A Comparative Study of Analgesic Efficacy of Intrathecal Bupivacaine with Ketamine Versus Bupivacaine with Magnesium Sulphate in Parturients Undergoing Elective Caesarian Sections.

Background and Aims: Spinal anaesthesia is the most preferred technique of anaesthesia in parturient, undergoing lower segment caesarean sections (LSCS) which provides effective pain relief during intra operative and early postoperative period. However, recent studies demonstrate that about 50%-70% of patients experience moderate to severe pain after LSCS indicating that postoperative pain remains poorly managed. The aim of our study was to compare intrathecal magnesium sulphate (Mgso4) and ketamine as adjuvants to hyperbaric bupivacaine in parturients posted for elective caesarean sections under spinal anaesthesia to determine their effectiveness in extending the duration of analgesia. Materials and
Methods: After institutional ethical committee approval, 82 parturient undergoing elective LSCS were enrolled into the prospective randomized double blinded study. Group BK (n = 41) received intrathecal ketamine (25 mg) as additive to hyperbaric bupivacaine and group BM (n = 41) received magnesium sulphate (75 mg) as additive to hyperbaric bupivacaine. Time of onset of sensory analgesia, motor blockade, duration of analgesia was noted down. Intraoperative hemodynamics and any adverse effects of study drugs were noted.
Results: The mean duration of analgesia in group BK was significantly longer (P < 0.05) than in Group BM. The onset of sensory and motor blockade was significantly early in Group BK compared to Group BM. Hemodynamics was better maintained in Group BK with less requirement of ephedrine compared to Group BM. The visual analog scale scores were significantly lower without side effects in both the groups.
Conclusion: The present study demonstrated that the duration, quality of analgesia, hemodynamic stability was better with intra thecal ketamine as an adjuvant to bupivacaine compared to intrathecal MgSo4 without any significant side effects on mother and child. Copyright:

INTRODUCTION

Spinal anaesthesia is the most preferred technique of anaesthesia in parturient, undergoing lower segment cesarean section (LSCS).[1] However short duration of spinal anesthesia may result in moderate to severe postoperative pain in most of the patients, which may interfere with the maternal psychological well-being, breast feeding and mother-child bonding.[2] Pain after cesarean section is often under estimated and under treated due to unfounded fears about maternal and neonatal side effects of analgesic drugs and interventions.[3] The safety of intrathecal ketamine and magnesium administration has been evaluated and established as an effective adjuvant to bupivacaine in parturient.[45]

We hypothesized that intrathecal additives like ketamine and magnesium sulphate (MgSO4) when added to hyperbaric bupivacaine can prolong the duration of analgesia and improve maternal well-being.

MATERIALS AND METHODS

After institutional ethical committee approval, a prospective randomized double blinded study was conducted over duration of 1 year. A total number of 82 parturients, undergoing elective LSCS, who gave informed written consent, belonging to ASA PS Classes I and II status, 18–35 years of age and height of the parturient 145–170 cm were included, whereas parturients with systemic diseases, body mass index >38, history of preeclampsia and eclampsia, fetal distress, allergy to study drugs, contra-indications to spinal anaesthesia and consumption of tranquilizers, hypnotics, sedatives, central nervous system depressants were excluded from the study.

This present study was designed to compare intrathecal MgSO4 and ketamine as adjuvants to hyperbaric bupivacaine in parturient posted for elective caesarean sections under spinal anaesthesia to determine the duration of analgesia as primary outcome along with secondary objectives to assess the analgesic efficacy, onset time of sensory block and motor block, time to first rescue analgesia. Hemodynamic changes and adverse effects associated with drugs under study.

Method of data collection

Randomization done by computer generated random number table. Allocation concealment was done by opaque sealed envelopes. The study drug solution was prepared by an anesthesiologist not involved in parturient care. Parturient and anesthesiologist who performed spinal anaesthesia and observed the results were blinded.

Preanaesthetic evaluation of all parturients was performed by an anesthesiologist a day before surgery. Height and weight were noted. Parturient was kept nil by mouth for 8 h before surgery and premedicated with tab. Ranitidine 150 mg day before surgery. All parturients, belonging to inclusion criteria, were randomly divided in to two groups.

Group BK (n = 41): Received intrathecal 0.5% hyperbaric bupivacaine 1.8 mL (9 mg) with 25 mg (0.5 mL) of preservative free ketamine.

Group BM (n = 41): Received intrathecal bupivacaine (0.5%) hyperbaric 1.8 mL (9 mg) with inj. MgSO4 (75 mg) 0.15 mL plus 0.35 mL of 0.9% normal saline. Each group received total volume of 2.3 mL.

In Operation theatre, a peripheral vein was cannulated. Ringer lactate solution 10 mL.kg− 1 infused. Baseline noninvasive blood pressure (BP), Pulse rate, electrocardiograph, pulse oximetry were recorded. Study drugs were taken in 5 mL syringes by coding them and administered randomly in the selected parturient, which were decoded after 24 h following the procedure. Lumbar puncture was performed at L2–L3 or L3–L4 level with 25G Quinke's needle and drug solution was injected intrathecally over 30 seconds. Patient placed in 15° left lateral position and Oxygen at 5 L.min−1 with a face mask administered to all the parturient during the surgery. Time of intrathecal injection, time for loss of sensation to pin prick and motor block were noted. BP, pulse rate (PR), respiratory rate and oxygen saturation (Spo2) were monitored intra operatively at every 5 min for 1st 15 min, later every 15 min till the end of procedure. Other side effects of ketamine and Magnesium sulphate like nausea, vomiting, hypotension, bradycardia, sedation and respiratory depression were monitored throughout the procedure. After the delivery of baby Inj. Oxytocin 10 IU was administered in the drip, APGAR scores were noted at 0 min and 5 min.

Cardio respiratory parameters were monitored continuously and recorded. Onset to sensory block i.e., time interval between the end of administration of study drug and the onset of cutaneous analgesia at T10 was evaluated using midline bilateral pin prick every minute.[6] Degree of motor block was assessed when cutaneous sensations were lost at T10 using modified Bromage scale 0-No motor block, (Nil), 1-Unable to raise the leg straight, (Partial), 2-Unable to flex the knee, almost complete, 3-Unable to flex the ankle, (Complete).[7]

Interpretation of Nausea and vomiting by score, Grade 0-No nausea and vomiting, Grade 1-Nausea, no vomiting Grade 2-Both nausea and vomiting present and Grade 3-more than 2 episodes of vomiting in 30 min.[8] Intraoperatively and postoperatively incidence of bradycardia (heart rate <50beats per minute) was treated with 0.6 mg of injection atropine and hypotension (systolic BP falling >20%mm of Hg) was treated with injection ephedrine 6 mg in bolus.[9] Duration of analgesia was recorded as time interval from the time of intra thecal injection of the drug to the time when the patient complains of pain or a visual analog scale (VAS) score of >/=4.[10] Post operatively patient was assessed for intensity of pain every 15 min for 1st h, every 30 min till 3rd h, every hourly till 6th h, 12th and 24 h for postoperative analgesia. 0 = No pain, 10-maximum pain.[1112] Following side effects are recorded for 24 h pertaining to drugs under study, nystagmus, delirium, salivation and Sedation by score-.0-Normal 1-Drowsiness 2-Sleep but arousable 3-Unarousable with loss of verbal contact.[7]

Statistical analysis

Sample size estimation

Sample size calculation was based on previous studies conducted by Patel et al. and Jabalameli and Pakzadmoghadam, with the significance level of 95%, power of study 80%, α error 0.05 and β error of 0.2 to show a 20% difference in the duration of analgesia, at least 38 parturients per group were needed.[913] Considering failed spinal and dropouts we decided to include 82 parturients (41 in each group).

Data were entered in MS Office Excel and were analyzed using IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp. Description of categorical variables like side effects of drugs used were done in frequency and percentage and that of continuous variable like pulse rate, SBP, DBP, etc., were summarized in mean and standard deviation after checking for distribution of data. Comparison of changes in mean of the dependent variables between two groups of patients was done using independent sample t-test at various time points. Association between the categorical dependent and independent variables were done using Chi-square test. All tests were two tailed and P < 0.05 was considered statistically significant.

RESULTS

A total of 82 patients were enrolled, 41 in each group [Figure 1]. The two groups were comparable with respect age, height, weight, gestational age, duration of surgery [Table 1]. The Table 2 represents the characteristics of spinal anaesthesia. The time for sensory onset was shorter in BK group (1.7 ± 0.6 min) compared to BM group (3.0 ± 0.7 min) and difference was statistically significant. Similarly, time to motor onset was significantly shorter in BK group (3.3 ± 0.8 min) compared to BM group (5.8 ± 0.8 min). The time taken for sensory regression to S1 was significantly longer in group BK (215 ± 26.8) compared to group BM (163 ± 18.2). The time taken for motor regression to Bromage 0 was also significantly longer in group BK (195.2 ± 24.3) compared to group BM (149.8 ± 17.2).Time to rescue analgesia was also significantly longer in ketamine group (241 ± 33.4 min vs. 180 ± 18.9 min).

Figure 1

Consort diagram

Table 1

Demographic profile

Features	Mean±SD*		P †
	Group-BK (1) (n=41)	Group-BM (2) (n=41)
Age in years	23.3±3	23.9±3.1	0.37
Height in cm	157.2±5	158.1±5	0.40
Weight in kg	57.7±4.7	58.6±4.4	0.39
BMI	23.3±1.5	23.4±1.7	0.79

*SD, †P value based on independent sample t test. Statistically significant (P<0.05). SD=Standard deviation, BMI=Body mass index

Table 2

Spinal anaesthesia characteristics between two groups

Features	Group-BK (1)		Group-BM (2)		P*
	n1	Mean±SD	n2	Mean±SD
Sensory onset (min)	41	1.7±0.6	41	3.0±0.7	0.001*
Motor onset (min)	41	3.3±0.8	41	5.8±0.8	0.001*
Time taken for sensory regression to S1 (min)	41	215±26.8	41	163±18.2	0.001*
Time taken to regression to Bromage 0 (min)	41	195.2±24.3	41	149±17.2	0.001*
Duration of analgesia (min)	41	241±33.4	41	180±18.9	0.001*

*P value balsed on independent sample t-test. Statistically significant (P<0.05). SD=Standard deviation

In intraoperative hemodynamics, change in pulse rate was significantly higher at 1, 5, 10 and 30 min in ketamine group [Table 3]. The intraoperative systolic BP was significantly lower in BM group compared to BK group, at 1 and 5 min after spinal anaesthesia [Figure 2]. The change in intraoperative diastolic BP was significantly similar for most time intervals except for 1st min when it was lower in group BM compared to group BK.

Table 3

Comparison of intra operative pulse rate at various time points between groups

Features	Group-BK (1)		Group-BM (2)		P*
	n1	Mean±SD	n2	Mean±SD
Preoperative basal value	41	101.5±13	41	92.3±10.9	0.001*
1 min	41	103.6±14.5	41	93.1±13.4	0.002*
5 min	41	101.5±15.6	41	92.3±15.5	0.008*
10 min	41	97.6±13.8	41	90.7±15.5	0.04*
15 min	41	98.7±15.2	41	113.3±12.7	0.46
30 min	41	102.2±17.8	41	94.1±13.7	0.03*
45 min	13	94.8±17.6	11	92±10.1	0.65

*P value based on independent sample t-test. Statistically significant (P<0.05). SD=Standard deviation

Figure 2

Comparison of intraoperative systolic and diastolic pressures between the two groups. P value based on independent sample t-test. Statistically significant (P < 0.05)

The VAS score was significantly higher in the magnesium group at 2 h (1.9 ± 0.8 vs. 1.3 ± 0.4), 2.5 h (3.2 ± 1 vs. 2 ± 0.9) and at 3 h (3.5 ± 1 vs. 2.5 ± 1.1) compared to ketamine group signifying better postoperative pain relief in ketamine group [Figure 3].

Figure 3

Spinal anaesthesia for cesarean section, even though being the most popular technique, lacks the advantage of postoperative analgesia. We hypothesized that adding intrathecal additives like ketamine and magnesium sulphate, will prolong the duration of analgesia. Eighty-two parturients, undergoing cesarean section were randomized into two groups to receive either intrathecal ketamine or magnesium sulphate. The duration, quality of analgesia was found to be better with ketamine than magnesium sulphate, and with advantage of better hemodynamic stability with ketamine

The requirement of vasopressor (ephedrine) was high in group BM compared to group BK with “P” value of 0.001 suggesting better hemodynamic stability with ketamine. No statistically significant difference was found among two groups regarding APGAR scores and adverse events like bradycardia, nausea and vomiting, sedation or excessive salivation.

DISCUSSION

The present study demonstrated that intrathecal ketamine 25 mg as an adjuvant to bupivacaine 9 mg for parturient posted for elective LSCS resulted in quicker onset of both sensory and motor action, prolongation of duration of postoperative analgesia, better VAS scores, less requirement of rescue analgesia and acceptable APGAR scores when compared to intrathecal magnesium sulphate 75 mg with bupivacaine 9 mg without significant effects to mother and child.

Intrathecal ketamine binds to phencyclidine site of NMDA receptor gated calcium channels and inhibits NMDA receptors noncompetitively.[1415] Even though magnesium also acts by blocking the spinal NMDA receptors,[161718] effectiveness of ketamine can be explained by its additional action at opiate, monoaminergic receptors and voltage sensitive calcium channels. Safety of both intrathecal ketamine and magnesium has been proven in several previous studies[418] and dosage in the present study was same as in previous studies.[1319]

Quicker onset of sensory block with intrathecal ketamine as observed in present study has also been reported by Shrestha et al., Unlugenc et al. and Basuni.[202122] This is contradicted in other studies by Murali Krishna et al. and Khezri et al. who found no difference with the onset of sensory blockade with intrathecal ketamine.[623] Delayed onset of sensory block as observed in magnesium group has also been reported by Ozalevli et al., Banihashem et al., Khalili et al. and Unlugenc et al.[12212425] These authors have suggested that the differences in the pH and baricity of the local anaesthetic solution with the addition of magnesium probably causes delay in the onset of sensory block. Onset of motor block was also rapid in the ketamine group in the present study similar to findings by Shrestha et al.[20] The finding of prolonged motor blockade in the ketamine group is in conjunction with Govindan et al.[26]

The duration of analgesia and time to rescue analgesia was prolonged in ketamine group compared to magnesium group, this finding is similar to previous studies by Khezri et al., Basuni et al.[622] and similar duration of analgesia is also noted by Kataria et al.[27] The longer duration of action of ketamine may be explained on the basis of slow release of ketamine due to liposomal impregnation.

Vasopressor (Ephedrine) requirement in ketamine group was significantly less than in magnessium group indicating intrathecal ketamine associated with minimal hemodynamic fluctuations. This finding has been consistently corroborated by several authors like Murali Krishna et al., Kathirvel et al., Khezri et al.[62829] This is probably due to systemic absorption of ketamine and resultant cardio vascular stimulation. This also explains higher pulse rate found in the ketamine group in the initial period of spinal anaesthesia. Even though, Jabalameli and Pakzadmoghadam and Arora et al. have shown stable hemodynamics with same dose of intrathecal magnesium used in present study, higher incidence of hypotension and vasopressor requirement was found in the magnesium group.[89]

APGAR scores, considered as surrogate for fetal well-being, at 1 and 5 min were comparable between two groups. Incidence of adverse effects was similar among two groups. Present study did not find any behavioural, psychomimetic and neurological complications in the patients receiving ketamine intrathecally.

CONCLUSION

Intra thecal 25 mg ketamine safely prolongs the duration of post-operative analgesia when it is used as an adjuvant to intrathecal bupivacaine in parturient undergoing elective cesarian surgeries. Also, our study shows that the addition of intrathecal magnesium sulfate 75mg to bupivacaine is not desirable in patients undergoing cesarean section due to the delay in the onset of sensory blockade and no significant effect of magnesium on post-operative pain.

Limitations of the study

Blood gas analysis of umbilical blood of neonates was not done in our study to determine the blood levels of study drugs and only APGAR score was used to assess neonatal outcome as mentioned in the study by Shrestha et al.[20]

Strength of the study

The strength of this study was use of time tested, easily available and safe study drugs, in appropriate doses and performance of the surgical procedures in a single centre and postoperative data collected by a single blinded investigator.

Hence intra thecal 25 mg ketamine safely prolongs the duration of postoperative analgesia when it is used as an adjuvant to intrathecal bupivacaine in parturient undergoing elective cesarian surgeries. Also, our study shows that the addition of intrathecal magnesium sulfate 75 mg to bupivacaine is not desirable in patients undergoing cesarean section due to the delay in the onset of sensory blockade and no significant effect of magnesium on postoperative pain.

To summarize, from above discussed results it can be clearly stated that intrathecal 25 mg ketamine as an adjuvant to bupivacaine 9 mg has early onset sensory as well as motor blockade, intra operative stable hemodynamic parameters with less requirement for vasopressor and it also prolongs the duration of analgesia without significant side effects on mother and the newborn in comparison with intrathecal 75 mg MgSo4 with bupivacaine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.