A study to compare the overall effectiveness between midazolam and dexmedetomidine during monitored anesthesia care: A randomized prospective study.

BACKGROUND: Monitored anesthesia care (MAC) combines intravenous sedation along with local anesthetic infiltration or nerve block. Several drugs have been used for MAC, but all are associated with complications. Dexmedetomidine is a selective α2-adrenoceptor agonist with both sedative and analgesic properties and is devoid of respiratory depressant effects. Its short elimination half-life makes it an attractive agent for sedation during MAC. AIM: Comparative evaluation of dexmedetomidine and midazolam for MAC.
METHODS: In this prospective, randomized, double-blind study, 50 American Society of Anesthesiologist I and II patients undergoing a surgical or diagnostic procedure of <1 h requiring MAC were enrolled. Dexmedetomidine-ketamine (Group "KD") patients (n = 25) received intravenous (I.V.) dexmedetomidine 1 mcg/kg over 10 min followed by 0.5 mg/kg of I.V. ketamine. Midazolam-ketamine patients (n = 25) received I.V. midazolam 0.05 mg/kg over 10 min followed by 0.5 mg/kg of I.V. ketamine to get a targeted level of sedation (≤4 using Observer's Assessment of Alertness/Sedation Scale score). Inadequate sedation (e.g., 15% increase in mean arterial blood pressure or heart rate, decrease in degree of calmness, increase in respiratory rate, physical movement) was treated by a ketamine bolus of 0.5 mg/kg as a rescue analgesia. STATISTICAL ANALYSIS: The statistical tests used in the study are unpaired Student's t-test for continuous variables and Chi-square test for categorical variables. Mann-Whitney test was used to assess the patient and surgeon satisfaction. Data were expressed as mean ± standard deviation. Value of P < 0.05 is considered significant and P < 0.0001 as highly significant.
RESULTS: Clinically desired sedation and analgesia was achieved earlier and better with dexmedetomidine. Patients and surgeons satisfaction were significantly higher with dexmedetomidine. The requirement of additional sedation and analgesia was less in dexmedetomidine (KD) group.
CONCLUSION: During MAC dexmedetomidine provides better sedation and analgesia than midazolam.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Monitored anesthesia care (MAC) combines intravenous sedation with local anesthetic infiltration or nerve blocks. MAC may be used for superficial surgical or diagnostic procedures with the primary aim of providing good analgesia and sedation without respiratory depression. It ensures a rapid recovery without any side effects.

The most commonly used medications for MAC are midazolam, propofol, and fentanyl.[1] But sometimes, the simultaneous administration of sedatives-hypnotics with analgesics can cause significant respiratory depression and/or transient upper airway obstruction. Rapid progression from a “light” level of sedation to “deep” sedation (or unconsciousness) may predispose the patient for airway obstruction, oxygen desaturation, and even aspiration, thus requiring vigilant monitoring during MAC.[2]

In contrast, dexmedetomidine is a centrally acting α-2 receptor agonist with both sedative and analgesic properties and devoid of respiratory depressant effect.[3] Because of its analgesic properties, and lack of respiratory depression, dexmedetomidine is increasingly being used as a sedative-analgesic for MAC. These properties along with its relatively short elimination half-life of 2 h make dexmedetomidine an attractive agent for sedation during MAC.[4] This prospective, randomized, double-blind clinical study was undertaken for comparative evaluation of dexmedetomidine-ketamine (Group “KD”) combination with that of midazolam-ketamine in patients undergoing minor superficial surgical procedures under local anesthesia infiltration.

METHODS

After institutional ethical committee approval, 50 American Society of Anesthesiologist (ASA) I–II patients were enrolled in this prospective randomized, double-blind clinical trial. Patients included in the study were between 20 and 50 years of age and were planned for elective minor superficial surgical procedures under local anesthesia. Patients with cardio-respiratory diseases, renal diseases, liver diseases, chronic users of sedatives and narcotics, alcoholic or drug abusers, or those allergic to any of the medications used in the study were excluded. Patients were randomized to receive either Group “KD” or midazolam-ketamine (Group “KM”) for sedation and analgesia during surgery by sealed envelope technique. Both patient and the anesthesiologist were blinded to the patient's group assignment.

After informed consent, patients were taken in the operating room and an intravenous (I.V) access was secured. All noninvasive monitoring devices (noninvasive blood pressure, electrocardiograph leads and pulse oxymeter) were attached, and the baseline cardiorespiratory parameters were recorded every 5 min following the administration of the drugs till the end of surgery. All the patients were premedicated with 0.2 mg of glycopyrrolate I.V., injection ondansetron 0.1 mg/kg. Lignocaine sensitivity was performed by the anesthesiologist. Group “KD” patients (n = 25) received dexmedetomidine 1 mcg/kg−1 in 10 ml normal saline intravenously over 2 min followed by 0.5 mg/kg I.V. ketamine while Group “KM” patients (n = 25) received I.V. midazolam 0.05 mg/kg in 10 ml normal saline over 2 min followed by 0.5 mg/kg of I.V. ketamine to get a targeted level of sedation (≤4 using Observer's Assessment of Alertness/Sedation Scale score-Reference 1). During the completion of loading dose of the study drug, the blinded surgeon infiltrated local anesthesia using 5 ml of 2% lidocaine with adrenaline. Any adverse events such as hypotension (mean arterial blood pressure [MABP] <60 mmHg) was treated with fluid administration (0.9% normal saline) and bradycardia (heart rate [HR] <55/min) was treated with an increment of 0.3 mg atropine I.V. and O2-desaturation (SpO2 < 95%) with 100% O2. Inadequate sedoanalgesia (e.g., 15% increase in MABP and HR, increase in respiratory rate, physical movement, Observer's Assessment of Alertness/Sedation Scale score >4) was treated by a ketamine bolus of 0.5 mg/kg as a rescue sedoanalgesic.

Reference 1:

Assessment of Alertness/Sedation Scale score

5: Responds readily to name spoken in normal tone

4: Lethargic response to name spoken in normal tone

3: Response only after name is called loudly and/or repeatedly

2: Response only after mild prodding or shaking

1: Response only after painful trapezius squeeze

0: No response after painful trapezius squeeze

The following data were recorded for evaluation:

Hemodynamic parameters during the intraoperative period

Duration of analgesia by the loading dose of study drug in the two groups

Mean total extra dose of ketamine required in the operative period in the two groups

Patient's and surgeon's satisfaction between the two groups at the end of surgery.

In the recovery room, patients were monitored at every 15 min for a period of 2 h for any untoward effects of study drugs like nausea, vomiting, changes in blood pressure, HR and respiratory rate, allergic rashes, and hallucination, etc. Patients were interviewed just before discharge regarding their experience with sedation/analgesia during surgery using a grading of good, better and best (by asking the question: How would you rate your experience with the sedation/analgesia you have received during surgery?). The surgeons were asked to rate their satisfaction with patient sedation and operative ease using the same set questions at the end of surgery. Satisfaction level of both patient and surgeon was assessed using Likert scale-Reference 2.

A 7-point Likert scale for assessment of patients’ and surgeon satisfaction

1----------2-------------3-------------4-------------5-----------6--------7—

Extremely dissatisfied

Dissatisfied

Somewhat dissatisfied

Undecided

Somewhat satisfied

Satisfied

Extremely satisfied.

Statistical analysis

Sample size was selected on the basis of sample size calculation formula for difference of effect size proportions in the two groups. The statistical tests used in the study are unpaired Student's t-test for continuous variables and Chi-square test for categorical variables. Mann–Whitney test was used to assess the patient and surgeon satisfaction.

SPSS 20.0 for used for statistical analysis. Data were expressed as mean ± standard deviation. Value of P < 0.05 is considered significant and P < 0.0001 as highly significant.

RESULTS

The demographic profile of the patients in both groups was comparable with regards to age, weight, and sex. Furthermore, the groups did not differ statistically regarding their baseline preexisting clinical disease and investigations which is evident from the nonsignificant difference observed in the ASA status in the two groups.

Regarding the duration of surgery, the significant difference was not revealed between the groups. The mean duration of surgery in the groups KD and group KM is 39.40 ± 6.51 and 39.60 ± 6.11, respectively.

No significant difference was found between the two groups in respect to the induction-incision time. The induction-incision time ranged from 11 to 14 min in group KD with mean value of 12.40 ± 0.65 min while in groups KM it ranged from 12 to 13 min with mean value of 12.40 ± 0.50 min [Table 1].

Table 1

Demographic and baseline clinical profile inclusive of duration of surgery and induction-incision time

Systolic blood pressure (SBP), diastolic blood pressure (DBP), and MABP recording was done at 5 min, 10 min, 15 min, and 20 min and was analyzed statistically. There was no statistical difference in SBP between the two groups. There was a statistically significant difference in both DBP and MABP at 5 min between the two groups, though the difference was not significant at 10.15 and 20 min [Table 2].

Table 2

Hemodynamic parameters at different intraoperative intervals

Heart rate and respiratory rate was also analyzed at 5, 10, 15, and 20 min. The difference in mean HR between the two groups was statistically significant at 5 min only with no significant difference seen at 10.15 and 20 min.

There was no statistically significant difference observed in the mean RR between the two groups [Table 3].

Table 3

Mean HR and RR at different intraoperative intervals

The time to first dose of analgesic after the loading dose in the two groups was analyzed. In group KD, the duration of analgesia because of the loading dose ranged from 30 to 45 min with mean value of 36.43 min and these values in the group KM ranged from 25 to 45 min having mean value of 30.00 min.

Because of sedo-analgesic property of dexmedetomidine the mean duration of analgesia is slightly more (36.43 min) as compared to the in group KM (30.00 min). The mean difference of 6.42 min in the mean duration of analgesia is found to be statistically significant [Table 4].

Table 4

Mean duration of analgesia by the loading dose of study drug

During the intraoperative, out of 25 patients in the group KD only 7 patients had required an extra dose of ketamine which ranged from 25 to 35 mg with mean ketamine dose of 29.86 mg. In the group KM, slightly more number of patients (n = 10) out of the 25 patients had needed an extra dose of ketamine ranging from 25 to 60 mg with mean value of ketamine dose of 32.20 mg.

The mean extra ketamine dose in group KM (32.20 mg) is greater than that in group KD (29.86 mg), but the observed mean difference of 2.34 mg is found to be statistically nonsignificant.

Likert's scale of 7 points has been used for the assessment of patient's satisfaction as well as for surgeon's satisfaction. The patient's satisfaction was found to be having a higher score (mean rank 32.62) in group KD than in the group KM (18.38). The surgeon satisfaction is also observed to be having a higher score (mean rank 34.14) in group KD than in the group KM (16.86). And the observed difference evident in the patient's and surgeon satisfaction between the two groups is found to be statistically significant [Table 5].

Table 5

Patient's and surgeon's satisfaction between the two groups

DISCUSSION

Monitored anesthesia care is the term used when an anesthesiologist monitors a patient undergoing diagnostic or therapeutic procedures with the help of local infiltration or nerve block. It has become a popular technique during day care surgery. Compared to general anesthesia and regional block, MAC-based techniques can facilitate a faster recovery during day care surgery. MAC achieves the goal of providing analgesia, sedation, anxiolysis with minimal residual sedation to achieve the goal of early discharge during ambulatory surgery. Sedative-hypnotic drugs administered during MAC make procedures more tolerable for patients by reducing anxiety and providing a degree of intraoperative amnesia while allowing them to rest (or sleep) during the operation.[5] Patients often become restless, bored or uncomfortable when forced to remain immobile for prolonged periods of time under local anesthesia. Sedatives and hypnotics in conjunction with analgesics are required to make patient calm during surgery, but they are associated with significant respiratory depression and/or transient upper airway obstruction.

Many drugs have been evaluated for their efficacy during MAC. Low dose ketamine (0.25–0.5 mg/kg) combined with either midazolam or propofol has also been administered to outpatients undergoing cosmetic surgical procedures with local anesthesia.[6] Ketamine produces lesser respiratory depression than the opioid compounds and better intraoperative analgesia than nonsteroidal anti-inflammatory drugs. It is the only anesthetic drug available with analgesic, hypnotic, and amnesic effects, but its main disadvantage is its cardiostimulant effect even in therapeutic doses, leading to an increase in mean arterial pressure, HR and cardiac output as observed by Knox et al.[7] and Gupta et al.[8]

The present study was designed to evaluate the efficacy of intravenous midazolam and dexmedetomidine when given along with ketamine on hemodynamic response, duration of analgesia, and to assess the patient and surgeon satisfaction at the end of the surgery.

It is a well-known fact that a benzodiazepine (midazolam) abolishes the post anesthetic psychotomimetic effects of ketamine by closing the N-Methyl-D-aspartate receptors, while an α2 adrenoceptor agonist (dexmedetomidine) induces central sympatholysis by activating presynaptic autoreceptors. Thus, dexmedetomidine induces sedation via central nervous system receptors which differ from those induced by the benzodiazepines drugs.[9101112]

Ketamine usually do not cause respiratory depression when given in an appropriate doses.[1314] Similar result was found in our study as none of the patient showed clinically significant respiratory depression. Intraoperatively, none of our patients had shown fall in oxygen saturation. No patient required a nasopharyngeal or oropharyngeal airway to maintain the patency of airway.

In the present study, at doses that induced comparable and clinically adequate sedation in our healthy patients, premedication with dexmedetomidine was statistically equivalent to midazolam for the attenuation of ketamine-induced intraoperative hypertension, tachycardia, and postoperative hallucinations. Thus, the sedative effects of dexmedetomidine and midazolam appear to be quantitatively similar.

Various studies have shown that dexmedetomidine has a propensity to cause bradycardia.[151617] However, in our study no patient suffered an episode of bradycardia, though there was a decrease in HR at 5 min in the KD group (statistically significant). This absence of bradycardia was probably because of the sympathetic stimulation produced by ketamine which probably counteracted the bradycardia causing characteristics of dexmedetomidine.

The main drawback of using ketamine is usually the sympathetic stimulation and postoperative hallucinations. Numerous drugs have been tried to attenuate these undesirable responses. Small doses of either midazolam and propofol can be administered to attenuate the adverse psychotomimetic reactions produced by ketamine.[18] Dexmedetomidine (1 μg/kg I.V.) significantly decreases anxiety levels and reduces the requirement for supplemental analgesic medications when given before intravenous regional anesthesia.[19] The α2 adrenergic agonists, such as clonidine and dexmedetomidine, induce preoperative sedation, reduce anesthetic requirements, and improve intraoperative hemodynamic stability with postoperative analgesia, thus making them suitable adjuncts to ketamine anesthesia.[20] We found the same result in our study that, there was no difference between dexmedetomidine and midazolam in terms of hemodynamic stability when given along with ketamine.

Dexmedetomidine is an a2 agonist similar to clonidine, with analgesic and sedative properties. We found that the duration of analgesia by the loading dose of dexmedetomidine and ketamine was significantly longer as compared to the duration of analgesia by midazolam and ketamine combination [Table 4]. Similar to the result found by Koruk et al.,[21] we also observed that fewer patients required supplemental analgesia in KD group as compared to KM group (7/10). Though the supplemental dose of ketamine was lower in the KD group (29.86 ± 3.29 mg) than in the KM group (32.20 ± 10.20 mg), the difference between the doses was statistically nonsignificant [Table 6]. Because supplementation was given whenever the sedation score was >4, lesser supplementation in KD group suggest better sedation in that group as compared to KM group.

Table 6

Mean total extra dose of ketamine requirement in the operative period in the two groups

Hence, we found that there was a synergistic effect between dexmedetomidine and ketamine in terms of analgesia and thus the duration of analgesia was longer in the KD group, with an added advantage of sedation. Furthermore, less no. of patients required lesser (though non-significant) supplemental doses of ketamine in the KD group.

Patients in KD group expressed significantly greater satisfaction than the KM group. Though Alhashemi[22] and Zeyneloglu et al.,[23] found the time for recovery and discharge from post-anesthesia care unit longer with dexmedetomidine as compared to propofol and midazolam/fentanyl respectively, all the patients in our study were ready for discharge after 2 h from the postoperative period.

Dexmedetomidine–treated patients were significantly more satisfied with their anesthesia experience than patients in the midazolam group. Patient in KD group felt less pain and were feeling better overall in the postoperative period, as assessed by our questionnaire. In the KM group, the main complaint was the perception of pain during the operative period and in the postoperative room.

Similarly, the surgeon satisfaction score was greater in KD group than in the KM group. They observed the lesser incidence of patient movement and a greater degree of patient sedation in KD group.

Overall, patients’ and surgeons’ satisfaction difference was statistically significant between the two groups.

Limitations

The main limitation of our study was the assessment of patient and surgeon satisfaction, which is totally subjective and depends on individual susceptibility to pain perception.

We also tabulated and evaluated the hemodynamic parameters for the first 20 min of surgery primarily because most of the surgeries lasted for around 20 min. We also restricted our study to the intraoperative period and did not compared the drugs in the postoperative period probably because we took the targeted sedation score of ≤4 and avoided deep sedation with a score of ≤3, hence all our patients had a score of >4 at the end of surgery.

CONCLUSION

Dexmedetomidine provides a superior analgesic effect in combination with ketamine, provides a better operating conditions for the surgeon, and a better patient satisfaction as compared to the midazolam and ketamine combination. At comparable sedation scores, dexmedetomidine is a better option as compared to midazolam for procedures requiring MAC.