Hypertension and tachycardia induced by irreversible electroporation in pancreatic cancer: An analysis based on clinical data

Abstract

BACKGROUND

Irreversible electroporation (IRE) is a novel non-thermal ablation technology for unresectable tumors. Hypertension and tachycardia usually occur during the IRE. To date, there has been little explanation about this phenomenon.

AIM

To investigate the reasons of hypertension and tachycardia and appropriate preventive measures.

METHODS

IRE was performed under general anesthesia and neuromuscular blockade. Systolic blood pressures, diastolic blood pressures, heart rate, and the distance of the electrode from abdominal aorta and adrenal gland during IRE were recorded.

RESULTS

All of 78 patients underwent 96 IRE sessions, 44 (56.4%) patients occurred hypertension when the electrode was close to the abdominal aorta (< 2.0 cm). The median systolic blood pressures and diastolic blood pressures was 194 and 108 mmHg. Furthermore, 11 (14.1%) patients occurred tachycardia when the electrode was close to the adrenal gland (< 1.3 cm). The median heart rate of patients with tachycardia was 114 beats per minute. Furthermore, hypertension and tachycardia can be prevented with nicardipine and esmolol before treatment.

CONCLUSION

Intraoperative hypertension and tachycardia occur because electrodes close to the abdominal aorta (< 2.0 cm) and adrenal glands (< 1.3 cm), which can be prevented by preoperative treatment of vasoactive drugs.

Key Words: Irreversible electroporation; Pancreatic cancer; Hypertension; Tachycardia; Adrenal gland proximity; Hemodynamic changes

Core Tip: This study highlights the incidence of intraoperative hypertension and tachycardia during irreversible electroporation for unresectable tumors, significantly correlated with electrode proximity to the abdominal aorta and adrenal glands. Notably, hypertension was observed in 56.4% of patients when electrodes were less than 2.0 cm from the aorta, while 14.1% experienced tachycardia with electrodes nearer than 1.3 cm to the adrenal glands. Preemptive administration of nicardipine and esmolol effectively mitigates these cardiovascular responses, suggesting essential preoperative management for enhancing patient safety during irreversible electroporation.

INTRODUCTION

Pancreatic cancer is a highly malignant tumor with very poor prognosis, the 5-year survival rate is reported to be less than 5%[1,2]. Surgical resection is the most effective treatment, but most patients have advanced disease at diagnosis and less than 20% are eligible for surgery[3-5]. Tumor ablation is a viable option when surgical resection is ruled out. However, traditional thermal ablation techniques may damage adjacent nontumor tissue, including bile ducts, pancreatic ducts, blood vessels, or other organs, and lead to various complications[6-10].

Irreversible electroporation (IRE) is a novel, nonthermal, ablation technique. It uses a high-voltage electric pulse to create irreversible nanoscale perforations in cell membranes, which leads to cell destruction[11-13]. IRE has two major advantages over other physical ablation methods: First, it is not affected by the so-called “heat-sink effect”[14] and, second, it does not cause denaturation of collagen fibers and other connective tissue components, thus avoiding damage to adjacent large blood vessels, bile ducts, or nerves[15-17]. However, IRE can induce abnormal action potentials in cardiac and skeletal muscle and cause muscular spasms, cardiac arrhythmias, and hemodynamic changes[18-20].

Hypertension and tachycardia have been observed during IRE ablation, even in patients under deep anesthesia and neuromuscular blockade. Researchers have not yet established the mechanisms by which IRE increases blood pressure and heart rate. We hypothesized that these changes might be related to the proximity of the electrodes to the abdominal aorta and adrenal glands, and this study aimed to evaluate whether hypertension and tachycardia during IRE of pancreatic cancer were associated with the distance of the electrodes from these structures, and preventive measures for intraoperative hypertension and tachycardia.

MATERIALS AND METHODS

Patients

This retrospective study was approved by the Ethics Committee of Guangzhou Fuda Cancer Hospital. All procedures were performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from each participant. A total of 78 patients undergoing IRE for locally advanced pancreatic cancer from February 2016 to February 2019 were enrolled for this study. The inclusion criteria were: (1) Pancreatic cancer with encasement of either the celiac axis or superior mesenteric artery or both[21,22]; (2) Preoperative performance status score < 2; and (3) Not fit for surgical resection. Exclusion criteria were: (1) Severe coagulopathy; (2) Unfit for general anesthesia; (3) Severe cardiac insufficiency or liver or kidney dysfunction; (4) Severe heart rhythm disorder or multiple ventricular premature beats or atrial fibrillation; or (5) Presence of a pacemaker.

Anesthesia and electrocardiographic synchronization

Anesthesia was induced with etomidate (0.3 mg/kg), remifentanil (3-5 μg/kg; 1.2-1.6 mg/hour pump injection), and cis-atracurium benzene sulfonate (0.1 mg/kg). Intraoperative maintenance medications included cis-atracurium benzene sulfonate 2-6 μg/kg/minute pump injection (started immediately after induction), remifentanil 0.1-0.3 μg/kg/minute, propofol 60-100 μg/kg/minute, and sevoflurane 0.8%-2% volume inhalation. Muscle contraction due to electric stimulation can cause electrode displacement, and so sufficient dose of muscle relaxant was administered to ensure that the muscles were completely relaxed when the electrical pulse was released. To minimize the risk of arrhythmia, electrocardiographic (ECG) synchronization was used to deliver the electric pulse in the absolute refractory period of myocardial contraction.

IRE procedure

All patients underwent percutaneous ablation. The NanoKnife System^™, Model HVP01, (Angiodynamics, United States) was used to perform IRE. The equipment includes a generator that releases a high-voltage current, the AccuSyneR Synchronizer device for ECG synchronization, a 15-cm pulse-start main electrode, and a 15-cm pulse standard electrode. The number of electrodes, the mode of insertion, and the intraoperative parameters were determined by the IRE ablation preoperative treatment plan. The fixed electrode tip distance was 1.5-2.0 cm, and the effective electrode exposure distance was 1.5-2.5 cm. Guided by combined computerized tomography and ultrasound (iU22, Philips, Bothell, WA, United States) and/or the MAXIO V2 image-guided puncture tool and positioning system (Perfint, Redmond, WA, United States), the electrode was percutaneously inserted into the tumor to a depth of 0-5 mm. The IRE generator was set to deliver pulses in clusters of 10, with pulse width of 70-90 μs. The average electric field strength was 1200-1500 V/cm. The onboard software visually simulates the IRE ablation range and uses the ECG synchronizer to emit pulses outside the atrial/ventricular systole. Each ablation session lasted for 1-2 minutes. For large tumors multiple ablation sessions were used. At the end of the procedure, IRE ablation was confirmed by real-time electrical changes and intraoperative ultrasound and computerized tomography. The patient was kept sedated and on ventilator-assisted breathing for 2 hours after the operation, then transferred to the intensive care unit for overnight ECG monitoring. After vital signs had stabilized, the patients were transferred to the general ward for further treatment and supportive care.

Data collection

Intraoperative fluctuations in blood pressure and heart rate and anesthetic management were noted. Hypertension was defined as systolic blood pressures (SBP) > 180 mmHg and/or diastolic blood pressures (DBP) > 100 mmHg. Tachycardia was defined as heart rate > 100 beats per minute (bpm). The distance of the electrodes from the abdominal aorta and adrenal glands during ablation was recorded.

Statistical analysis

Normally distributed continuous variables were summarized as mean ± SD and non-normally distributed variables as medians (and range). Categorical variables were summarized as frequency and percentage. Correlation analysis was performed using linear regression analysis. P < 0.05 was considered statistically significant. Graph Pad 5 (Graph Pad Software, San Diego, CA, United States) was used to plot graphs.

RESULTS

Between February 2016 and February 2019, 78 patients with pancreatic cancer underwent 96 IRE treatment sessions. The median age was 59 years (range 43 to 78 years). The median tumor size was 38 mm (range 28 mm to 50 mm). The IRE technical success rate was 92.7% (89/96). Table 1 presents the baseline characteristics of the study population, while Figure 1 illustrates typical hemodynamic changes during IRE.

Figure 1 The distances between the electrodes and the abdominal aorta/adrenal gland when blood pressure and heart rate increase during irreversible electroporation in one of the patients. A: Baseline blood pressure was 126/66 mmHg; B: Intro-irreversible electroporation blood pressure was 194/107 mmHg; C: The distance between the electrode and the abdominal aorta was 0.70 cm (arrows); D: Baseline heart rate was 92 beats per minute; E: Intro-irreversible electroporation heart rate was 134 beats per minute; F: The distance between the electrode and the adrenal gland was 0.52 cm (arrows).

Table 1 Characteristics of the study population (n = 78), median (range).

Characteristic	Data
Age, years	59 (43-78)
Sex, n
Male	46
Female	32
Location of pancreatic cancer, n
Head	52
Body/tail	26
Number of lesions	89
Number of irreversible electroporation procedures	96
Tumor size, mm	38 (28-50)
Past medical history, n
Cardiac	4
Vascular	4
Pulmonary	6
Diabetes	10
Smoking	13
Hypertension	6
Other	21

Hemodynamic changes and distance of electrode from aorta/adrenal glands

We analyzed how distance of the electrodes from the abdominal aorta and the adrenal gland was related to hypertension and tachycardia.

Hypertension

A transient increase in SBP of 20-40 mmHg was seen in all patients as the electrodes were being inserted. Forty-four (56.4%) patients experienced hypertension during IRE. Among the patients with hypertension, the median SBP and DBP were 194 mmHg (range, 180 to 263 mmHg) and 108 mmHg (range, 100 to 128 mmHg), respectively. Elevated blood pressure was negatively correlated with the distance of the electrode from the abdominal aorta (R² = 0.31, P < 0.001; Figure 2A). The median increases in SBP and DBP were 38 (range, -11 to 100) and 18 (range, 12 to 34) mmHg, respectively. The mean distance of the electrodes from the abdominal aorta in patients who had hypertension was 1.4 ± 0.6 cm. Thus, when the distance between the two is less than 2.0 cm, hypertension should be noted (Table 2). Blood pressure returned to baseline levels within a few minutes after intravenous nicardipine treatment in all cases.

Figure 2 Correlation between hemodynamic parameters and distance of electrode from aorta/adrenal gland in pancreatic cancer patients treated with irreversible electroporation. A: Correlation between systolic blood pressure and distance of electrode from abdominal aorta; B: Correlation between heart rate and distance of electrode from adrenal gland. bpm: Beats per minute.

Table 2 Hemodynamic parameters and changes during irreversible electroporation, median (range).

Hemodynamic parameter	Data
Baseline SBP, mmHg	122 (98-163)
Baseline DBP, mmHg	85 (66-94)
Baseline HR, bpm	68 (56-78)
Intraoperative maximum SBP, mmHg	160 (87-263)
Intraoperative maximum DBP, mmHg	103 (78-128)
Intraoperative maximum HR, bpm	87 (60-145)
SBP > 180, mmHg	194 (180-263)
DBP > 100, mmHg	108 (100-128)
HR > 100 bpm	114 (100-145)
Distance to abdominal aorta, cm (hypertension)	1.4 ± 0.6
Distance to adrenal gland, cm (tachycardia)	0.9 ± 0.4

SBP: Systolic blood pressures; DBP: Diastolic blood pressures; HR: Heart rate; bpm: Beats per minute.

Arrhythmia

During IRE, 11 patients (14.1%) experienced tachycardia with heart rates ranging from 100 to 145 bpm. Elevated heart rate was negatively correlated with the distance between the electrodes and the adrenal gland (R² = 0.43, P < 0.001; Figure 2B). The mean distance of the electrode from the adrenal gland was 0.9 ± 0.4 cm in patients whose heart rate increased above 100 bpm. When the distance is less than 1.3 cm, clinicians should closely monitor for arrhythmia (Table 2). In all cases, the heart rate returned to baseline levels within a few minutes after treatment with esmolol.

DISCUSSION

This study aimed to investigate the reasons of hypertension and arrhythmia during IRE ablation and to identify preventive measures. We found that hypertension and tachycardia occurred when the distances from the electrode tip to the abdominal aorta and to the adrenal gland were less than 2.0 cm and 1.3 cm, respectively. Moreover, treatment with nicardipine and esmolol can completely prevent hypertension before the start of IRE ablation.

Adverse reactions during IRE include cardiac arrhythmia, transient elevated blood pressure, and muscle spasms; however, these are usually mild and easily managed. Previous studies have shown that elevated blood pressure was transient and not usually accompanied by elevated heart rate. Our results are consistent with the previous research[20]. Forty-four patients (56.4%) experienced hypertension during IRE, and the anesthesiologist administered intravenous nicardipine to bring their blood pressure back to normal baseline levels. Nielsen et al[18] and Martin et al[19] controlled the blood pressure rise by increasing the doses of the anesthetics (propofol and remifentanil), they suggested elevated blood pressure was caused by pain. Unlike, we believe that deepening anesthesia alone does not achieve stable performance. If possible, opioids with an analgesic effect should be given at the initiation of the anesthetic operation to enhance the intensity of the analgesia. On this premise, if hemodynamic instability is still present, it may be related to the stimulation of catecholamine release from the adrenal cortex during manipulation and should be treated with appropriate vasoactive drugs rather than increasing the depth of anesthesia. The release of high-voltage electric pulses may disrupt the heart’s electrical conduction, causing vasoconstriction and leading to hypertension. We consider vasodilation by nicardipine to be better for rapid control of elevated blood pressure during IRE. Moreover, interventionalist physicians should pay attention to the puncture path and the distance between the electrode tip and the abdominal aorta.

In our study, elevated heart rate above 100 bpm was noted in 11 (14.1%) patients. Tachycardia occurred when the distance between the electrode and the adrenal was less than 1.3 cm. Heart rates returned to baseline levels after treatment with esmolol. These results were similar to those reported by Ball et al[20], there were 21 patients with 28 IRE procedures, of these, 7 patients (25%) experienced ventricular tachycardia, hemodynamics returned to normal in all patients when the IRE procedure was completed. The anesthesiologist should perform prophylactic treatment or reserve adrenergic receptor blockers for prompt symptomatic treatment.

A previous animal study on IRE showed arrhythmia occurred when the electrode was less than 1.7 cm from the heart[23]. The authors demonstrated that delivering IRE microseconds after the R wave, during the absolute refractory period, could help prevent ventricular arrhythmias[23]. Nielsen et al[18] reported a mild transient arrhythmia in 7% (2/28) of their patients, which is consistent with the 11 (14.1%) patients in our study. Therefore, ECG synchronization appears to effectively minimize the risk of arrhythmias during IRE. Intraoperative care was also needed to protect the patient, maintain immobilization, and have a defibrillator on standby.

There were several reasons for hypertension and tachycardia during intraoperative period. First, the depth of anesthesia required for IRE ablation varies considerably during positioning and initiation. Bispectral index monitoring provides a better understanding of the depth of anesthesia required for this procedure. The anesthesiologist adjusts the appropriate depth of anesthesia in advance based on experience. Second, the pancreas is a retroperitoneal organ closely associated with the kidney and adrenal gland. IRE stimulation may directly cause the release of catecholamines from adrenal tissue, leading to dramatic changes in blood pressure and heart rate. The anesthesiologist should provide prophylactic treatment or alternatively, an adrenergic receptor blocker for prompt symptomatic management. Finally, effect of the ablation mechanism of IRE itself, IRE induces abnormal action potentials and causes muscle spasms, arrhythmias, and blood pressure fluctuation[19,24]. Anesthesiologists should thoroughly assess the patient’s cardiac condition before surgery, closely monitor during the procedure, promptly manage any emerging complications, and suspend treatment if necessary to ensure patient safety. This is the first study to identify the reasons of hypertension and tachycardia and appropriate preventive measures. However, a limitation of this study is the small sample size. Future research should focus on multicenter studies with larger sample sizes to validate our findings.

CONCLUSION

In conclusion, hypertension and tachycardia will occur when the distance from the electrode tip to the abdominal aorta and adrenal gland was less than 2.0 cm and 1.3 cm, which can be prevented by preoperative treatment of appropriate vasoactive drugs.

ACKNOWLEDGEMENTS

We would like to acknowledge the participating patients and their families, physicians, and the data and coordination center for continuous support.