Backup_of_medica innovatica-1.

Original Article
Pre-emptive Epidural Analgesia with
Bupivacaine, Diltiazem and Ketamine Singly
or In Combination- A Randomised Trial.
Associate Professor, Professor & Head, Professor, Department of Anesthesiology and Critical Care, Pravara Institute of Medical Sciences, Loni- 413736. INDIA.
2 Senior Registrar, Department of Anesthesiology and Critical Care, 5Assistant Professor, Department of Physiology,Dr.Vikhe Patil Medical College & Hospital, Ahmednagar-414111. INDIA.
Abstract
Background: A randomized control study was designed to compare postoperative epidural analgesia by preemptive use of
epidural administration of local anesthetic- bupivacaine alone and in combination with NMDA blocker- ketamine or calcium
channel blocker- diltiazem singly or both in combination .
Methods: Sixty female patients in age group 35-50 yrs with ASA grade I and II, posted for open abdominal hysterectomy were
randomly distributed in four groups after ethical committee approval and written consent. They were given epidurally 0.4 ml /kg of
0.5 % Bupivacaine in Control group, 0.4 ml /kg of 0.5 % Bupivacaine + Ketamine 5mg in BK group , 0.4 ml /kg of 0.5 %
Bupivacaine + Diltiazem 10 mg in BD group and 0.4 ml /kg of 0.5 % Bupivacaine + Ketamine 5 mg + Diltiazem 10 mg in BKD
group.
Results: BK group had significant pain free period (8.8 ± 1.37) post operatively as compared to rest three groups (P < 0.01). BD
group (5.8 ± 0.94) also had comparable pain relief. BK group needed three to four number of top-up's in first 24 hours (3.37 ± 0.46)
where as BD group needed five to seven number of top-up's in next 24 hours (5.93 ± 0.70) (P < 0.01). BK group and BKD group
patients were sedated resulting in reduced number of top-ups required in first 24 hours.
Conclusion: Ketamine and diltiazem were found to be synergetic with bupivacaine for preemptive epidural analgesia. Diltiazem
was better option over ketamine when sedation is not desirable.
Key-Words: Pre-Emptive Analgesia, Epidural, Ketamine, Diltiazem.
Introduction
neurotransmitters, acting through N-Methyl-D An important goal of modern anaesthesia is aspartate (NMDA) receptors have been related to to ensure that the patient undergoing surgery the development and maintenance of pathological awakens from anaesthesia totally pain free and that pain states after tissue injury especially this state is maintained satisfactorily in the post- operative period as well. Good pain control not only speeds up the recovery of patients but also level is essential for neurotransmitter effectivity shortens their length of hospital stay. Pre-emptive and for nociceptive perception. A disruption of analgesia is an attractive concept of addressing pain calcium ion movement interferes with sensory processing and contributes to antinociception [1, 2, There is substantial amount of evidence that important in sustaining and magnifying excitability evaluation of NMDA receptor antagonists [4], and of neurons in the spinal cord.[1] Excitatory calcium channel blockers[5], in different pain Address for correspondence
Dr. Vinod V Kharde. Senior Registrar,
Department of Anesthesiology and Critical Care,Dr.Vikhe Patil
Medical College & Hospital, Ahmednagar-414111. INDIA.
Medica Innovatica Vol. 1 Issue 1 July 2012 Landge,et al, : Pre-emptive epidural analgesia states. Studies using epidural ketamine with bupivacaine for preemptive analgesia are limited and to our knowledge limited studies have used epidural diltiazem prompting us to design this Both the patient and the anesthesiologist study. This study was taken up postulating addition were blinded to the study solutions. Syringes were of NMDA antagonist ketamine and/or calcium prepared by the third person who did randomized channel blocker- diltiazem to epidural bupivacaine allocation, immediately before the epidural would improve analgesic quality as well as reduce injection, ensuring total volume of 20ml and postoperative analgesic consumption.
labeled as “Epidural Study Drug” and the patient’s Material and Methods
name. Anticholinergic, benzodiazepines and opioid A prospective randomized control study was premedication was avoided to prevent interference designed to compare postoperative analgesia by with intraoperative and postoperative assessment.
preemptive use of epidural administration of local All the baseline parameters were recorded. After anesthetic-bupivacaine alone or in combination fulfilling all the pre-requisties of regional with NMDA blocker- ketamine or calcium channel anaesthesia, under all aspetic precautions in sitting blocker- diltiazem singly or both in combination.
position, epidural space was identified using a After obtaining the approval from the Institutional midline approach at L3-4 inter space with 18 G ethics committee the present study was undertaken Tuohys epidural needle by loss of resistance to air technique. An 18 G epidural catheter was inserted Inclusion Criteria: Patients aged between 35- in cephaloid direction gently to an intraepidural 45 years in ASA grade I and II posted for abdominal distance of 3-4 cm in all the patients. Patients were then put in supine position and a test dose of 3 ml of 2 % lignocaine with adrenaline (1:2,00,000) was chronic backache, coagulopathy, local sepsis, given. All the patients were given respective study spinal deformities, cardiovascular problems and drugs 30 minutes prior to induction of general those patients using the study drugs pre-operatively anaesthesia. The extent of sensory blockade was assessed by pinprick method and after desired After valid informed consent, the selected patients were randomly allocated by block c o n v e n t i o n a l g e n e r a l a n a e s t h e s i a w a s randomization method to four groups of 15 patients administered. Induction was done with inj.
each and group 1 acted as the Control group.
Block size :4 Allocation Ratio: 1:1:1:1. For intubation facilitated by inj. Vecuronium 0.1mg/kg.
allocation concealment, randomization was done Anaesthesia was maintained with O2, N2O and by third person other than the Anaesthesiologist halothane. Neuromuscular block was reversed at who administered the drugs and later on made the the end of surgery by inj.neostigmine 0.05 mg/kg observations. All the patients were explained the and inj.glycopyrrolate 0.01mg/kg. Intraoperatively use of visual analogue scale and Prince Henry Scale systemic analgesics were avoided in all groups.
preoperatively. Drugs administered epidurally 30 Routine monitoring was done throughout the minutes before induction of general anaesthesia for intraoperative period with special attention for signs of inadequate analgesia such as tachycardia, Group 1 (Control group): 0.4 ml /kg of 0.5 % hypertension and excessive lacrimation.
were recorded both before and after the incision and later at frequent intervals. Postoperatively all the patients received analgesia through epidural catheter with fixed dose of 20 ml of 0.2 % of local Medica Innovatica Vol. 1 Issue 1 July 2012 Landge,et al, : Pre-emptive epidural analgesia anaesthetic- bupivacaine as and when required in baseline subject characteristics (age in years and first 48 hrs using pain score. All patients were weight in kgs.) were tested using ANOVA F-test for continuous variables. Mean duration of analgesia postoperative period. Pain was assessed using the and mean no. of top-ups required in first 24 hours Prince Henry Score, Visual analouge scale and and next 24 hours for each group was compared sedation score every 4 hours till 48 hours using simple linear regression. Hemodynamic parameters (systolic blood pressure, diastolic blood pressure and pulse rate) were measured at baseline, 0- when patient has no pain on taking a deep breath pre-incision and post-incision and the difference in the mean at these three time points was tested using 1- when patient had no pain at rest nor on taking a linear regression with generalized estimating equations to take care of clustering of the 2- when patient had no pain at rest but pain on observations at individual patient level.
Comparison of mean hemodynamic parameters at 3- when patient had mild pain at rest.
different time points was done separately for each 4- when patient had severe pain at rest.
group. The level of significance was set at 0.05. The statistical analysis was done using STATA 11 IC.
It consists of a scale marked from 0 to 100 mm where 0 indicates no pain and 100 indicates worst Our study included 60 patients divided into 4 groups belonging to ASA Grade I and II who were posted for elective abdominal hysterectomy. Range of age was 35 to 45 years and weight was 42 to 58 kgs in all groups. Table I shows baseline, pre- 2 - When patient is sleeping but responds to verbal 3 - Sleeping but responding to tactile stimulus.
haemodynamic parameters were lower than the baseline and post-incision parameters were lower When the visual analogue score was 20 or the than the pre-incision, suggesting adequate Prince Henry score was 2 on assessment, the analgesic effect. The first analgesic requirement in analgesic drug was given epidurally even if the the post-operative period was compared in all 4 patient did not ask for it. Epidural catheter was groups. BK group had significant pain free period removed post operatively after 48 hours. Efficacy (8.8 ±1.37 hrs.) post operatively as compared to the of different drug combinations as regards post rest three groups (P< 0.05) BD group (5.8 ± 0.94 operative pain relief indicated by duration of hrs.) also had comparable pain relief. Though BKD analgesia i.e: 1st top-up requirement and total group (7.53 ± 1.14) did not offer any advantage analgesic requirement in first and next 24 hours over BK group it is better than BD group. BK group period i.e: number of top-ups required in the first needed least number of top-up's in first 24 hours and next 24 hours was noted and compared in all (3.37 ± 0.46) where as BD group needed least groups. Patients satisfaction was assessed by number of top-up's in next 24 hours (5.93 ± 0.70).
questioning patients at the end of 48 hours about The total number of top-up's required for BK group pain relief, postoperative sedation, comparison of in the first 24 hours were doubled in the next 24 pain relief with previous experience if any.
hours which was correlated with decreasing Data analysis
sedation. Control group received the maximum Descriptive statistics for all the continous amount of drug in 48 hours (395.73 ± 20.81 mg) variables was expressed in terms of mean and while BK group received the minimum amount of standard deviation. Differences in group mean of drug in 48 hours (281.87 ± 30.79 mg) (Table II).
Medica Innovatica Vol. 1 Issue 1 July 2012 Landge,et al, : Pre-emptive epidural analgesia The sedation scores taken at the end of every 4 effective than giving them after the stimulus. This is hours showed that in BK group and BKD group reffered to as ''PRE-EMPTIVE ANALGESIA " and patients were sedated. BK group patients were is one of the new treatment protocols. The accepted sedated upto grade 2 in initial 24 hours which method for postoperative analgesia till now was to correlated with the reduced number of top-ups begin the analgesic treatment when the pain starts required in first 24 hours. No side effects were in the post-operative period. Pre-emptive analgesia noted in any of the above groups. When patients is an attractive concept of addressing pain even were assessed for satisfaction, BK group patients were most satisfied followed by BD group (Table postoperative epidural analgesia after open Discussion
abdominal hystrectomy by preemptive use of epidural administration of bupivacaine alone or in transmitter release, which is coupled with combination with ketamine or diltiazem singly or both in combination. Opioids were avoided conductance in synaptic terminal membranes of because they could have prevented or attenuated neurons. A disruption of calcium influx into the central sensitization, thus leading to questionable cells interferes with normal sensory processing and results [9,12]. A sub-anesthetic ketamine dose, defined as intravenous or epidural bolus below 1 mg.kg-1 is related to analgesic effects, as compared peripheral and central sensitization. Peripheral sensitization is a reduction in the threshold of symptoms and dissociative anaesthesia [13]. At nociceptor-afferent peripheral terminals and subanesthetic (i.e. low) doses, ketamine exerts a central sensitization is an activity dependent specific NMDA blockade and hence modulates increase in the excitability of spinal neurons [6].
central sensitization induced both by the incision There is considerable evidence that excitatory and tissue damage and by perioperative analgesics amino acids and neuropeptides are involved in such as opioids[14]. We used very low dose of nociceptive transmission in the dorsal horn of the ketamine (5mg) along with bupivacaine. No spinal cord [7, 8]. The actions of excitatory amino studies have evaluated the effects of epidural acids are mediated by the N-methyl-n-aspartate bupivacaine and verapamil before Choe H.et al (NMDA) receptor and non-NMDA receptors.
Activation of NMDA receptors leads to Ca++ entry bupivacaine or bupivacaine plus verapamil to into the cell and initiates a series of central investigate the possible role of the calcium channel sensitization such as wind-up and long-term blocker, verapamil, in postoperative pain. Later on potentiation in the spinal cord in the responses of Lin XM [16], also used epidural Bupivacaine + cells to prolonged stimuli. This central sensitization Verapamil. We decided to test diltiazem by epidural may be prevented by preemptive analgesia not only route along with bupivacaine and compare it with with NMDA antagonists such as ketamine, but also ketamine and bupivacaine. Analgesia was adequate with calcium channel blockers that block Ca++ in all the groups during intraoperative period as pulse rate and blood pressure remained stable. Both ketamine and diltiazem proved to be an effective focused on new methods of pain relief to improve adjuvant to plain bupivacaine for epidural patient care. Good pain control can speed up the analgesia as control group showed the shortest recovery of patients and shorten their hospital stay.
duration of postoperative pain free period (4.6 ± Evidence from the basic research in the mechanism 0.74 hrs.) and required maximum number of top- of pain suggests that administration of analgesic ups in first (6.0 ± 0.85 ) and next 24 hours (8.13 ± drugs much before surgical stimulus may be more 0.83). Ketamine proved to be better than diltiazem Medica Innovatica Vol. 1 Issue 1 July 2012 Landge,et al, : Pre-emptive epidural analgesia as BK group showed the longest duration of Kawana Y et al [17], who also administered low postoperative pain free period (8.8 ± 1.37 hrs.) and doses ketamine (4, 6, 8 mg) found that ketamine required minimum number of top-ups in first 24 administered epidurally was inadequate for hours (3.37 ± 0.46). Sedation was also noted during postoperative pain relief after gynecologic this period (Sedation score more than 2 in 9 patients operations. This may be due to the fact they and 1 in 6 patients) which would have contributed for the pain relief as the requirement of top-ups administered it along with bupivacaine. Choe H. et increased in next 24 hours (6.8 ± 0.77). As against al [15] and Lin XM [16] also had similar results like this, number of top-up's in BD group did not vary us regarding use of calcium channel blocker though much in the study period of 48 hours.(4.93 ± 0.80 they used verapamil and we used diltiazem.
and 5.93 ± 0.70 respectively), showing well balanced level of analgesia without associated ketamine and calcium channel blocker diltiazem sedation. Duration of postoperative pain free were found to be synergestic with local anesthetic period was less (5.8 ± 0.94 : 8.8 ± 1.37) and total bupivacaine when used for preemptive epidural consumption of bupivacaine was more (304.27 ± analgesia and provided excellent intraoperative and 37.96 : 281.87 ± 30.79) in BD group as compared to postoperative analgesia in patients who had BK group. Neverthless as sedation was not noted in undergone abdominal hysterectomy. Diltiazem this group, (sedation score 0 in 93.33% patients) was found to be a better option than ketamine when diltiazem can be a better option over ketamine in sedation is not desirable in postoperative period. A whom sedation is not desirable. Combining detailed study in larger number of patients is ketamine and diltiazem with bupivacaine did not recommended for full exploitation of analgesic offer much advantage. Contrary to our results Table I : Comparison of Haemodynamic Parameters Control Group
BKD Group
Baseline
117.06±8.09** 120 ± 7.41
114.26±7.62** 115.33±6.56**
Pre-Incision
76.53 ± 4.70** 78.4 ± 3.57**
74.8 ± 7.86**
80.46 ± 3.75 ††
113.6 ± 6.16**
118.1 ± 7.74**
112.8 ± 6.76**
114.3 ± 5.4**
Post-Incision
74.93 ± 4.12**
76.93 ± 4.06**
74.4 ± 5.8**
76.4 ± 6.07*
BKD Group= Bupivacaine + Ketamine + Diltiazem group ** p-value significant at 0.01 (When Baseline SBP, DBP and PR are compared to pre incision and post incision SBP, DBP and PR respectively)¶ P-value significant at 0.05 †† p-value significant at 0.01 (When SBP, DBP and PR are compared in all Medica Innovatica Vol. 1 Issue 1 July 2012 Landge,et al, : Pre-emptive epidural analgesia Table II : Comparison of duration of analgesia and number of top-ups required in first and next 24 hours.
Control Group
BKD Group
8.8 ± 1.37**
5.8 ± 0.94 **
7.53 ± 1.14**
3.37 ± 0.46**
4.93 ± 0.80** 5.36 ± 0.80**
6.8 ± 0.77**
5.93 ± 0.70**
395.73 ± 20.81 281.87 ± 30.79 304.27 ± 37.96 358.4 ± 35.42 BK Group = Bupivacaine + Ketamine groupBD Group = Bupivacaine + Diltiazem groupBKD Group= Bupivacaine + Ketamine + Diltiazem group Table III :Number of patients showing sedation score in first and next 24 hours.
Sedation score
BKD Group
in first 24 hours
Sedation score
in next 24 hours
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