Comparison of Morphine and Dexmedetomidine as Adjuvants to Isobaric Levobupivacaine for Spinal Anesthesia in Patients Undergoing Abdominal Hysterectomy.

Introduction: Various adjuvants to local anesthetics are used in spinal anesthesia for improving the quality and prolonging postoperative analgesia. We aim to compare the analgesic efficacy of morphine or dexmedetomidine given intrathecally as adjuvants to isobaric levobupivacaine. Materials and
Methods: Seventy patients of age group 18-60 years, American Society of Anesthesiologists 1 and 2 undergoing elective abdominal hysterectomy, were randomized into two groups. Group M received spinal anesthesia with 3 mL of 0.5% isobaric levobupivacaine with 250 μg of preservative-free morphine. Group D received 3 mL of 0.5% isobaric levobupivacaine with 5 μg of dexmedetomidine. Quality of anesthesia, sensory and motor block characteristics, duration of effective analgesia, and incidence of side effects were compared.
Results: The time for the first analgesic request was 320.80 ± 41.75 min in the dexmedetomidine group as compared to the morphine group (451.63 ± 38.55 min), P = 0.000. The analgesic requirement in the first 24 h was significantly higher in Group D as compared to Group M, P = 0.000. Adverse effects were similar in both the groups, except pruritus which was seen only in Group M.
Conclusion: Our study shows that the use of intrathecal morphine as an adjuvant to isobaric levobupivacaine provides better analgesia than intrathecal dexmedetomidine; however, adverse effects such as nausea and pruritus may be seen. Copyright:

INTRODUCTION

Total abdominal hysterectomy is considered a major surgery and is associated with a medium to high pain level.[1] Insufficient pain control may result in less patient satisfaction, delayed mobilization, and delayed functional recovery.

Spinal anesthesia is the preferred mode of anesthesia in patients undergoing total abdominal hysterectomy because of its rapid onset, superior blockade, lower failure rates, and cost-effectiveness. However, intrathecal local anesthetic drugs given alone have a relatively short duration of action, and thus, early analgesic intervention is often needed in the postoperative period.

Over the years, many adjuvants have been used to improve postoperative analgesia, such as opioids, neostigmine, ketamine, and α2 adrenergic agonists.[23] Intrathecal morphine (ITM) is the most widely used hydrophilic opioid adjuvant to intrathecal local anesthetics as it provides prolonged postoperative analgesia, but it has its associated side effects including nausea, vomiting, pruritus, and urinary retention. It can also lead to the most feared complication of delayed respiratory depression.[4]

Dexmedetomidine, a new highly selective α2 agonist, is rapidly emerging as the choice of additive to spinal anesthesia as it provides stable hemodynamic conditions, good quality of intraoperative analgesia, and prolonged postoperative analgesia with minimal side effects.[567]

Levobupivacaine, a newer amide local anesthetic, is emerging as an effective alternative to hyperbaric bupivacaine because of its lesser central nervous system and cardiovascular system toxicity.[8]

As there are few studies[67] comparing the efficacy of ITM with intrathecal dexmedetomidine added to hyperbaric bupivacaine, we planned to compare ITM with intrathecal dexmedetomidine as an adjuvant to isobaric levobupivacaine in abdominal hysterectomies.

In this study, the primary aim was to compare the analgesic efficacy of these two adjuvants, while the secondary aim was to compare the adverse effects (hypotension, bradycardia, nausea, vomiting, and respiratory depression), the characteristics of spinal block, and the perioperative vital parameters.

MATERIALS AND METHODS

This prospective, randomized, double-blinded clinical trial was conducted after approval by the Institutional Ethics Committee and was registered in the Clinical Trial Registry, India (www.ctri.nic.in) prospectively with identification number CTRI/2018/01/011178.

After obtaining written informed consent, 70 female patients in the age group ranging 18–60 years, belonging to physical status American Society of Anesthesiologists (ASA) 1 and 2, who underwent abdominal hysterectomy, were included.

Patients with ASA physical status grade 3 and above, known allergy to any of the study medications, acute or chronic respiratory disease, hypertension or other cardiovascular abnormalities, and cognitive or psychiatric disturbances, as well as patients on α adrenergic receptor antagonist, ACE inhibitors, angiotensin receptor blockers, and chronic opioid therapy were excluded from the study.

Intervention and study groups

Routine preoperative assessment was performed 1 day before the surgery. Patients were explained the study protocol and the potential benefits and side effects of both groups. Randomization of patients into two groups was achieved by generating a computer-generated sequence using an online random number generator. For blinding, patient codes along with instructions about the dose and preparation of the drug were placed into sequentially numbered sealed opaque envelopes by an anesthesiologist who was not involved in the study. An anesthesia resident not involved in patient management was responsible for opening the envelope. The anesthesia resident prepared the study drug according to the instructions contained and gave it to the anesthesiologist managing the patient.

Patients were randomly allocated to two groups (Group M and Group D) of 35 each. Group M patients received 3 mL of 0.5% isobaric levobupivacaine with 250 μg of preservative-free morphine. Group D patients received 3 mL of 0.5% isobaric levobupivacaine with 5 μg of dexmedetomidine.

On the arrival of the patient to the operating room, ASA standard monitors were applied. An intravenous (iv) line was established, and the patients were co-loaded with lactated Ringer's solution. Under all aseptic precautions, lumbar puncture was performed at the L3–4 or L4–5 level by using a 26-gauge Quincke's spinal needle in a sitting position.

Both the groups received 3 mL 0.5% isobaric levobupivacaine in 5 mL syringes. For Group M, injection (Inj) morphine 10 mg.mL−1 was first diluted to 5 mg.mL−1, and then 1 mL of this was loaded in an insulin syringe. 2 units or 0.05 mL (250 μg) was added to 3 mL of 0.5% intrathecal levobupivacaine. For Group D, Inj dexmedetomidine 100 μg.mL−1 was also loaded in an insulin syringe. 2 divisions or 0.05 mL (5 μg) was added to 3 mL of 0.5% intrathecal levobupivacaine. To ensure blinding, an equal volume of the adjuvant was given in both groups.

Immediately after giving the Inj, patients were turned to supine position. The completion of injection was taken as time zero of anesthesia. The surgery was started after the complete establishment of sensory and motor blockade.

Sensory block was assessed bilaterally every 2 min for initial 20 min by using analgesia to pin-prick with a short hypodermic needle in the midclavicular line. The time to achieve the sensory level of T10, the highest sensory level achieved, and the time taken to achieve that were also noted. After the initial 20 min, the sensory level was monitored every 15 min till the end of surgery.

The time to two-segment regression of sensory block and regression to T12 level was also noted. Motor blockade was assessed using a modified Bromage scale [Annexure 1].[9] Heart rate (HR), blood pressure, oxygen saturation (SpO2), and sedation score were monitored every 2 min for the initial 20 min and later on every 15 min till the end of surgery. Hypotension was defined as a fall in BP of more than 20% from baseline value and was treated with phenylephrine or ephedrine boluses and iv crystalloids. Bradycardia was defined as HR <50/min and was treated with injection atropine.

The total duration of surgery was noted. Postoperatively, the time for regression to S2 dermatome was noted. The time to reach Bromage grade 6 was noted. All the patients were monitored for the presence of nausea/vomiting, pruritus, sedation, signs of respiratory depression (respiratory rate/min and SpO2), HR, and Non Invasive Blood Pressure (NIBP) every 2 hourly for 12 h and then every 4 hourly for the next 12 h.

Nausea/vomiting was treated with Inj ondansetron 4 mg iv. Pruritus was treated with Inj promethazine 25 mg intramuscularly, which was repeated after 1 h if needed. Oxygen by Hudson mask was provided if SpO2 decreased to <94%. Inj naloxone in the dose of 0.1–0.2 mg iv bolus, to be repeated as needed every 3–4 min, was reserved for patients with a respiratory rate of less than 8/min.

The study ended 24 h after induction of anesthesia. Inj tramadol 50 mg iv was given as rescue analgesia. The time for the first rescue analgesia and the total number of analgesic doses used were noted.

Statistical analysis

Data were entered in the MS Excel spreadsheet and were analyzed using the Statistical Package for the Social Sciences version 21 (IBM Corporation, USA) for Windows (Microsoft Corporation, USA). The sample size was calculated based on a previous study according to the time for the first analgesic demand.[5] A sample size of 31 patients in each group was needed for 80% power of the study with a 5% significance level. Thirty-five patients were included in each group to take care of possible dropouts.

The quantitative data were expressed as mean and standard deviation, whereas the qualitative data were expressed as frequencies and percentages. Further, Student's t-test was used to compare means between the groups, and the Chi-square test was used to compare proportions. P < 0.05 was considered to be statistically significant. One-way analysis of variance followed by Bonferroni correction was performed for comparison among the groups.

RESULTS

Seventy-five patients were assessed for eligibility, and five patients were excluded from the study due to not meeting inclusion criteria or not willing to participate in the study. The CONsolidated Standards Of Reporting Trials flowchart showing the flow of patients in the study is depicted in Figure 1. No patients were lost to follow-up. The demographic profile of the patients, including age, sex, height, and weight, were similar in both groups [Table 1]. There was no difference in the duration of surgery.

Figure 1

CONSORT flow diagram

Table 1

Demographic characteristics

	Mean±SD		P value*
	Group D (n=35)	Group M (n=35)
Age (years)	49.02±3.14	47.48±4.13	0.240
Height (m)	1.61±0.06	1.62±0.06	0.482
Weight (kg)	57.17±6.55	59.28±6.57	0.182
BMI (kg/m2)	21.95±2.14	22.47±2.18	0.319
Duration of surgery (min)	92.25±10.31	91.02±9.93	0.613

*P<0.05 significant, Analysis is done by using Independent t test, SD=Standard deviation

The characteristics of sensory and motor block are summarized in Table 2. There was no difference between Group D and Group M in the highest level of block achieved in the two groups or in the time to reach the T10 level. Time to reach peak sensory level (12.20 ± 1.82 vs. 14.22 ± 3.06 min, P = 0.001) and Bromage 1 (5.14 ± 1.39 vs. 6.02 ± 1.50 min, P = 0.013) score was significantly faster with Group D as compared to Group M.

Table 2

Characteristics of sensory and motor block

	Mean±SD		P*
	Group D (n=35)	Group M (n=35)
Time to reach T10 (min)	3.85±1.26	4.54±2.13	0.107
Maximum sensory level	T5.31±0.96	T5.48±0.88	0.441
Time to reach highest sensory block (min)	12.20±1.82	14.22±3.06	0.001*
Time to reach bromage 1 (min)	5.14±1.39	6.02±1.50	0.013*
Time for 2 segment regression (min)	105.86±14.75	95.20±16.34	0.006*
Time for regression to S2 (min)	380.97±40.46	400.63±38.55	0.041*
Time to reach bromage 6 (min)	319.97±40.46	280.20±38.17	0.000†

Analysis is done by using independent t-test, *P<0.05 significant; †P<0.001 highly significant. SD=Standard deviation

Block regression was significantly slower in Group D as compared with Group M, as both time to two-segment regressions and time to S2 regression were significantly more with Group D. There was a significant difference in the onset time to Bromage 1 motor block (5.14 ± 1.39 min in Group D and 6.02 ± 1.50 min in Group M), but the regression of motor block to Bromage 6 was significantly slower with the addition of dexmedetomidine [Table 2]. The time to rescue analgesia was significantly longer in Group M as compared to Group D. The requirement of tramadol in the first 24 h was significantly higher in Group D as compared to Group M [Table 3].

Table 3

Postoperative analgesia

	Group D (n=35)	Group D (n=35)	P*
Time to rescue analgesia (min)	320.80±41.75	451.63±38.55	0.000†
Total tramadol consumption (min)	180.00±30.79	125.00±29.07	0.000†

*Independent t-test, †P<0.001 highly significant

The patients in both groups remained hemodynamically stable intraoperatively, and there were no significant differences in bradycardia, hypotension, nausea, and vomiting in patients of either group. Pruritus was significantly higher in Group M compared to Group D [Table 4].

Table 4

Comparison of side effects

	Group D, n (%)	Group M, n (%)	P*
Bradycardia	5 (14.3)	1 (2.9)	0.198
Hypotension	4 (11.4)	2 (5.7)	0.673
Nausea	5 (14.3)	10 (28.6)	0.244
Vomiting	3 (8.6)	6 (17.1)	0.477
Pruritis	0	14 (40)	0.000†
Respiratory depression	0	0

*Chi-square test, †P<0.001 highly significant

DISCUSSION

A subarachnoid block is an established technique for surgeries on the lower abdomen. Levobupivacaine and bupivacaine are equally effective local anesthetics for spinal anesthesia. However, many studies have reported fewer adverse effects, e.g. hypotension and bradycardia, with intrathecal levobupivacaine as compared to bupivacaine.[810]

The short duration of postoperative analgesia after spinal anesthesia is a limitation. Numerous adjuvants have been used intrathecally to extend the duration of analgesia of the subarachnoid block.

In this prospective randomized study, the postoperative analgesic efficacy of intrathecal dexmedetomidine with ITM was compared in patients who underwent total abdominal hysterectomies.

Morphine injected intrathecally results in analgesia by acting on opioid receptors in the dorsal horn of the spinal cord. Analgesia is adequate and long-lasting due to its hydrophilicity, decreased systemic absorption, cephalad spread in the cerebrospinal fluid, and slow rate of clearance from the opioid receptors.[11]

Dexmedetomidine is a highly selective α2 adrenergic receptor agonist which is being increasingly used as an adjuvant to regional anesthesia. α2 adrenergic agonists act on prejunctional and postjunctional α2 receptors in the dorsal horn of the spinal cord. Activation of presynaptic receptors reduces neurotransmitter release, whereas postjunctional receptor activation results in hyperpolarization and reduction of pulse transmission.[12] Motor block prolongation by α2 adrenergic agonists may result from the binding of α2 agonists to motor neurons in the dorsal horn of the spinal cord.[13]

Guidelines for the equianalgesic conversion of ITM to intrathecal dexmedetomidine are not yet established, leaving clinicians to rely on expert opinion and clinical experience. In the case of ITM, the optimal dose appears to be 100–300 μg, and as the adverse effects increase at higher doses, it has been suggested that doses less than 300 μg should be used.[14]

Many studies have been done with 5 μg of intrathecal dexmedetomidine, and they have found good results in terms of duration of analgesia and side effects.[61516]

In similar studies comparing ITM and intrathecal dexmedetomidine for abdominal surgeries, Kurhekar et al.[5] have compared ITM 250 μg with dexmedetomidine 2.5 μg and Khandelwal et al.[6] have compared morphine 200 μg with dexmedetomidine 5 μg. In both these studies, the authors found comparative analgesic effects of both the drugs.

Based on the dosing recommendations and the previous studies, we chose to compare 250 μg of ITM and 5 μg of intrathecal dexmedetomidine.

The results of the current study showed that intrathecal supplementation of morphine with isobaric levobupivacaine significantly prolonged time to first rescue analgesia and also less total analgesic consumption was required in 24 h as compared to dexmedetomidine.

In another study, the authors found that both ITM and intrathecal dexmedetomidine were similar in first analgesic demand time and total analgesic requirement, and the difference between total analgesic dose required between two groups was not significant.[5]

In the current study, we found faster onset with a longer duration of motor block with intrathecal dexmedetomidine as compared to ITM. The binding of α2 adrenergic agonists to motor neurons in the dorsal horn causes prolongation of the motor block of spinal anesthetics, or prolonged motor blockade might be caused by the direct impairment of excitatory amino acids from the spinal interneurons. These findings are similar to the studies comparing intrathecal dexmedetomidine with morphine which found prolonged motor blockade with intrathecal dexmedetomidine.[56]

An opioid is a traditional analgesic for postoperative pain control but has drawbacks such as respiratory depression, vomiting, nausea, and pruritus in terms of adverse effects. In our study, the incidence of pruritus in morphine group was 40% which is comparable to previous studies.[4517] No pruritus was seen in the dexmedetomidine group, which is an obvious benefit as compared to morphine.

The incidence of nausea was 29% in the morphine group, which is higher than that reported by Khandelwal et al.[6]

Respiratory rate was less in Group BM than Group BD at different time intervals during the intraoperative and postoperative periods, but none of the patients had respiratory depression, so no active intervention was required in any patient. The incidence of respiratory depression at low doses of ITM (<0.3 mg) is negligible, which is confirmed by our study.[418]

The most significant side effects reported about the use of intrathecal α2 adrenoceptor agonists are bradycardia and hypotension.[12] Although hypotension and bradycardia were seen more frequently in the dexmedetomidine group than the morphine group, there was no statistically significant difference between the two groups.

Enhanced Recovery After Surgery Society recommendations about guidelines for postoperative care in gynecologic/oncology surgery clearly states that spinal anesthesia with low-dose ITM is an alternative to thoracic epidural anesthesia (TEA). As a single injection, it has benefits over TEA in allowing early mobilization and removal of urinary catheter as well as facilitating early discharge from hospital. When compared to a general anesthetic without neuraxial block, spinal anesthesia with ITM significantly reduces pain and morphine consumption both for hysterectomy.[19]

CONCLUSION

Our study shows that the use of ITM as an adjuvant to isobaric levobupivacaine provides better analgesia than intrathecal dexmedetomidine; however, adverse effects such as nausea and pruritus may be seen. Respiratory depression is not seen with low doses of ITM. Intrathecal dexmedetomidine also provides satisfactory postoperative analgesia without much adverse effects.

Limitations

This study was done only on ASA 1 and 2 patients. The effects of these drugs on patients with comorbidities or of extremes of age were not studied.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.