Comparison between analgesic effect of bupivacaine thoracic epidural and ketamine infusion plus wound infiltration with local anesthetics in open cholecystectomy.

BACKGROUND: Neuraxial blocks result in sympathetic block, sensory analgesia and motor block. Continuous epidural anesthesia through a catheter offers several options for perioperative analgesia. Local anesthetic boluses or infusions can provide profound analgesia. Although the role of low-dose ketamine (<2 mg/kg intramuscular, <1 mg/kg intravenous [IV] or ≤ 20 μg/kg/min by IV infusion) in the treatment of post-operative pain is controversial, perioperative administration of a small dose of ketamine may be valuable to a multimodal analgesic regimen. A local anesthetic can be used for wound infiltration intra-operative to minimized the surgical pain. PATIENTS AND METHODS: A prospective randomized study was performed in which 40 patients scheduled for elective open cholecystectomy under general anesthesia admitted to the Medical Research Institute were included and further subdivided into two groups, group A, received thoracic epidural catheter at T7-8, activation was done 20 min before induction of anesthesia with plain bupivacaine at a concentration of 0.25% at a volume of 1 ml/segment aiming to block sensory supply from T4-L2, then received continuous thoracic epidural infusion intra and postoperatively with plain bupivacaine at a concentration of 0.125% at a rate of 5 ml/h for 24 h, group B received 0.3 mg/kg bolus of ketamine at the time of induction then 0.1 mg/kg/h ketamine IV infusion during surgery followed by wound infiltration with 15 ml of plain bupivacaine 0.5% at the time of skin closure.
RESULTS: Bupivacaine thoracic epidural analgesia had better control on heart rate and mean arterial blood pressure than ketamine infusion plus wound infiltration with local anesthetic in patients undergoing open cholecystectomy.
CONCLUSION: Thoracic epidural analgesia had better control on hemodynamic changes intra-and postoperatively than ketamine infusion with local wound infiltration in open cholecystectomy.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

The relief of pain has been one of the primary reasons for development of health care. It is well-documented that inadequately relieved pain is deleterious and can lead to a number of complications in the post-operative period. Therefore, the pain of surgery must be relieved totally.[1] As a result of a better understanding of the mechanisms and physiology of acute pain and nociceptors, the goal of a stress-free anesthesia with a minimal post-operative discomfort is attainable. No single therapy can achieve this goal.[2] Principles of multimodal strategy refer to the simultaneous use of multiple analgesic methods or drugs. A multimodal approach typically deploys interventions such as local anesthesia, a non-steroidal anti-inflammatory drug, or an opioid so as to achieve combination analgesic effect.[3] Neuro-axial blocks result in sympathetic block, sensory analgesia and motor block (depending on dose, concentration, volume or type of local anesthetic).[4] Ketamine traditionally recognized as an intraoperative anesthetic agent; however low dose ketamine for post-operative analgesia has developed in part due to its N-Methyl-D-aspartate (NMDA) antagonistic properties in attenuating central sensitization and opioid tolerance.[5] Ketamine may be a valuable addition to the multimodal analgesic regimen and an adjunct enhancing analgesia and reducing opioid related side-effects.[678] A local anesthetic is a drug that causes reversible local anesthesia and a loss of nociception. When it is used on specific nerve pathways (nerve block), effects such as analgesia can be achieved. A local anesthetic can be used for wound infiltration intra-operatively to minimize the surgical pain.[9] The choice of local anesthetic agent is important. Agents of long lasting effects should be chosen for wound infiltration whether they are used alone or as an adjunct to a balanced pain management plan.[10] The primary objective of this study is to compare the analgesic effect of thoracic epidural versus ketamine infusion plus wound infiltration. The secondary objectives included differences between groups regarding total dose of analgesia, the time of first analgesic use and sedation score postoperatively in patients undergoing open cholecystectomy under general anesthesia.

PATIENTS AND METHODS

A prospective randomized study was performed in which 40 adult patients American Society of Anesthesiologists (ASA) physical status class I or II aged between 25 and 45-year-old scheduled for open cholecystectomy under general anesthesia. After approval of the medical ethical committee, an informed written consent was taken from every patient enrolled in this study including a detailed explanation of the study, benefits and possible side-effects. A power analysis showed that 60 patients should be included in the study to get an 81% difference in post-operative analgesia between the two groups, however, due to the diminished application of open cholecystectomy, only 40 patients were included in the study, they were randomly assigned into two groups, 20 patients each.

Group A

A thoracic epidural catheter was inserted for each patient of this group using paramedian approach at the level of T7-T8 and activation was done 20 min before induction of anesthesia with plain bupivacaine 0.25% (1 ml/segment) aiming to block sensory supply from T4-L2, then continuous infusion intra and postoperatively was started with plain bupivacaine 0.125% (5 ml/h) for 24 h through syringe pump. Exclusion criteria include any contraindication to epidural anesthesia (patient refusal, coagulopathy, skin infection at the injection site, raised intracranial pressure, hypovolemia and low fixed cardiac output states), any known allergies to the drugs used and patients on cardiac and antihypertensive medications.

Group B

Patients of this group received 0.3 mg/kg bolus of ketamine at the time of induction then 0.1 mg/kg/h intravenous (IV) infusion during surgery followed by wound infiltration with 15 ml of plain bupivacaine 0.5% at the time of skin closure. Induction of anesthesia was carried out with propofol (1.5-2 mg/kg) followed by rocuronium (0.6 mg/kg) to facilitate endotracheal intubation, then mechanical ventilation was started. Maintenance of anesthesia was done with isoflurane 1.5% in 100% oxygen and respiration was controlled to maintain EtCO2 between 30 and 40 mmHg. Recovery of anesthesia was done by neostigmine (0.05 mg/kg) and atropine (0.015 mg/kg) for reversal of residual muscle relaxation. Electrocardiography, heart rate (beat/min), non-invasive mean arterial blood pressure (mmHg) and oxygen saturation (SpO2) were recorded and compared between the two groups, before induction of general anesthesia, every 10 min during the surgery and post-operatively (immediately after full recovery, every 30 min for 2 h, then every 4 h for the first 24 h). Post-operative visual analog scale (VAS) was assessed by direct questioning immediately after full recovery of the patient and then every 4 h for the first 24 h. Patients received a rescue dose of IV tramadol (30 mg) if VAS is more than 4, with a maximum dose limit of 400 mg/day. First time of rescue analgesia and total dose of IV tramadol (during the first 24 h post-operatively) were recorded. Side effects such as nausea, vomiting, arrhythmia, itching, hallucinations or tremors were recorded. Sedation score[11] was recorded post-operatively, at recovery and every 4 h for 24 h. For data analysis, post-operative VAS between the two groups was considered the primary outcome variable, with a difference considered significant at the P < 0.05 level. The secondary variables were the first time of rescue analgesic use, total dose of post-operative analgesia and sedation score, these variables were estimated by an observer using a sedation score for sedation assessment and calculating the total dose of post-operative analgesia. These were compared by analysis of variance for the two groups and confirmed with Wilcoxon's nonparametric test. The frequency of side effects among the groups was compared by χ2 analysis with Fisher's exact test. 0.05 level with 80% power.

RESULTS

There was no statistical significant difference between the studied groups regarding age, gender, weight, height, SpO2 (intra- and post-operatively), total dose of analgesia, the time for first rescue analgesia and side-effects [Tables 1-4]. Patients of group A showed significant decrease in heart rate and mean arterial pressure than patients of group B intra- and post-operatively [Tables 5-8]. There were significant changes as regards the mean values of VAS in the post-operative periods in the studied groups with higher values in group B [Table 9]. There was statistical significant difference between the studied groups regarding post-operative changes in sedation score with higher values in group B except at 8 and 12 h post-operatively [Table 10].

Table 1

Demographic data of patients

Table 4

Comparison between both groups as regards side effects

Table 5

Comparison between both groups as regards intra-operative heart rate (beats/min)

Table 8

Comparison between both groups as regards post-operative mean blood pressure

Table 9

Comparison between both groups as regards visual analog score

Table 10

Comparison between both groups as regards sedation score

DISCUSSION

Although the role of low-dose ketamine (<2 mg/kg intramuscular, <1 mg/kg IV or ≤ 20 μg/kg/min by IV infusion) in the treatment of post-operative pain is controversial, perioperative administration of a small dose of ketamine may be valuable to a multimodal analgesic regimen and an adjuvant to opioids and local anesthetics by enhancing analgesia and reducing opioid-related side-effects.[812]

This study indicated that intraoperative and post-operative heart rate and mean arterial blood pressure were better controlled with bupivacaine thoracic epidural analgesia than IV ketamine infusion plus wound infiltration with bupivacaine local anesthetic. This can be explained by the good analgesic effect achieved by bupivacaine thoracic epidural plus the depressive effect of epidural analgesia on the sympathetic nervous system decreasing the heart rate and blood pressure.[13] On the contrary, ketamine was known to increase arterial blood pressure and heart rate due to central stimulation of the sympathetic nervous system and inhibition of the reuptake of nor-epinephrine.[14] Bidwai et al.[14] showed a significant increase in heart rate and blood pressure following ketamine bolus followed by ketamine infusion in upper abdominal surgery. Arai et al.[15] had suggested that the combined use of epidural analgesia and volatile anesthetics had hemodynamic benefits such as inhibition of tachycardia, hypertension and suppression of an increase in pulmonary vascular resistance due to surgical stress, this randomized trial was performed on 34 patients physical status ASA I or II received thoracic epidural anesthesia for cholecystectomy.

The significant decrease in VAS encountered in bupivacaine thoracic epidural group was explained by its effective analgesic action. The mechanism of such analgesic action was suggested to be that bupivacaine injected into the epidural space caused nerve blocks at three possible sites; the spinal nerves intra-durally (this was probably the essential site of blockade), the spinal cord and the spinal nerves in the paravertebral space.[16] Malik[17] stated that “The use of intra-operative and post-operative epidural analgesia was found to be associated with reduction in the post-operative pain in patients undergoing open cholecystectomy”. Vukosavljevic[18] found that thoracic epidural analgesia during upper abdominal surgery provided better hemodynamic stability and lower blood loss due to intraoperative bleeding, statistically and clinically significant better analgesia in the first post-operative 72 h, compared with systemic analgesia. Lavand’homme et al.[19] had suggested that intraoperative epidural analgesia provided effective preventive analgesia after major digestive surgery.

In a study by Edwards et al.[20] found that the addition of ketamine infusion to a continuous infusion of morphine did not significantly improve analgesia in patients undergoing upper abdominal surgery. Aida et al.[21] had suggested that for definitive preemptive analgesia, blockade of opioid and NMDA receptors is necessary for upper abdominal surgery such as gastrectomy; Epidural bupivacaine may affect the spinal cord segmentally, whereas IV ketamine may block brain stem sensitization via the vagus nerve during upper abdominal surgery. In that randomized double-blind study, Preemptive analgesia by epidural bupivacaine and by IV low-dose ketamine were significantly effective but not definitive. With epidural bupivacaine, a significant reduction in visual analog scale scores at rest was observed at 24 and 48 h. With IV ketamine, visual analog scale scores at rest was lower than epidural group at 6, 12, 24 and 48 h. Although in our study better analgesia (lower VAS) at full recovery, 4, 16, 20 and 24 h was recorded in the epidural group. This may be explained by the difference in number of cases and difference in doses between the two studies.

Subramaniam[22] found that Intra and post-operative IV ketamine infusion does not increase pain relief after major spine surgery, the study was performed on two groups, 15 patients each, group (1) received general anesthesia plus ketamine infusion and group (2) received general anesthesia plus saline infusion. No difference in pain scores at rest and movement was noted between the groups. VAS results in ketamine infusion group was within the range of our study.

Webb et al.[23] had suggested that small-dose ketamine was a useful addition to tramadol and morphine after major abdominal surgery. In this double-blind randomized controlled trial, adult patients (n = 120) having elective laparotomy were randomly assigned to a ketamine group (intraoperative ketamine 0.3 mg/kg and post-operative infusion at 0.1 mg/kg/h or control group (equivalent volume/rate of normal saline). All patients received intraoperative tramadol 3 mg/kg and a tramadol infusion 0.2 mg/kg/h for 48 h post-operatively and had morphine patient-controlled analgesia available for rescue analgesia. The ketamine group had less pain at rest (P = 0.01) and with movement (P = 0.02) and required less morphine (P = 0.003) throughout the 48-h study period.

Laskowski et al.[5] had suggested that IV ketamine is an effective adjunct for post-operative analgesia. Particular benefit was observed in painful procedures, including upper abdominal, thoracic and major orthopedic surgeries. The analgesic effect of ketamine was independent on the type of intraoperative opioid administered, timing of ketamine administration and ketamine dose. In a double-blinded and placebo-controlled study using IV ketamine (bolus or infusion) to decrease post-operative pain. A reduction in total opioid consumption and an increase in time to first analgesic were observed across all studies (P < 0.001). This finding implies an improved quality of pain control in addition to decreased opioid consumption.

It was found that there was statistical significant difference between the studied groups regarding post-operative changes in sedation score except in 8 and 12 h. This may be attributed to the undesirable psychotomimetic side effects (e.g. illusions, disturbing dreams and delirium) during emergence and recovery of ketamine group.[24]

In this study, there was no statistical significant difference between the studied groups regarding intraoperative and post-operative changes in SpO2, total dose of analgesia (mg), the time for first need of analgesia (min) and side-effects (nausea, vomiting, itching, arrhythmia, hallucination, tremors, headache, back pain) (P > 0.05). Thus, it was found that both techniques are effective but bupivacaine thoracic epidural was better than ketamine infusion plus wound infiltration with bupivacaine in patients undergoing open cholecystectomy under general anesthesia as regards analgesia, sedation, controlling heart rate and blood pressure intra-operatively and post-operatively with less side-effects.

CONCLUSION

Both the epidural and ketamine infusion with local anesthetic infiltration have a good effect on post-operative analgesia in the doses used in this study. General anesthesia with thoracic epidural analgesia compared with ketamine infusion provided better post-operative analgesia (significantly lower VAS). Preemptive thoracic epidural analgesia had better control on hemodynamic changes intra-and postoperatively than intraoperative ketamine infusion plus wound infiltration with local anesthetic in open cholecystectomy. Thoracic epidural analgesia showed better sedation score than ketamine infusion. No significant differences were encountered as regards the incidence of side-effects, total dose of post-operative tramadol and first need of analgesia.

Table 2

Comparison between both groups as regards intra-operative oxygen saturation

Table 3

Comparison between both groups as regards post-operative oxygen saturation

Table 6

Comparison between both groups as regards post-operative heart rate (beats/min)

Table 7

Comparison between both groups as regards intra-operative mean blood pressure