Comparison of two different doses of intrathecal dexmedetomidine as adjuvant with isobaric ropivacaine in lower abdominal surgery.

BACKGROUND: To augment the subarachnoid block utility, the efficacy of newer molecules as an adjuvant is investigated constantly. Considering the favorable profile of dexmedetomidine, it could have a potential role as an adjuvant to ropivacaine. AIM: We evaluated the efficacy of two different doses of dexmedetomidine as an adjuvant to isobaric ropivacaine, intrathecally.
METHODS: Ninety patients scheduled for lower abdominal surgery under spinal anesthesia were randomized into three groups to receive 2.5 ml of isobaric ropivacaine (0.75%, 7.5 mg/ml) added to 5 µg (10 µg/ml) or 10 µg (20 µg/ml) of dexmedetomidine or 0.5 ml of normal saline in group A, B or C, respectively. Block characteristics were compared as a primary outcome. STATISTICAL ANALYSIS: One-way analysis of variance test, Fisher's exact test/Chi-square test, whichever appropriate. A P < 0.05 was considered significant.
RESULTS: Time to achieve desired block was least in group B and maximum in group C. The sensory-motor blockade remained significantly prolonged in group B compared to other groups. Hemodynamic parameters remained stable in all three groups.
CONCLUSION: Among the investigated doses, dexmedetomidine augments the efficacy of intrathecal ropivacaine in a dose-dependent manner, without any untoward side effects.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Spinal anesthesia is a customary regional anesthetic technique, having a decent safety-efficacy profile in lower abdominal surgeries. With the advent of newer molecules, there have been time and again efforts to improve its efficacy and utility even for longer duration surgeries. Among the various adjuvants added to intrathecal doses of ropivacaine, dexmedetomidine has attained an admirable position owing to its selective α2-adrenergic agonistic action offering prolongation in sensory-motor blockade and enhanced analgesic effects in spinal anesthesia.[1] Literature supports its usage over a dose range of 3–15 µg with hyperbaric bupivacaine, while up to 5 µg with isobaric ropivacaine.[2345] Considering the dose-dependent action of intrathecal dexmedetomidine, we hypothesize that higher dose of dexmedetomidine used as an adjuvant in spinal anesthesia with isobaric ropivacaine would result in better efficacy profile by further prolongation of sensory-motor blockade in patients undergoing lower abdominal surgery.

METHODS

After Institutional Ethical Approval and written informed consent, 90 patients aged 18–60 years, of either sex, of American Society of Anesthesiologist (ASA) grade I or II scheduled for lower abdominal surgery in between September 2012 and August 2014 were included in this prospective, randomized-controlled, double-blinded trial. Patient with a history of end-organ dysfunction, morbid obesity, pregnancy, hypersensitivity to study drugs, and general contraindication to spinal anesthesia were excluded.

All patients were randomly (computer generated randomization and concealment via sealed opaque envelope technique) assigned to three equal groups to receive spinal anesthesia by 2.5 ml of isobaric ropivacaine (0.75%, 7.5 mg/ml) added to 5 µg (10 µg/ml) or 10 µg (20 µg/ml) of dexmedetomidine or 0.5 ml of normal saline in group A, B or C, respectively. Randomization was performed by an anesthesiologist involved in studied drug preparation. Further procedure and monitoring were performed by another investigator unaware of group allocation; patients were also blinded to the drug regimen utilized for spinal anesthesia.

Premedication included tablet alprazolam (0.25 mg) and tablet ranitidine (150 mg) administered orally on the evening before surgery, and 2 h before the scheduled procedure. On arrival to the operating room, standard monitors were placed and baseline parameters recorded. All patients were preloaded with lactated ringer solution (15 mg/kg) via peripheral 18 gauge intravenous (IV) catheter. Before the commencement of spinal anesthesia, patients were explained about the procedure and methodology of monitoring methods. In the lateral decubitus position under standard aseptic precautions, using a midline approach lumbar puncture was performed at L3-L4 or L4-L5 intervertebral space by 25 gauge Quincke spinal needle (BD, Gurgaon, Haryana, India). Having confirmed the free flow of cerebrospinal fluid through the spinal needle, the studied drug solution was injected intrathecally over a period of 10–15 s and patients were turned to the supine position.

Primary outcome included the duration of sensory-motor blockade measured from the time point of commencement of spinal anesthesia. The level of sensory blockade was assessed bilaterally (by pinprick method) at the midclavicular line in an ascending fashion from T12 dermatome. Motor blocked was assessed according to modified Bromage score where 0: Patient able to move hip, knee, ankle, 1: Unable to move hip, able to move knee and ankle, 2: Unable to move hip and knee, able to move ankle, 3: Unable to move hip, knee and ankle. The block assessment was performed every 2 min after the commencement of spinal anesthesia until the T6 dermatomal level and Bromage score of “3” has been achieved (desired criteria to initiate surgery). Further assessments were performed at 20 min intervals, until the recovery of S2 dermatome (duration of the sensory block) and Bromage score of “0” (duration of the motor block). All patients where desired level of anesthesia was not achieved within 20 min were regarding as block failures, and managed by performing general anesthesia. These cases were excluded from the study. Hemodynamic variables (heart rate [HR], mean blood pressure [MBP]) were monitored continuously, and any incidence of associated side-effects was documented till sensory-motor levels regressed to above-mentioned threshold during the postoperative period. Any episode of hypotension (systolic blood pressure <90 mmHg or >25% below baseline) was managed by Ephedrine (5 mg) and an additional fluid bolus of ringer lactate solution. Bradycardia (<50 beats/min) was managed by injection atropine 0.5 mg IV bolus.

To detect a 20% difference in the primary outcome between the compared groups with a standard deviation of 25% (estimated from initial pilot observations), with 80% power and 5% α error (two-sided); a sample size of 26 per group was required. The sample size was calculated by power and sample size calculator of Department of Biostatics, Vanderbilt University, USA. To take care of any dropouts, we selected 90 patients (30 in each group) for our study.

The statistical analysis was performed with IBM SPSS Statistics for Windows, Version 16.0 (IBM Corp., Armonk, NY, USA). The continuous variables were compared by one-way analysis of variance test. Discrete variables were compared by Fisher's exact test/Chi-square test, whichever appropriate. A P < 0.05 was considered significant.

RESULTS

All 90 patients completed the study successfully [Figure 1]. The study groups were comparable in terms of demographic profile, baseline hemodynamic variables, ASA status, type of surgical procedure, IV fluid infused, estimated blood loss, and the duration of surgery [Table 1].

Figure 1

Flow chart of patients studied

Table 1

Comparison of demographic data and baseline parameters between the groups (n=30)

The median height of maximal sensory blockade was comparable between the groups, while the time required to achieve the desired T6 sensory level was least in group B and maximum in group C (P < 0.001) [Table 2]. Average time required to achieve a Bromage score of "3"varied similarly among the groups [Table 2]. Minimal intraoperative MBP, maximal intraoperative HR, and dose requirement of ephedrine did not vary significantly among the groups. None of the patients required supplemental analgesia for the duration of surgery [Table 2].

Table 2

Comparison of block characteristics and intraoperative hemodynamic parameters among the groups (n=30)

The time required for sensory regression to S2 level and the duration of motor block was maximal in group B and minimum in group C (P < 0.001). Observed side-effects included hypotension, nausea and vomiting, and shivering in few patients and did not vary significantly among the groups [Table 3].

Table 3

Comparison of side-effects between the groups (n=30)

DISCUSSION

Ropivacaine, a newer amide local anesthetic, is considered to have a better tolerability profile for neuro-cardiovascular tissues and has signaled as an alternative to bupivacaine.[67] Hyperbaric ropivacaine though produces a more consistent nerve block than isobaric preparation, unavailability of commercial hyperbaric preparations have invited investigations on addition of adjuvant to isobaric ropivacaine to overcome its drawbacks.[89] Among the investigated adjuvant, dexmedetomidine appears to have noteworthy potential, though investigated over a limit dose range up to 5 µg.[1] In this study, we investigated its efficacy over a dose range of 5–10 µg and observed that dexmedetomidine has a dose-dependent augmentation of anesthetic efficacy of isobaric ropivacaine in terms of greater duration of sensory-motor blockade, and also the lesser time required to achieve the desired blockade.

Dexmedetomidine, owing to its α2 adrenergic agonistic action has a synergistic effect on local anesthetics through prolongation of the sensory block by depressing neurotransmitter release from C-fibers of the spinal cord leading to hyperpolarization of postsynaptic dorsal horn neurons.[10] Motor block prolongation also occurs in conjunction by binding of α2 agonists to motor neuron in the dorsal horn of spinal cord. Besides this, direct antinociceptive action for control of both somatic and visceral pain further contributes to the prolongation of analgesia duration.[1112] Above properties could have contributed to enhance anesthetic effects with the usage of 10 µg of Dexmedetomidine under the methodology utilized in our study. Above results are coherent with previous investigations by Al-Mustafa et al. demonstrating similar results with 10 µg of dexmedetomidine added to intrathecal bupivacaine for urosurgical procedures.[2]

Various animal models have documented a dose-dependent synergistic efficacy of α2 agonists added to local anesthetics in spinal anesthesia, with a plateau after a certain dose.[13] Further increase in α2 agonist dose contributes only to increase in the incidence of associated side-effects. Previous literature shows a 1:10 equivalence dose ratio between dexmedetomidine and clonidine, with a maximally effective dose of intrathecal clonidine equating to 150 µg.[13] Considering the dose ratio, theoretically maximal effective dose of dexmedetomidine comes out to be 15 µg. We chose to investigate a submaximal dose of 10 µg of dexmedetomidine to avoid any dramatic increase in associated side-effects while assessing the efficacy of increased dose. Under the studied methodology (ropivacaine 18.75 mg), all the selected patients achieved the desired level of anesthesia without any block failures. Previous studies on isobaric ropivacaine observed similar results at a dose of 22.5 mg, but 10% failure rate was reported with a dose of 15 mg.[714]

It is a well-known fact that intrathecal local anesthetics block the sympathetic outflow and reduces the hemodynamic parameters during the intraoperative period.[15] We observed a similar decrease in hemodynamic parameters in all the patients, irrespective of group distribution. However, Al-Mustafa et al. demonstrated a dose-dependent, but still insignificant decrease in MAP by addition of dexmedetomidine to bupivacaine over a dose range of 5–10 µg, when compared with bupivacaine alone.[2] As bupivacaine and ropivacaine share a similar pharmacodynamics profile, difference in above observations could be attributed to dissimilar dose-response relationship of above drugs at a particular concentration and volume used in respective studies. Thus, the addition of different doses of α2 agonist to isobaric ropivacaine did not affected the sympatholysis any further and manifested as the similar incidence of hypotensive episodes and dose requirement of vasopressors among the groups.[1617]

Our study has two main limitations. First, these results may vary from investigations performed on other ethnic groups considering the disparity in body height and variations in subjective anesthetic sensitivity. Second, safety-efficacy profile of any drug could be better delineated by performing a dose-dependent study. Thus, the maximally effective dose of dexmedetomidine could go well beyond 10 µg. Future trials could investigate these aspects, with emphasis on effect of variation in dose of local anesthetics on the maximally effective dose of dexmedetomidine.

CONCLUSION

Dexmedetomidine appears to augment the efficacy of intrathecal ropivacaine in a dose-dependent manner without associated increase in the incidence of associated adverse effects. It could be an attractive alternative for long duration surgeries performed under spinal anesthesia, where cardiovascular stability is a priority.