Intrathecal 1% 2-Chloroprocaine with Fentanyl in Comparison with Ropivacaine (0.5%) with Fentanyl in Day Care Perianal Surgery: Prospective Randomized Comparative Study.

BACKGROUND: Spinal anesthesia is a reliable and safe technique for perianal surgeries; the changing trend of surgical practice from an inpatient to outpatient has urged us to use lower dose of local anesthetic providing segmental block with adjuvants such as opioids. Ropivacaine is a long acting; amide local anesthetic, with greater sensory motor differentiation. Chloroprocaine (CP) is an amino-ester local anesthetic with a very short half-life. This study was designed to compare CP with ropivacaine for spinal anesthesia in an elective ambulatory setting.
METHODS: This prospective, randomized, comparative study included 60 adult patients scheduled to undergo perianal surgeries under subarachnoid block with intrathecal 3.0 mL of 1% CP with 12.5 μg fentanyl (Group C) or 1.5 mL of 0.5% ropivacaine with 12.5 μg fentanyl (Group R). STATISTICAL ANALYSIS: Chi-square test used to assess significance for qualitative data, independent t-test for significance of the mean difference between two quantitative variables.
RESULTS: Meantime of onset of sensory block at T10 in both the groups were comparable (Group C - 4.7 min, Group R - 4.8 min). Maximum upper level of sensory block was at T8 in both the groups, time for regression of sensory level to L1 was significantly longer with ropivacaine (Group R - 135 min, Group C - 76 min, P < 0.0001), and the duration of motor blockade (Group C - 81 min, Group R - 145 min P < 0.0001) was significantly short in the Group C with early ambulation (160 min).
CONCLUSION: CP provides adequate duration and depth of surgical anesthesia for short procedures with the advantages of faster block resolution and earlier hospital discharge compared with spinal ropivacaine. Copyright:

INTRODUCTION

Spinal anesthesia is a reliable and safe technique for perianal surgeries. Nevertheless, some of its characteristics may limit its use for ambulatory surgery, including delayed ambulation, risk of urinary retention, and pain after block regression.[1] The changing trend of surgical practice from an inpatient to outpatient convention has urged us to modify our anesthetic drug to suit the ambulatory setting. The primary goal of ambulatory anesthesia is rapid recovery leading to early patient discharge with minimal side effects.

Although low doses of long-acting local anesthetics such as bupivacaine, ropivacaine, and levobupivacaine are usually administered intrathecally, they are associated with significant delays in hospital discharge and less reliability of block efficacy, onset, and spread.[2]

Ropivacaine is a long-acting, enantiomerically pure (S-enantiomer) amide local anesthetic, with low lipid solubility, which blocks nerve fibers involved in pain transmission (Aδ and C fibers) to a greater degree than those controlling motor functions (Aβ fibers), thus lesser motor blockade with greater sensory motor differentiation, ropivacaine produces similar sensory block at equipotent doses and a shorter duration of motor block (50%–67% that of bupivacaine) and it may, therefore, be a potentially useful agent in an ambulatory setting.[3]

The newer trend in regional anesthesia for ambulatory surgeries is to use lower dose of local anesthetic providing segmental block with adjuvants such as opioids; opioids produce a synergistic effect by acting directly on opioid receptors in the spinal cord. Fentanyl, a short-acting lipophilic opioid stimulates μ1 and μ2 receptors, it potentiates the afferent sensory blockade and facilitates reduction in the dose of local anesthetics without intensifying the motor block or prolonging recovery, fentanyl provides good quality of intraoperative analgesia, hemodynamic stability, minimal side effects, and excellent quality of postoperative analgesia.[4]

Chloroprocaine (CP) is an aminoester local anesthetic with a very short half-life, and it was introduced and has been successfully used for spinal anesthesia since 1952, and sodium bisulfite was then added as a preservative after 1956. The drug was then abandoned in the 1980s for several reports of neurological deficits in patients receiving accidentally high doses of intrathecal CP during epidural labor analgesia, recently the preservative-free formulation has been extensively evaluated in clinical practice with a favorable profile in terms of both safety and efficacy.[5]

In comparison with bupivacaine, CP showed faster offset times to end of anesthesia, unassisted ambulation, and quicker discharge from hospital, and these findings suggest that CP may be a suitable alternative to low doses of long-acting local anesthetics in ambulatory surgery.[6]

Our primary outcome was motor block duration and our hypothesis was that due to its pharmacological characteristics, CP would show a significantly shorter motor block regression time. The secondary outcomes were the time to ambulation, to discharge, sensory onset and offset block time, and complication rate.

METHODS

The study was conducted after being duly approved by the institutional ethics committee. Patients were enrolled between September 2018 and April 2019, after obtainment of written informed consent. This prospective, randomized clinical trial included 60 adult patients belonging to the American Society of Anesthesiologist (ASA) physical status Classes 1 and 2, in the age group of 18–55 years, weighing between 50 and 75 kg with height ranging from 150 to 180 cm, scheduled to undergo perianal surgeries under subarachnoid block (SAB) were included in the study. Exclusion criteria included patients with contraindications to spinal anesthesia [International Normalized Ratio 1.3, Platelets - 75,000, use of anticoagulant drugs], neurologic disease (multiple sclerosis, symptomatic lumbar herniated disc, spinal stenosis), fluid restriction (cardiac or renal insufficiency), allergy or intolerance to local anesthetics or para-aminobenzoic acid, and atypical plasma cholinesterase. Patients were randomized to one of two groups using computer-generated random allocation chart, Group C – intrathecal 3.0 mL of 1% CP with 12.5 μg fentanyl or Group R – 1.5 mL of 0.5% ropivacaine with 12.5 μg fentanyl.

The anesthetic technique was standardized for all patients, after a thorough preoperative evaluation, patients were premedicated with oral alprazolam 0.25 mg at night, before surgery patients were given instructions to use a 10-point verbal rating scale (VRS) with 0 indicating no pain and 10 indicating the worst imaginable pain.[7] In the operation room, intravenous (i.v.) access was secured and patients were preloaded with 10 mL/kg of Ringer lactate over 15 min. Noninvasive blood pressure, pulse oximetry, and three-lead electrocardiogram were connected. The baseline mean arterial pressure (MAP), heart rate (HR), and oxygen saturation were recorded. Sedation was assessed using the Ramsay Sedation Score and baseline sedation score was noted.[8] Patients in the sitting position, under all aseptic precautions; SAB was performed in L3–L4 interspace using a 25 gauge Quincke spinal needle. The study medication was prepared by a consultant staff member of the Department of Anesthesiology who was not further involved in the perioperative care of the respective patients or in data gathering and study visits. Both the patients and the observer who recruited the patients and collected the data were blinded, the study medication, defined following subset allocation, was injected, patients were placed supine immediately after the procedure, and the operating table was maintained horizontal. The time at which injection was completed was considered zero time of the study and all measurements were recorded from this point. Sensory testing was assessed by loss of pinprick sensation to 23 G sterile hypodermic needle for onset and dermatomal levels were tested every 2 min until the highest level had been achieved and stabilized for four consecutive tests, time of onset of motor block was assessed using Modified Bromage Scale, data regarding the time to reach highest dermatomal level of sensory blockade from the time of injection, and time for two segment sensory regression was collected. Hemodynamic variables were recorded every minutes for first 5 min, at 5 min for next half an hour after the administration of SAB and every 10 min thereafter up to 120 min after the block, postoperatively patients were monitored every hour for the first 4 h. Hypotension defined as fall in systolic blood pressure 20% from baseline and was treated with i.v. fluids and injection mephentermine 6 mg i.v., bradycardia defined as fall in HR 20% from baseline and was treated with i.v. atropine 0.6 mg. The time for rescue analgesia was when patient complains of pain at surgical site was recorded (VRS > 3) and treated with injection paracetamol 15 mg.kg-1 as rescue analgesia.

The primary outcome of the study was the time until recovery of the motor block (defined as reaching Bromage scale = 0). Other outcome variables included the time until complete recovery of the sensory block (defined as the return of pinprick sensation down to the level of S5), voiding times, ambulation times (defined as time until the first mobilization), and patients met the discharge criteria when they achieved at least ten points of the postanesthetic discharge scoring system for ambulatory surgery.[9]

Sample size was calculated by keeping the confidence limits at 95% and power of study at 80% to detect differences as large as 10%, the study has only been powered for the primary endpoint, which is the time until complete recovery of motor block, expecting a minimum difference between the two groups as 30 min were taken from literature.[10] The sample size calculated was 30 in each group.

Statistical analysis

Chi-square test was used as test of significance for qualitative data. Independent t-test was used as test of significance to identify the mean difference between two quantitative variables. P (probability that the result is true) < 0.05 was considered as statistically significant after assuming all the rules of statistical tests. Statistical software: MS Excel, SPSS version 22 (IBM SPSS Statistics, Somers NY, USA) was used to analyze data.

RESULTS

The demographic profile of patients was comparable between the groups in terms of age, height, weight, and duration of surgery was found to be similar [Table 1], mean time of onset of sensory block at T 10 in both the groups were comparable and short (Group C – 4.7 ± 0.79 min, Group R – 4.8 ± 0.74 min; P = 0.614). There was no difference between Group C and R in the maximum level of blocks achieved [Table 2], mode and median of maximum upper level of sensory block were at T8 in both the groups.

Table 1

Patient demographics

	Mean±SD		P
	GROUP C	GROUP R
Age (years)	31.77±8.617	30.3±6.508	0.4589
Height (cm)	156.1±6.133	157.87±7.366	0.316
Weight (kg)	65.87±7.886	67.57±9.726	0.4601
Duration of surgery (min)	27.83±6.909	28.17±4.997	0.8279

Group C=Chloroprocaine group, Group R=Ropivacaine group, SD=Standard deviation

Table 2

Comparison of spinal block characteristics in two groups of patients studied

Parameters	Group C	Group R	P
Time to sensory block T10	4.7±0.79	4.8±0.74	0.614
Maximum sensory block	T8 (L1-T4)	T8 (L1-T4)	1
Time to maximum sensory block	6.2±0.76	6.48±0.68	0.138
Time to maximum motor block	5.36±0.74	5.53±1.5	0.579
Time for regression till L1	76.87±12.47	135.24±18.54	<0.0001*
Time to end of sensory block	94.72±5.32	163.18±14.82	<0.0001*
Time to end of motor block	81.46±10.54	145.27±17.44	<0.0001*
Time to first analgesic	105.00±7.18	196.31±19.62	<0.0001*
Time to unassisted ambulation	163.43±16.37	286.82±23.21	<0.0001*
Time to micturition	172±27.06	261.81±35.12	<0.0001*
Time to discharge	176.72±12.22	294.36±25.71	<0.0001*

Values are in mean±SD. P>0.05 nonsignificant, *P<0.05 significant. SD=Standard deviation, Group C=Chloroprocaine group, Group R=Ropivacaine group

There was no significant difference between groups in the meantime to onset of the maximum sensory block, there was no significant difference in time to onset of the maximum motor block, quality of motor block and analgesia was adequate, and there was no statistically significant difference between the groups [Table 2].

Time for regression of sensory level to L 1 (Group C – 76.87 ± 12.47 min, Group R – 135.24 ± 18.54 min; P < 0.0001) was significantly longer with ropivacaine, the duration of motor blockade (81.46 ± 10.54 min and 145.27 ± 17.44 min in Group C and Group R, respectively, P < 0.0001) was significantly shorter in the Group C.

Time for first administration of rescue analgesic (105.00 ± 7.18 min and 196.31 ± 19.62 min in Group C and Group R, respectively, P < 0.001) were statistically prolonged in Group R. Time to void in Group C (172 ± 27.06 min) and Group R (261.81 ± 35.12 min) (P < 0.0001) was significantly delayed in Group R [Table 3]. None of the patients in both groups required catheterization for urinary retention.

Table 3

Side effects

Parameters	Group C	Group R	P
Intraoperative period
Bradycardia (pulse <60 bpm), n (%)	2 (6.6)	3 (10)	0.6433
Hypotension, n (%)	0	2	0.2923
RSS, mean±SD	2.19±0.38	2.06±0.24	0.118
Pruritis, n (%)	3 (10)	2 (6.6)	0.6433
Nausea	0	1	0.4958
Postoperative period
PONV, n (%)	0	2 (6.6)	0.2923
VRS (180), n	12	1	0.0014*
RSS, mean±SD	2.32±0.42	2.16±0.44	0.155
Postoperative urinary retention	0	0	1

P>0.05 nonsignificant, *P<0.05 significant. SD=Standard deviation, Group C=Chloroprocaine group, Group R=Ropivacaine group, PONV=Postoperative nausea vomiting, VRS (180)=Verbal Rating Scale scores at 180 min, RSS=Ramsay Sedation Score

All patients in both the groups were calm and cooperative and no undue sedation (sedation score > 3) was observed intraoperatively (Group C – 2.19 ± 0.38, Group R – 2.06 ± 0.24, P = 0.118). The postoperative mean sedation scores were also comparable (Group C – 2.32 ± 0.42 Group R – 2.16 ± 0.44, P = 0.155). The postoperative VRS scores were significantly higher in Group C than in Group R after 180 min in the postoperative period [Table 3], no patients required supplemental analgesia intraoperatively, patients in CP group had significantly early discharge time (176.72 ± 12.22) than ropivacaine group (294.36 ± 25.71).

Heart rate changes were comparable between the groups [Figure 1], both the groups had an initial moderate fall in MAP in keeping with the expected sympathetic blockade produced by the spinal anesthesia, although the MAP stabilized after 15 min. There was no statistically significant difference in two groups throughout the postoperative period [Figure 2]. Hypotension requiring treatment with injection mephentermine 6 mg i.v. occurred in 2 (6.6%) patients in Group R, bradycardia occurred in 2 (6.6%) patients in Group C as compared to 3 (10%) patients in Group R treated with 0.6 mg atropine. The most commonly occurring adverse effect was the pruritus, experienced in 3 (10%) patients in Group C as compared to 2 (6.6%) patients in Group R. One patient in Group R had nausea as compared to none in Group C [Table 3] and postoperatively 2 (6.6%) patients in Group R had nausea/vomiting as compared to none in Group C.

Figure 1

Comparison of mean arterial pressure (mmHg) in two groups of patients studied. Changes in mean arterial pressure (mean ± standard deviation)

Figure 2

Comparison of heart rate (bpm) in two groups of patients studied. Changes in heart rate (mean ± standard deviation)

DISCUSSION

CP has been reintroduced recently into the market after being initially withdrawn due to concerns of neurotoxicity and is being increasingly used in day care procedures. Studies have shown that intrathecal opioids can greatly enhance analgesia of subtherapeutic doses of local anesthetics.[1112]

Fentanyl added to local anesthetic agent seems to be the most frequently used combination to enhance and increase the duration of sensory analgesia without intensifying the motor blockade or prolonging recovery from spinal anesthesia.[13]

In our study, both the groups were comparable with respect to age, sex, height, weight and ASA physical status, duration, and type of surgery. No patients had to be excluded from the study. Similar findings were seen in study done by Soumya.[14]

Changes in HR and MAP were similar in both the groups in our study, and similarly, other clinical studies have found no difference in the hemodynamic profile between isobaric bupivacaine and ropivacaine.[1516]

Our study findings were consistent with the findings of Gautier et al., where three patients in ropivacaine group received atropine for bradycardia and two patients received ephedrine for intraoperative hypotension, even though they had used lesser doses of the drugs. Similarly, a study by McNamee et al. found the incidence of intraoperative hypotension requiring treatment i.v. ephedrine to be 12% and 26% with isobaric ropivacaine and bupivacaine, respectively, two patients in their ropivacaine group required atropine for the treatment of bradycardia compared with none in the bupivacaine group.[1718] Here, our study highlights here lesser or nil requirement of treatment of bradycardia and hypotension in CP group as compared to ropivacaine.

Our study showed meantime of onset of sensory block at T10 in both the groups comparable and short (Group C – 4.7 ± 0.79 min, Group R – 4.8 ± 0.74 min; P = 0.614), time to maximum sensory block (Group C – 6.2 ± 0.76 min, Group R – 6.48 ± 0.68 min; P = 0.138). Even though it was not statistically significant onset was faster in CP. Similar finding was seen in a study done by Camponovo et al. where CP showed faster maximum sensory block level (8.5 vs. 14 min), and study done by Lacasse et al. which showed CP to be better than bupivacaine, time to maximum sensory block (15 vs. 18 min).[610]

In our study, time to maximum motor block (Group C – 5.36 ± 0.74, Group R – 5.53 ± 1.5) was also short and the duration of motor blockade (81.46 ± 10.54 min, 145.27 ± 17.44 min in Group C and Group R, respectively, P < 0.0001) was significantly shorter in the Group C. Similarly, onset of motor block (5 vs. 6 min) was better in CP than bupivacaine in study done by Camponovo et al. and duration of motor blockade was shorter in CP than bupivacaine (76 vs. 119 min) by Lacasse et al.[610]

In our study, time for regression of sensory level to L1 (Group C – 76.87 ± 12.47 min, Group R – 135.24 ± 18.54 min; P < 0.0001) was significantly longer with ropivacaine. Time to end of sensory block was (Group C – 94.72 ± 5.32, Group R – 163.18 ± 14.82, P < 0.0001) and time to end of motor block (Group C – 81.46 ± 10.54, Group R – 145.27 ± 17.44, P < 0.0001). Similar findings were seen in the study by Lacasse et al., in which time of regression was (CP – 82 ± 24, bupivacaine – 160 ± 62) and by Camponovo et al. (CP – 100, bupivacaine – 210 min).[610]

Time for the first administration of rescue analgesic was prolonged in Group R and time to void was significantly delayed in Group R. These findings were similar to study by Soumya and were greater in our study as compared to by Singhal and Agrawal.[1419]

The incidence of postoperative pain can be effectively decreased by prolonging the sensory block and thus providing better postoperative analgesia by addition of adjuvants such as fentanyl to ropivacaine as found in a study conducted by Seetharam and Bhat, consistent with our study findings.[4]

Patients given intrathecal ropivacaine had a significantly higher incidence of delayed voiding of urine compared to CP, but none required catheterization for urinary retention, time taken to void was not found to be significantly different between ropivacaine and bupivacaine, and there was no incidence of urinary retention in other studies, similar to the findings of our study.[1720]

Literature suggests a dose ranging between 30 and 60 mg of CP for procedures lasting 60 min or less, while 10 mg is considered the no-effect dose, there are only few studies in literature which have compared these two drugs but we tried comparing minimum dose of each drug required to achieve spinal anesthesia sufficient for perianal surgeries.

One of the biggest limitations of this study is that it was not perfectly blinded. Since the volumes of the drugs are different and the block in the 2-CP Group regressed earlier and faster, the blinded observer could guess the group to which the patient had been assigned. Although this limitation was identified prior to the enrolment of the first patient, no better alternative to the protocol was determined, this was minimized by having the same blinded observer responsible for collecting all data during the entire study.

CONCLUSION

In patients undergoing ambulatory perianal surgeries under spinal anesthesia, CP 30 mg had the shortest time until complete recovery of sensory and motor block when compared with ropivacaine 7.5 mg, voiding, ambulation, and discharge times were shorter for CP when compared with ropivacaine, and there were no differences in adverse events between the groups, this suggests CP provides adequate duration and depth of surgical anesthesia for short procedures with the advantages of faster block resolution and earlier hospital discharge compared with spinal ropivacaine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.