Comparison of sodium diclofenac, ketamine and propofol with fentanyl and midazolam in balanced anaesthesia.

CONTEXT: Analgesia is based on balanced anaesthesia, which is usually maintained by administration of narcotic agents. In some patients, it is not possible to use narcotics. We compared hemodynamic changes, anaesthesia depth, emetic sequelae and post-operative pain between sodium Diclofenac, Ketamine-Propofol (DKP) and Fentanyl-Midazolam (FM). AIMS: The effectiveness of an anaesthetic technique employing sodium was compared against in patients undergoing elective surgery. SETTINGS AND
DESIGN: In a clinical trial study, 82 patients who attended for an elective surgery were randomly divided into two groups.
MATERIALS AND METHODS: In DKP group pre-medication included Sodium Diclofenac 1 mg/kg and Midazolam 0.02 mg/kg, whereas, in FM group they were Fentanyl 2 μg/kg and Midazolam 0.02 mg/ kg. Anaesthesia induction in both groups was the same. Anaesthesia was conserved in DKP group by using Propofol plus Ketamine infusion plus N2O 50% and in FM group with Fentanyl plus Midazolam plus N2O 50%. Hemodynamic changes, depth of anaesthesia, nausea and vomiting, post operative analgesic effects were recorded.
RESULTS: Hemodynamic changes and depth of anaesthesia were similar throughout the maintenance phase in two groups. In FM group, significant increase in heart rate was recorded in recovery room. Pain score according to visual analogue scale (VAS) and need for analgesics, was significantly more in FM group compared to DKP group (P = 0.000). No patient suffered from nausea, vomiting or hallucinations.
CONCLUSIONS: This study revealed that intravenous administration of Sodium Diclofenac along with Ketamine and Propofolplus N2O 50% for general anaesthesia provides a balanced anaesthesia as well as hemodynamic stability, and adequate depth of anaesthesia. It also reduces the postoperative pain and need for narcotics. We recommended DKP plus N2O 50% method for patients prohibited from opioid administration. It will be an acceptable method in sensitive patients.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

The term balanced anaesthesia was introduced by Lundy in 1926 which consists of amnesia, analgesia, muscle relaxation and autonomic reflexes suppression as well as hemodynamic stability. The use of opioids in general anaesthesia is a key component in the current notion of “balanced anaesthesia”. Opioid administration in balanced anaesthesia reduces anxiety and pain before the operation, decreases somatic and autonomic responses of airway stimulations, corrects hemodynamic stability and lowers the need for vaporizing anaesthetic drugs as well as a post-operation analgesia.[1] Fentanyl is one of the most common parenteral opioid analgesics administered in balanced anaesthesia because it allows smooth emergence from anaesthesia without coughing and bucking, and provides residual postoperative analgesia.[23]

In some conditions like surgical squint correction, the anaesthesiologist prefers to avoid opioid analgesic agents to reduce the post-operation nausea and vomiting (PONV);[45] Also, concern over opioid side effects can cause practitioners to hesitate to use opioids. In patients undergoing ultra rapid opiate detoxification who are applied with naltrexone, there are some limitations for opioids, but not for other analgesic such as Ketamine and Non steroidalanti inflammatory drugs (NSAIDs);[67] thus, opioids cannot be used always, and therefore, the need for anaesthetic technique with no opioid side effects emerges.[5]

Propofol is the most frequently used intravenous (IV) anaesthetic today. It is suitable for the induction and maintenance of anaesthesia. Compared with volatile anaesthetics, the use of propofol for general anaesthesia has been purported to reduce postoperative emesis and requirements for antiemetic[89] Sodium diclofenac is one of the common NSAIDs with anti inflammatory, analgesic and anti pyretic effects, which can be used to reduce pain.[10] Ketamine is a non barbiturate anaesthetic drug with analgesic effects, which is fast-acting and used for premedication, sedation, induction or maintenance of anaesthesia and postoperative analgesia.[11] There has been increased interest in the routine use of ketamine in small doses for preventive analgesia and for the treatment or prevention of opiate tolerance and hyperalgesia.[12-14] Benzodiazepines are among the most frequently prescribed drugs. Midazolam is often used for sedation as a premedication for balanced anaesthesia; however, there is often a disparity in the level of sedation compared with the presence of amnesia.[14]

The study was designed to test the hypothesis that administration of sodium diclofenac and ketamine accompanied with propofol instead of fentanyl in balanced anaesthesia may adversely affect the quality of anaesthesia and postoperative outcome in patients receiving the total intra venous anaesthesia (TIVA) method plus N2O 50%, in patients prohibited from opioid administration. To attempt this, hemodynamic changes, anaesthesia depth, emetic sequelae and post-operative pain were studied in usual methods for opioid administration (fentanyl and midazolam - FM group) and the other group without administration of opioids by sodium diclofenac, ketamine and propofol (DKP). We substituted fentanyl by sodium diclofenac and ketamine in patients undergoing surgery who received TIVA in balanced anaesthesia.

MATERIALS AND METHODS

This experimental study was conducted on a single surgical population of patients undergoing elective inguinal hernioraphy with duration of surgery under 1 hour. The study was approved by our institutional review board, and the written informed consent was obtained from all of the participants. Some of our exclusion criteria were a history of current NSAIDs use, analgesic or psychotropic drug therapy, alcohol or substance abuse, NSAID allergy, bronchial asthma, peptic ulcer disease, renal disease, or bleeding disorders, end stage disease and confounding underlying diseases. Patients who had the above mentioned criteria were excluded from the study, and 82 patientsof American Society of Anesthesiologists (ASA) Class I, between 15 and 55 years of age old were included.

The patients were divided into two groups randomized. In DKP group, premedication included sodium diclofenac 1 mg/kg and midazolam 0.02 mg/kg, whereas in FM group fentanyl 2 μg/kg and midazolam 0.02 mg/kg were administered. Hemodynamic factors like systolic and diastolic Blood Pressure (BP), Heart Rate (HR) and Bispectrial index monitoring (with Danmeter CSM 06 Denmark instrument), emetic sequelae were evaluated and recorded before, during and after the surgery up to discharge time from post anaesthetic care unit (PACU).

Anaesthesia induction in both the groups was performed using sodium thiopental 5 mg/kg and atracorium 0.5 mg/ kg and tracheal tube was inserted. Anaesthesia in FM group was conserved with the infusion of midazolam 1 μg/kg/min plus fentanyl 0.05 μg/kg/min using infusion pump along with 50% Oxygen and Nitrous Dioxide 50%. DKP group was conserved using propofol and ketamine infusion (each 50 μg/kg/min) using infusion pump in a syringe mixed along with 50% Oxygen and Nitrous dioxide.

Metoclopramide 10 mg and Dexamethasone 8 mg was injected IV in order to avoid post operative nausea and vomiting prophylactically 10 minute before end of surgery. In both groups, hemodynamic changes (systolic and diastolic blood pressure and heart rate) and Bispectral index monitoring (BIS) as anaesthesia depth were recorded every 5 minutes and 10 minutes prior to the end of operation. Emetic sequelae and postoperative analgesia was evaluated at the end of the surgery and after patient awareness every 5 minutes up to the patients′ discharge time of PACU. The patients were monitored in PACU and their pain score according to visual analogue scale (VAS), facial expression type, was evaluated and recorded through the next two hours.

A VAS is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. From the patient's perspective, this spectrum appears continuous - their pain does not take discrete jumps, as a categorization of none, mild, moderate and severe would suggest.[15] We explain pain score according to visual analogue scale based on facial expression as: 0-1, no pain; 2-4 slight pain (Class I); 5-6 moderate pain (Class II); 7-8 Considerable pain (Class III); 9-10 severe pain (Class IV).

The scores 0 and Class I were considered as no pain or slight pain and if the score was under Class II, III or IV, 30-50 mg of Meperidine (pethidine) was injected, and the score and dosage were recorded.

The data was analyzed using t-test for hemodynamic changes and Mann Whitney for Pain Score and chi-square for nausea and vomiting and other appropriate statistical methods for data analysis were used. P value less than 0.05 was considered significant.

RESULTS

Among the 82 cases, 34 were female and 48 were male, there was no statistically significant difference between the two groups with regard to demographics data (P=0.122). Mean age in FM group was 29/10±10.62 years old and in DKP 33.76±11.22 years old which was not significantly different (P=0.180).

There was no significant difference in the mean systolic and diastolic BP before anaesthesia induction and after pre-medication between the two groups and also until the end of operation [Figure 1]. The mean systolic and diastolic BP fluctuation did not differ significantly among the two groups.

Figure 1

Comparison of hemodynamic changes in FM and DKP groups throughout the general anaesthesia

HR in both groups was similar prior to anaesthesia, then a little increased after anaesthesia induction and reduced to a same ratio throughout the anaesthesia. After the operation and in PACU, there was a significant increase in heart rate in FM group in the 5th minute of recovery (P=0.001) and 10th minute of recovery (P=0.009) compared to DKP group [Figure 2].

Figure 2

Comparison of heart rate fluctuations in FM and DKP groups throughout general anaesthesia

The need for analgesics was significantly different in two groups. Thirty eight patients in FM group experienced II, III or IV scores for pain and needed analgesics; however, in DKP group no patient had such a need (P=0.000). Pain score was significantly different between the two groups in recovery (P<0.001). Table 1 shows the comparison of pain scale in FM and DKP groups in recovery period. There was no significant difference in mean depth of anaesthesia based on BIS in two groups and it was in the range of 40 to 60 (which is an appropriate range for general anaesthesia and surgery). There was no significant difference between the two groups regarding BIS fluctuations (P=0.06), also no patient suffered from nausea, vomiting. Figure 3 illustrate BIS changes in both FM and DKP groups.

Table 1

Comparison of pain scale in FM and DKP groups in recovery

Figure 3

BIS changes in both FM and DKP groups

DISCUSSION

This research was aimed to evaluate the effects of sodium diclofenac, ketamine and propofol versus fentanyl and midazolam in balance analgesia during and after operation based on usual and standard monitoring to evaluate efficacy of two methods. There was no significant difference in hemodynamic fluctuations and depth of anaesthesia (as seen by the BIS values) throughout maintenance of general anaesthesia between the two groups. There was merely a heart rate increase in recovery period of FM group which can be justified with the post operation pain. A similar result was found in a study conducted by Oztekin, et al. in 2002.[6] IV prescription of NSAIDs as a sole analgesic failed to control postoperative pain following major surgery,[16] but we could get a good response in combination of NSAID and ketamine in our study. Postoperative nausea and vomiting continue to be problematic areas in anaesthesia.[17] Regarding clinical signs and symptoms (nausea, vomiting), there was no significant difference between FM and DKP groups; perhaps due to prophylactic drug administration of midazolame in pre-medication and metoclopramide plus dexamethasone 10 minutes prior to the end of the operation.

Fuji study on preventing postoperative nausea and vomiting after middle ear surgery in adult patients showed that none of the available antiemetic is entirely effective, perhaps because most of them act through the blockage on one type of receptor.[18] Maybe combined antiemetic with different sites of activity would be more effective.[19] Riad, et al. demonstrated that the prophylactic administration of combination of midazolam and dexamethasione was superior to each drug alone in reduction of nausea and vomiting.[20] Multi disciplinary approach is advisable for prevention and therapy of PONV nowadays;[2122] and it is similar to our results.

Anaesthetic techniques have a major role in post operative nausea and vomiting (PONV), and without prescription of antiemetic drugs for prophylaxis of PONV, the incidence of the latter is highest in balanced anaesthesia, followed by inhalational based anaesthesia and least for total intra venous anaesthesia (TIVA) based on propofol.[2324] In our study, we used TIVA technique plus N2O 50%, based on fentanyl, midazolam (FM) and sodium diclofenace, ketamine andpropofol (DKP), with a premedication induction policy and anti emetic drugs for prophylaxis during the anaesthesia period, because of which we could achieve an overall low incidence of PONV.

In the group receiving sodium diclofenac and ketamine, there was no need for pethidine post-operatively due to significantly low pain score. A similar finding was reported by a study conducted by Oztekin, et al. which showed that patients, who received 1 mg/kg sodium diclofenac intravenously, had a lesser pain and the need for morphine was also redcued.[6] Dhawan et al. conducted a study which showed the effect of rectal sodium diclofenac in reducing post-operative pain after cardiac surgery.[25] Achariyapota, et al. and their collaborated study showed similar results about efficacy of rectal suppositories of sodium diclofenac in perinea pain after perinearhaphy.[26] In contrast, Canbay, et al. have reported that there was no significant difference in post-operative pain and necessary dosage of analgesics when sodium diclofenac 1 mg/kg intramuscular (IM) were added to ketamine and remifentanyl.[27]

In an investigation, 0.5 mg/kg ketamine was prescribed prior to incision in major abdominal surgeries and ketamine was repeated at a dose of 0.2 mg/kg after 20 minutes of operation. Good responses were obtained in comparison with placebo in their investigation.[28]

It has been reported that ketamine reduces postoperative pain and morphine consumption in post- thoracotomy.[121329] A comparison between propofol-ketamine versus protocol-fentanyl combinations for deep sedation and analgesia in pediatric patient in 2008 showed superiority of propofol-ketamine combination over propofol-fentanyl combination, because of more restlessness in patients given propofol-fentanyl. A clinical investigation in 2008 showed that sub dissociative-dose ketamine is safer than fentanyl for analgesia during propofol procedural sedation.[3031] A study showed that use of NSAIDS instead of opioid or reduction of opioid dose could be reducing the complication of opioids without qualification impairment. In addition they discoveredthat intravenous NSAIDs and fentanyl could produce a greater decrease in the propofol sedation requirement during anaesthesia, and the use of NSAID in combination with propofol for anaesthesia was associated with an improved recovery profile.[32] These results are further emphasized in our study as well. Two different groups of clinical investigators evaluated the efficacy of total intravenous anaesthesia with propofol, pentazocine and ketamine in mastectomy. They reported that patients had hemodynamic stability, rapid recovery and effective postoperative pain relief.[3334]

Several studies have been shown that midazolam and ketamine seem to be acceptable drugs for use during assisted reproduction[3536] and recent data also suggests that propofol may be a safe alternative for use during assisted reproduction.[37-39] Felfering et al. reported that no unpleasant emergence phenomenon could be observed in patients who received total intravenous anaesthesia with ketamine and propofol;[40] and in our study, no patient suffered from hallucination in the recovery room or other side effects of ketamine which are especially related to the psychological aspects, maybe due to benzodiazepine administration.

In the present study, we compared the clinical efficacy and safety of two different kind of balanced anaesthesia; anaesthesia by fentanyl and midazolam (FM) administration and a kind of TIVA anaesthesia by helping intravenous sodium diclofenac along with ketamine and propofol (DKP) without opioids. There were no noticeable effects on the depth of anaesthesia and hemodynamic stability during TIVA method plus N2O 50% accompanied with DKP, and balanced anaesthesia was also achieved. The incidence of PONV with respect to our policy was also low, so our method can be regarded as acceptable in susceptible patients.DKP significantly leads to a reduced post operative pain and need for opioid prescription. We recommended TIVA method plus N2O 50% accompany with DKP for patients with prohibited opioid administration.