Optimal single-dose epidural neostigmine for postoperative analgesia after partial hepatectomy.

OBJECTIVE: Neostigmine can produce analgesia by acting on the spinal cord. This study was to determine the optimal single-dose of epidural neostigmine for postoperative analgesia after partial hepatectomy. PATIENTS AND METHODS: Twenty-six patients undergoing elective partial hepatectomy under general anesthesia combined with epidural block were studied. The dose of epidural neostigmine was determined using Dixon's up-and-down method, starting from neostigmine 100 μg with an interval of 25 μg. Thirty minutes after skin incision, a predetermined dose of neostigmine was injected via the epidural catheter. Each patient received 0.125% bupivacaine and fentanyl 2 μg/ml for patient controlled epidural analgesia (PCEA) after the operation. Assessment of analgesia quality was performed at 8 h and 24 h after the operation.
RESULTS: The ED50 of epidural neostigmine in combination with PCEA for satisfactory analgesia was 226.78 ± 33.20 μg. Probit analysis showed that the ED50 and ED95 of epidural neostigmine were 228.63 μg (95% CI = 197.95-299.77 μg) and 300.12 μg (95% CI = 259.44-741.65 μg), respectively.
CONCLUSION: The ED50 and ED95 of epidural neostigmine in combination with PCEA for satisfactory analgesia after partial hepatectomy were 228.63 μg (95% CI = 197.95-299.77 μg) and 300.12 μg (95% CI = 259.44-741.65 μg).

Introduction

Patient controlled epidural analgesia (PCEA) provides effective postoperative analgesia using local anesthetics combined with opioids.[1] But the side effects associated with opioids such as nausea, vomiting, pruritus, respiratory depression and urinary retention are dose-dependent. It has been proved that neuraxial adjuvant drug, acetylcholine esterase inhibitors (neostigmine), can produce analgesia by acting on the spinal cord.[2] Some studies demonstrated that administration of epidural neostigmine in combination with local anesthetics and opioids prolonged the duration of postoperative analgesia and decreased the visual analog scale (VAS) score using a single dose ranging from 1 μg/kg–10 μg/kg.[34567] However, there is no report on the optimal single-dose of epidural neostigmine for postoperative analgesia. In this study, we sought to estimate the optimal single-dose of epidural neostigmine in combination with PCEA for satisfactory postoperative analgesia after partial hepatectomy.

Patients and Methods

Patients

This study was approved (#B2012-091) by the Ethics Committee of Zhongshan Hospital, Fudan University, Shanghai, China. Informed consent was obtained from the subjects. Twenty-six patients, aged 18–64 years, ASA I-II, undergoing elective partial hepatectomy were enrolled in this study. The exclusion criteria included a history or laboratory evidence of cardiac disease, pulmonary disease, severe hepatic insufficiency, renal insufficiency, coagulation disorder, and receiving medication for chronic pain. All patients received routine preoperative preparation. All patients fasted for more than 10 h before the operation. No premedication was given.

Anesthesia

Each patient received an epidural catheter, inserted between T8 and T9, and 1% lidocaine 4 ml was administered to confirm the location. General anesthesia was induced with fentanyl 3 μg/kg and plasma concentration target controlled infusion of propofol 4 μg/ml. Tracheal intubation was facilitated by rocuronium 0.6 mg/kg and the lungs were ventilated to normocapnia (ETCO2 35-40 mmHg) with 50% oxygen with air. After induction, 8–12 ml 0.5% bupivacaine was administered in increments and maintained with intermittent boluses of 3-5 ml every hour during the operation. General anesthesia was maintained with desflurane which was administered at an end-tidal concentration of approximately 4.5-6.0 vol%, changing with hemodynamic monitoring. Thirty minutes after the skin incision, neostigmine diluted in 5 ml normal saline was injected via the epidural catheter. Supplemental doses of rocuronium were given to achieve complete surgical muscle relaxation throughout the operation. Hemodynamic monitoring was performed using a three-lead electrocardiogram monitor, finger pulse oximetry and radial artery catheterization for continuous arterial pressure measurement. Boluses of phenylephrine were given if the mean arterial pressure decreased to a value less than 60 mmHg. Lactated Ringer's solution and Hydroxyethyl Starch 130/0.4 Sodium Chloride Injection were infused with a ratio of 3:1 during the operation, as per the blood loss and hemodynamic monitoring. Tropisetron 6 mg was given intravenously 30 min before the end of operation. Each patient received 0.125% bupivacaine and fentanyl 2 μg/ml for PCEA with background infusion rate 2.5 ml/h, bolus 4 ml, and locktime 10 min after the operation.

Experimental Protocol

The dose of epidural neostigmine was determined to be 100 μg for the first patient, referring to a previous study.[8] Dose adjustment interval was defined according to the expected standard deviation of the ED50.[910] Assessment of analgesia quality was performed at 8 h and 24 h after the operation by a scoring system using the following variables: Duration of analgesia before the first bolus of PCEA, VAS score and numbers of bolus of PCEA. Each of these variables was rated as good or poor. Analgesia quality was regarded as satisfactory if all variables were good, and dissatisfactory if any variable was poor [Table 1]. The investigator performing the assessment of analgesia quality was an experienced anesthesiologist who was blind to the dose of epidural neostigmine used. Satisfactory or dissatisfactory analgesia was defined as follows:

Table 1

Assessment of analgesia quality at 24 h after the operation

Satisfactory: Good analgesia quality at 24 h after the operation. A result defined as satisfactory directed a decrement (25 μg of epidural neostigmine) for the next patient.

Dissatisfactory: Poor analgesia quality at 24 h after the operation. A result defined as dissatisfactory directed an increment (same interval as above) for the next patient. At 24 h (end of the protocol), participants who complained of dissatisfactory analgesia quality were given rescue analgesia (lidocaine 1% 5 ml injected via epidural catheter and morphine 2 mg intravenously).

In addition, side effects such as nausea, vomiting, pruritus and respiratory depression were recorded.

Statistical analysis

Numerical data including gender and ASA physical status were compared with Chi-squared analysis and Fisher's exact test. Measurement data were expressed as mean ± SD and analyzed using independent-samples t-test. Data were collected from 26 patients using Dixon's up-and-down method to provide seven pairs of data when an increase in neostigmine dose changed a negative response to a positive response. The 50% effective dose (ED50) of epidural neostigmine was determined by calculating the midpoints dose of all independent pairs from consecutive patients after seven crossover points were obtained.[11] The data were also subjected to Probit regression analysis to obtain the ED50 and 95% effective dose (ED95) and the 95% confidence intervals (CI). Probit analysis was performed using Statistical Package for the Social Sciences (SPSS) 19.0 for windows. Probability value < 0.05 was considered statistically significant.

Results

Twenty-six patients were enrolled in this study when seven pairs of dissatisfactory-satisfactory results had occurred. The postoperative analgesia quality for each consecutive patient, using Dixon's up-and-down method, is shown in Figure 1.

Figure 1

Satisfactory or dissatisfactory analgesia quality at 24 h after the end of the operation on the determined epidural neostigmine dose. The arrow represents the mean dose of epidural neostigmine when crossing a dissatisfactory analgesia to a satisfactory analgesia. The average of the median epidural neostigmine dose of seven dissatisfactory- satisfactory pairs is 226.78 ± 33.20 μg

There were no significant differences in the demographic data and surgical characteristic profiles between the satisfactory group and the dissatisfactory group [Table 2]. The results of the calculations for the seven crossover pairs indicated that the ED50 of epidural neostigmine for satisfactory analgesia in combination with PCEA was 226.78 ± 33.20 μg [Figure 1]. Probit analysis showed that the ED50 and ED95 of epidural neostigmine were 228.63 μg (95% CI = 197.95–299.77 μg) and 300.12 μg (95% CI = 259.44–741.65 μg), respectively.

Table 2

Demographic data and surgical characteristic profiles of the patients

Between the satisfactory and dissatisfactory groups, significant differences were observed in duration of analgesia before the first bolus of PCEA, VAS score at 24 h and numbers of bolus of PCEA [Table 3]; and there were no significant differences in the incidence of side effects including nausea (1/10 vs. 1/16), vomiting (0/10 vs. 1/16), pruritus (2/10 vs. 3/16), and respiratory depression (0/10 vs. 0/16).

Table 3

PCEA data at 24 h after the elective partial hepatectomy

Discussion

Some studies have proved that adjuvant neostigmine have additive or synergistic effect in combination with local anesthetics and opioids during postoperative period. Epidural neostigmine (1, 2, or 4μg/kg) in lidocaine produced a dose-independent analgesic effect (approximately 8 h) compared to the control group (approximately 3.5 h);[3] 0.6 mg of epidural morphine combined with 60 μg of epidural neostigmine resulted in postoperative analgesia (11 h) devoid of side effects in patients undergoing orthopedic surgery;[4] Epidural combination of neostigmine 500 μg with sufentanil 10 μg provided similar duration of analgesia (119 min) as epidural sufentanil 20 μg (118 min) and allowed effective and selective analgesia devoid of side effects in the first stage of labor;[5] Epidural neostigmine 10 μg/kg combined with low dose of bupivacaine (10 mg) provided a longer duration of analgesia (223 min) than did bupivacaine alone (78 min) after abdominal hysterectomy;[6] The time to first rescue analgesic was 10 h after epidural neostigmine 300 μg was administered with 10 mL of 0.75% ropivacaine before the induction of general anesthesia.[7] Recent studies of combinations of epidural neostigmine with local anesthetics and opioids for labor analgesia[512] and caesarean section[13] also showed an analgesia effect without unexpected maternal and neonatal outcomes.

The analgesic effects of epidural neostigmine may be attributed to the fact that neostigmine inhibits the breakdown of acetylcholine in the dorsal horn[1415] and spinal meninges[16] after transdural diffusion to the cerebrospinal fluid (CSF), then acetylcholine causes analgesia through the following paths: 1) Directly acting on spinal cholinergic muscarinic M1 and M3 receptors;[17] 2) Acting on nicotinic receptor subtypes;[18] 3) Indirectly stimulating the spinal cord to release nitric oxide.[19] In addition, epidural neostigmine produces analgesia effects perhaps through central cholinergic mechanisms.[20] Eisenach JC[21] has also demonstrated that neostigmine is a well tolerated neuraxial drug that produces muscarinic receptor-mediated analgesia by reducing the breakdown of acetylcholine in enhancing the dorsal horn of the spinal cord.

Earlier studies[142223] have proved the safety and analgesic efficacy of intrathecal neostigmine in animals and humans, but the intrathecal route has been largely limited by a high incidence of nausea (33%-67%) and vomiting (17%-50%).[24]

An interesting study of Chia et al.,[25] showed that preoperative use of epidural neostigmine 500 μg for thoracotomy patients followed by continuous infusion 17.5 μg/h during surgery with extension into the postoperative period provided preemptive and preventive analgesia effects on postoperative pain intensity and provided an analgesic-sparing effect on PCEA consumption, with both effects achieved without increasing the incidence of side effects. Moreover, a potential advantage of epidural neostigmine is that it may enable faster restoration of bowel sounds and shorten duration of postoperative ileus after abdominal surgery.[26]

The present study has limitations that we assessed the analgesia quality only at 8 h and 24 h after the end of the operation and our data did not include all information regarding the outcome of participants. Another limitation is the criteria of the scoring system in this study, although the criteria of VAS score is commonly accepted, the criteria of time to the first PCEA bolus and numbers of PCEA bolus were based on our pilot study and the clinical practice. Furthermore, some patient complained that more pain from the site of abdominal drain tube than that from abdominal incision. Future clinical research is required to identify that whether the optimal dose of epidural neostigmine in our study can improve the outcomes of patients undergoing the upper abdominal surgery without other side effects. It is to be noted that the 95% CI for ED50 and ED95 values are rather wide because of the sample size limitation.

We conclude that the ED50 and ED95 of epidural neostigmine in combination with PCEA for satisfactory analgesia after partial hepatectomy were 228.63 μg and 300.12 μg using Dixon's up-and-down method. Satisfactory analgesia of epidural neostigmine makes this drug an attractive alternative to the currently used epidural antinociceptive drugs.