evaluated in the ICU by bowel sounds and were noted every hour at the four quadrants of the abdomen. Times of first bowel sounds were recorded. Times of the daily passage of flatus and defecation also were recorded. Patients in both groups received continuous epidural infusion of 0.1% bupivacaine at a rate of 6–12 mL/h in the ICU for 2 days after surgery. The segmental sensory block was assessed daily by the same team, and the infusion was adjusted to maintain a bilateral sensory block between areas of surgical incision.

VAS scores were recorded at rest and while coughing at 1, 2, 4, 6, 12, 24, and 48 h after tracheal extubation. If a patient's pain relief was unsatisfactory (VAS >4), acetaminophen (2 g PO) twice daily and tramadol (50 mg PO) three times daily were administered on the first postoperative day. Acetaminophen (2 g PO) twice daily and ibuprofen (600 mg PO) three times daily were given the second postoperative day for additive analgesia. Epidural catheters were removed on the second postoperative day and from that point on, patients were given acetaminophen as needed.

Each patient's sedation level was recorded after tracheal extubation according to an Observer Sedation and Alertness Scale (0 = does not respond to noxious stimulus; 1 = does not respond to mild prodding or shaking; 2 = responds only after mild prodding or shaking; 3 = responds only after name is called loudly or repeatedly; 4 = lethargic response to name spoken in normal tone; 5 = responds readily to name spoken in normal tone).

The incidence of postoperative nausea and vomiting, medical and surgical complications, as well as length of stay in the ICU and in the hospital also were recorded. Standardized perioperative care protocols (such as stomach decompression via a nasogastric tube, early oral feeding, and mobilization from bed) were performed on all patients. The nasogastric tube was extracted during the first postoperative day.

We examined whether epidural administration of neostigmine stimulates bowel sounds after abdominal aortic surgery. Norris et al.17 reported that first bowel sounds start at a mean of 21 ± 14 h after abdominal aortic surgery. On the basis of the published data, we assumed that the time of our patients’ first bowel sounds decreased 50% after administering epidural neostigmine. If we assumed a two-tailed type-1 error of 0.05 and a power of 0.80, the necessary sample size of patients to be included in each group was 16.

Statistical analyses were performed with SPSS software (Statistical Package for the Social Sciences, version 11.0, SSPS Inc., Chicago, IL). Between-group differences were analyzed using an independent samples t-test or its nonparametric counterpart, the Mann–Whitney U-test. ² or the Fisher's exact test was used to analyze categorical variables where appropriate. Homogeneity of variance was calculated using Levene's and Lilliefors tests. Data are expressed as means ± sd. Values for P < 0.05 were considered statistically significant.

	RESULTS

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Of the 45 patients enrolled in this study, four patients in Group 1 and six patients in Group 2 were excluded because we could not place the epidural catheter at the desired level. Additionally, one patient in Group 1 was excluded because the neostigmine dosage was miscalculated. These 11 patients were excluded from the study. The analysis was performed on the remaining 34 patients (18 patients in Group 1 and 16 patients in Group 2). The demographic characteristics and intraoperative data of the two groups are presented in Tables 1 and 2. There were no significant differences between the groups with regard to age, sex, body mass index, ASA physical status, and duration of surgery and anesthesia.

View larger version (24K): [in this window] [in a new window]   Figure 1. The time intervals from surgery to the first bowel sounds and first flatus. Values are expressed as means ± sd. *P < 0.05 versus Group 2.

Patients’ pain scores were recorded at rest and during coughing at 1, 2, 4, 6, 12, 24, and 48 h after tracheal extubation. There were no between-group differences regarding postoperative VAS scores at rest and during coughing (Figs. 2 and 3). Patients’ sedation scores were not significantly different between groups (P > 0.05), and all patients were awake for postoperative assessment.

View larger version (11K): [in this window] [in a new window]   Figure 2. Pain intensity of the patients during cough (VAS-C) among the two groups. VAS = Visual Analog Score.

View larger version (12K): [in this window] [in a new window]   Figure 3. Pain intensity of the patients during at rest (VAS-R) among the two groups. VAS = Visual Analog Score.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
Our study indicates that thoracic epidural bupivacaine with supplemental neostigmine shortened the time to return of bowel sounds and time to passage of flatus after abdominal aortic surgery. Additionally, nausea was less frequent in patients who were administrated epidural neostigmine. However, coadministration of epidural neostigmine (1 µg/kg) did not increase the analgesic effect of bupivacaine.

Neostigmine is an acetylcholinesterase inhibitor used as a neuroaxial adjuvant drug to enhance the analgesic effect of local anesthetics.18,19 Although neostigmine accomplishes analgesia by inhibiting endogen neurotransmitter acetylcholine degradation, increased acetylcholine in the medulla spinalis stimulates all muscarinic and nicotinic receptors. Therefore, increased acetylcholine together with analgesia leads to many adverse effects, such as motor weakness, hypertension, tachycardia, vaginal contraction, ejaculation, urinary retention, and bowel incontinence.14,20

The neural mechanisms underlying the gastrointestinal effects of intrathecal neostigmine remain unknown. Although little is known about the gastrointestinal effects of intrathecal cholinergic agonists, diarrhea after intrathecal injection of an anticholinesterase has been reported in rats.21 Klamt et al.11 noted that intrathecal administration of neostigmine can cause involuntary defecation. In our study, we observed that the time intervals from surgery to the first bowel sounds and flatus were significantly shorter for patients in Group 1 than in Group 2. Additionally, time to first defecation was shorter for patients in Group 1 than for patients in Group 2 (58 h vs 75 h, respectively); however, this difference was not statistically significant. This effect may depend on direct cholinergic stimulation of neostigmine in the medulla spinalis. However, the peripheral and central effects with low does (1 µg/kg epidural neostigmine) are somewhat unusual. The plasma concentration of neostigmine remains at a low-level for the peripheral effect after this lower dose. In addition, higher dosages and more time are needed for neostigmine to move through the central nervous system and to be effective in the brainstem. For this reason, the administration of neostigmine epidurally probably had such an effect via spinal cholinergic stimulation in our study.

Nausea and vomiting are significant adverse effects of neostigmine that preclude its intrathecal use. The adverse effects occur in a dose-dependent manner and appear within 60–120 min. Intrathecal use of a hyperbaric solution of neostigmine has been reported to significantly reduce these adverse effects, which may be the result of cranial spread of neostigmine in the cerebrospinal fluid.10,22 Neostigmine is a hydrophilic drug, and cephalad spread of neostigmine in cerebrospinal fluid could lead to a central cholinergic crisis. Interestingly, in our study, nausea was more frequent in patients in Group 2 than in Group 1; this difference was statistically significant (P < 0.05). Epidural administration of neostigmine shortens the recovery period of bowel sounds. This could be the reason for the low incidence of postoperative nausea in Group 1.

Roelants18 reported that neostigmine appears to alleviate somatic pain better than visceral pain. However, in our study, there were no statistically significant group differences regarding postoperative pain. The dosage used in our study might have been insufficient to produce an analgesic effect during major surgery.

The limitation of the current study is that it was under-powered to detect adverse effects, complications, and the lengths of stay in the ICU and the hospital because the power analysis was performed for bowel sounds only. Table 1 shows the patients in our study undergoing abdominal aortic surgery also had severe comorbid diseases. Owing to these comorbid diseases, gastrointestinal complications were seen during the early postoperative period, as were other complications (e.g., cardiac, renal, and pulmonary diseases). Also, in our patients these complications (i.e., arrhythmia, respiratory failure, and renal failure) affected early and late postoperative outcomes. In our study, although early bowel sounds and flatus were present in patients administered epidural neostigmine after abdominal aortic surgery, time in the ICU and time to discharge from the hospital were perhaps affected by these comorbid conditions. In spite of this, there were no statistically significant differences in patients given epidural neostigmine. Both excessive preoperative drug use (especially β-blocker) and intraoperative blood loss might have been impeded by the effects of epidural neostigmine as was time in the ICU and time until discharge from the hospital. However, we believe that the results of our study offer useful information on the effectiveness of epidural neostigmine on early restoration of bowel functions after abdominal aortic surgery.

We concluded that the addition of neostigmine to thoracic epidural bupivacaine allows early restoration of bowel sounds after abdominal aortic surgery with no adverse effects. However, we could not demonstrate the effects of epidural administration of neostigmine on the clinical outcomes of patients in this study. We suggest that thoracic epidural neostigmine provides faster restoration of bowel sounds and shortens the duration of postoperative ileus after abdominal aortic surgery.

	Footnotes

 
Accepted for publication November 20, 2007.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 

1. Malinzak LE, Long GW, Bove PG, Brown OW, Romano W, Shanley CJ, Zelenock GB, Bendick PJ. Gastrointestinal complications following infrarenal endovascular aneurysm repair. Vasc Endovascular Surg 2004;38:137–42[Abstract/Free Full Text]
2. Sicard GA, Reilly JM, Rubin BG, Thompson RW, Allen BT, Flye MW, Schechtman KB, Young-Beyer P, Weiss C, Anderson CB. Transabdominal versus retroperitoneal incision for abdominal aortic surgery: report of a prospective randomized trial. J Vasc Surg 1995;21:174–81; discussion 181–3
3. Person B, Wexner SD. The management of postoperative ileus. Curr Probl Surg 2006;43:6–65[Web of Science][Medline]
4. Carli F, Trudel JL, Belliveau P. The effect of intraoperative thoracic epidural anesthesia and postoperative analgesia on bowel function after colorectal surgery: a prospective, randomized trial. Dis Colon Rectum 2001;44:1083–9[Web of Science][Medline]
5. Mattei P, Rombeau LJ. Review of the pathophysiology and management of postoperative ileus. World J Surg 2006;30: 1382–91[Web of Science][Medline]
6. Kehlet H, Holte K. Review of postoperative ileus. Am J Surg 2001;182(5 A suppl):3S–10S[Web of Science][Medline]
7. Luckey A, Livingston E, Tache Y. Mechanisms and treatment of postoperative ileus. Arch Surg 2003;138:206–14[Abstract/Free Full Text]
8. Kreis ME, Kasparek M, Zittel TT, Becker HD, Jehle EC. Neostigmine increases postoperative colonic motility in patients undergoing colorectal surgery. Surgery 2001;130:449–56[Web of Science][Medline]
9. Kirdemir P, Ozkocak I, Demir T, Gogus N. Comparison of postoperative analgesic effects of preemptively used epidural ketamine and neostigmine. J Clin Anesth 2000;12:543–8[Web of Science][Medline]
10. Klamt JG, Garcia LV, Prado WA. Analgesic and adverse effects of low dose of intrathecally administered hyperbaric neostigmine alone or combined with morphine in patients submitted to spinal anesthesia: pilot studies. Anesthesia 1999;54:27–31[Web of Science][Medline]
11. Klamt JG, Slullitel A, Garcia IV, Prado WA. Postoperative analgesic effect of intrathecal neostigmine and its influence on spinal anesthesia. Anesthesia 1997;52:547–51[Web of Science][Medline]
12. Lauretti GR, Reis MP. Subarachnoid neostigmine does not affect blood pressure or heart rate during bupivacaine spinal anesthesia. Reg Anesth 1996;21:586–91[Web of Science][Medline]
13. Lauretti GR, Reis MP. Postoperative analgesia and antiemetic efficacy after subarachnoid neostigmine in orthopedic surgery. Reg Anesth 1997;22:337–42[Web of Science][Medline]
14. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology 1995;82:331–43[Web of Science][Medline]
15. Lauretti GR, Hood DD, Eisenach JC, Pfeifer BL. A multi-center study of intrathecal neostigmine for analgesia following vaginal hysterectomy. Anesthesiology 1998;89:913–8[Web of Science][Medline]
16. 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;90:1534–8[Web of Science][Medline]
17. Norris EJ, Beattie C, Perler BA, Martinez EA, Meinet CL, Anderson GF, Grass JA, Sakima NT, Gorman R, Achuff SC, Martin BK, Minken SL, Williams GM, Traysmann RJ. Double-masked randomized trial comparing alternate combinations of intraoperative anesthesia and postoperative analgesia in abdominal aortic surgery Anesthesiology 2001;95:1054–67[Web of Science][Medline]
18. Roelants F. The use of neuroaxial adjuvant drugs (neostigmine, clonidine) in obstetrics. Curr Opin Anaesthesiol 2006;19:233–37[Medline]
19. Chia YY, Chang TH, Liu K, Chang HC, Ko NH, Wang YM. The efficacy of thoracic epidural neostigmine infusion after thoracotomy. Anesth Analg 2006;102:201–8[Abstract/Free Full Text]
20. Gordh T Jr, Jansson J, Hartvig P, Gillberg PG, Post C. Interactions between noradrenergic and cholinergic mechanisms involved in spinal nociceptive processing. Acta Anaesthesiol Scand 1989;33:39–47[Web of Science][Medline]
21. Gilberg PG, Hartiv P, Gordh T. Behavioral effects after intrathecal administration of cholinergic receptor agonist in rat. Psychopharmacology 1990;100:464–9[Medline]
22. Eisenach JC, Hood DD, Curry R. Phase I human safety assessment of intrathecal neostigmine containing methyl-and propylparabens. Anesth Analg 1997;85:842–6[Abstract]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Caliskan, E. Articles by Turkoz, R. Search for Related Content PubMed PubMed Citation Articles by Caliskan, E. Articles by Turkoz, R. Related Collections Anesthetic Techniques Complications Pain Medicine Regional Anesthesia Pain