European Journal of Cardiovascular Medicine

Subarachnoid block is one of the most commonly used regional anesthesia technique for lower abdominal and lower limb surgeries 1. Use of local anesthetic like bupivacaine has been practiced in subarachnoid block, but it has a short and limited duration of action if used alone which requires use of rescue analgesics post-operatively. Also, use of higher doses of bupivacaine can produce cardiac toxicity 2. Thus, addition of adjuvants in small doses is used to extend duration of anesthesia and analgesia 1, reduce patient discomfort and hemodynamic disturbances. Drugs like opioids, clonidine, midazolam, ketamine and neostigmine, are some adjuvants that are used intrathecally but no drug is without associated adverse effects3.

Natural opioids like morphine can produce late respiratory depression4. Neostigmine an anticholinesterase has shown to produce excessive nausea whereas ketamine is linked with hallucinations5.

Fentanyl citrate, a µ1 and µ2 receptor agonist is the most commonly used synthetic opioid as an adjuvant in regional anesthesia. It is highly lipophilic which makes it highly potent and is preferred because of its rapid onset, short duration of action and minimal cephalic spread6. Nevertheless, the hunt for best non opioid adjuvant continues because of typical side effects of opioid such as pruritus, nausea, vomiting, urinary retention and respiratory depression.7

Clonidine an α2 adrenergic agonist is a safe non opioid adjuvant to local anesthetic to prolong the duration of analgesia without causing any significant adverse effects. It slows down conduction via Aδ and C fibers and extends the duration of local anesthetic activity. It induces analgesia when administered intrathecally by activating the post synaptic α2 receptors in the spinal cord [12]. Clonidine provides advantageous benefits like anti emesis, decreased post spinal shivering, anxiolysis and sedation thereby reducing opioid related side effects 8,9.

Both Clonidine and Fentanyl when used with intrathecal Bupivacaine prolong duration of analgesia, although controversy still arises in the literature regarding their onset and duration of analgesia.10

Thus, the present study aims at comparing effects of clonidine and fentanyl as intrathecal adjuvants to bupivacaine against plain bupivacaine in patients undergoing lower abdominal and lower limb surgeries

This Prospective study was performed over the span of 1.5 years (May 2023 – October 2024) at FH Medical College, Agra, UP, after receiving clearance from ethics committee of the institute as well as informed consent from all the enrolled patients.

In the present study, patients were divided into 3 groups with 30 patients in each group, randomly selected using a simple sealed envelope technique.

Group A (Control Group) – 12.5 mg of 0.5% hyperbaric bupivacaine with normal saline

Group B (Fentanyl group) – 12.5 mg of 0.5% hyperbaric bupivacaine with 25 µg of fentanyl.

Group C (Clonidine group) - 12.5 mg of 0.5% hyperbaric bupivacaine with 50 µg of clonidine.

Inclusion Criteria:

1. ASA Grade I and II
2. Age between 18 to 60
3. Patients of both
4. Patients posted for lower abdomen and lower limb surgeries

Exclusion Criteria:

1. Patient refusal
2. ASA Grade III and above
3. Parturient
4. Patients allergic to any drug related to this study
5. Any contraindication to Spinal Anesthesia such as raised Intracranial tension (ICT), local infections, bleeding diathesis etc.
6. Gross deformity of spine
7. Patient posted for emergency surgeries
8. Patients who have addiction to opioid or other anesthetic
9. Failed subarachnoid block

During Pre-anesthesia checkup, relevant investigations were ordered after clinically examining all patients, screening was done to rule out allergic reaction to any drugs. Allocated patients were advised to remain nil per mouth for at least 8 hours for a heavy meal, 6 hours for a light meal and 1-2 hours for clear liquids. They were prescribed Tab. Alprazolam 0.25 mg a night before surgery to mitigate anxiety and written informed consent was obtained after explaining about the procedure, study, benefits and possible consequences in simple language.

On the day of surgery, two wide bore (16-18G) intravenous cannula were secured, preloading with 10-20 ml/kg of Ringer’s Lactate was started 20 mins before surgery. Preoperative ASA standard monitors were attached and baseline vitals like HR, NIBP, SpO2, ECG and RR was noted. Patients were premedicated with Inj. Ranitidine 50 mg IV.

The procedure was conducted in a sterile manner under strict aseptic measures. Patients were positioned in the sitting or lateral decubitus position. The lumbar region was exposed and Tuffier’s Line was identified by palpation

which coincides with L3-L4 interspace or L4 vertebral body. L4-L5 intervertebral space was used as an alternative. The selected puncture site was cleaned with Povidone Iodine solution followed by alcohol swab in circular motion starting from centre to periphery. A sterile cut sheet was then draped. Puncture site was infiltrated with 2% Lignocaine using 26G needle. A 25G Quincke spinal needle was inserted at L3-L4 or L4-L5 interspace via midline/paramedian approach. After advancing up until subarachnoid space, stylet was withdrawn and free flow of clear CSF was noted after which the study drug was injected slowly, ensuring no resistance. After injection, spinal needle was carefully removed, and puncture wound was covered with a sterile bandage.

The study drugs were prepared by an anesthesiologist not involved in the study, to ensure that the volume of the injectable remained consistent across all patients. Both the observer and the patient were blinded to the study drug used for subarachnoid block.

After the procedure patient was immediately turned to supine position with OR table being neutral. The surgery was started only after confirmation of sensory block at least up to T10 dermatome.

General anaesthesia was planned for patients in whom spinal anaesthesia failed, and such patients would have been excluded from the study. However, there were no instances of block failure.

Evaluation of Sensory Blockade:

• Surgical intervention commenced upon achieving a sensory blockade at least at T10 The extent of sensory blockade was assesses using a pinprick test with a hypodermic needle.
• The onset of sensory blockade was defined as the interval from intrathecal drug administration to the attainment of the highest sensory level, confirmed by two consecutive readings indicating stabilization.
• The duration of sensory blockade was determined from the time of intrathecal injection until regression to the L5-1 level, as evidenced by the return of sensation in the heel and sole of the foot.
• Additionally, pain-free interval was documented, representing the duration from the onset of sensory blockade to the administration of the first rescue analgesic.

Evaluation of Motor Blockade:

Motor blockade was assessed using the Bromage Scale. [39]

The onset of motor blockade was defined as the time from intrathecal injection to achieving a Bromage score of 3.

The duration of motor blockade was recorded from intrathecal injection until the patient regained the ability to flex hip, knee and ankle of the limb.

Sedation level was evaluated using the Ramsay Sedation Score and documented.

Postoperative pain was evaluated using a visual analog scale (VAS)

[40], where 0 represented no pain and 10 indicated severe pain.

STATISTICAL ANALYSIS

28 patients per group was the suggested sample size on the basis of Power analysis which achieved a power of 80% and level of significance of 0.05 to be able to detect a difference in mean onset of analgesia by 5 mins between the groups. Thus, our study included 30 patients per group with anticipation for possibility of dropouts. Data are expressed as the Mean ± SD and median (range) as appropriate. SPSS 20.0 software was used to perform statistical analysis.

To compare spinal block characteristics, a one-way ANOVA was used for normally distributed continuous variables, while the Kruskal-Wallis test will be applied for non-normal data. The paired t-test or Wilcoxon signed-rank test was used for within-group comparisons. All statistical analyses were performed using Python (SciPy, Statsmodels) or R (ggplot2, survival, dplyr), with a significance level of p < 0.05.

TABLE 1: DESCRIPTIVE FOR AGE ACROSS GROUPS

The mean age of patients was highest in the Bupivacaine group (41.13 ± 12.62 years), followed by the Bupivacaine + Fentanyl group (40.40 ± 12.57 years), and lowest in the Bupivacaine + Clonidine group (37.43 ± 11.78 years). The median ages closely align with the mean values, suggesting that the age distribution within each group is fairly symmetric. The interquartile range (IQR) reveals that the middle 50% of patients in the Bupivacaine group were aged between 33.25 and 51.75 years, while for the Bupivacaine + Clonidine group, the range was slightly lower (29.25 to 46.00 years), and for Bupivacaine + Fentanyl, it spanned from 29.50 to 48.00 years. (p-value >0.05) the groups are comparable in terms of patient age distribution.

Bupivacaine + Clonidine group had the greatest number of females (67%) and least number of males (33%) in comparison to Plain Bupivacaine [male (57%) & female (43%)] and Bupivacaine + Fentanyl [male (37%) & female (63%)]. (p-value > 0.05),

Bupivacaine, Bupivacaine + Clonidine, and Bupivacaine + Fentanyl. The Bupivacaine group had an average height of 162.4 ± 4.75 cm and a weight of 62.67 ± 7.81 kg. The Bupivacaine + Clonidine group showed a slightly lower average height of 161.17 ± 4.68 cm and a weight of 62.3 ± 5.43 kg. Similarly, the Bupivacaine + Fentanyl group had a mean height of 161.37 ± 5.08 cm and the highest average weight of 63.43 ± 6.89 kg. These findings suggest minimal variation in height across the groups, while weight differences were slightly more pronounced.

TABLE 2: SENSORY AND MOTOR BLOCK CHARACTERISTICS (PLAIN BUPIVACAINE)

The mean sensory onset time was 3.97 ± 1.22 minutes, with a median of 4.15 minutes (IQR: 3.00–4.57), indicating moderate variability in sensory block initiation. The sensory block lasted on average 129.85 ± 31.22 minutes, with a median of 123.90 minutes (IQR: 99.10–160.05), suggesting a wide range in sensory duration. The motor block onset occurred at 4.96 ± 1.29 minutes on average, with a median of 4.75 minutes (IQR: 4.03– 6.00). The motor block duration was 123.50 ± 24.91 minutes, with a median of 124.45 minutes (IQR: 102.90–144.43), indicating a slightly shorter duration than the sensory block. The minimum and maximum values show some variation, reflecting individual patient differences in response to anesthesia.

TABLE 3: SENSORY AND MOTOR BLOCK CHARACTERISTICS (BUPIVACAINE + FENTANYL)

The sensory onset time (3.72 ± 1.23 min) for the Bupivacaine + Fentanyl group was slightly faster than with clonidine. The sensory block duration was the longest among the three groups (139.92 ± 26.19 min), showing that fentanyl effectively extends the sensory blockade. The motor onset time (4.83 ± 1.21 min) was comparable to the other groups, and the motor block duration (124.61 ± 22.80 min) remained stable. The interquartile range (IQR) and min-max values suggest some variability in individual response.

TABLE 4: SENSORY AND MOTOR BLOCK CHARACTERISTICS (BUPIVACAINE + CLONIDINE)

The sensory onset time for the Bupivacaine + Clonidine group had a mean of 4.12 ± 1.40 minutes, slightly longer than plain Bupivacaine. However, the sensory block duration was prolonged (130.39 ± 24.73 minutes), indicating clonidine’s effect in extending the block. The motor onset time (5.08 ± 1.05 minutes) was slightly delayed compared to plain Bupivacaine, while the motor block duration (118.76 ± 26.20 minutes) remained comparable. The interquartile ranges and min-max values highlight some variability in block duration among patients.

TABLE 5: ANOVA COMPARISON TABLE FOR SENSORY AND MOTOR BLOCK CHARACTERISTICS

ANOVA Results for Sensory and Motor Block Characteristics

The analysis compared Sensory Onset, Sensory Duration, Motor Onset, and Motor Duration across three groups: Plain Bupivacaine, Bupivacaine + Clonidine, and Bupivacaine + Fentanyl using ANOVA. (p-values > 0.05)

The Sensory Onset time was fastest in the Bupivacaine + Fentanyl group (3.72± 1.23 min), followed by Plain Bupivacaine (3.97 ± 1.22 min), and was slightly longer in the Bupivacaine + Clonidine group (4.12 ± 1.40 min). p-value > 0.05 suggest that these minor variations are not statistically significant.

For Sensory Duration, the Bupivacaine + Fentanyl group had the longest sensory block duration (139.92 ± 26.19 min) compared to Bupivacaine + Clonidine (130.39 ± 24.73 min) and Plain Bupivacaine (129.85 ± 31.22 min).

Despite this apparent difference, the ANOVA test (F = 1.270, p = 0.286) confirms that the variation in sensory duration among the three groups is not statistically significant.

The Motor Onset time was slightly delayed in the Bupivacaine + Clonidine group (5.08 ± 1.05 min) compared to Plain Bupivacaine (4.96 ± 1.29 min) and Bupivacaine + Fentanyl (4.83 ± 1.21 min). Again, this difference was not statistically significant (F = 0.333, p = 0.718), suggesting that the addition of Clonidine or Fentanyl did not meaningfully alter the motor block onset time.

Similarly, the Motor Duration was longest in the Bupivacaine + Fentanyl group (124.61 ± 22.80 min), followed by Plain Bupivacaine (123.50 ± 24.91 min), and was slightly shorter in the Bupivacaine + Clonidine group (118.76 ± 26.20 min). However, with F = 0.475 and p = 0.623, these differences were not statistically significant, indicating that all three groups exhibited similar motor block durations.

FIGURE 1: SENSORY AND MOTOR BLOCK CHARACTERISTICS FOR THE THREE GROUPS

• Sensory Onset (Top Left): The Bupivacaine + Fentanyl group shows a slightly faster onset compared to the other groups, but variability is

• Sensory Duration (Top Right): The Bupivacaine + Fentanyl group appears to have a prolonged sensory duration compared to the other groups, with a wider distribution.

• Motor Onset (Bottom Left): The motor onset times are fairly consistent across the groups, with minor variations.

• Motor Duration (Bottom Right): The Bupivacaine + Fentanyl group has a slightly longer motor duration, but no extreme differences between

Although Bupivacaine + Fentanyl showed a slightly faster sensory onset and prolonged sensory duration, these differences were not statistically significant when compared to the other groups. The motor onset and duration also did not show any significant variation across groups. This suggests that while Clonidine and Fentanyl may have pharmacological effects, their impact on the overall sensory and motor block characteristics was not strong enough to produce statistically significant differences in this study

Rationale for Dose of Fentanyl

In a study consisting of 60 patients, Reuben SS, Dunn SM et al.11, were concluded that analgesia was adequate when doses exceeded 20 mcg but, at 50 mcg 5 out of 10 patients experienced side effects like pruritus. Their study suggested the use of 25 mcg of fentanyl in our present study.

Concurrently in a study conducted by Rahul Seewal et al.12, fentanyl was added to hyperbaric bupivacaine in various doses (10 mcg, 20 mcg, 30 mcg or 40 mcg) for infraumbilical surgeries. He concluded that addition of fentanyl did not provide any increase in duration of analgesia even when doses were increased up to 40 mcg. It was reported that only 10 mcg of fentanyl should be adequate. Therefore, 25 mcg of fentanyl was used in our study on the basis of previous studies.

Rationale for dose of Clonidine

In 2003, Dobdyndjoy et al.13 used Clonidine (15 mcg, 30 mcg and 17.5 mcg) as adjuvant to bupivacaine in subarachnoid block for inguinal surgeries. It was concluded that motor and sensory block duration increased with increase in dose of clonidine. Duration of postoperative analgesia also increased with stable hemodynamics.

In 2014, Raj Bahadur Singh et al.14 divided patients in two groups to study the addition of clonidine to bupivacaine in subarachnoid block for infraumbilical surgeries. Group A was administered normal saline (0.33ml) with bupivacaine (3ml) and Group B was administered clonidine 50 mcg (0.33 ml) with 3 ml of bupivacaine. Group B reported increased motor and sensory block compared to Group A. Group B had a prolonged duration of postsurgical anesthesia with decreased mean VAS score, although Group A was better hemodynamically. Thus, a dose of 50 mcg of Clonidine was used in our study while monitoring hemodynamic parameters closely.

Sensory Block Characteristics

The mean sensory onset time was 3.97 ± 1.22 minutes, with a median of 4.15 minutes (IQR: 3.00–4.57), indicating moderate variability in sensory block initiation. The sensory block lasted on average 129.85 ± 31.22 minutes, with a median of 123.90 minutes (IQR: 99.10–160.05), suggesting a wide range in sensory duration.

The sensory onset time (3.72 ± 1.23 min) for the Bupivacaine + Fentanyl group was slightly faster than with clonidine. The sensory block duration was the longest among the three groups (139.92 ± 26.19 min), showing that fentanyl effectively extends the sensory blockade. The sensory onset time for the Bupivacaine + Clonidine group had a mean of 4.12 ± 1.40 minutes, slightly longer than plain Bupivacaine. However, the sensory block duration was prolonged (130.39 ± 24.73 minutes), indicating clonidine’s effect in extending the block. Bupivacaine + Fentanyl provided faster onset of sensory block (p = 0.472) along with longest duration of sensory block (p = 0.286) when compared to plain bupivacaine and bupivacaine + clonidine group. Although the difference in both was not statistically significant.

Our findings were similar to Mahendru et al.15 who in 2013 compared fentanyl, dexmedetomidine and clonidine as adjuvants to bupivacaine and reported that duration of onset of sensory block was similar in clonidine and fentanyl with no statistical significance (p = 0.039).

In a study conducted by Gajannan Chavan, Aparna Chavan et al.16 Fentanyl was added as an adjuvant to Hyperbaric bupivacaine intrathecally. The time of onset of sensory block for bupivacaine with in his study was 2.2 ± 0.372 which is similar to our study.

Motor Block Characteristics

The motor block onset in Plain Bupivacaine Group occurred at 4.96 ± 1.29 minutes on average, with a median of 4.75 minutes (IQR: 4.03–6.00). The motor block duration was 123.50 ± 24.91 minutes, with a median of 124.45 minutes (IQR: 102.90–144.43). The motor onset time in Bupivacaine + Fentanyl Group was (4.83 ± 1.21 min) which was comparable to the other groups, and the motor block duration (124.61 ± 22.80 min) remained stable.

The motor onset time in Bupivacaine + Clonidine Group was (5.08 ± 1.05 minutes) which was slightly delayed compared to plain Bupivacaine, while the motor block duration (118.76 ± 26.20 minutes) remained comparable.

The onset of motor block was slightly delayed with bupivacaine + clonidine group while it was the shortest in bupivacaine + fentanyl group. Similarly, bupivacaine + fentanyl group had the longest duration of motor block when compared to bupivacaine + clonidine and plain bupivacaine although the difference was not statistically significant (p = 0.623).

In a study conducted by Harbhej Singh et al.6, fentanyl was added to plain bupivacaine for intrathecal administration and he concluded that fentanyl when added to bupivacaine has faster onset of motor block which is also seen in our study.

Gajanan Chavan, Aparna Chavan et al.16 also reported a faster mean onset time to achieve Bromage 3 which is similar to our study.

Duration of Analgesia and Time for First Rescue Analgesic

The mean time to first rescue analgesia is highest in the Bupivacaine + Clonidine group (207.74 min), followed by Bupivacaine + Fentanyl (203.79 min), and Plain Bupivacaine (198.33 min).

Bajwa et al.17 reported that 50 mcg of clonidine when added to bupivacaine prolonged duration of analgesia and need for rescue analgesic in comparison to 25 mcg of fentanyl. This was similar to our study.

Chhabra et al.18 in his study used clonidine 60 mcg in comparison to fentanyl and reported that duration of spinal anesthesia was prolonged with clonidine along with decreased need for rescue analgesic.

Khezri et al.,[52] used 75 mcg of clonidine with plain bupivacaine and compared to fentanyl for intrathecal blocks and reported increased time for requirement of first rescue analgesic which was concurrent with our study

We can conclude the following statements from our study that addition of Fentanyl to bupivacaine provides early onset and prolonged duration of sensory and motor block. This is not statistically significant when compared to clonidine and plain bupivacaine, although fentanyl can be used when rapid onset of analgesia is required for e.g. short duration surgeries. Fentanyl can also be used in conditions where dense motor blockade is required for muscle relaxation. Both clonidine and fentanyl are superior to plain bupivacaine and addition of them can improve the quality of subarachnoid block.

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