|Year : 2017 | Volume
| Issue : 1 | Page : 279-286
Clinical evaluation of intravenous dexmedetomidine and intravenous midazolam for hysterectomy under subarachnoid blockade with 0.5% hyperbaric bupivacaine
Kumkum Gupta1, Bhawana Rastogi1, Prashant K Gupta2, Ivesh Singh1, Manoranjan Bansal1, Vasundhera Tyagi1
1 Department of Anaesthesiology and Critical Care, Subharti Medical College, Swami Vivekanand University, Meerut, Uttar Pradesh, India
2 Department of Radio-diagnosis and Interventional Imaging, Subharti Medical College, Swami Vivekanand University, Meerut, Uttar Pradesh, India
|Date of Web Publication||3-Aug-2018|
108-109, Chanakyapuri, Shastri Nagar, Meerut 250004, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background The excellence of subarachnoid blockade (SAB) can be improved with a variety of adjuvants, used either intrathecally or intravenously.
Objective The present study aimed to compare the clinical efficacy of intravenous dexmedetomidine with midazolam for hysterectomy under SAB with 0.5% hyperbaric bupivacaine.
Materials and methods After approval, 90 adult consenting middle-aged female patients of American Society of Anesthesiologists (ASA) physical status I and II scheduled for hysterectomy under SAB were blindly randomized into three groups of 30 patients each, to receive either intravenous dexmedetomidine 0.5 μg/kg (group I) or intravenous midazolam 0.05 mg/kg (group II) or normal saline (group III), 20 min after the SAB. Patients were assessed for the onset and duration of sensory and motor blockade, maximum cephalic spread, and intraoperative hemodynamic changes as primary endpoints. The study also evaluated the sedation level and visual analogue scale score for postoperative pain as secondary outcome.
Results Patients in the dexmedetomidine group showed a higher cephalic level of sensory blockade. Time for two dermatomes’ sensory regression (144.33±19.2 min) and duration of sensory analgesia (270.10±16.6 min) in the dexmedetomidine group was extended, with a statistically highly significant difference among the groups and no hemodynamic variability. Ramsay sedation score was higher in the dexmedetomidine and midazolam groups than in the saline group. Respiratory depression was not observed in any patient. The incidence of postspinal shivering was low in patients of the dexmedetomidine group.
Conclusion Midazolam provided only sedation, whereas dexmedetomidine extended the duration of sensory analgesia of SAB, maintained hemodynamic stability, and also provided arousable sedation without respiratory depression.
Keywords: bupivacaine, dexmedetomidine, midazolam, subarachnoid blockade
|How to cite this article:|
Gupta K, Rastogi B, Gupta PK, Singh I, Bansal M, Tyagi V. Clinical evaluation of intravenous dexmedetomidine and intravenous midazolam for hysterectomy under subarachnoid blockade with 0.5% hyperbaric bupivacaine. Ain-Shams J Anaesthesiol 2017;10:279-86
|How to cite this URL:|
Gupta K, Rastogi B, Gupta PK, Singh I, Bansal M, Tyagi V. Clinical evaluation of intravenous dexmedetomidine and intravenous midazolam for hysterectomy under subarachnoid blockade with 0.5% hyperbaric bupivacaine. Ain-Shams J Anaesthesiol [serial online] 2017 [cited 2020 Apr 1];10:279-86. Available from: http://www.asja.eg.net/text.asp?2017/10/1/279/238448
| Introduction|| |
Subarachnoid blockade (SAB) is indicated for a wide range of surgeries of the lower abdomen, pelvic organs, and lower limbs along with acute postoperative pain management. Neuraxial techniques are valuable due to the decreased chances of airway compromise and excellent muscle relaxation, and have been proven beneficial in some pre-existing medical conditions.
A single intrathecal injection produces intense surgical anesthesia, and distribution of a local anesthetic drug through the cerebrospinal fluid determines the extent of the neural blockade. The hemodynamic changes are generally proportional to the cephalic level of sympathetic blockade.
Different adjuvants are used with local anesthetic drugs to extend the duration of spinal anesthesia and postoperative analgesia whether they are given intrathecally or systemically. Sedation and stable hemodynamics are the other desirable endpoints for an adjuvant in neuraxial anesthesia.
Dexmedetomidine, an α-2 adrenoceptor agonist, is used as an adjuvant to spinal anesthesia either through the intrathecal or through the intravenous route for its sedative, analgesic, and hemodynamic stabilizing properties. It also extends the duration of spinal analgesia and produces sedation without respiratory depression ,.
Midazolam exerts its effect by modulating the γ-amino butyric acid (GABA) in the brain to produce sedation. Midazolam at a dosage of 0.05 mg/kg gives enough amnesia and sedation without any adverse effect on hemodynamic parameters and respiration.
Considering above facts, this prospective double-blind placebo-controlled study was designed to compare the clinical efficacy of intravenous dexmedetomidine with intravenous midazolam on SAB with 0.5% hyperbaric bupivacaine in patients undergoing hysterectomy.
| Materials and methods|| |
After approval from the Institutional Ethical Committee and obtaining written informed consent, 90 female patients of American Society of Anesthesiologists (ASA) physical status I and II between 35 and 60 years, height 150–165 cm, and weighing 50–70 kg scheduled for elective hysterectomy under SAB were enrolled for this prospective double-blind randomized placebo-controlled study from December 2014 to February 2015, at the Department of Anesthesiology and Critical Care, CSS Hospital, associated to NSCB Subharti Medical College, Meerut, UP, India.
All patients were subjected to preanesthetic assessment before enlistment. Patients with a history of severe cardiac or pulmonary diseases, obstructive sleep apnea, morbid obesity, neurologic or psychological disease, hepatic or renal dysfunction, endocrinal or metabolic disorders, or any coagulation disorder were excluded from the study. Patients with deformity of the spinal column, known hypersensitivity to study drugs or using any drug that modifies pain perception, infection at the site of lumbar puncture, or those who refused the technique were also excluded from the study.
All patients were admitted before the day of surgery and were premedicated with alprazolam 0.25 mg tab. and ranitidine 150 mg tab. the night before surgery. Nil per oral status of all patients was maintained on the day of surgery.
The selected patients were randomized into three comparable groups of 30 patients each according to a computer-generated randomized number table. Patients of group I were given intravenous dexmedetomidine at a dose of 0.5 μg/kg; patients of group II were given intravenous midazolam at a dose of 0.05 mg/kg; and patients of group III were given normal saline.
The study drug solution was premixed to a total volume of 10 ml and was administered intravenously over a period of 10 min as a single dose, after 20 min of SAB with 0.5% hyperbaric bupivacaine. Study medication was prepared by an anesthesiologist who was not involved in the study.
Subarachnoid blockade technique
On arrival to the operation theater, baseline heart rate, noninvasive arterial blood pressure, ECG, and peripheral oxygen saturation were recorded. An intravenous access was established and lactated Ringer infusion at a rate of 10 ml/kg was started, 15 min before initiation of the SAB. Before commencement of SAB, patients were instructed on the methods of sensory and motor assessments.
Under all aseptic precautions, the lumbar puncture was performed at the L2–L3 or the L3–L4 intervertebral space with a 25-G Quincke’s spinal needle through midline approach in sitting position, and 3.5 ml of 0.5% hyperbaric bupivacaine (17.5 mg) was injected slowly. Immediately, patients were placed in supine position with 10° Trendelenberg tilt of table for bilateral block and were supplemented with oxygen at a rate of 4 ml/min through venti mask.
A premixed total volume of 10 ml of the study drug solution, according to a computer-generated randomization schedule, was administered intravenously over a period of 10 min as a single dose, after 20 min of SAB.
Assessment of sensory and motor block characteristics
All time intervals were calculated from the time of end of intrathecal injection. The sensory and motor block characteristics were recorded at 2-min intervals until adequate surgical anesthesia was achieved. The segmental level of sensory block to pin prick was assessed bilaterally along the midclavicular line using a short beveled 26-G hypodermic needle. The motor block of the lower extremities was evaluated bilaterally using the modified Bromage scale (0–3): 0, full movement and able to raise straight leg against resistance; 1, unable to raise extended leg at the hip but able to flex the knee; 2, unable to flex the knee but able to move ankle joint; and 3, unable to move the hip, knee, or ankle (no motor activity).
The onset time of sensory blockade at T10 dermatome, maximum cephalic level, time taken to achieve maximum sensory block, and time taken to two-dermatome regression of sensory analgesia were recorded. Time taken to achieve complete motor blockade and time to complete motor recovery were also noted. The surgical anesthesia was considered to be achieved when at least T10 dermatome level was anesthetized.
Duration of sensory analgesia was taken from onset of spinal anesthesia to time of administration of first rescue analgesic, reflected on visual analogue scale (VAS) 0–10: 0 cm=no pain to 10 cm=worst possible pain. VAS was assessed at 2, 4, 8, 12, and 24 h. Patients with VAS score of 3 or more received diclofenac 75 mg intramuscularly as rescue analgesia. Postoperatively, the sensory and motor block levels were assessed at 15-min intervals until normal sensations returned.
Systemic blood pressure, heart rate, pulse oximetry, and ECG were recorded at baseline, after SAB, and thereafter at every 5-min interval until the end of hysterectomy and at every 15-min intervals postoperatively. An increase or decrease of more than 20% from the baseline in heart rate and blood pressure was considered significant. Respiratory depression was defined as respiratory rate less than 8 breaths/min.
For the present study, hypotension (systolic blood pressure<90 mmHg) was treated primarily by increasing the crystalloid infusion rate and additionally with an intravenous bolus of mephenteramine 6 mg, if required. Bradycardia (heart rate<60 beats/min) was treated with atropine sulphate 0.6 mg.
The sedation score was evaluated at every 15 min after intravenous administration of study drugs using the Ramsay sedation scale : 1,patient anxious, agitated, or restless; 2, patient cooperative, oriented, and tranquil alert; 3, patient responding to commands; 4, asleep but arousable with brisk response to light glabellar tap or loud auditory stimulus; 5, asleep with sluggish response to light glabellar tap or loud auditory stimulus; 6, asleep with no response. All sedation scores were documented considering the time of start of the study drug infusion as zero.
Intraoperative requirement of any analgesic medication, respiratory depression, shivering, pruritus, nausea, and vomiting were also documented and were treated symptomatically.
Postoperatively, the patients were monitored for vital signs and VAS score at every 15 min for the first hour and then every 30 min until patients became conscious and oriented. They were also evaluated for any possible adverse effects of study medications and were managed accordingly.
Study population size and statistical analysis
The sample size was calculated with standard computer program, which computed that ∼23–25 patients should be included in each group to detect a clinically significant difference of at least 20% in the mean duration of sensory/motor block and postoperative analgesia among the groups for type 1 error of 0.05 and power of 80%. Assuming a 5% dropout rate, the final sample size was set at 90 patients for better validation of results.
The obtained data are expressed as mean and SD, considering the latter as best predictor. The demographic data for the categorical variables and adverse effects were compared using the χ2-test. Block characteristics were compared using the Kruskal Wallis H-test. Statistical analysis of mean difference was performed using analysis of variance. A P-value of less than 0.05 was considered to indicate statistical significance.
| Results|| |
The present study has comparatively evaluated the clinical efficacy of intravenous dexmedetomidine with intravenous midazolam on 90 adult middle-aged consented female patients scheduled for elective hysterectomy under SAB. All patients had successfully completed the study and were co-operative with their subsequent assessment. There were no surgical or anesthetic complications.
The demographic data for age, weight, height, BMI, ASA physical status, and duration of hysterectomy were comparable among the groups and are summarized in [Table 1].
Sensory and motor blockade profile
The mean time required to achieve complete sensory blockade was 4.16±1.2 min in all patients, with no significant difference among the groups. Median maximal cephalic dermatome level was T6, T7, and T7 for group I, group II, and group III, respectively, with a statistically significant difference among the groups ([Table 2]).
The mean time for two-segment regression was 144.33±19.2 min in group I, 105.67±23.6 min in group II, and 102.67±15.1 min in group III. The mean duration of sensory analgesia was 216.20±35.1 min in group I, 136.00±20.9 min in group II, and 122.50±16.4 min in group III, with a statistically significant difference.
The mean duration of complete sensory blockade was 270.10±16.6 min in group I, 219.50±8.5 min in group II, and 169.30±10.7 min in group III. Multiple comparisons between group I versus group II, group I versus group III, and group II versus group III were statistically highly significant ([Table 3]).
|Table 3 Multiple comparisons among the groups for sensory blockade profile|
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The mean time required for achieving complete motor block was 5.33±0.7 min in group I, 5.87±0.4 min in group II, and 6.87±0.4 min in group III, with a statistically highly significant difference among the groups.
The baseline mean heart rate of patients among the groups was comparable. After 5 min of SAB, the heart rate in patients of all groups showed a gradual decline until after 30 min of SAB. Thereafter, the trend reversed upward and continued until the last reading recorded at 120 min. The variation in mean heart rate changes among the groups were not statistically significant ([Table 4]).
The mean changes in systolic blood pressure were recorded immediately before the commencement of SAB and then at every 5-min intervals until 120 min postoperatively. After 5 min of SAB, the systolic blood pressure of all patients showed a constant decline until after 90 min. Later, there appeared an upward trend in all patients. The variations in mean systolic blood pressure were not statistically significant among the groups ([Table 5]).
The baseline mean changes in mean arterial pressure among the three groups were comparable. After commencement of SAB, the changes were recorded at every 5-min intervals until 120 min postoperatively. After 5 min of SAB, the mean arterial pressure of all patients showed a gradual decline until after 60 min. After 90 min, there appeared a slight upward trend in all patients. However, in group III, declining trend continued until after 120 min postoperatively. The variations in the mean arterial pressure were not statistically significant among the groups ([Table 6]).
Sedation score after 30 min of intravenous dexmedetomidine and intravenous midazolam was 3 when patients of group C were not sedated. The variation in the sedation score values between groups I and II after 30 min of study drug was statistically nonsignificant.
Visual analogue scale
VAS was recorded at 2, 4, 8, 12, and 24 h. The difference in the intensity of pain was highly significant between group I and group III and between group I and group II, until 8 h after operation. The pain variation after the operation was also significant between groups II and III ([Table 7] and [Table 8]).
Hypotension was observed in 7/90 (7.7%) patients, bradycardia in 7/90 (7.7%) patients, and shivering was observed in 10/90 (9%) patients during the study period. Hypotension was treated by increasing the rate of crystalloid solution infusion only and no vasopressor medication was required. Bradycardia was treated with a bolus of atropine sulphate at a dose of 0.6 mg. None of the patients of group II showed slowing of heart rate, and no patient of group I suffered from shivering. None of the patients suffered from nausea, vomiting, or pruritus ([Table 9]).
| Discussion|| |
SAB with hyperbaric bupivacaine is commonly used for surgeries on lower abdomen, pelvis, and lower extremities. Several adjuvants are used either intrathecally or systemically to improve the excellence and extent of spinal anesthesia. The combination of adjuvants allows for a reduction in doses of local anesthetics and hence a decline in their systemic side effects .
Our study showed that intravenous dexmedetomidine extended the duration of sensory blockade induced with 0.5% hyperbaric bupivacaine, compared with intravenous midazolam, with a statistically significant difference. Dexmedetomidine also produced the desired level of sedation, which was comparable to midazolam. Intraoperatively, the hemodynamic indices did not show any significant difference among the groups.
Dexmedetomidine, an α-2-adrenergic agonist, possesses sedative, analgesic, sympatholytic, and hemodynamic stabilizing properties, as well as it extends the duration of the sensory analgesia. Postsynaptic activation of central α-2-adrenoreceptors results in sympatholytic effect leading to dose-dependent hypotension and bradycardia with an acceptable safety margin. As an intrathecal adjuvant, it allows reduction in the dose of local anesthetic to produce intense surgical anesthesia and sedation. Intravenous dexmedetomidine is associated with a reduced incidence of shivering, nausea, and vomiting, hence reducing postoperative morbidity ,.
Midazolam exerts its effect by occupying benzodiazepine receptors that modulate GABA, the major inhibitory neurotransmitter in the brain. The hypnotic, sedative, amnesic, and anticonvulsant effects are mediated by α-1 GABA receptors, whereas anxiolysis and centrally acting muscle relaxant properties are mediated by α-2 GABA receptors.
It is recommended that dexmedetomidine be infused slowly over 10 min, as rapid administration might produce tachycardia, bradycardia, and hypertension. Jaakola et al.  demonstrated moderate analgesia with a ceiling effect at 0.5 μg/kg. With this in mind, dexmedetomidine at a dose of 0.5 μg/kg was infused slowly over 10 min in the present study.
Nishiyama et al.  reported that bolus administration of midazolam 0.05 mg/kg gives enough sedation and amnesia without any adverse effects on hemodynamics and respiration in patients aged 30–70 years under spinal anesthesia. Therefore, midazolam 0.05 mg/kg was also infused slowly over 10 min in this study.
The present study showed that intravenous dexmedetomidine extended the duration of sensory block, which may be due to its supraspinal, direct analgesic, and/or vasoconstrictive actions. The suppression of activity in the descending noradrenergic pathway modulates nociceptive neurotransmission to terminate the propagation of pain signals, leading to analgesia. Coskuner et al.  have demonstrated the prolonged recovery time of the sensory blockade of epidural bupivacaine after intravenous dexmedetomidine.
When compared with the extension of the sensory blockade, the duration of motor block was not affected by intravenous dexmedetomidine or midazolam. It may be due to a greater inhibition of sensory nerve fiber conduction compared with motor nerve fibers at the same concentration of study drugs, as reported by Rhee et al.  in their study with clonidine.
In the present study, the time for two-dermatome regression in the dexmedetomidine group was significantly slower when compared with other groups. Intravenous midazolam did not enhance the analgesic effects of spinal anesthesia, whereas dexmedetomidine provided additional analgesia. Our results are consistent with the study by Kaya et al.  using intravenous dexmedetomidine.
Rapid or bolus administration of dexmedetomidine produces sudden hypertension and bradycardia, resulting in moderate decreases in both mean arterial pressure and heart rate from baseline. In the present study, no biphasic change or significant cardiovascular variability was observed. This might be attributed to sympathetic blockade associated with spinal anesthesia, slow rate, and a low dose of administration of dexmedetomidine, and sufficient preoperative hydration.
Kaya and colleagues recorded the lowest heart rate in patients of the dexmedetomidine group when compared with the normal saline group with comparable statistics. The incidence of bradycardia requiring treatment with atropine was higher in patients of the dexmedetomidine group, with no statistically significant difference . We also observed decreased heart rate in patients receiving intravenous dexmedetomidine, comparable to those patients who were administered normal saline.
In the present study, only seven patients suffered episodes of hypotension, which was managed by increasing the rate of intravenous lactated Ringer infusion, and no vasopressor was required to maintain the hemodynamic stability. Previous studies, by Aantaa et al. , and Hogue et al. , have shown that the hypotensive effect of dexmedetomidine persists in the intraoperative as well as in the postoperative period.
The hypnotic effects of dexmedetomidine are mediated by the hyperpolarization of noradrenergic neurons, which suppresses neuronal firing in the locus coeruleus to inhibit the norepinephrine release. This suppression of inhibitory control triggers neurotransmitters and produces hypnosis similar to normal sleep, without ventilatory depression.In the present study the Ramsay sedation score after 30 min of dexmedetomidine was comparable to that of midazolam; the oxygen saturation remained comparable among the groups, suggesting that dexmedetomidine produces sleep, without respiratory depression. Patients sedated with dexmedetomidine were easily arousable and cooperative. Kaya et al.  reported excessive sedation in 2/25 patients in the dexmedetomidine group and 5/25 in the midazolam group compared with no sedation in the saline group. Koroglu et al.  concluded that the quality of sedation was better with dexmedetomidine when compared with midazolam, with no significant adverse effects on hemodynamic or respiratory function in their study. Eren et al.  observed sedation with decreased anxiety in patients of the dexmedetomidine and midazolam groups with minimal hemodynamic and respiratory effects.
Clinically, it was observed that dexmedetomidine caused no or minimal respiratory depression, whereas midazolam is known to cause apnea and arterial desaturation even in sedative doses. In the present study, respiratory depression was not recorded in any patient and respiratory parameters (respiratory rate) remained within acceptable limits throughout the study duration in all patients.
| Conclusion|| |
Midazolam showed only sedative properties, whereas dexmedetomidine showed both analgesic and sedative properties. Intravenous dexmedetomidine also extended the duration of sensory analgesia of SAB, maintained hemodynamic stability, and provided arousable sedation without respiratory depression.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Gupta K, Tiwari V, Gupta PK, Pandey MN, Agarwal S, Arora A. Prolongation of subarachnoid block by intravenous dexmedetomidine for sub umbilical surgical procedures: a prospective control study. Anesth Essays Res 2014; 8:175–178.
Al-Mustafa MM, Badran IZ, Abu-Ali HM, Al-Barazangi BA, Massad IM, Al-Ghanem SM. Intravenous dexmedetomidine prolongs bupivacaine spinal analgesia. Middle East J Anesthesiol 2009; 20:225–231.
Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2:656–659.
Harsoor S, Rani DD, Yalamuru B, Sudheesh K, Nethra S. Effect of supplementation of low dose intravenous dexmedetomidine on characteristics of spinal anaesthesia with hyperbaric bupivacaine. Indian J Anaesth. 2013; 57:265–269.
Lee MH, Ko JH, Kim EM, Cheung MH, Choi YR, Choi EM. The effects of intravenous dexmedetomidine on spinal anesthesia: comparison of different dose of dexmedetomidine. Korean J Anesthesiol 2014; 67:252–257.
Dinesh CN, SaiTej NA, Yatish B, Pujari VS, Mohan Kumar RM, Mohan CVR. Effects of intravenous dexmedetomidine on hyperbaric bupivacaine spinal anesthesia: a randomized study. Saudi J Anaesth. 2014; 8:202–208.
Jaakola ML, Salonen M, Lehtinen R, Scheinin H. The analgesic action of dexmedetomidine − a novel alpha 2-adrenoceptor agonist in healthy volunteers. Pain 1991; 46:281–285.
Nishiyama T, Hirasaki A, Odaka Y, Iwasaki T, Seto K. Midazolam sedation during spinal anesthesia: optimal dosage (Japanese). J Jpn Soc Clin Anesth 1994; 14:257–262.
Coskuner I, Tekin M, Kati I, Yagmur C, Elcicek K. Effects of dexmedetomidine on the duration of anaesthesia and wakefulness in bupivacaine epidural block. Eur J Anaesthesiol 2007; 24:535–540.
Rhee K, Kang K, Kim J, Jeon Y. Intravenous clonidine prolongs bupivacaine spinal anesthesia. Acta Anaesthesiol Scand 2003; 47:1001–1005.
Kaya FN, Yavascoaglu B, Turker G, Yildirium A, Gurbet A, Mogel B et al.
Intravenous dexmedetomidine, but not midazolam prolongs bupivacaine spinal anesthesia. Can J Anaesth 2010; 57:39–45.
Aantaa R, Jaakola ML, Kallio A, Kanto J, Scheinin M, Vuorinen J. A comparison of dexmedetomidine, and alpha 2-adrenoceptor agonist, and midazolam as intramuscular premedication for minor gynaecological surgery. Br J Anaesth 1991; 67:402–409.
Hogue CW, Talke XXX, Stein PK, Richardson C, Domitruvich PP, Sessler DI. Autonomic nervous system response during sedative infusion of dexmedetomidine. Anaesthesiology 2002; 97:592–598.
Koroglu A, Demirbilek S, Teksan H, Sagir O, But AK, Ersoy MO. Sedative, hemodynamic and respiratory effects of dexmedetomidine in children undergoing magnetic resonance imaging examination: preliminary results. Br J Anaesth 2005; 94:821–824.
Eren G, Cukurova Z, Demir G, Hergunsel O, Kozanhan B, Emir NS. Comparison of dexmedetomidine and three different doses of midazolam in preoperative sedation. J Anaesth Clin Pharma 2011; 27:367–372.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]