The effect of spermatic cord block on reducing the risk of vagal reflex during microsurgical subinguinal varicocelectomy: A randomized trial

Abstract

Purpose

This study aimed to compare the risk of vagal reflex during microsurgical subinguinal varicocelectomy (MSV) under general anesthesia (GA) with or without additional local anesthetic (LA) spermatic cord block (SCB).

Method

A single-center randomized controlled trial was conducted between January 2022 and June 2023.300 patients with left-sided grade Ⅲ varicocele were randomly divided into two groups: SCB group (n = 153) and control group (n = 147)（computer-generated random numbers list）. During MSV under GA, the SCB group was given of ropivacaine for SCB before pulling the spermatic cord, while the control group was directly lifted. The primary outcome was the reduction in the lowest heart rate in the SCB group as compared with the control group during spermatic cord traction (SCT). Secondary outcomes included the reduction in the lowest blood pressure in the SCB group as compared with the control group; and the reductions in the lowest heart rate and lowest blood pressure as compared with baseline during SCT. The number of times that surgery and medications were suspended because of symptomatic reflex bradycardia was also recorded. Adverse events were also recorded as secondary outcomes.

Result

Five patients in the SCB group and 10 patients in the CG were excluded. The lowest heart rate and systolic blood pressure during SCT in the SCB group and the control group were significantly lower than the baseline values (P < 0.05). However, the decrease in the SCB group (70-73bpm VS 108–115 mmHg) was milder than that of the control group（66–72 bpm VS 105–114 mmHg）(P < 0.05). The number of surgeries and medication pauses due to symptomatic reflex bradycardia during surgery was significantly lower in the SCB group (2 VS 1) than in the control group (9 VS 7) (P < 0.05).

Conclusion

SCB can effectively reduce the vagal reflex caused by pulling the spermatic cord during MSV, and reduce the risk of anesthesia and surgery.

1. Introduction

Varicocele accounts for approximately 15 %–20 % in the male population, up to 40 % in infertile males, and is widely recognized as a cause of decreased testicular function [1]. It is one of the causes of chronic scrotal content pain (CSCP) [2]. Adult varicocele surgery has two main indications: (I) testicular pain or spasm, and (II) abnormal semen parameters in infertile men [3]. Multiple clinical studies and meta-analysis results have shown that microsurgical varicocelectomy (MV) has a more significant improvement in semen quality, higher pain relief rate, lower recurrence rate, and fewer complications compared to open ligation and laparoscopic varicocelectomy [[4], [5], [6]]. Specifically, MV can be divided inguinal and subinguinal approaches. Studies of the two approaches have shown that the inguinal approach increases postoperative pain and recovery time by opening the external oblique fascia [7,8].

The vagus nerve serves as a crucial neural pathway connecting the body and brain, regulating vital aspects of autonomic function including respiration, heart rate, blood pressure, reflexes, and responses to disease [9]. The vagal reflex causes sudden slowing of the heart rate, weakening of the heart muscle, and widening of small blood vessels, resulting in low blood pressure [10]. Reflex bradycardia may occur during various surgical procedures, such as neurosurgery, obstetrics, abdominal surgery, ophthalmology, facial surgery, and anal surgery due to vagus nerve stimulation or compression from surgical manipulation [11]. Most cases occur due to a reflex increase in vagus nerve tension immediately after peritoneal stretching or visceral organ operation [11,12]. Severe vagal reflex can lead to malignant arrhythmias and even cardiac arrest [13]. The occurrence of severe bradycardia is an adverse event in patients with impaired cardiac function [12]. In addition, pre-administration of anticholinergic drugs cannot reliably prevent reflex bradycardia, which may be incorrect in some situations [14]. MSV has been routinely applied in our center. During this procedure, we found that the vagal reflex occasionally occurred during the process of spermatic cord traction, leading to a decrease in the patient's heart rate and blood pressure, increasing the risk of anesthesia and surgery. Our hypothesis is that symptomatic reflex bradycardia may occur during spermatic cord lifting during GA, and these effects will be weakened or prevented by LA. Therefore, the purpose of this single-center, randomized clinical trial was to analyze and compare the risk of vagal reflex during MSV under GA with or without LA SCB.

2. Participants and methods

2.1. Participants

This single-center randomized controlled trial was conducted at Department of Andrology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China from January 2022 to June 2023 (Fig. 1). The randomisation process was conducted using a computer-generated list of numbers on an electronic case report form, without employing blocking or stratification. Surgeons and anesthesiologists were not blinded, whereas data analysts and participants were blinded. This study was approved by the Institutional Review Committee of The Affiliated Hospital of Nanjing University Medical School (No. 2015-053-01). All patients signed with informed consent and recorded the results.

Fig. 1.

Flowchart of Patient Enrollment and Admission SCB: spermatic cord block.

2.2. Inclusion criteria

• ①Primary left-sided grade III VC confirmed by clinical and imaging examination. Diagnostic criteria: Based on Dubin and Amela grading combined with color doppler flow imaging (CDFI) reference standards. grade III VC refers to the visible varicose veins within the scrotum, which can be palpated during palpation and can significantly increase the number of varicose venous masses. Ultrasound calm breathing examination showed that the inner diameter of the spermatic vein was greater than 3.1 mm, and there was reflux during Valsalva's action, with a duration of reflux greater than 6s.

• ②Preoperative semen analysis must reveal at least one abnormal parameter.

• ③Pain-related criteria include intermittent or persistent sensations of swelling, discomfort, or dull pain in the scrotal or inguinal region. Symptoms worsen after prolonged standing or physical activity and relieve after resting supine.

Patients need to meet both the first criteria and the second or third criteria.

2.3. Exclusion criteria

• ①Right-sided or bilateral varicoceles.

• ②Secondary varicocele due to renal or retroperitoneal tumors, extensive renal hydronephrosis, renal cysts, or vascular compression.

• ③Preoperative presence of sinus bradycardia or tachycardia, other arrhythmias, abnormal blood pressure, low blood oxygen saturation, electrolyte imbalance, or acid-base disturbances.

• ④History of cardiovascular or neurological diseases.

• ⑤Exclusion of other known causes of scrotal pain besides varicocele (e.g., prostatitis, infection, trauma, prior inguinal surgery, post-vasectomy pain syndrome, vasculitis, anorectal diseases, testicular torsion, and malignancies).

• ⑥Present utilization of analgesic medications.

• ⑦Ongoing or recent participation in another clinical study incompatible with the current research within the last 30 days.

• ⑧Patients with significant communication barriers.

2.4. Reflex bradycardia criteria and management

Due to vagal reflex, some patients may have a higher risk of reflex bradycardia during surgery, which is also associated with increased mortality. Reflex bradycardia is defined as a sudden heart rate decrease to <60 beats per minute (bpm) due to SCT. The threshold for bradycardia is chosen based on its clinical significance for organ perfusion [12]. Severity is categorized as mild (50–59 bpm), moderate (40–49 bpm), or severe (<40 bpm). Hypotension is defined as systolic blood pressure <80 mmHg, with severity classified as mild (70–79 mmHg), moderate (60–69 mmHg), or severe (<60 mmHg) [12]. Table 1 details the specific management protocol, and the minimum heart rate is documented during each reflex bradycardia episode.

Table 1.

Predefined treatment protocol for bradycardia and hypotension.

SBP/HR	50–59 bpm (mild bradycardia)	40–49 bpm (moderate bradycardia)	<40 bpm (severe bradycardia)
≥80 mmHg		Pause the operation and 10s observation →if persistent, atropine 0.3 mg IV	Pause the operation，atropine 0.3 mg IV immediately→if persistent, atropine 0.2 mg IV immediately→if persistent, atropine 0.5 mg IV immediately→if persistent, anisodamine 0.3 mg IV immediately→if persistent, isoproterenol (1 mg diluted to 100 ml) 1–2 ml IV immediately
70–79 mmHg	Pause the operation and 10s observation →if persistent, atropine 0.3 mg IV	Pause the operation and 10s observation →if persistent, atropine 0.3 mg IV	Same treatment as HR < 40 bpm (severe bradycardia) and SBP ≥80 mmHg
60–69 mmHg	Pause the operation and 10s observation →if persistent, atropine 0.3 mg IV	Pause the operation，atropine 0.3 mg IV immediately	Same treatment as HR < 40 bpm (severe bradycardia) and SBP ≥80 mmHg
<60 mmHg	Pause the operation，atropine 0.3 mg IV immediately	Pause the operation，atropine 0.3 mg IV immediately	Same treatment as HR < 40 bpm (severe bradycardia) and SBP ≥80 mmHg

SBP: systolic blood pressure, HR: heart rate, BPM: beats per minute.

3. Treatment methods

3.1. Anesthetic approach

Surgical anesthesia was performed by six experienced anesthesiologists, each of whom had participated in more than 500 MVC anesthesia. The selection of anesthesia method was typically determined by the preferred approach and clinical expertise of the anesthesiologist. All patients had standard preoperative anesthesia assessments, with baseline examinations within normal ranges. Microscopic ligation of the spermatic vein was performed under general anesthesia. Induction included propofol 80 mg, intravenous fentanyl 200 μg, vecuronium bromide 8 mg, and rocuronium 2 mg. Maintenance involved propofol at 400 mg per hour, remifentanil at 0.5 mg, and dexmedetomidine at 12 μg (adjusted based on patient weight) to ensure consistent anesthesia control. In the event of significant bradycardia or a blood pressure drop during SCT, the anesthesiologist followed the reflex bradycardia protocol. Instances of surgery pauses and medication use were recorded.

3.2. SCB and surgical procedure

MSV was performed in all patients. The surgery was performed by three experienced andrologists, each of whom had performed more than 500 MVC. Under GA, after the tissues were dissected layer by layer, the incision was exposed with a pull hook until the spermatic cord became visible. In the SCB group, 10 ml of 1 % ropivacaine was injected under direct vision for SCB before traction and mobilization of the spermatic cord. The control group underwent direct traction and mobilization of the spermatic cord. The spermatic cord was lifted out with appendage forceps and was followed by the placement of a rubber tube below the spermatic cord. The external spermatic vein was located and ligated. During surgery, untreated vas deferens veins were not manipulated. The internal spermatic fascia was opened under the microscope to locate the testicular arteries and lymphatic vessels. All visible veins were carefully examined, ligated with 4–0 silk threads, and then transected. When no veins were missed on the same plane or visible bleeding points were observed, the spermatic cord was returned to its usual position. The incision was closed layer by layer using 4–0 absorbable sutures, and the outer layer of the skin incision was closed with a continuous subcuticular suture.

3.3. Observational indices

The primary outcome was the reduction in the lowest heart rate in the SCB group as compared with the control group during SCT. Secondary outcomes included the reduction in the lowest blood pressure in the SCB group as compared with the control group; and the reductions in the lowest heart rate and lowest blood pressure as compared with baseline during SCT. The number of times that surgery and medications were suspended because of symptomatic reflex bradycardia was also recorded. Adverse events were also recorded as secondary outcomes.

3.4. Record adverse events

Adverse events included any perioperative complications such as spermatic cord puncture site hematoma and local anesthetic toxicity.

3.5. Statistical analysis

The Statistical Package for the Social Sciences (SPSS) software version27.0 (IBM, Chicago, IL, USA) was used for statistical analysis. The normality and homogeneity of variance were tested by Shapiro-Wilk test and Levene's test, respectively. Differences of data between groups were detected by one-way ANOVA and two-sample t-tests (two-tailed) when normality and homogeneity of variance assumptions were satisfied, otherwise, the non-parametric test (Mann-Whitney) was used for analysis. In addition, count data were analyzed with the Chi-squared test. The significant level was set at P < 0.05.

4. Results

4.1. Comparisons of demographic and baseline characteristics before treatment between groups

A total of 315 participants were considered for enrollment between January 2022 and June 2023 (refer to Fig. 1). 15 individuals were excluded due to ineligibility or refusal to participate. The remaining 300 patients (SCB group = 153, CG = 147) showed no significant differences in demographic and baseline characteristics (age, BMI, medical history, basal heart rate, and basal blood pressure). (P > 0.05) (Table 2). The median age of the SCB group was 32.50 (range: 21–49 years), the median age of the control group was 33.00 (range: 19–49 years).

Table 2.

Demographics and baseline patient characteristics between the two groups.

	SCB group（n＝153）	control group（n＝147）	P value
age (years)a	32.647 ± 6.658	33.048 ± 7.241	0.618
BMI (kg/m2)a	22.124 ± 2.833	21.981 ± 2.476	0.643
Duration of varicocele (months)a	16.902 ± 10.803	16.388 ± 10.728	0.68
basal heart rate (bpm)a	73.157 ± 5.218	72.796 ± 5.011	0.542
basal blood pressure（mmHg）a	114.876 ± 12.022	114.299 ± 11.881	0.677

SCB: spermatic cord block.

^aData are expressed as mean ± standard deviation.

4.2. Heart rate and blood pressure changes during SCT

During SCT, the minimum heart rate and minimum systolic blood pressure (70.869 ± 6.805bpm, 108.196 ± 13.755 mmHg) in the SCB group were significantly lower than those at baseline (73.157 ± 5.218bpm, 114.876 ± 12.022 mmHg) (P < 0.05); the minimum heart rate and minimum systolic blood pressure (66.143 ± 8.570bpm, 105.027 ± 13.266 mmHg) in the CG group were significantly lower than those at baseline (72.796 ± 5.011bpm, 114,299 ± 11,881 mmHg) (P < 0.05) (Table 3). However, the SCB group showed a significantly higher minimum heart rate and minimum systolic blood pressure during SCT than the CG (P < 0.05) (Table 3). Meanwhile, we observed that the absolute differences between the minimum heart rate and baseline heart rate during SCT in the SCB group and the control group were (2.240 ± 4.291, 6.726 ± 7.123) (P < 0.05), and the absolute differences between the lowest blood pressure and baseline heart rate were (6.680 ± 6.376, 9.272 ± 8.305) (P < 0.05)The anesthesiologist's interventions for symptomatic reflex bradycardia, including surgery pauses and medication administration during SCT were evaluated. The SCB group had 2 instances of surgery pauses and 1 instances of medication administration, while the CG had 9 instances of surgery pauses and 7 instances of medication administration. The SCB group had significantly fewer interventions (intraoperative pauses and medication times) compared to the CG, with a statistically significant difference between the two groups (P < 0.05, P < 0.05). No severe cardiovascular events, such as cardiac arrest, occurred in either group (Table 4).

Table 3.

The changes of heart rate and blood pressures between the two groups.

Group	basal heart rate (bpm)a	the slowest heart rate (bpm)a	basal blood pressure (mmHg)a	the slowest blood pressure (mmHg)a
SCB group （n＝153）	73.157 ± 5.218	70.869 ± 6.805*#	114.876 ± 12.022	108.196 ± 13.755*#
control group（n＝147）	72.796 ± 5.011	66.143 ± 8.570#	114.299 ± 11.881	105.027 ± 13.266#

SCB: spermatic cord block. *: P＜0.05 versus the CG ^#: P < 0.05 versus basal value.

^aData are expressed as mean ± standard deviation.

Table 4.

Reflex bradycardia caused by SCT requires surgery suspension and medication frequency between the two groups.

		SCB group（n＝153）a	control group（n＝147）a	P value
surgery pauses
	YES	2（1.307）	9（6.122）	0.027
	NO	151（98.693）	138（93.878）
medication administration	YES	1（0.654）	7（4.762）	0.027
	NO	152（99.346）	140（95.238）

SCB: spermatic cord block.

^aData are expressed as frequency (%).

4.3. Adverse events to SCB

No significant adverse events were observed.

5. Discussion

This research aimed to compare physiological and clinical parameters during MSV under GA, with or without LA for SCB. The primary focus is on changes in heart rate, blood pressure, and VR before and during the traction of the spermatic cord under GA, considering scenarios with and without LA for SCB. Key findings: 1. Both the SCB group and control group experienced significantly lower minimum heart rates and minimum systolic blood pressure than baseline values during SCT (P < 0.05). However, the decrease in the SCB group was significantly less than in the control group (P < 0.05). 2. The incidence of anesthesia-induced symptomatic bradycardia, resulting in the suspension of surgery and medication during the procedure, was significantly lower in the SCB group than the control group (P < 0.05, P < 0.05). 3. No significant adverse reactions were observed with SCB.

In varicocelectomy, bradycardia often occurs with SCT, believed to result from surgical stimulation of vagus nerve terminals. Mechanically sensitive afferent nerve fibers, responding to stretching or twisting, trigger a reflexive efferent response leading to bradycardia and/or hypotension [15]. Several factors during surgery can activate the VR, including age, baseline heart rate, blood pressure, intraoperative manipulations, anesthetic drug choice, depth of anesthesia, and core temperature [[16], [17], [18], [19]]. To maintain consistency and control variables, this study compared age, baseline heart rate, and baseline blood pressure between patient groups, finding no statistically significant differences（P > 0.05）(Table 2). Uniformity in intraoperative methods, anesthesia choice, depth, and core temperature were also upheld. The type and concentration of anesthetics are crucial in determining the blockade effect. Commonly used local anesthetics include ropivacaine, bupivacaine, and lidocaine. Ropivacaine has lower cardiotoxicity and a shorter onset time compared to bupivacaine, making it more suitable for this study [20]. However, further research is needed to investigate potential correlations between different concentrations and types of anesthetics.

Intraoperative bradycardia is an adverse event with potential harm to patients with reduced cardiac reserve and, in some cases, may progress to cardiac arrest [11,12,21]. Studies indicate that the likelihood of reflex bradycardia during open gastric resection is around 30 % [12], while during laparoscopic gastric resection, it is approximately 13.0 % [12,22,23]. The periscrotal innervation includes the reproductive branch of the femoral nerve, as well as the ilioinguinal and iliohypogastric nerves [24]. There is a dense innervation of the spermatic cord and fascia, with sensory and autonomic nerve fibers co-localizing on the same nerve [24]. During the process of spermatic cord traction, it is often necessary to perform multiple repetitions in order to accurately record changes in heart rate and blood pressure. The surgeon may encounter increased difficulty in dissecting the spermatic cord and require a greater pulling force, particularly in heavier patients with deeper spermatic cords, resulting in more significant decreases in heart rate and blood pressure. However, further studies are needed to confirm these findings. In the control group of this study, during SCT the average minimum heart rate was 66.143 ± 8.570 bpm, significantly different from the baseline heart rate (P < 0.05). The diagnosis of bradycardia caused by vagal reflex was primarily based on subjective judgment and conducted by multiple anesthesiologists following the established protocol for managing reflex bradycardia (as previously described), resulting in 9 episodes of bradycardia, 7 of which required medication. Patients with varicocele included in this study had no preoperative sinus bradycardia, sinus tachycardia, or other arrhythmias. They had no history of cardiovascular or neurological diseases, and their electrolyte and acid-base balance were within the normal range. Anesthesia was administered by experienced senior anesthesiologists, and all procedures were conducted under GA. Consequently, the observed decreases in heart rate, blood pressure, and vagal reflex in patients are primarily attributed to the traction stimulation of the spermatic cord during the procedure. This suggests that GA may be insufficient to adequately block the vagus nerve in the spermatic cord.

Effective management of intraoperative bradycardia is crucial as it can signal a potential severe cardiac arrest. When the vagal reflex induces bradycardia, promptly discontinuing the stimulus is the initial and paramount step. Intravenous administration of atropine or ephedrine may be necessary, and if conventional treatment proves ineffective, vasopressors like epinephrine may be required [25,26]. However, the onset of drug action takes seconds to tens of seconds, and cardiovascular accidents may occur within this timeframe. The documented cases of vagal-reflex-induced cardiac arrest requiring cardiopulmonary resuscitation emphasize the need for preventive measures in advance rather than relying solely on monitoring and remedial interventions [27,28]. Given the high incidence of vagal reflex during anesthesia and surgical procedures, scholars have explored ways to reduce symptomatic reflex bradycardia, hypotension, and cardiac arrest caused by vagal reflex by adding LA during intraoperative manipulations [[27], [28], [29]]. Previous studies show the effectiveness of LA nerve blockade in preventing the trigeminocardiac reflex (TCR) [13]. Local lidocaine has been shown to inhibit the reflex during microvascular decompression surgery involving the trigeminal nerve [14]. In patients undergoing ophthalmic surgery, bupivacaine peribulbar block has proven effective in attenuating the oculocardiac reflex (OCR), a form of the TCR [30]. Campbell et al. suggest that TCR could be prevented by LA infiltration and nerve blockade in maxillofacial surgery [30]. In the SCB group, during SCT, the average minimum heart rate was 70.869 ± 6.805bpm, significantly different from the baseline heart rate of this group (P < 0.05). Leading to the temporary suspension of surgery 2 times, with medication required in 1 instance. Compared to the SCB group, the control group exhibited a more pronounced decrease in the average minimum heart rate (P < 0.05). Additionally, the instances of surgery pause (or drug times) in the SCB group were significantly lower than those in the control group (P < 0.05, P < 0.05). Therefore, during MSV under GA, LA can significantly reduce or prevent the incidence of VR and symptomatic reflex bradycardia during SCT.

Several key points should be noted, firstly, the vagal reflexes observed in this study did not lead to serious consequences like shock or cardiac arrest, possibly because the subjects had no underlying diseases and tolerated anesthesia and surgery well. General anesthesia also largely inhibited vagal activity, preventing it from becoming overexcited [11]. Secondly, despite the administration of GA and SCB, a very small number of patients in the SCB group still experienced bradycardia. This situation may be attributed to the pre-existing high vagal nerve tone in these patients, and the combination of GA and local block anesthesia may have failed to adequately suppress their vagal nerve activity. Thirdly, in the SCB group, the slowest heart rate and lowest systolic blood pressure during the traction of the spermatic cord were significantly lower than the baseline values (P < 0.05). Moreover, in both the SCB group and control group, patients who did not experience vagal reflex also generally exhibited a slight decrease in heart rate and blood pressure compared to baseline values. This may be because GA or GA combined with local block anesthesia cannot completely suppress vagal nerve activity. This may be due to the younger age of the study population, as previous research has shown that younger patients have higher vagal tone, leading to more frequent sinus bradycardia [12]. Sensory fibers of the vagus nerve may still undergo mild excitation when subjected to traction, although these afferent impulses may not elicit central outgoing effects. Nevertheless, they can still increase serotonin release in the brainstem, leading to a certain degree of inhibition of sympathetic nerve activity and subsequently causing a mild decrease in heart rate and blood pressure. The aforementioned process typically does not result in unfavorable clinical outcomes or impact patient prognosis.

This study has some limitations. Firstly, as this study was a single-center clinical trial, a multi-center clinical trial is necessary to verify the results' reliability. Secondly, only patients with left grade III varicocele were included in order to control variables and maintain sample homogeneity. Although spermatic cord block may also be applicable for right varicocele patients, this hypothesis needs verification in subsequent clinical practice. Thirdly, the vagal reflex observed did not lead to serious consequences in this study due to the subjects' good tolerance to anesthesia and surgery; however, further studies with a larger sample size are needed to confirm the conclusion's robustness.

6. Conclusion

SCB is a straightforward and effective strategy to mitigate VR during MSV. It reduces circulatory fluctuations, minimizes anesthesia and surgery risks, and enhances overall safety.

Funding

The work was supported by the grants of: Nanjing Medical Technology Development Project (No. YKK23071). Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (No. 2023-LCYJ-PY-41). National Natural Science Foundation of China (grant No. 82271649).

Ethical approval

This study was approved by the Institutional Review Committee of The Affiliated Hospital of Nanjing University Medical School (No. 2015-053-01). All patients signed with informed consent and recorded the results.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Date availability

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

CRediT authorship contribution statement

Qing-Qiang Gao: Writing – original draft, Investigation, Formal analysis, Data curation, Conceptualization. Ning Wu: Writing – original draft, Validation, Methodology, Data curation, Conceptualization. Yuan-Zhi Li: Writing – review & editing, Validation, Supervision. Yu-Tian Dai: Writing – review & editing, Validation, Supervision, Formal analysis.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.