INTRODUCTION:

Spinal anaesthesia lowers postoperative pain, analgesic requirements and shortens the length of stay (LOS).¹The analgesic agents act on the sodium channels of the cardiovascular system causing sympathetic blockade.²

The anaesthetic effects include hypotension that is characterised by abnormal decline of blood pressure and inadequate blood flow to body organs and tissues.^3-5Prilocaine and lidocaine are amide-type local anaesthesia for specific body part surgical procedures. However, they differ based on pharmacology and clinical attributes². Lidocaine 5% is a potent, short acting (a rapid onset of action but moderate action duration) while Prilocaine 2% is less potent, intermediate (rapid onset but a longer action duration) acting drug.³ Both anaesthesia are well-tolerated when used appropriately, but in rare cases, adverse effects like allergic reactions, systemic toxicity, or methemoglobinemia can arise. Methemoglobinemia reduces the blood’s oxygen-carrying capacity, leading to tissue hypoxia and in severe cases, multi-organ dysfunction, including the kidneys.⁶

Due to its low potency, higher doses of Prilocaine 2% than Lidocaine 5% may be required for the same procedure, leading to systemic toxicity.⁷Such toxicity properties can damage other organs like kidneys and harm their function⁸The hypotension impacts linked to analgesia can help to determine its suitability for surgery. Hs-CRP and hs-Troponin are vital biomarkers for cardiac and inflammatory responses to anaesthesia. No contemporary literature compares the hypotension impacts of Priolocaine 2% and Lidocaine 5% and their comparisons have never been studied based to generate information about the efficacy and safety of the two agents.⁹This research compares the postsurgical serum hs-CRP and hs-Troponin concentration and associated side effects in cystoscopy patients to demonstrate the effects of the two analgesic agents. The authors intend to compare newcomer drug (Prilocaine) in the country as to be considered for alternative local anaesthesia use instead of Lidocaine 5%, that has been widely used for a long time in the nation.

MATERIAL AND METHODS:

Trial design and participants:

This study utilized a prospective parallel, double-blind, randomised controlled trial. Before the study, an approval was obtained from The Health Research Ethics Committee of Dr. Moewardi General Hospital Surakarta with registered number 1.133/VIII/HREC/2022. It is registered at clinicaltrials.gov (NCT05834647, 28 April 2023). Written informed consent was obtained from all subjects, a legal surrogate, the parents, or legal guardians for minor subjects.

Study Sample:

The study subjects comprised adult patients undergoing cystoscopy in the Surgery Installation at Dr. Moewardi General Hospital Surakarta from May to October 2023. The sample size was calculated using the following formular^10-12:

Where:

Mean in treatment group is 15.00

Mean in control grup is 12.00

Standard deviation in treatment group is 4.00

Standard deviation in control group is 5.00

Ratio (r) = 1.00

Alfa (α) = 0,05, Z (0,95) = 1,959964

Beta (β) = 0,20, Z (0,800) = 0,841621

A 90% confidence level, and a margin of error or confidence interval of ±5% were used in the sample calculation. Prior computation showed a minimum requirement of 72 participants was essential for successful comparison of the two groups with a 5% type I error and a power of 90% using a two-tailed test. The actual minimal number of patients enrolled was set at 90. There was a 20% loss to follow-up or drop out.^10-12

Trial participants:

For inclusion, only patients aged 18 to 60, undergoing urological surgery involving spinal anaesthesia use, having WHO normal BMI (18.5-24.9kg/m²), in American Society of Anaesthesiologists 2020 I or II physical status category, no history medications of diabetes mellitus or coronary heart disease-related procedures, no absolute spinal anaesthesia contraindications, no non-steroidal and being in steroidal analgesic drug two weeks before surgery were considered. Additionally, all participants with a history of autoimmune disorders or on immunosuppressant medication, hypersensitivity to Prilocaine or Lidocaine and impaired liver function, heart rhythm, neurological disorders, myopathy disorders, thrombocytopenia (<100,000/mL), and coagulopathy (international normalized ratio >1.5) were identified and excluded from this research.

Nonetheless, all patients who changed from spinal to general anaesthesia; whose surgical procedure was>90 minutes; receiving dexamethasone or methylprednisolone before anaesthesia; having arrhythmia during surgery (tachyarrhythmia> 150x/minute or non-sinus ECG rhythm), high spinal, or total spinal; use of adjuvant to hyperbaric Lidocaine 5% or prilocaine 2%;deciding to withdraw from the study; and whose blood samples were not taken to examine postoperative hs-CRP and hs-Troponin levels were dropped from the study.

Randomisation and masking:

Computer generated tables were used to allocate participants into two group in a 1:1 ratio. A numerical sequence was generated and stored in serially numbered opaque envelopes, separate from the investigators. The spinal anaesthetic drug dose standardized based on concentration, and route of administration, was handed over to the anaesthesiologist blindly in a previously prepared 3 mL syringe arranged by the pharmacist, who had prior knowledge of the required dosage for each drug, with specific registry number for each patient.

Data Collection Procedure:

For each patient. 4mL blood sample was collected to check creatinine, hs-CRP and hs-Troponin levels within 24 hours before spinal anaesthesia. The patients were randomised and categorised into two groups. The first group, P, received 2.5mL of commercially available Prilocaine 2%/Takipril (B. Braun, Melsungen, Germany, 100mg/5mL). The second group, L, received 1 mL of hyperbaric Lidocaine 5% (Bernofarm, Sidoarjo, Indonesia, 100mg/2mL). In any serious adverse event, the study was postponed till its cause clearly established and reviewed. Intravenous bolus of Ephedrine (Ethica, Bekasi, Indonesia, 50mg/mL) 5-10mg was administered to patients who experienced hypotension. Blood pressure, mean arterial pressure (MAP), and heart rate were also recorded perioperatively.

Again, 4 mL blood sample was taken from each patient in the ward to check hs-CRP and hs-Troponin levels 4 hours after surgery. Each patient was given a postoperative analgesic infusion of Paracetamol (Hexpharm Jaya Kalbe, Bekasi, Indonesia) 1 gram every 8 hours intravenously to relieve pain.

Study Outcomes:

Primary Outcomes:

The primary outcome was hs-CRP (using particle enhanced immunoturbidimetry method) and hs-Troponin serum level [using Enzyme-Linked Fluorescent Assay (ELFA)].

Secondary Outcomes:

Secondary outcomes were the regression of sensory block, duration of stay in the recovery room (RR), pain score, and the incidence of hypotension, bradycardia, and nausea. Visual Analogue Scale (VAS), ranging from 1 to 10 representing no pain to extreme pain was used to measure postoperative pain. Facility stay duration (RR) in minutes was measured at the time of discharge and this occurred when Bromage scale <2. Hypotension was determined by a systolic blood pressure of < 90 mmHg or mean arterial pressure (MAP in mmHg) ≥20% from baseline preoperative value. Bradycardia was evaluated by a heart rate < 50 beat/min. VAS for Postoperative Nausea and Vomiting (PONV) was used with classification of 0-1 (no nausea), 1-4 (mild), 4-7 (moderate) and 7-10 (severe) groups.^13,14

Statistical Analysis:

Statistical Package for Social Scientists (SPSS v.26) was used to analyse and present the descriptive and empirical results in tables and graphs. A 2-tailed independent t-test set at 95% confidence interval was used to compare the pre-and post-rest results of the selected variables.

RESULTS:

Trial population:

Notably, 95 patients were recruited into this study; five patients were lost to follow up for not giving blood samples after surgery after being discharged at their own discretion. Thus, the findings are based on 90 adult patients (45 from each anaesthesia intervention group) who met the inclusion criteria. Notably, for the Prilocaine 2% group, there were 21 males and 24 females. On the other hand, Lidocaine 5% group had 19 males and 26 females. Neither of the groups recorded severe adverse events and nor moderately adverse events in the study period. The flow diagram of patient selection is presented in Figure 1.

Figure 1. CONSORT Diagram

Table 1 presents the study’s descriptive statistics. Age, gender, BMI, ASA status, and pre-test baseline blood sample variables were not significant different for the two groups (p>0.05).

Table 1. Baseline characteristics.

Description	Prilocaine 2% (N=45)	Lidocaine 5% (N=45)	p-value
Age	48.02 ± 8.73	48.00 ± 9.26	0.981^*
Sex			0.671^†
Male	21 (46.7%)	19 (42.2%)
Female	24 (53.3%)	26 (57.8%)
BMI (kg/m²)	21.86 ±1.65	22.01 ±1.89	0.787^*
ASA physical status			0.814^†
1	13 (28.9%)	12 (26.7%)
2	32 (71.1%)	33 (73.3%)
Baseline Blood Sample
Serum Ureum	25.62 ± 10.67	25.52 ± 12.82	0,660^*
Serum Creatinine	1.662 ± 1.518	1.731 ± 1.524	0,802^*
hs-CRP	5.168 ± 3.330	5.406 ± 2.329	0,696^‡
hs-Troponin	5.64 ± 2.327	5.76 ± 2.002	0,615^*

hs-CRP: high-sensitivity-C-Reactive Protein, hs-Troponin: high-sensitive Troponin, BMI: Body Mass Index, ASA: American Society of Anaesthesiologists

^*Mann Whitney U test; unpaired group (non-normal distribution)

^†Chi Square (nominal data)

^‡Independent T-test; unpaired group (normal distribution

Primary Outcomes:

Serum Ureum (in mg/dL):

Table 2 shows the baseline inflammatory and renal function parameter values of all subjects in both groups was relatively indifferent (25.62±10.67 for prilocaine 2% and 25.52±12. 82 for Lidocaine 5%,). The post-treatment serum Ureum mean (g/dL) for Lidocaine 2% group rose by 11.78±4.24 while for prilocaine 2%, it rose to 37.31±13.40. A paired sample T-test showed that the change was significant for both groups at p<0.05. Thus, Prilocaine 2% use in urological surgery produced a higher serum urea concentration than Lidocaine 5%.

Serum Creatinine (in mg/dL):

The baseline mean serum creatinine for Prilocaine 2% group (1.73±1.52) rose by 1.68±1.87 or 96.8% (3.41± 2.55). The average change was significantly different at p<0.05 For Lidocaine % group, the baseline Serum creatinine mean (1.66±1.52) and increased to 2.23±1.47 or 34.2%.

Table 2. Differences in Serum Ureum and Creatinine

Serum Ureum (in mg/dL)
	Prilocaine 2%	Lidocaine 5%	p-value
Pretest	25.62 ± 10.67	25.52 ± 12.82	0.660
Post-test	29.02 ± 9.77	37.31 ± 13.40	<0.001^*^‡
p-value	<0.001^1*	<0.001^1*
∆Serum Ureum	3.40±5.36	11.78±4.24	<0,001^*
Serum Creatinine (in mg/dL)
Pretest	1.66 ± 1.52	1.73 ± 1.52	0.802^*^‡
Post-test	2.23 ± 1.47	3.41± 2.55	0.029^*^‡
p-value	<0.001^*^†	<0,001^*^†
∆Serum Creatinine	0.57 ±0.42	1.68 ±1.87	0.027^*^‡

*Significant at p<0.05

^† Wilcoxon; paired group (non-normal distribution)

^‡ Mann Whitney; unpaired group (non-normal distribution)

Differences in hs-CRP (in mg/dL) between Lidocaine 5% and Prilocaine 2% Intervention:

The baseline hs-CRP mean for Lidocaine 5% (5.41± 2.33) rose by 4.09±1.60(75.7%) to 9.50±3.25. The baseline mean (1.66±1.52) serum hs-CRP content for Prilocaine 2% group rose by 30.6% to 2.23±1.47. A paired group difference test results indicated that the pre and post-test hs-CRP means were significantly different for both groups. The results imply that Prilocaine 2% results in lower hs-CRP after urological surgery than Lidocaine 5%. Table 3 will demonstrate these results.

Table 3. Differences in hs-CRP

Group	hs-CRP		p-value	∆ hs-CRP
Group	Pretest	Post-test	p-value	∆ hs-CRP
Prilocaine 2%	5.17 ± 3.33	6.75 ± 3.57	<0,001^*^‡	1.58 ±1.58
Lidocaine 5%	5.41 ± 2.33	9.50 ± 3.25	<0,001^*^†	4.09 ±1.60
p-value	0.696^§	<0.001^*^\|\|		<0.001^*^\|\|

hs-CRP: high-sensitivity-C-Reactive Protein

* Significant at p<0.05

^†Wilcoxon; paired group (non-normal distribution)

^‡Paired T-test ; paired group (normal distribution)

^§Independent T-test; unpaired group (normal distribution)

^|| Mann Whitney; unpaired group (non-normal distribution)

Differences in hs-Troponin (in ng/L) between Lidocaine 5% Intervention and Prilocaine 2%:

The baseline hs-Troponin mean Lidocaine 5% group (5.76±2.00) rose by 5.64±2.61(98.1%), to 11.40±3. 85. For Prilocaine 2% group, the baseline hs-Troponin level (5.17±3.33) increased to 6.75±3.57, representing a 61.4% increase. Further tests showed that showed these average differences were statistically significant for both groups. The studies confirm that Prilocaine 2% use as anaesthesia results in lower hs-Troponin than Lidocaine 5% in a urological surgery (Table 4).

Table 4. Differences in hs-Troponin

Group	hs-Troponin		p-value	∆ hs-Troponin
Group	Pretest	Post-test
Prilocaine 2%	5.64 ± 2.33	9.11 ± 2,82	<0. 001^*^†	3.47± 2.00
Lidocaine 5%	5.76 ± 2.00	11.40 ± 3,85	<0.001^*^†	5.64± 2.61
p-value	0,615^‡	0.001^*^‡		<0,001^*^‡

hs-Troponin: high-sensitive Troponin

* Significant at p<0.05

^† Wilcoxon; paired group (non-normal distribution)

^‡Mann Whitney; unpaired group (non-normal distribution)

Secondary Outcomes:

Differences in Duration of Stay in Recovery Room, Block Regression, VAS, and Side Effects after Cystoscopy Procedures:

The duration of stay in the recovery room (RR) and full sensory block regression were significantly different between the two groups, implying that RR and block regression were influenced by the anaesthesia agent. Post-hoc tests showed that the duration of stay in the recovery room and sensory block regression were longer in the Prilocaine 2% group than in the Lidocaine 5% group. That said, no significant difference between the two groups was noted in the VAS postoperatively. (see table 5). The post-hoc tests showed that these side effects were more frequent and severe in the lidocaine 5% group than in the prilocaine 2% group.

Table 5. Differences in RR duration, block regression, VAS, and side effects

Description	Prilocaine 2% (N=45) N (%)	Lidocaine 5% (N=45) N (%)	OR (lidocaine vs prilocaine)	p
RR duration	40,00 ± 5.33	30.00 ± 3.99	-	<0.001*^†
Block regression	128.00 ± 7.34	94.00 ± 11.51	-	<0.001*^†
VAS	1.91 ± 0.70	1.96 ± 0.796	-	0.808
Side effect
Hypotension^‡				<0.001*^†
Yes	5 (11.1%)	24 (53.3%)	9.14
No	40 (88.9%)	21 (46.7%)
Bradycardia^‡				0.001*^†
Yes	7 (15.6%)	21 (46.7%)	4.75
No	38 (84.4%)	24 (53.3%)
Nausea^‡
None	30 (66.7%)	7 (15.6%)	10.86	<0.001*^†
Mild	15 (33.3%)	24 (53.3%)
Moderate	0 (0%)	14 (31.3%)
Severe	0 (0%)	0 (0%)

RR: recovery room, VAS: Visual Analogue Scale

* Significant at p<0.05

^†Mann Whitney; unpaired group (non-normal distribution/ordinal data)

^‡Chi Square (nominal data)

DISCUSSION:

Main Findings:

The action of anaesthesia during endoscopy procedures cause pain receptor numbness. However, the resultant hypotension adversely affects vascular blood flow and induces release of Damage- Associated Molecular Patterns (DAMPs) that trigger organ inflammation^15,16. The inflammatory response impairs kidney function (filtration and excretion of urea and creatinine), raising serum urea, creatinine, and troponin levels^17,18. Hs-CRP is a critical marker for various inflammatory conditions, including kidney damage^6,7,16,19-20.

In this study, the hypotensive impacts Lidocaine and Prilocaine in adult patients undergoing cystoscopy were noteworthy. First, it was established that both anaesthesia triggered inflammatory responses and hurt kidney function, affirming similarities in the action path of the two agents. Precisely, the inflammatory response was due to the anaesthesia’s action on sodium channels in nerve cell membrane, diffusing into the nerve sheath, ionizing hydrogen ions and generating cations that bind reversibly to the sodium channel to open it. The process prevents nerve depolarization, blocking motor senses^.[9] The sensory blockade action is similar for both agents, but the temporary side effects like urological impacts are higher for lidocaine than Prilocaine³. These results are consistent with the extant literature^7,8,21.

Hypotension, bradycardia, and nausea are common side effects that arise using anaesthetic agents^6,22-24. The degree of side effects that occur is individual depends on the anaesthetic agent used to facilitate sympathetic blockade^6,25-26. Remarkable parameter differences were established in the pre and post-test within and between group results across the four assessment dimensions (serum urea, creatinine, hs-CRP, and hs-Troponin).

Lidocaine 5% and prilocaine 2% have different effects on hs-CRP (C-Reactive Protein) due to the different mechanisms and concentrations of the two drugs. Lidocaine can influence several steps in the inflammatory process, such as the inhibition of leukocyte cell adherens and their absorption into the exudate^.High concentrations of lidocaine can reduce inflammation and affect leukocyte function^22,27-29.

Another finding from this study is that prilocaine 2% (p=0.001) and lidocaine 5% (p=0.001) have a significant impact on hs-Troponin. Lidocaine 5% (pretest 5.76± 2.00; posttest 11.40±3.85) provided a higher increase in hs-Troponin than prilocaine 2% (pretest 11.40±3.85; posttest 9.11±2.82). Lidocaine 5% does not directly cause an increase in hs-Troponin, however several conditions can affect hs-Troponin and are related to the use of lidocaine. Increased hs-Troponin can occur due to various factors, such as cardiac infarction, myocardial infection, and use of drugs that interfere with heart function. An increase in hs-Troponin can occur due to several factors related to the use of lidocaine, such as hyper permeability of capillaries which can be caused by lidocaine, so that it can increase the release of enzymes from myocardial cells. The use of lidocaine together with general anaesthesia, which reduces cardiac oxygenation and impairs cardiac perfusion, can increase hs-Troponin^27-29. The use of lidocaine in conditions that result in heart damage may increase hs-Troponin. However, the increase in hs-Troponin associated with lidocaine use is unique and not common.

The comparative data analysis showed significant differences for the two groups in terms of duration of stay in the recovery room and the complete sensory block regression period, but no significant differences in VAS between the two groups. Normal creatinine levels in the blood are 1.2mg/dL for women, while 1.4 mg/dL for men. If the levels exceed this figure, it means that the kidneys are experiencing impaired function.²⁴Prilocaine 2% showed better results than lidocaine 5% across these parameters. Lidocaine showed a higher urea and creatinine concentration than Prilocaine, indicating a higher toxicity rate than Prilocaine. The result is consistent with the findings of extant literature^30-32. However, from comparative data analysis of side effect parameters, it was established that hypotension, bradycardia, and nausea were more pronounced in the Lidocaine 5% group than in the Prilocaine 2% group.

The findings from the research shed light on the action mechanisms of these two anaesthetic agents that underscore the variation of hemodynamic side effects^19,21. They confirm the extant literature knowledge that Prilocaine has cardiotoxicity effects despite its similarities in excretion as lidocaine^6,22. The lower side effects of Lidocaine than prilocaine are due to the metabolism and excretion differences. Prilocaine by is excreted from plasma and tissue faster than lidocaine as shown in previous studies⁶. Also, the contemporary literature affirms that being more potent, Lidocaine minimizes sympathetic blockade better, lowering cardiovascular effects, hence lower bradycardia, and hypotension⁴.

LIMITATIONS:

The limitation of this study is the time for recording the critical data. Notably, urea and creatinine levels were only measured 4 hours after surgery, yet serum and creatinine may increase up to the 2^nd day after surgery¹⁸. Also, the results are based on cystoscopy urological surgery with a duration of <90 minutes, implying that the results may not apply to other surgeries.

CONCLUSION:

The short-term hypotension impacts of Lidocaine and Prilocaine as analgesic agents for cystoscopy was examined. The study found a significant difference in hs-CRP levels [prilocain 1.58±1.58mg/dL compared to lidocaine 4.09±1,60 mg/dL (p<0.001)] and hs-Troponin level [prilocaine 3.47±2.00 ng/L compared to lidocaine 5.64±2.61ng/L (p<0.001)). Side effects of hypotension, bradycardia, and nausea are more frequent and severer in Lidocaine 5%. The study was, however, limited by the subject characteristics (emphasise on adults) and the period at which the post-test results were obtained for analysis.

CONFLICT OF INTEREST:

The authors state no conflict of interest. This research funding is supported by the Indonesia Endowment Fund for Education (Lembaga Pengelola Dana Pendidikan [LPDP] Republic of Indonesia).

ACKNOWLEDGMENT:

The author would like to thank you for the opportunity provided by the Faculty of Medicine, Universitas Sebelas Maret.

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Received on 13.02.2024 Revised on 17.06.2024

Accepted on 29.08.2024 Published on 28.01.2025

Available online from February 27, 2025

Research J. Pharmacy and Technology. 2025;18(2):632-638.

DOI: 10.52711/0974-360X.2025.00094

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.