A Study to Evaluate Intrathecal 1% Chloroprocaine and 0.5% Levobupivacaine in Perianal Surgeries: A Prospective Randomized Study.

BACKGROUND: With increasing focus on outpatient care, there has been an increased demand for short-acting spinal anesthetics, facilitating early recovery and mobilization of the patient. AIMS: The aim of the study was to compare 1% chloroprocaine, characterized by short latency and short duration with 0.5% levobupivacaine, which has shown to preserve motor function at low concentrations, with recovery from motor block as the primary objective and recovery from sensory block and hemodynamic stability as secondary objectives. SETTINGS AND
DESIGN: A prospective study to evaluate newer isobaric chloroprocaine and levobupivacaine intrathecally in a cohort of patients using randomization and double blinding.
MATERIALS AND METHODS: Sixty American Society of Anesthesiologist physical status Classes I and II patients undergoing perianal surgeries were randomly divided into Group C (n = 30) receiving intrathecal 1% chloroprocaine 3 mL and Group L (n = 30) receiving 0.5% levobupivacaine 1.5 mL. Patients were assessed for sensory and motor block characteristics, hemodynamic changes, period of analgesia, time for ambulation, and urination. STATISTICAL ANALYSIS: Qualitative data were analyzed using Chi-square test and quantitative data using Independent t-test.
RESULTS: There was no significant difference in highest sensory level, onset of motor block, maximum Bromage scale achieved, and hemodynamic changes between the two groups. There was a significant difference in mean Time for Maximum Bromage scale, Time for Sensory regression (Lumbar-L1), Duration of Motor Block (Group C 50.7 ± 5.7 min and Group L 181 ± 27.8 min), Time for rescue Analgesia, Time for 1st void, and Time for ambulation (Group C 88.3 ± 9.1 min and Group L2 06.7 ± 27.2 min) between chloroprocaine and levobupivacaine group. The above duration was shorter in chloroprocaine group than in levobupivacaine group.
CONCLUSION: Thus, chloroprocaine provides good surgical anesthesia and early motor recovery than levobupivacaine and is well suited for day care surgeries. Copyright:

INTRODUCTION

Subarachnoid block (SAB) is one of the most versatile regional anesthesia techniques available today. Spinal anesthesia offers several advantages over general anesthesia by blunting the surgical stress response, reducing intraoperative blood loss and also by providing analgesia in early postoperative period. SAB provides adequate anesthesia for patients undergoing infraumbilical surgeries.[1]

With the current trend shifting toward outpatient care, we should choose spinal anesthetics which provide short acting and also adequate anesthesia. During this process, early ambulation and discharge of the patient should not be compromised. However, spinal anesthesia for ambulatory lower abdominal and perineal surgeries is more complicated.

Increasing the dose of long-acting local anesthetics to fulfill the requirement of a higher sensory block may produce extensive sensory and motor block as well as arterial hypotension, risk of urinary retention, and this might cause a delay in discharge from hospital, thus limiting its use for ambulatory surgery.

Short-acting spinal anesthetic with minimum motor block can be useful and assumed that recovery and mobilization of the patient could be faster, if the motor block is less intense. For this purpose, short acting or low doses of local anesthetics can be used.[2]

Chloroprocaine was introduced to replace lidocaine in 1952, as the latter was associated with transient neurological symptoms.

Chloroprocaine, an ester anesthetic is characterized by short latency, and short duration was developed to meet the need for a short-acting spinal anesthetic that is reliable and now has a favorable safety profile to support the growing need for day-care surgery.[3]

Levobupivacaine, the S (-) enantiomer of racemic bupivacaine, has shown to produce differential neuraxial block and preservation of motor function at low concentration when used for anorectal surgery.[4]

This study was designed to prospectively evaluate newer isobaric chloroprocaine compared to levobupivacaine for spinal anesthesia in a cohort of patients undergoing day-care perianal surgeries as there were limited studies comparing these drugs.

The primary objective of our study was to compare the time required for complete recovery from motor block between the two groups and other secondary outcomes were sensory onset and regression time, time for ambulation, and 1st void of urine.

We hypothesized that intrathecal 1% 2-chloroprocaine has faster offset of motor block enabling early ambulation of the patient when compared to 0.5% isobaric levobupivacaine with insignificant hemodynamic changes and side effects such that the drug may be proposed for day-care perianal surgeries.

MATERIALS AND METHODS

After obtaining institutional ethics committee clearance (certificate number: BMCRI/PS/205/2018-19, Dated 21-01-2019) and written informed consent from patients during preoperative visit, sixty patients were enrolled for the study between June 2019 and December 2019 (6 months). CTRI Reg no: CTRI/2019/04/018485 http://www.ctri.nic.in/CTRI Reference number: REF/2019/03/024893. The procedure followed was in accordance with the guidelines laid down in the Declaration of Helsinki (2013).

This prospective randomized study included patients belonging to the American Society of Anesthesiologist physical status Classes I and II, in the age group of 18–55 years, having a body mass index (BMI) between 19 and 26 kg.m − 2, scheduled to undergo perianal surgeries under SAB. The exclusion criteria for our study were patients having contraindications to undergo spinal anesthesia (International normalized ratio >1.3, platelet count <75,000, use of anticoagulant drugs, neurological disease like multiple sclerosis, spinal stenosis, and cardiac or renal insufficiency), allergy, or intolerance to the study drug.

Patients were randomly assigned to one of the two groups of thirty patients each by using the computer-generated randomization chart:

Group C (n = 30) − 3.0 mL volume of isobaric 1% 2-chloroprocaine

Group L (n = 30) − 1.5 mL volume of 0.5% isobaric levobupivacaine.

The anesthetic technique was standardized for all patients, after a thorough preoperative evaluation, patients were premedicated with tablet alprazolam 0.5 mg, and tablet ranitidine 150 mg the night before the surgery. Patients were allowed for a period of absolute fasting of at least 8 h before surgery. Before surgery, patients were given instructions to use a 10-point visual analog scale (VAS) with 0 indicating no pain and 10 indicating worst imaginable pain. On arrival at the operating room, intravenous access was secured with 18G intravenous cannula and patients were preloaded with Ringer's Lactate/Normal Saline at 10 mL.kg− 1 over 15 min. Noninvasive blood pressure, pulse oximetry, and electrocardiogram were connected. Baseline heart rate, systolic and diastolic blood pressures, and oxygen saturation were recorded.

Under all aseptic precautions, with the patients in sitting position, SAB was performed at L3-L4 (L-Lumbar) intervertebral space with 25G or 26G Quincke spinal needle, and the total volume of drug was injected intrathecally over 10–15 s. The study drug 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. Following SAB with the study medication, patients were made to sit for 5 min and were then made to lie in the supine position. The operation table was maintained horizontal. The time at which the injection was completed was considered as zero time of the study, and all measurements were recorded from this point.

Patients were monitored every minute for first 15 min, then every 5 min for next half an hour after the administration of the drug intrathecally and every 10 min thereafter up to 120 min after the block. Postoperatively, patients were monitored every 1 h for the 1st 4 h.

Oxygen was administered through a mask if the pulse oximetry reading decreased below 90%. Hypotension (defined as a decrease in systolic blood pressure by more than 20% from baseline or <80 mm Hg) was treated with incremental intravenous doses of ephedrine 6 mg and further intravenous fluid as required. Bradycardia (defined as fall in heart rate 20% from the baseline or <60 beats per minute) was treated with intravenous atropine 0.6 mg.

Time for onset of sensory blockade was assessed by loss of pinprick sensation to 23G hypodermic needle bilaterally along the midclavicular line and dermatomal levels were tested every 2 min until the highest level was stabilized for two consecutive tests. Data regarding the time to reach highest dermatomal level of sensory blockade from the time of injection and time for two segment sensory regression were collected.

The time for rescue analgesia was when patient complains of pain (VAS >3) at surgical site. This was recorded and treated with injection paracetamol 15 mg.kg− 1 as rescue analgesia.

Time required for complete recovery from motor block, the primary outcome of our study was noted (Modified Bromage scale = 0). Other parameters such as time to complete recovery of sensory block (return of pinprick sensation till the level of S5; S-Sacral), time for 1st void of urine, and time for ambulation (time for 1st mobilization) were noted. Patients met the discharge criteria when they achieved at least 10 points of the postanesthetic discharge scoring system for ambulatory surgery.[5]

Sample size was calculated by keeping the confidence limits at 95% and power of the study at 80% for each pair-wise comparison to detect differences as large as 10%. The study has only been powered for the primary end point, which is the time until complete recovery of motor block, presuming a difference of at least 30 min between the two groups based on previous literature.[26] The sample size required was 25 patients in each group. Taking into account the dropout cases, the sample size was taken as 30 in each group.

Statistical analysis

Data were analyzed using MS Excel, SPSS version 22 software (IBM SPSS Statistics, Somers NY, USA). Categorical data were represented in the form of frequencies and proportions. Chi-square test was used as test of significance for qualitative data. Continuous data were represented as mean and standard deviation. Independent t-test was the test of significance to identify the mean difference between more than two groups for quantitative data. P value (probability that the result is true) of <0.05 was considered as statistically significant after assuming all the rules of statistical tests. All the quantitative variables were normally distributed in the study.

RESULTS

The two groups were comparable in terms of demographic profile (age, height, weight, and BMI). Chloroprocaine showed a significantly faster onset of sensory blockade at L2 level compared to levobupivacaine. Nearly 66.7% of the patients in Group C attained sensory blockade at L2 level by 2 min, whereas 63.3% of the patients in Group L showed onset of sensory blockade at 3 min (P < 0.001).

There was no significant difference between the two groups in terms of highest level of sensory block, time to attain highest sensory block, onset of motor block and maximum Bromage scale achieved, and duration of surgery. Patients receiving chloroprocaine required a shorter duration to achieve maximum Bromage scale compared to those receiving levobupivacaine (Group C –4.4 ± 1.3 min and Group L − 8.3 ± 1.3 min, P < 0.001).

The time for sensory regression to L1 was significantly longer with levobupivacaine (Group C – 59 ± 8.7 min and Group L − 126.8 ± 20.1 min, P < 0.001). Patients belonging to Group C recovered faster from motor block (50.7 ± 5.7 min) than the ones belonging to Group L (181.0 ± 27.8 min, P < 0.001).

The 1st requirement of rescue analgesia was earlier in chloroprocaine group (85.3 ± 5.1 min) compared to levobupivacaine group (156.0 ± 24.4 min, P < 0.001). Time to void urine was significantly delayed in Group L compared to Group C (152.3 ± 26.9 min and 79.8 ± 10.1 min, respectively, P < 0.001). Patients belonging to chloroprocaine group showed early ambulation postoperatively (88.33 ± 9.13 min) compared to prolonged time for ambulation seen in levobupivacaine (206.67 ± 27.21 min, P < 0.001). The above data are summarized in Table 1.

Table 1

Spinal Block Characteristics: Comparison between the 2 groups

	Group				Statistical test used	Degree of freedom	P
	Chloroprocaine		Levobupivacaine
	Mean†	SD	Mean	SD‡
Onset time for sensory L2 level (min)¦	2.27	0.52	3.37	0.49	Chi square test	3	<0.001*
Maximum Level of sensory blockade	T8	T8-T10	T6	T6-T10	Chi square test	1	0.536
Time for Highest Sensory Level (min)	6.43	1.55	6.70	1.0	Independent t-test	-	0.173
Onset of Motor block (min)	1.43	0.50	1.57	0.50	Chi square test	1	0.302
Maximum Bromage scale achieved	3	-	3	-	Chi square test	-	0.132
Time for Maximum Bromage scale (min)	4.40	1.30	8.30	1.29	Independent t-test	-	<0.001*
Duration of Surgery (min)	30.17	10.71	26.67	8.64	Independent t-test	--	0.320
Time for Sensory regression L1 (min)	59.00	8.75	126.83	20.11	Independent t-test	--	<0.001*
Duration of Motor Block (min)	50.67	5.68	181.00	27.84	Independent t-test	--	<0.001*
Time for rescue Analgesia (min)	85.33	5.07	156.00	24.44	Independent t-test	--	<0.001*
Time for 1st void (min)	79.83	10.13	152.33	26.87	Independent t-test	--	<0.001*
Time for ambulation (min)	88.33	9.13	206.67	27.21	Independent t-test	--	<0.001*

*P<0.05 are significant. †Values are in Mean±SD. ‡SD=Standard deviation. §Min=Minute

In the study, there was no significant difference in mean heart rate between three groups at all the intervals of follow-up as shown in Figure 1.

Figure 1

Line diagram showing comparison of heart rate (bpm) between the two groups

Patients belonging to levobupivacaine group showed a fall in mean arterial pressure (MAP) at 5 min to 9 min, 15 min intraoperatively, postoperative 15 min, and postoperative 30 min. Although the fall in blood pressure was not severe enough to administer injection ephedrine, it was statistically significant when compared to the chloroprocaine group. The Chloroprocaine group showed stable hemodynamics intraoperatively and postoperatively as shown in Figure 2.

Figure 2

Line diagram showing comparison of mean arterial pressure (mm Hg) between the two groups

There were no side effects observed in both the groups.

DISCUSSION

In the quest to find an ideal local anesthetic agent for SAB in patients undergoing ambulatory surgery, chloroprocaine was introduced in 1952 with the potential to replace lidocaine.[7] However, concern about the potential neurotoxicity of CP was raised in 1980s, which was attributed to the presence of a preservative sodium metabisulphite.

Preservative-free chloroprocaine was reintroduced in 1996, and in the retrospective studies conducted by Yoos and Kopacz[8] and Hejtmanek and Pollock,[9] no cases of transient neurological symptoms (TNS) were reported, thus reestablishing the role of CP in ambulatory surgeries.

Literature suggests a dose between 30 and 60 mg of CP to be used for surgical procedures lasting 60 min or less. Moreover, a dose of 10 mg being no effect dose.[10] Minimum local anesthetic dose of levobupivacaine for cesarean section being 10 mg.[11] Therefore, in our study, we chose minimum dose of each drug required to produce effective surgical anesthesia for perianal surgeries.

In our study, demographic data such as age, gender, weight, and height were comparable between the two groups and did not show any significant statistical difference.

Chloroprocaine did not show much hemodynamic changes from the baseline, whereas there was fall in MAP in the levobupivacaine group. Our results are consistent with the results of the study conducted by Camponovo et al.,[6] in which chloroprocaine was hemodynamically stable even with a dose of 50 mg. In the study by Brahmbhatt N P et al. (2015),[2] hypotension was noted among 5 out of 32 patients, who received 7.5 mg of 0.5 % Isobaric Levobupivacaine.

Our study results showed a significant difference in the mean time for onset of sensory block at L2 among the three groups. Chloroprocaine showed faster onset of sensory block at 2.26 ± 0.52 min than levobupivacaine at 3.36 ± 0.49 min. In the study by Camponovo et al.,[6] Chloroprocaine showed a mean time of onset of sensory block of 7 min, but this was to attain a block of T10 dermatomal level. Vampugalla et al.[12] study comparing 3 mL each of 0.75% ropivacaine versus 0.5% levobupivacaine demonstrated a mean onset of sensory block at 7.98 ± 2.2 min in the levobupivacaine group. This difference from our result can be attributed to the volume of the drug used, positioning of the patient, and the addition of fentanyl as adjuvant in their study.

There was no significant difference in highest sensory level and the time required to attain it, between two groups, in our study. Nearly 66.7% of the patients in the Group C and 70% of the patients in Group L attained a sensory level of T10. However, 13.3% of patients in Group L showed a maximum sensory level of T6. Whereas, CP showed a “tailored block” by expanding only to the dermatomes relevant to the designated surgery and the drug did not ascend above T8 level. Nevertheless, it provided adequate intraoperative analgesia. The above findings are consistent with the study conducted by:

1% Chloroprocaine: Gebhardt et al.(2017)[10]−> peak sensory level of T7-T8

Bhaskara et al.[13] −> peak sensory level of T8

0.5% Levobupivacaine: Vampugalla et al.:[12] Peak sensory level: T6

Choudhary et al.[14] peak sensory level: T6.

The Maximum Bromage scale attained in all three groups was 3. The time to attain maximum Bromage scale was significantly shorter with chloroprocaine group (4.40 ± 1.30 min) and significantly longer with levobupivacaine group (8.30 ± 1.29 min). The observations made in the below mentioned studies are consistent with the findings in our study [Table 2].

Table 2

Maximum Motor blockade : comparison with other studies

Drug Motor block	Chloroprocaine		Levobupivacaine
	Our study	Camponovo C et al. (2014)[6]	Our study	Brahmbhatt N P et al. (2015)[2]
Maximum Bromage scale	3	3	3	3
Time to attain maximum Bromage scale*	4.40±1.30 min†	5 min (1-26)	8.30±1.29 min	9.06±1.76 min

*Values are in Mean±SD. SD=Standard deviation. †Min=Minute

Sensory regression time in chloroprocaine group was the shortest (59.0 ± 8.75 min) and longest in the levobupivacaine group (126 ± 20.11 min) (P < 0.001).

Lacasse et al.[15] also found in their study that the sensory regression to L1 with 40 mg of chloroprocaine was 50 ± 18 min, which was significantly shorter than hyperbaric bupivacaine 0.75%. Onur et al.,[16] in their study, found the sensory regression time of 7.5 mg of isobaric levobupivacaine to be 135–182 min which was significantly shorter when compared to 10 mg, 12.5 mg, and 15 mg of levobupivacaine. These results are in agreement with the results obtained in our study.

Duration of motor blockade was considered as the primary objective of our study. There was significantly faster recovery from motor block in the chloroprocaine group (50.67 ± 5.68 min) compared to levobupivacaine (181 ± 27.84 min). The results mentioned above are in agreement with the results of the following studies [Table 3].

Table 3

Total duration of Motor blockade : comparison with other studies

Drug Motor block	Chloroprocaine		Levobupivacaine
	Our study	Gebhardt V et al. (2017)[10]	Our study	Vampugalla P S et al.[12] (2015)
Duration of motor block*	50.67±5.68 min†	72 (50-110 min)	181±27.84 min	181±21.3 min

*Values are in Mean±SD. SD=Standard deviation. †Min=Minute

Analgesic supplementation was required within short span following the surgery in Group C compared to Group L. Similar results were seen in the studies conducted by Gebhardt et al. (2017)[10] where the time for rescue analgesia with 30 mg of chloroprocaine was 111 min (86–185 min). Early requirement of supplemental analgesic with chloroprocaine is a downside, but nevertheless, patient's faster discharge time consistently outweighs the early requirement of analgesia.

Patients undergoing perianal/anorectal surgeries are at high risk of urinary retention. Therefore, spontaneous micturition is an obligatory condition for discharging the patient. Chloroprocaine group showed a significantly early voiding of urine postoperatively (Group C: 79.83 ± 10.13 min and Group L: 152.33 ± 26.87 min) which concurs with the study conducted by Camponovo et al.[6] and Mantouvalou et al.[17] (levobupivacaine − 120 ± 35 min).

Chloroprocaine showed a favorable profile for early discharge as the patients could be ambulated earlier than those receiving levobupivacaine.

Results of the studies mentioned below are in agreement with the results of our study [Table 4].[1618]

Table 4

Time for unassisted ambulation: comparison with other studies

Ambulation	Chloroprocaine		Levobupivacaine
	Our study	Casati A et al. (2006)[18]	Our study	Onur O Z et al. (2010)[16]
Time for unassisted ambulation*	88.33±9.13 min†	85 min (45-198 )	206.67±27.21 min	265 min (139-400)

*Values are in Mean±SD. SD=Standard deviation. †Min=Minute

There were no cases of partial block requiring intraoperative analgesic supplementation, conversion to general anesthesia, or urinary retention in the two groups. No case of TNS was noted in the two groups.

From the above points, the use of intrathecal chloroprocaine with the advantage of early ambulation seems to be a promising option in day-care perianal surgeries, leading to shorter hospital stay, more economical, and overall improvement in patient care.

Limitations of our study were that it was restricted to perianal surgeries. Furthermore, the volume of the two drugs were different and hampered the process of blinding. This bias was minimized by entrusting the same blinded observer to collect all the data during the study. There is future scope in extending this study to evaluate the effects of the above drugs in surgeries involving the lower limb, abdomen, and gynecological procedures.

CONCLUSION

Our study demonstrates that 30 mg of isobaric 1% 2-chloroprocaine has a faster onset of sensory blockade along with the advantage of faster recovery from motor blockade, early ambulation and discharge, and better hemodynamic stability when compared to 7.5 mg of 0.5% isobaric levobupivacaine.

Therefore, intrathecal isobaric 2-Chloroprocaine may be proposed as a better alternative for conventionally used drugs in day-care perianal surgeries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.