The Effect of Midazolam and Dexmedetomidine Sedation on Block Characteristic Following Spinal Bupivacaine: A Randomized Comparative Study.

BACKGROUND: Dexmedetomidine is widely used as an adjunct to general as well as regional anesthesia. AIMS: This study was conducted to compare and evaluate the synergistic effect of single intravenous (i.v.) bolus dose of dexmedetomidine with midazolam on spinal block duration, analgesia, and sedation in patients undergoing infra-umbilical surgeries. SETTINGS AND
DESIGN: Prospective, randomized, comparative, and double-blinded study.
MATERIALS AND METHODS: One hundred patients between 18 and 60 years of age of American Society of Anesthesiologists physical status I and II posted for elective infra-umbilical surgery under subarachnoid block were randomly divided into two groups (Group D and Group M). Patients of Group D received i.v. dexmedetomidine 0.5 μg.kg-1 and of Group M received i.v. midazolam 0.05 mg.kg-1 as premedication 5 min before spinal anesthesia over 10 min. Vital parameters, Ramsay sedation score, level of sensory and motor block, recovery time for sensory blockade, postoperative numerical rating scale, time of requirement of the first dose of postoperative rescue analgesic, and duration of analgesia were recorded and analyzed. STATISTICAL ANALYSIS: Chi-square test, t-test, and analysis of variance test were applied to analyze data using SPSS package for Windows. RESULTS AND
CONCLUSION: Premedication with single i.v. dexmedetomidine prolonged the duration and increased the maximum upper level of only sensory component of spinal anesthesia (6.42 ± 3.21 vs. 4.8 ± 1.21 thoracic segments higher than with midazolam sedation). This property can be beneficial in preventing undesirable prolongation of motor block and facilitating early ambulation in shorter duration of infra-umbilical surgeries. In addition, dexmedetomidine slowed the regression of sensory block and increased the time of the first request of analgesic. Copyright:

INTRODUCTION

Dexmedetomidine is a highly selective α2-adrenoreceptor agonist. It is widely used as an adjunct to general as well as regional anesthesia for better hemodynamic stability, sedation, and prolonged duration of regional anesthesia.[123456] Synergistic interaction between intrathecal dexmedetomidine and local anesthetic agents has also been found in previous studies.[78] Intravenous midazolam premedication is commonly used for conscious sedation, anxiolysis, and amnesia with spinal anesthesia.[910] To isolate the analgesic effect of dexmedetomidine from its sedative effects, a comparison was made with midazolam.

There are limited clinical data comparing the effect of intravenous (i.v.) dexmedetomidine and midazolam premedication on spinal anesthesia. This study was conducted to compare and evaluate the synergistic effect of i.v. dexmedetomidine with i.v. midazolam on spinal block duration, requirement of analgesia and sedation in patients undergoing infra-umbilical surgeries.

Aims and objectives

Our primary objective was to assess the effect of i.v. dexmedetomidine and i.v. midazolam on the onset of sensory and motor block, prolongation of block, sedation, and postoperative analgesia. The secondary objective was to study any adverse effect of these drugs.

MATERIALS AND METHODS

This is a randomized and comparative study conducted after obtaining ethical clearance from the Institute Ethical Committee. The trial was registered with Clinical Trial Registry, India (ctri.nic. in) vide registration number CTRI/2019/06/019605. Written informed consent was obtained from all the patients before enrolling them for the study. Based on the previous study keeping alpha error <0.05 and beta error <0.2, power of study <0.001, 100 patients between 18 and 60 years of age, of either sex, of American Society of Anesthesiologists (ASA) physical status I and II, posted for elective infraumbilical surgery under subarachnoid block (SAB) were included in this study. Patients who refused to take part in the study, with any contraindication to SAB like coagulopathy, deformity of the spine, raised intracranial tension, preexisting neurological disease, and with a history of alcohol or drug abuse and those who have received any opioids or sedative medication in the week prior to surgery were excluded from this study.

After enrolment in the study, clinical examination and routine investigation of all patients were done. All patients were educated about 11-point numerical rating scale (NRS) from 0 to 10, where 0 means no pain and 10 means maximum pain. Patients were kept overnight fasting and then shifted to the operation theater. On arrival to the operation theater, the standard monitors (like electrocardiogram, noninvasive blood pressure, and pulse oximeter) were attached to the patients, i.v cannula of 18-Gauze was secured in all patients, and 500 mL of loading dose of lactated Ringer's solution was administered before spinal anesthesia. Patients were randomly divided into two groups (Group D and Group M), 50 in each group using a closed envelope technique. Patients of Group D received i. v. dexmedetomidine 0.5 μg.kg−1 and patients in Group M received i.v. midazolam 0.05 mg.kg−1 as premedication 5 min before spinal anesthesia. The study drugs were premixed to a total volume of 5 mL in the 5 mL syringe and prepared by an independent anesthesiologist for blinding. The patient and attending anesthesiologist were unaware of the group allocation. The study drug was administered intravenously over a period of 10 min as a single dose. Five minutes after the end of infusion, patients were placed in the lateral position and dural puncture was performed at the interspace between third and fourth lumbar vertebrae (L3–L4), using a standard midline approach with a 25-Gauze Quincke-type spinal needle, and 3 mL of 0.5% bupivacaine was injected intrathecally. All patients received oxygen (O2) 4 L min− 1 via a facemask throughout the procedure.

Baseline vital parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), and oxygen saturation (SPO2) were recorded. Then, these parameters were recorded after dural puncture and every 5 min for 15 min and then every 15 min interval up to 90 min after spinal anesthesia. The Ramsay sedation score was used for assessment of level of sedation at an interval of 10 min after administration of spinal block till 120 min. Postprocedure level of sensory block achieved was assessed using pinprick and cold (iced) tube in the mid-axillary line. Recovery time for sensory blockade defined as two-dermatome regression of anesthesia from the maximum level was recorded. Motor block was assessed using a modified Bromage scale. Postoperative pain was assessed by NRS at the interval of 4 h, 8 h, 12 h, and 24 h after the administration of SAB. The time of requirement of the first dose of postoperative rescue analgesic was recorded. The duration of analgesia was recorded as the time from the onset of analgesia to the time when the patient demanded rescue analgesia.

Episode of hypotension (defined by a decrease in MAP below 20% of baseline or SBP <90 mmHg) was treated with i.v. ephedrine 5 mg and additional lactated Ringer's solution (200 mL over a 5 min period). Bradycardia (HR <50 beats per min) was treated with i.v. atropine 0.6 mg. The presence of any other complication in the preoperative and postoperative period was recorded.

The recorded data were presented as descriptive statistics for continuous variables and percentage for categorical variables and was subjected to Chi-square test, t-test, and analysis of variance test. All the data were analyzed using the SPSS package (Stata, version 23.0 SPSS INC, Chicago, IL, USA) for Windows. In all parameters, the value of P < 0.05 was considered significant.

RESULTS

A total of 100 patients were enrolled and randomly allocated into two groups in this study; various predecided outcome parameters were recorded and analyzed, as shown in the consort diagram [Figure 1]. The demographic data of all the patients and duration of surgery were comparable [Table 1].

Figure 1

Consort flow diagram

Table 1

Demographic data

Parameter	Mean±SD		P
	Group D	Group M
Age (years)	39.86±13.51	39.8±13.75	0.072
Male:female (%)	70:30	66:34	0.299
Weight (kg)	52.22±6.02	52.18±6.08	0.255
Height (cm)	167.54±3.71	165.09±6.21	0.617
Duration of surgery (min)	51.23±2.02	55.35±3.74	0.832

SD=Standard deviation

All patients of both the groups were hemodynamically stable throughout the surgical procedure. Mean HR, mean SBP, mean DBP, MAP, and mean SPO2 were comparable in both the groups [Graphs 1-5]. The mean SBP and DBP decreased after SAB but remained stable after 90 min [Graphs 2 and 3]. The mean sedation score at all time intervals in both the groups was found to be comparable [Graph 6]. There was no statistically significant difference. Maximum Ramsay sedation score of 5 was found in 6 patients of the Group D and in 15 patients of the Group M.

Graph 1

Mean heart rate in the study groups at different time intervals

Graph 5

Mean oxygen saturation in the study groups at different time intervals

Graph 2

Systolic blood pressure (mmHg) in study groups at different time intervals

Graph 3

Diastolic blood pressure (mmHg) in the study groups at different time intervals

Graph 6

Sedation score in groups

Munich blood pressure (mmHg) in the study groups at different time intervals

The mean time of onset of sensory block in both the groups, Group D (2.52 ± 0.32 min) and Group M (2.97 ± 0.64), was comparable (P = 0.169). The maximum level of sensory block achieved in Group D patients was 6.42 ± 3.21 thoracic segments higher, which was found to be significantly higher (P = 0.001) than in Group M patients which was recorded to be 4.8 ± 1.21 thoracic segments higher. While observing the pattern of regression of spinal block, we found that there was not any statistically significant difference (P = 0.181) in the regression time of motor block in Group D (4.28 ± 0.09) and Group M (3.16 ± 0.13), while the mean time for two-segment regression of sensory block was recorded to be significantly earlier (P = 0.001) in Group M (2.12 ± 0.21), as compared to Group D (3.24 ± 0.12) [Table 2].

Table 2

Effect on onset and regression of block

Parameter	Mean±SD		P
	Group D	Group M
Mean time of onset of sensory block (min)	2.52±0.32	2.97±0.64	0.169
Mean time of onset of motor block (min)	3.21±0.79	3.64±0.84	0.342
Maximum level of sensory block (thoracic segments)	6.42±3.21	4.8±1.21	0.001
Mean regression time of motor block (h)	4.28±0.09	3.16±0.13	0.181
Mean time for two-segment regression of sensory block (h)	3.24±0.12	2.12±0.21	0.001
Mean time to first request of analgesia (h)	5.39±0.34	3.29±0.14	<0.001

SD=Standard deviation

The mean NRS score of Group D at 4 h, 8 h, 12 h, and 24 h after spinal block was 2.23, 4.5, 5.8, and 4.3, respectively. The mean NRS score of Group M at 4 h, 8 h, 12 h, and 24 h was 4.9, 5.1, 5.2, and 5.12, respectively. At 4 h after spinal block, the mean NRS of Group D was recorded to be significantly lower than of Group M (P < 0.001). However at 8 h, 12 h, and 24 h, the mean NRS was comparable in both the groups. There was no statistically significant difference [Table 3]. There was a statistically significant difference (P < 0.001) in the time of first request of analgesia in Group D (5.39 ± 0.34 h) and Group M (3.29 ± 0.14 h) [Table 2].

Table 3

Numerical Rating Scale score

Mean VAS score	Mean		P
	Group D	Group M
4 h	2.32	4.9	0.001
8 h	4.5	5.2	0.823
12 h	5.8	5.4	0.829
24 h	4.3	5.12	0.754

VAS=Visual Analog Scale

Incidence of episode of hypotension and bradycardia was recorded to be significantly greater in Group D (6 patients [12%] and 3 patients [4%], respectively), as compared to in Group M (2 patient [4%] and 1 patient [2%], respectively) [Table 4].

Table 4

Side effects

Side effect	Group D, n (%)	Group M, n (%)	P
Hypotension	6 (12)	2 (4)	<0.001
Bradycardia	3 (4)	1 (2)	<0.001

DISCUSSION

Dexmedetomidine when combined with intrathecal bupivacaine facilitates spinal block.[11] It has been suggested that the spinal mechanism is the principal mechanism for the analgesic action of dexmedetomidine.[12] Although dexmedetomidine has supraspinal and peripheral sites of action, when administered intravenously, it produces analgesia by acting at both spinal and supraspinal levels.[1314]

In a meta-analysis conducted by Abdallah et al., 364 patients were analyzed from 7 intermediate to high-quality randomized controlled trials investigating the facilitatory effects of i.v. administration of dexmedetomidine compared with placebo on spinal anesthesia. It was found that the duration of sensory and motor block was prolonged by 34% and 17%, respectively and the time to the first analgesic request was increased by 53%. It was associated with a 3.7-fold increase in transient reversible bradycardia without any difference in the incidence of hypotension, sedation, and respiratory depression.[15]

These clinical advantages of dexmedetomidine premedication compared with midazolam premedication are contributed by its supraspinal, direct analgesic, and vasoconstricting actions. i.v dexmedetomidine acts by terminating the propagation of pain signal by inhibiting norepinephrine release in descending medullo-spinal-norepinephrine pathway. It produces sedation by suppressing neuronal firing in the locus coeruleus. At the spinal level, it acts by inhibition of glutamate and substance P. It also causes activation of potassium channels causing hyperpolarization of interneurons.[1617] The effect of dexmedetomidine is not dependent on the route of administration.[4] Midazolam has been reported to have an antinociceptive effect through the neuraxial pathway, but this effect was not seen after systemic administration.[1819] This explains why i.v. midazolam premedication did not enhance the analgesic effect of spinal block.

Rapid administration of dexmedetomidine might produce bradycardia and hypertension so it should be administered slowly over 10 min.[20] A study was conducted on healthy volunteers by Liu et al. in 2013 to evaluate the analgesic effect of different doses of i.v. dexmedetomidine (0.25, 0.5 and 1 μg.kg−1) on ischemic pain and they demonstrated moderate analgesia with a ceiling effect at a dose of 0.5 μg.kg−1.[21] An intravenous dose of 0.05 mg.kg−1 of midazolam was reported to induce sedation and amnesia without any adverse effects on hemodynamic parameters and respiration in adults under spinal anesthesia.[22] Keeping this in mind, 0.5 μg.kg−1 and 0.05 mg.kg−1 i.v. doses of dexmedetomidine and midazolam, respectively, were used in this study. Both the drugs were administered intravenously over 10 min for blinding. We did not observe biphasic changes associated with dexmedetomidine. This may be due to sympathetic blockade associated with spinal anesthesia, slow administration of a low dose of drug, and adequate preoperative hydration.

Harsoor et al. and Kolarkar et al. had concluded that i. v. dexmedetomidine in a bolus dose of 0.5 μg.kg−1 followed by infusion at the rate of 0.5 μg.kg−1 h−1 prolonged the duration of sensory as well as motor blockade of spinal bupivacaine with hemodynamic stability and arousable sedation.[2324] Prolongation in the duration of sensory and motor block was also found in a similar study done by Shmruthi et al. where dexmedetomidine was administered in a bolus dose of 1 μg.kg−1 followed by infusion at the rate of 0.5 μg.kg h−1.[25]

Interestingly, we found prolongation in only the sensory component of the spinal block. There was no statistically significant difference in the regression time of motor block. Then, we searched for the studies by different investigators who also found only prolongation in sensory block. Annamalai et al. while comparing the effect of single i.v. bolus doses of dexmedetomidine 1 μg.kg − 1 at different times (10 min before and 30 min after) on SAB, they found that sensory block was higher and prolonged in the group receiving premedication later, without any difference in duration of motor block.[26] Observation of Kaya et al. with single i.v. dose of dexmedetomidine is also similar to ours.[27] In all the above studies with a similar outcome as ours, dexmedetomidine was given in only a single bolus dose, whereas in all the studies where the prolongation of both sensory and motor blockade was found, dexmedetomidine was given as a bolus, followed by continuous infusion throughout the surgery. The difference in the amount of dexmedetomidine received as an infusion by the study group might explain the difference in effect on the regression time of motor block. Thus, it can be assumed that single-dose i.v. dexmedetomidine premedication affects only regression time of sensory component of SAB, sparing motor component. Rhee et al. had observed that clonidine had a concentration-dependent effect on motor blockade of bupivacaine spinal anesthesia.[28] The same theory might be the possible explanation with dexmedetomidine as well. This property can be beneficial in preventing undesirable prolongation of motor block, facilitating early ambulation and decreasing patient's discomfort in a shorter duration of infraumbilical surgeries.

A randomized controlled trial was conducted by Sivachalam et al. to compare the effect of conscious sedation with i.v. dexmedetomidine at a loading dose of 0.5 μg.kg − 1, followed by 0.5 μg.kg − 1 h − 1 infusion to i.v. midazolam at a loading dose of 0.03 mg.kg − 1 followed by 0.03 mg.kg h − 1 infusion on spinal anesthesia in patients undergoing infraumbilical surgeries. They found that the mean time for sensory regression was prolonged in dexmedetomidine group (5.2 ± 0.83 h) than in midazolam group (4.4 ± 0.87 h, P = 0.01). They did not mention anything about the prolongation in motor block.[29]

Kumar compared i.v. dexmedetomidine and clonidine as premedication in pediatric patients undergoing SAB and found that dexmedetomidine is superior to clonidine as a premedication drug in pediatric patients.[30] Agrawal et al. have also concluded that i.v. α2 agonists are useful adjuvants for prolongation of the duration of spinal block.[31] Similar effects of i.v. dexmedetomidine premedication were also observed on ropivacaine spinal block by Rekhi et al.[32] CosKuner et al. had investigated that i.v. administration of dexmedetomidine might also prolong the recovery time of the sensory blockade of bupivacaine during epidural anesthesia.[7]

In our study, patients of both the groups were equally hemodynamically stable (P = 0.12 for HR and P = 0.41 for MAP). We recorded more episodes of hypotension and bradycardia with dexmedetomidine premedication, which were easily reversed by a bolus dose of 5 mg ephedrine and fast infusion of 200 mL Ringer Lactate over 5 min. This can be explained by the healthy ASA I and II study population and single-dose administration of study drugs.

However, midazolam is known to cause arterial desaturation in sedative doses. No respiratory depression was found in any patients in this study, and respiratory parameters (respiratory rate and SpO2) remained within normal limits throughout the procedure. Previous studies have also shown that sedation caused by dexmedetomidine is of better quality than that of midazolam sedation in terms of easy arousability, hemodynamic stability, respiratory depression, and anxiolysis.[3334]

Our observations and results indicate that premedication with single-dose i.v. dexmedetomidine before spinal anesthesia increased the maximum upper level and prolonged the duration of bupivacaine induced sensory blockade without affecting motor blockade. In addition, dexmedetomidine slowed the regression of sensory block and thus increased the time of the first request of analgesic for postoperative pain relief. It also provided sedation comparable to midazolam premedication. Although the incidence of bradycardia and hypotension was more, it was reversible and easily treatable.

CONCLUSION

i.v. premedication of dexmedetomidine in a single dose of 0.5 μg.kg− 1 over 10 min is comparable with bolus dose, followed by continuous infusion throughout the surgery. It has a synergistic and facilitating effect on the sensory component of bupivacaine-induced SAB. It has the added advantage of sparing of undesirable prolongation of motor block. However, further studies are required to validate our observations.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.