Arousal from sedation in lower abdominal surgeries under spinal anesthesia: Comparison between dexmedetomidine and clonidine.

BACKGROUND AND AIM: Dexmedetomidine and clonidine are commonly used drugs for sedation during regional anesthesia. However, data regarding arousal time from sedation with these drugs is sparse. Hence, we designed a study to compare arousal time from sedation with dexmedetomidine and clonidine during spinal anesthesia. We also tried to find out the correlation between clinical and objective method used for assessing the depth of sedation.
MATERIALS AND METHODS: In this study, 120 patients were randomly assigned in two groups to receive either dexmedetomidine (Group DE, n = 60) or Clonidine (Group CL, n = 60). Group DE received 1 μg/kg of dexmedetomidine followed by infusion at 0.5 μg/kg/h while Group CL received 1 μg/kg of clonidine followed by infusion at 1 μg/kg/h and titration until targeted Ramsay sedation scale (RSS) score of 3-5 was achieved and maintained. RSS and bispectral (BIS) were monitored until arousal of the patients. The time to achieve RSS of 2 and BIS of 90 during recovery, the correlation between BIS and RSS score in both the study groups and duration of postoperative analgesia were noted. STATISTICAL ANALYSIS USED: Chi-square tests for nonparametric data and Student's t-test for parametric data were used. Correlation between RSS and BIS was calculated with spearman correlation method.
RESULTS: Arousal time from sedation and time to reach BIS score 90 was lower for Group DE as compared to Group CL (P = 0.001). Dexmedetomidine also increased the time to first postoperative analgesic request when compared with clonidine (198.23 ± 33.15 min vs. 150.65 ± 28.55 min, P = 0.01).
CONCLUSIONS: Intravenous dexmedetomidine infusion has shorter arousal time from sedation than clonidine during spinal anesthesia. A strong correlation exists between BIS and RSS during recovery from sedation.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Spinal anesthesia has the advantage of being cardiorespiratory stable, rapid postoperative recovery, and preservation of protective airway reflexes. However, there are some drawbacks also which include pain at the puncture site, fear of needles, and recall of the procedure. These factors stress the importance of sedation that offers analgesia, anxiolysis, and amnesia. Sedation can increase the patient's acceptance of the regional anesthetic technique.[1]

When surgeries are done under spinal anesthesia, adequate sedation is very important for both patient and surgeon comfort. Under sedation lead to increased incidence of awareness, while over-sedation leads to untoward effects of respiratory and cardiovascular depression, higher chances of airway instrumentation and prolonged recovery.[2] Thus, for appropriate monitoring of the depth of sedation, various methods including a subjective scoring system and bispectral (BIS) index monitor are being used widely. The BIS index monitor offers a distinct advantage of objective, real-time assessment of the sedated patient without the application of external stimuli.[3] Along with monitoring of the depth of sedation, search for the agents with faster recovery is also important. α2 adrenergic agonists are commonly used drugs as an adjuvant to regional anesthesia due to its analgesic and sedative properties.[4]

Dexmedetomidine is a highly selective α2-adrenoreceptor agonist which has α2:α1 selectivity ratio of 8 to 10 times higher than that of clonidine.[56] Various studies have shown its analgesic and sedative action with intrathecal, epidural, or intravenous use as an adjuvant.[78] A variety of beneficial effects such as sedation, analgesia, and increased cardiovascular stability with improved outcome have also been attributed to clonidine.[9]

Numerous studies have compared sedation with dexmedetomidine and clonidine during regional anesthesia.[10] However, with best of our knowledge, no study has compared their recovery characteristics by utilizing the clinical and BIS monitor. Thus, we planned this study to compare the recovery characteristics from sedation with dexmedetomidine and clonidine during spinal anesthesia. The two drugs have been evaluated with respect to arousal times from sedation, postoperative analgesia, and the correlation between the observed BIS and Ramsay sedation scale (RSS) score.

MATERIALS AND METHODS

In this prospective randomized double-blind study, 120 patients of American Society of Anesthesiologists Grades I and II of either sex, in the age group of 25–55 years scheduled for elective lower abdominal surgery (surgical and gynecological) under subarachnoid block (SAB) were included after approval from the Institutional Ethics Committee. Patients with any known allergy to study drugs, contraindication for central neuroaxial block, obesity, (body mass index >30 kg/m2), neurological or psychiatric disease on concurrent medication, heart disease, renal disease, liver disease, and refusal were excluded from the study.

Patients were randomly allocated into two groups by drawing sequential numbered, opaque sealed envelopes containing a code based on a computer generated random number list.

Group DE: Received intravenous dexmedetomidine 1 µg/kg diluted to 20 ml with normal saline and infused over 10 min as a loading dose prior to SAB, followed by a maintenance dose of 0.5 µg/kg/h. Group CL: Received intravenous clonidine 1 µg/kg diluted to 20 ml with normal saline and infused over 10 min as a loading dose prior to SAB, followed by a maintenance dose of 1 µg/kg/h. To maintain blinding, drug preparations were clear solution and procedure of SAB was performed by an independent anesthesiologist blinded to the study while the observation was done by the attending anesthesiologist.

On arrival at the operation-theater, routine monitor such as an electrocardiogram, pulse oximetry, and noninvasive blood pressure (BP) was attached. An 18-gauge intravenous cannula was secured and patients were preloaded with 500 ml of Ringer lactate. The BIS electrodes were placed on the forehead and on the lateral angle of orbit and connected to BIS monitoring system. The 20 ml of solution of the drug as per study group (loading dose: Dexmedetomidine or clonidine 1 µg/kg) was infused for the first 10 min. 5 min after the end of the loading dose, SAB was performed under all aseptic precautions in right or left lateral position at L3-L4 level through a standard midline approach using a 25-gauge Quincke spinal needle and 15 mg of 0.5% heavy bupivacaine was injected after confirmation of clear cerebrospinal fluid.

After obtaining sensory block up to T6 level, the infusion was initiated as appropriate for the group of study with the help of a manually controlled variable rate infusion pump and the surgery was started. The patients in the Group DE were given an infusion of dexmedetomidine at 0.5 µg/kg/h. The Group CL received an infusion of clonidine at 1 µg/kg/h. On achieving the targeted RSS[11] scores of 3, the BIS score was also noted as patient's sedation status. The infusion was then titrated to maintain the RSS between 3 and 5. The infusion was stopped approximately 5 min before the end of surgery.

Hemodynamics including heart rate (HR), BP as well as oxygen saturation and RSS scores, were recorded every 10 min intraoperatively and then at 15 min interval until arousal of the patient. BIS index score was observed continuously after the induction of spinal anesthesia till the arousal of the patient. The arousal time from sedation (i.e. time from the stoppage of infusion of study drug till RSS score of 2 is achieved) was recorded. We also observed the correlation between electroencephalogram and clinical based recovery profiles from the recorded data. Postoperative pain was assessed by using the visual analog scale.[12] (VAS; 0 – No pain; 10 – Worst possible pain) at 4, 8, 12, and 24 h. Patients with a VAS score of 3 or more received injection morphine 0.05 mg/kg intravenously. The time of the first request for postoperative analgesia after surgery was recorded as the duration of postoperative analgesia.

Statistical considerations

The data were analyzed using IBM SPSS Statistics for Windows, Version 16.0 (Armonk, NY: IBM Corp). Considering a difference of 30% regarding the arousal time to be clinically significant and taking an α error of 0.05 and power of the study (1-β) to be 80%, the number of patients was calculated to be 44 in each group. The inclusion of 60 patients in each group was done for better validation of results. P < 0.05 was considered as statistically significant. The patient characteristics (nonparametric data) was analyzed using the “Chi-square tests” and the inter group comparison of the parametric data was done using the Student's t-test.

RESULTS

One hundred twenty patients were enrolled and completed the study duringNovember 2014 to May 2015. Spinal anesthesia was successful in all the patients. Thus, data from 120 patients (Group DE [n = 60], Group CL [n = 60]) were analyzed. Both the groups were found to be comparable in respect of age, weight, height, sex distribution, and duration of surgery [Table 1]. The trend of mean HR and mean arterial pressure (MAP) [Figures 1 and 2] indicated that HR and MAP in the dexmedetomidine group appears to be lower than that of clonidine group, but there is no statistically significant difference among the groups except 10 min after loading dose and recovery where the mean HR and MAP were significantly lower in the dexmedetomidine group (P = 0.021 and P = 0.033). Targeted sedation score range was maintained during surgery in both the groups [Figure 3] but BIS were significantly lower in Group DE during surgery [Figure 4].

Table 1

Patient characteristics

Figure 1

Heart rate (HR) at different time interval

Figure 2

Mean arterial pressure (MAP) at different time intervals

Figure 3

Ramsay sedation scores (RSS) at different time intervals in the group DE and CL Group DE: Dexmedetomidine group, Group CL: Clonidine group

Figure 4

Bispectral index (BIS) at different time intervals in the group DE and CL. Group DE: Dexmedetomidine group, Group CL: Clonidine group

The arousal time from sedation was significantly lower for the Group DE when compared with Group CL (P = 0.001), the time taken to reach a BIS score of 90 was also found to be lower for dexmedetomidine group (P = 0.001) [Table 2].

Table 2

Recovery characteristics

The mean arousal time from sedation (RSS score of 2) in Group DE was 37.23 ± 2.42 min, whereas in Group CL, it was 57.26 ± 4.11 min and the difference was found statistically significant. The time taken to reach a BIS score of 90 was 39.12 ± 5.11 min with dexmedetomidine versus 58.13 ± 3.25 min with clonidine [Table 2]. At RSS score of 2, the number of patients with BIS ≥ 90 that is, the point of recovery, were 48 (in Group DE) and 46 (in Group CL), respectively.

The calculated Spearman's correlation during recovery from sedation was − 0.67 (P = 0.001) and − 0.62 (P = 0.001) in Group DE and Group CL, respectively, which indicate strong relation between RSS and BIS in both the study group.

Dexmedetomidine also increased the time to first request for postoperative analgesia (198.23 ± 33.15 min) when compared with clonidine (150.65 ± 28.55 min). Complications such as bradycardia, hypotension, nausea/vomiting, and shivering were recorded in both the groups, but the difference were not statistically significant [Table 3].

Table 3

Adverse effects

DISCUSSION

Dexmedetomidine has been used intravenously in doses ranging from 0.1 to 10 μg/kg/h, but the higher doses have been associated with a significant incidence of bradycardia and hypotension.[1314] Thus, we used 1 μg/kg as a bolus dose. As the rapid administration of dexmedetomidine might produce tachycardia, bradycardia, and hypertension,[15] we administered a loading dose of dexmedetomidine, slowly, over a period of 10 min in our study. A study showed an infusion of a maintenance dose of 0.4 μg/kg/h brought adequate sedation for 120 min after loading dose used during spinal anesthesia.[16] Thus, we selected a dose of 0.5 μg/kg/h as an infusion in our study. Based on the observations of previous studies, a dose of 1.0 μg/kg of clonidine was selected in our study.[1718]

RSS used in our study is universally accepted subjective method for sedation assessment which employs a numeric scale through which an observer can catalog the patient's response to a verbal command.[11] However, the scoring systems present some problems regarding the reproducibility, validity, and interpretation of results across studies. Hence, we also employed an objective method for sedation assessment, that is, BIS index monitor and then tried to analyze the correlation between them.

The major findings of this research are as follows: (a) Compared with clonidine, arousal from sedation was faster after dexmedetomidine infusion (b) a strong correlation was present between the time to reach BIS score of 90 and RSS score of 2 (arousal time from sedation), at which the patient was awake on clinical observation (c) the time to first analgesic request was significantly longer in patients receiving dexmedetomidine for sedation during their surgery.

The time to get RSS score 2 (arousal time from sedation) was lower with dexmedetomidine than clonidine. The time to reach BIS score of 90 was also earlier when sedated with dexmedetomidine. A previous study also found that the recovery was more rapid with dexmedetomidine than with clonidine.[1920] Sümpelmann et al. found that clonidine treated patients were later in opening their eyes (22.5 ± 11.9 min vs. 17.9 ± 10.9) and the ability to state their dates of birth returned later (32.2 ± 11.6 min vs. 25.7 ± 12.8).[21]

The difference in reversibility of sedation may be due to differences of the elimination half-life of both the drugs. An elimination half-life of 14.6 h of clonidine indicates a slow on and offset of the drug in comparison to an elimination half-life of 2 h of dexmedetomidine.[22] Therefore, dexmedetomidine is more titrable than clonidine, and recovery is more rapid. However, the incidences of delayed recovery and longer discharge time with dexmedetomidine were also observed by other investigators.[1423] The variation in different studies may be due to the use of different premedicants, differences in the methodology of study, and type of surgical procedures.

Our other finding is that at comparable RSS scores, intraoperative BIS values were lower with dexmedetomidine sedation than with clonidine. This was also observed by another study in which patients getting dexmedetomidine infusion showed statistically significant lower values of BIS when compared with propofol (BIS value 60–65 in propofol as opposed to 50–55 with dexmedetomidine). Despite the difference in BIS, equal depth of sedation was achieved with both the drugs with no recall in any patient as assessed by modified Brice questionnaire.[24] Hence, these results indicate that BIS values do depend on the specific sedative agent and clinicians should interpret BIS values in light of the drugs being used.

In our study, a strong correlation was present between the time to reach RSS score of 2 (arousal time from sedation) and BIS score of 90 at which the patient was awake on objective assessment. More than 75% of the patients in both the groups had achieved BIS score ≥90 when RSS score was 2 (arousal time from sedation). This above finding was also supported by other studies, which imply that both the BIS and clinical monitoring (RSS) techniques are equally effective in monitoring sedation and, thus, either can be relied upon independent of the other.[2526]

The incidence of hypotension and bradycardia were more in the dexmedetomidine group but not statistically significant. These hemodynamic changes were due to decrease in central sympathetic outflow and decreased circulating levels of nor epinephrine. In the recovery period, time of the first request for analgesic was significantly prolonged in the dexmedetomidine group than clonidine. This could be attributed to dexmedetomidine in being highly selective α2-adrenoreceptor agonist with α2:α1 binding ratio of 1620:1 as compared to 220:1 for clonidine.[27]

The limitation of our study is that we could not follow the placebo-controlled study design because it's unethical to deny sedation in one group of patients. Moreover, data from the literature supporting our results on arousal time with dexmedetomidine and clonidine is very sparse. Hence, further multicenter trials on a large scale are needed to yield newer aspects of observation.

CONCLUSIONS

We conclude that intravenous dexmedetomidine infusion have shorter arousal time from sedation and prolonged postoperative analgesia in lower abdominal surgeries under spinal anesthesia when compared with clonidine. Both objective and clinical monitoring systems correlate strongly during the recovery period.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest