European Journal of Cardiovascular Medicine

Spinal anaesthesia is generally employed for lower abdominal and lower limb surgeries. Amongst numerous local anaesthetic agents Ropivacaine – an amino-amide, shows reversible inhibition of sodium ion influx [1], added by dose-dependent potassium channel inhibition [2], thus blocking the conduction in nerve fibres. Ropivacaine which was first used clinically in 1992 [3], is less lipophilic than Bupivacaine, hence provides shorter duration of sensory and motor block. It mainly acts by blocking the pain transmission through A δ and C nerves owing to its lack of penetrating ability of large myelinated motor route  like Aβ fibres.

Adjuvants are the drugs that enhance efficiency or potency of other drugs when given simultaneously. Neuraxial adjuvants, in addition to their dose sparing effects, are also utilised to increase the speed of onset of neural blockade, improve the quality and extend the duration of neural blockade [4]. They include Opioids, α-2 adrenoceptor agonists, N-methyl-D-aspartate (NMDA) antagonists, Cholinergic agonists and Vasoconstrictors. Intrathecal opioids are synergistic with local anaesthetics and intensify the sensory block without increasing the sympathetic block while achieving satisfactory quality of spinal anaesthesia at a much lower dose of local anaesthetic [5].

Dexmedetomidine, an excellent adjuvant to intrathecal Ropivacaine offers prolonged sensory-motor blockade and enhanced analgesic effects in spinal anaesthesia due to it’s selective alpha-2 adrenergic agonistic action [6]. Dexmedetomidine causes conscious sedation, resembles a physiologic sleep state through activation of endogenous sleep pathways [7, 8]. It has been shown to be neuroprotective [9]. Alpha-2 adrenoceptor agonist action of Dexmedetomidine leads to a decrease in heart rate, cardiac output and a transient increase in arterial blood pressure and systemic vascular resistance. Although bradycardia may be a problem with alpha-2 agonists due to central sympatholytic actions or due to presynaptic mediated reduction of noradrenaline release, or a direct vagomimetic action, Dexmedetomidine has been shown to protect against adrenaline-induced arrhythmias during halothane anaesthesia by stimulation of imidazoline receptors [10].

Fentanyl is a synthetic opioid, also used as an additive is a tertiary amine and a phenylpiperidine derivative used as an adjuvant. Primarily a mu receptor agonist with an analgesic potency higher than Morphine, pethidine and Alfentanil. It also binds to a lesser degree to kappa receptor, Substantia gelatinosa of spinal cord. It is a CNS depressant. At low doses, it is devoid of hypnotic and sedative activity. Miosis is seen as a result of stimulation of the Edinger Westphal nucleus. Fenatnyl has dose dependent action on cardiovascular and hemodynamic system ranging from decreased heart rate, decreased myocardial contractility, decreased heart rate, Mean arterial pressure, systemic and pulmonary vascular resistance. The side effect of great concern after epidural or spinal opioid administration is respiratory depression. Use of more lipid-soluble opioids like Fentanyl decreases the potential occurrence of the problem [11]. It increases the common bile duct pressure by causing spasm of the sphincter of Oddi. It causes nausea, vomiting and decreases GI motility.

Information regarding comparisons of Fentanyl and Dexmedetomidine as adjuvants with Ropivacaine, especially in terms of onset and duration of sensory and motor block, maximum height of sensory block, intraoperative hemodynamic changes and adverse reactions, if any, in this population is not documented. Therefore the present study is designed to compare the effects of adding Dexmedetomidine and Fentanyl as adjuvants to intrathecal isobaric Ropivacaine.

This study was conducted at Siddhartha Medical College, Vijayawada, after institutional Ethical committee approval and informed consent from each patient was taken. Sixty patients between the age group of 18-60 years, posted for lower abdominal and lower limb surgeries with physical grade of American society of Anesthesiologists I-II were included. Sample size was calculated using OpenEpi software with assumptions of prevalence being 90%, [12] [13] confidence intervals (CI) of 95%, power of the study (α) as 80%, while primary outcome variable is the efficiency of the drug. The minimum sample number works out to be 30 per group [14].

Patients on drugs like Angiotensin-converting enzyme inhibitors, Calcium channel blockers, Alpha 2 – adrenergic receptor antagonists, comorbidities like obesity, Coagulopathy, spine deformities/surgeries, Dysrhythmia, allergy to drugs under the study, Pregnancy, Neurological disorders were excluded.

Each patient was visited pre-operatively, and assessed for the study. All the investigations as a part of pre-anaesthetic checkup and of the respective surgery were done. The participants were all pre-medicated overnight with Tab. Alprazolam. Also patients were kept on strict fasting of 8 hours duration. Patients were randomised to two groups of 30 each based on a sealed envelope technique to receive one of the following for the intrathecal injection. Group RD consisting of 30 patients received 15 mg of 0.75% isobaric Ropivacaine along with 5µg Dexmedetomidine. Group RF consisting of 30 patients received 15 mg of 0.75% isobaric Ropivacaine along with 25µg Fentanyl. Details of information regarding gender, ASA grdaes and type of surgical procedures are tabulated. [Table 1]

Haemodynamic profile like heart rate (HR), non-invasive blood pressure, SPO₂ were observed and recorded at every 5 minutes for the first one hour and then at 15 minute intervals till the end of surgery using an automated multiparameter monitor.

The drugs of interest were deposited intrathecally by traditional spinal anaesthesia procedure through midline approach. Information about onset of sensory, motor blocks and their respective duration was noted. Patients were monitored perioperatively by recording Systolic blood pressure (SBP), Diastolic blood pressure (SBP), Mean arterial pressure (MAP). Postoperatively patients were monitored continuously for any adverse events like nausea, vomiting, pruritus, shivering etc., were noted. Time to regain the motor (Bromage 0) and sensory response (reversion to S1 level) was noted. Time duration of surgeries ranged from 25 minutes to 90 minutes subjective to procedures followed. The patients were kept on various analgesics like NSAIDs (Diclofenac), Opioids (Tramadol, Buprenorphine, Nalbuphine) as required along with fluids such as Normal saline and Ringer lactate. All the above mentioned time lines were noted in regard to the spinal injection.

The observations are presented as Mean with standard deviation and percentages. Two-tailed, independent Student t-test was applied to evaluate the differences. The p-value <0.05 was considered as statistically significant. SPSS 15.0 and Microsoft Excel were used for the statistical analysis of the data.

Sixty patients categorized in to two groups namely: a. Group RD (n = 30) receiving Ropivacaine with Dexmedetomidine and b. Group RF (n = 30) receiving Ropivacaine with Fentanyl. The data reveals that both the groups are comparable in age, height, and sex weight with no statistically significant difference between them. [Table 2]

Time of onset of sensory block in group RD (156.4 ± 33.7 seconds) was lesser than in group RF (185.2 ± 35.1 seconds) and is statistically significant (p = 0.002). Total duration of sensory block in group RD (194.4 ± 23 minutes) was higher than in group RF (139.9 ± 27.5 minutes) which was statistically and clinically significant (p = 0.000).

Even though, time of motor block onset in group RD (448.2 ± 113.9 seconds) was lesser than in group RF (491.2 ± 86.2 seconds), it is not statistically significant (p = 0.104). Total duration of motor block in group RD (136.7 ± 13.9 minutes) was higher than in group RF (94.8 ± 11.4 minutes) which was both statistically and clinically significant (p = 0.000). [Table 2]

All patients in each group achieved sensory blockade at T10 level for surgery. Highest level of block reached in both groups was T5. Complete motor blockade was observed in all patients in both groups. [Table 3]

Fall in systolic blood pressure, diastolic blood pressure and mean arterial blood pressure was observed in both the groups following institution of spinal anaesthesia. The decrease was similar in both groups, and it was not clinically or statistically significant. There was no observable difference in heart rate due to the drugs in both groups. However, after 10 minutes of administration of drugs, a statistically significant drop in SBP (P = 0.03) and heart rate (P = 0.05) in group RD was noted. [Table 4]

Eight (26.67%) patients in group RD, and 2 (6.67%) patients in Group RF have shown bradycardia, which was the only statistically significant side effect (p = 0.03). Hypotension, vomiting, nausea and pruritis were other side-effects noted, however were statistically insignificant. Sedation was not observed in either of the groups. [Table 5]

Table 1 : Distribution of gender, type of surgeries, ASA grades across both groups

ASA - American Society of Anesthesiologists

Table 2: Baseline characteristics of the study population and sensory / motor blocks :

Unpaired t-test was applied

* p value <0.05 is considered significant

Table 3: Comparison of height and degree of sensory / motor blocks:

Table 4: Comparison of hemodynamic parameters:

Unpaired t-test was applied

* p value <0.05 is considered significant.

DBP – Diastolic blood pressure; HR – Heart rate; MAP – Mean arterial pressure; SBP - Systolic blood pressure

Table 5: Comparison of side-effects:

Unpaired t-test was applied

* p value <0.05 is considered significant

Subarachnoid block is one of the most commonly used technique to provide anaesthesia for lower limb and lower abdominal surgeries. The advantages of this approach is that it’s easy to administer, simple, safe, and an inexpensive procedure with rapid onset of action. It also offers a high level of satisfaction for patients during post-anaesthetic recovery. Owing to its high potency and minimal neurological side-effects, Bupivacaine, a local anaesthetic agent is preferred for lower limb/abdominal surgeries. The quality of sensory blockade, motor blockade, hemodynamic changes and side effect profile are some considerations in selecting a drug for spinal anaesthesia.

Ropivacaine is a long-acting, amide local anaesthetic, with low lipid solubility, it is preferred agent for spinal anaesthesia in lower limb surgeries, obstetric and gynecological procedures, perineal, lower abdominal orthopedic surgeries. Shorter duration of motor block with similar sensory block properties compared to Bupivacaine are few added advantages. [5]

Various adjuvants are used intrathecally to potentiate the effect of local anaesthetics and to allow a decrease in required doses. Adjuvants generally used are alpha-2 agonists such as Clonidine and recently Dexmedetomidine or opioids such as Buprenorphine and Fentanyl.

Dexmedetomidine is a new, highly selective alpha-2 adrenoceptor agonist, used as an intravenous sedative and co-analgesic drug. It is now studied and used as an intrathecal adjuvant to local anaesthetic drug. The discovery of spinal opioid receptors led to the use of spinal opioids in clinical practice in an attempt to produce intense analgesia intrathecally. [6] Fentanyl acts primarily as agonist at μ opioid receptors to enhance spinal analgesia.

This study was done on 60 patients who underwent elective lower limb and lower abdominal surgeries under subarachnoid block. Demographic data like age, height, weight of the patients in two groups RD and RF were comparable and not statistically different from each other, hence age, weight, height didn’t play any confounding effect on the results.

In this study, all patients receiving either drug achieved an adequate level of anaesthesia. Mean time needed for sensory blockade at T10 was 156.4 ± 33.7 sec in group RD and 185.2 ± 35.1 sec in group RF. The results are clinically and statistically significant (p = 0.002). A study that compared Dexmedetomidine as an additive with Bupivacaine to Fentanyl, noted that intrathecal Dexmedetomidine with Bupivacaaine has quicker sensory loss onset compared to Fentanyl as an additive. [8] These findings are similar to our observations. However, Nayagam, H. A et al. [15] who compared intrathecal Dexmedetomidine, Clonidine, and Fentanyl as adjuvants to hyperbaric Bupivacaine for lower limb surgery observed no significant difference in the time of onset of sensory block. This shows that a quick onset of sensory block can be achieved with Dexmedetomidine as an additive with Rupivacaine in comparision with Fentanyl.

In the present study, the mean total duration of sensory block in the group RD was 194.4 ± 23 (min), which is longer than 139.9 ± 27.5 (min) in group RF. This is both statistically and clinically significant (p = 0.00). Similar observations were made by several other studies [16-18]. This proves that at similar doses greater sensory block can be achieved with Rupivacaine- Dexmedetomidine combination in comparison with Fentanyl.

The average time of onset of motor block was lower in the group RD (448.2 ± 113.9 sec) while it was 491.2 ± 86.2 sec in group RF which was statistically not significant (p = 0.104). These findings were similar to the study done by Mahendru V et al. [18], however in contrast with studies [16, 17] who observed that Dexmedetomidine has significantly quicker onset of motor block than Fentanyl when administered intrathecally.

The average total duration of motor block was 136.7 ± 13.9 (min) in the patients of group RD which was longer than  94.8 ± 11.4 (min) in the group RF. This difference was statistically significant (p = 0.000). Similar results were seen in various studies [15-17], that compared the role of additives such as Dexmedetomidine and Fentanyl to Bupivacaine. They observed, when given intrathecally, Dexmedetomidine achieves prolonged motor block as compared to Fentanyl as an additive to local anaesthetic. Similar to sensory block, motor block seems to be quicker and more pronounced with Rupivacaine and Dexmedetomidine over Fentanyl.

Sensory blockade at T10 was achieved, which progressed to T5 level in all the patients. Mahendru V et al. [18] noticed that T6 level was the maximum height of sensory block with either of the additives. But, Gupta R et al. [16] noticed that Dexmedetomidine has achieved a sensory block upto T5 level, while it was T6 with Fentanyl as an additive. Along with the advantages of sensory and motor block, the said combination seems to achieve better level of block, as high as T5.

The decrease in Systolic and Diastolic blood pressure, Mean arterial pressure was similar in both RD and RF groups with no statistical significance. Similar observations were made by various other workers [15,18,19]. The combination of Ropivacaine and Dexmedetomidine doesn’t seem to have any added advantage on hemodynamics of patients when compared to Fentanyl.

In our observations, only bradycardia was noted as statistically significant (p = 0.03) side-effect. Others like hypotension, pruritis, nausea, vomiting were not significant between the two groups. Similarly, El-Attar, Ahmed et al. [8] Gupta R et al. [17] have shown no significant side-effects in their studies.

The above made observations are based on only 30 cases in each of the group, which is a major limitation. Hence, the advantages like early onset of sensory block and motor block duration and side-effects like bradycardia cannot be generalized. The pharmacokinetics of respective drugs in this population were also not considered.

In age and gender matched groups, Dexmedetomidine and Ropivacaine seem to have early onset and longer duration of sensory, motor block when compared to Fentanyl as an additive. Early bradycardia and decreased SBP seem to be the few significant observations, however larger number of patients of the same region should be evaluated to understand these effects. Nevertheless, these observations prove that a combination of Ropivacaine and Dexmedetomidine seems to have definite neurological and hemodynamic advantages when compared to Fentanyl as an additive.

1. Safari, F., Aminnejad, R., Mohajerani, S. A., Farivar, F., Mottaghi, K., & Safdari, H. (2016). Intrathecal Dexmedetomidine and Fentanyl as Adjuvant to Bupivacaine on Duration of Spinal Block in Addicted Patients. Anesthesiology and pain medicine, 6(1), e26714. https://doi.org/10.5812/aapm.26714
2. Hansen T. G. (2004). Ropivacaine: a pharmacological review. Expert review of neurotherapeutics, 4(5), 781–791. https://doi.org/10.1586/14737175.4.5.781
3. Berde CB, Strichartz GR. Local anaesthetics. In: Miller RD, editor. Miller's Anaesthesia. 7th ed. Philadelphia (PA): Churchill Livingstone Elsevier; 2010. p. 916. https://books.google.co.in/books?id=L2ckBQAAQBAJ&lpg=PP1&ots=jcMWakdkOG&lr&pg=PP1#v=onepage&q&f=false
4. khangure. Adjuvants agents in neuraxial blockade cited on 4th July 2011 in anaesthesia tutorial of the week 230. http://www.totw.anaesthesiologists.org
5. Horvàth, G., Szikszay, M., & Benedek, G. (1992). Calcium channels are involved in the hypnotic-anesthetic action of dexmedetomidine in rats. Anesthesia and analgesia, 74(6), 884–888. https://pubmed.ncbi.nlm.nih.gov/1375817/
6. Robert SK. Opioid agonists and antagonists. Chapter 3. In: pharmacology and physiology in anaesthesia practice. 3rd ed. New York: Lippincott-Raven Publishers;1999;77-112. https://anesthesiology.lwwhealthlibrary.com/signin.aspx?returnUrl=%2fcontent.aspx%3fsectionid%3d72888384%26bookid%3d1357
7. Maier, C., Steinberg, G. K., Sun, G. H., Zhi, G. T., & Maze, M. (1993). Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology, 79(2), 306–312. https://doi.org/10.1097/00000542-199308000-00016
8. El-Attar, Ahmed; Aleem, Mohamed Abdel; Beltagy, Ragab; Ahmed, Wafaa. A comparative study of intrathecal dexmedetomidine and fentanyl as additives to bupivacaine. Research and Opinion in Anesthesia and Intensive Care 2(2):p 43-49, Apr–Jun 2015. https://journals.lww.com/raic/fulltext/2015/02020/a_comparative_study_of_intrathecal_dexmedetomidine.6.aspx
9. Hayashi, Y., Sumikawa, K., Maze, M., Yamatodani, A., Kamibayashi, T., Kuro, M., & Yoshiya, I. (1991). Dexmedetomidine prevents epinephrine-induced arrhythmias through stimulation of central alpha 2 adrenoceptors in halothane-anesthetized dogs. Anesthesiology, 75(1), 113–117. https://doi.org/10.1097/00000542-199107000-00018
10. Murthy, TVSP; Singh, Ranju. Alpha 2 Adrenoceptor Agonist - Dexmedetomidine Role in Anaesthesia and Intensive Care: A Clinical Review. Journal of Anaesthesiology Clinical Pharmacology 25(3):p 267-272, Jul–Sep 2009. https://journals.lww.com/joacp/citation/2009/25030/alpha_2_adrenoceptor_agonist___dexmedetomidine.2.aspx
11. Gautier, P. E., De Kock, M., Van Steenberge, A., Poth, N., Lahaye-Goffart, B., Fanard, L., & Hody, J. L. (1999). Intrathecal ropivacaine for ambulatory surgery. Anesthesiology, 91(5), 1239–1245. https://doi.org/10.1097/00000542-199911000-00013
12. Lomanto, D., Cheah, W. K., Faylona, J. M., Huang, C. S., Lohsiriwat, D., Maleachi, A., Yang, G. P., Li, M. K., Tumtavitikul, S., Sharma, A., Hartung, R. U., Choi, Y. B., & Sutedja, B. (2015). Inguinal hernia repair: toward Asian guidelines. Asian journal of endoscopic surgery, 8(1), 16–23. https://doi.org/10.1111/ases.12141
13. GBD 2019 Fracture Collaborators (2021). Global, regional, and national burden of bone fractures in 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019. The lancet. Healthy longevity, 2(9), e580–e592. https://doi.org/10.1016/S2666-7568(21)00172-0
14. Murphy, K.R., Myors, B., Murphy, K.R., Murphy, K., Myors, B., & Wolach, A. (2003). Statistical Power Analysis: A Simple and General Model for Traditional and Modern Hypothesis Tests (2nd ed.). Routledge. https://doi.org/10.4324/9781410609267
15. Nayagam, H. A., Singh, N. R., & Singh, H. S. (2014). A prospective randomised double blind study of intrathecal fentanyl and dexmedetomidine added to low dose bupivacaine for spinal anesthesia for lower abdominal surgeries. Indian journal of anaesthesia, 58(4), 430–435. https://doi.org/10.4103/0019-5049.138979
16. Gupta, R., Verma, R., Bogra, J., Kohli, M., Raman, R., & Kushwaha, J. K. (2011). A Comparative study of intrathecal dexmedetomidine and fentanyl as adjuvants to Bupivacaine. Journal of anaesthesiology, clinical pharmacology, 27(3), 339–343. https://doi.org/10.4103/0970-9185.83678
17. Gupta, R., Bogra, J., Verma, R., Kohli, M., Kushwaha, J. K., & Kumar, S. (2011). Dexmedetomidine as an intrathecal adjuvant for postoperative analgesia. Indian journal of anaesthesia, 55(4), 347–351. https://doi.org/10.4103/0019-5049.84841
18. Mahendru, V., Tewari, A., Katyal, S., Grewal, A., Singh, M. R., & Katyal, R. (2013). A comparison of intrathecal dexmedetomidine, clonidine, and fentanyl as adjuvants to hyperbaric bupivacaine for lower limb surgery: A double blind controlled study. Journal of anaesthesiology, clinical pharmacology, 29(4), 496–502. https://doi.org/10.4103/0970-9185.119151
19. Kindler, C. H., Paul, M., Zou, H., Liu, C., Winegar, B. D., Gray, A. T., & Yost, C. S. (2003). Amide local anesthetics potently inhibit the human tandem pore domain background K+ channel TASK-2 (KCNK5). The Journal of pharmacology and experimental therapeutics, 306(1), 84–92. https://doi.org/10.1124/jpet.103.049809